ATLAS OF GENETIC DIAGNOSIS AND COUNSELING
ATLAS
OF
GENETIC
DIAGNOSIS AND
COUNSELING
HAROLD CHEN,
MD, FAAP, FACMG
Professor of Pediatrics, Obstetrics and Gynecology, and Pathology, Louisiana State University Health Science Center, Shreveport, LA
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Library of Congress Cataloging-in-Publication Data Atlas of genetic diagnosis and counseling / authored by Harold Chen. p. cm. Includes bibliographical references. ISBN 1-58829-681-4 (alk. paper) 1. Genetic disorders--Diagnosis--Atlases. 2. Genetic counseling--Atlases. [DNLM: 1. Genetic Diseases, Inborn--Atlases. 2. Genetic Counseling--Atlases. 3. Prenatal Diagnosis--Atlases. QZ 17 A880383 2006] I. Chen, Harold. RB155.6.A93 2006 616'.042--dc22 2005005388
Preface This book, Atlas of Genetic Diagnosis and Counseling, reflects my experience in 38 years of clinical genetics practice. During this time, I have cared for many patients and their families and taught innumerable medical students, residents, and practicing physicians. As an academic physician, I have found that a picture is truly “worth a thousand words,” especially in the field of dysmorphology. Over the years, I have compiled photographs of my patients, which are incorporated into this book to illustrate selected genetic disorders, malformations, and malformation syndromes. A detailed outline of each disorder is provided, describing the genetics, basic defects, clinical features, diagnostic investigations, and genetic counseling, including recurrence risk, prenatal diagnosis, and management. Color photographs are used to illustrate the clinical features of patients of different ages and ethnicities. Photographs of prenatal ultrasounds, imagings, cytogenetics, and postmortem findings are included to help illustrate diagnostic strategies. The cases are supplemented by case history and diagnostic confirmation by cytogenetics, biochemical, and molecular studies, if available. An extensive literature review was done to ensure up-to-date information and to provide a relevant bibliography for each disorder. This book was written in the hope that it will help physicians improve their recognition and
understanding of these conditions and their care of affected individuals and their families. It is also my intention to bring the basic science and clinical medicine together for the readers. Atlas of Genetic Diagnosis and Counseling is designed for physicians involved in the evaluation and counseling of patients with genetic diseases, malformations, and malformation syndromes, including medical geneticists, genetic counselors, pediatricians, neonatologists, developmental pediatricians, perinatologists, obstetricians, neurologists, pathologists, and any physicians and health care professionals caring for handicapped children such as craniofacial surgeons, plastic surgeons, otolaryngologists, and orthopedics. I am grateful to many individuals for their invaluable help in reading and providing cases for illustration. The acknowledgments are provided on a separate page. Without the patience and encouragement of my dear wife, Cheryl, this atlas would not have been possible. I would like to dedicate this book to Children’s Hospital, Louisiana State University Health Sciences Center in Shreveport, for its continued excellence in pediatric care and education. I would welcome comments, corrections, and criticism from readers. Harold Chen, MD, FAAP, FACMG
v
Contents Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi Acardia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Achondrogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Achondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Adams-Oliver Syndrome . . . . . . . . . . . . . . . . . . . . . . 23 Agnathia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Aicardi Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Alagille Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Albinism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Amniotic Band Syndrome . . . . . . . . . . . . . . . . . . . . . 42 Androgen Insensitivity Syndrome . . . . . . . . . . . . . . . 50 Angelman Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 56 Apert Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Aplasia Cutis Congenita . . . . . . . . . . . . . . . . . . . . . . . 70 Arthrogryposis Multiplex Congenita . . . . . . . . . . . . . 74 Asphyxiating Thoracic Dystrophy . . . . . . . . . . . . . . . 84 Ataxia Telangiectasia . . . . . . . . . . . . . . . . . . . . . . . . . 92 Atelosteogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 Autism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 Beckwith-Wiedemann Syndrome . . . . . . . . . . . . . . . Behcet Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bladder Exstrophy . . . . . . . . . . . . . . . . . . . . . . . . . . Body Stalk Anomaly . . . . . . . . . . . . . . . . . . . . . . . . Branchial Cleft Anomalies . . . . . . . . . . . . . . . . . . . .
109 114 118 122 126
Campomelic Dysplasia . . . . . . . . . . . . . . . . . . . . . . . Cat Eye Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . Cerebro-Costo-Mandibular Syndrome . . . . . . . . . . . Charcot-Marie-Tooth Disease . . . . . . . . . . . . . . . . . CHARGE Association . . . . . . . . . . . . . . . . . . . . . . . Cherubism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chiari Malformation . . . . . . . . . . . . . . . . . . . . . . . . . Chondrodysplasia Punctata . . . . . . . . . . . . . . . . . . . Chromosome Abnormalities in Pediatric Solid Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cleft Lip and/or Cleft Palate . . . . . . . . . . . . . . . . . .
131 136 139 142 149 153 157 161
Cleidocranial Dysplasia . . . . . . . . . . . . . . . . . . . . . . Cloacal Exstrophy . . . . . . . . . . . . . . . . . . . . . . . . . . Collodion Baby . . . . . . . . . . . . . . . . . . . . . . . . . . . . Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency) . . . . . . . . . . . . . . . . Congenital Cutis Laxa . . . . . . . . . . . . . . . . . . . . . . . Congenital Cytomegalovirus Infection . . . . . . . . . . Congenital Generalized Lipodystrophy . . . . . . . . . . Congenital Hydrocephalus . . . . . . . . . . . . . . . . . . . . Congenital Hypothyroidism . . . . . . . . . . . . . . . . . . . Congenital Muscular Dystrophy . . . . . . . . . . . . . . . Congenital Toxoplasmosis . . . . . . . . . . . . . . . . . . . . Conjoined Twins . . . . . . . . . . . . . . . . . . . . . . . . . . . . Corpus Callosum Agenesis/Dysgenesis . . . . . . . . . . Craniometaphyseal Dysplasia . . . . . . . . . . . . . . . . . Cri-Du-Chat Syndrome . . . . . . . . . . . . . . . . . . . . . . Crouzon Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
185 191 195
Dandy-Walker Malformation . . . . . . . . . . . . . . . . . . De Lange Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . Del(22q11.2) Syndromes . . . . . . . . . . . . . . . . . . . . . Diabetic Embryopathy . . . . . . . . . . . . . . . . . . . . . . . Down Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dyschondrosteosis (Leri-Weill Syndrome) and Langer Mesomelic Dysplasia . . . . . . . . . . . . . . . . Dysmelia (Limb Deficiency/Reduction) . . . . . . . . . Dysplasia Epiphysealis Hemimelica . . . . . . . . . . . . Dystonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dystrophinopathies . . . . . . . . . . . . . . . . . . . . . . . . . .
273 276 282 289 295
Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . Ehlers-Danlos Syndrome . . . . . . . . . . . . . . . . . . . . . Ellis-van Creveld Syndrome . . . . . . . . . . . . . . . . . . Enchondromatosis (Maffucci Syndrome; Ollier Syndrome) . . . . . . . . . . . . . . . . . . . . . . . . . Epidermolysis Bullosa . . . . . . . . . . . . . . . . . . . . . . . Epidermolytic Palmoplantar Keratoderma . . . . . . . .
169 180 vii
198 207 212 217 221 227 231 236 241 247 252 256 261 265
305 312 323 326 331
339 342 350 355 360 366
viii
CONTENTS
Faciogenital (Aarskog) Dysplasia . . . . . . . . . . . . . . Facioscapulohumeral Muscular Dystrophy . . . . . . . Familial Adenomatous Polyposis . . . . . . . . . . . . . . . Familial Hyperlysinemia . . . . . . . . . . . . . . . . . . . . . Fanconi Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . Femoral Hypoplasia-Unusual Facies Syndrome . . . Fetal Akinesia Syndrome . . . . . . . . . . . . . . . . . . . . . Fetal Alcohol Syndrome . . . . . . . . . . . . . . . . . . . . . . Fetal Hydantoin Syndrome . . . . . . . . . . . . . . . . . . . Fibrodysplasia Ossificans Progressiva . . . . . . . . . . . Finlay-Marks Syndrome . . . . . . . . . . . . . . . . . . . . . . Fragile X Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . Fraser Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . Freeman-Sheldon Syndrome . . . . . . . . . . . . . . . . . . Frontonasal Dysplasia . . . . . . . . . . . . . . . . . . . . . . .
371 375 380 386 389 395 398 403 407 410 415 417 423 427 431
Galactosemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastroschisis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gaucher Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . Generalized Arterial Calcification of Infancy . . . . . Glucose-6-Phosphate Dehydrogenase Deficiency . . . Glycogen Storage Disease, Type II . . . . . . . . . . . . . Goldenhar Syndrome . . . . . . . . . . . . . . . . . . . . . . . .
437 442 446 452 457 461 465
Hallermann-Streiff Syndrome . . . . . . . . . . . . . . . . . Harlequin Ichthyosis (Harlequin Fetus) . . . . . . . . . . Hemophilia A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hereditary Hemochromatosis . . . . . . . . . . . . . . . . . . Hereditary Multiple Exostoses . . . . . . . . . . . . . . . . . Holoprosencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . Holt-Oram Syndrome . . . . . . . . . . . . . . . . . . . . . . . . Hydrops Fetalis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hyper-IgE Syndrome . . . . . . . . . . . . . . . . . . . . . . . . Hypochondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . . Hypoglossia-Hypodactylia Syndrome . . . . . . . . . . . Hypohidrotic Ectodermal Dysplasia . . . . . . . . . . . . Hypomelanosis of Ito . . . . . . . . . . . . . . . . . . . . . . . . Hypophosphatasia . . . . . . . . . . . . . . . . . . . . . . . . . .
469 473 476 482 487 493 502 506 513 517 521 524 528 532
Incontinentia Pigmenti . . . . . . . . . . . . . . . . . . . . . . . 539 Infantile Myofibromatosis . . . . . . . . . . . . . . . . . . . . 545 Ivemark Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 549 Jarcho-Levin Syndrome . . . . . . . . . . . . . . . . . . . . . . 553 Kabuki Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 559
Kasabach-Merritt Syndrome . . . . . . . . . . . . . . . . . . KID Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Klinefelter Syndrome . . . . . . . . . . . . . . . . . . . . . . . . Klippel-Feil Syndrome . . . . . . . . . . . . . . . . . . . . . . . Klippel-Trenaunay Syndrome . . . . . . . . . . . . . . . . . Kniest Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . .
563 567 570 575 580 585
Larsen Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . LEOPARD Syndrome . . . . . . . . . . . . . . . . . . . . . . . Lesch-Nyhan Syndrome . . . . . . . . . . . . . . . . . . . . . . Lethal Multiple Pterygium Syndrome . . . . . . . . . . . Lowe Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . .
589 597 600 604 613
Marfan Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . McCune-Albright Syndrome . . . . . . . . . . . . . . . . . . Meckel-Gruber Syndrome . . . . . . . . . . . . . . . . . . . . Menkes Disease (Kinky-Hair Syndrome) . . . . . . . . Metachromatic Leukodystrophy . . . . . . . . . . . . . . . Miller-Dieker Syndrome . . . . . . . . . . . . . . . . . . . . . Möbius Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . Mucolipidosis II (I-Cell Disease) . . . . . . . . . . . . . . . Mucolipidosis III (Pseudo-Hurler Polydystrophy) . Mucopolysaccharidosis I (MPS I) (α-L-Iduronidase Deficiency): Hurler (MPS I-H), Hurler-Scheie (MPS I-H/S), and Scheie (MPS I-S) Syndromes . . . . . . . . . . . . Mucopolysaccharidosis II (Hunter Syndrome) . . . . Mucopolysaccharidosis III (Sanfilippo Syndrome) . Mucopolysaccharidosis IV (Morquio Syndrome) . . Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Multiple Epiphyseal Dysplasia . . . . . . . . . . . . . . . . Multiple Pterygium Syndrome . . . . . . . . . . . . . . . . . Myotonic Dystrophy Type 1 . . . . . . . . . . . . . . . . . .
619 630 636 639 646 650 655 660 664
Netherton Syndrome . . . . . . . . . . . . . . . . . . . . . . . . Neu-Laxova Syndrome . . . . . . . . . . . . . . . . . . . . . . . Neural Tube Defects . . . . . . . . . . . . . . . . . . . . . . . . . Neurofibromatosis I . . . . . . . . . . . . . . . . . . . . . . . . . Noonan Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . .
715 718 721 731 744
Oblique Facial Cleft Syndrome . . . . . . . . . . . . . . . . Oligohydramnios Sequence . . . . . . . . . . . . . . . . . . . Omphalocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Osteogenesis Imperfecta . . . . . . . . . . . . . . . . . . . . . Osteopetrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
751 755 758 762 773
669 678 682 687 692 697 702 708
CONTENTS
Pachyonychia Congenita . . . . . . . . . . . . . . . . . . . . . Pallister-Killian Syndrome . . . . . . . . . . . . . . . . . . . . Phenylketonuria (PKU) . . . . . . . . . . . . . . . . . . . . . . Pierre Robin Sequence . . . . . . . . . . . . . . . . . . . . . . . Polycystic Kidney Disease, Autosomal Dominant Type . . . . . . . . . . . . . . . . . . . . . . . . . . Polycystic Kidney Disease, Autosomal Recessive Type . . . . . . . . . . . . . . . . . . . . . . . . . . . Prader-Willi Syndrome . . . . . . . . . . . . . . . . . . . . . . . Progeria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prune Belly Syndrome . . . . . . . . . . . . . . . . . . . . . . . Pseudoachondroplasia . . . . . . . . . . . . . . . . . . . . . . .
781 784 788 793 797 803 809 815 821 826
R(18) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . Retinoid Embryopathy . . . . . . . . . . . . . . . . . . . . . . . Rett Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rickets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Roberts Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . Robinow Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . Rubinstein-Taybi Syndrome . . . . . . . . . . . . . . . . . . .
831 835 839 844 852 856 860
Schizencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Schmid Metaphyseal Chondrodysplasia . . . . . . . . . Seckel Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . Severe Combined Immune Deficiency . . . . . . . . . . . Short Rib Polydactyly Syndromes . . . . . . . . . . . . . . Sickle Cell Disease . . . . . . . . . . . . . . . . . . . . . . . . . . Silver-Russell Syndrome . . . . . . . . . . . . . . . . . . . . . Sirenomelia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Smith-Lemli-Opitz Syndrome . . . . . . . . . . . . . . . . . Smith-Magenis Syndrome . . . . . . . . . . . . . . . . . . . . Sotos Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . Spinal Muscular Atrophy . . . . . . . . . . . . . . . . . . . . .
867 870 874 878 884 892 899 903 907 912 916 921
ix
Spondyloepiphyseal Dysplasia . . . . . . . . . . . . . . . . . 927 Stickler Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 934 Sturge-Weber Syndrome . . . . . . . . . . . . . . . . . . . . . 939 Tay-Sachs Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 943 Tetrasomy 9p Syndrome . . . . . . . . . . . . . . . . . . . . . 947 Thalassemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950 Thanatophoric Dysplasia . . . . . . . . . . . . . . . . . . . . . 955 Thrombocytopenia-Absent Radius Syndrome . . . . . 962 Treacher-Collins Syndrome . . . . . . . . . . . . . . . . . . . 967 Trimethylaminuria . . . . . . . . . . . . . . . . . . . . . . . . . . 972 Triploidy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976 Trismus Pseudocamptodactyly Syndrome . . . . . . . . 982 Trisomy 13 Syndrome . . . . . . . . . . . . . . . . . . . . . . . 985 Trisomy 18 Syndrome . . . . . . . . . . . . . . . . . . . . . . . 990 Tuberous Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . 997 Turner Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 1007 Twin–Twin Transfusion Syndrome . . . . . . . . . . . . 1015 Ulnar-Mammary Syndrome . . . . . . . . . . . . . . . . . . 1021 VATER (VACTERL) Association . . . . . . . . . . . . . 1025 Von Hippel-Lindau Disease . . . . . . . . . . . . . . . . . . 1029 Waardenburg Syndrome . . . . . . . . . . . . . . . . . . . . . 1035 Williams Syndrome . . . . . . . . . . . . . . . . . . . . . . . . 1040 Wolf-Hirschhorn Syndrome . . . . . . . . . . . . . . . . . . 1047 X-Linked Ichthyosis . . . . . . . . . . . . . . . . . . . . . . . . XXX Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . XXXXX Syndrome . . . . . . . . . . . . . . . . . . . . . . . . XXXXY Syndrome . . . . . . . . . . . . . . . . . . . . . . . . XY Female . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XYY Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . .
1057 1061 1064 1068 1071 1075
Acknowledgments HIROKO TANIAI, MD • A case of Finlay-Marks syndrome and help in searching of references for the Atlas. THEODORE THURMON, MD • Comments on the Atlas and cases on achondrogenesis, arthrogryposis, cleidocranial dysplasia, chondrodysplasia punctata, de Lange syndrome, Crouzon syndrome, cutis laxa, Freeman-Sheldon syndrome, hypophosphatasia, multiple epiphyseal dysplasia, omphalocele, prune belly syndrome, Sturge-Weber syndrome, and Treacher-Collins syndrome. CATHY TUCK-MULLER, PhD • A karyotype on Roberts syndrome. SUSONNE URSIN, MD • Cases of galactosemia and Gaucher disease and helps covering patient care for me during the last stage of preparing the Atlas. WLADIMIR WERTELECKI, MD • Enjoy working together on birth defects and congenital malformations and appreciate friendship and encouragement. SAMUEL YANG, MD • Meticulous reading and editing of the whole manuscript from the start to the end during his retirement and encouragement throughout the preparation of the Atlas. Special thanks to contribution of his life-time collection of cases on skeletal dysplasias and malformation syndromes (acardius, achondrogenesis, achondroplasia, amniotic band syndrome, anencephaly, asphyxiating thoracic dystrophy, body stalk anomaly, cebocephaly, campomelic dysplasia, Chiari malformation, colon polyposis, congenital cytomegalovirus infection, congenital toxoplasmosis, cyclopia, cystic fibrosis, Duchenne muscular dystrophy, Ellis van Creveld syndrome, gastroschisis, hypophosphatasia, I-cell disease, Kniest syndrome, polycystic kidney diseases, premaxillary agenesis, prune belly syndrome, SED congenita, sirenomelia, short rib polydactyly syndromes, Tay-Sachs disease, thanatophoric dysplasia, twin-twin transfusion placentas, VATER association, and Werdnig-Hoffman syndrome). CHENG W. YU, PhD • Karyotypes/FISH on pediatric tumors (meningioma, Wilms tumor), Cri-du-chat syndrome, and Wolf-Hirschhorn syndrome.
Individuals DIANA BIENVENU, MD • A case of Marfan syndrome with apical bleb rupture. SAMI BAHNA, MD • Comments on del(22q11.2), hyper IgE syndrome, Netherton syndrome, and severe combined immunodeficiency. JOSEPH BOCCHINI, JR. MD • Comments on congenital cytomegalovirus infection and congenital toxoplasmosis and encouragement and support throughout preparation of the Atlas. CHUNG-HO CHANG, MD • Cases on Duchenne muscular dystrophy and congenital toxoplasmosis. SAU CHEUNG, PhD • FISH on a case of STS deficiency. JAMES GANLEY, MD • Cases on ophthalmology (Behcet disease, Lisch nodule in NF1, cherry spot in Tay-Sachs disease, and retinal changes in congenital toxoplasmosis, von-Hippel Lindal disease, and Waardenburg syndrome). ENRIQUE GONZALEZ, MD • Valuable comments on pathological aspects of clinical entities and cases on acardius, agnathia, cloacal exstrophy, congenital cytomegalovirus infection, omphalocele, pediatric solid tumors (meningioma, neuroblastoma, retinoblastoma, and Wilms tumor), phocomelia, sickle cell anemia, thalassemia, and Gaucher disease. WILLIAM HOFFMAN, MD • Comments on topics of endocrinological interest and cases on androgen insensitivity and hypophosphatemic rickets. RACHEL FLAMHOLZ, MD • Peripheral blood smears on sickle cell anemia and thalassemia. MAJED JEROUDI, MD • A case of sickle cell anemia dactylitis. DANIEL LACEY, MD • Comments on dystrophinopathy, spinal muscular atrophy, neural tube defects, and holoprosencephaly. MARY LOWERY, MD • Comments on the Atlas and cases on molecular cytogenetics/pathology (FISH on trisomy 21, trisomy 13, trisomy 18, X/XXX, Williams syndrome, and neuroblastoma; mutation analysis on cystic fibrosis and hereditary hemochromatosis). LYNN MARTIN, LPN • Help in caring for the patients including obtaining the photographs of patients and searching for clinical information of the old files. LEONARD PROUTY, PhD • Reading of several topics in the Atlas. DAN SANUSI, MD • A case of X-linked ichthyosis. TOHRU SONODA, MD • Cases on chondrodysplasia punctata, del(22q11.2), Kabuki syndrome, KlippelTrenaunay syndrome, and tuberous sclerosis.
Institutions Louisiana State University Health Sciences Center in Shreveport, Louisiana (Drs. Joseph Bocchini, Jr., David Lewis, Rose Brouillette, Rodney Wise) Pinecrest Developmental Center in Pineville, Louisiana (Drs. Gaylon Bates, Tony Hanna, Renata Pilat) Shreveport Shriner’s Hospital for Children (Dr. Richard McCall) xi
Acardia b) Presence of rudimentary nerve tissue in addition to anatomical features in acardius amorphous iii. Acardius acephalus a) The most common type b) Missing head, part of the thorax, and upper extremities c) May have additional malformations in the remaining organs iv. Acardius anceps a) Presence of a partially developed fetal head, a thorax, abdominal organs, and extremities b) Lacks even a rudimentary heart v. Acardius acormus a) The rarest type b) Lacks thorax c) Presence of a rudimentary head only d) The umbilical cord inserts in the head and connects directly to the placenta 4. The acardia a. Characterized by the absence of a normally functioning heart b. Acardia as a recipient of twin transfusion sequence i. Reversal of blood flow in various types of acardia, hence the term “twin reversed arterial perfusion (TRAP) sequence” has been proposed ii. Receiving the deoxygenated blood from an umbilical artery of its co-twin through the single umbilical artery of the acardiac twin and returning to its umbilical vein. Therefore, the circulation is entirely opposite to the normal direction c. Usually the severe reduction anomalies occur in the upper part of the body d. May develop various structural malformations i. Growth retardation ii. Anencephaly iii. Holoprosencephaly iv. Facial defects v. Absent or malformed limbs vi. Gastrointestinal atresias vii. Other abnormalities of abdominal organs 5. The co-twin a. Also known as the “pump twin or donor twin” b. The donor “pump” twin perfuses itself and its recipient acardiac twin through abnormal arterial anastomosis in the fused placenta c. Increased cardiac workload often leads to cardiac failure and causes further poor perfusion and oxygenation of the acardiac co-twin d. May develop various malformations (about 10%)
Acardia is a bizarre fetal malformation occurring only in twins or triplets. It is also called acardius acephalus, acardiac twinning, or twin reversed arterial perfusion (TRAP) syndrome or sequence. This condition is very rare and occurs 1 in 35,000 deliveries, 1 in 100 monozygotic twins, rarely in triplet pregnancy, and even in quintuplet gestations.
GENETICS/BASIC DEFECTS 1. Etiology a. Rare complication of monochorionic twinning, presumably resulting from the fused placentation of monochorionic twins b. Represents manifestation of abnormal embryonic and fetal blood flow rather than a primary defect of cardiac formation c. Heterogeneous chromosomal abnormalities are present in nearly 50% of the cases, although chromosome errors are not underlying pathogenesis of the acardiac anomaly. i. 45,XX,t(4;21)del(4p) ii. 46,X,i(Xp) iii. 47,XX,+2 iv. 47,XX,+11 v. 47,XY,+G vi. 47,XXY vii. 69,XXX viii. 70,XXX,+15 ix. 94,XXXXYY 2. Pathogenesis: reversal of fetal arterial perfusion a. First hypothesis i. A primary defect in the development of the heart ii. Survival of the acardiac twin as a result of the compensatory anastomoses that develop b. Second hypothesis i. The acardiac twin beginning life as a normal fetus ii. The reversal of the arterial blood flow resulting in atrophy of the heart and the tributary organs 3. Classification of TRAP sequence (syndrome) a. Classification according to the status of the heart of the acardiac twin i. Hemiacardius (with incompletely formed heart) ii. Holoacardius (with completely absent heart) b. Morphologic classification of the acardiac twin i. Acardius amorphous a) The least differentiated form; no resemblance to classical human form b) Anatomical features: presence of only bones, cartilage, muscles, fat, blood vessels, and stroma ii. Acardius myelacephalus a) Resembles the amorphous type, except for the presence of rudimentary limb formation
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CLINICAL FEATURES 1. Perinatal problems associated with acardiac twinning a. Pump-twin congestive heart failure b. In utero fetal death of the pump fetus c. Maternal polyhydramnios d. Premature rupture of membrane e. Preterm delivery f. Spontaneous abortions g. Soft tissue dystocia h. Uterine rupture i. Postpartum hemorrhage j. Increased rate of cesarean section, up to 50% 2. Majority of acardiac twins and their normal twin counterparts are females 3. Nonviable 4. Gross features a. Severe reduction anomalies, particularly of the upper body b. Characteristic subcutaneous edema c. Internal organs: invariably missing d. Absent or rudimentary cardiac development: the key diagnostic feature i. Pseudoacardia (rudimentary heart tissue) ii. Holoacardia (completely lacking a heart) 5. Growth abnormality 6. Cranial vault a. Absent b. Partial c. Intact 7. Brain a. Absent b. Necrotic c. Open cranial vault d. Holoprosencephaly 8. Facial features a. Absent facial features b. Rudimentary facial features c. Present with defects d. Anophthalmia/microphthalmia e. Cleft lip/palate 9. Upper limbs a. Absent b. Rudimentary c. Radial aplasia d. Syndactyly/oligodactyly 10. Lower limbs a. Absent b. Rudimentary/reduced c. Syndactyly/oligodactyly d. Talipes equinovarus 11. Thorax a. Absent b. Reduced c. Diaphragmatic defect 12. Lungs a. Absent b. Necrotic or rudimentary c. Single midline lobe
13. Cardiac a. Absent heart tissue b. Unfolded heart tube c. Folded heart with common chamber 14. Gastrointestinal a. Esophageal atresia b. Short intestine c. Interrupted intestine d. Omphalocele e. Incomplete rotation of the gut f. Imperforated anus g. Ascites 15. Liver a. Absent b. Reduced 16. Kidney a. Absent (bilateral) b. Hypoplastic and/or lobulated 17. Other viscera a. Absent gallbladder b. Absent spleen c. Absent-to-reduced pancreas d. Absent adrenal e. Absent-to-hypoplastic gonads f. Exstrophy of the cloaca g. Skin with myxedematous thickening 18. Umbilical cord vessels a. Two vessels b. Three vessels 19. Severe obstetrical complications a. Maternal polyhydramnios b. Preterm labor c. Cord accidents d. Dystocia e. Uterine rupture 20. Severe neonatal complications a. Hydrops b. Intrauterine demise c. Prematurity d. Heart failure e. Anemia f. Twin-to-twin transfusion syndrome 21. Outcome for the normal sib in an acardiac twin pregnancy a. Unsatisfactory i. Adapting to the increasing circulatory load, resulting in the following situations: a) Intrauterine growth retardation b) Hydrops c) Ascites d) Pleural effusion e) Hypertrophy of the right ventricle f) Hepatosplenomegaly g) Severe heart failure resulting in pericardial effusion and/or tricuspid insufficiency ii. Stillbirth iii. Prematurity iv. Neonatal death b. Mortality for the normal twin reported as high as 50% without intervention
ACARDIA
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Absent or rudimentary skull b. Absent or rudimentary thorax c. Absent or rudimentary heart d. Vertebral anomalies e. Rib anomalies f. Limb defects, especially upper limbs 2. Pathology a. Microcephaly b. Severely rudimentary brain c. Developmental arrest of brain at the prosencephalic stage (holoprosencephaly) d. Hypoxic damage to the holospheric brain mantle with cystic change (hydranencephaly)
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: overall recurrence risk of about 1 in 10,000 (The recurrence risk is for monoamniotic twinning [1% for couples who have had one set of monozygotic twins] times the frequency of the occurrence of TRAP sequence with near-term survival [about 1% of monozygotic twin sets]) b. Patient’s offspring: not applicable (a lethal condition) 2. Prenatal ultrasonography a. Monochorionic placenta with a single umbilical artery in 2/3 of cases b. Acardiac fetus i. Unrecognizable head or upper trunk ii. Without a recognizable heart or a partially formed heart iii. A variety of other malformations iv. Reversal of blood flow in the umbilical artery with flow going from the placenta toward the acardiac fetus (reversed arterial perfusion). Such a reversal of the blood flow in the recipient twin can be demonstrated in utero by transvaginal Doppler ultrasound as early as 12 weeks of gestation v. Early diagnosis by transvaginal sonography on the following signs: a) Monozygotic twin gestation (absence of the lambda sign) b) Biometric discordance between the twins c) Diffuse subcutaneous edema or morphologic anomalies of one of the twins, or both d) Detection of reversed umbilical cord flow; cardiac activity likely to disappear as the pregnancy progresses e) Absence of cardiac activity, although hemicardia or pseudocardia may be present c. The donor fetus i. Hydrops ii. Cardiac failure (cardiomegaly, pericardial effusion, and tricuspid regurgitation)
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2. Amniocentesis to diagnose associated chromosome abnormalities (about 10% of pump twins) 3. Management of pregnancies complicated by an acardiac fetus a. Conservative treatment i. Monitor pregnancy by serial ultrasonography ii. Conservative approach as long as there is no evidence of cardiac circulatory decompensation in the donor twin b. Termination of pregnancies c. Treatment and prevention of preterm labor by tocolytics i. Magnesium sulphate ii. Beta-Sympathomimetics iii. Indomethacin d. Treatment of pump fetus heart failure involving maternal digitalization e. Treatment of polyhydramnios by therapeutic repeated amniocentesis f. Selective termination of the acardiac twin i. To occlude the umbilical artery of the acardiac twin in order to stop umbilical flow through the anastomosis a) Intrafunicular injection and mechanical occlusion of the umbilical artery b) Embolization by steel or platinum coil, alcohol-soaked suture material, or ethanol c) Hysterotomy and delivery of acardiac twin d) Ligation of the umbilical cord e) Hysterotomy and umbilical cord ligation ii. Fetal surgery: best available treatment for acardiac twinning a) Endoscopic laser coagulation of the umbilical vessels at or before 24 weeks of gestation b) Endoscopic or sonographic guided umbilical cord ligation after 24 weeks of gestation iii. Summary of acardiac twins treated with invasive procedures reported in the literature a) Mortality of the pump twin (13.6%) b) Preterm delivery (50.3%) c) Delivery before 30-weeks gestation (27.2%) d) Perinatal mortality, if untreated, is at least 50%
REFERENCES Aggarwal N, Suri V, Saxena SV, et al.: Acardiac acephalus twins: a case report and review of literature. Acta Obstet Gynecol Scand 81:983–984, 2002. Alderman B: Foetus acardius amorphous. Postgrad Med J 49:102–105, 1973. Arias F, Sunderji S, Gimpelson R, et al.: Treatment of acardiac twinning. Obstet Gynecol 91:818–821, 1998. Benirschke K, des Roches Harper V: The acardiac anomaly. Teratology 15:311–316, 1977. Blaicher W, Repa C, Schaller A: Acardiac twin pregnancy: associated with trisomy 2. Hum Reprod 15:474–475, 2000. Blenc AM, Gömez JA, Collins D, et al.: Pathologic quiz case. Pathologic diagnosis: acardiac fetus, acardius acephalus type. Arch Pathol Lab Med 123:974–976, 1999. Bonilla-Musoles F, Machado LE, Raga F, et al.: Fetus acardius. Two- and threedimensional ultrasonographic diagnoses. J Ultrasound Med 20:1117–1127, 2001. Chen H, Gonzalez E, Hand AM, Cuestas R: The acardius acephalus and monozygotic twinning. Schumpert Med Quart 1:195–199, 1983.
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Donnenfeld AE, Van de Woestijne J, Craparo F, et al.: The normal fetus of an acardiac twin pregnancy: perinatal management based on echocardiographic and sonographic evaluation. Prenat Diagn 11:235–244, 1991. French CA, Bieber FR, Bing DH, et al.: Twins, placentas, and genetics: acardiac twinning in a dichorionic, diamniotic, monozygotic twin gestation. Hum Pathol 29:1028–1031, 1998. Hanafy A, Peterson CM: Twin-reversed arterial perfusion (TRAP) sequence: case reports and review of literature. Aust N Z J Obstet Gynaecol 37:187–191, 1997. Healey MG: Acardia: predictive risk factors for the co-twin’s survival. Teratology 50:205–213, 1994.
Sanjaghsaz H, Bayram MO, Qureshi F: Twin reversed arterial perfusion sequence in conjoined, acardiac, acephalic twins associated with a normal triplet. A case report. J Reprod Med 43:1046–1050, 1998. Søgaard K, Skibsted L, Brocks V: Acardiac twins: Pathophysiology, diagnosis, outcome and treatment. Six cases and review of the literature. Fetal Diagn Ther 14:53–59, 1999. Van Allen MI, Smith DW, Shepard TH: Twin reversed arterial perfusion (TRAP) sequence: a study of 14 twin pregnancies with acardius. Semin Perinatol 7:285–293, 1983.
ACARDIA
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Fig. 2. Radiographs of the above acardiac fetus showing a missing head, cervical vertebrae and part of upper thoracic vertebrae, rudimental lower ribs, malformed lower thoracic and lumbar vertebrae, and relatively well-formed lower limbs.
Fig. 1. Ventral view of an acardiac acephalus fetus (upper photo) shows a large abdominal defect, gastroschisis (arrow), through which small rudiments of gastrointestinal tract are seen. Dorsal view (lower photo) shows a very underdeveloped cephalic end and relatively welldeveloped lower limbs. The co-twin had major malformations consisting of a large omphalocele, ectopia cordis, and absent pericardium, incompatible with life. Fig. 3. The head and part of the thorax of this acardiac fetus are completely missing with relatively well-formed lower limbs.
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Fig. 4. Another acardiac fetus with a missing head and part of the upper thorax. Radiograph shows missing head, and cervical and part of thoracic vertebrae and ribs. Pelvis and lower limbs are well formed.
Fig. 5. Acardius (second twin, 36-weeks gestation) showing spherical body with a small amorphous mass of leptomeningeal and glial tissue at the cephalic end. There were one deformed lower extremity and a small arm appendage. Small intestinal loops, nodules of adrenal glands, and testicles were present in the body. There was no heart or lungs. The placenta was nonoamniotic monochorionic with velamentous insertion of the umbilical cord. The other identical twin was free of birth defects. Radiograph of acardius twin shows a short segment of the spine, a femur, a tibia, and a fibula.
Achondrogenesis e. Heart i. Patent ductus arteriosus ii. Atrial septal defect iii. Ventricular septal defect f. Protuberant abdomen g. Limbs i. Extremely short (micromelia), shorter than type II ii. Flipper-like appendages 3. Achondrogenesis type II a. Growth i. Lethal neonatal dwarfism ii. Mean birth weight of 2100 g b. Craniofacial features i. Disproportionately large head ii. Large and prominent forehead iii. Midfacial hypoplasia a) Flat facial plane b) Flat nasal bridge c) Small nose with severely anteverted nostrils iv. Normal philtrum v. Micrognathia vi. Cleft palate c. Extremely short neck d. Thorax i. Short and flared thorax ii. Bell-shaped cage iii. Lung hypoplasia e. Protuberant abdomen f. Extremely short limbs (micromelia)
Achondrogenesis is a heterogeneous group of lethal chondrodysplasias. Achondrogenesis type I (Fraccaro-Houston-Harris type) and type II (Langer-Saldino type) were distinguished on the basis of radiological and histological criteria. Achondrogenesis type I was further subdivided, on the basis of convincing histological criteria, into type IA, which has apparently normal cartilage matrix but inclusions in chondrocytes, and type IB, which has an abnormal cartilage matrix. Classification of type IB as a separate group has been confirmed recently by the discovery of its association with mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene, making it allelic with diastrophic dysplasia.
GENETICS/BASIC DEFECTS 1. Type IA: an autosomal recessive disorder with an unknown chromosomal locus 2. Type IB a. An autosomal recessive disorder b. Resulting from mutations of the DTDST gene, which is located at 5q32-q33 3. Type II a. Autosomal dominant type II collagenopathy b. Resulting from mutations in the COL2A1 gene, which is located at 12q13.1-q13.3
CLINICAL FEATURES 1. Prenatal/perinatal history a. Polyhydramnios b. Hydrops c. Breech presentation d. Perinatal death 2. Achondrogenesis type I a. Growth i. Lethal neonatal dwarfism ii. Mean birth weight of 1200 g b. Craniofacial features i. Disproportionately large head ii. Soft skull iii. Sloping forehead iv. Convex facial plane v. Flat nasal bridge, occasionally associated with a deep horizontal groove vi. Small nose, often with anteverted nostrils vii. Long philtrum viii. Retrognathia ix. Increased distance between lower lip and lower edge of chin x. Double chin appearance c. Extremely short neck d. Thorax i. Short and barrel-shaped thorax ii. Lung hypoplasia
DIAGNOSTIC INVESTIGATIONS 1. Radiological features a. Variable features b. No single obligatory feature c. Distinction between type IA and type IB on radiographs not always possible d. Degree of ossification: age dependent, and caution is needed when comparing radiographs at different gestational ages e. Achondrogenesis type I i. Skull: Varying degree of deficient cranial ossification consisting of small islands of bone in membranous calvaria ii. Thorax and ribs a) Short and barrel-shaped thorax b) Thin ribs with marked expansion at costochondral junction, frequently with multiple fractures iii. Spine and pelvis a) Poorly ossified spine, ischium, and pubis b) Poorly ossified iliac bones with short medial margins 7
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ACHONDROGENESIS
iv. Limbs and tubular bones a) Extreme micromelia, with limbs much shorter than in type II b) Prominent spike-like metaphyseal spurs c) Femur and tibia frequently presenting as short bone segments v. Subtype IA (Houston-Harris type) a) Poorly ossified skull b) Thin ribs with multiple fractures c) Unossified vertebral pedicles d) Arched ilium e) Hypoplastic but ossified ischium f) Wedged femur with metaphyseal spikes g) Short tibia and fibula with metaphyseal flare vi. Subtype IB (Fraccaro type) a) Adequately ossified skull b) Absence of rib fractures c) Total lack of ossification or only rudimentary calcification of the center of the vertebral bodies d) Ossified vertebral pedicles e) Iliac bones with ossification only in their upper part, giving a crescent-shaped, “paragliderlike” appearance on X-ray f) Unossified ischium g) Shortened tubular bones without recognized axis h) Metaphyseal spurring giving the appearance of a “thorn apple” or “acanthocyte” (a descriptive term in hematology) i) Trapezoid femur j) Stellate tibia k) Unossified fibula l) Poorly ossified phalanges f. Achondrogenesis type II i. Skull a) Normal cranial ossification b) Relatively large calvaria ii. Thorax and ribs a) Short and flared thorax b) Bell-shaped cage c) Shorter ribs without fractures iii. Spine and pelvis: relatively well-ossified iliac bones with long, crescent-shaped medial and inferior margins iv. Limbs and tubular bones a) Short, broad bones, usually with some diaphyseal constriction and flared, cupped metaphyseal ends b) Metaphyseal spurs, usually smaller than type I 2. Histologic features a. Achondrogenesis type IA i. Normal cartilage matrix ii. Absent collagen rings around the chondrocytes iii. Vacuolated chondrocytes iv. Presence of intrachondrocytic inclusion bodies (periodic acid-Schiff [PAS] stain positive, diastase resistant) v. Extraskeletal cartilage involvement
vi. Enlarged lacunas vii. Woven bone b. Achondrogenesis type IB i. Abnormal cartilage matrix: presence of “demasked” coarsened collagen fibers, particularly dense around the chondrocytes, forming collagen rings ii. Abnormal staining properties of cartilage a) Reduced staining with cationic dyes, such as toluidine blue or Alcian blue, probably because of a deficiency in sulfated proteoglycans b) This distinguishes type IB from type IA, in which the matrix is close to normal and inclusions can be seen in chondrocytes, and from achondrogenesis type II, in which cationic dyes give a normal staining pattern c. Achondrogenesis type II i. Cartilage a) Slightly larger than normal b) Grossly distorted (lobulated and mushroomed) ii. Markedly deficient cartilaginous matrix iii. Severe disturbance in endochondral ossification iv. Hypercellular and hypervascular reserve cartilage with large, primitive mesenchymal (ballooned) chondrocytes with abundant clear cytoplasm (vacuoles) (“Swiss cheese-like”) v. Overgrowth of membranous bones resulting in cupping of the epiphyseal cartilages vi. Decreased amount and altered structure of proteoglycans vii. Relatively lower content of chondroitin 4-sulfate viii. Lower molecular weight and decreased total chondroitin sulfation ix. Absence of type II collagen x. Increased amounts of type I and type III collagen 3. Biochemical testing a. Lack of sulfate incorporation: cumbersome and not used for diagnostic purposes b. Sulfate incorporation assay in cultured skin fibroblasts or chondrocytes: recommended in the rare instances in which the diagnosis of achondrogenesis type IB is strongly suspected but molecular genetic testing fails to detect SLC26A2 (DTDST) mutations 4. Molecular genetic studies a. Mutation analysis of the DTDST gene, reported in: i. Achondrogenesis type IB (the most severe form) ii. Atelosteogenesis type II (an intermediate form) iii. Diastophic dysplasia (the mildest form) iv. Recessive multiple epiphyseal dysplasia b. Achondrogenesis type IB i. Mutation analysis: testing of the following four most common SLC26A2 (DTDST) gene mutations (mutation detection rate about 60%) a) R279W b) IVS1+2T>C (“Finnish” mutation) c) delV340 d) R178X
ACHONDROGENESIS
ii. Sequence analysis of the SLC26A2 (DTDST) coding region (mutation detection rate over 90%) a) Private mutations b) Common mutations c. Achondrogenesis type II: mutation analysis of the COL2A1 gene
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Achondrogenesis type IA and type IB (autosomal recessive disorders) a) Recurrence risk: 25% b) Unaffected sibs of a proband: 2/3 chance of being heterozygotes ii. Achondrogenesis type II a) Usually caused by a new dominant mutation, in which case recurrence risk is not significantly increased b) Asymptomatic carrier parent (germline mutation for a dominant mutation) may be present in the families of affected patients, in which case recurrence risk is 50% b. Patient’s offspring: lethal entities not surviving to reproduction 2. Prenatal diagnosis a. Ultrasonography i. Polyhydramnios ii. Fetal hydrops iii. Disproportionally big head iv. Nuchal edema v. Cystic hygroma vi. A narrow thorax vii. Short limbs viii. Poor ossification of vertebral bodies and limb tubular bones (leading to difficulties in determining their length) ix. Suspect achondrogenesis type I a) An extremely echo-poor appearance of the skeleton b) A poorly mineralized skull c) Short limbs d) Rib fractures b. Molecular genetic studies i. Prenatal diagnosis of achondrogenesis type IB and type II by mutation analysis of chorionic villus DNA or amniocyte DNA in the first or second trimester ii. Achondrogenesis type IB a) Characterize both alleles of DTDST beforehand b) Identify the source parent of each allele c) Theoretically, analysis of sulfate incorporation in chorionic villi might be used for prenatal diagnosis, but experience is lacking iii. Achondrogenesis type II a) The affected fetus usually with a new dominant mutation of the COL2A1 gene
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b) Possible presence of asymptomatic carriers in families of an affected patient c) Prenatal diagnosis possible if the mutation has been characterized in the affected family 3. Management a. Supportive care b. No treatment available for the underlying lethal disorder
REFERENCES Balakumar K: Antenatal diagnosis of Parenti-Fraccaro type achondrogenesis. Indian Pediatr 27:496–499, 1990. Bonafé L, Ballhausen D, Superti-Furga A: Achondrogenesis type 1B. Gene reviews, 2004. http://www.genetests.org Borochowitz Z, Lachman R, Adomian GE, et al.: Achondrogenesis type I: delineation of further heterogeneity and identification of two distinct subgroups. J Pediatr 112:23–31, 1988. Borochowitz Z, Ornoy A, Lachman R, et al.: Achondrogenesis II-hypochondrogenesis: variability versus heterogeneity. Am J Med Genet 24:273–288, 1986. Benacerraf B, Osathanondh R, Bieber FR: Achondrogenesis type I: ultrasound diagnosis in utero. J Clin Ultrasound 12:357–359, 1984. Chen H: Achondrogenesis. Emedicine, 2001. http://www.emedicine.com Chen H: Skeletal dysplasia. Emedicine, 2002. http://www.emedicine.com Chen H, Liu CT, Yang SS: Achondrogenesis: a review with special consideration of achondrogenesis type II (Langer-Saldino). Am J Med Genet 10:379–394, 1981. Faivre L, Le Merrer M, Douvier S, et al.: Recurrence of achondrogenesis type II within the same family: Evidence for germline mosaicism. Am J Med Genet 126A:308–312, 2004. Godfrey M, Hollister DW: Type II achondrogenesis-hypochondrogenesis: identification of abnormal type II collagen. Am J Hum Genet 43:904–913, 1988. Horton WA, Machado MA, Chou JW, et al.: Achondrogenesis type II, abnormalities of extracellular matrix. Pediatr Res 22:324–329, 1987. Körkkö J, Cohn DH, Ala-Kokko L, et al.: Widely distributed mutations in the COL2A1 gene produce achondrogenesis type II/hypochondrogenesis. Am J Med Genet 92:95–100, 2000. Langer LO, Jr, Spranger JW, Greinacher I, et al.: Thanatophoric dwarfism. A condition confused with achondroplasia in the neonate, with brief comments on achondrogenesis and homozygous achondroplasia. Radiology 92:285–294 passim, 1969. Meizner I, Barnhard Y: Achondrogenesis type I diagnosed by transvaginal ultrasonography at 13 weeks’ gestation. Am J Obstet Gynecol 173:1620–1622, 1995. Molz G, Spycher MA: Achondrogenesis type I: light and electron-microscopic studies. Eur J Pediatr 134:69–74, 1980. Mortier GR, Wilkin DJ, Wilcox WR, et al.: A radiographic, morphologic, biochemical and molecular analysis of a case of achondrogenesis type II resulting from substitution for a glycine residue (Gly691>Arg) in the type II collagen trimer. Hum Mol Genet 4:285–288, 1995. Ornoy A, Sekeles E, Smith P, et al.: Achondrogenesis type I in three sibling fetuses. Scanning and transmission electron microscopic studies. Am J Pathol 82:71–84, 1976. Smith WL, Breitweiser TD, Dinno N: In utero diagnosis of achondrogenesis, type I. Clin Genet 19:51–54, 1981. Soothill PW, Vuthiwong C, Rees H: Achondrogenesis type 2 diagnosed by transvaginal ultrasound at 12 weeks’ gestation. Prenat Diagn 13:523–528, 1993. Spranger J: International classification of osteochondrodysplasias. Eur J Pediatr 151:407–415, 1992. Spranger J, Winterpacht A, Zabel B: The type II collagenopathies: a spectrum of chondrodysplasias. Eur J Pediatr 153:56–65, 1994. Superti-Furga A: Achondrogenesis type 1B. J Med Genet 33:957–961, 1996. Superti-Furga A, Hästbacka J, Wilcox WR, et al.: Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene. Nat Genet 12:100–102, 1996. Superti-Furga A, Rossi A, Steinmann B, et al.: A chondrodysplasia family produced by mutations in the diastrophic dysplasia sulfate transporter gene: genotype/phenotype correlations. Am J Med Genet 63:144–147, 1996.
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Tongsong T, Srisomboon J, Sudasna J: Prenatal diagnosis of Langer-Saldino achondrogenesis. J Clin Ultrasound 23:56–58, 1995. van der Harten HJ, Brons JT, Dijkstra PF, et al.: Achondrogenesis-hypochondrogenesis: the spectrum of chondrogenesis imperfecta. A radiological, ultrasonographic, and histopathologic study of 23 cases. Pediatr Pathol 8:571–597, 1988. Yang SS, Bernstein J: Letter: Proposed readjustment of eponyms for achondrogenesis. J Pediatr 87:333–334, 1975. Yang S-S, Heidelberger KP, Brough AJ, et al.: Lethal short-limbed chondrodysplasia in early infancy. Persp Pediatr Pathol 3:1–40, 1976.
Yang SS, Bernstein J: Achondrogenesis type I. Arch Dis Child 52:253–254, 1977. Yang SS, Gilbert-Barnes E: Skeletal system. In: Gilbert-Barness E (ed): Potter’s Pathology of the Fetus and Infant. St Louis: Mosby, 1997, pp 1423–1478. Yang SS, Brough AJ, Garewal GS, et al.: Two types of heritable lethal achondrogenesis. J Pediatr 85:796–801, 1974. Yang SS, Heidelberger KP, Bernstein J: Intracytoplasmic inclusion bodies in the chondrocytes of type I lethal achondrogenesis. Hum Pathol 7:667–673, 1976.
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Fig. 1. A neonate with achondrogenesis type I showing large head, short trunk, and extreme micromelia. Radiograph shows unossified calvarium, vertebral bodies and some pelvic bones. The remaining bones are extremely small. There are multiple rib fractures. The sagittal section of the femora and the humeri are similar. An extremely small ossified shaft is capped by a relatively large epiphyseal cartilage at both ends. Photomicrographs of resting cartilage with high magnification show many chondrocytes that contain large cytoplasmic inclusions which are within clear vacuoles (Diastase PAS stain). Electron micrograph shows inclusion as a globular mass of electron dense material. It is within a distended cistern of rough endoplasmic reticulum.
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Fig. 2. Achondrogenesis type II. As in type I, this neonate shows large head, short trunk, and micromelia. Sagittal section of the femur shows much better ossification of the shaft than type I. The cartilage lacks glistering appearance due to cartilage matrix deficiency. Photomicrograph of the entire cartilage shows severe deficiency of cartilage matrix. The cartilage canals are large, fibrotic, and stellate in shape. Physeal growth zone is severely retarded.
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Fig. 3. Two infants with achondrogenesis type II showing milder spectrum of manifestations, bordering the type II and spondyloepiphyseal congenita.
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Fig. 4. A newborn girl with achondrogenesis type II showing large head, midfacial hypoplasia, short neck, small chest, and short limbs. The radiographs shows generalized shortening of the long bones of the upper and lower extremities with marked cupping (metaphyseal spurs) at the metaphyseal ends of the bones. This is most evident at the distal ends of the tibia, fibular, radius and ulna, and distal ends of the digits. Radiographs also shows short ribs without fractures and hemivertebrae involving thoracic vertebrae as well as the sacrum. Conformation-sensitive gel electrophoresis analysis indicated a sequence variation in the fragment containing exon 19 and the flanking sequences of the COL2A1 gene (Gly244Asp). Similar mutations in this area have been seen in patients diagnosed with hypochondroplasia and achondrogenesis type II.
Achondroplasia CLINICAL FEATURES
Achondroplasia is the most common form of short-limbed dwarfism. Gene frequency is estimated to be 1/16,000 and 1/35,000. There are about 5000 achondroplasts in the USA and 65,000 on Earth. The incidence for achondroplasia is between 0.5 and 1.5 in 10,000 births. The mutation rate is high and is estimated to be between 1.72×10–5 and 5.57×10–5 per gamete per generation. Most infants with achondroplasia are born unexpectedly to parents of average stature.
1. Major clinical symptoms a. Delayed motor milestones during infancy and early childhood b. Sleep disturbances secondary to both neurological and respiratory complications c. Breathing disorders i. A high prevalence (75%) of breathing disorders during sleep ii. Obstructive apnea caused by upper airway obstruction iii. The majority of respiratory complaints due to restrictive lung disease secondary to diminished chest size or upper airway obstruction and rarely due to spinal cord compression d. Symptomatic spinal stenosis in more than 50% of patients as a consequence of a congenitally small spinal canal i. Back pain ii. Lower extremity sensory changes iii. Incontinence iv. Paraplegia v. Onset of symptoms: usually after 20 seconds or 30 seconds e. Neurologic symptoms classified based on neurologic severity and presentation of spinal stenosis (Lutter and Langer, 1977) i. Type I (back pain with sensory and motor change of an insidious nature) ii. Type II (intermittent claudication limiting ambulation) iii. Type III (nerve root compression) iv. Type IV (acute onset paraplegia) f. Symptoms secondary to foramen magnum stenosis i. Respiratory difficulty ii. Feeding problems iii. Cyanosis, quadriparesis iv. Poor head control g. Symptoms secondary to cervicomedullary compression i. Pain ii. Ataxia iii. Incontinence iv. Apnea v. Progressive quadriparesis vi. Respiratory arrest 2. Major clinical signs a. Disproportionate short stature (dwarfism) b. Hypotonia during infancy and early childhood c. Relative stenosis of the foramen magnum in all patients, documented by CT d. Foramen magnum stenosis considered as the cause of increased incidence of:
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant disorder with complete penetrance b. Sporadic in about 80% of the cases, the result of a de novo mutation c. Presence of paternal age effect (advanced paternal age in sporadic cases) d. Gonadal mosaicism (two or more children with classic achondroplasia born to normal parents) 2. Caused by mutations in the gene of the fibroblast growth factor receptor 3 (FGFR3) on chromosome 4p16.3 a. About 98% of achondroplasia with G-to-A transition and about 1% G-to-C transversion at nucleotide 1138. Both mutations resulted in the substitution of an arginine residue for a glycine at position 380 (G380A) of the mature protein in the transmembrane domain of FGFR3 b. A rare mutation causing substitution of a nearby glycine 375 with a cysteine (G375C) c. Another rare mutation causing substitution of glycine346 with glutamic acid (G346E) d. The specific mechanisms by which FGFR3 mutations disrupt skeletal development in achondroplasia remain elusive 3. Basic defect: zone of chondroblast proliferation in the physeal growth plates a. Abnormally retarded endochondral ossification with resultant shortening of tubular bones and flat vertebral bodies, while membranous ossification (skull, facial bones) is not affected b. Physeal growth zones show normal columnization, hypertrophy, degeneration, calcification, and ossification. However, the growth is quantitatively reduced significantly c. Achondroplasia as the result of a quantitative loss of endochondral ossification rather than the formation of abnormal tissue d. Normal diameter of the bones secondary to normal subperiosteal membranous ossification of tubular bones; the results being production of short, thick tubular bones, leading to short stature with disproportionately shortened limbs 15
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i. Hypotonia ii. Sleep apnea iii. Sudden infant death syndrome e. Symptomatic hydrocephalus in infancy and early childhood rarely due to narrowing of the foramen magnum f. Characteristic craniofacial appearance i. Disproportionately large head ii. Frontal bossing iii. Depressed nasal bridge iv. Midfacial hypoplasia v. Narrow nasal passages vi. Prognathism vii. Dental malocclusion g. A normal trunk length h. A thoracolumbar kyphosis or gibbus usually present at birth or early infancy i. Exaggerated lumbar lordosis when the child begins to ambulate j. Prominent buttocks and protuberant abdomen secondary to increased pelvic tilt in children and adults k. Generalized joint hypermobility, especially the knees l. Rhizomelic micromelia (relatively shorter proximal segment of the limbs compared to the middle and the distal segments) m. Limited elbow and hip extension n. Trident hands (inability to approximate the third and fourth fingers in extension produces a “trident” configuration of the hand) o. Short fingers (brachydactyly) p. Bowing of the legs (genu varum) due to lax knee ligaments q. Excess skin folds around thighs 3. Complications/risks a. Recurrent otitis media during infancy and childhood i. Conductive hearing loss ii. Delayed language development b. Thoraco-lumbar gibbus c. Osteoarthropathy of the knee joints d. Neurological complications i. Small foramen magnum ii. Cervicomedullary junction compression causing sudden unexpected death in infants with achondroplasia iii. Apnea iv. Communicating hydrocephalus v. Spinal stenosis vi. Paraparesis vii. Quadriparesis viii. Infantile hypotonia e. Obesity i. Aggravating the morbidity associated with lumbar stenosis ii. Contributing to the nonspecific joint problems and to the possible early cardiovascular mortality in this condition f. Obstetric complications i. Large head of the affected infant ii. An increased risk of intracranial bleeding during delivery iii. Marked obstetrical difficulties secondary to very narrow pelvis of achondroplastic women
4. Prognosis a. Normal intelligence and healthy, independent, and productive lives in vast majority of patients. Rarely, intelligence may be affected because of hydrocephalus or other CNS complications b. Mean adult height i. Approximately 131 ± 5.6 cm for males ii. Approximately 124 ± 5.9 cm for females c. Psychosocial problems related to body image because of severe disproportionate short stature d. Life- span for heterozygous achondroplasia i. Usually normal unless there are serious complications ii. Mean life expectancy approximately 10 years less than the general population e. Homozygous achondroplasia i. A lethal condition with severe respiratory distress caused by rib-cage deformity and upper cervical cord damage caused by small foramen magnum. The patients die soon after birth ii. Radiographic changes much more severe than the heterozygous achondroplasia f. Normal fertility in achondroplasia i. Pregnancy at high risk for achondroplastic women ii. Respiratory compromise common during the third trimester iii. Advise baseline pulmonary function studies before pregnancy to aid in evaluation and management iv. A small pelvic outlet usually requiring cesarean section under general anesthesia since the spinal or epidural approach is contraindicated because of spinal stenosis g. Anticipatory guidance: patients and their families can benefit greatly from anticipatory guidance published by American Academy of Pediatrics Committee on Genetics (1995) h. Adaptations of patients to the environment to foster independence i. Lowering faucets and light switches ii. Using a step stool to keep feet from dangling when sitting iii. An extended wand for toileting iv. Adaptations of toys for short limbs i. Support groups: Many families find it beneficial to interact with other families and children with achondroplasia through local and national support groups
DIAGNOSTIC INVESTIGATIONS 1. Diagnosis of achondroplasia made by clinical findings, radiographic features, and/or FGFR3 mutation analysis 2. Radiologic features a. Skull i. Relatively large calvarium ii. Prominent forehead iii. Depressed nasal bridge iv. Small skull base v. Small foramen magnum vi. Dental malocclusion
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b. Spine i. Caudal narrowing of interpedicular distances in the lower lumbar spine ii. Short vertebral pedicles iii. Wide disc spaces iv. Dorsal scalloping of the vertebral bodies in the newborn v. Concave posterior aspect of the vertebral bodies in childhood and adulthood vi. Different degree of anterior wedging of the vertebral bodies causing gibbus c. Pelvis i. Lack of iliac flaring ii. Narrow sacroiliac notch iii. Horizontal acetabular portions of the iliac bones d. Limbs i. Rhizomelic micromelia ii. Square or oval radiolucent areas in the proximal humerus and femur during infancy iii. Tubular bones with widened diaphyses and flared metaphyses during childhood and adulthood iv. Markedly shortened humeri v. Short femoral neck vi. Disproportionately long fibulae in relation to tibiae 3. Craniocervical MRI a. Narrowing of the foramen magnum b. Effacement of the subarachnoid spaces at the cervicomedullary junction c. Abnormal intrinsic cord signal intensity d. Mild-to-moderate ventriculomegaly 4. Histology a. Normal histologic appearance of epiphyseal and growth plate cartilages b. Shorter than normal growth plate: the shortening is greater in homozygous than in heterozygous achondroplasia, suggesting a gene dosage effect 5. Mutation analysis a. G1138A substitution in FGFR3 (about 98% of cases) b. G1138C substitution in FGFR3 (about 1% of cases)
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Recurrence risk of achondroplasia in the sibs of achondroplastic children with unaffected parents: presumably higher than twice the mutation rate because of gonadal mosaicism. Currently, the risk is estimated as 1 in 443 (0.2%) ii. 50% affected if one of the parents is affected iii. 25% affected with homozygous achondroplasia (resulting in a much more severe phenotype that is usually lethal early in infancy) and 50% affected with heterozygous achondroplasia if both parents are affected with achondroplasia b. Patient’s offspring i. 50% affected (with heterozygous achondroplasia) if the spouse is normal ii. 25% affected with homozygous achondroplasia and 50% affected with heterozygous achondropla-
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sia if the spouse is also affected with achondroplasia. There is still a 25% chance that the offspring will be normal 2. Prenatal diagnosis a. Prenatal ultrasonography i. Suspect achondroplasia on routine ultrasound findings of a fall-off in limb growth, usually during the third trimester of pregnancy, in case of parents with normal heights. About one-third of cases are suspected this way. However, one must be cautious because disproportionately short limbs are observed in a variety of conditions ii. Inability to make specific diagnosis of achondroplasia with certainty by ultrasonography unless by radiography late in gestation or after birth iii. Request of prenatal ultrasonography by an affected parent, having 50% risk of having a similarly affected child, to optimize obstetric management iv. Follow pregnancy by a femoral growth curve in the second trimester by serial ultrasound scans to enable prenatal distinction between homozygous, heterozygous, and unaffected fetuses, in case of both affected parents b. Prenatal molecular testing i. Molecular technology applied to prenatal diagnosis of a fetus suspected of or at risk for having achondroplasia ii. Simple methodology requiring only one PCR and one restriction digest to detect a very limited number of mutations causing achondroplasia iii. Preimplantation genetic diagnosis a) Available at present (Montou et al., 2003) b) The initial practice raising questions on the feasibility of such a test, especially with affected female patients 3. Management a. Adaptive environmental modifications i. Appropriately placed stools ii. Seating modification iii. Other adaptive devices b. Obesity control c. Obstructive apnea i. Adenoidectomy and tonsillectomy ii. Continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) for clinically significant persistent obstruction iii. Extremely rare for requiring temporary tracheostomy d. Experimental growth hormone therapy resulting in transient increases in growth velocity e. Hydrocephalus i. Observation for benign ventriculomegaly ii. May need surgical intervention for clinically significant hydrocephalus f. Kyphosis i. Adequate support for sitting in early infancy ii. Bracing using a thoracolumbosacral orthosis for severe kyphosis in young children iii. Surgical intervention for medically unresponsive cases
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g. Surgical decompression for unequivocal evidence for cervical cord compression h. Decompression laminectomy for severe and progressive lumbosacral spinal stenosis i. Limb lengthening through osteotomy and stretching of the long bones i. Controversial ii. Difficult to achieve the benefits of surgery a) Need strong commitment on the part of the patients and their families for the time in the hospital and the number of operations b) Occurrence of possible severe permanent sequelae j. Potential anesthetic risks related to: i. Obstructive apnea ii. Cervical compression k. Risks associated with pregnancy in women with achondroplasia: relatively infrequent i. Worsening neurologic symptoms related to increasing hyperlordosis and maternal respiratory failure ii. Anticipate a scheduled cesarean delivery due to cephalopelvic disproportion iii. Preeclampsia iv. Polyhydramnios
REFERENCES Allanson JE, Hall JG: Obstetrics and gynecologic problems in women with chondrodystrophies. Obstet Gynecol 67:74–78, 1986. American Academy of Pediatrics Committee on Genetics: Health supervision for children with achondroplasia. Pediatrics 95:443–451, 1995. Bellus GA, Hefferon TW, Ortiz de Luna RI, et al.: Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am J Hum Genet 56:368–373, 1995. Chen H, Mu X, Sonoda T, et al.: FGFR3 gene mutation (Gly380Arg) with achondroplasia and i(21q) Down syndrome: phenotype-genotype correlation. South Med J 93:622–624, 2000. Francomano CA: Achondroplasia. Gene Reviews, 2003. http:// www.genetests.org Fryns JP, Kleczkowska A, Verresen H, et al.: Germinal mosaicism in achondroplasia: a family with 3 affected siblings of normal parents. Clin Genet 24:156–158, 1983. Hall JG: The natural history of achondroplasia. In: Nicoletti B, Kopits SE, Ascani E, et al. (eds): Human Achondroplasia: A Multidisciplinary Approach. New York: Plenum Press, 1988 pp 3–10. Hall JG, Dorst J, Taybi H, et al.: Two probable cases of homozygosity for the achondroplasia gene. Birth Defects Orig Art Ser V(4):24–34, 1969. Hecht JT, Butler IJ: Neurologic morbidity associated with achondroplasia. J Child Neurol 5:84–97, 1990. Hecht JT, Francomano CA, Horton WA et al.: Mortality in achondroplasia. Am J Hum Genet 41:454–464, 1987. Henderson S, Sillence D, Loughlin J, et al.: Germline and somatic mosaicism in achondroplasia. J Med Genet 37:956–958, 2000. Horton WA: Molecular genetic basis of the human chondrodysplasias. Endocr Metabol Clin 25:683–697, 1996. Horton WA: Fibroblast growth factor receptor 3 and the human chondrodysplasias. Curr Opin Pediatr 9:437–442, 1997. Horton WA, Rotter JI, Rimoin DL, et al.: Standard growth curves for achondroplasia. J Pediatr 93:435–438, 1978. Horton WA, Hood OJ, Machado MA, et al.: Growth plate cartilage studies in achondroplasia. In: Nicoletti B, Kopits SE, Ascani E, et al. (eds): Human Achondroplasia: A Multidisciplinary Approach. New York: Plenum Press 1988, pp 81–89.
Horton WA, Hecht JT, Hood OJ, et al.: Growth hormone therapy in achondroplasia. Am J Med Genet 42: 667–670, 1992. Hunter AGW, Hecht JT, Scott CI: Standard weight for height curves in achondroplasia. Am J Med Genet 62:255–261, 1996. Hunter AGW, Bankier A, Rogers JG, et al.: Medical complications of achondroplasia: a multicenter patient review. J Med Genet 35:705–712, 1998. Kornblum M, Stanitski DF: Spinal manifestations of skeletal dysplasias. Orthop Clin N Amer 30:501–520, 1999. Langer LO Jr, Baumann PA, Gorlin RJ: Achondroplasia. Am J Roentgen 100:12–26, 1967. Lattanzi DR, Harger JH: Achondroplasia and pregnancy. J Reprod Med 27:363–366, 1982. Mettler G, Fraser FC: Recurrence risk for sibs of children with “sporadic” achondroplasia. Am J Med Genet 90:250, 251, 2000. Mogayzel PJ Jr, Carroll JL, Loughlin GM, et al.: Sleep-disordered breathing in children with achondroplasia. J Pediatr 132:667–671, 1998. Moutou C, Rongieres C, Bettahar-Lebugle K, et al.: Preimplantation genetic diagnosis for achondroplasia: genetics and gynaecological limits and difficulties. Hum Reprod 18:509–514, 2003. Overlaid F, Danks DM, Jensen F, et al.: Achondroplasia and hypochondroplasia. Comments on frequency, mutation rate, and radiological features in skull and spine. J Med Genet 16:140–146, 1979. Patel MD, Filly RA: Homozygous achondroplasia: US distinction between homozygous, heterozygous, and unaffected fetuses in the second trimester. Radiology 196:541–545, 1995. Pauli RM: Achondroplasia. In: Cassidy SB, Allanson JE (eds): Management of Genetic Syndromes. New York: Wiley-Liss, 2001. Philip N, Auger M, Mattei JF, et al.: Achondroplasia in sibs of normal parents. J Med Genet 25:857–859, 1988. Pierre-Kahn A, Hirsch JF, Renier D, et al.: Hydrocephalus and achondroplasia. A study of 25 observations. Child’s Brain 7:205–219, 1980. Prinos P, Kilpatrick MW, Tsipouras P, et al.: A novel G346E mutation in achondroplasia. Pediatr Res 37:151, 1994. Rimoin DL: Limb lengthening: past, present, and future. Growth Genet Hormones 7:4–6, 1991. Rousseau F, Bonaventure J, Legeal-Mallet L, et al.: Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371:252–254, 1994. Shiang R, Thompson LM, Zhu Y-Z, et al.: Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78:335–342, 1994. Shohat M, Tick D, Barakat S, et al.: Short-term recombinant human growth hormone treatment increases growth rate in achondroplasia. J Clin Endocr Metab 81:4033–4037, 1996. Spranger JW, Langer LO Jr, Wiedemann HR: Bone dysplasias.An atlas of constitutional disorders of skeletal development. Philadelphia: WB Saunders Co., 1974. Todorov AB, Scott CI, Warren AE, et al.: Developmental screening tests in achondroplastic children. Am J Med Genet. 9:19–23, 1981. Vajo Z, Francomano CA, Wilkin DJ: The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: The achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocr Rev 21:23–39, 2000. Velinov M, Slaugenhaupt SA, Stoilov I, et al.: The gene for achondroplasia maps to the telomeric region of chromosome 4p. Nature Genet 6:318–321, 1994. Yang SS, Corbett DP, Brough AJ, et al.: Upper cervical myelopathy in achondroplasia. Am J Clin Path 68:68–72, 1977. Yang SS, Gilbert-Barnes E: Skeletal system. In: Gilbert-Barness E (ed): Potter’s Pathology of the Fetus and Infant. St Louis: Mosby, 1997, pp 1423–1478. Yasui N, Kawahata H, Kojimoto H, et al.: Lengthening of the lower limbs in patients with achondroplasia and hypochondroplasia. Clin Orthop 344:298–306, 1997. Zucconi M, Weber G, Castronova V, et al.: Sleep and upper airway obstruction in children with achondroplasia. J Pediatr 129:743–749, 1996.
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Fig. 2. A 4-month-old boy with achondroplasia showing typical craniofacial features and rhizomelic shortening of limbs (confirmed by radiograms). Molecular study revealed 1138 G-to-A transition mutation.
Fig. 1. A newborn with achondroplasia showing large head, depressed nasal bridge, short neck, normal length of the trunk, narrow chest, rhizomelic micromelia, and trident hands. The radiographs showed narrow chest, characteristic pelvis, micromelia, and oval radiolucent proximal portion of the femurs. Molecular analysis showed 1138G→C mutation.
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Fig. 3. Another achondroplastic neonate with typical clinical features and radiographic findings. Note the abnormal vertebral column with wide intervertebral spaces and abnormal vertebral bodies.
Fig. 5. Two older children with achondroplasia showing rhizomelic micromelia, typical craniofacial features, exaggerated lumbar lordosis, and trident hands.
Fig. 4. A boy (7 month and 2 year 7 month old) with achondroplasia showing a large head, small chest, normal size of the trunk, rhizomelic micromelia, and exaggerated lumbar lordosis.
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Fig. 6. A boy with achondroplasia and i(21q) Down syndrome presented with diagnostic dilemma. Besides craniofacial features typical for Down syndrome, the skeletal findings of achondroplasia dominate the clinical picture. The diagnosis of Down syndrome was based on the clinical features and the cytogenetic finding of i(21q) trisomy 21. The diagnosis of achondroplasia was based on the presence of clinical and radiographic findings, and confirmed by the presence of a common FGFR3 gene mutation (Gly380Arg) detected by restriction enzyme analysis and sequencing of the PCR products.
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Fig. 7. Schematic of the FGFR3 gene and DNA sequence of normal allele and mutant FGFR3 achondroplasia allele (modified from Shiang et al., 1994). Fig. 9. Homozygous achondroplasia. Both parents are achondroplastic. The large head, narrow chest, and severe rhizomelic shortening of the limbs are similar to those of thanatophoric dysplasia. Radiograph shows severe platyspondyly, small ilia, and short limb bones. Photomicrograph of the physeal growth zone shows severe retardation and disorganization, similar to that of thanatophoric dysplasia.
Fig. 8. Nucleotide change in the 1138C allele creates a Msp1 site and nucleotide change in the 1138A allele creates a Sfc1. The base in the coding sequence that differs in the three alleles is boxed (modified from Shiang et al., 1994).
Adams-Oliver Syndrome d. May involve other areas of the body e. Severe end of the spectrum of scalp defects i. Encephalocele ii. Acrania 4. Congenital cardiovascular malformations (13.4–20%) a. Mechanisms proposed to explain the pathogenesis of congenital cardiovascular malformations i. Alteration of mesenchymal cell migration resulting in conotruncal malformations; e.g., tetralogy of Fallot, double outlet right ventricle, and truncus arteriosus ii. Alteration of fetal cardiac hemodynamics resulting in different malformations such as coarctation of the aorta, aortic stenosis, perimembranous VSD, and hypoplastic left heart iii. Persistence of normal fetal vascular channels resulting in postnatal vascular abnormalities b. Diverse vascular and valvular abnormalities i. Bicuspid aortic valve ii. Pulmonary atresia iii. Parachute mitral valve iv. Pulmonary hypertension 5. Other associated anomalies a. Cutis marmorata telangiectasia congenita (12%) b. Dilated and tortuous scalp veins (11%) c. Poland anomaly d. Encephalocele e. Facial features i. Hemihypoplasia ii. Hypertelorism iii. Epicanthal folds iv. Microphthalmia v. Esotropia vi. High arch palate vii. Cleft palate f. Cryptorchidism g. Lymphatic abnormalities i. Lymphedema of the leg ii. Chylothorax iii. Dilated pulmonary lymphatics iv. Intestinal lymphangiectasia v. Marmorata telangiectasia congenita (a cutaneous vascular abnormality) h. CNS abnormalities: unusual manifestation i. Mental retardation ii. Learning disability iii. Epilepsy i. Short stature j. Renal malformations k. Spina bifida occulta l. Accessory nipples
In 1945, Adams and Oliver described congenital transverse limb defects associated with aplasia cutis congenita in a threegeneration kindred with typical autosomal dominant inheritance and intrafamilial variable expressivity.
GENETICS/BASIC DEFECTS 1. Genetic heterogeneity a. Autosomal dominant in most cases b. Autosomal recessive in some cases 2. Pathogenesis a. Trauma b. Uterine compression c. Amniotic band sequelae d. Vascular disruption sequence i. Concomitant occurrence of Poland sequence ii. Both Poland sequence and Adams-Oliver syndrome: secondary to vascular disruption due to thrombosis of subclavian and vertebral arteries e. Massive thrombus from the placenta occluding the brachial artery f. Abnormalities in small vessel structures manifesting during embryogenesis g. A developmental disorder of morphogenesis
CLINICAL FEATURES 1. Marked intrafamilial and interfamilial variability 2. Terminal transverse limb defects a. Most common manifestation (84%) b. Usually asymmetrical c. Tendency toward bilateral lower limb rather than upper limb involvement d. Mild spectrum of defects i. Nail hypoplasia ii. Cutaneous syndactyly iii. Bony syndactyly iv. Ectrodactyly v. Brachydactyly e. Severe spectrum of transverse defects i. Absence of the hand ii. Absence of the foot iii. Absence of the limb 3. Aplasia cutis congenita a. Second most common defect (almost 75%) b. Associated with skull defect (64%) i. Small lesion: 0.5 cm in diameter ii. Intermediate lesion: 8–10 cm involving the vertex iii. Severe lesion: involves most of the scalp with acrania c. Skull defect without scalp defect, often mistaken for an enlarged fontanelle
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DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Transverse limb defects b. Ectrodactyly c. Brachydactyly d. Syndactyly e. Nail hypoplasia f. Skull defect 2. CT scan or MRI of the brain a. Polymicrogyria b. Ventriculomegaly c. Irregular cortical thickening d. Cerebral cortex dysplasia e. Microcephaly f. Arhinencephaly g. Periventricular and parenchymal calcium deposits
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal dominant: not increased unless a parent is affected in which case the risk is 50% ii. Autosomal recessive: 25% b. Patient’s offspring i. Autosomal dominant: 50% ii. Autosomal recessive: not increased unless the spouse carries the gene or is affected 2. Prenatal diagnosis by ultrasonography a. Transverse limb defects b. Concomitant skull defect 3. Management a. Treat minor scalp lesions with daily cleansing of the involved areas with applications of antibiotic ointment b. Surgically close larger lesions and exposed dura with minor or major skin grafting procedure (split-thickness or full-thickness) c. Prevent sepsis and/or meningitis from an open scalp lesion which is highly vascular and rarely involves the sagittal sinus predisposing to episodes of spontaneous hemorrhage d. Orthopedic care for various degrees of limb defects
REFERENCES Adams FH, Oliver CP: Hereditary deformities in man due to arrested development. J Hered 36:3–7, 1945. Arand AG, et al.: Congenital scalp defects: Adams-Oliver syndrome. A case report and review of the literature. Pediatr Neurosurg 17:203–207, 1991. Bamforth JS, Kaurah P, Byrne J, et al.: Adams Oliver syndrome: a family with extreme variability in clinical expression. Am J Med Genet 49: 393–396, 1994.
Becker R, Kunze J, Horn D, et al.: Autosomal recessive type of Adams-Oliver syndrome: prenatal diagnosis. Ultrasound Obstet Gynecol 20:506–-510, 2002. Bonafede RP, Beighton P: Autosomal dominant inheritance of scalp defects with ectrodactyly. Am J Med Genet 3:35–41, 1979. Bork K, Pfeifle J: Multifocal aplasia cutis congenita, distal limb hemimelia, and cutis marmorata telangiectatica in a patient with Adams-Oliver syndrome. Br J Dermatol 127:160–163, 1992. Burton BK, Hauser H, Nadler HL: Congenital scalp defects with distal limb anomalies: report of a family. J Med Genet 13:466–468, 1976. Frieden I: Aplasia cutis congenita: a clinical review and proposal for classification. J Am Acad Dermatol 14:646–660, 1986. Fryns JP: Congenital scalp defects with distal limb reduction anomalies. J Med Genet 24:493–496, 1987. Fryns JP, Leigius E, Demaere P, et al.: Congenital scalp defects, distal limb reduction anomalies, right spastic hemiplegia and hypoplasia of the left arterial cerebri media. Clin Genet 50:505–509, 1996. Hoyme HE, Der Kaloustian VM, Entin M, et al.: Possible common pathogenetic mechanisms for Poland sequence and Adams-Oliver syndrome: an additional clinical observation. Am J Med Genet 42:398–399, 1992. Klinger G, Merlob P: Adams-Oliver syndrome: autosomal recessive inheritance and new phenotypic-anthropometric findings. Am J Med Genet 79:197–199, 1998. Koiffmann CP, Wajntal A, Huyke BJ, et al.: Congenital scalp skull defects with distal limb anomalies (Adams-Oliver syndrome—McKusick 10030): further suggestion of autosomal recessive inheritance. Am J Med Genet 29:263–268, 1988. Küster W, Lenz W, Kaariainen H, et al.: Congenital scalp defects with distal limb anomalies (Adams-Oliver syndrome): report of ten cases and review of the literature. Am J Med Genet 31:99–115, 1988. Lin AE, Wesgate MN, van der Velde ME, et al.: Adams-Oliver syndrome associated with cardiovascular malformation. Clin Dysmorphol 7:235–241, 1998. Mempel M, Abeck D, Lange I, et al.: The wide spectrum of clinical expression in Adams-Oliver syndrome: a report of two cases. Br J Dermatol 140:1157– 1160, 1999. Pauli RM, et al.: Familial recurrence of terminal transverse defects of the arm. Clin Genet 27:555–563, 1985. Pereira-da-Silva L, Leal F, Cassiano Santos G, et al.: Clinical evidence of vascular abnormalities at birth in Adams-Oliver syndrome: report of two further cases. (Letter) Am J Med Genet 94:75–76, 2000. Pousti TJ, Bartlett RA: Adams-Oliver syndrome: genetics and associated anomalies of cutis aplasia. Plast Reconstr Surg 100:1491–1496, 1997. Shapiro SD, Escobedo MK: Terminal transverse defects with aplasia cutis congenita (Adams-Oliver syndrome). Birth Defects Orig Artic Ser 21(2):135–142, 1985. Stevenson RE, Deloache WR: Aplasia cutis congenita of the scalp. Proc Greenwood Genet Center 7:14–18, 1988. Sybert VP: Congenital scalp defects with distal limb anomalies (Adams-Oliver Syndrome—McKusick 10030): further suggestion of autosomal recessive inheritance. Am J Med Genet 32:266–-267, 1989. Tekin M, Bodurtha J, Çiftçi E, et al.: Further family with possible autosomal recessive inheritance of Adams-Oliver syndrome. (Letter) Am J Med Genet 86:90–91, 1999. Toriello HV, Graff RG, Florentine MF, et al.: Scalp and limb defects with cutis marmorata telangiectatica congenita: Adams-Oliver syndrome?. Am J Med Genet 29:269–276, 1988. Verdyck P, Holder-Espinasse M, Hul WV, et al.: Clinical and molecular analysis of nine families with Adams-Oliver syndrome. Eur J Hum Genet 11:457–463, 2003. Whitley CB, Gorlin RJ: Adams-Oliver syndrome revisited. Am J Med Genet 40:319–326, 1991. Zapata HH, Sletten LJ, Pierpont MEM: Congenital cardiac malformations in Adams-Oliver syndrome. Clin Genet 47:80–84, 1995.
ADAMS-OLIVER SYNDROME
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Fig. 1. A 9-month-old boy with Adams-Oliver syndrome showing alopecia, absent eyebrows and eyelashes, scalp defect, tortuous scalp veins, and limb defects (brachydactyly, syndactyly, broad great toes, and nail hypoplasia). Radiography showed absent middle and distal phalanges of 2nd–5th toes and absent distal phalanges of the great toes.
Agnathia Agnathia is an extremely rare lethal neurocristopathy. The disorder has also been termed agnathia-holoprosencephaly, agnathia-astomia-synotia, or cyclopia-otocephaly association. The incidence is estimated to be 1/132,000 births in Spain.
11. Cleft lip/palate 12. Occular malformations a. Microphthalmos/anophthalmia b. Proptosis (protruding eyes) c. Absence of the eyelids d. Epibulbar dermoid e. Aphakia f. Retinal dysplasia g. Microcornea h. Anterior segment dysgenesis i. Uveal colobomas 13. Nasal anomalies a. Absence of the nasal cavity b. Cleft nose c. Blind nasal pharynx 14. Various visceral malformations a. Choanal atresia b. Tracheoesophageal fistula c. Absence of the thyroid gland d. Absence of the submandibular and parotid salivary glands e. Abnormal glottis and epiglottis f. Thyroglossal duct cyst g. Carotid artery anomalies h. Situs inversus i. Cardiac anomalies j. Unlobulated lungs k. Renogenital anomalies i. Unilateral renal agenesis ii. Renal Ectopia iii. Cystic kidneys iv. Horseshoe kidneys v. Solitary kidney vi. Mullerian duct agenesis vii. Cryptorchidism 15. Skeletal anomalies a. Vertebral anomalies b. Rib anomalies c. Tetramelia 16. Anatomical variations a. Ears i. Absence of the tragus ii. Synotia b. Mandible i. Rudimentary ii. Absent iii. Two small separate masses c. Mouth: microstomia with vertical orientation d. Buccopharyngeal membrane: absent to present e. Tongue i. Small to absent body ii. Present in (hypo)pharynx f. Absent submandibular glands
GENETICS/BASIC DEFECTS 1. Sporadic occurrence in majority of cases 2. Rare autosomal recessive inheritance 3. Possible autosomal dominant inheritance a. Supported by an observation of dysgnathia in mother and daughter b. Possibility of a defect in the OTX2 gene as the basis of the disorder 4. A prechordal mesoderm inductive defect affecting neural crest cells a. A developmental field defect b. Different etiologic agents (etiological heterogeneity) acting on the same developmental field producing a highly similar complex of malformations 5. Possible existence of a mild form of agnathia without brain malformation (holoprosencephaly) a. Situs inversus-congenital hypoglossia b. Severe micrognathia, aglossia, and choanal atresia 6. A well-recognized malformation complex in the mouse, guinea pig, rabbit, sheep, and pig
CLINICAL FEATURES 1. Polyhydramnios due to persistence of oropharyngeal membrane or blind-ending mouth 2. Agnathia (absence of the mandible) 3. Microstomia or astomia (absence of the mouth) 4. Aglossia (absence of the tongue) 5. Blind mouth 6. Ear anomalies a. Otocephaly (variable ear positions) b. Synotia (external ears approaching one another in the midline) c. Dysplastic inner ear d. Atretic ear canal 7. Down-slanting palpebral fissures 8. Variable degree of holoprosencephaly a. Cyclopia b. Synophthalmia c. Arrhinencephaly 9. Other brain malformations a. Cerebellar hypoplasia b. Septum pellucidum Cavum c. Absence of cranial nerves (I-IV) d. Absence of the corpus callosum e. Meningocele 10. Intrauterine growth retardation 26
AGNATHIA
g. Other skull bones: approximated maxillae, palatine, zygomatic, and temporal
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Reduced maxilla b. Absence of the zygomatic process c. Absence of the hyoid bone d. Vertebral anomalies e. Absence of the ribs f. Sprengel deformity 2. Cranial ultrasonography to define holoprosencephaly 3. Chromosome analysis a. Normal in majority of cases b. Unbalanced der(18),t(6;18)(pter→p24.1;p11.21→qter) in two female sibs with agnathia-holoprosencephaly 4. Autopsy to define postmortem findings
GENETIC COUNSELING 1. Recurrence risks a. Risk to patient’s sib: not increased unless in a rare autosomal recessive inheritance b. Risk to patient’s offspring: not applicable since affected patients do not survive to reproduce 2. Prenatal diagnosis by ultrasonography or three-dimensional imaging by helical computed tomography (CT) a. Polyhydramnios b. Intrauterine growth retardation c. Mandibular absence (agnathia) or major hypoplasia d. Holoprosencephaly e. Cyclopia, marked hypotelorism or frontal proboscis 3. Management: a lethal entity
REFERENCES Bixler D, Ward R, Gale DD: Agnathia-holoprosencephaly: a developmental field complex involving face and brain. Report of 3 cases. J Craniofac Genet Dev Biol (Suppl) 1:241–249, 1985. Blaas HG, Eriksson AG, Salvesen KA, et al.: Brains and faces in holoprosencephaly: pre- and postnatal description of 30 cases. Ultrasound Obstet Gynecol 19:24–38, 2002.
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Carles D, Serville F, Mainguene M, et al.: Cyclopia-otocephaly association: a new case of the most severe variant of Agnathia-holoprosencephaly complex. J Craniofac Genet Dev Biol 7:107–113, 1987. Cohen MM: Perspectives on holoprosencephaly: Par III. Spectra, distinctions, continuities and discontinuities. Am J Med Genet 34:271–288, 1989. Ebina Y, Yamada H, Kato EH, et al.: Prenatal diagnosis of agnathia-holoprosencephaly: three-dimensional imaging by helical computed tomography. Prenat Diagn 21:68–71, 2001. Erlich MS, Cunningham ML, Hudgins L: Transmission of the dysgnathia complex from mother to daughter. Am J Med Genet 95: 269–274, 2000. Gaba AR, et al.: Alobar holoprosencephaly and otocephaly in a female infant with a normal karyotype and placental villitis. J Med Genet 19:78, 1982. Henekam RC: Agnathia-holoprosencephaly: a midline malformation association. Am J Med Genet 36:525, 1990. Hersh JH, McChane RH, Rosenberg EM, et al.: Otocephaly-midline malformation association. Am J Med Genet 34:246–249, 1989. Hinojosa R, Green JD, Brecht K, et al.: Otocephalus: histopathology and threedimensional reconstruction. Otloaryngol Head neck Surg 114:44–53, 1996. Johnson WW, Cook JB: Agnathia associated with pharyngeal isthmus atresia and hydramnios. Arch Pediatr 78:211–217, 1961. Kamiji T, Takagi T, Akizuki T, et al.: A long surviving case of holoprosencephaly agnathia series. Br J Plast Surg 44:386–389, 1991. Krassikoff N, Sekhon GS: Familial agnathia-holoprosencephaly caused by an inherited unbalanced translocation and not autosomal recessive inheritance. Am J Med Genet 34:255–257, 1989. Lawrence D, Bersu ET: An anatomical study of human otocephaly. Teratology 30:155–165, 1985. Leech RW, Bowlby LS, Brumback RA, et al.: Agnathia, holoprosencephaly, and situs inversus: report of a case. Am J Med Genet 29:483–490, 1988. Meinecke P, Padberg B, Laas R: Agnathia, holoprosencephaly, and situs inversus: a third report. Am J Med Genet 37:286–287, 1990. Özden S, Fiçiciog˘lu C, Kara M, et al.: Agnathia-holoprosencephaly-situs inversus. Am J Med Genet 91:235–236, 2000. Pauli RM, Graham JM Jr, Barr M Jr: Agnathia, situs inversus, and associated malformations. Teratology 23:85–93, 1981. Pauli RM, Pettersen JC, Arya S, et al.: Familial agnathia-holoprosencephaly. Am J Med Genet 14:677–698, 1983. Rolland M, Sarramon MF, Bloom MC: Astomia-agnathia-holoprosencephaly association. Prenatal diagnosis of a new case. Prenat Diagn 11:199–203, 1991. Santana SM et al.: Agnathia and associated malformations. Dysmorph Clin Genet 1:58–63, 1987. Scholl HW Jr: In utero diagnosis of agnathia, microstomia, and synotia. Obstet Gynecol 49(1 Suppl):81–83, 1977. Suda Y, Nakabayashi J, Matsuo I, Aizawa S: Functional equivalency between Otx2 and Otx1 in development of the rostral head. Development 126: 743–757, 1999.
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AGNATHIA
Fig. 1. A neonate (28 week gestation) with agnathia-holoprosencephaly complex showing a large defect involving entire midface area with almost total absence of jaw, absence of eyes and nose, and severe microtia. Absence of olfactory bulbs and grooves (arrhinencephaly) were demonstrated by necropsy. Additional anomalies included 13 pairs of ribs, atresia of left ureter with resultant hydronephrosis, and left renal cortical cysts. Maternal hydramnios was present.
Aicardi Syndrome 5. Extra-CNS tumors a. Soft palatal benign teratoma b. Hepatoblastoma c. Parapharyngeal embryonal cell carcinoma d. Limb angiosarcoma e. Scalp lipoma f. Multiple gastrointestinal polyps 6. Scoliosis or costovertebral anomalies 7. Severe cognitive and physical handicaps a. Global developmental delay b. Moderate to severe mental retardation in most patients c. Unable to ambulate in most children d. Limited visual ability 8. New diagnostic criteria (Aicardi, 1999) a. Classic triad i. Infantile spasms ii. Chorioretinal lacunae iii. Agenesis/dysgenesis of the corpus callosum b. New major features (present in most patients studied by MRI) i. Cortical malformations, mostly microgyria (probably constant but may not be possible to evidence) ii. Periventricular and subcortical heterotopia iii. Cysts around the third ventricle and/or choroid plexuses iv. Papillomas of choroid plexuses v. Optic disc/nerve coloboma c. Supporting features (present in some cases) i. Vertebral and costal abnormalities ii. Microphthalmia and/or other eye abnormalities iii. “Split-brain” EEG (associated suppression-burst tracing) iv. Gross hemispheric asymmetry 9. Estimated survival rate a. 76% at 6 years of age b. 40% at 15 years of age
In 1965, Aicardi et al. reported a new syndrome consisting of spasms in flexion, callosal agenesis, and ocular abnormalities. Actual frequency of the condition is not known, but about 1–4% of cases of infantile spasms from tertiary referral centers may be due to Aicardi syndrome.
GENETICS/BASIC DEFECTS 1. Inheritance a. X-linked dominant, lethal in males b. Almost exclusively affects females (heterozygous for a particular mutant X-chromosome gene to manifest) c. Exception: boys with XXY chromosome constitution allowing heterozygous expression of the gene as in the female d. Not known to be a familial condition, except an isolated familial instance involving two sisters 2. Gene map postulated on chromosome Xp22 from an observation in an affected girl with t(X;3)(p22;q12)
CLINICAL FEATURES 1. Classic triad a. Pathognomonic chorioretinal lacunae i. Multiple, rounded, unpigmented, and yellowwhite lesions ii. Occasionally unilateral iii. May be absent in rare cases b. Infantile spasms/seizures i. Frequently asymmetric ii. Often preceded or precipitated by a focal clonic or tonic seizure limited to the side in which the spasms predominate c. Agenesis of the corpus callosum 2. Other CNS abnormalities a. Ependymal cysts b. Choroid plexus papillomas c. Cortical migration abnormalities d. Optic disk coloboma e. Hydrocephaly f. Porencephaly g. Cerebellar agenesis h. Heterotopias 3. Variable neurologic abnormalities a. Hemiparesis or hemiplegia i. The most frequent abnormality ii. Often on the side where the spasms predominate b. Quadriplegia c. Hypotonia d. Hypertonia e. Development of microcephaly, though head circumference is normal at birth 4. Microphthalmia
DIAGNOSTIC INVESTIGATIONS 1. Ophthalmological examination a. Choroid retinal lacunae b. Optic disc coloboma 2. Electroencephalograms a. Asymmetry or asynchrony b. Quasiperiodicity c. Hypsarrhythmia 3. CT or MRI of the brain a. Agenesis or partial agenesis of the corpus callosum b. Choroid plexus papillomas c. Cerebellar dysgenesis d. Cortical heterotopias e. Porencephaly f. Agenesis or hypoplasias of the cerebellar vermis 29
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AICARDI SYNDROME
4. Radiography for skeletal malformations 5. Chromosome analysis in case of Klinefelter syndrome 6. Histopathology a. Multiple brain malformations i. Complete or partial agenesis of the corpus callosum ii. Cortical heterotopias iii. Gyral malformation iv. Intraventricular cysts v. Microscopic evaluation of the parenchyma a) Disordered cellular organization b) Disruption of the normal layered appearance of the cortex b. Chorioretinal lacunae i. Well-circumscribed, punched-out lesions in the retinal pigment epithelium and choroid ii. Severely disrupted retinal architecture a) All layers are thinned b) Choroidal vessel number and caliber are decreased c) Presence of pigmentary ectopia and pigmentary epithelial hyperplasia
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sibs: recurrence not likely (exception with one report of two affected sibs, likely due to gonadal mosaicism in one of the parent) b. Patient’s offspring: 50% of offspring of affected females are expected to carry the abnormal X chromosome but affected individuals are not expected to survive to reproduce 2. Prenatal diagnosis: not available currently. The prenatal ultrasonographic findings include: a. Arachnoid cysts b. Agenesis of the corpus callosum (development of the corpus callosum may not be complete until 22 weeks of gestation) c. Ventriculomegaly 3. Management a. Anticonvulsants for control of seizures b. Specific therapy for infantile spasm i. Adrenocorticotropic hormone (ACTH): effective for some patients ii. Vigabatrin, a more recently introduced therapy for infantile spasm a) An enzyme that breaks down GABA, the major inhibitory neurotransmitter in the brain b) Effective for infantile spasm without the serious life-threatening adverse effects of ACTH c) Possible ophthalmologic sequelae of constriction of the visual fields d) Not currently approved for use in the US c. A multidisciplinary team approach to developmental handicaps
REFERENCES Aicardi J: Aicardi syndrome: old and new findings. Int Pediatr 14:5–8, 1999. Aicardi J, Lefèbvre J, Lerique-Koechlin A: A new syndrome: spasms in flexion, callosal agenesis, ocular abnormalities. Electroenceph Clin Neurophysiol 19:609–610, 1965. Bertoni JM, von Loh S, Allen RJ: The Aicardi syndrome: report of 4 cases and review of the literature. Ann Neurol 5:475–482, 1979. Bromley B, Krishnamoorthy KS, Benacerraf BR: Aicardi syndrome: prenatal sonographic findings. A report of two cases. Prenat Diagn 20:344–346, 2000. Costa T, Greer W, Rysiecki M, et al.: Monozygotic twins discordant for Aicardi syndrome. J Med Genet 34:688–691, 1997. De Jong JGY, Delleman JW, Houben M, et al.: Agenesis of the corpus callosum, infantile spasms, ocular anomalies (Aicardi’s syndrome). Clinical and pathological findings. Neurology 26:1152–1158, 1976. Dennis J, Bower BD: The Aicardi syndrome. Dev Med Child Neurol 14:382–390, 1972. Difazio MP, Davis RG: Aicardi syndrome. Emedicine, 2003. http://www. emedicine.com. Donnenfeld AE, Packer RJ, Zackai EH, et al.: Clinical, cytogenetic, and pedigree findings in 18 cases of Aicardi syndrome. Am J Med Genet 32:461–467, 1989. Donnenfield AE, Graham JM, Packer RJ, et al.: Microphthalmia and chorioretinal lesions in a girl with Adv Neurol Xp22-pter deletion and partial 3p trisomy: clinical observation relevant to Aicardi syndrome gene location. Am J Med Genet 37:182–186, 1990. Font RL, Marines HM, Cartwright J, et al.: Aicardi syndrome. A clinicopathological case report including electron microscopic observations. Ophthalmology 98:1727–1731, 1991. Gorrono-Echebarria MB: Genetics of Aicardi syndrome. Surv Ophthalmol 38:321, 1993. Hoag HM, Taylor SAM, Duncan AMV, et al.: Evidence that skewed X inactivation is not needed for the phenotypic expression of Aicardi syndrome. Hum Genet 100:459–464, 1997. Hopkins IJ, Humphrey J, Keith CG, et al.: The Aicardi syndrome in a 47,XXY male. Aust Pediatr J 15:278–280, 1979. McMahon RG, Bell RA, Moore GRW, et al.: Aicardi syndrome. A clinicopathologic study. Arch Ophthalmol 102:250–253, 1984. Menezes AV, McGregor DL, Buncic JR: Aicardi syndrome: Natural history and possible predictors of severity. Pediatr Neurol 11:313–318, 1994. Menezes AV, Enzenauer RW, Buncic JR: Aicardi syndrome: the elusive mild case. Br J Ophthalm 78:494–496, 1994. Molina JA, Mateos F, Merino M, et al.: Aicardi syndrome in two sisters. J Pediatr 115:282–283, 1989. Neidich JA, Nussbaum RL, Packer RJ, et al.: Heterogeneity of clinical severity and molecular lesions in Aicardi syndrome. J Pediatr 116:911–917, 1990. Ohtsuka Y, Oka E, Terasaki T: Aicardi syndrome: a longitudinal clinical and electroencephalographic study. Epilepsia 1993 Jul-Aug; 34(4): 627–634. Robinow M, Johnson GJ, Minella PA: Aicardi syndrome: papilloma of the choroid plexus, cleft lip and cleft of the posterior palate. J Pediatr 104:404, 405, 1984. Ropers HH, Zuffardi O, Blanchi E, et al.: Agenesis of corpus callosum, ocular, and skeletal anomalies (X-linked dominant Aicardi’s syndrome) in a girl with balanced X/3 translocation. Hum Genet 61:364–368, 1982. Rosser T: Aicardi syndrome. Arch Neurol 60:1471-1473, 2003. Rosser TL, Acosta MT, Packer RJ: Aicardi syndrome: spectrum of disease and long-term prognosis in 77 females. Pediatr Neurol 27:343–346, 2002. Tachibana H, Matsui A, Takeshita K, et al.: Aicardi syndrome with multiple papilloma of the choroids plexus. Arch Neurol 39:194, 1982. Trifiletti RR, Incorpora G, Polizzi A, et al.: Aicardi syndrome with multiple tumors: a case report with literature review. Brain Dev 17:283–285, 1995.
AICARDI SYNDROME
Fig. 1. A 8 month old girl with Aicardi syndrome characterized by infantile spasms, chrioretinopathy, brain malformation, and costovertebral anomalies.
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Alagille Syndrome In 1969, Alagille et al. described a syndrome characterized by chronic cholestasis resulting from paucity of interlobular bile ducts, peripheral pulmonary stenosis, butterfly-like vertebral arch defect, posterior embryotoxon, and peculiar facies. The syndrome is also known as arteriohepatic dysplasia. Alagille syndrome occurs in approximately 1 in 100,000 live births.
vi. Tricuspid regurgitation vii. Right ventricular hypertrophy d. Vertebral arch anomalies (butterfly-like vertebrae) e. Posterior embryotoxon (prominent Schwalbe’s ring) 3. Less frequently associated features a. Growth retardation b. Neurologic complications from vitamin E deficiency c. Mental retardation (2–30%) d. Systemic vascular malformations i. Coarctation of the aorta ii. Middle aortic syndrome iii. Arterial hypoplasia (hepatic, renal, carotid, celiac) iv. Artery stenosis (renal, subclavian) v. Moyamoya disease vi. Carotid artery aneurysm vii. Intracranial hemorrhage viii. Hypoplastic portal vein branch e. Renal abnormalities i. Interstitial nephritis ii. Glomerular intramembranous and mesangial lipidosis iii. Tubular dysfunction iv. Renal hypoplasia v. Renal agenesis vi. Horseshoe kidney vii. Cystic disease f. Small bowel atresia or stenosis g. Pancreas i. Diabetes ii. Exocrine pancreatic insufficiency h. Lung: tracheal and bronchial stenosis i. Larynx: high-pitched voice j. Eye abnormalities i. Retinal pigmentation ii. Iris strands iii. Cataract iv. Myopia v. Strabismus vi. Glaucoma vii. Optic disk drusen viii. Fundus hypopigmentation k. Skeletal abnormalities i. Lack of normal progression of interpedicular distance in the lumbar spine ii. Spina bifida iii. Shortening of distal phalanges and metacarpal bones iv. Clinodactyly 4. Prognosis a. Characterized by recurrent episodes of cholestasis b. Often associated with common respiratory tract infections, especially during the first year of life c. Good long survival but mortality rate may be up to 25%
GENETICS/BASIC DEFECTS 1. Inheritance: a. Sporadic in 45–50% of cases b. Autosomal dominant i. Reduced penetrance ii. Variable expressivity c. Alagille syndrome gene mapped to 20p12 2. Molecular defect a. Caused by mutations or deletions of Jagged-1 gene (JAG1), encoding a ligand for the Notch transmembrane receptor, implicated in cell differentiation b. More than 120 described intragenic mutations of the JAG1 gene c. No clear genotype-phenotype correlation in Alagille syndrome
CLINICAL FEATURES 1. High variability of phenotypic findings 2. Major features a. Neonatal chronic cholestasis i. Episodes of jaundice separated by periods of remission ii. Pruritus iii. Hepatomegaly iv. Splenomegaly: may be associated with portal hypertension v. Xanthoma: progressive and observed in: a) Extensor surface of the fingers b) Palmar creases c) Nape of the neck d) Anal folds e) Popliteal fossa f) Inguinal areas b. Facial features i. Broad prominent forehead ii. Deep-set, widely spaced eyes iii. Long, straight nose iv. Underdeveloped mandible c. Complex congenital cardiovascular anomalies i. Pulmonary artery stenosis (67%) ii. Ventricular septal defects iii. Patent ductus arteriosus iv. Pulmonary valve atresia v. Tetralogy of Fallot (7–16%) 32
ALAGILLE SYNDROME
DIAGNOSTIC INVESTIGATIONS 1. Biochemical studies a. Hypercholesterolemia b. Hyperphospholipidemia c. Hypertriglyceridemia d. Prominent increase in the pre-β-lipoprotein and apolipoprotein B levels e. Very high total bile acids, gammaglutamyl transferase, and alkaline phosphatase blood levels 2. Ophthalmologic assessment for posterior embryotoxon and other ocular anomalies 3. Abdominal ultrasonography a. Evaluation of the hepatobiliary tree and hepatic parenchyma b. Evaluation of renal anomalies 4. Radiography for vertebral anomalies 5. Other imagings a. Dimethyl iminodiacetic acid scanning b. Magnetic resonance cholangiopancreatography c. Endoscopic retrograde cholangiopancreatography d. Intraoperative cholangiography 6. Echocardiography for cardiovascular malformations 7. Histology (liver biopsy) a. Paucity of interlobular bile ducts b. Cholestasis in hepatocytes and canaliculi 8. Molecular genetic analysis a. Sequence analysis of the JAG1 gene detects mutations in approximately 70% of individuals who meet clinical diagnostic criteria b. FISH detects a microdeletion of 20p12, including the entire JAG1 gene, in approximately 5–7% of cases
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. A low but slightly increased risk due to parental germline mosaicism in clinically normal appearing parents ii. A 50% risk if a parent is affected b. Patient’s offspring: a 50% risk of having an offspring with Alagille syndrome 2. Prenatal diagnosis a. Prenatal ultrasonography i. Severe pulmonary artery stenosis ii. Progressive severe intrauterine growth retardation b. Prenatal molecular diagnosis on fetal DNA obtained from amniocentesis or CVS is available if a diseasecausing mutation (demonstrated by molecular genetic testing) or a deletion (detected by FISH) is identified in an affected family member 3. Management a. Medical care i. Low-fat diets with medium-chain triglyceride supplementation ii. Hypercaloric diets to severely malnourished patients iii. Vitamin supplements
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iv. Pruritus a) Antihistamine agents b) Cholestyramine or rifampin in management of bile acid-induced pruritus b. Surgical care for patients with refractory disease i. Biliary diversion ii. Eventual orthotopic liver transplantation with following indications: a) Progressive hepatic dysfunction b) Severe portal hypertension c) Failure to thrive d) Intractable pruritus and osteodystrophy iii. Cardiac surgery for complex congenital heart defects
REFERENCES Alagille D: Alagille syndrome today. Clin Invest Med 19:325–330, 1996. Alagille D, Estrada A, Hadchouel M, et al.: Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr 110:195–200, 1987. Albayram F, Stone K, Nagey D, et al.: Alagille syndrome: prenatal diagnosis and pregnancy outcome. Fetal Diagn Ther 17:182–184, 2002. Anad F, Burn J, Matthews D, et al.: Alagille syndrome and deletion of 20p. J Med Genet 27:729–737, 1990. Berrocal T, Gamo E, Navalon J, et al.: Syndrome of Alagille: radiological and sonographic findings. A review of 37 cases. Eur Radiol 7:115–118, 1997. Brodsky MC, Cunniff C: Ocular anomalies in the Alagille syndrome (arteriohepatic dysplasia). Ophthalmology 100:1767–1774, 1993. Cardona J, Houssin D, Gauthier F, et al.: Liver transplantation in children with Alagille syndrome—a study of twelve cases. Transplantation 60:339–342, 1995. Colliton RP, Bason L, Lu FM, et al.: Mutation analysis of Jagged1 (JAG1) in Alagille syndrome patients. Hum Mutat 17:151–152, 2001. Connor SE, Hewes D, Ball C, et al.: Alagille syndrome associated with angiographic moyamoya. Childs Nerv Syst 18:186–190, 2002. Crosnier C, Attie-Bitach T, Encha-Razavi F, et al.: JAGGED1 gene expression during human embryogenesis elucidates the wide phenotypic spectrum of Alagille syndrome. Hepatology 32:574–581, 2000. Crosnier C, Driancourt C, Raynaud N, et al.: Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome. Gastroenterology 116:1141–1148, 1999. Crosnier C, Driancourt C, Raynaud N, et al.: Fifteen novel mutations in the JAGGED1 gene of patients with Alagille syndrome. Hum Mutat 17:72– 73, 2001. Crosnier C, Lykavieris P, Meunier-Rotival M, et al.: Alagille syndrome. The widening spectrum of arteriohepatic dysplasia. Clin Liver Dis 4:765–778, 2000. Deleuze F, Hadchouel M: Submicroscopic deletions are rare in Alagille syndrome. Am J Hum Genet 59:477, 478, 1996. Desmaze C, Deleuze JF, Dutrillaux AM, et al.: Screening of microdeletions of chromosome 20 in patients with Alagille syndrome. J Med Genet 29:233–235, 1992. Emerick KM, Rand EB, Goldmuntz E, et al.: Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology 29:822–829, 1999. Giannakudis J, Ropke A, Kujat A, et al.: Parental mosaicism of JAG1 mutations in families with Alagille syndrome. Eur J Hum Genet 9:209–216, 2001. Hingorani M, Nischal KK, Davies A, et al.: Ocular abnormalities in Alagille syndrome. Ophthalmology 106:330–337, 1999. Jones EA, Clement-Jones M, Wilson DI: JAGGED1 expression in human embryos: correlation with the Alagille syndrome phenotype. J Med Genet 37:663–668, 2000. Kamath BM, Loomes KM, Oakey RJ, et al.: Facial features in Alagille syndrome: specific or cholestasis facies? Am J Med Genet 112:163–170, 2002. Kamath BM, Bason L, Piccoli DA, et al.: Consequences of JAG1 mutations. J Med Genet 40:891–895, 2003.
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Kasahara M, Kiuchi T, Inomata Y, et al.: Living-related liver transplantation for Alagille syndrome. Transplantation 75:2147–2150, 2003. Krantz ID, Colliton RP, Genin A, et al.: Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. Am J Hum Genet 62:1361–1369, 1998. Krantz ID, Piccoli DA, Spinner NB: Alagille syndrome. J Med Genet 34:152–157, 1997. Krantz ID, Piccoli DA, Spinner NB: Clinical and molecular genetics of Alagille syndrome. Curr Opin Pediatr 11:558–564, 1999. Krantz ID, Rand EB, Genin A, et al.: Deletions of 20p12 in Alagille syndrome: frequency and molecular characterization. Am J Med Genet 70:80–86, 1997. Laufer-Cahana A, Krantz ID, Bason LD, et al.: Alagille syndrome inherited from a phenotypically normal mother with a mosaic 20p microdeletion. Am J Med Genet 112:190–193, 2002. Li L, Krantz ID, Deng Y, et al.: Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16:243–251, 1997. Piccoli DA, Spinner NB: Alagille syndrome and the Jagged1 gene. Semin Liver Dis 21:525–534, 2001. Ropke A, Kujat A, Graber M, et al.: Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome. Hum Mutat 21:100, 2003.
Raas-Rothschild A, Shteyer E, Lerer I, et al.: Jagged1 gene mutation for abdominal coarctation of the aorta in Alagille syndrome. Am J Med Genet 112:75–78, 2002. Ropke A, Kujat A, Graber M, et al.: Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome. Hum Mutat 21:100,2003. Scheimann A: Alagille syndrome. Emedicine, 2003. http://www.emedicine.com. Shulman SA, Hyams JS, Gunta R, et al.: Arteriohepatic dysplasia (Alagille syndrome): extreme variability among affected family members. Am J Med Genet 19:325–332, 1984. Spinner NB, Colliton RP, Crosnier C, et al.: Jagged1 mutations in Alagille syndrome. Hum Mutat 17:18–33, 2001. Spinner NB: Alagille syndrome and the notch signaling pathway: new insights into human development. Gastroenterology 116:1257–1260, 1999. Spinner NB, Krantz ID: Alagille syndrome. Gene Reviews, 2004. http://www. genetests.org. Spinner NB, Rand EB, Fortina P, et al.: Cytologically balanced t(2;20) in a twogeneration family with Alagille syndrome: cytogenetic and molecular studies. Am J Hum Genet 55:238–243, 1994. Witt H, Neumann LM, Grollmuss O, et al.: Prenatal diagnosis of Alagille syndrome. J Pediatr Gastroenterol Nutr 38:105, 106, 2004.
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Fig. 1. An infant with Alagille syndrome showing neonatal jaundice, broad forehead, and underdeveloped mandible. This infant had peripheral pulmonary artery stenosis and paucity of interlobular bile ducts.
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Albinism Albinism refers to a group of inherited abnormalities of melanin synthesis resulting in congenital hypopigmentation. It involves the skin, hair, and eyes (oculocutaneous albinism) or may be limited primarily to the eyes (ocular albinism). The estimated frequency of affected individuals in the USA is approximately 1/17,000.
v. OCA1ts (tyrosinase related albinism with thermolabile enzyme) a) A temperature sensitive tyrosinase is only partly functional b) The first reported cases had a missense substitution within the tyrosinase gene b. OCA2 (tyrosinase positive albinism) i. OCA2 gene: the pink-eye dilution gene (p) located at 15q11-13 ii. Caused by mutations of the P gene on the chromosome 15, homologous to the mouse pinkedeye dilution, or P gene iii. The mutated region is also deleted in PraderWilli syndrome (PWS) and Angelman syndrome (AS), accounting for close linkage of OCA2 to PWS and AS c. OCA3 (Brown albinism) i. OCA3 gene: tyrosinase-related protein-1 gene (TRP1) located at 9p23 ii. The gene homologous to the mouse “brown” gene iii. Mutation of the gene possibly synergistic with a polymorphism or partially active mutation in OCA1 or OCA2 d. OA1 (X-linked ocular albinism) i. OA1 gene located at Xp22.3-22.2 ii. Intragenic deletions, frameshift mutations, and point mutations identified e. OAR (autosomal recessive ocular albinism) i. Gene mapping: 6q13-q15 ii. May not be a clinical entity iii. Tyrosinase in some cases iv. P protein in some cases f. Hermansky-Pudlak syndromes (HPS): a group of related disorders i. Hermansky-Pudlak syndrome 1 is caused by mutations of the HPS1 gene which is localized to 10q23 ii. HPS2 gene was localized to 5q13. HermanskyPudlak syndrome 2 is caused by mutation of the APB1 gene, which is localized to 5q13, resulting in a defect in adapter complex 3 AP-3, β3A subunit g. Chediak-Higashi syndrome: defect in CHS1 gene (lysosomal trafficking regular gene LYST) located at 1q42.1-q42.2 3. Pathophysiology a. Melanin in the skin i. Melanin, a photoprotective pigment in the skin, absorbs UV light from the sun, thus preventing skin damage ii. Normal skin tans upon sun exposure due to increased melanin pigment in the skin iii. Patient with albinism developing sunburn because of the lack of melanin
GENETICS/BASIC DEFECTS 1. Classification of albinism (genetic heterogeneity) a. Oculocutaneous albinism (OCA): a common phenotype for a group of recessive genetic disorders of melanin synthesis. Mutations in at least 12 genes are responsible for this phenotype. Mutations in OCArelated genes result in reduction of melanin synthesis by the melanocytes i. Common types of OCA with cutaneous and ocular hypopigmentation without significant involvement of other tissue a) Oculocutaneous albinism 1 (OCA1): subdivided into OCA1A, OCA1B, OCA1ts b) Oculocutaneous albinism 2 (OCA2) c) Oculocutaneous albinism 3 (OCA3) ii. Less common types of OCA with more complex manifestations a) Hermansky-Pudlak syndromes b) Chediak-Higashi syndrome b. Ocular albinism i. Ocular albinism 1 (OA1): X-linked recessive ii. Autosomal recessive ocular albinism (AROA) 2. Molecular defects causing albinism a. OCA1 (tyrosinase related albinism) i. Caused by mutations of tyrosinase gene (TYR) located at 11q14-21 ii. Several different types of mutations to the tyrosinase gene (missense, nonsense, and frameshift) are responsible for producing OCA1A and OCA1B iii. OCA1A (tyrosinase negative albinism with inactive enzyme) produced by null mutations of the Tyr gene a) 0% tyrosinase enzyme activity b) Over 100 mutations spanning all parts of the gene reported c) Compound heterozygotes with different maternal and paternal alleles in majority of patients iv. OCA1B (tyrosinase related albinism with partially active enzyme) produced by leaky mutations of the Tyr gene a) “Yellow” form of albinism with 5–10% activity of tyrosinase b) A base substitution within the gene may result in reduced rather than completely abolished enzyme activity 36
ALBINISM
b. Consequence of the absence of melanin during the development of the eye i. Hypoplasia of fovea ii. Alteration of neural connections between the retina and the brain c. Melanin pathway i. Consisting of a series of reactions that converts tyrosine into 2 types of melanin, black-brown eumelanin and red-blond pheomelanin ii. Tyrosinase: a major enzyme in a series of conversions to melanin from tyrosine and it is also responsible for converting tyrosine to DOPA and then to dopaquinone, which subsequently converts to either eumelanin or pheomelanin iii. Two other enzymes involved in the formation of eumelanin: tyrosinase-related protein 1 (TRP1, DHICA oxidase) and tyrosinase-related protein 2 (TRP2, dopachrome tautomerase). Mutation of the TRP1 results in OCA3; mutation of the TRP2 does not cause albinism iv. P protein, a melanosomal membrane protein, believed to be involved in the transport of tyrosine prior to melanin synthesis. Mutation of this P gene causes OCA2 4. Pathogenesis of the ocular features a. Development of the optic system highly dependent on the presence of melanin b. Ocular features appear if melanin is reduced or absent c. Mechanisms i. Misrouting of the retinogeniculate projections resulting in abnormal decussation of optic nerve fibers ii. Sensation of photophobia and decreased visual acuity caused by light scattering within the eye iii. Light-induced retinal damage postulated as a contributing mechanism to decreased visual acuity iv. Foveal hypoplasia: the most significant factor causing decreased visual acuity
CLINICAL FEATURES 1. General clinical features of albinism a. Skin, hair, and eye discoloration caused by abnormalities of melanin metabolism (might not be obvious in ocular albinism) b. Reduced visual acuity due to foveal hypoplasia c. Translucent iris due to reduction in iris pigment d. Visible choroid vessels due to reduction in retinal pigment e. Photophobia due to iris pigmentary abnormalities f. Anomalous visual pathway projections due to misrouting of the optic nerves at the chiasm g. Nystagmus due to abnormal decussation of optic nerve fibers h. Alternating strabismus i. Hyperopia, myopia, and astigmatism 2. Oculocutaneous albinism 1 (OCA1) a. Incidence: approximately 1 in 40,000 individuals b. Oculocutaneous albinism 1A (OCA1A)
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i. ii. iii. iv.
Classic tyrosinase-negative OCA phenotype Most severe form of OCA White hair and white skin that does not tan Blue and translucent irides that do not darken with age v. Foveal hypoplasia vi. No tanning potential vii. At risk for sun burning and skin cancer viii. Diminished visual acuity as low as 20/400 ix. Photophobia and nystagmus worst in this subtype c. Oculocutaneous albinism 1B (OCA1B) i. Yellow mutant type OCA, referred to as Amish albinism, or xanthous albinism ii. Variable pigmentation ranging from very little cutaneous pigmentation to nearly normal skin pigmentation iii. Increased skin, hair, and eye pigment with age and tan with sun exposure iv. Yellow hair pigment develops in the first few years of life and continuously accumulates pigment, principally yellow-red pheomelanin, in the hair, eyes, and skin in the later life v. Decreased visual acuity improving with age d. Temperature-sensitive albinism (OVA1ts) i. A subtype of OCA1B ii. Mutation of the tyrosinase gene that produces a temperature-sensitive tyrosinase enzyme iii. The heat-sensitive tyrosinase enzyme activity is approximately 25% of the normal tyrosinase activity at 37°C. The activity improves at lower temperatures iv. Dark hair pigment in the arms and legs (cooler areas of the body) while axillary and scalp hair remains white v. Pigment is absent in the fetus because of high fetal temperature 3. Oculocutaneous albinism 2 (OCA2) a. Tyrosinase positive OCA b. Incidence: approximately 1 in 15,000 individuals c. Most prevalent type of albinism in all races and especially frequent among African-American population (1 in 10,000) d. Phenotypic variability i. Ranging from absence of pigmentation to almost normal pigmentation ii. Absence of black pigment (eumelanin) in the skin, hair, or eyes at birth iii. Gradual development of pigmentation with age iv. Increased pigmentation resulting in improved vision 4. Oculocutaneous albinism 3 (OCA3) a. Previously known as red/rufous OCA b. Incidence of the disease unknown c. Phenotype in African patients i. Light brown skin and hair ii. Blue-brown irides iii. Ocular features not fully consistent with diagnosis of OCA (no iris translucency, nystagmus, strabismus, or foveal hypoplasia) d. Phenotype in Caucasians and Asians: not known
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5. Ocular albinism 1 (OA1) a. X-linked recessive OA (XLOA) b. Incidence of the disease approximately 1 in 50,000 individuals c. Extreme variability in clinical expression d. Involving eyes only i. Decreased visual acuity ii. Refractive errors: typical findings a) Hypermetropia b) Astigmatism iii. Hypopigmentation of the fundus and the iris iv. Absent foveal reflex (foveal hypoplasia) v. Congenital nystagmus vi. Photophobia vii. Strabismus viii. Iris translucency ix. Posterior embryotoxon x. Loss of stereoscopic vision due to misrouting of the optic tracts e. Normal skin f. Male manifesting complete phenotype g. Carrier females i. Normal vision ii. Hypopigmented streaks (characteristic patchy hypopigmentation as a result of mosaic inactivation of the affected X chromosomes) in the periphery iii. Marked iris translucency h. Severity depending on ethnic background: less severe in races exhibiting very dark constitutive skin pigmentation than those more lightly pigmented 6. Autosomal recessive ocular albinism (OAR) a. Children with ocular features of albinism and normal cutaneous pigmentation born to normally pigmented parents b. Classified as autosomal recessive because both males and females are affected c. Not considered a clinical entity 7. Hermansky-Pudlak syndrome a. A group of related disorders i. Common oculocutaneous albinism ii. A platelet storage disorder iii. Ceroid-lipofuscin lysosomal storage disease b. An autosomal recessive disorder with very variable expression c. Incidence of the disease rare, except in Puerto Rico where its frequency is 1 in 1800 individuals d. Bleeding diathesis resulting from a platelet storage pool deficiency e. Ceroid storage disease i. Accumulation of a Ceroid-lipofuscin material in various organ systems ii. Pulmonary fibrosis iii. Granulomatous colitis and gingivitis iv. Kidney failure v. Cardiomyopathy 8. Chediak-Higashi syndrome a. An autosomal recessive disorder with variable expression b. Consisting of a very rare group of conditions c. Severe immune disorder
d. e.
f.
g.
h.
i. Abnormal intracellular granules in most cells, especially white cells ii. Susceptible to bacterial infections iii. Defective neutrophils function iv. Episodes of macrophage activation known as accelerated phases: a) Fever b) Anemia c) Neutropenia d) Occasionally thrombocytopenia e) Hepatosplenomegaly f) Lymphadenopathy g) Jaundice Hypopigmentation of skin, hair, irides, and ocular fundi Bleeding diathesis i. Easy bruising ii. Mucosal bleeding iii. Epistaxis iv. Petechiae Eye symptoms i. Photophobia ii. Nystagmus iii. Reduced stereoacuity iv. Strabismus Often succumb during childhood to severe viral and bacterial infections, bleeding or development of the accelerated phase May develop a peripheral and cranial neuropathy in survivors i. Autonomic dysfunction ii. Weakness and sensory deficits iii. Loss of deep tendon reflexes iv. Clumsiness with a wide-based gait v. Seizures vi. Abnormal EEG vii. Abnormal EMG with decreased motor nerve conduction velocities
DIAGNOSTIC INVESTIGATIONS 1. Ophthalmologic examination for detection of reduced retinal pigment with visualization of the choroidal blood vessels (OCA1) and foveal hypoplasia 2. Visual acuity reduction 3. Hair bulb incubation assay for tyrosinase activity a. OCA1A: no tyrosinase activity b. OCA1B: greatly reduced activity of tyrosinase but still present 4. Visual-evoked potential (VEP): an accurate diagnostic test for albinism by demonstrating an asymmetry of VEP between the two eyes secondary to misrouting of optic pathways 5. Electron microscopy of skin and hair bulb: not routinely performed but probably the best diagnostic method for albinism 6. Ultrastructural examination of skin: The presence of macromelanosomes in the skin is considered specific for OA1 7. Molecular genetic analysis
ALBINISM
a. Genetic sequence analysis of the tyrosinase (TYR) gene to differentiate between various forms of albinism i. Rarely used for confirmatory diagnostic testing ii. Most commonly used for carrier detection iii. Prenatal diagnosis b. Molecular genetic testing is available clinically by sequencing of the entire coding region of mutation scanning of OCA1 gene c. Testing for the 2.7-kb deletion found in individuals of African heritage: available clinically. Sequence analysis of the OCA2 gene is available on a research basis d. Molecular genetic testing of the gene OA1 is available clinically and detects mutations in >90% of affected males 8. Hermansky-Pudlak syndrome a. Simple blood clotting tests b. Electron microscopic examination of platelets for identification of the absence of dense bodies (delta granules) 9. Chediak-Higashi syndrome a. Blood smear: identification of neutrophils containing giant cytoplasmic granules b. Defective neutrophils chemotaxis or killing c. Prolonged bleeding time caused by impaired platelet function
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal recessive oculocutaneous albinism: 25% recurrence risk of being affected ii. X-linked recessive ocular albinism: a) If the mother is a carrier: 50% of brothers affected and 50% of sisters carriers b) If the mother is not a carrier: The recurrence risk is low but still exists since the risk of germline mosaicism in mothers is not known but is likely rare b. Patient’s offspring i. Autosomal recessive oculocutaneous albinism: recurrence risk not increased unless the spouse is also a carrier in which case, there is a 50% recurrence risk (as in the pseudodominance) ii. X-linked recessive ocular albinism: none of the sons will be affected; all daughters will be carriers 2. Prenatal diagnosis a. Genetic sequence diagnosis possible on fetal DNA obtained from amniocentesis or CVS for pregnancies at 25% risk when the disease-causing mutations of the TYR gene in an affected family member is known i. OCA1: available clinically in families with an identified OCA1 mutation ii. OCA2: possible in families with an identified OCA2 mutation iii. XLOA: available clinically in families with an identified OA1 mutation b. Fetoscopy (a high risk procedure) to obtain fetal skin biopsy to demonstrate the lack of melanin in skin melanocytes: an invasive procedure not recommended clinically
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3. Management a. Albinism i. Skin care: avoid prolonged sun exposure to protect skin from ultraviolet radiation and minimize the risk of malignancy a) Protective clothing b) Sun screens ii. Ophthalmologic care a) Use of sunglasses for photophobia b) Correction of refractory errors secondary to hyperopia, myopia, or astigmatism to improve visual acuity c) Considering strabismus surgery for better ocular alignment iii. Ensure full benefits of a good education a) Provide large print textbooks b) Seating at the front of classroom b. Hermansky-Pudlak syndrome i. Treat extreme bleeding diathesis with platelet and blood transfusions ii. High dose of steroids for Granulomatous colitis or pulmonary fibrosis c. Chediak-Higashi syndrome i. Treat infections ii. Bone marrow transplantation: improves immunological status but no effect on ocular and cutaneous albinism
REFERENCES Abadi R, Pascal E: The recognition and management of albinism. Ophthalmic Physiol Opt 9:3–15, 1989. Biswas S, Lloyd IC: Oculocutaneous albinism. Arch Dis Child 80:565–569, 1999. Boissy RE, Nordlund JJ: Albinism. Emedicine, 2001. http://www.emedicine.com Carden SM, Boissy RE, Schoettker PJ, et al.: Albinism: modern molecular diagnosis. Br J Ophthalmol 82:189–195, 1998. Creel DJ, Summers CG, King RA: Visual anomalies associated with albinism. Ophthalmic Paediatr Genet 11:193–200, 1990. Hasanee K, Ahmed IIK: Albinism. Emedicine, 2001. http://www.emedicine.com Hsieh YY, Wu JY, Chang CC, et al.: Prenatal diagnosis of oculocutaneous albinism two mutations located at the same allele. Prenat Diagn 21:200–201, 2001. King RA: Oculocutaneous albinism type 1. Gene Reviews, 2002. http://www. genetests.org King RA: Oculocutaneous albinism type 2. Gene Reviews, 2003. http://www. genetests.org King RA, Summers GC, Haefemeyer JW, et al.: Facts about albinism. Available at: www.cbc.umn.edu/iac/facts.htm King RA, Summers CG: Albinism. Dermatol Clin 6:217–228, 1988. King RA, Hearing VJ, Creed DJ, et al.: Albinism. In Scriver CR, Beaudet al., Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001, Chapter 220, pp 5587–5627. King RA, Pietsch J, Fryer JP, et al.: Tyrosinase gene mutations in oculocutaneous albinism 1 (OCA1): definition of the phenotype. Hum Genet 113:502–513, 2003. Lang GE, Rott HD, Pfeiffer RA: X-linked ocular albinism. Characteristic pattern of affection in female carriers. Ophthalmic Paediatr Genet 11:265–271, 1990. Nagle DL, Karim MA, Woolf EA, et al.: Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nat Genet 14:307–311, 1996. Oetting WS: Albinism. Curr Opin Pediatr 11:565–571, 1999. Oetting WS: New insights into ocular albinism type 1 (OA1): Mutations and polymorphisms of the OA1 gene. Hum Mutat 19:85–92, 2002. Oetting WS, King RA: Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Hum Mutat 13:99–115, 1999.
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Oetting WS, Brilliant MH, King RA: The clinical spectrum of albinism in humans. Mol Med Today 2:330–335, 1996. Oetting WS, Gardner JM, Fryer JP, et al.: Mutations of the human P gene associated with Type II oculocutaneous albinism (OCA2). Hum Mutat 12:434, 1998. Oetting WS, Fryer JP, Shriram S, et al.: Oculocutaneous albinism type 1: the last 100 years. Pigment Cell Res 16:307–311, 2003. Okulicz JF, Shah RS, Schwartz RA, et al.: Oculocutaneous albinism. J Eur Acad Dermatol Venereol 17:251–256, 2003. Peracha MO, Eliott D, Garcia-Valenzuela E: Ocular manifestations of albinism. eMedicine J, 2001. Emedicine, 2001. http://www.emedicine.com
Rosenberg T, Schwartz M: Ocular albinism, X-linked. Gene Reviews, 2004. http://genetests.org Rosenberg T, Schwartz M: X-linked ocular albinism: prevalence and mutations-a national study. Eur J Hum Genet 6:570–577, 1998. Russell-Eggitt I: Albinism. Ophthalmol Clin North Am 14:533–546, 2001. Sarangarajan R, Boissy RE: Tyrp1 and oculocutaneous albinism type 3. Pigment Cell Res 14:437–444, 2001. Shen B, Samaraweera P, Rosenberg B, et al.: Ocular albinism type 1: more than meets the eye. Pigment Cell Res 14:243–248, 2001. Spritz RA: Molecular genetics of oculocutaneous albinism. Semin Dermatol 12:167–172, 1993.
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Fig. 1. Oculocutaneous albinism in different age groups including one set of identical twins.
Amniotic Band Syndrome Amniotic band syndrome occurs in one of every 5000 to 15,000 births and had been demonstrated in 1–2% of malformed infants.
h. Incompetent cervix i. Amniocentesis implicated. An increased incidence of anomalies related to amniotic band syndrome in association with prenatal amniocentesis in animal models j. Familial occurrences reported despite no evidence for a genetic predisposition to amniotic band syndrome 5. Synonyms and acronyms a. Congenital band syndrome b. Streeter’s dysplasia c. Simonart’s bands d. Amniotic band disruption complex e. Congenital annular defects f. Congenital ring constrictions g. Constriction ring syndrome h. ADAM (Amniotic Deformity, Adhesion, Mutilations) complex i. TEARS (The Early Amnion Rupture Spectrum)
GENETICS/BASIC DEFECTS 1. Streeter intrinsic theory a. An intrinsic defect of the subcutaneous germ plasm causes soft tissue to slough. The resulting external healing leads to the constriction ring b. Significant rate of associated anomalies as indirect proof of existence of some genetic force at work to cause the syndrome 2. Torpin extrinsic theory (currently most popular theory) a. Early amniotic rupture leading to the formation of mesodermal fibrous strands that entangle limbs and appendages b. Amnion rupture without injury to the chorion resulting in amniotic bands c. Oligohydramnios playing a major role in the development of the constricting bands d. Higher incidence of club feet possibly resulting from continuous pressure on the feet from the undersized uterus e. Amniotic bands essentially encircling the affected part resulting in constricting rings f. Supporting evidence i. Constriction rings often occurring in a straight line across multiple digits as if one external band affects multiple adjacent digits ii. Frequent involvement of the central digits iii. Occasional attachment of amnion in the constricting ring iv. Facial clef ting which does not follow developmental planes 3. Other theory: simultaneous occurrence of both extrinsic and intrinsic factors in the development of constriction band syndrome 4. Other factors/mechanisms implicated in the etiology of amniotic band syndrome: The cause of amniotic band syndrome remains elusive and controversial a. Simple oligohydramnios b. Fetal hypertension c. Venous stasis d. Localized fetal ischemia caused by uterine contractions e. Intrauterine hemorrhage as the precipitating event f. Vascular compromise (lack of distal blood flow demonstrated in association with forearm amputation defects) g. Cocaine drug abuse: cocaine acting as a teratogen by inducing fetal hypoxemia through impaired uteroplacental fetal blood flow and directly through its vasoconstrictive properties on the fetal vasculature
CLINICAL FEATURES 1. The nature and severity of deformities: related to the timing and initiating event of amniotic rupture 2. Triad of amniotic band syndrome a. Amnion-denuded placenta b. Fetal attachment or entanglement by amniotic remnants c. Fetal deformation, malformation, and/or disruption i. Fetal deformation (fetal compression secondary to oligohydramnios; fetal entanglement by amniotic bands) ii. Fetal malformation resulting from amniotic band interfering with the normal sequence of embryologic development iii. Fetal disruption secondary to cleavage of structures that have already developed normally 3. Craniofacial disruptions (up to one third of cases) a. Facial clefting i. Most likely associated with swallowing of band at about 5 months of gestation ii. Unusual extensions with asymmetric locations, such as oblique facial clefting b. Orbital defects i. Anophthalmos ii. Microphthalmos iii. Enophthalmos iv. Hypertelorism c. Corneal abnormalities i. Anomalous eyelid configuration ii. Ineffective eye closure d. Other ocular abnormalities i. Strabismus due to defects in extraocular muscles ii. Epiphora related to either lacrimal system involvement or eyelid abnormalities 42
AMNIOTIC BAND SYNDROME
4.
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8.
9.
e. CNS involvement: usually associated with amniotic band rupture before 45 days of gestation i. Neural tube defects (cranioschisis, atypical or asymmetrical meningocele, myelomeningocele, encephalocele, or anencephaly) ii. Ventriculomegaly iii. Pressure defects of the parenchyma f. Calvarial defects g. Cleft lip/palate Limb abnormalities a. Limb reduction defects b. Intrauterine amputations c. Ring constrictions with or without distal lymphedema, clubbing, or syndactyly i. Deeper rings ii. Circumferential rings d. Club feet e. Digital anomalies: frequently involved i. Syndactyly ii. Acrosyndactyly iii. Digital hypoplasia iv. Symphalangism v. Symbrachydactyly vi. Camptodactyly f. Significant neurovascular impairment distal to the constricting band Umbilical cord strangulation by amniotic bands a. Common occurrence (10%) b. Cord strangulation c. Severe strangulation of the umbilical cord may result in fetal death d. Stillbirths observed in about 97% of umbilical cord strangulation by amniotic bands Associated anomalies a. Hemangiomas b. Cardiac defect c. Limb/body wall defects d. Thoracoabdominal wall defects i. Thoracoschisis ii. Extrathoracic heart iii. Omphalocele iv. Gastroschisis e. Aplasia cutis f. Short umbilical cord g. Oligohydramnios sequence Patterson’s classification system of congenital ring constriction based on the severity of the syndrome a. Simple constriction rings b. Constriction rings associated with deformity of the distal part, with or without lymphedema c. Constriction rings associated with soft tissue fusions of distal parts (acrosyndactyly) d. Intrauterine amputation Hall’s classification system for amniotic band syndrome a. Mild constriction without lymphedema b. Moderate constriction with lymphedema c. Severe constriction with amputation Weinzweig’s classification system for amniotic band syndrome
43
a. Mild constriction without lymphedema b. Moderate constriction with distal deformity, syndactyly, or discontinuous neurovascular or musculotendinous structures without vascular compromise i. Without lymphedema ii. With lymphedema c. Severe constriction with progressive lymphaticovenous or arterial compromise i. Without soft-tissue loss ii. With soft-tissue loss d. Intrauterine amputation 10. Lockwood’s classification of fetal anomalies in amniotic band syndrome according to their presumed mechanism a. Anomalies caused by interruption of embryonic morphogenesis i. Cleft lip and palate ii. Omphalocele iii. Cardiac anomalies iv. Renal agenesis or dysplasia v. Bladder exstrophy vi. Imperforate anus b. Anomalies caused by fetal vascular compromise i. Gastroschisis ii. Gallbladder agenesis iii. Single umbilical artery c. Anomalies caused by intrauterine constraint i. Club foot ii. Clubbed hands iii. Abnormal facies iv. Valgus-varus deformities v. Kyphoscoliosis d. Anomalies caused by disruption of normally developed structures i. Severe central nervous system or calvarial defect ii. Acrosyndacytly iii. Amputations iv. Constriction bands v. Facial clefts (anatomically inappropriate) vi. Aplasia cutis 11. Prognosis a. Prenatally diagnosed amniotic adhesion with a grim prognosis b. Most cases of cranial and body wall defects incompatible with extrauterine life c. Infants born with limited limb abnormalities: better prognosis with good results after surgical repair of the constrictions or syndactyly
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Syndactyly with amputation of distal parts b. Intrauterine amputation of limbs and digits 2. MRI imagings a. Delineate the depth of the constriction band b. Delineate the extent of the resultant lymphedema c. Delineate the integrity of the musculature d. Define the vascular anatomy, which may be anomalous; may help to prevent injury to the vessels during surgery
44
AMNIOTIC BAND SYNDROME
3. Histology a. Absence of amniotic membrane on the fetal surface of the chorionic sac, including the placental sac b. Presence of amnion remnant as a cuff of thick membrane at the base of the umbilical cord at its insertion site c. Amniotic squames and cellular debris are frequently embedded in the superficial soft tissue of the chorion indicating chronic amniotic rupture d. Constricting bands encircling digits
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: not increased 2. Prenatal diagnosis possible by ultrasonography during second and third trimester a. Visualization of amniotic sheets or bands attached to the fetus. The diagnosis of amniotic band syndrome should not be made solely on the basis of a membrane observed in the uterine cavity b. Restricted fetal movement c. Characteristic asymmetric fetal anomalies d. Constriction bands around the limbs 3. Management a. Surgery not needed for shallow constriction bands that are not circumferential and without distal swelling b. Distal edema or impairment of neurovascular function requiring staged constriction band excision, Zplasty, or W-plasty c. Digital amputation may be required for a ring so constrictive that distal edema is massive d. Multiple plastic surgical procedures required for corrections of the complex craniofacial abnormalities e. Procedures for the upper-extremity deformities i. Band release, Z- or W-plasty ii. Syndactyly/web space release iii. Skin graft iv. Stump revision v. Osteotomy/osteoclasis vi. Hardware removal vii. Ray resection/transposition viii. Distraction osteogenesis ix. Pollicization/osteocutaneous transfer x. Tendon transfer xi. Excision supernumerary digit xii. Amputation f. Procedures for the lower-extremity deformities i. Band release, Z- or W-plasty ii. Syndactyly release iii. Simple revision iv. Amputation/excision toe v. Clubfoot procedure vi. Hip procedure vii. Tibial derotation viii. Removal of skin tag g. Careful follow-up on congenital constriction band of the trunk because the evolution of this condition is benign
h. In utero surgical intervention proposed to avoid amputation or permanent damage to the extremity of the fetus, provided the maternal and fetal risks of surgery are small
REFERENCES Al-Qattan MM: Classification of the pattern of intrauterine amputations of the upper limb in constriction ring syndrome. Ann Plast Surg 44:626–632, 2000. Askin G, Ger E: Congenital constriction band syndrome. J Pediatr Orthop 8:461–466, 1988. Bagatin M, Der Sarkissian R, Larrabee WF Jr: Craniofacial manifestations of the amniotic band syndrome. Otolaryngol Head Neck Surg 116:525–528, 1997. Bahadoran P, Lacour JP, Terrisse A, et al.: Congenital constriction band of the trunk. Pediatr Dermatol 14:470–472, 1997. Baker CJ, Rudolph AJ: Congenital ring constrictions and intrauterine amputations. Am J Dis Child 121:393–400, 1971. Bourne MH, Klassen RA: Congenital annular constricting bands: Review of the literature and a case report. J Pediatr Orthop 7:218–221, 1987. Burton DJ, Filly RA: Sonographic diagnosis of the amniotic band syndrome. Am J Roentgenol 156:555–558, 1991. Chen H, Gonzalez E: Amniotic band sequence and its neurocutaneous manifestations. Am J Med Genet 28:661–673, 1987. Day-Salvatore DL, Guzman E, Weinberger B, et al.: Genetics casebook. Amniotic band disruption sequence. J Perinatol 15:74–77, 1995. De Pablo A, Calb I, Jaimovich L: Congenital constriction bands: Amniotic band syndrome J Am Acad Dermatol 32:528–529, 1995. Eppley BL, David L, Li M, et al.: Amniotic band facies. J Craniofac Surg 9:360–365, 1998. Foulkes GD, Reinker K: Congenital constriction band syndrome: a seventyyear experience. J Pediatr Orthop 14:242–248, 1994. Garza A, Cordero JF, Mulinare J: Epidemiology of the early amnion rupture spectrum (TEARS) of defects. Am J Dis Child 142:541–544, 1988. Hall EJ, Johnson-Giebina R, Vascones LO: Management of the ring constriction syndrome: a reappraisal. Plast Reconst Surg 69:532–536, 1982. Higginbottom MC, Jones KL, Hall BD, et al.: The amniotic band disruption complex: timing of amniotic rupture and variable spectra of consequent defects. J Pediatr 95:544–549, 1979. Heifitz SA: Strangulation of the umbilical cord by amniotic bands: Report of 6 cases and literature review. Pediatr Pathol 2:285–304, 1984. Hollsten DA, Katowitz JA: The ophthalmic manifestations and treatment of the amniotic band syndrome. Ophthal Plast Reconstr Surg 6:1–15, 1990. Keller H, Neuhauser G, Durkin-Stamm MV, et al.: “ADAM complex” (amniotic deformity, adhesions, mutilations)-a pattern of craniofacial and limb defects. Am J Med Genet 2:81–98, 1978. Kino Y: Clinical and experimental studies of the congenital constriction band syndrome, with an emphasis on its etiology. J Bone Joint Surg Am 57:636, 1975. Laberge LC, Rszkowski A, Morin F: Amniotic band attachment to a fetal limb: demonstration with real-time sonography. Ann Plast Surg 35:316–319, 1995. Laor T, Jaramillo D, Hoffer FA, et al.: MR imaging in congenital lower limb deficiencies. Pediatr Radiol 26:381–387, 1996. Levy PA: Amniotic bands. Pediatr Rev 19:249, 1998. Light TR, Ogden JA: Congenital constriction band syndrome. Pathophysiology and treatment. Yale J Biol Med 66:143–155, 1993. Lockwood C, Ghidini A, Romero R, et al.: Amniotic band syndrome: Reevaluation of its pathogenesis. Am J Obstet Gynecol 160:1030–1033, 1989. Lubinsky M, Sujansky E, Sanders W, et al.: Familial amniotic bands. Am J Med Genet 14:81–87, 1983. Mahony BS, Filly RA, Callen PW, et al.: The amniotic band syndrome: antenatal sonographic diagnosis and potential pitfalls. Am J Obstet Gynecol 152:63–68, 1985. Mishima K, Sugahara T, Mori Y, et al.: Three cases of oblique facial cleft. J Cranio-Maxillofac Surg 24:372–377, 1996. Moerman P, Fryns JP, Vandenberghe L, et al.: Constrictive amniotic bands, amniotic adhesions, and limb body wall complex, discrete disruption sequence with pathogenic overlap. Am J Med Genet 42:470–479, 1992.
AMNIOTIC BAND SYNDROME Nishi T, Nakano R: Amniotic band syndrome: Serial ultrasonographic observations in the first trimester. J Clin Ultrasound 22:275–278, 1994. Ossipoff V, Hall BD: Etiologic factors in the amniotic band syndrome: a study of 24 patients. Birth Defects Orig Artic Ser 13:117–132, 1977. Patterson TJS: Congenital ring constrictions. Br J Plast Surg 14:1–31, 1961. Quintero RA, Morales WJ, Phillips J, et al.: In utero lysis of amniotic bands. Ultrasound Obstet Gynecol 10:316–320, 1997. Seidman JD, Abbondanzo SL, Watkins WG, et al.: Amniotic band syndrome. Arch Pathol Lab Med 113:891–897, 1989. Streeter GL: Focal deficiencies in fetal tissues and their relationship to intrauterine amputation. Contributions to Embryology of the Carnegie Institute 22:1–44, 1930. Takayuki M: Congenital constriction band syndrome. J Hand Surg Am 9:82, 1984. Temtamy SA, McKusick VA: Digital and other malformations associated with congenital ring constrictions. Birth Defects 14:547, 1978.
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Torpin R: Amniochorionic mesoblastic fibrous strings and amniotic bands; associated constricting fetal malformations or fetal death. Am J Obstet Gynecol 91:65–75, 1965. Torpin R: Intrauterine amputation with the missing member found in the fetal membranes. JAMA 198:205–207, 1966. Trasler DG: Congenital malformations produced by amniotic sac puncture. Science 124:439, 1988. Walter JH Jr, Goss LR, Lazzara AT: Amniotic band syndrome. J Foot Ankle Surg 37:325–333, 1998. Weinzweig N: Constriction band-induced vascular compromise of the foot: classification and management of the “intermediate” stage of constriction-ring syndrome. Plast Reconstr Surg 96:972–977, 1995. Yamaguchi M, Yasuda H, Kuroki T, et al.: Early prenatal diagnosis of amniotic band syndrome. Am J Perinatol 5:5–7, 1988. Yang SS: ADAM sequence and innocent amniotic band: Manifestations of early amnion rupture. Am J Med Genet 37:562–568, 1990.
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Fig. 1. A small stillborn fetus (110 gm) showing amniotic constriction band at left ankle. Amputation and pseudosyndactyly of fingers and toes are present.
Fig. 2. A small stillborn fetus (60gm) with a fibrous amniotic band constricting a portion of the head and facial cleft.
Fig. 3. A small fetus with a large amniotic band which caused anencephaly.
AMNIOTIC BAND SYNDROME
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Fig. 4. The left hand of a 1–100 gm fetus showing in utero amputation of the 3rd and 4th fingers.
Fig. 7. A fetus with a large meningoencephalocele and an amniotic band attaching to its base. Facial defects, a large gastroschisis, and talipes equinovarus were also present. Histology of the scalp shows an amniotic band fused with the soft tissue of the upper dermis. The amniotic epithelium of the band is visible as a darker line on the surface. The epidermis of the scalp is denuded at the site of band attachment.
Fig. 5. A placenta with a long strand of amniotic band which was pulled out of the mouth of the premature neonate at birth. The baby did not have amniotic band syndrome.
Fig. 6. Cord strangulation by amniotic band.
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AMNIOTIC BAND SYNDROME
Fig. 8. A fetus with marked craniofacial defects and the site of amniotic band attachment at the base of the skull. The fetus also had amputation of the distal left great toe (not shown). Prenatal ultrasonography showed a complex structures arising from the top and front of the craniofacial region. Fig. 10. An infant with club left hand with a missing finger, constricting rings with marked distal lymphedema of the right index finger, and pseudosyndactyly of the right foot.
Fig. 9. An infant with marked craniofacial anomalies, a constricting ring of a finger with distal lymphedema, and an amputation of the 5th finger.
AMNIOTIC BAND SYNDROME
Fig. 11. An infant with deep constricting groove around the lower onethird of both legs. The patient also had terminal amputation and constriction rings of fingers with a small amniotic band still attached to the constricting ring of the second finger (not shown).
Fig. 12. A hand of an infant with constriction bands of the fingers with amputations, shown by the radiograph.
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Androgen Insensitivity Syndrome c. Incomplete androgen insensitivity syndrome (IAIS): partial resistance to the action of testosterone and dihydrotestosterone d. Reifenstein syndrome: Variable resistance to the action of testosterone and dihydrotestosterone e. Mild androgen insensitivity syndrome (MAIS): Resistance to the action of androgen varies in different tissues
Androgen insensitivity syndrome (AIS) is a disorder of male sexual differentiation caused by a defective, deficient, or absent androgen receptor. The syndrome was first described by Morris in 1953 who coined the term testicular feminization syndrome, based on the observation of the complete absence of signs of virilization in phenotypic females with testes and a 46,XY karyotype. AIS probably represents the most common cause of male pseudohermaphroditism. It is an X-linked recessive disorder in 46,XY individuals with normal androgen production and metabolism. The AIS is estimated to be present in 1 in 20,000 to 1 in 64,000 male births.
CLINICAL FEATURES 1. Variable phenotypic expression allowing the classification of AIS into complete and partial forms, and a rare group of phenotypically normal men with azoospermia 2. Complete androgen insensitivity syndrome a. Presumptive diagnosis of CAIS i. Absence of extragenital abnormalities ii. Two nondysplastic testes iii. Absent or rudimentary müllerian structures (absence of fallopian tubes, uterus, or cervix) iv. A short vagina v. Undermusculinization of the external genitalia at birth vi. Impaired spermatogenesis (sterility) and/or somatic virilization at puberty b. External phenotype i. Invariably presenting as a normal female external appearance (female habitus) ii. Female external genitalia (“testicular feminization;” Tfm) iii. Underdeveloped, short blind-ending vagina iv. Normal breast and female adiposity development v. Unaffected sexual identity and orientation vi. Scant or absent pubic and/or axillary hair c. Urogenital tract i. Absent or rudimentary Wolffian duct derivatives (epididymides and/or vas deferens) ii. Inguinal or labial masses subsequently identified as testes d. Other features i. Primary amenorrhea at puberty ii. Complete androgen insensitivity syndrome almost always runs true in families (i.e., affected XY relatives usually have normal female external genitalia and seldom have any sign of external genital masculinization, such as clitoromegaly or posterior labial fusion) 3. Partial androgen insensitivity syndrome (PAIS) a. Predominantly female external genitalia (incomplete androgen insensitivity syndrome) i. Signs of external genital masculinization a) Clitoromegaly b) Partial fusion of the labioscrotal folds
GENETICS/BASIC DEFECTS 1. Inheritance a. X-linked recessive inheritance i. Affected XY individuals ii. Carrier XX females b. Manifesting carrier females (about 10% of carrier females) 2. Caused by mutations of androgen receptor (AR) gene (mapped to chromosomal locus Xq11-q12) a. Mutations of androgen receptor: responsible for a variable degree of impaired androgen action b. De novo mutations i. De novo mutation rate close to 30% ii. Somatic or germ-line mosaicism observed for “de novo” mutations in which the mutation is present in some of the cells in one of the clinically unaffected parents c. Type of mutations i. Point mutations ii. Complete and partial gene deletions iii. Small insertions/deletions d. Variable expressivity of a particular point mutation attributable to somatic mosaicism for the mutation 3. Pathogenesis a. Androgen insensitivity syndrome i. The result of an end-organ resistance to androgens caused by an abnormality of the androgen receptor ii. Normal production of testosterone and normal conversion to dihydrotestosterone (DHT) by the normal testes in affected individuals, differentiating this condition from 5α reductase deficiency iii. Absence of fallopian tubes, uterus or proximal (upper) vagina in affected individuals because testes produce normal amounts of müllerianinhibiting factor (MIF) b. Complete androgen insensitivity syndrome (CAIS) i. Most severe form ii. Complete resistance to all actions of testosterone and dihydrotestosterone 50
ANDROGEN INSENSITIVITY SYNDROME
ii. iii. iv. v.
Female habitus and breast development Normal axillary and pubic hair Inguinal or labial testes as in CAIS Wolffian duct derivatives emptying into the vagina vi. Distinct urethral and vaginal openings or a urogenital sinus vii. No Müllerian duct derivatives b. Ambiguous external genitalia (Reifenstein syndrome) i. Microphallus (<1 cm) with clitoris-like underdeveloped glans ii. Labia majora-like bifid scrotum iii. Descended or undescended testes iv. Perineoscrotal hypospadias or urogenital sinus v. Gynecomastia in puberty c. Predominantly male external genitalia (Reifenstein syndrome) i. Simple (glandular or penile) or severe (perineal) “isolated” hypospadias with a normal-sized penis and descended testes or severe hypospadias with micropenis ii. Bifid scrotum iii. Either descended or undescended testes iv. Gynecomastia in puberty 4. Mild androgen insensitivity syndrome a. Two phenotypic forms at puberty i. Impaired spermatogenesis and fertility ii. Normal or sufficient spermatogenesis to preserve fertility b. Clinical features common to both forms i. Male external genitalia (“undervirilized male syndrome”) ii. Gynecomastia in puberty iii. High-pitched voice iv. Sparse sex hair v. Impotence 5. Manifesting carrier females a. Asymmetric distribution and sparse or delayed growth of pubic or axillary hair b. A history of late (15 years) or delayed (16 years or older) menarche
DIAGNOSTIC INVESTIGATIONS 1. Diagnostic work-up a. Diagnosis of CAIS usually based on: i. Clinical findings ii. Laboratory evaluation b. Diagnosis of PAIS and MAIS based on: i. Clinical findings ii. Laboratory evaluation iii. Family history consistent with X-linked recessive inheritance 2. Laboratory investigations a. AIS i. Chromosome analysis: 46,XY karyotype ii. Evidence of normal or increased synthesis of testosterone by the testes iii. Evidence of normal conversion of testosterone to 5α-dihydrotestosterone
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iv. Evidence of normal or increased luteinizing hormone production by the pituitary gland v. Evidence of deficient or defective androgenbinding activity of genital skin fibroblasts b. CAIS, IAIS, Reifenstein syndrome, and MAIS i. Chromosome analysis: 46,XY karyotype ii. Testosterone: Normal or high male plasma levels and production rates iii. Estrogen: Plasma levels and production rates higher than in normal men iv. Gonadotropin: Elevated plasma LH levels (may be normal in MAIS) c. Additional findings of sporadic cases of predominantly male phenotype of PAIS i. Impaired development of the prostate and of the Wolffian duct derivatives demonstrated by ultrasonography or genitourography ii. Less than normal decline of sex hormone-binding globulin in response to a standard dose of the anabolic androgen, Stanozolol iii. Higher than normal levels of anti-müllerian hormone during the first year of life or at the beginning of puberty 3. Histologic investigations a. CAIS i. Testes: apparently normal in early life but begin to lose their germ cell population in late childhood ii. Development of testicular hamartomas (composed of Sertoli and Leydig cells, spindle cells, stroma, and germ cells in varying proportion), benign and malignant tumors beginning in the postpubertal period iii. Germinal cell tumors, usually seminomas, in approximately 8% of CAIS cases b. IAIS i. Histologic appearance of the gonads similar to that of CAIS ii. Cryptorchid testes, usually containing spermatocytes and rare observation of spermatozoa in a minority of patients c. MAIS with oligospermia or azoospermia in phenotypically normal males with testicular biopsy showing: i. Presence of Sertoli cell only ii. Arrest of spermatogenesis at the spermatid stage 4. Detection of known mutations of the androgen receptor gene clinically available by sequencing a. CAIS: detected in >95% of patients b. PAIS: detected in <50% of patients c. MAIS: proportion of patients with detected mutations unknown
GENETIC COUNSELING 1. Recurrence risk: genetic counseling according to X-linked recessive inheritance a. Patient’s sib i. Recurrence risk low provided the mother is not a carrier ii. 50% of sibs inheriting the mutation from the carrier mother
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a) Sibs with a 46,XY karyotype who inherit the mutation will be affected b) Sibs with a 46,XX karyotype who inherit the mutation will be carriers b. Patient’s offspring i. 46,XY individuals with AIS (i.e., CAIS, PAIS, MAIS): infertile ii. Manifesting carrier females: 50% risk of transmitting the AR gene mutation in each pregnancy c. Offspring of a known AR mutation carrier female i. 50% of 46,XY children affected ii. 50% of 46,XY children unaffected iii. 50% of 46,XX children carrier iv. 50% of 46,XX children not a carrier v. A wide range of phenotypes observed for the same mutation in different families making genetic counseling more difficult 2. Carrier detection a. Family pedigree b. Clinical features i. Asymmetric distribution and sparse or delayed growth of pubic or axillary hair in manifesting carriers (10% of carriers), resulting from skew X chromosome inactivation ii. Normal pubic and axillary hair do not rule out the 46,XX carrier state c. Deficient or defective androgen-binding activity of single-cell clones from a genital skin fibroblast line, provided an affected 46,XY family member is known to have deficient or defective androgen-binding activity in a genital skin fibroblast cell line d. Molecular genetic testing i. A complete screening strategy of the entire androgen receptor gene needed to find the mutation in a new case of androgen insensitivity syndrome. Once the mutation is identified in the proband, carrier detection of other family members is possible ii. Intragenic polyglutamine and polyglycine trinucleotide repeats in the N-terminal region of the androgen receptor may be used as polymorphisms to follow the affected X chromosome through the family and used for carrier status determination 3. Prenatal diagnosis a. Request for prenatal diagnosis uncommon i. AIS does not affecting intellect ii. Some treatment modalities available b. Prenatal diagnosis by mutation analysis: clinically available in families in which the disease-causing allele has been identified in an affected family member c. Fetal sex determination by amniocentesis or CVS i. XX fetus: additional testing not warranted ii. XY fetus: extract DNA for mutation analysis 4. Management a. Psychological support i. Probably the most important aspect of medical care ii. Psychologist or psychiatrist consultations to help adjust to child’s condition, including support on
b.
c.
d.
e.
how to inform the child, over time and in an ageappropriate manner iii. Androgen Insensitivity Syndrome Support Group (http://www.medhelp.org/www/ais) CAIS i. Remove testes (gonadectomy) as soon as the diagnosis is made ii. The rationale for postpubertal gonadectomy: testicular malignancy seldom occurs before puberty unlike that of usual cryptorchid testes iii. Estrogen replacement therapy necessary to initiate puberty, maintain feminization, and avoid osteoporosis iv. Dilatation of short vaginal length (vaginoplasty) to avoid dyspareunia v. Systemic disclosure of the condition to parents and patients in an empathic setting PAIS with predominantly female genitalia i. Management issues similar to CAIS ii. Prepubertal gonadectomy helps avoid discomfort of increasing clitoromegaly at the time of puberty PAIS with ambiguous genitalia or predominantly male genitalia i. Sex of rearing based on the genital phenotype, genital reconstructive surgery and hormone therapy ii. Sex assignment in infants with ambiguous genitalia requires delicate decision-making by parents and healthcare personnel and should be resolved as early as is feasible iii. A male sex-of-rearing demands a therapeutic trial with pharmacologic doses of androgen to predict potential androgen responsiveness at puberty and to facilitate reconstructive surgery iv. Reduction mammoplasty for gynecomastia developing in puberty MAIS i. Reduction mammoplasty often required for gynecomastia ii. A trial of androgen pharmacotherapy to improve virilization
REFERENCES Boehmer ALM, Brinkmann Arch Otolaryngol, Niermeijer MF, et al.: Germ-line and somatic mosaicism in the androgen insensitivity syndrome: implications for genetic counseling. Am J Hum Genet 60:1003–1006, 1997. Boehmer ALM, Bruggenwirth H, Assendelft CV, et al.: Genotype versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab 86:4151–4160, 2001. Davies HR, Hughes IA, Patterson MN: Genetic counselling in complete androgen. insensitivity syndrome-trinucleotide repeat polymorphisms, single strand conformational polymorphisms and direct detection of 2 novel mutations in the androgen receptor gene. Clin Endocrinol Oxf 43:69–77, 1995. Evans BA, Hughes IA, Bevan CL, et al.: Phenotypic diversity in siblings with partial androgen insensitivity syndrome. Arch Dis Child 76:529–531, 1997. Gottlieb B, Beitel LK, Lumbroso R, et al.: Update of the androgen receptor gene mutations database. Hum Mutat 14:103–114, 1999. Gottlieb B, Pinsky L, Beitel LK, et al.: Androgen insensitivity. Am J Med Genet (Semin Med Genet) 89:210–217, 1999. Gottlieb B, Beitel LK, Triffiro MA: Androgen insensitivity syndrome. Gene Reviews, 2004. http://genetests.org
ANDROGEN INSENSITIVITY SYNDROME Hiort O, Huang Q, Sinnecker GHG, et al.: Single strand conformation polymorphism analysis of androgen receptor gene mutations in patients with androgen insensitivity syndromes: application for diagnosis, genetic counseling, and therapy. J Clin Endocrinol Metab 77:262–266, 1993. Hiort O, Sinnecker GHG, Holterhus P-M, et al.: Inherited and de novo androgen receptor gene mutations investigation of single-case families. J Pediatr 132:939–943, 1998. Holterhus PM, Bruggenwirth HT, Hiort O, et al.: Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome. J Clin Endocrinol Metab 82:3584–3589, 1997. Hughes IA, Evans BAJ: Androgen insensitivity in forty-nine patients: classification based on clinical and androgen receptor phenotypes. Horm Res 28:25–29, 1987. Hughes IA, Patterson Muscle Nerve: Prenatal diagnosis of androgen insensitivity. Clin Endocrinol 40:295, 296, 1994. Jukier L, Kaufman M, Pinsky L, et al.: Partial androgen resistance associated with secondary 5α-reductase deficiency: identification of a novel qualitative androgen receptor defect and clinical implications. J Clin Endocrinol Metab 59:679–688, 1984. Katz MD, Cai L-Q, Zhu Y-S, et al.: The biochemical and phenotypic characterization of females homozygous for 5α-reductase-2 deficiency. J Clin Endocrinol Metab 80:3160–3167, 1995. Keenan BS, Meyer III WJ, Hadjian AJ, et al.: Syndrome of androgen insensitivity in man: absence of 5-dihydrotestosterone binding protein in skin fibroblasts. J Clin Endocrinol Metab 38:1143–1146, 1974. Gottlieb V, Pinsky L, Beitel LK, et al.: Androgen insensitivity. Am J Med Genet (Semin Med Genet) 89:210–217, 1999. Griffin JE, McPhaul MJ, Russell DW, et al.: The androgen resistance syndromes: steroid 5α-reductase 2 deficiency, testicular feminization, and related disorders. In Scriver CR, Beaudet al., Sly WS, Valle D (eds): The
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Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001. Holterhus PM, Bruggenwirth HT, Hiort O: Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome J Clin Endocrinol Metab 82:3584–3589, 1997. Lubahn DB, Joseph DR, Sullivan PM, et al.: Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science 240:327–330, 1988. Quigley CA, De Bellis A, Marschke KB, et al.: Androgen receptor defects: historical, clinical and molecular perspectives. Endocr Rev 16:271–321, 1995. Simpson JL: Disorders of the Gonads, Genital tract and Genitalia. In Rimoin DL, Connor JM, Pyeritz RE, Korf BR (eds): Emery and Rimoin’s Principles and Practice of Medical Genetics. 4th ed. Vol 2, pp 2315–2351, 2002. Sinnecker GH, Hiort O, Nitsche EM, et al.: Functional assessment and clinical classification of androgen sensitivity in patients with mutations of the androgen receptor gene. German Collaborative Intersex Study Group. Eur J Pediatr 156:7–14, 1997. Rutgers JL, Scully RE: The androgen insensitivity syndrome (testicular feminisation): a clinicopathological study of 43 cases. Int J Gynecol Pathol 10:126–144, 1991. Tsukada T, Inoue M, Tachibana S, et al.: An androgen receptor mutation causing androgen resistance in undervirilized male syndrome. J Clin Endocrinol Metab 79:1202–1207, 1994. Viner RM, Teoh Y, Williams DM, et al.: Patterson MN, Hughes IA. 1997 Androgen insensitivity syndrome: a survey of diagnostic procedures and management in the UK. Arch Dis Child 77:305–309, 1997. Weidemann W, Linck B, Haupt H, et al.: Clinical and biochemical investigations and molecular analysis of subjects with mutations in the androgen receptor gene. Clin Endocrinol (Oxf) 45:733–739, 1996. Wilson BE: Androgen insensitivity syndrome. Emedicine, 2003. http:// emedicine.com
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Fig. 1. A 24-year-old 46,XY individual with incomplete androgen insensitivity syndrome showing female habitus, normal axillary and pubic hair, and clitoromegaly.
Fig. 2. A 14-year-old sibling (46,XY) with incomplete androgen insensitivity syndrome showing the same phenotype.
ANDROGEN INSENSITIVITY SYNDROME
Fig. 3. Appearance of external genitalia of another patient with androgen insensitivity syndrome.
Fig. 4. A neonate with androgen insensitivity syndrome showing a mass in the left labioscrotal fold which proved to be a testis.
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Angelman Syndrome In 1965, Angelman reported three children with a similar pattern of severe learning disability, seizures, ataxic jerky movements, easily provoked laughter, absent speech, and dysmorphic facial features. The syndrome, which bears his name, was originally called the “happy puppet” syndrome. The incidence is estimated to be 1 in 10,000 to 1 in 40,000.
a) Normal methylation analysis with the presence of both maternal and paternal bands b) Other diagnostic tests: screening of UBE3A for mutations c. Imprinting defects (2–5%) i. A mutation within the “imprinting center,” located within 15q11-q13 on chromosome 15, renders the imprinting center unable to function properly (2%). Normally imprinting center regulates which segments of DNA are imprinted a) Abnormal methylation analysis with the presence of paternal band only b) Positive screening for imprinting center for mutation ii. Imprinting defect without imprinting center mutation (2%) a) Abnormal methylation analysis with the presence of paternal band only b) Negative screening for imprinting center for mutation iii. Mosaic imprinting defect (frequency unknown) a) Abnormal methylation analysis with the presence of a faint maternal band b) Usually negative screening for imprinting center for mutation iv. Microdeletions reported in the imprinting center d. Paternal uniparental disomy (UPD) (both copies of a chromosome come from the father) of the chromosome 15 (2%) i. Affected individuals having two alleles of all genes (both derived from the father) but remain silenced with no production of functional protein ii. Milder phenotypic manifestations (lower incidence of seizures) iii. Abnormal methylation analysis with the presence of paternal band only iv. Other diagnostic tests: RFLP analysis e. No genetic abnormality identified: Patients with clinical features of Angelman syndrome but no demonstrable cytogenetic or molecular abnormality of chromosome 15q11-q13
GENETICS/BASIC DEFECTS 1. Inheritance a. Sporadic in most cases b. Rare familial transmission (always transmitted through maternal lineage) 2. Caused by deficiency of gene expression from abnormality on the maternally derived chromosome 15 because of genomic imprinting a. The relevant region on chromosome 15q i. Normally expressed on the maternally derived chromosome ii. Normally imprinted on the paternally derived chromosome b. Inability of the imprinted paternal allele to produce functional protein since the normally expressed maternal copy is often deleted in Angelman syndrome 3. Genetic mechanisms responsible for the disorder a. Chromosome deletions and translocations i. Deletion of the maternally derived chromosome region 15q11-q13, which affects several imprinted genes including UBE3A (E6AP-3A ubiquitin protein ligase gene) and SNRPN (small nuclear ribonucleoprotein polypeptide N) (70%) a) Abnormal methylation analysis with the presence of paternal band only b) Other diagnostic tests: high resolution cytogenetics or FISH ii. Rare families with deletion due to unique chromosome 15 rearrangement within 15q11-q13 (<1%) a) Abnormal methylation analysis with the presence of paternal band only b) Other diagnostic tests: high resolution cytogenetics or FISH b. UBE3A and other presumed single gene mutations (20–25%) i. Imprinting of the UBE3A gene with paternal silencing in human brain ii. Inability to degrade unwanted proteins iii. Compromised cellular functions secondary to absence of UBE3A iv. Resulting in abnormal cortical functioning with severe mental retardation v. Diagnostic tests for mutations
CLINICAL FEATURES 1. Consistent cardinal features (100%) a. Normal newborn phenotype i. Normal prenatal and birth history ii. Normal head circumference iii. Absence of major birth defects b. Developmental delay
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i. Starting around 6 months of age ii. Eventually classified as severe developmental delay and/or mental retardation c. Profound speech impairment i. Absent or minimal use of words ii. Receptive and nonverbal communication skills better than verbal capability d. Movement or balance disorder i. Abnormal ataxic gait ii. Puppet-like jerky movements of limbs iii. Hand flapping movement e. Typical behavioral pattern i. An easily excitable personality, often with hand flapping movements ii. Short attention span iii. A happy, sociable disposition iv. Inappropriately happy affect v. Bouts of inappropriate laughter vi. Hypermotoric behavior 2. Frequent features (>80%) a. Delayed, disproportionate growth in head circumference, usually resulting in microcephaly by age 2 b. Seizures (80%) i. Onset usually before 3 years of age (1–5 years) ii. Variety of seizures (tonic–clonic, atypical absences, complex partial, myoclonic, atonic, and tonic seizures to status epilepticus) c. Characteristic EEG with large amplitude slow spike waves and triphasic waves 3. Associated features (20–80%) a. Characteristic craniofacial appearance i. Flat occiput ii. Occipital groove iii. Strabismus iv. Tongue thrusting v. Prognathia vi. Wide mouth vii. Widely spaced teeth viii. Frequent drooling ix. Excessive chewing/mouthing behaviors b. Swallowing disorder c. Feeding problems during infancy d. Hypopigmented skin e. Light hair and eye color, compared to other family members, seen only in deletion cases f. Hyperactive lower limb deep tendon reflexes g. Uplifted, flexed arm position especially during ambulation h. Increased sensitivity to heat i. Sleep disturbance j. Attention to and fascination with water k. Hypotonia at birth 4. Adolescent and adult phenotype a. More striking facial features i. Marked mandibular prognathism ii. Pointed chin iii. Macrostomia iv. Prominent lower lip v. Deeply set eyes vi. Keratoconus, secondary to eye rubbing
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b. c. d. e.
Scoliosis and joint contractures increasing with age Improved hyperactivity and concentration Persistent sociable disposition A good quality of life maintained despite the above problems f. Lifespan not greatly reduced 5. Phenotype-genotype correlations a. Patients with chromosome 15 deletions: in general, the most severely affected i. Higher incidence of seizures, microcephaly, and hypopigmentation. Severe epilepsy seen in these patients is considered to be the result of the absence of one copy of the GABA receptor genes ii. Greater delay in motor milestones iii. Absent speech iv. Severe clinical features thought to be the result of haploinsufficiency for a number of genes within the 15q11-q13 region b. Phenotype in the nondeletion cases: milder than that of the deletion cases c. Phenotype in the paternal UPD: milder than that of the deletion cases i. A low incidence of seizures, microcephaly, and hypopigmentation ii. Able to say a few words in many patients iii. Better growth parameters iv. Less obvious dysmorphic features v. Typical behavioral pattern d. Imprinting defects i. Less likely to have microcephaly, hypopigmentation, or seizures ii. More able than the deletion group with less delay in motor milestones and better communication skills iii. Growth better than the deletion patients iv. Obesity relatively common within this group e. Milder phenotype associated with incomplete imprinting defect or cellular mosaicism (displayed as Angelman syndrome methylation pattern) f. Point mutations in the UBE3A i. Phenotype between the deletion group and the UPD group ii. Frequently with mild or absence of ataxia, epilepsy, and microcephaly iii. Not hypopigmented iv. Better motor and communication skills than the deletion group
DIAGNOSTIC INVESTIGATIONS 1. Normal metabolic, hematologic, and chemical laboratory profiles 2. Normal brain imagings (MRI, CT) with occasional mild cortical atrophy and dysmyelination 3. Abnormal EEG a. High-amplitude slow spike-wave activities (most common) b. Hypsarrhythmia (infantile spasm) 4. Cytogenetic studies a. To detect visible chromosome rearrangement (<1%) i. Translocation ii. Inversion
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b. High-resolution chromosome studies to demonstrate large del(15)(q11-q13) c. Fluorescence in situ hybridization (FISH) to identify 15q11-q13 microdeletions, using D15S10 and/or SNRPN probes: detects about 70% of patients 5. DNA methylation studies a. To demonstrate characteristic DNA methylation pattern (i.e., paternal imprint only) of 15q11-q13 cloned DNA sequences using methylation-sensitive restriction endonucleases i. Diagnose about 80% of classic Angelman syndrome including patients with a deletion, uniparental disomy, or an imprinting defect ii. Certain maternally inherited genes are extensively methylated and thus inactivated while the paternal alleles are unmethylated and active in normal individuals iii. Unmethylated SNRPN alleles in patients with Angelman syndrome: caused by a) Uniparental disomy b) Imprinting center defects c) Typical 15q11-q13 deletion iv. Inability to distinguish the molecular classes (15q11-q13 deletion, uniparental disomy, or imprinting center defect) b. UBE3A mutation analysis i. Detect mutations in the E6-AP ubiquitin-protein ligase gene ii. Detect additional 11% of patients 6. DNA polymorphisms to demonstrate absence of maternal alleles at 15q11-q13 loci, which may result either from maternal deletion or from paternal uniparental disomy a. Determined by analysis of simple sequence repeats (microsatellites) in the parents and the affected individual b. Determine parental origin of 15q11-q13 and the rest of chromosome 15 c. Detect patients with deletions and uniparental disomy but not the UBE3A mutation class of patients d. Detect biparental inheritance of 15q11-q13 with abnormal DNA methylation in patients with imprinting center defects 7. Simple algorithm for genetic testing in patients with clinical suspicion of Angelman syndrome (Clayton-Smith and Laan, 2003) a. Abnormal methylation analysis i. FISH analysis a) Presence of del(15)(q11-q13) b) Absence of del(15)(q11-q13) ii. RFLP analysis if FISH analysis is negative a) Presence of UPD b) Absence of UPD iii. Screen imprinting center mutation for imprinting defect if UPD is absent b. Normal methylation analysis i. Screen UBE3A mutation in clinically typical patients a) If positive, check parents b) If negative, keep on review
ii. No further testing required for clinical normal patients (not Angelman syndrome) 8. Currently, about 10% of patients with classic phenotypic features of Angelman syndrome are not amenable to diagnostic testing due to presently unidentified genetic mechanisms
GENETIC COUNSELING 1. Recurrence risks: depending on the genetic mechanism involved and on whether the mother is shown to carry genetic abnormalities of 15q11-q13 a. De novo cytogenetic and molecular deletion of the maternal chromosome 15q11-q13: low risk of recurrence (1–2%) in the subsequent children in families with a child who has a de novo cytogenetic and molecular deletion of the maternal chromosome 15q11-q13 b. Uniparental disomy in the absence of a parental translocation: risk likely to be extremely low (<1%) c. Parental structurally or functionally unbalanced chromosome complement leading to 15q11-q13 deletions or to uniparental disomy: case-specific recurrence risks d. Methylation imprinting mutations in a number of familial cases: risk to subsequent children as high as 50% e. UBE3A mutations i. Near 0% risk to subsequent children when there is a new mutation in the proband (de novo) ii. 50% risk to subsequent children when it is inherited from a mother who has a new mutation or from a mother who inherited the mutation from her father f. Remaining patients showing no genetic abnormalities mentioned above: up to 50% risk g. Reasons of difficulty in providing recurrence risk estimation i. Causal heterogeneity of Angelman syndrome ii. Maternal germ cell mosaicism 2. Prenatal diagnosis a. Possible when the underlying genetic mechanism is as follows: i. A deletion ii. Uniparental disomy iii. An imprinting defect iv. A UBE3A mutation v. A chromosome rearrangement b. Combined use of methylation analysis, FISH, and DNA marker studies: to identify the common approximately 4 Mb deletion, paternal UPD, or imprinting mutation in about 70–80% of cases with Angelman syndrome c. Mutation analysis for UBE3A d. Readily accomplished if a disease-causing mutation is identified and is present in the mother 3. Management a. Physical therapy for unstable or nonambulatory children b. Occupational therapy for improving fine motor and oral-motor control c. Speech and communication therapy
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d. Consistent behavioral modifications e. Seizure control difficult with antiepileptic drugs, especially in childhood i. Sodium valproate as monotherapy or in combination with clonazepam or other benzodiazepines ii. Experience with the newer antiepileptic drugs very limited
REFERENCES American Society for Human Genetics: Diagnostic testing for Prader-Willi and Angelman syndromes: Report of the ASHG/ACMG Test and Technology Transfer Committee. Am J Hum Genet 58:1085–1088, 1996. Angelman H: “Puppet children”: a report of three cases. Dev Med Child Neurol 7:681–688,1965. Brannan CI, Bartolomei MS: Mechanisms of genomic imprinting. Curr Opin Genet Dev 9:164–170, 1999. Brockmann K, Bohm R, Burger J: Exceptionally mild Angelman syndrome phenotype associated with an incomplete imprinting defect. J Med Genet 39:e51–e53, 2002. Buiting K, Dittrich B, Gross S, et al.: Sporadic imprinting defects in PraderWilli syndrome and Angelman syndrome: implications for imprint-switch models, genetic counseling, and prenatal diagnosis. Am J Hum Genet 63:170–180, 1998. Buntinx IM, Henneckam RCM, Brouwer OF, et al.: Clinical profile of Angelman syndrome at different ages. Am J Med Genet 56:176–183, 1995. Cassidy SB: Prader-Willi and Angelman syndromes: sister imprinted disorders. Am J Med Genet 97:136–146, 2000. Cassidy SB, Schwartz S: Prader-Willi and Angelman syndromes: Disorders of genomic imprinting. Medicine 77:140–151, 1998. Chan CT, Clayton-Smith J, Cheng XJ, et al.: Molecular mechanisms in Angelman syndrome: a survey of 93 patients. J Med Genet 30:895–902, 1993. Cheung SW, Shaffer LG, Richards CS, et al.: Prenatal diagnosis of a fetus with a homologous Robertsonian translocation of chromosome 15. Am J Med Genet 72:47–50, 1997. Clayton-Smith J: Clinical research on Angelman syndrome in the United Kingdom: observations on 82 affected individuals. Am J Med Genet 46:12–15, 1993. Clayton-Smith J, Pembrey M: Angelman syndrome. J Med Genet 29:412–415, 1992. Clayton-Smith J, Laan L: Angelman syndrome: a review of the clinical and genetic aspects. J Med Genet 40:87–95, 2003. Engel E, Antonarakis SE: Genomic Imprinting and Uniparental Disomy in Medicine. Clinical and Molecular Aspects. New York: Wiley-Liss, 2002. Fang P, Lev-Lehman E, Tsai TF, et al.: The spectrum of mutations in UBE3A causing Angelman syndrome. Hum Mol Genet 8:129–135, 1999. Fridman C: Origin of uniparental disomy 15 in patients with Prader-Willi or Angelman syndrome. Am J Med Genet 94:249–253, 2000. Fryburg JS, Breg WR, Lindgren V: Diagnosis of Angelman syndrome in infants. Am J Med Genet 38:58–64, 1991. Glenn CC, Saitoh S, Jong MTC, et al.: Expression, DNA methylation, and gene structure of the human SNRPN gene. Am J Hum Genet 58:335–346, 1996. Glenn CC, Deng G, Michaelis RC, et al.: DNA methylation analysis with respect to prenatal diagnosis of the Angelman and Prader-Willi syndromes and imprinting. Prenat Diagn 20:300–306, 2000. Gilbert HL, Buxton JL, Chan CT, et al.: Counselling dilemmas associated with the molecular characterization of two Angelman syndrome families. J Med Genet 34:651–655, 1997. Gyftodimou J: Angelman syndrome with uniparental disomy due to paternal meiosis II nondisjunction. Clin Genet 55:483–486, 1999. Jiang Y-h, Lev-Lehman E, Bressler J, et al.: Genetics of Angelman syndrome. Am J Hum Genet 65:1–6, 1999.
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Khan NL: Prader-Willi and Angelman syndromes: update on genetic mechanisms and diagnostic complexities. Curr Opin Neurol 12:149–154, 1999. Kishino T, Lalande M, Wagstaff J: UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet 15:70–73, 1997. Knoll JHM, Nicholls RD, Magenis RR, et al.: Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion. Am J Med Genet 32:285–290, 1989. Laan LA: Angelman syndrome: a review of clinical and genetic aspects. Clin Neurol Neurosurg 101:161–170, 1999. Lalande M: Parental imprinting and Angelman syndrome. Adv Neurol 79:421–429, 1999. Ledbetter D, Niikawa N: Molecular and clinical study of 61 Angelman syndrome patients. Am J Med Genet 52:158–163, 1994. Lossie AC, Whitney MM, Amidon D, et al.: Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J Med Genet 38:834–845, 2001. Malzac P, Webber H, Moncla A, et al.: Mutation analysis of UBE3A in Angelman syndrome patients. Am J Hum Genet 62:1353–1360, 1998. Moncla A, Malzac P, Livet MO, et al.: Angelman syndrome resulting from UBE3A mutations in 14 patients from eight families: clinical manifestations and genetic counselling. J Med Genet 36:554–560, 1999. Nicholls RD: Genomic imprinting and uniparental disomy in Angelman and Prader-Willi syndromes: a review. Am J Med Genet 46:16–25, 1993. Nicholls R, Saitoh S, Horsthemke B: Imprinting in Prader-Willi and Angelman syndromes. Trends Genet 14:194–200, 1998. Ohta T, Buiting K, Kokkonen H, et al.: Molecular mechanism of Angelman syndrome in two large families involves an imprinting mutation. Am J Hum Genet 64:385, 386, 1999. Petersen MB, Brondum-Nielsen K, Hansen LK, et al.: Clinical, cytogenetic, and molecular diagnosis of Angelman syndrome: estimated prevalence rate in a Danish county. Am J Med Genet 60:261, 262, 1995. Rougeulle C, Glatt H, Lalande M: The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nat Genet 17:14–15, 1997. Saitoh S, Harada N, Jinno Y, et al.: Molecular and clinical study of 61 Angelman syndrome patients. Am J Med Genet 52:158–163, 1994. Smith JC: Angelman syndrome: evolution of the phenotype in adolescents and adults. Dev Med Child Neurol 43:476–480, 2001. Stalker HJ, Williams CA: Genetic counseling in Angelman syndrome: the challenges of multiple causes. Am J Med Genet 77:54–59, 1998. Stalker HJ, Williams CA, Wagstaff J: Genetic counseling in Angelman syndrome: gonadal mosaicism. Am J Med Genet 78:482, 1998. Tsai TF, Raas-Rothschild A, Ben-Neriah Z, et al.: Prenatal diagnosis and carrier detection for a point mutation in UBE3A causing Angelman syndrome. Am J Hum Genet 63:1561–1563, 1998. Van Lierde A, Atza MG, Giardino D, et al.: Angelman’s syndrome in the first year of life. Dev Med Child Neurol 32:1011–1016, 1990. Webb T, Malcolm S, Pembrey ME, et al.: Inheritance of parental chromosomes 15 in Angelman syndrome-implications for the family. Genet Counsel 4:1–6, 1993. Willems RJ, Dijkstra I, Brouwer OF, et al.: Recurrence risk in the Angelman (“happy puppet”) syndrome. Am J Med Genet 27:773–780, 1987. Williams CA: Angelman syndrome. In: Cassidy SB, Allanson JE (eds): Management of Genetic Syndromes. New York: Wiley-Liss, 2001. Williams CA, Lossie A, Driscoll D: Angelman syndrome: mimicking conditions and phenotypes. Am J Med Genet 101:59–64, 2001. Williams CA, Angelman H, Clayton-Smith J, et al.: Angelman syndrome: Consensus for diagnostic criteria. Am J Med Genet 56:237–238, 1995. Williams CA, Zori RT, Hendrickson JE, et al.: Angelman syndrome. Curr Probl Pediatr 25:216–231, 1995. Williams CA, Dong H-J, Driscoll DJ: Angelman syndrome. Gene Reviews, 2003. http://genetests.org Yu TH, Hoffman AR: Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain. Nat Genet 17:1213, 1997.
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Fig. 1. Two children with Angelman syndrome showing happy disposition, an open mouth expression, widely spaced teeth, and a pronounced mandible. The diagnoses were confirmed cytogenetically [del(15)(q11-13)].
Apert Syndrome c. Syndactyly of Apert syndrome i. A keratinocyte growth factor receptor (KGFR)mediated effect, provided by the observation of the correlation between KGFR expression in fibroblasts and severity of syndactyly ii. Different phenotypic expression in patients with Ser252Trp and those with Pro253Arg. The syndactyly is more severe with Pro253Arg mutation for both hands and feet, whereas cleft palate is significantly more common with Ser252Try mutation d. During early infancy (younger than 3 month of age) i. Premature closure of the coronal suture area, evident by a bony condensation line beginning at the cranial base and extending upward with a characteristic posterior convexity ii. Widely patent anterior and posterior fontanelles iii. Presence of a gaping defect of the midline of the calvaria, extending from the glabellar area to the posterior fontanelle via the metopic suture area, anterior fontanelle, and sagittal suture area. The skull with gaping midline defect appears to permit adequate accommodation of the growing brain iv. Normal lambdoidal sutures in all cases e. During the first 2–4 years of life i. Obliteration of the midline defect by coalescence of the enlarging bony islands without evidence of any proper formation of sutures ii. Very early onset in fetal life of growth inhibition in the sphenofrontal and coronal suture area, suggested by an extremely short squama and orbital part of the frontal bone together with the posterior convexity of the coronal bone condensation line
Apert syndrome is named after the French physician who described the syndrome acrocephalosyndactylia in 1906. Apert syndrome is a rare autosomal dominant disorder characterized by craniosynostosis, craniofacial anomalies, and severe symmetrical syndactyly (cutaneous and bony fusion) of the hands and feet. It probably is the most familiar and best-described type of acrocephalosyndactyly. Prevalence is estimated at 1 in 65,000 (approximately 15.5 in 1,000,000) live births. Apert syndrome accounts for 4.5% of all cases of craniosynostosis.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant b. Sporadic in majority (>98%) of cases, resulting from new mutations with a paternal age effect c. Rarity of familial cases can be explained by reduced genetic fitness of individuals because of severe malformations and the presence of mental retardation in many cases 2. Cause a. Caused by specific missense substitution mutations, involving adjacent amino acids (i.e., Ser252Trp or Pro253Arg) in the linker between the second and third extracellular immunoglobulins domains of FGFR2, which maps to chromosome bands 10q25q26 (more than 98% of cases with Apert syndrome) b. Remaining cases are caused by Alu-element insertion mutations in or near exon 9 of FGFR2 3. Pathogenesis a. Unique fibroblast growth factor receptor 2 (FGFR2) mutations i. Leading to an increase in the number of precursor cells that enter the osteogenic pathway ii. Ultimately leading to increased subperiosteal bone matrix formation and premature calvaria ossification during fetal development b. Fusion of the cranial sutures i. The order and rate of suture fusion determine the degree of deformity and disability ii. Once a suture becomes fused, growth perpendicular to that suture becomes restricted, and the fused bones act as a single bony structure iii. Compensatory growth occurs at the remaining open sutures to allow continued brain growth iv. Complex, multiple sutural synostosis frequently extends to premature fusion of the sutures at the base of the skull, causing midfacial hypoplasia, shallow orbits, a foreshortened nasal dorsum, maxillary hypoplasia, and occasional upper airway obstruction
CLINICAL FEATURES 1. History a. Headache and vomiting: signs of acute increase of intracranial pressure, especially in cases of multiple suture involvement b. Stridor and sleep apnea indicates upper airway problems, due to craniosynostosis of the base of the skull c. Visual disturbance due to exposure keratitis and conjunctivitis d. Mental retardation in many patients, though patients with normal intelligence have been reported 2. Skull a. Craniosynostosis b. Coronal sutures most commonly involved, resulting in acrocephaly, brachycephaly, turribrachycephaly, flat occiput, and high, prominent forehead
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c. Large late-closing fontanels d. Gaping midline defect e. Rare cloverleaf skull anomaly in approximately 4% of infants 3. Facial features a. Horizontal grooves above the supraorbital ridges that disappear with age b. A break in the continuity of the eyebrows c. A trapezoid-shaped mouth at rest d. Flattened, often asymmetric face e. Maxillary hypoplasia with retruded midface f. Eyes i. Down-slanting palpebral fissures ii. Hypertelorism iii. Shallow orbits iv. Proptosis v. Exophthalmos vi. Lateral ptosis vii. Widened palpebral fissures viii. Tearing secondary to exposure keratitis ix. Prolonged corneal exposure resulting in corneal scars and opacification x. Partially open eye during sleep xi. Strabismus xii. Amblyopia xiii. Optic atrophy xiv. Keratoconus xv. Ectopic lentis xvi. Congenital glaucoma xvii. Lack of pigment in the fundi with occasional papilledema xviii. Rare luxation of the eye globes as an extreme complication of severe exorbitism, producing possible strangulation of the circulation of the globe and blindness g. Mouth i. A prominent mandible ii. Down-turned corners iii. High-arched palate iv. Bifid uvula v. Cleft palate vi. Crowded upper teeth vii. Malocclusion viii. Delayed dentition ix. Ectopic eruption x. Shovel-shaped incisors xi. Supernumerary teeth xii. V-shaped maxillary dental arch xiii. Bulging alveolar ridges h. Ears i. Apparent low-set ears ii. Occasional conductive hearing loss iii. Congenital fixation of stapedial footplate 4. Extremities and digits a. The upper limbs affected more severely than lower limbs b. Coalition of distal phalanges and synonychia of the hands (never present in the feet) c. The glenohumeral joint and proximal humerus affected more severely than the pelvic girdle and femur
5.
6.
7.
8.
d. The elbow involved much less severely than the proximal portion of the upper limb e. Syndactyly of the hands and feet with partial-tocomplete fusion of the digits, often involving second, third, and fourth digits. These often are termed mitten hands and socked feet. In severe cases, all digits are fused, with the palm deeply concave or cup-shaped and the sole supinated f. Hitchhiker posture or radial deviation of short or broad thumbs resulting from abnormal proximal phalanx g. Brachydactyly h. Contiguous nailbeds (synonychia) i. Subacromial dimples and elbow dimples during infancy j. Limited mobility at the glenohumeral joint with progressive limitation in abduction, forward flexion, and external rotation k. Limited elbow mobility common with decreased elbow extension, flexion, pronation, and supination l. Short humeri, a constant finding beyond infancy m. Limited genu valga present in many cases Other skeletal and cartilaginous segmentation defects a. Congenital cervical spinal fusion (68%), especially C5-C6 b. Aplasia or ankylosis of shoulder, elbow, and hip joints c. Tracheal cartilage anomalies d. Rhizomelia CNS a. Intelligence varying from normal to mental deficiency, though a significant number of patients are mentally retarded. Malformations of the CNS may be responsible for most cases b. Common CNS malformations i. Megalencephaly ii. Agenesis of the corpus callosum iii. Malformed limbic structures iv. Variable ventriculomegaly. Progressive hydrocephalus is uncommon v. Encephalocele vi. Gyral abnormalities vii. Hypoplastic cerebral white matter viii. Pyramidal tract abnormalities ix. Heterotopic gray matter x. Papilledema and optic atrophy with loss of vision in cases with insidious intracranial pressure increase Cardiovascular (10%) a. Atrial septal defect b. Patent ductus arteriosus c. Ventricular septal defect d. Pulmonary stenosis e. Overriding aorta f. Coarctation of aorta g. Dextrocardia h. Tetralogy of Fallot i. Endocardial fibroelastosis Genitourinary (9.6%) a. Polycystic kidneys b. Duplication of renal pelvis
APERT SYNDROME
9.
10.
11.
12.
13.
c. Hydronephrosis d. Stenosis of bladder neck e. Bicornuate uterus f. Vaginal atresia g. Protuberant labia majora h. Clitoromegaly i. Cryptorchidism Gastrointestinal (1.5%) a. Pyloric stenosis b. Esophageal atresia and tracheoesophageal fistula c. Ectopic or imperforate anus d. Partial biliary atresia with agenesis of gallbladder Respiratory (1.5%) a. Anomalous tracheal cartilage b. Tracheoesophageal fistula c. Pulmonary aplasia d. Absence of right middle lobe of the lung e. Absence of interlobular lung fissures Skin a. Hyperhidrosis (common) b. Acneiform lesions frequent after adolescence c. Interruption of the eyebrows d. Hypopigmentation e. Hyperkeratosis in the plantar surface f. Paronychial infections more commonly affected in feet than hands and observed more commonly in institutionalized patients g. Excessive skin wrinkling of forehead h. Skin dimples at knuckles, shoulders, and elbows At risk for complications resulting from elevated intracranial pressure despite surgical attempts to increase cranial capacity in infancy Early death a. Upper airway compromise i. Reduction in nasophrynx size ii. Choanal patency iii. Obstructive sleep apnea iv. Cor pulmonale b. Lower airway compromise due to anomalies of the tracheal cartilage
DIAGNOSTIC INVESTIGATIONS 1. Psychometric evaluation 2. Hearing assessment 3. Imaging studies a. Skull radiography to evaluate craniostenosis, which usually involves coronal sutures and maxillary hypoplasia i. Sclerosis of suture line ii. Bony bridging and beaking along the suture line iii. An indistinct suture line iv. Turribrachycephaly v. Shallow orbits vi. Hypoplastic maxillae b. Spine radiography i. Spinal fusions, most commonly at the levels of C3-4 and C5-6, appearing to be progressive and occurring at the site of subtle congenital anomalies ii. Small-sized vertebral body and reduced intervertebral disc space: indicators of subsequent bony fusion
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c. Limb radiography i. Multiple epiphyseal dysplasia ii. Short humeri iii. Glenoid dysplasia iv. Cutaneous and osseous syndactyly v. Complete syndactyly involving the second and fifth digits (mitten hands) vi. Multiple progressive synostosis involves distal phalanges, proximal fourth and fifth metacarpals, capitate, and hamate vii. Progressive symphalangism of interphalangeal joints viii. Shortened and radial deviation of distal phalanx ix. Delta-shaped deformity of proximal phalanx of the thumbs x. Complete syndactyly involving the second and fifth toes (socked feet) xi. Fusion of tarsal bones, metatarsophalangeal and interphalangeal joints, and adjacent metatarsals xii. Delta-shaped proximal phalanx of the first toes xiii. Occasional partial or complete duplication of the proximal phalanx of the great toes and first metatarsals d. Computed tomography i. CT scan with comparative three-dimensional reconstruction analysis of the calvaria and cranial bases: the most useful radiological examination in identifying skull shape and presence or absence of involved sutures ii. Precise definition of the pathological anatomy, permitting specific operative planning e. Magnetic resonance imaging i. Demonstration of the anatomy of the soft-tissue structures and associated brain abnormalities ii. Visualization of the spatial arrangement of the bones 4. Molecular analysis a. Exquisitely specific molecular mechanism with a narrow mutational spectrum b. More than 98% of cases: caused by specific missense substitution mutations, involving adjacent amino acids (Ser252Trp, Ser252Phe, or Pro253Arg) in exon 7 of FGFR2 c. The remaining cases: due to Alu-element insertion mutations in or near exon 9
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. A negligible recurrence risk for patient’s sib when parents are not affected except in the case of germinal mosaicism in which the risk for future sibs depends on the proportion of germ cells bearing the mutant allele ii. 50% risk if a parent is also affected b. Patient’s offspring: a 50% recurrence risk for an affected individual to have an affected offspring c. Advanced paternal age effect in new mutations has been shown clinically and demonstrated conclusively at the molecular level
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2. Prenatal diagnosis a. Prenatal ultrasonography in low-risk pregnancies with finding of abnormal fetal skull shape i. Prenatal diagnosis of Apert syndrome suspected with findings of fetal “mitten hands” associated with abnormal skull shape, and midfacial hypoplasia and confirmed by molecular diagnosis. Craniosynostosis is usually not detected until the third trimester ii. Low yield for testing mutations in the FGFR2 gene iii. Mutation identification not helpful in determining the prognosis of a fetus, which is largely determined by the clinical diagnosis and not by the molecular diagnosis b. Fetoscopy to visualize fetal anomalies comparable to Apert syndrome in a pregnancy at risk: an invasive procedure not used currently c. Molecular genetic analysis i. An affected parent with identified mutation of FGFR2 gene: prenatal diagnosis available on fetal DNA obtained through amniocentesis or chorionic villus sampling ii. An affected parent without identified mutation of FGFR2 gene: linkage analysis available to an informative family with at least two affected family members based on an accurate clinical diagnosis and an accurate understanding of genetic relationships in the family 3. Management a. Protection of the cornea i. Instill lubricating bland ointments in the eyes at bedtime to protect corneas from desiccation ii. Artificial teardrops during the day iii. Lateral or medial tarsorrhaphy in severe cases to narrow the palpebral fissure cosmetically and protect the corneas and the vision b. Upper airway obstruction during the neonatal period i. Remove excessive nasal secretions ii. Treat upper airway infection iii. Humidification with added oxygen iv. Judicious use of topic nasal decongestants v. Rarely requires orotracheal intubation c. Sleep apnea i. Polysomography (a sleep recording of multiple physiologic variables), currently the most reliable method for determining the presence of sleep apnea ii. Continuous positive pressure iii. Tracheostomy indicated in severely affected children d. Chronic middle ear effusion associated with bilateral conductive hearing deficit i. Antimicrobial therapy ii. Bilateral myringotomy and placement of ventilation tubes: the most effective treatment e. Craniofacial surgery i. Cranium a) Removes synostotic sutures b) Reshapes the calvaria
c) Allows more normal cranial development to proceed with respect to shape, volume, and bone quality d) Relieves increased intracranial pressure ii. Orbits a) Correction of ocular proptosis: the primary objective of orbital surgery b) Reduction of increased interorbital distance (hypertelorism) c) Correction of increased interior malrotation iii. Nose a) Infants and child: nasal reconstruction focusing on correction of the excessively obtuse nasofrontal angle, flat nasal dorsum, and ptotic nasal tip b) Teenager and adult: reduction of the nasal tip bulk iv. Midface a) Normalization of midface appearance b) Expansion of the inferior orbit c) Volumetric expansion of the nasal and nasopharyngeal airways d) Establishment of a normal dentoskeletal relationship v. Mandible: mandibular osteotomies to improve dentoskeletal relations for masticatory and aesthetic benefit f. Surgical reconstruction of syndactyly g. Psychological and social challenges confronted by individuals with Apert syndrome i. Emotional adjustment ii. Body image development iii. Impact of surgery and hospitalization on children with Apert syndrome
REFERENCES Allanson JE: Germinal mosaicism in Apert syndrome. Clin Genet 29: 429–433, 1986. Biesecker LG: Lumping and splitting: molecular biology in the genetics clinic. Clin Genet 54(Suppl 1):1–5, 1998. Blank CE: Apert’s syndrome (a type of acrocephalosyndactyly): observations on a British series of thirty-nine cases. Ann Hum Genet 24:151–164, 1960. Buncic JR: Ocular aspects of Apert syndrome. Clin Plast Surg 18:315–319, 1991. Campis LB: Children with Apert syndrome: developmental and psychologic considerations. Clin Plast Surg 18:409–416, 1991. Chang CC, Tsai FJ, Tsai HD, et al.: Prenatal diagnosis of Apert syndrome. Prenat Diagn 18:621–625, 1998. Chen H: Apert syndrome. Emedicine, 2003. http://www.emedicine.com Cohen MM Jr: An etiologic and nosologic overview of craniosynostosis syndromes. BDOAS XI(2):137–189, 1973. Cohen MM Jr: Genetic perspectives on craniosynostosis and syndromes with craniosynostosis. J Neurosurg 47: 886–898, 1977. Cohen MM Jr (ed): Craniosynostosis. Diagnosis, Evaluation, and Management. New York: Raven Press, 1986. Cohen MM Jr: Craniosynostosis update 1987. Am J Med Genet Suppl 4:99–148, 1988. Cohen MM Jr: Craniosynostoses: phenotypic/molecular correlations. Am J Med Genet 56:334–339, 1995. Cohen MM Jr, Kreiborg S: The central nervous system in the Apert syndrome. Am J Med Genet 35:36–45, 1990. Cohen MM Jr, Kreiborg S: Upper and lower airway compromise in the Apert syndrome. Am J Med Genet 44:90–93, 1992. Cohen MM Jr, Kreiborg S: Visceral anomalies in the Apert syndrome. Am J Med Genet 45:758–760, 1993.
APERT SYNDROME Cohen MM Jr, Kreiborg S: Hands and feet in the Apert syndrome. Am J Med Genet 57:82–96, 1995. Cohen MM Jr, Kreiborg S: Cutaneous manifestations of Apert syndrome. Am J Med Genet 58:94–96, 1995. Cohen MM Jr, Kreiborg S, Lammer EJ, Cordero JF, et al.: Birth prevalence study of the Apert syndrome. Am J Med Genet 42:655–659, 1992. Cohen MM Jr, Kreiborg S: Growth pattern in the Apert syndrome. Am J Med Genet 47 (5):617–623, 1993. Cohen MM Jr, Kreiborg S: Skeletal abnormalities in the Apert syndrome. Am J Med Genet 47:624–632, 1993. Cohen MM Jr, Kreiborg S: Suture formation, premature sutural fusion, and suture default zones in Apert syndrome. Am J Med Genet 62:339–344, 1998. Cohen MM Jr, Kreiborg S: An updated pediatric perspective on the Apert syndrome. Am J Dis Child 147:989–993, 1993. Cohen MM Jr, Kreiborg S: A clinical study of the craniofacial features in Apert syndrome. Int J Oral Maxillofac Surg 25:45–53, 1996. Cohen MM Jr, MacLean RE: Craniosynostosis: Diagnosis, Evaluation, and Management, 2nd ed, New York: Oxford University Press, New York, 2000. Do Amaral CMR, Di Domizio G, Buzzo CL: Surgical treatment of Apert syndrome and Crouzon anomaly by gradual bone distraction. Online J Plast Reconstr Surg 1: 1998. Ferreira JC, Carter SM, Bernstein PS, et al.: Second-trimester molecular prenatal diagnosis of sporadic Apert syndrome following suspicious ultrasound findings. Ultrasound Obstet Gynecol 14:426–430, 1999. Gould HJ, Caldarelli DD: Hearing and otopathology in Apert syndrome. Arch Otolaryngol 108:347–399, 1982. Hill LM, et al.: The ultrasound detection of Apert syndrome. J Ultrasound Med 6:601–604, 1987. Holten IWR, et al.: Apert syndrome hand: Pathologic anatomy and clinical manifestations. Plast Reconstr Surg 99:1681–1687, 1997. Jabs EW: Toward understanding the pathogenesis of craniosynostosis through clinical and molecular correlates. Clin Genet 54(Suppl 1):6–13, 1998. Kaufmann K, Baldinger S, Pratt L: Ultrasound detection of Apert syndrome: a case report and literature review. Am J Perinatol 14:427–430, 1997. Kreiborg S, Cohen MM Jr: Characteristics of the infant Apert skull and its subsequent development. J Craniofac Genet Dev Biol 10:399–410, 1990. Kreiborg S, Cohen MM Jr: The oral manifestations of Apert syndrome. J Craniofac Genet Dev Biol 12:41–48, 1992. Kreiborg A, et al. Cervical spine in the Apert syndrome. Am J Med Genet 43:704–708, 1992. Lajeunie E, et al. Clinical variability in patients with Apert’s syndrome. J Neurosurg 90:443–447, 1999.
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Leonard CO, et al. Prenatal fetoscopic diagnosis of the Apert syndrome. Am J Med Genet 11:5–9, 1982. Liptak GS, Serletti JM: Pediatric approach to craniosynostosis [published erratum appears in Pediatr Rev Jan; 20(1):20, 1999]. Pediatr Rev 19:352, quiz 359, 1998. Lomri A, Lemonnier J, Hott M, et al.: Increased calvaria cell differentiation and bone matrix formation induced by fibroblast growth factor receptor 2 mutations in Apert syndrome. J Clin Invest 101:1310–1317, 1998. Marsh JL, Galic M, Vannier MW: Surgical correction of the craniofacial dysmorphology of Apert syndrome. Clin Plast Surg 18:251–275, 1991. Moloney DM, Slaney SF, Oldridge M, et al.: Exclusive paternal origin of new mutations in Apert syndrome. Nat Genet 13:48–53, 1996. Oldridge M, Zackai EH, McDonald-McGinn DM, et al.: De novo alu-element insertions in FGFR2 identify a distinct pathological basis for Apert syndrome. Am J Hum Genet 64:446–461, 1999. Park WJ, Theda C, Maestri NE, et al.: Analysis of phenotypic features and FGFR2 mutations in Apert syndrome. Am J Hum Genet 57:321–328, 1995. Patton MA et al.: Intellectual development in Apert’s syndrome: a long term follow up of 29 patients. J Med Genet 25:164–167, 1988. Peterson-Falzone SJ, et al.: Nasopharyngeal dysmorphology in the syndromes of Apert and Crouzon. Cleft Palate J 18:237–250, 1981. Renier D, Arnaud E, Cinalli G, et al.: Prognosis for mental function in Apert’s syndrome. J Neurosurg 85:66–72, 1996. Skidmore DL, Pai AP, Toi A, et al.: Prenatal diagnosis of Apert syndrome: report of two cases. Prenat Diagn 23:1009–1013, 2003. Slaney SF, Oldridge M, Hurst JA, et al.: Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome. Am J Hum Genet 58:923–932, 1996. Thompson DN, Slaney SF, Hall CM, et al.: Congenital cervical spinal fusion: a study in Apert syndrome. Pediatr Neurosurg 25:20–27, 1996. Tolarova MM, et al.: Birth prevalence, mutation rate, sex ratio, parents’ age, and ethnicity in Apert syndrome. Am J Med Genet 72: 394–398, 1997. Upton J: Classification and pathologic anatomy of limb anomalies. Clin Plast Surg 18: 321–355, 1991. von Gernat S et al.: Genotype-phenotype analysis in Apert syndrome suggests opposite effects of the two recurrent mutations on syndactyly and outcome of craniofacial surgery. Clin Genet 57:137–139, 2000. Wilkie AO, Slaney SF, Oldridge M, et al.: Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet 9:165–172, 1995. Witters I, et al.: Diaphragmatic hernia as the first echographic sign in Apert syndrome. Prenat Diagn 20:404–406, 2000.
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Fig. 2. A 13-year-old girl with Apert syndrome showing characteristic facial appearance and postoperative status of the fingers and toes. Fig. 1. An infant with Apert syndrome showing characteristic facial appearance and typical mitten hands and socked feet.
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Fig. 3. An adult with Apert syndrome showing typical craniofacial appearance, hearing loss (wearing hearing aids), and mitten hands. Radiographs showed cutaneous and osseous syndactyly, complete syndactyly involving the second through fifth digits (mitten hands), symphalangism of interphalangeal joints, delta-shaped proximal phalanx of the thumbs, complete syndactyly involving the second through fifth digits (socked feet), and partial duplication of the proximal phalanx of the great toes and first metatarsals.
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Fig. 4. An adult with Apert syndrome showing typical craniofacial appearance with mitten hands and socked feet. Radiographs of hands and feet and skull showed cutaneous and osseous syndactyly, turribrachycephaly, shallow orbits, and hypoplastic maxilla.
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Fig. 5. A daughter and a mother with Apert syndrome showing characteristic craniofacial features, mitten hands, and socked feet.
Aplasia Cutis Congenita Aplasia cutis congenita (ACC) is a clinical description of the absence of the skin at birth, first described by Cordon in 1767. It is a heterogeneous group of disorders characterized by absence of epidermis, dermis, and, sometimes, subcutaneous tissue, muscle, or bone on one or more parts of the body. The incidence is estimated to be 1 in 10,000 births.
i. Group IX: ACC associated with malformation syndromes i. Trisomy 13 ii. Trisomy 18 iii. Monosomy 4 iv. Ectodermal dysplasias v. Johanson-Blizzard syndrome vi. Focal dermal hypoplasia vii. 46,XY gonadal dysgenesis viii. Amniotic band disruption complex 3. Aplasia cutis congenita associated with epidermolytic bullosa a. Simplex i. An autosomal dominant disorder ii. Lysis of the epidermis occurring within the cytoplasm of the basal cell layer b. Junctional i. An autosomal recessive disorder ii. Damage at the level of the lamina lucida c. Dystrophic (scarring) i. An autosomal dominant or recessive disorder ii. Defect situated in the anchoring fibrils attaching the basal lamina to the dermis
GENETICS/BASIC DEFECTS 1. Etiological theories a. Amniogenic theory i. Adhesion of the amniotic membrane to the fetal skin might tear off, leaving absent areas of skin ii. Not supported by the study of placentas because most placentas are normal b. Vascular theory: assumes thromboplastic material from a fetus papyraceus (mummified dead fetus) as the causes of skin damage c. Placental abnormalities d. Biomechanical forces on the vertex during the embryogenesis e. Intrauterine trauma: a history of trauma in only a minority of cases f. Intrauterine infections i. Varicella ii. Herpes simplex g. Intrauterine involution of a hemangioma h. Teratogens i. Methimazole ii. Misoprostol i. Genetic factors 2. Frieden’s classification of aplasia cutis congenita a. Group I: ACC of the scalp without multiple anomalies: sporadic occurrence or autosomal dominant inheritance b. Group II: ACC of the scalp with associated limb abnormalities: autosomal dominant inheritance c. Group III: ACC of the scalp with associated epidermal, organoid nevus, or epidermal nevus syndrome: sporadic occurrence d. Group IV: ACC overlying embryologic malformations: inheritance depending on underlying conditions e. Group V: ACC with associated fetus papyraceous or placental infarcts: sporadic occurrence f. Group VI: ACC associated with epidermolysis bullosa: autosomal dominant or recessive inheritance depending on the type of the epidermolysis bullosa g. Group VII: ACC localized to extremities without blistering: autosomal dominant or recessive inheritance h. Group VIII: ACC caused by specific teratogens: scalp (methimazole), any area (varicella, H. simplex)
CLINICAL FEATURES 1. Aplasia cutis of the scalp (aplasia cutis vertices) a. The most common form b. Single or multiple noninflammatory ulcers c. Occurrence at or near the scalp vertex d. Variable in shape and size e. Heals leaving a hairless scar f. Occurrence i. An isolated condition ii. Associated with other congenital abnormalities 2. Aplasia cutis with extracranial symmetrical involvement (a distinctive type of “nonscalp” aplasia cutis congenita) a. Linear lesions with a symmetrical pattern of distribution on the trunk and limbs b. Aplasia cutis with fetus papyraceous: usually associated with in utero death of a monozygotic twin during pregnancy, with or without the presence of a fetus papyraceous (persistence of a mummified dead fetus) c. Other terms i. Truncal aplasia cutis ii. Bilateral abdominal aplasia cutis 3. Associated congenital anomalies a. Craniofacial anomalies i. Microphthalmia ii. Colobomas iii. Myopia 70
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iv. Epibulbar dermoid v. Cleft lip vi. Cleft palate vii. Ear malformations b. CNS malformation i. Hydrocephalus ii. Mental retardation iii. Spastic paralysis c. Ectodermal dysplasia i. Hypoplasia of the teeth ii. Delayed dentition iii. Nail hypoplasia iv. Skin blisters v. Skin hyperpigmentation vi. Cutis marmorata d. Gastrointestinal abnormalities i. Tracheoesophageal fistula/esophageal atresia ii. Omphalocele iii. Gastroschisis iv. Pyloric atresia: especially in association with junctional (atrophicans) type of epidermolysis bullosa v. Ileal atresia vi. Mesenteric herniation vii. Biliary atresia viii. Midgut atresia ix. Intestinal lymphangiectasia e. Musculoskeletal abnormalities i. Arthrogryposis ii. Polydactyly iii. Syndactyly 4. Prognosis a. Scalp lesion (1–3 cm): resolves spontaneously in majority of cases (>85%) b. Prognosis usually determined by underlying anomalies and extent of the lesions
DIAGNOSTIC INVESTIGATIONS 1. Imaging a. Radiography i. Scalp/skull ii. Hands iii. Feet b. CT scan or MRI of the brain 2. Karyotyping to detect chromosome abnormality 3. Histology: heterogeneous appearance of lesions a. Ulcerated lesions at birth i. Complete absence of all layers of skin ii. Occasionally extending to the bone or dura b. In utero healing of some lesions c. Healed lesions i. Flattened epidermis ii. Proliferation of fibroblasts in a loose connective tissue stroma iii. Newly formed capillaries iv. Complete absence of adnexal structures 4. Culture/serology a. Varicella zoster b. H. simplex virus
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5. Amniotic fluid findings in some cases a. Elevated amniotic fluid AFP levels b. Positive acetylcholinesterase
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal dominant: not increased unless a parent is affected ii. Autosomal recessive: 25% b. Patient’s offspring i. Autosomal dominant: 50% ii. Autosomal recessive: not increased unless the spouse is a carrier 2. Prenatal diagnosis a. Ultrasonography for at risk family with aplasia cutis congenita associated with epidermolysis bullosa and pyloric atresia i. Hydramnios ii. A dilated stomach iii. A deformed external ear iv. A contracted fisted hand b. Amniocentesis for associated chromosomal abnormality 3. Management a. Careful and standard wound treatment for small defects involving only epidermis: usually uneventful healing of the lesion b. Control of infection c. Control of electrolyte abnormalities, especially with larger wounds d. Requires a scalp flap for most lesions e. A split-thickness skin grafting or full-thickness pedicle grafts (for defects of the scalp extending to the dura mater) f. Reconstruction of skull and scalp for a large lesion involving scalp, skull, and dura g. Emergency intervention to control life-threatening hemorrhage h. Surgical intervention also useful later in life for revision of scars and correction of alopecia with rotation flaps, simple excision and closure, scalp reduction techniques, or local hair transplantation i. Management of associated anomalies
REFERENCES Achiron R, Hamel-Pinchas O, Engelberg S, et al.: Aplasia cutis congenita associated with Epidermolysis bullosa and pyloric atresia: the diagnostic role of prenatal ultrasonography. Prenat Diagn 12:765–771, 1992. Al-Sawan RMZ, Soni AL, Al-Kobrosly AM, et al.: Truncal aplasia cutis congenita associated with ileal atresia and mesenteric defect. Pediatr Dermatol 16:408–409, 1999. Argenta LC, Dingman RO: Total reconstruction of aplasia cutis congenita involving scalp, skull, and dura. Plast Reconstr Surg 77:650–653, 1986. Boente MC, Frontini MV, Acosta MI, et al.: Extensive symmetric truncal aplasia cutis congenita without fetus papyraceous or macroscopic evidence of placental abnormalities. Prenat Diagn 12:228–230, 1995. Cambiaghi S, Gelmetti C, Nicolini U: Prenatal findings in membranous aplasia cutis. J Am Acad Dermatol 39:638–640, 1998. Cambiaghi S, Schiera A, Tasin L, et al.: Aplasia cutis congenita in surviving cotwins: four unrelated cases. Pediatr Dermatol 18:511–515, 2001.
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Carmi R, Sfer S, Karplus M, et al.: Aplasia cutis congenita in two sibs discordant for pyloric atresia. Am J Med Genet 11:319–329, 1982. Chitnis MR, Carachi R, Galea P. Familial aplasia cutis congenita. Eur J Pediatr Surg 35:100–101, 1996. Classen DA: Aplasia cutis congenita associated with fetus papyraceous. Cutis 64:104–106, 1999. Cowton JAL, Beattie TJ, Gibson AAM, et al.: Epidermolysis bullosa in association with aplasia cutis congenita and pyloric atresia. Acta Paediatr Scand 71:155–160, 1982. Cordon M: Extrait d’une lettre au sujet de trois enfants de la même mère né avec partie des extrémités denuée de peau. J Med Chir Pharm 26:556–557, 1767. De Groot WG, Postuma R, Hunter AGW: Familial pyloric atresia associated with epidermolysis bullosa. J Pediatr 92:429–431, 1978. Demmel U: Clinical aspects of congenital skin defects. I. Congenital skin defects on the head of the newborn. II. Congenital skin defects on the trunk and extremities of the newborn. III. Causal and formal genesis of congenital skin defects of the newborn. Eur J Pediatr 121:21–50, 1975. Dror Y, Gelman-Kohan Z, Hagai Z, et al.: Aplasia cutis congenita, elevated alpha-fetoprotein, and a distinct amniotic fluid acetylcholinesterase electrophoretic band. Am J Perinatol 11:149–152, 1994. Evers MEJW, Steijlen PM, Hamel BCJ: Aplasia cutis congenita and associated disorders: an update. Clin Genet 47:295–301, 1995. Farine D, Maidman J, Rubin S, et al.: Elevated α-fetoprotein in pregnancy complicated by aplasia cutis after exposure to methimazole. Obstet Gynecol 35:996–997, 1988. Fisher M, Schneider R: Aplasia cutis congenita in three successive generations. Arch Dermatol 108:252–253, 1973.
Fonseca W, Alencar Am J Cardiol, Pereira RMM, et al.: Congenital malformation of the scalp and cranium after failed first trimester abortion attempt with Misoprostol. Clin Dysmorphol 2:76–80, 1993. Frieden U: Aplasia cutis congenita: a clinical review and proposal for classification. J Am Acad Dermatol 14:646–660, 1986. Gerber M, de Veciana M, Towers CV, et al.: Aplasia cutis congenita: a rare cause of elevated alpha-fetoprotein levels. Am J Obstet Gynecol 172:1040-1041, 1995. Irons GB, Olson RM: Aplasia cutis congenita. Plast Reconstr Surg 66:199–203, 1980. Joshi RK, Majeed-Saidan MA, Abanmi A, et al.: Aplasia cutis congenita with fetus papyraceous. J Am Acad Dermatol 25:1083–1085, 1991. Kelly BJ, Samolitis NJ, Xie DL, et al.: Aplasia cutis congenita of the trunk with fetus papyraceus. Pediatr Dermatol 19:326–329, 2002. Kosnik EJ, Sayers MP: Congenital scalp defects: aplasia cutis congenita. J Neurosurg 42:32–36, 1975. Lane W, Zanol K: Duodenal atresia, biliary atresia, and intestinal infarct in truncal aplasia cutis congenita. Pediatr Dermatol 17:290–292, 2000. Mannino FL, Lyons Jones K, Benirschke K: Congenital skin defects and fetus papyraceous. J Pediatr 91:559–564, 1977. McCray MK, Roenigk HH: Scalp reduction for correction of cutis aplasia congenita. J Dermatol Surg Oncol 7:655–658, 1981. Sybert VP: Aplasia cutis congenita: a report of 12 new families and review of the literature. Pediatr Dermatol 3:1–4, 1985. Vogt T, Stolz W, Landthaler M: Aplasia cutis congenita after exposure to methimazole: a causal relationship? Br J Dermatol 133:994–996, 1995.
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Fig. 1. An infant with aplasia cutis congenita with epidermolysis bullosa showing lesions on the face, trunk, and extremities.
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Arthrogryposis Multiplex Congenita Arthrogryposis multiplex congenita comprises nonprogressive conditions characterized by multiple joint contractures throughout the body at birth. The term encompasses a very heterogeneous group of disorders having the common feature of multiple congenital joint contractures. The frequency is approximately 1 in 3000 live births.
a) Multiple births b) Uterine structural abnormalities such as bicornuate uterus c) Umbilical cord wrapping d) Oligohydramnios in renal agenesis e) Early persistent leakage of amniotic fluid v. Intrauterine vascular compromise resulting in loss of nerve and muscle function with development of fetal akinesia and secondary joint contractures. Examples include: a) Severe maternal bleeding during pregnancy b) Failed attempts at termination of pregnancy c. Fetal akinesia due to maternal disorders. Examples include: i. Infections a) Rubella b) Poliomyelitis ii. Drugs/chemicals a) Methocarbamol b) Alcohol c) Carbon monoxide poisoning iii. Trauma iv. Vitamin deficiency v. Hyperthermia (e.g., prolonged sauna) vi. Radiation vii. Other maternal illnesses a) Maternal autoantibodies b) Diabetes mellitus c) Myotonic dystrophy d) Maternal multiple sclerosis 2. Pathophysiology a. Joint development i. Almost always normal during early embryogenesis ii. Fetal motion essential for normal development of joints and their contiguous structures b. Lack of fetal movement i. Causing extra connective tissue to develop around the joint ii. Resulting in fixation of the joint iii. Limiting movement further aggravates the joint contracture iv. Contractures secondary to fetal akinesia: more severe in patients who are diagnosed early in pregnancy and who experience akinesia for longer periods of time during gestation
GENETICS/BASIC DEFECTS 1. Major causes a. Arthrogryposis as a physical sign observed in many specific clinical conditions i. Single gene defects ii. Chromosomal abnormalities iii. Known or unknown syndromes or conditions iv. Environmental effects b. Fetal akinesia due to fetal abnormalities i. Neurogenic abnormalities: the most common cause of arthrogryposis a) Meningomyelocele b) Anencephaly c) Hydranencephaly d) Holoprosencephaly e) Spinal muscular atrophy f) Cerebrooculofacial-skeletal syndrome g) Marden-Walker syndrome ii. Muscular abnormalities: relatively rare causes of arthrogryposis a) Congenital muscular dystrophies b) Congenital myopathies c) Intrauterine myositis d) Mitochondrial disorders iii. Connective tissue abnormalities in tendon, bone, joint, or joint lining restricting fetal movements, resulting in congenital contractures. Examples include: a) Synostosis b) Lack of joint development c) Aberrant fixation of joints (as in diastrophic dysplasia and metatropic dwarfism) d) Aberrant laxity of joints with dislocations (as in Larsen syndrome) e) Aberrant soft tissue fixations (as in popliteal pterygium syndrome) f) Failure of normally developed tendon to attach to the appropriate place around the joint or bone in some forms of distal arthrogryposis, resulting in abnormal lack of movement of the joints with secondary contractures at birth iv. Mechanical limitations to movement. Limited space for fetal movement inside the uterus may contribute to development of contractures. Examples include:
CLINICAL FEATURES 1. Family history a. Presence of congenital contractures in the family i. Affected siblings ii. Other affected family members 74
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b. Marked intrafamilial variability i. Mildly affected parent ii. A parent with contractures early in infancy c. Consanguinity i. Increasing the chance that the parents will both carry the same disease gene ii. Observed more frequently in families with rare recessive diseases than in those with common recessive diseases d. Increased parental age i. Some chromosomal abnormalities: increasing dramatically with advanced maternal age ii. Single-gene dominant mutations: increasing with advanced paternal age e. History of previous miscarriages or stillbirths 2. Pregnancy history a. Diminished fetal movement b. Infants born to mothers affected with the following disorders: i. Myotonic dystrophy: a child who inherits the gene and is severely affected with resistant contractures ii. Myasthenia gravis and multiple sclerosis: children may be born with congenital contractures c. Maternal infections leading to CNS or peripheral nerve destruction with secondary congenital contractures i. Rubella ii. Rubeola iii. Coxsackievirus iv. Enterovirus v. Akabane d. Maternal fever or hyperthermia causing contractures due to abnormal nerve growth or migration e. Exposure to teratogens leading to decreased fetal movement i. Drugs ii. Alcohol iii. Curare iv. Methocarbamol v. Phenytoin vi. Radiation f. Amniotic fluid volume i. Oligohydramnios: causes fetal constraint and secondary deformational contractures ii. Polyhydramnios: indicating fetal compromise g. Uterine abnormalities i. Bicornuate uterus with a septum ii. Uterine fibroid h. Other maternal complications i. Toxemia ii. Severe hypotension at critical time iii. Severe hypoxia (e.g., carbon monoxide poisoning) during pregnancy iv. Abnormal fetal lies v. Threatened abortion vi. Attempted termination vii. Trauma such as trauma to the abdomen 3. Delivery history a. Breech or transverse fetal position
i. ii. iii. iv.
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Relatively common Usually normal length of gestation Induction of labor often prolonged Fracture of a limb during traumatic delivery in 5–10% of cases b. Abnormal placenta, membranes, or cord insertion in case of amniotic bands or vascular compromise. The umbilical cord may be shortened or wrapped around a limb, leading to compression c. Prematurity d. Multiple births or twins i. Lack of movement due to uterine crowding ii. The death of one twin may lead to vascular compromise in the remaining twin 4. Common physical characteristics a. Involved extremities i. Fusiform or cylindrical in shape ii. Thin subcutaneous tissue iii. Absence of skin creases b. Deformities i. Usually symmetric ii. Severity increasing distally iii. Hands and feet typically being the most deformed c. Joint rigidity d. Associated joint dislocations, especially the hips and, occasionally, the knees e. Muscles i. Atrophy ii. Absence f. Sensation i. Usually intact ii. Diminished or absent deep tendon reflexes 5. Contractures a. Distal joints affected more frequently than proximal joints b. Types of contractures i. Flexion vs extension ii. Limitation of movement (fixed vs passive vs active) iii. Complete fusion vs ankylosis and soft-tissue contracture c. Intrinsically derived contractures i. Frequently associated with polyhydramnios ii. Symmetric contractures iii. Accompanied by taut skin iv. Pterygia across joints v. Lack of flexion creases vi. Recurrence risk and prognosis dependent on etiology d. Extrinsically derived contractures i. Associated with positional limb anomalies, large ears, loose skin, and normal or exaggerated flexion creases ii. Excellent prognosis iii. A low recurrence risk 6. Deformities a. Limb deformities i. Pterygium (webbing) ii. Shortening
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iii. Amniotic bands iv. Compression (e.g., due to cord wrapping) v. Absent patella vi. Dislocated radial heads vii. Dimples b. Face deformities i. Asymmetry ii. Flat nasal bridge iii. Hemangioma iv. Jaw deformities including micrognathia and trismus c. Other deformities i. Scoliosis ii. Genital deformities a) Cryptorchidism b) Microphallus c) Lack of labia iii. Hernias a) Inguinal b) Umbilical d. Other features of the fetal akinesia sequence i. Intrauterine growth retardation ii. Pulmonary hypoplasia iii. Craniofacial anomalies a) Hypertelorism b) Cleft palate c) Depressed nasal tip d) High nasal bridge iv. Functional short gut with feeding problems v. Short umbilical cord e. Absent or distorted crease abnormalities resulting from aberrant form or function in early hand or foot development 7. Malformations a. Craniofacial malformations i. CNS a) Structural malformations b) Seizures c) Mental retardation ii. Skull a) Craniosynostosis b) Asymmetry c) Microencephaly iii. Eyes a) Small and malformed eyes b) Corneal opacities c) Ptosis d) Strabismus iv. Palate a) High-arched b) Cleft c) Submucous cleft b. Respiratory problems affecting lung function i. Tracheal and laryngeal clefts and stenosis ii. Hypoplasia or weak muscles of diaphragm c. Limb malformations i. Reduction anomalies ii. Radioulnar synostosis iii. Syndactyly iv. Shortened digits
d. Skin/vasculature abnormalities i. Hemangiomas and cutis marmorata ii. Cold and blue distal limbs e. Cardiac problems i. Congenital heart defects ii. Cardiomyopathy f. Urogenital structural anomalies i. Kidneys ii. Ureters iii. Bladder g. Nervous system problems i. Loss of vigor ii. Lethargy iii. Slow, fast, or absent deep tendon reflexes iv. Sensory deficits h. Muscle malformations i. Decreased muscle mass ii. Soft muscle texture iii. Fibrous bands iv. Abnormal tendon attachments v. Muscle changing with time 8. Connective tissue abnormalities a. Skin webs (pterygia) across joints with limitation of movement b. Skin dimples observed frequently over joints where movement is limited c. Soft, doughy, thick, or extensible skin d. Decreased or increased subcutaneous fat e. Inguinal, umbilical, or diaphragmatic hernias f. Thickness in joints g. Symphalangism h. Abnormalities in tendon attachment and length i. Associated skin defects including scalp defects, amniotic bands on limbs, and nail defects 9. Disorders with mainly limb involvement a. Amyoplasia i. The most common type of arthrogryposis seen in clinical practice and constitutes about one-third of cases ii. Incidence: about 1 in 10,000 live births iii. A sporadic condition, not observed in siblings or offspring (recurrence risk not increased) iv. Characterized by typical and symmetric positioning of the limbs v. Internally rotated and adducted shoulders vi. Fixed extended elbows vii. Pronated forearms viii. Flexed wrists and fingers ix. A severe talipes equinovarus deformity x. Muscles: hypoplastic and usually replaced by fibrous and fatty tissue xi. Normal intelligence b. Distal arthrogryposes i. Type I: an autosomal dominant disorder characterized by medially overlapping fingers, tightly clenched fists at birth, ulnar deviation of fingers and camptodactyly in adults, and positional foot contractures. Intelligence is usually normal
ARTHROGRYPOSIS MULTIPLEX CONGENITA
ii. Type II (Freeman-Sheldon syndrome, also known as whistling face syndrome): an autosomal dominant disorder characterized by a masklike face with a small mouth, giving a whistling face appearance, deep-set eyes, small nose with a broad nasal bridge, epicanthal folds, strabismus, high arched palate, small tongue, an H-shaped cutaneous dimpling on the chin, flexion of fingers, equinovarus feet with contracted toes, and kyphoscoliosis iii. Type III (Gordon syndrome): characterized by short stature (90%), cleft palate, bifid uvula, epicanthal folds, congenital ptosis, short neck, and camptodactyly iv. Type IV (scoliosis) v. Type V (ophthalmoplegia, ptosis) vi. Type VI (sensorineural hearing loss) vii. Type VII (trismus pseudocamptodactyly) viii. Type VIII (autosomal dominant multiple pterygium syndrome) ix. Type IX (congenital contractural arachnodactyly): an autosomal dominant disorder characterized by joint contractures, a long, thin body builds, crumpling ears but lacking cardiovascular and ocular abnormalities of Marfan syndrome c. Bony fusion likely to be confused with arthrogryposis i. Symphalangism (e.g., fusion of phalanges) ii. Coalition (e.g., fusion of the carpals and tarsal bones) iii. Synostosis (e.g., fusion of long bones) d. Other associated syndromes and conditions i. Absence of dermal ridges ii. Absence of distal interphalangeal joint (DIP) creases iii. Amniotic bands iv. Antecubital webbing v. Camptodactyly vi. Congenital clapsed thumbs vii. Familial impaired pronation and supination of forearm viii. Humeroradial synostosis ix. Liebenberg syndrome x. Nail-patella syndrome xi. Nievergelt-Pearlman syndrome xii. Poland anomaly xiii. Radioulnar synostosis xiv. Tel-Hashomer camptodactyly 10. Disorders with involvement of limbs and other body parts a. Multiple pterygium syndrome i. Autosomal recessive type: characterized by multiple joint contractures with marked pterygia, dysmorphic facies (flat, sad, motionless facial appearance), and cervical vertebral anomalies ii. Autosomal dominant type: characterized by multiple pterygia with or without mental retardation b. Multiple pterygium syndrome (pterygia with flexion contractures) associated with scoliosis, cleft palate, and malignant hyperthermia
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c. Multiple pterygium syndrome, Escobar type i. Webbing of the neck that increases with age ii. Webbing of the knees and elbows that develops before adolescence iii. Multiple joint contractures iv. Lumbar lordosis d. Lethal multiple pterygium syndrome i. An autosomal recessive disorder ii. Early lethality iii. Hydrops fetalis iv. Cystic hygroma v. Dysmorphic facies (hypertelorism, markedly flattened nasal bridge with hypoplastic nasal alae, cleft palate, micrognathia, low-set ears) vi. Marked webbing and flexion contractures of multiple joints vii. Short neck viii. Small chest ix. Hypoplastic lungs e. Popliteal pterygium syndrome i. An autosomal dominant disorder ii. Popliteal webs iii. Cleft lip or palate iv. Webs in the mouth v. Unusual nails f. Lethal popliteal pterygium syndrome (BartsocasPapas syndrome) i. An autosomal recessive disorder ii. Severe webs across the knee iii. Associated with facial clefting and fused digits (synostosis of the hand and foot bones) in the newborn period iv. Usually lethal g. Osteochondrodysplasias known to be associated congenital contractures i. Camptomelic dysplasia ii. Conradi-Hünermann (chrondrodysplasia punctata) iii. Diastrophic dysplasia iv. Focal femoral dysplasia v. Geleophysic syndrome vi. Kniest dysplasia vii. Metaphyseal dysplasia, Jansen type viii. Metatropic dysplasia ix. Larsen dysplasia x. Nail-patella syndrome xi. Oculodentodigital syndrome xii. Orocraniodigital syndrome xiii. Osteogenesis imperfecta type II xiv. Otopalatodigital syndrome xv. Parastremmatic dysplasia xvi. Perinatal lethal osteogenesis imperfecta xvii. Pfeiffer syndrome xviii. Saul-Wilson syndrome xix. Synspondylism xx. Spondyloepiphyseal dysplasia congenita xxi. Otospondylometaepiphyseal dysplasia h. Other associated syndromes and conditions i. Hand-muscle wasting and sensorineural deafness ii. Holt-Oram syndrome
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iii. iv. v. vi. vii. viii. ix.
Kuskokwim syndrome Leprechaunism Megalocornea with multiple skeletal anomalies Möbius syndrome Nemaline myopathy Ophthalmomandibulomelic dysplasia Prader-Willi habitus/osteoporosis/hand contractures x. Pseudothalidomide syndrome xi. Puretic-Murray syndrome xii. Sacral agenesis xiii. Schwartz-Jampel syndrome xiv. Sturge-Weber syndrome xv. Tuberous sclerosis xvi. VATER (vertebral defects, imperforate anus, tracheoesophageal fistula, radial and renal dysplasia) complex xvii. Weaver syndrome xviii. Winchester syndrome xix. X-trapezoidocephaly with midfacial hypoplasia and cartilage abnormalities 11. Disorders with limb involvement and CNS dysfunction a. Associated chromosome abnormalities i. Sex chromosome anomalies (45,X, 47,XXY/ 48,XXXY, 49,XXXXX, 49,XXXXY) ii. Autosomal trisomies (4p, 8, 8 mosaicism, 9, 9q, 10p, 10q, 11q, 13, 14, 15, 18, 21) iii. Other chromosome anomalies b. Cerebro-oculofacio-skeletal syndrome i. A common lethal condition ii. Contractures iii. Brain anomalies iv. Dysmyelination v. Microphthalmia vi. Cataracts vii. Renal anomalies viii. Other visceral anomalies c. Neu-Laxova syndrome i. A lethal autosomal recessive disorder ii. Dramatic contractures iii. Intrauterine growth retardation iv. Microcephaly v. Open eyes vi. Tight ichthyotic skin vii. Severe CNS anomalies d. Restrictive dermopathy i. A lethal autosomal recessive disorder ii. Contractures and failure of fetal skin to grow normally restricting fetal movement and leading to secondary contractures e. Pena-Shokeir phenotype: Phenotype is caused by fetal akinesia rather than a specific syndrome i. Short, fixed limbs ii. Pulmonary hypoplasia iii. Intrauterine growth retardation iv. Polyhydramnios v. Short umbilical cord vi. Unusual craniofacies 12. Other associated syndromes and conditions a. Adducted thumbs b. Bowen-Conradi syndrome
c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. t.
C syndrome Congenital myotonic dystrophy Congenital myasthenia gravis Faciocardiomelic syndrome Fetal alcohol syndrome FG syndrome Marden-Walker syndrome Meckel syndrome Meningomyelocele Mietens-Weber syndrome Miller-Dieker syndrome Neu-Laxova syndrome Neurofibromatosis Popliteal pterygium with facial clefts Potter syndrome Pseudotrisomy 18 Spinal muscular atrophy Syndrome of cloudy cornea, diaphragmatic defects, and distal limb deformities u. Syndrome of craniofacial and brain anomalies and intrauterine growth retardation v. Syndrome of cryptorchidism, chest deformity, and contractures w. Toriello-Bauserman syndrome x. Walker-Warburg syndrome y. X-linked lethal arthrogryposis z. Zellweger syndrome 13. Prognosis a. Poor prognosis for ventilator dependent neonates b. Prenatal factors that potentially predict respiratory insufficiency i. Decreased fetal movements ii. Polyhydramnios iii. Micrognathia iv. Thin ribs v. Decreased fetal movement often resulting in delayed developmental milestones c. Skeletal changes secondary to the original deformities i. Scoliosis ii. Deformed carpal and tarsal bones iii. Under growing of limbs after longstanding contractures iv. External genitalia often abnormal (e.g., cryptorchidism and absent labia majora) because of abnormal hip position d. Intrinsically or extrinsically derived defects i. Extrinsically derived contractures: an excellent prognosis ii. Intrinsically derived contractures: a prognosis dependent on etiology e. Prognosis depending on the condition’s natural history i. Developmental landmarks (attainment of motor, social, and language milestones) ii. Growth of affected limbs iii. Progression of contractures iv. CNS damage (lethal, stable, improving) v. Asymmetry of contractures (improving, worsening) vi. Changes in trunk or limbs vii. Intellectual ability viii. Socialization
ARTHROGRYPOSIS MULTIPLEX CONGENITA
f. Prognosis depending on the patient’s response to therapy i. Spontaneous improvement ii. Response to physical therapy iii. Response to casting iv. Types of surgery at appropriate time v. Development of motor strength proportionate to limb size
DIAGNOSTIC INVESTIGATIONS 1. Lab studies a. Laboratory tests, in general, are not useful b. Creatine phosphokinase (CPK) levels when the following conditions are present: i. Generalized weakness ii. Doughy or decreased muscle mass iii. Progressive worsening c. Viral cultures for an infectious process (intrauterine growth retardation, eye involvement, and hepatosplenomegaly) d. Immunoglobulin M levels and specific viral titers (e.g., coxsackievirus, enterovirus, and Akabane virus) in the newborn for intrauterine infection e. Maternal antibodies to neurotransmitters in the infant indicating myasthenia gravis f. Cytogenetic study indicated in the following situations: i. Multiple organ or system involvement ii. Presence of CNS abnormalities, such as microcephaly, mental retardation, lethargy, degenerative changes, or eye anomalies iii. Fibroblast chromosome study if lymphocyte chromosomes are normal and the patient has mental retardation without diagnosis g. Nuclear DNA mutation analysis to identify certain disorders, such as spinal muscular dystrophy h. Mitochondrial mutation analysis to identify certain disorders, such as mitochondrial myopathy 2. Imaging studies a. Patient’s photographs i. To document the extent of deformities (range of motion and position of arthrogryposis) ii. To assess progress during treatment b. Radiographs to evaluate the following skeletal and joint abnormalities: i. Bony abnormalities (e.g., gracile bones, fusions,and extra or missing carpals and tarsals) ii. Disproportionately short stature (i.e., skeletal dysplasias) iii. Scoliosis iv. Ankylosis v. Absence of patella vi. Humeroradial synostosis c. Ultrasonography i. To evaluate the CNS and other viscera for anomalies ii. To establish potential muscle tissue d. CT scan to evaluate the CNS and the muscle mass e. MRI to evaluate muscle mass obscured by contractures f. Ophthalmological evaluation for opacity and retinal degeneration
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3. Histologic studies a. Neurogenic types i. Muscle fiber type predominance or disproportion is the most common neurogenic abnormality in arthrogryposis (26%). These are nonspecific alterations ii. Dysgenesis of the motor nuclei of the spinal cord and brainstem causes the replacement of fasciculi of muscle fibers by small muscle fibers and adipose tissue. Examples include Pierre-Robin syndrome and Möbius syndrome iii. Dysgenesis of the CNS: the second most common neurogenic abnormality in arthrogryposis (23%), with disorganization and decrease in neurons of the cortex and motor nuclei of the brainstem and spinal cord. Clinical syndromes with this abnormality include trisomy 18, partial deletion of the long arm of chromosome 18 syndrome, and Zellweger syndrome iv. Dysgenesis of the anterior horn, another common neurogenic abnormality in arthrogryposis v. Spinal muscular atrophy (e.g., WerdnigHoffmann disease): another neurogenic abnormality in arthrogryposis b. Myopathic types i. Central core disease: a form of arthrogryposis in which the central portion of each muscle fiber contains a zone in which oxidative enzyme activity is absent ii. Nemaline myopathy indicated by abnormal threadlike structures in muscle cells. In type I nemaline myopathy, nemaline rods are present. In type II, the number of fibers with central nuclei is increased iii. Congenital muscular dystrophy indicated by muscle fibers that demonstrate a rounded configuration and conspicuous variation in diameter. Perimysial and endomysial connective tissues are increased markedly iv. Mitochondrial cytopathy indicated by numerous ragged-red fibers on muscle biopsy. It is associated with CNS abnormalities consistent with mitochondrial disease v. Myoneural junction abnormality (e.g., congenital myasthenia gravis): another myopathic type of arthrogryposis 4. Procedures a. Skin biopsy for culture of fibroblasts to be used for chromosome analysis and metabolic studies b. Muscle biopsy i. Probably the most important diagnostic procedure. It should be included in all autopsies and at time of surgery ii. Distinguish myopathic from neuropathic conditions by obtaining muscle specimens from normal and affected areas iii. Special histopathologic and electron micrographic studies to evaluate fatty and connective tissue replacement of muscle fibers and variations in fiber size, such as decreased fiber diameter. All are nonspecific signs of muscle atrophy
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c. Electromyography (EMG) in normal and affected areas useful in differentiating neurogenic and myopathic causes d. Nerve conduction tests to measure conduction velocities in motor and sensory nerves. These should be performed when a peripheral neuropathy is suspected e. An autopsy to investigate the following: i. CNS (i.e., brain neuropathology) ii. Spinal cord (number and size of anterior horn cells, presence or absence of tracts at various levels) iii. Ganglia and peripheral nerves iv. Eye (i.e., neuropathology) v. Muscle tissue from different muscle groups (i.e., electron microscopy and special stains) vi. Fibrous bands replacing muscle vii. Tendon attachments viii. Other visceral anomalies, malformations, deformations, and disruptions
GENETIC COUNSELING 1. Recurrence risk: Recurrence risk depends on whether the contractures are extrinsically or intrinsically derived. Extrinsically derived contractures have a low recurrence risk, while the recurrence risk for intrinsically derived contractures depends on etiology. Arthrogryposis may be inherited in the following ways with different recurrence risks: a. Patient’s sib i. Autosomal recessive: 25% ii. Autosomal dominant: not increased unless a parent is affected or having gonadal mosaicism iii. X-linked recessive: 50% of male sibs affected if the mother is a carrier b. Patient’s offspring i. Autosomal recessive: not increased unless the spouse is also a carrier ii. Autosomal dominant: 50% iii. X-linked recessive: All daughters of affected males will be carriers. All sons of an affected male will be normal c. Multifactorial: Combined effects of multiple genes and environmental factors cause multifactorial traits. For most multifactorial diseases, empirical risks (risks based on direct observation of data) have been derived. For example, empirical recurrence risks of neural tube defects for siblings of an affected individual range from 2 to 5% in most populations d. Mitochondrial: A small but significant number of diseases are caused by mitochondrial mutations. Because of the unique properties of mitochondria, these diseases display characteristic modes of inheritance (i.e., inherited exclusively through the maternal line) with wide phenotypic variability. Only females can transmit the disease mutation to their offspring (e.g., distal type IIB arthrogryposis) e. Sporadic: For those families in which a specific diagnosis cannot be made, the empiric recurrence risk to unaffected parents of an affected child, or to the affected individual with arthrogryposis, is about 3–5%
2. Prenatal diagnosis a. Prenatal ultrasonography to detect the following: i. Diminished fetal movement (main manifestation shared by various conditions with congenital contractures) ii. Joint contractures (bilateral fixed flexion deformities of the hands, elbows, shoulders, hips, and knees, or talipes) iii. Detection of subcutaneous edema (fetal hydrops) iv. Cystic hygroma v. Increased nuchal translucency vi. Abnormal fetal lie vii. Polyhydramnios or oligohydramnios viii. Other associated anomalies (e.g., distended bladder in early urethral obstruction sequence; microcephaly, hydrocephaly, or hydranencephaly in “cerebral dysgenesis” induced congenital contractures) b. Chromosome analysis by amniocentesis or CVS for chromosome disorders c. Molecular genetic analysis for certain genetic disorders with demonstrable mutations 3. Management a. No completely successful approach to treatment b. Overall goals i. Proper alignment of the lower limbs ii. Upper limb function for self-care c. Early vigorous physical therapy to stretch contractures i. To improve joint motion ii. To avoid muscle atrophy iii. Excellent functional outcome in patients with amyoplasia or distal arthrogryposis iv. May be harmful in diastrophic dysplasia because it may lead to joint ankylosis v. Frequent recurrence of deformities following stretching, often requires surgery d. Splinting combined with physical therapy i. Preferable to continuous casting ii. Night splinting after surgical procedures indicated to maintain increased range of motion e. Feeding assistance and intubation needed in patients with severe trismus f. Specific joint problems i. Should be addressed with regard to treatment of other joints and the goals for the patient ii. Early soft-tissue surgery with osteotomies when the growth is completed iii. Tenotomies accompanied by capsulotomies in soft-tissue release procedures iv. Long-term bracing and assistive devices usually needed g. Feet i. A rigid talipes equinovarus deformity: the most common deformity ii. Goal of treatment: a plantigrade, braceable foot h. Knees i. Goal of treatment: an extended knee for ambulation ii. Flexion knee deformities more common than fixed knee deformities and more resistant to treatment
ARTHROGRYPOSIS MULTIPLEX CONGENITA
i. Hips i. Hip surgery follows foot and knee surgery, especially in the presence of knee extension deformities ii. Hip surgery in patients younger than 1 year to facilitate ambulation. In some patients with bilateral hip dislocations and extremely mobile hips, open reduction may be attempted j. Upper extremities i. Treatment involves development of self-help skills (e.g., feeding and toileting) and mobility skills (e.g., pushing out of chair and using crutches) ii. Consider overall function of the entire extremity rather than function of the individual joints in evaluating the upper extremities iii. Consider upper extremity surgery until the patient is older than 5–6 years k. Elbows i. Goals: passive or active flexion capability (feeding arm) and extension capability (toilet arm) ii. Achieve elbow mobility before correcting a wrist deformity because the elbow is crucial to hand function l. Wrists i. Stretching and splinting for the major wrist deformity (flexion with ulnar deviation) ii. Proximal row carpectomy with or without fusion for a severe deformity m. Fingers i. Passive stretching and splinting for minimal to moderate flexion deformities ii. Soft-tissue releases with proximal interphalangeal joint fusions for more severe deformities iii. Thumb-in-palm deformity to be corrected to provide opposition-improved grasp n. Spine i. The spine affected in about one-third of patients ii. Scoliosis beginning early and progressing to become a long, severe, rigid, C-shaped curve. This curve responds poorly to orthoses, as it is progressive iii. Curves greater than 35°: treated with spinal fusion and instrumentation o. Complications i. Anesthesia: difficult to administer because vascular access often is restricted ii. Intubation: posing problems for patients with a small underdeveloped jaw, limited movement of the temporomandibular joint, or a narrow airway iii. Osseous hypoplasia associated with decreased mechanical use in developing bone: prone to fracture at multiple sites. Multiple perinatal fractures have been observed in osteopenic bones p. Physical activity i. Limited, because of existing orthopedic problems ii. As a group, patients cope well socially and participate in social activities corresponding to their needs
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iii. More restricted walking in patients with flexion contractures of the lower extremities than in those with extension contractures. Flexion contractures of the hips severely impair walking ability iv. Contracture of the elbow causing a significant degree of disability in hand function v. Impossible to use crutches in patients with upper extremity involvement associated with severe spinal deformity vi. Dependent on help from other people to a higher degree in patients with more severe joint involvement than those with less severe joint involvement vii. Independent living with productive lives for most children with normal intelligence despite severe handicaps. However, many remain partially dependent on others, such as parents, relatives, and government subsidy. Dependency is related more closely to personality, education, and overall coping skills than to the degree of physical deformity viii. Good family support, a proper educational environment, and promotion of independence at an early age: required to achieve maximal function in addition to appropriate surgical correction
REFERENCES Axt MW, Niethard FU, Doderlein L, et al.: Principles of treatment of the upper extremity in arthrogryposis multiplex congenita type I. J Pediatr Orthop [Br] 6:179–185, 1997. Bamshed M, Jorde LB, Carey JC: A revised and extended classification of the distal arthrogryposes. Am J Med Genet 65:277–281, 1996. Banker BQ: Neuropathologic aspects of arthrogryposis multiplex congenita. Clin Orthop 194:30–43, 1985. Banker BQ: Arthrogryposis multiplex congenita: spectrum of pathologic changes. Hum Pathol 17:656–672, 1986. Baty BJ, Cubberley D, Morris C, et al.: Prenatal diagnosis of distal arthrogryposis. Am J Med Genet 29:501–510, 1988. Bayne LG: Hand assessment and management of arthrogryposis multiplex congenita. Clin Orthop 194:68–73, 1985. Bendon R, Dignan P, Siddiqi T: Prenatal diagnosis of arthrogryposis multiplex congenita. J Pediatr 111:942–947, 1987. Bennett JB, Hansen PE, Granberry WM, et al.: Surgical management of arthrogryposis in the upper extremity. J Pediatr Orthop 5:281–286, 1985. Bianchi DW, Van Marter LJ: An approach to ventilator-dependent neonates with arthrogryposis. Pediatrics 94:682–686, 1994. Carlson WO, Speck GJ, Vicari V, et al.: Arthrogryposis multiplex congenita. A long-term follow-up study. Clin Orthop 194:115–123, 1985. Chen H: Arthrogryposis. eMedicine J 2001. www.emedicine.com Chen H, Chang CH, Misra RP, et al.: Multiple pterygium syndrome. Am J Med Genet 7:91–102, 1980. Chen H, Blumberg B, Immken L: The Pena-Shokeir syndrome: report of five cases and further delineation of the syndrome. Am J Med Genet 16:213–224, 1983. Chen H, Immken L, Lachman R, et al.: Syndrome of multiple pterygia, camptodactyly, facial anomalies, hypoplastic lungs and heart, cystic hygroma, and skeletal anomalies: delineation of a new entity and review of lethal forms of multiple pterygium syndrome. Am J Med Genet 17:809–826, 1984. Chen H, Blackburn WR, Wertelecki W: Fetal akinesia and multiple perinatal fractures. Am J Med Genet 55:472–477, 1995. Gordon N: Arthrogryposis multiplex congenita. Brain Dev 20:507–511, 1998. Guidera KJ, Drennan JC: Foot and ankle deformities in arthrogryposis multiplex congenita. Clin Orthop 194:93–98, 1985. Hageman G, Willemse J: Arthrogryposis multiplex congenita. Review with comment. Neuropediatrics 14:6–11, 1983.
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Hageman G, Ippel EPF, Beemer FA, et al.: The diagnostic management of newborns with congenital contractures: a nosologic study of 75 cases. Am J Med Genet 30:883–904, 1988. Hahn G: Arthrogryposis. Pediatric review and habilitative aspects. Clin Orthop 194:104–114, 1985. Hall JG: An approach to congenital contractures (arthrogryposis). Pediatr Ann 10:15–26, 1981. Hall JC: An approach to research on congenital contractures. Birth Defects Original Article Series 20(6):8–30, 1984. Hall JG: Craniofacial development in arthrogryposis (congenital contractures). Birth Defects Orig Artic Ser 20:99–111, 1984. Hall JG: Genetic aspects of arthrogryposis. Clin Orthop 194:44–53, 1985. Hahn G: Arthrogryposis. Pediatric review and habilitative aspects. Clin Orthop 194:104–114, 1985. Hall JG: In utero movement and use of limbs are necessary for normal growth: a study of individuals with arthrogryposis. Prog Clin Biol Res 200:155–162, 1985. Hall JG: Diagnostic approaches and prognosis in arthrogryposis (congenital contractures). Pathologica 78:701–708, 1986. Hall JG: Arthrogryposis. Am Fam Physician 39:113–119, 1989. Hall JG: Arthrogryposes (multiple congenital contractures). In: Principles and Practice of Medical Genetics. 1990, II 989–1035. Hall JG: Arthrogryposis associated with unsuccessful attempts at termination of pregnancy. Am J Med Genet 63:293–300, 1996. Hall JG: Arthrogryposis multiplex congenita: etiology, genetics, classification, diagnostic approach, and general aspects. J Pediatr Orthop B6:159–166, 1997. Hall JG, Truog WE, Plowman DL: A new arthrogryposis syndrome with facial and limb anomalies. Am J Dis Child 129:120–122, 1975. Hall KW, Hammock M: Feeding and toileting devices for a child with arthrogryposis. Am J Occup Ther 33:644–647, 1979. Hall JG, Reed SD, Scott CI, et al.: Three distinct types of X-linked arthrogryposis seen in 6 families. Clin Genet 21:81–97, 1982. Hall JG, Reed SD, Greene G: The distal arthrogryposes: delineation of new entities—review and nosologic discussion. Am J Med Genet 11:185–239, 1982. Hall JG, Reed SD, Driscoll EP: Part I. Amyoplasia: a common, sporadic condition with congenital contractures. Am J Med Genet 15:571–590, 1983. Hall JG, Reed SD, McGillivray BC, et al.: Part II. Amyoplasia: twinning in amyoplasia—a specific type of arthrogryposis with an apparent excess of discordantly affected identical twins. Am J Med Genet 15:591–599, 1983. Huurman WW, Jacobsen ST: The hip in arthrogryposis multiplex congenita. Clin Orthop 194:81–86, 1985.
Letts M: The role of bilateral talectomy in the management of bilateral rigid clubfeet. Am J Orthop 28:106–110, 1999. Madazli R, Tüysüz B, Aksoy F, et al.: Prenatal diagnosis of arthrogryposis multiplex congenita with increased nuchal translucency but without any underlying fetal neurogenic or myogenic pathology. Fetal Diagn Ther 17:29–33, 2002. McCall R, Gates P: Personal communication. 1999. Moerman P, Fryns JP: The fetal akinesia deformation sequence. A fetopathological approach. Genetic Counseling 1:25–33, 1990. Murray C, Fixsen JA: Management of knee deformity in classical arthrogryposis multiplex congenita (amyoplasia congenita). J Pediatr Orthop B6:186–191, 1997. Palmer PM, MacEwen GD, Bowen JR, et al.: Passive motion therapy for infants with arthrogryposis. Clin Orthop 194:54–59, 1985. Porter HJ: Lethal arthrogryposis multiplex congenital (fetal akinesia deformation sequence, FADS). Pediatr Pathol Lab Med 15:617–637, 1995. Sarwark JF, MacEwen GD, Scott CI: Amyoplasia (a common form of arthrogryposis). J Bone Joint Surg 72-A:465–469, 1990. Sells JM, Jaffe KM, Hall JG: Amyoplasia, the most common type of arthrogryposis: the potential for good outcome. Pediatrics 97:225–231, 1996. Shapiro F, Bresnan MJ: Orthopaedic management of childhood neuromuscular disease. Part II. peripheral neuropathies, Friedreich’s ataxia, and arthrogryposis multiplex congenita. J Bone Joint Surg 64-A:949–953, 1982. Södergård J, Hakamies-Blomqvist L, Sainio K, et al.: Arthrogryposis multiplex congenita: perinatal and electromyographic findings, disability, and psychosocial outcome. J Pediatr Orthop B-6:167–171, 1997. St. Clair HS, Zimbler S: A plan of management and treatment results in the arthrogrypotic hip. Clin Orthop 194:74–80, 1985. Staheli LT, Chew DE, Elliott JS: Management of hip dislocations in children with arthrogryposis. J Pediatr Orthop 7:681–685, 1987. Swinyard CA, Bleck EE: The etiology of arthrogryposis (multiple congenital contracture). Clin Orthop Rel Res 194:15–29, 1985. Thomas B, Schopler S, Wood W: The knee in arthrogryposis. Clin Orthop 194:87–92, 1985. Thompson GH, Bilenker RM: Comprehensive management of arthrogryposis multiplex congenita. Clin Orthop 194:6–14, 1985. Verloes A, Mulliez N, Gonzales M, et al.: Restrictive dermopathy, a lethal form of arthrogryposis multiplex with skin and bone dysplasia: Three new cases and review of the literature. Am J Med Genet 43:539–547. 1992. Williams PF: Management of upper limb problems in arthrogryposis. Clin Orthop 194:60–67, 1985.
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Fig. 1. An infant with amyoplasia congenita showing typical, symmetrical positioning of the limbs, internally rotated and adducted shoulders, fixed extended elbows, pronated forearms, flexed wrists and fingers, and severe talipes equinovarus deformity.
Fig. 3. An infant with distal arthrogryposis showing predominantly distal contractures with overlapping finger contractures, ulnar deviation of fingers, and clubfeet.
Fig. 2. Two infants with arthrogryposis multiplex congenita characterized by flexion contractures of the knees and fingers, and equinovarus deformities of the feet.
Asphyxiating Thoracic Dystrophy In 1955, Jeune et al. described familial asphyxiating thoracic dystrophy (ATD) in a pair of siblings with severely narrow thoraxes. This condition is also known as Jeune syndrome. Incidence is estimated at 1 per 100,000–130,000 live births. Jeune syndrome, a potentially lethal congenital dwarfism, is a rare autosomal recessive disorder characterized by typical skeletal dysplasias, such as a narrow thorax and micromelia, with respiratory and renal manifestations. Respiratory manifestations vary widely from respiratory failure and infantile death to a latent phenotype without respiratory symptoms.
7. Limbs a. Variable micromelia and short digits with bulbous terminal phalanges b. Occasional postaxial polydactyly of the hands and feet 8. Eyes: occasional retinal degeneration 9. Occasional intestinal malabsorption 10. Renal failure developing during infancy, early adolescence, or second decade of life 11. Polyuria, polydipsia, and hypertension occur during the second or third year of life 12. Occasional involvement of the liver a. Prolonged neonatal jaundice b. Polycystic liver disease c. Hyperplasia of the bile ducts d. Congenital hepatic cirrhosis 13. Occasional involvement of the heart a. Cardiac failure secondary to increased pulmonary vascular resistance, thoracic constriction, and alveolar hypoplasia b. Possible intrinsic myocardial disease 14. Cystic changes of pancreatic ducts and pancreatic exocrine insufficiency occur in long-term survivors 15. Occasional involvement of the teeth, nails, and other organs 16. Prognosis a. Difficult to predict in each individual case because frequent pulmonary complications and cystic renal lesions are not always directly related to severity of skeletal changes b. The skeletal dysplasia of this entity is compatible with life, though respiratory failure and infections are often fatal during infancy c. Considerable variation in the severity of thoracic constriction: For those patients who survive infancy, the thorax tends to revert to normal with improving respiratory function. This suggests that the lungs have a normal growth potential and the respiratory problems are secondary to restricted rib cage deformity d. Renal failure: Renal involvement is the major prognostic factor in those patients who survive the respiratory insufficiency during infancy e. Short stature in survivors 17. Morbidity and mortality a. Alveolar hypoventilation i. The most common and prominent clinical presentation ii. Caused by impaired chest expansion as a result of short, horizontally placed ribs b. Bilateral microcystic renal disease gradually progressing to tubular atrophy and renal failure
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. The gene for ATD a. Mapped to chromosome 15q13 b. Families with both mild and severe forms of ATD mapped to 15q13 c. Five consanguineous families sharing a 1.2 cm region of homozygosity between D15S165 and D15S1010 d. No pathogenic mutations detected in two candidate genes, GREMLIN and FORMIN, by mutation analysis
CLINICAL FEATURES 1. Wide phenotypic variability 2. Classification of ATD a. Lethal form b. Severe form c. Mild form d. Latent form 3. Short-limbed dwarfism 4. Growth retardation 5. Respiratory distress a. Respiratory distress secondary to a small thorax i. Motionless thorax ii. Abdominal respiration iii. Considerable supraclavicular, suprasternal, and intercostal space retraction on inspiration b. Severe dyspnea and extreme cyanosis in severe cases c. Some infants with only respiratory symptoms in conjunction with infection d. Some individuals lack respiratory symptoms in infancy or childhood 6. Chest deformity of varying degrees a. A long, narrow, and abnormally small thorax with reduced thoracic cage capacity b. Lung hypoplasia and respiratory distress, usually leading to early death c. The symptoms of small thorax usually improves with age for those who survive early childhood
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c. Most patients (approximately 60–70%) dying from respiratory failure in early infancy and early childhood d. Chronic renal failure ensuing in survivors e. Few patients reaching adolescence or adulthood
DIAGNOSTIC INVESTIGATIONS 1. Laboratory studies a. Urinalysis i. Hematuria ii. Proteinuria iii. Defective urine concentrating capacity b. Arterial blood gas (ABG): hypoxia and hypercarbia in room air reflecting severe restrictive lung disease 2. Imaging studies a. Newborn and infant radiography i. Small and bell-shaped thorax with reduced transverse and anterior-posterior diameter ii. Abnormal clavicles (“bicycle handlebar shaped”) iii. Short and horizontally oriented ribs with irregular costochondral junctions and bulbous and irregular anterior ends iv. Abnormal pelvis a) Short squared iliac wings b) Trident appearance of acetabular margin v. Short limbs relative to trunk vi. Variable limb-shortening vii. Short phalanges, metacarpals, or metatarsals with or without polydactyly viii. Premature ossification of the capital femoral epiphyses b. Childhood radiology i. Relatively larger thorax with growth of ribs compared to infancy ii. Short ilium with normal flaring of iliac wings iii. Striking cone-shaped epiphyses and early fusion between the epiphyses and metaphyses of the distal and middle phalanges iv. Short distal and middle phalanges v. Varying shortening of extremities relative to trunk c. Subtypes of ATD i. Type I: irregular metaphyseal ends ii. Type II: smooth metaphyseal ends 3. Pulmonary function test to detect severe restrictive lung disease 4. Histology a. Lungs: Hypoplastic due to a marked reduction in the number of alveolar ducts and alveoli (hypoplasia of alveoli) b. Cartilages: retarded endochondral ossification in both types i. ATD type I: irregular cartilage-bone junction with patchy distribution of physeal growth zone of chondrocytes ii. ATD type II: smooth cartilage bone junctions c. Kidneys i. Cystic renal dysplasia and hypoplasia ii. Nephronophthisis or interstitial nephritis
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a) Diffuse interstitial and periglomerular fibrosis b) Round-cell lymphocytic infiltration c) Hyalinized glomeruli d) Pericapsular thickening e) Thickened basement membrane f) Dilated or atrophic tubules iii. Pyelonephritis with scarring iv. Distortion of renal parenchyma d. Liver i. Periportal hepatic fibrosis ii. Bile duct proliferation iii. Early cirrhosis
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: usually lethal, not surviving to reproductive age 2. Prenatal diagnosis by ultrasonography a. Detection of affected second- and third-trimester fetuses of at-risk families b. Characteristic ultrasonographic findings i. Narrow thorax ii. Short hypoplastic ribs iii. Short tubular bones iv. Renal cystic changes c. Other ultrasonographic findings i. Polyhydramnios ii. Absent or feeble fetal respiratory movements iii. Increased nuchal translucency iv. With or without polydactyly v. Ventriculomegaly vi. A single umbilical artery 3. Management a. Medical care i. Supportive care ii. Mechanical ventilation a) Urgently required in the most severe cases, those when respiratory distress develops immediately after birth b) Less-severe cases gradually progressing to respiratory failure as a result of multiple recurrent pulmonary infections iii. Treat respiratory infections vigorously with antibiotics, endotracheal suctioning, and postural drainage iv. Nasogastric or gastrostomy feedings, if needed v. Ursodeoxycholic acid used to control the progression of the hepatic dysfunction b. Surgical care i. Surgery indicated only in the most severe cases in which failure to intervene will result in progressive pulmonary damage and eventual death. No data are currently available on long-term follow-up care of patients who have been surgically treated ii. Expansion thoracoplasty utilizing various surgical techniques a) Splitting the sternum or the rib cage and maintaining the separation with methacrylate
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b) Rib grafts c) Homologous bone grafts d) Lateral rib cage expansion using staggered superiosteal rib osteotomies and rigid titanium miniplate and screw augmentation and stabilization e) Modified bailey rib approximator to provide a calibrated dynamic separation for the sternum after the primary procedure of midsternotomy and methylmethacrylate sternoplasty iii. Dialysis and renal transplantation indicated for renal failure. Recently, cadaver renal transplantation was successful in a 10-year-old boy with Jeune syndrome type 2 iv. Surgical complications a) Pneumothorax b) Mucous plugging of a bronchus c) Repeated infections d) Progressive herniation of lung through sternal defect e) Cardiac insufficiency
REFERENCES Allen AW, Moon JB, Hovland KR, et al.: Ocular findings in thoracic-pelvicphalangeal dystrophy. Arch Ophthalmol 97:489–492, 1979. Amirou M, Bourdat-Michel G, Pinel N, et al.: Successful renal transplantation in Jeune syndrome type 2. Pediatr Nephrol 12:293, 294, 1998. Aronson DC, Van Nierop JC, Taminiau A, et al.: Homologous bone graft for expansion thoracoplasty in Jeune’s asphyxiating thoracic dystrophy. J Pediatr Surg 34:500–503, 1999. Aurora P, Wallis CE: Jeune syndrome (asphyxiating thoracic dystrophy) associated with Hirschsprung disease. Clin Dysmorphol 8:259–263, 1999. Bard LA, Bard PA, Owens GW, et al.: Retinal involvement in thoracic-pelvicphalangeal dystrophy. Arch Ophthalmol 96:278–281, 1978. Barnes ND, Hull D, Milner AD, et al.: Chest reconstruction in thoracic dystrophy. Arch Dis Child 46:833–837, 1971. Bernstein J, Brough AJ, McAdams AJ: The renal lesion in syndromes of multiple congenital malformations. Cerebrohepatorenal syndrome; Jeune asphyxiating thoracic dystrophy; tuberous sclerosis; Meckel syndrome. Birth Defects Orig Artic Ser 10:35–43, 1974. Borland LM: Anesthesia for children with Jeune’s syndrome (asphyxiating thoracic dystrophy). Anesthesiology 66:86–88, 1987. Chen CP, Lin SP, Liu FF, et al.: Prenatal diagnosis of asphyxiating thoracic dysplasia (Jeune syndrome). Am J Perinatol 13:495–498, 1996. Chen H: Asphyxiating thoracic dystrophy (Jeune syndrome). Emedicine, 2004. http://www.emedicien.com Cortina H, Beltran J, Olague R, et al.: The wide spectrum of the asphyxiating thoracic dysplasia. Pediatr Radiol 8:93–99, 1979. Copeland-Fields LD, Singleton KA, Racela C, et al.: Discharge planning: pediatric case study of Jeune’s asphyxiating thoracic dystrophy. Crit Care Nurse 5:61–70, 1985. Das BB, Nagaraj A, Fayemi A, et al.: Fetal thoracic measurements in prenatal diagnosis of Jeune syndrome. Indian J Pediatr 69:101–103, 2002. Davis JT, Ruberg RL, Leppink DM, et al.: Lateral thoracic expansion for Jeune’s asphyxiating dystrophy: a new approach. Ann Thorac Surg 60:694–696, 1995. den Hollander NS, Robben SG, Hoogeboom AJ, et al.: Early prenatal sonographic diagnosis and follow-up of Jeune syndrome. Ultrasound Obstet Gynecol 18:378–383, 2001. Elçioglu NH, Hall CM: Diagnostic dilemmas in the short rib-polydactyly syndrome group. Am J Med Genet 111:392–400, 2002. Elejalde BR, de Elejalde MM, Pansch D: Prenatal diagnosis of Jeune syndrome. Am J Med Genet 21:433–438, 1985.
Finegold MJ, Katzew H, Genieser NB: Lung structure in thoracic dystrophy. Am J Dis Child 122:153–159, 1971. Friedman JM, Kaplan HG, Hall JG: The Jeune syndrome (asphyxiating thoracic dystrophy) in an adult. Am J Med 59:857–862, 1975. Giorgi PL, Gabrielli O, Bonifazi V, et al.: Mild form of Jeune syndrome in two sisters. Am J Med Genet 35:280–282, 1990. Herdman RC, Langer LO: The thoracic asphyxiant dystrophy and renal disease. Am J Dis Child 116:192–201, 1968. Hsieh YY, Hsu TY, Lee CC, et al.: Prenatal diagnosis of thoracopelvic dysplasia. A case report. J Reprod Med 44:737–740, 1999. Jeune M, Beraud C, Carron R: Dystrophic thoracique asphxiante de caractere familial. Arch Fr Pediatr 12:886–891, 1955. Kaddoura IL, Obeid MY, Mroueh SM, et al.: Dynamic thoracoplasty for asphyxiating thoracic dystrophy. Ann Thorac Surg 72:1755–1758, 2001. Kozlowski K, Masel J: Asphyxiating thoracic dystrophy without respiratory disease: report of two cases of the latent form. Pediatr Radiol 5:30–33, 1976. Labrune P, Fabre M, Trioche P, et al.: Jeune syndrome and liver disease: report of three cases treated with ursodeoxycholic acid. Am J Med Genet 87:324–328, 1999. Langer LO Jr: Thoracic-pelvic-phalangeal dystrophy: asphyxiating thoracic dystrophy of the newborn, infantile thoracic dystrophy. Radiology 91:447–456, 1968. Morgan NV, Bacchelli C, Gissen P, et al.: A locus for asphyxiating thoracic dystrophy, ATD, maps to chromosome 15q13. J Med Genet 40:431–435, 2003. Oberklaid F, Danks DM, Mayne V, et al.: Asphyxiating thoracic dysplasia. Clinical, radiological, and pathological information on 10 patients. Arch Dis Child 52:758–765, 1977. Özçay F, Derbent M, Demirhan B, et al.: A family with Jeune syndrome. Pediatr Nephrol 16:623–626, 2001. Phillips CI, Stokoe NL, Bartholomew RS: Asphyxiating thoracic dystrophy (Jeune’s disease) with retinal aplasia: a sibship of two. J Pediatr Ophthalmol Strabismus 16:279–283, 1979. Pirnar T, Neuhauser EB: Asphyxiating thoracic dystrophy of the newborn. Am J Roentgenol Radium Ther Nucl Med 98:358–364, 1966. Sarimurat N, Elcioglu N, Tekant GT, et al.: Jeune’s asphyxiating thoracic dystrophy of the newborn. Eur J Pediatr Surg 8:100,101, 1998. Schinzel A, Savoldelli G, Briner J, et al.: Prenatal sonographic diagnosis of Jeune syndrome. Radiology 154:777–778, 1985. Shah KJ: Renal lesion in Jeune’s syndrome. Br J Radiol 53:432–436, 1980. Sharoni E, Erez E, Chorev G, et al.: Chest reconstruction in asphyxiating thoracic dystrophy. J Pediatr Surg 33:1578–1581, 1998. Skiptunas SM, Weiner S: Early prenatal diagnosis of asphyxiating thoracic dystrophy (Jeune’s syndrome). Value of fetal thoracic measurement. J Ultrasound Med 6:41–43, 1987. Tahernia AC, Stamps P: “Jeune syndrome” (asphyxiating thoracic dystrophy). Report of a case, a review of the literature, and an editor’s commentary. Clin Pediatr (Phila) 16:903–908, 1977. Todd DW, Tinguely SJ, Norberg WJ: A thoracic expansion technique for Jeune’s asphyxiating thoracic dystrophy. J Pediatr Surg 21:161–163, 1986. Tongsong T, Chanprapaph P, Thongpadungroj T: Prenatal sonographic findings associated with asphyxiating thoracic dystrophy (Jeune syndrome). J Ultrasound Med 18:573–576, 1999. Turkel SB, Diehl EJ, Richmond JA: Necropsy findings in neonatal asphyxiating thoracic dystrophy. J Med Genet 22:112–118, 1985. Weber TR, Kurkchubasche AG: Operative management of asphyxiating thoracic dystrophy after pectus repair. J Pediatr Surg 33:262–265, 1998. Wiebicke W, Pasterkamp H: Long-term continuous positive airway pressure in a child with asphyxiating thoracic dystrophy. Pediatr Pulmonol 4:54–58, 1988. Yang SS, Heidelberger KP, Brough AJ, et al.: Lethal short-limbed chondrodysplasia in early infancy. Perspect Pediatr Pathol 3:1–40, 1976. Yang SS, Langer LO Jr, Cacciarelli A, et al.: Three conditions in neonatal asphyxiating thoracic dysplasia (Jeune) and short rib-polydactyly syndrome spectrum: a clinicopathologic study. Am J Med Genet Suppl 3:191–207, 1987. Yerian LM, Brady L, Hart J: Hepatic manifestations of jeune syndrome (asphyxiating thoracic dystrophy). Semin Liver Dis 23:195–200, 2003.
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Fig. 1. A neonate died of respiratory insufficiency. The chest is severely narrow and limbs are mildly shortened (Perspect Pediatr Pathol 3:1–40, 1976). The longitudinal section of the humerus shows irregular cartilage-bone junctions. There is a premature ossification center in the proximal epiphysis. The photomicrograph of the physeal growth zone shows scattered areas (left 2/3rd of the picture) of severe retardation and disorganization. Consequently, the cartilage-bone junction is irregular.
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Fig. 2. Radiographs of the skeletal system of a neonate with type II asphyxiating thoracic dystrophy. The ribs are short. The ilia are vertically shortened. The findings are similar in both types I and II. However, the metaphyseal ends of tubular bones do not show irregularity or spurs as in type I. Photomicrograph of the proximal femur shows generalized retardation and disorganization of the physeal growth zone. The cartilage columns in the metaphysis form a latticelike meshworks.
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Fig. 3. An infant with type II asphyxiating thoracic dystrophy showing a narrow thorax and short upper extremities. The radiographs showed the handlebar clavicles, short horizontal ribs with widened/cupped anterior rib ends, and square-shaped iliac bones with the medial spurs of both acetabular roofs. The necropsy showed lung hypoplasia and renal cystic dysplasia and hypoplasia.
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Fig. 5. A boy with type II asphyxiating thoracic dystrophy at 7 month and 15 month.
Fig. 4. A 7-year-old boy with asphyxiating thoracic dystrophy showing a narrow thorax and short limbs. He had dwarfism, postaxial polydactyly, and respiratory distress since birth. Radiographs showed a handlebar clavicles, short horizontal ribs, oblique superior acetabular margins, shortened tubular bones, shortened phalanges especially the middle and distal phalanges, and cone-shaped epiphyses. CT of the chest showed a narrow thorax, shortened ribs, and lung hypoplasia. Histology of the ribs showed that resting chondrocytes were widely separated by abundant cartilaginous matrix. Histology of a rib physeal growth zone shows greatly reduced number of chondrocytes. In some areas, they are completely nonexistent.
Ataxia Telangiectasia CLINICAL FEATURES
Ataxia telangiectasia is a rare hereditary disorder characterized by progressive cerebellar ataxia, conjunctival telangiectasias, recurrent sinopulmonary infections, radiosensitivity, and a predisposition to malignancy. It is the most common cause of progressive cerebellar ataxia in childhood. The prevalence is estimated to be 1 in 40,000 to 1 in 100,000 live births.
1. CNS manifestations a. Functional neurologic abnormalities rare in infancy b. Cerebellar ataxia i. A presenting symptom ii. Slowly progressive iii. Truncal ataxia preceding appendicular ataxia and peripheral incoordination iv. Swaying of the head and trunk while standing and sitting: early sign of ataxia c. Diminished or absent deep reflexes by school age d. Hypotonia e. Dystonia and progressive spinal muscular atrophy affecting hands and feet in affected young adults, resulting in extension contractures f. Dysarthric speech g. Flexor plantar response h. Choreoathetosis in almost all patients i. Myoclonic jerking and intention tremors in about 25% of patients j. Drooling k. Oculomotor apraxia (total or partial loss of the ability to perform coordinated movement or manipulate objects in the absence of motor or sensory impairment) affecting reading (eye tracking) and writing (affected by 7–8 years of age) l. Intellectual function generally preserved 2. Telangiectasias (dilated small blood vessels) a. Ocular conjunctiva: most frequently observed b. Other sites: nose, ears, behind the knees, antecubital fossae, suprasternal notch, dorsum of the hands and feet, and hard and soft palate c. Usually noticed during 3–6 years of age, i.e., a few years after ataxia 3. Immunodeficiency a. Frequent sinopulmonary infections i. Mucopurulent rhinitis, retropharyngeal discharge, otitis media, and sinusitis ii. Bronchitis and pneumonia iii. Progress to chronic lung disease: bronchiectasis, pulmonary fibrosis, and respiratory insufficiency b. A small embryoniclike thymus c. Problems associated with defects in humoral and cellular immunity i. T-cell deficiency in about 30% of patients ii. Severe immunodeficiency in about 10% of patients iii. IgA deficiency d. Most frequent cause of death in adolescence: bronchiectasis complicated by pneumonitis
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal recessive b. Genetic heterogeneity in at least 5 complementation groups (A–E) 2. Cause a. Mutations in the ataxia telangiectasia mutated gene (ATM) which is mapped to 11q22.3 b. Affected individuals completely lack functional ATM protein c. A high prevalence of specific ATM mutations in certain ethnic groups (Amish, Mennonite, Costa Rican, Polish, British, Italian, Turkish, Iranian, and Israeli) with a founder effect, resulting in a small number of mutations that accounts for the majority of diseasecausing mutant alleles 3. Pathophysiology a. Basic defect: abnormal sensitivity of A-T cells to X-rays and certain radiomimetic chemicals, leading to chromosome and chromatid breaks. However, sensitivity of A-T cells to ultraviolet irradiation is normal b. Random distribution of breakpoints c. Nonrandom chromosome rearrangements selectively affect chromosomes 7 and 14 at sites that are concerned with T-cell receptors and heavy-chain immunoglobulin coding and with the development of hematologic malignancies d. Mechanisms responsible for neurologic disease, thymus aplasia, telangiectasias, growth retardation, and impaired organ mutation i. Have not been elucidated ii. Most likely linked to accelerated telomere loss 4. Genotype-phenotype correlations a. 576ins137nt mutation i. Somewhat slower rate of neurological deterioration ii. Later onset of symptoms iii. Intermediate radiosensitivity iv. Little or no cancer risk b. 8494C>T mutation i. Milder phenotype ii. Longer lifespan
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4. Malignancy a. The second most frequent cause of death b. Eventual malignancy during lifetime in 38% of patients c. Malignancy of hematologic origin most common (85% of patients) i. Predominance of malignant lymphomas, usually of B-cell type ii. Acute lymphocytic leukemia of T-cell origin in younger patients iii. T-cell prolymphocytic leukemia in older patients d. Other neoplasms i. Breast cancer, even in female relatives who do not have ataxia telangiectasia ii. Gastric cancer iii. Melanoma iv. Leiomyoma v. Sarcoma 5. Ectodermal changes a. Appearance of premature aging i. Diffuse graying of the hair ii. Atrophic and hidebound facial skin iii. Inelastic ears iv. Facial wasting b. Frequent pigmentary changes: hyperpigmentation/ hypopigmentation with cutaneous atrophy and telangiectasia c. Partial albinism d. Vitiligo e. Café-au-lait spots f. Seborrheic dermatitis 6. Endocrine manifestations a. Occasional female hypogonadism associated with ovarian hypoplasia or dysplasia b. Male hypogonadism with delayed puberty and characteristic high-pitched voice 7. Clubbing: observed in 40% of Costa Rican patients not correlated with chronic lung disease, humoral immunodeficiency, or with a particular mutation 8. Other features a. Mild postnatal growth retardation b. Hypersensitivity to ionizing radiation c. Wheelchair-bound by 10 years of age
DIAGNOSTIC INVESTIGATIONS 1. Significant humoral and cellular immune defects in most patients a. Thymic hypoplasia b. Low numbers of circulating T-cells c. Functional impairment of T-cell-mediated immunity d. Selective deficiencies of IgA, IgE, IgG2, and IgG4 e. Low or absent serum levels of IgA in 60% of patients f. Low or absent serum levels of IgG2 in 80% of patients g. Hyper-IgM in approximately 1% of patients, sometimes associated with myeloma-like gammopathy, lymphadenopathy, hepatosplenomegaly, and lymphocytic interstitial pneumonitis 2. Increased serum levels of alpha-fetoprotein (AFP) levels in over 90% of older children with A-T 3. Increased plasma levels of carcinoembryonic antigen
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4. Colony survival assay by in vitro testing for radiosensitivity on lymphoblastoid cell line to measure the colony survival fraction after 1 Gy of in vitro radiation: sensitivity and specificity exceeding 95% but takes 2–3 months to complete 5. Western blot analysis to detect ATM protein in lysates of a lymphoblastoid cell line 6. DNA-based mutation analysis of the ATM gene available clinically a. Sequence analysis of the ATM coding region b. Linkage analysis to identify carriers among family members at risk if direct DNA testing fails to identify two disease-causing mutations in the index case 7. Chromosome analysis to identify genetic instability, a hallmark of the A-T phenotype a. Types of spontaneous in vitro chromosome aberrations, frequent in both lymphoid and nonlymphoid cells i. Chromosome breaks ii. Acentric fragments iii. Dicentric chromosomes iv. Structural arrangements v. Aneuploidy b. A-T lymphocytes i. Increased chromosome breaks. Common breakage points include 7p14, 7q35, 14q12, 14qter, 2p11, 2p12, and 22q11-q12 ii. Clonal rearrangements involving abnormalities of chromosome 14, especially tandem duplication of 14q at 14q11-q12 and t(7;14) c. Nonlymphoid cells: break points randomly distributed 8. Radiography a. Decreased or absent adenoidal tissue in the nasopharynx b. Small or absent thymic shadow c. Decreased mediastinal lymphoid tissue d. Pulmonary changes similar to those seen in cystic fibrosis 9. EMG and nerve conduction velocities a. Frequently normal in children b. Showing denervation on EEG and reduced nerve conduction in the late stage of the disease, especially in sensory fibers 10. Electrooculography a. Shows characteristic oculomotor abnormality of A-T b. Differentiates A-T from Friedreich ataxia 11. MRI of the brain a. A small cerebellum b. Widened sulci c. Enlargement of the fourth ventricle 12. Histology a. Degeneration of Purkinje and granule cells in the cerebellum: the major pathological marker of A-T in the CNS b. Late degenerative gliovascular nodules in the white matter c. Lesions of the basal ganglia observed only occasionally d. Degeneration of spinal tracts and anterior horn cells often present in late stages e. Nucleocytomegaly, a feature of several cell types throughout the body
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GENETIC COUNSELING 1. Recurrence risk: counseling according to autosomal recessive inheritance a. Patient’s sib i. A 25% recurrence risk ii. Two-thirds of unaffected sibs are carriers b. Patient’s offspring: most patients with A-T do not reproduce 2. Prenatal diagnosis a. Elevated maternal serum AFP levels b. Demonstration of chromosome breaks in amniocytes c. Molecular genetic analysis i. Direct DNA mutation analysis on fetal DNA obtained from amniocentesis or CVS for pregnancies at-risk with previously identified specific disease-causing mutation ii. DNA-based testing with linkage analysis for atrisk family members if no specific disease-causing mutation identified 3. Management a. No specific treatment available b. Early physical therapy, occupational therapy, and speech therapy c. Antibiotics for infections d. Prevention of infection by regular injection of immunoglobulins in patients with antibody deficiency e. Beta-Adrenergic blockers may improve fine motor coordination in some cases f. Controversial use and doses of radiation therapy and chemotherapy g. Avoid bleomycin, actinomycin D, and cyclophosphamide h. Regular cancer surveillance of heterozygotes essential. ATM heterozygosity is a risk factor for breast and lung cancers i. Desferroxamine: recently shown to increase genomic stability of A-T cells and may present a promising tool in A-T treatment j. Usually requires wheelchair by ten years of age
REFERENCES Anmann AJ, Cain WA, Ishizaka K, et al.: Immunoglobulin deficiency in ataxiatelangiectasia. N Engl J Med 281:469–472, 1969. Calonje D, El-Harazi SM: Ataxia-telangiectasia. Emedicine, 2001. http://www. emedicine.com Chessa L, Piane M, Prudente S, et al.: Molecular prenatal diagnosis of ataxia telangiectasia heterozygosity by direct mutational assays. Prenat Diagn 19:542–545, 1999. Concannon P, Gatti RA: Diversity of ATM gene mutations detected in patients with ataxia-telangiectasia. Hum Mutat 10:100–107, 1997. Gatti RA: Diversity of ATM gene mutations detected in patients with ataxiatelangiectasia. Hum Mutat 10:100–107, 1997. Gatti RA: Ataxia-telangiectasia. Gene Reviews, 2003. http://genetests.org Gatti RA, Boder E, Vinters H, et al.: Ataxia-telangiectasia: an interdisciplinary approach to pathogenesis. Medicine 70:99–117, 1991. Huo YK, Wang Z, Hong JH, et al.: Radiosensitivity of ataxia-telangiectasia, Xlinked agammaglobulinemia, and related syndromes using a modified colony survival assay. Cancer Res 54:2544–2547, 1994. Jozwiak S, Janniger CK: Ataxia-telangiectasia. Emedicine, 2004. http://www. emedicine.com Meyn MS: Ataxia-telangiectasia, cancer and the pathobiology of the ATM gene. Clin Genet 55:289–304, 1999. Petersen RD, Kelly WD, Good RA: Ataxia-telangiectasia: its association with a defective thymus, immunological-deficiency disease and malignancy. Lancet 1:1189–1193, 1964. Regueiro JR, Porras O, Lavin M, et al.: Ataxia-telangiectasia. A primary immunodeficiency revisited. Immunol Allergy Clin N Am 20(1):177–206, 2000. Spacey SD, Gatti RA, Bebb G: The molecular basis and clinical management of ataxia telangiectasia. Can J Neurol Sci 27:184–191, 2000. Sparkes RS, Como R, Golde DW: Cytogenetic abnormalities in ataxia telangiectasia with T-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet 1:329–336, 1980. Sun X, Becker-Catania SG, Chun HH, et al.: Early diagnosis of ataxia-telangiectasia using radiosensitivity testing. J Pediatr 140:724–731, 2002. Swift M, Morrell D, Cromartie E, et al.: The incidence and gene frequency of ataxia-telangiectasia in the United States. Am J Hum Genet 39:573–583, 1986. Swift M, Reitnauer PJ, Morrell D, et al.: Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med 316:1289–1294, 1987. Swift M, Morrell D, Massey RB, et al.: Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med 325:1831–1836, 1991. Taylor AM, Metcalfe AJA, Thick J, et al.: Leukemia and lymphoma in ataxia telangiectasia. Blood 87:423–438, 1996. Taylor M, Teraoka S, Wang Z, et al.: Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet 62:86–97, 1998. Woods CG, Taylor AMR: Ataxia-telangiectasia in the British Isles: the clinical and laboratory features of 70 affected individuals. Quart J Med 82:169–179, 1992.
ATAXIA TELANGIECTASIA
Fig. 1. A boy with ataxia-telangiectasia showing conjunctival telangiectasis and chronic lung disease requiring oxygen support.
Fig. 2. A girl with ataxia-telangiectasia showing conjunctival telangiectasis and anemia.
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Atelosteogenesis In 1982, Maroteaux et al. proposed the term “atelosteogenesis” for a newborn skeletal dysplasia characterized by specific patterns of aplasia/hypoplasia of humeri, femora, spine, and other skeletal elements. Atelosteogenesis encompasses a heterogeneous group of disorders with overlapping phenotypic features.
ii. Reduced sulfate transport in chondrocytes of individuals with DTDST mutations resulting in the undersulfation of proteoglycans, which in turn leads to abnormal cartilage formation g. Factors in addition to the intrinsic sulfate transport properties of the DTDST protein may influence the phenotype in individuals with DTDST mutations 3. Atelosteogenesis III (AOIII) a. Inheritance: autosomal dominant b. Features overlapping with AOI and AOII but most similar to those of AOI c. Caused by mutations in FLNB gene 4. Genotype–phenotype correlation in a compound heterozygote (atelosteogenesis type-II diastrophic dysplasia) a. Atelosteogenesis type II i. R178X mutations of the SLC26A2 gene ii. Features typical of AOII a) Severe and progressive cervical kyphosis b) V-shaped distal humerus c) Bowed radii d) Horizontal sacrum e) Gap between the first and second toes b. Diastrophic dysplasia i. R279W mutations of the SLC26A2 gene ii. Features suggestive of diastrophic dysplasia a) Cystic swelling of the external ears b) Cervical kyphosis c) Rhizomelia d) “Hitchhiker” thumbs e) Bilateral talipes equinovarus f) Short toes c. Combination of a severe and a mild mutation leads to an intermediate clinical picture, representing an apparent genotype-phenotype correlation
GENETICS/BASIC DEFECTS 1. Atelosteogenesis I (AOI)/boomerang dysplasia (BD) a. Inheritance: de novo autosomal dominant mutation, suggested by: i. Sporadic in all observed cases ii. No familial cases reported b. Previously known as spondylohumerofemoral dysplasia and giant cell chondrodysplasia c. Caused by mutations in filamin B (FLNB) gene, which also causes the following disorders: i. Atelosteogenesis type III ii. Autosomal recessive spondylocarpotarsal syndrome iii. Autosomal dominant Larsen syndrome d. A common pathogenesis suggested for atelosteogenesis type I and BD i. Forming a spectrum of findings within the same nosologic entity with BD ii. Similar histopathology in BD iii. Overlapping radiologic features with BD 2. Atelosteogenesis II (AOII) a. Inheritance: autosomal recessive suggested by: i. Recurrence in the subsequent pregnancy ii. Parental consanguinity b. Synonymous with De la Chapelle dysplasia c. Phenotypic and radiographic overlap with AOI but with distinctive matrix histopathology with a major disturbance in cartilage matrix macromolecules d. Common pathogenetic features with disorders of sulfation of connective tissue matrix macromolecules. An overlap of phenotypic, radiographic, morphological, and cartilage histochemical features with the following conditions: i. Diastophic dysplasia ii. Achondrogenesis type IB e. Caused by mutated diastrophic dysplasia sulfate transporter (DTDST; SLC26A2) gene which also causes the following recessively inherited chondrodysplasias: i. Diastrophic dysplasia ii. Multiple epiphyseal dysplasia iii. Achondrogenesis IB f. The DTDST gene i. Encodes a sulfate transporter that also accepts chloride and possibly bicarbonate as substrates
CLINICAL FEATURES 1. AOI a. Stillborn or neonatal death due to respiratory distress b. Polyhydramnios c. Facial dysmorphism i. Depressed nasal bridge ii. Eyelid edema iii. Micrognathia iv. Cleft soft palate d. Small chest e. Protuberant abdomen f. Deficient ossification of various bones i. Humerus ii. Femur iii. Thoracic spine iv. Hand bones 96
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g. Rhizomelic micromelic dwarfism i. Short and broad hands ii. Incurved legs iii. Club feet iv. Often dislocation of the elbows h. Laryngeal hypoplasia: an important role in the respiratory failure and death 2. BD a. Distinct facial features i. Horizontal palpebral fissures ii. Broad nasal root iii. Hypoplastic nasal septum iv. Prominent philtrum v. Cleft palate b. Small chest c. Protuberant abdomen d. Marked rhizo/mesomelic shortening of limbs e. Well-developed hands (broad, paddle-shaped) and feet f. Bowed lower limbs g. Calcaneovalgus deformities 3. AOII a. Lethal in neonatal period i. Pulmonary hypoplasia ii. Tracheobronchomalacia iii. Laryngeal stenosis b. Deficient ossification of parts of the skeleton c. Facial dysmorphism i. Midface hypoplasia ii. Depressed nasal bridge iii. Epicanthal folds iv. Micrognathia v. Cleft palate d. Small chest e. Protuberant abdomen f. Extremities i. Severe rhizomelic limb shortening ii. Talipes iii. Abducted (hitch-hiked) thumbs and toes iv. Ulnar deviation of the fingers v. Gap between the first and second toes 4. AOIII a. Milder, usually nonlethal b. Limb anomalies i. Rhizomelic shortening ii. Clubfeet iii. Short broad thumbs and great toes c. Craniofacial abnormalities i. Ocular hypertelorism ii. A flat nasal bridge iii. Micrognathia iv. Cleft palate d. Small chest e. Protuberant abdomen f. Multiple dislocations of elbows, hips, and knees g. Respiratory and feeding difficulties secondary to laryngomalacia h. Apparent cause of death i. Respiratory complications ii. Cervical spine instability i. Long survival possible
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DIAGNOSTIC INVESTIGATIONS 1. AOI a. Radiography: overlapping radiological features with BD i. Humeri: absent/geometric (AOI), absent (AOI/BD), absent (BD) ii. Hand phalanges: presence of distal and absent middle (AOI), hypoplastic middle (AOI/BD), presence of distal and absent proximal/middle (BD) iii. Femora: pointed distally (AOI), geometric (AOI/BD), absent (BD) iv. Tibia: bowed (AOI), hypoplastic (AOI/BD), bowed/boomerang (BD) v. Fibula: absent (AOI), absent (AOI/BD), absent (BD) vi. Spine: coronal clefts in the lumbar vertebrae (AOI) and vertebrae, and uniform lack of ossification of the centra of the vertebral bodies (BD) vii. Pelvis: hypoplasia of the ischiopubis (AOI), lack of ossification of ischiopubis (BD), flared ilia with hypoplasia of the inferior one-third (AOI, BD), producing a key-hole shape viii. Foot: lack of ossification of the calcaneal centers (AOI, BD) ix. Ribs: 10–13 pairs (BD) b. Histopathology i. Uniformly abnormal ii. Lack of ossification iii. Nonhomogeneous cell distribution with hypocellular and acellular areas iv. Occasional multinucleated giant chondrocytes in the relatively acellular areas of resting cartilage (alternatively named “giant cell chondrodysplasia”) v. Disorganized growth plate in some cases vi. Similar histopathology in BD 2. BD a. Radiography i. Triangular, boomerang-shaped long bones, diagnostic of the syndrome ii. Missing some tubular bone ossification centers iii. Ossified fingers and toes from the periphery iv. Characteristic shaped pelvis v. Retarded ossification of the spine, especially cervical and thoracic spine vi. Coronal clefts in the lower thoracic and lumbar spine b. Histopathology i. Chondrocytes in the resting cartilage are irregularly reduced in number with focal acellularity. Multinucleated giant chondrocytes have been noted ii. The physeal growth zones are markedly retarded and disorganized 3. AOII a. Radiography i. Humeri: pointed distally and bifurcated ii. Hand phalanges: irregular size and shape, hitchhiker thumbs
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iii. iv. v. vi.
Femora: clubbed distally Tibia: bowed/hypoplastic Fibula: hypoplastic Spine: more completely formed vertebral centra but coronal clefts present in some cases, a Sshaped cervical spine with a kyphosis in lateral profile vii. Pelvis: flared ilia with horizontal acetabula and a spicule at the medial border of the acetabula b. Histopathology i. Irregularly distributed resting cartilage chondrocytes ii. Attenuation of cartilage matrix with concentric matrix condensation rings around degenerating chondrocytes iii. Shortened proliferative and hypertrophic zones iv. Histopathology of cartilage essentially similar to that of diastrophic dysplasia and achondrogenesis IB reflecting the paucity of sulfated proteoglycans in cartilage matrix c. Mutation analysis (mutation detection rate about 60%) and sequence analysis (mutation detection rate >90%) of DTDST gene: Mutations in the DTDST gene can be found in more than 90% of patients with radiologic and histologic features compatible with the diagnosis of AOII d. Carrier testing for AOII i. Carrier testing available to at-risk family members once the mutation of the DTDST gene has been identified in the proband ii. For the partner of a heterozygous individual. The partners can be screened for the four most common pathogenic alleles, R279W, IVS1+2T>C, delV340, and R178X. When these four alleles are excluded, the risk of carrying DTDST mutation is reduced from the general risk of 1 : 100 to about 1 : 300 4. AOIII a. Radiography i. Humeri: pointed distally ii. Hand phalanges: tombstone-shaped proximal phalanges, widened distal phalanges iii. Femora: pointed distally iv. Tibia: short v. Fibula: absent vi. Spine: coronal clefts in the lumbar vertebrae, severe thoracolumbar kyphosis with an S-shaped cervical spine in lateral profile vii. Pelvis: hypoplastic ischiopubis, banana-shaped pubic rami b. Histopathology: hypocellularity without clustering, acellular areas, or “giant cells”
GENETIC COUNSELING 1. Recurrence risk a. AOI i. Patient’s sib: low ii. Patient’s offspring: a lethal entity not surviving to reproduce
b. AOII i. Patient’s sib: 25% ii. Patient’s offspring: a lethal entity not surviving to reproduce c. AOIII i. Patient’s sib: low ii. Patient’s offspring: 50% 2. Prenatal diagnosis a. Fetal ultrasonography i. Short limbs (micromelia) ii. Abnormal facial profile (depressed nasal base, micrognathia, apparent hypertelorism) iii. Absence of ossification in the humerus, radius, ulna, and cervical and upper thoracic vertebral bodies iv. Coronal clefts in the ossified vertebral bodies v. Talipes equinovarus b. Fetal MRI using an ultrafast sequence i. Dysmorphic features ii. Pulmonary hypoplasia iii. A large cysterna magna c. Mutation analysis of DTDST gene for pregnancy at risk: possible for AOII 3. Management a. AOI and AOII: supportive measures for these two lethal conditions b. AOIII i. Ventilatory support and tracheostomy often necessary for respiratory distress due to laryngotracheomalacia ii. Treat recurrent respiratory tract infections iii. Cleft palate repair iv. Conductive hearing loss evaluation and management v. Orthopedic care for club feet and joint dislocations
REFERENCES Bejjani BA, Oberg KC, Wilkins I, et al.: Prenatal Ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1. Am J Med Genet 79:392–395, 1998. Bonafe L, Ballhausen D, Superti-Furga A: Atelosteogenesis type 2. Gene Reviews, 2002. http://www.genetests.org Cai G, Nakayama M, Hiraki Y, et al.: Mutational analysis of the DTDST gene in a fetus with Atelosteogenesis type 1B. Am J Med Genet 78:58–60, 1998. Chervenak FA, Isaacson G, Rosenberg JC, et al.: Antenatal diagnosis of frontal cephalocele in a fetus with atelosteogenesis. J Ultrasound Med 5:111–113, 1986. Den Hollander NS, Stewart PA, Brandenburg H, et al.: Atelosteogenesis, type I. The Fetus 3:23–26, 1993. Fallon MJ, Hockey A, Hallam LA: Atelosteogenesis type III: A case report. Pediatr Radiol 24:47–49, 1994. Fryer AE, Carty H: A new lethal skeletal dysplasia or the severe end of the atelosteogenesis spectrum? Pediatr Radiol 26:678–679, 1996. Greally MT, Jewett T, Smith WL Jr, et al.: Lethal bone dysplasia in a fetus with manifestations of atelosteogenesis I and boomerang dysplasia. Am J Med Genet 47:1086–1091, 1993. Hastbacka J, Superti-Furga A, Wilcox WR, et al.: Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): Evidence for a phenotypic series involving three chondrodysplasias. Am J Med Genet 58:255–262, 1996. Herzberg AJ, Effmann EL, Bradford WD: Variant of atelosteogenesis? Report of a 20-week fetus. Am J Med Genet 29:883–890, 1988. Hunter AGW, Carpenter BF: Atelosteogenesis I and boomerang dysplasia: A question of nosology. Clin Genet 39:471–480, 1991.
ATELOSTEOGENESIS International Working Group on Constitutional Diseases of Bone: International nomenclature and classification of the osteochondrodysplasias. Am J Med Genet 79:376–382, 1998. Kozlowski K, Sillence D, Cortis-Jones R, Osborn R: Boomerang dysplasia. Br J Radiol 58:369–371, 1985. Krakow D, Robertson SP, King LM, et al.: Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formations and skeletogenesis. Nat Genet 36:405–410, 2004. Krakow D, Robertson SP, Sebald ET, et al.: Clustering of mutations in the actin-binding domain of filamin B leads to atelosteogenesis types I and III. American Society of Human Genetics Annual meeting. Abstract No.2416, 2004. Kuwashima S, Nishimura G, Kikushima H, et al.: Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year. Acta Paediatr Jpn 34:543–546, 1992. Macias-Gomez NM, Megarbane A, Leal-Ugarte E, et al.: Diastrophic dysplasia and atelosteogenesis type II as expression of compound heterozygosis: first report of a Mexican patient and genotype-phenotype correlation. Am J Med Genet 129A:190–192, 2004. Mansberg VJ, Mansberg G: Atelosteogenesis type 1. Australas Radiol 37:283–285, 1993. Maroteaux P, Spranger J, Stanescu V, et al.: Atelosteogenesis. Am J Med Genet 13:15–25, 1982. Newbury-Ecob R: Atelosteogenesis type 2. J Med Genet 35:49–53, 1998. Nishimura G, Horiuchi T, Kim OH, et al.: Atypical skeletal changes in otopalatodigital syndrome type II: phenotypic overlap among otopalatodigital syndrome type II, Boomerang dysplasia, atelosteogenesis type I and type III, and lethal male phenotype of Melnick-needles syndrome. Am J Med Genet 73:132–138, 1997. Nores JA, Rotmensch S, Romero R, et al.: Atelosteogenesis type II: sonographic and radiological correlation. Prenat Diagn 12:741–753, 1992. Odent S, Loget P, Le Marec B, et al.: Unusual fan shaped ossification in a female fetus with radiological features of boomerang dysplasia. J Med Genet 36:330–332, 1999. Rimoin DL, Sillence DO, Lachman R, et al.: Giant cell chondrodysplasia: second case of a rare lethal newborn skeletal dysplasia. Am J Hum Genet 32:125A, 1980. Rossi A, Superti-Furga A: Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutations review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat 17(3):159–171, 2001. [Erratum in Hum Mutat 18:82, 2001.]
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Rossi A, van der Harten HJ, Beemer FA, et al.: Phenotypic and genotypic overlap between atelosteogenesis type 2 and diastrophic dysplasia. Hum Genet 98:657–661, 1996. Schrander-Stumpel C, Havenith M, Linden EV, et al.: De la Chapelle dysplasia (atelosteogenesis type II): case report and review of the literature [corrected]. Clin Dysmorphol 3:318–327, 1994. Schultz C, Langer LO, Laxova R, et al.: Atelosteogenesis type III: Long term survival, prenatal diagnosis, and evidence for dominant transmission. Am J Med Genet 83:28–42, 1999. Sillence DO, Rimoin DL, Lachman R, et al.: Giant cell chondrodysplasia. A new lethal newborn skeletal dysplasia. Proceedings of the 1978 Birth Defects Conference, 193A, 1978. Sillence DO, Lachman RS, Jenkins T, et al.: Spondylohumerofemoral hypoplasia (giant cell chondrodysplasia): a neonatally lethal short-limb skeletal dysplasia. Am J Med Genet 13:7–14, 1982. Sillence D, Kozlowski K, Rogers J, et al.: Atelosteogenesis: Evidence for heterogeneity. Pediatr Radiol 17:112–118, 1987. Sillence D, Worthington S, Dixon J, et al.: Atelosteogenesis syndromes: A review, with comments on their pathogenesis. Pediatr Radiol 27:388–396, 1997. Spranger JW, Brill PW, Poznanski A: Bone Dysplasias. An Atlas of Genetic Disorders of Skeletal Development. 2nd ed. Oxford: Oxford Univ Press, 2002. Stern HJ, Graham JM Jr, Lachman RS, et al.: Atelosteogenesis type III: A distinct skeletal dysplasia with features overlapping Atelosteogenesis and oto-palato-digital syndrome type II. Am J Med Genet 36:183–195, 1990. Superti-Furga A, Bonafe L, Rimoin DL: Molecular-pathogenetic classification of genetic disorders of the skeleton. Am J Med Genet (Semin Med Genet) 106:282–293, 2001. Temple K, Hall CA, Chitty L, et al.: A case of atelosteogenesis. J Med Genet 27:194–197, 1990. Tenconi R, Kozlowski K, Largaiolli G: Boomerang dysplasia. Fortschr Röntgenstr 138:378–380, 1983. Ueno K, Tanaka M, Miyakishi K, et al.: Prenatal diagnosis of atelosteogenesis type I at 21 weeks’ gestation. Prenat Diagn 22:1071–1075, 2002. Whitley C, Burke B, Gnaroth G, et al.: De la Chapelle dysplasia. Am J Med Genet 25:29–39, 1986. Winship I, Cremin B, Beighton P: Boomerang dysplasia. Am J Med Genet 36:440–443, 1990. Yang SS, Roskamp J, Liu CT, et al.: Two lethal chondrodysplasias with giant chondrocytes. Am J Med Genet 15:615–625, 1983.
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Fig 1. A male infant with AOI/BD. Prenatal ultrasound showed polyhydramnios and a short limb dwarf. The infant died at 57 days. He showed relatively large head, hypertelorism, depressed nasal bridge, midfacial hypoplasia, micrognathia, cleft palate, short neck, relatively narrow chest, protuberant abdomen, severe “rhizomelic” micromelia, absent elbow joints, genu varus, and talipes equinovarus. Radiographic features included unossified vertebrae (T6–T9), single boomeranglike long bone (between acromion and wrist), short tapered femora, short bowed tibias, absent fibulas, calcified distal phalanges, nonossified carpals, metacarpals and proximal phalanges, and irregularly ossified tarsals and metatarsals. Histopathology of the cartilage showed disorganized physeal growth zones and irregular areas of hypocellularity in the resting cartilage. Multinucleated giant chondrocytes were not observed.
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Autism Autism is a pervasive developmental disorder, defined by impairments in social and communication function, and repetitive and stereotyped behavioral patterns. It occurs in approximately 7–40 out of 10,000 persons.
GENETICS/BASIC DEFECTS 1. Secondary autism (nongenetic and genetic conditions associated with autism): accounts for a small minority of individuals with autism (<10%) in population-based studies a. Obstetric complications including uterine bleeding, despite absence of demonstrable causal relationship in many studies b. Intrauterine exposure to teratogenic drugs in a few affected children i. Thalidomide ii. Valproate c. Elevated cord blood levels of the following substances: i. Neuropeptides substance P ii. Vasoactive intestinal peptide iii. Pituitary adenylate cyclase-activating polypeptide iv. Calcitonin gene-related peptide v. Neurotrophin nerve growth factor d. Various epidemiologic data i. Cerebral palsy (a static motor deficit of brain origin present from early life): present in 2.1–2.9% of individuals with autism and mental retardation ii. Congenital rubella infection: present in 0.75% of cases iii. Other pre- and postnatal infections (e.g., Hemophilus influenza and cytomegalovirus): may cause autism when they significantly damage the immature brain iv. No association between autism and inflammatory bowel disease or with a live MMR vaccination v. Epilepsy with the highest association with autism: reported in up to one-third of individuals with an autistic spectrum disorder in adulthood vi. Behavioral symptoms of autism: frequent in tuberous sclerosis complex and fragile X syndrome but account for only a minority of the total cases of autism e. Genetic mutations associated with autism i. Chromosomal causes of autism a) Angelman syndrome (more commonly associated with autism than Prader-Willi syndrome) can result from the loss or mutations of the maternally derived UBE3A or the ATP10C gene in 15q11-q13 region b) Chromosomal duplication in the PraderWilli/Angelman region of proximal 15q in 102
about 3% of individuals with autism: more commonly a supernumerary iso-dicentric 15q chromosome detectable by routine cytogenetic studies or less commonly an interstitial duplication of the region detected by FISH analysis of the SNRPN gene c) Other chromosome abnormalities in 3–5% of individuals with autism d) A subtelomeric deletion detected by FISH telomere studies in 10% of unselected patients with autism e) Down syndrome: Autism was found in at least 7% in one study in children with Down syndrome ii. Single-gene causes of autism a) Fragile X syndrome found in a few percent of children with autism: at least 50% of children with fragile X syndrome have autistic behaviors, including avoidance of eye contact, language delays, repetitive behaviors, sleep disturbances, tantrums, self-injurious behaviors, hyperactivity, impulsiveness, inattention, and sound sensitivities b) Rett syndrome: children affected with both autism and Rett syndrome (almost universally female sex) have a period of normal development, followed by loss of language with stereotypic hand movements (hand-wringing behavior) c) Tuberous sclerosis complex: Mentally retarded individuals with tuberous sclerosis complex frequently have autism (almost 50% in some studies) d) Neurofibromatosis: much less frequently associated with autism than is tuberous sclerosis and fragile X syndrome e) Duchenne muscular dystrophy: an unexpectedly large proportion of boys with Duchenne muscular dystrophy have autistic spectrum f) Sotos syndrome g) Joubert syndrome h) Williams syndrome i) Hypomelanosis of Ito j) Cowden syndrome k) Moebius syndrome iii. Metabolic cause associated with autism a) Mitochondrial disease or dysfunction b) Untreated phenylketonuria 2. Idiopathic autism (inherited autism of unknown cause) a. Family studies indicates genetics play the major causative role in most individuals with “idiopathic” autism (90–95%)
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b. Epidemiologic studies i. A prevalence of 5–10 cases of classic autism per 10,000 (3–6 per 1000 if the entire spectrum of autism is included) ii. A male-to-female ratio of 3 : 1 a) The preponderance of males suggests an Xlinked disorder b) Linkage to the X chromosome suggested by recent genome-wide screens, although the data are inconsistent c) Male-to-male transmission of autism in multiplex families (families with more than a single affected family member) ruled out Xlinkage in these families d) No significant associations of autism to Y chromosome based on Y haplotype analysis, although Y chromosome abnormalities have been documented c. Classification of idiopathic autism i. Essential autism a) Defined by the absence of physical abnormalities b) Seen in about 70% of children with idiopathic autism c) Associated with better outcome overall d) More likely a male e) A higher sibling recurrence risk ii. Complex autism a) Defined by the presence of dysmorphic features (microcephaly and/or a structural brain malformation) b) Seen in about 30% of children with idiopathic autism c) Associated with a poorer prognosis d) A lower male-to-female ratio e) A lower sibling recurrence risk d. Evidence suggesting genetic basis of autism without a diagnosable cause i. 25% rate of recurrence in siblings of affected individuals from family studies: much greater than the prevalence rate in the general population ii. Greater than 60% rate of concordance for classic autism in monozygotic twins, compared with no concordance found between dizygotic twins e. The identity and the number of genes involved in autistic disorders: remained unknown i. Multigenic a) Similar autistic phenotypes may arise from different genes or gene combinations in different families (single-mutation genetic heterogeneity) b) Example: tuberous sclerosis caused by TSC1 on chromosome 9q in some families and TSC2 on 16p in others ii. Polygenic a) Several synergistically acting genes in an affected individual’s genome may be required to produce the full autistic phenotype
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b) Lowering of a theoretical threshold by certain sets of genes acting in concert to allow the development of autism, either by themselves or given the right set of environmental or immunologic modifiers c) Other related developmental disorders in family members presumed to have inherited some of the susceptibility genes found in the affected family member or to have the same set of susceptibility genes without exposure to the same environmental “trigger factors” for autism 3. Search for candidate genes a. Cytogenetics: scrutinize the region involved in visible breakpoints, translocations, duplications, inversions, and deletions for the presence of genes that potentially may be involved in the pathogenesis of autistic spectrum disorders b. Whole genome search: microsatellite markers screening in multiplex family uncovers specific chromosomal regions that affected individuals inherit more often than predicted by chance
CLINICAL FEATURES 1. Early signs of infants with autism a. Do not care to be held or cuddled b. Do not reach out to be picked up c. Often “colicky” and hard to console d. Typically quieting more readily when left alone e. Avoid and fail to initiate eye contact f. Stare into space g. Sleep disturbances h. Usually do not come to medical attention until after the second year when language delays are evident 2. Natural history a. Onset of autism: prior to age three b. Gradual onset of autism in most children c. “Regressive” onset of autism in about 30% of children i. Initially begin to talk ii. Then often precipitously lose language and become distant iii. Refuse to make eye contact within a matter of days and no longer respond to his or her name iv. Repetitive movements may develop immediately or by 3 or 4 years of age. d. About 25% of children who fit diagnostic criteria for autism at age 2 or 3 years i. Subsequently begin to talk and communicate ii. Blend to varying degrees into the regular school population by 6 or 7 years e. Remaining 75% of children with autism continue to have a life-long disability requiring intensive parental, school, and societal support f. Fewer than 5% of children with autism completely recover. 3. Mental retardation by nonverbal IQ testing in 50–70% of children with autism 4. Seizures develops in about 25% of children with autism
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5. Idiopathic autism a. About 30% of children have complex autism, defined by presence of the following features: i. Dysmorphic features ii. Microcephaly iii. Structural brain malformation b. About 70% of children have essential autism, defined by absence of physical abnormalities 6. Behavioral impairments a. Impairments in social interaction: separates individuals with autism from individuals around them i. Unable to “read” other people, ignoring them and often strenuously avoiding eye contact ii. Do not comfort others or seek comfort and do not share interests with others iii. Usually prefer to be by themselves, engaging in their own, often repetitive, activities at home iv. Fail to develop friendship with peers and siblings v. Demonstrate a marked deficit in imitating other’s actions, which may impede the development of interpersonal synchrony, communication, symbolic play, and the learning of new behaviors b. Impairments in communication i. Fail to develop reciprocal communication either by speech, gestures, or facial expression in most children with autism ii. Fail to use eye gaze to communicate and direct attention in young children iii. Display stereotypic speech that may involve echolalia or unusual inflections and intonations when children with autism learn to talk c. Repetitive and stereotypic behaviors i. Staring or rocking ii. Toddlers may have motor “stereotypies” a) Movements of fingers b) Twirling strings c) Flicking pages of books d) Licking iii. Repetitive whole body movements a) Spinning b) Running back and forth iv. Complex repetitive movements may last for hours v. Develop elaborate rituals in which the order of events, the exact words, and the arrangement of objects must be followed d. Other symptoms i. Hyper- and hyposensitivities to sensory stimulation of all types (e.g., visual, auditory, tactile, and pain) ii. Odd behaviors around foods and their presentation iii. Abnormal sleep patterns iv. Tantrums and/or self-injurious and aggressive behaviors brought on by a change in routine, an offending touch, or no apparent reason v. Impaired motor development with toe walking early in life and general clumsiness
vi. Total disregard for danger, resulting in high risk of early death, most commonly from drowning 7. Diagnostic criteria for autistic disorder (American Psychiatric Association, 1994) a. Presence of a total of >6 of the following areas: i. Qualitative impairment in social interaction, in at least two of the following areas: a) Marked impairment in the use of multiple nonverbal behaviors, such as eye-to-eye gaze, facial expression, body postures, and gestures, to regulate social interaction b) Failure to develop peer relationships appropriate to developmental level c) Lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g., by lack of showing, bringing, or pointing out objects of interest) d) Lack of social or emotional reciprocity ii. Qualitative impairment in communication, in at least one of the following areas: a) Delay in, or total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication, such as gesture or mime) b) Marked impairment in the ability to initiate or sustain a conversation with others in individuals with adequate speech c) Stereotyped and repetitive use of language, or idiosyncratic language d) Lack of varied, spontaneous make-believe, or social imitative play appropriate to developmental level iii. Restrictive repetitive and stereotypic patterns of behavior, interests, and activities, in at least one of the following areas: a) Encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus b) Apparently inflexible adherence to specific nonfunctional routines or rituals c) Stereotyped and repetitive motor mannerisms (e.g., hand or finger flapping or twisting, or complex whole-body movements) d) Persistent preoccupation with parts of objects b. Delays or abnormal functioning with onset prior to 3 years of age, in at least one of the following areas: i. Social interaction ii. Language as used in social communication iii. Symbolic or imaginative play c. The disturbance is not better accounted for by Rett syndrome or childhood disintegrative disorder 8. Differential diagnosis with other pervasive developmental disorders a. Asperger disorder i. A variant of autism typically occurring in highfunctioning individuals without mental retardation, not considered as a separate disorder
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ii. Language develops better than classic autism iii. Problems with the semantic and pragmatic use of language iv. Many individuals are misdiagnosed early on and in adulthood as odd or eccentric b. Rett syndrome i. A specific genetic disorder of postnatal brain development, caused by a single-gene defect predominantly affecting girls ii. Cause: de novo mutations or microdeletions of the methyl-CpG-binding protein 2 (MeCP2) gene on Xq28 in the majority of cases c. Childhood disintegrative disorder i. Behavioral, cognitive, and language regression between 2 and 10 years of age after entirely normal early development ii. Experience in at least two of the following areas: language, social skills, bowel or bladder control, and play or motor skills iii. Cognitive skills usually impaired significantly d. Pervasive developmental disorder, not otherwise specified i. Onset after 3 years of age ii. Individuals who have autistic features but do not fit any of the other subtypes iii. Presence of a wide range of cognitive and behavioral problems iv. In general, less severe social, communicative, and behavioral deficits
DIAGNOSTIC INVESTIGATIONS 1. Cytogenetic studies and molecular genetic analyses a. High-resolution or multi-FISH telomere chromosome studies i. Chromosomal abnormality involving the proximal long arm of chromosome 15 (15q11-q13) observed in more than 1% of autistic individuals. Duplication is usually maternally derived, with one or two extra copies of the area roughly corresponding to the typical Angelman syndrome/Prader Willi syndrome deletion region: a) Pseudodicentric 15 (inverted duplication 15) b) Atypical marker chromosomes ii. Other chromosome abnormality: cytogenetic abnormalities have been found on virtually every chromosome in individuals with autism b. Molecular genetic testing for fragile X syndrome: unlikely positive in the presence of high-functioning autism 2. Metabolic studies: positive in probably <5% of children with autism a. Inborn errors in amino acid, carbohydrate, purine, peptide, and mitochondrial metabolism b. Toxicologic studies 3. Increased serum serotonin in about one-third of individuals with autistic disorder 4. Electrophysiologic studies: epileptiform EEG abnormalities in autistic children with a history of regression 5. Neuroimaging: absence of significant structural brain abnormalities
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GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Secondary autism: The recurrence risk is based on information relevant to the primary diagnosis a) Supernumerary iso-dicentric 15q chromosome: no increased recurrence risk since it is a de novo occurrence b) Duplication of proximal 15q: an increased recurrence risk since it may result from segregation of a parental chromosome translocation or a maternally-derived interstitial 15q duplication ii. Idiopathic autism a) The empiric aggregate risk to sibs: 4% b) An additional 4–6% risk for milder symptoms including language, social, and psychiatric disorders c) For families with ≥2 children: the recurrence risk approaches 35% iii. Essential autism a) For male sibs: 7% of risk for autism and an additional 7% risk for milder autism spectrum symptoms b) For female sibs: a 1% risk for autism and an unknown risk for a milder autism spectrum disorder iv. Complex autism: the sib recurrence risk of a proband with complex autism a) 1% for autism b) An additional 2% for a milder autism spectrum disorder b. Patient’s offspring: no available data 2. Prenatal diagnosis: not available 3. Management a. General goals of treatment i. Improve language and social skills ii. Decrease stereotypic and disruptive behaviors iii. Support parents and families in their adjustment and to educate their children iv. Foster independence b. Early intervention programs: focused on developing the following areas: i. Language ii. Cognitive and imitation skills iii. Social responsiveness iv. Appropriate behavior c. Behavior modification programs i. Structure the environment ii. Provide consistent responses to behaviors iii. Reward a desired behavior (positive reinforcement) iv. No reward for undesirable behavior (negative reinforcement) v. Apply an adverse stimulus to deter an unwanted response (punishment) vi. Reinforcing closer and closer approximations to the desired behavior (shaping)
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d. School-aged children with autism i. Need a curriculum that is tailored to individual strengths and needs ii. Effective education programs a) Well-structured, systematic teaching routines b) Consistency and repetition c) Concrete and functional learning objectives e. Adolescents and adults with autism i. Need specific help in vocations and avocations in adult life ii. Social skills groups iii. Recreational activities iv. Individual psychotherapy v. Vocational coaching and assistance f. Medications: no medications are autism-specific i. Antidepressants: Selective serotonin reuptake inhibitors with some success in treating preoccupations, ritualized behaviors, mood disorders, and anxiety ii. Stimulant medications: little or no clinical improvement to decrease the activity levels and to improve the attention span of some children iii. Antipsychotic medications: New atypical antipsychotic medications may be useful in treating aggressive and hyperactive behavior with fewer side effects iv. Anticonvulsant medications: used to treat individuals with autism who suffer from seizures and may be effective in decreasing aggressive behavior and episodic behavioral outbursts, particularly in children with seizure disorder
REFERENCES American Psychiatric Association: Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC. 1994, pp 70, 71.
Bailey A, Phillips W, Rutter M: Autism: toward an integration of clinical, genetic, neuropsychological, and neurobiological perspectives. J Child Psychol Psychiatry 37:89–126, 1996. Bennetto L, Rogers SJ: Autism spectrum disorders. In: Jacobson: Psychiatric Secrets, 2nd ed. Hanley and Belfus, 2001, Chap 55, 2001, pp 295–302. Bryson S, Smith I: Epidemiology of autism: Prevalence, associated characteristics, and implications for research and service delivery. Ment Retard Dev Disabil Res Rev 4:97–103, 1998. Cohen DJ, Volkmar FR (eds): Handbook of Autism and Pervasive Developmental Disorders, 2nd ed. New York: John Wiley & Sons, 1997. Cook EH: Genetics of autism. Ment Retard Dev Disabil Res Rev 4:113–120, 1998. Dawson G (ed): Autism: Nature, Diagnosis, and Treatment. New York: Guilford Press, 1989. Farber JM: Autism and other communication disorders. In: Capute AJ, Accardo PJ (eds): Developmental Disabilities in Infancy and Childhood. 2nd ed. Baltimore, MD: Brookes, 1996, pp 347–364. Filipek PA, Accaardo PJ, Ashwal MD, et al.: Practice parameter: Screening and diagnosis of autism. Report of the quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society. Neurology 55:468, 2000. Fombonne E: The prevalence of autism. J Am Med Assoc 289:87–89, 2003. Frith U: Emanuel Miller lecture: Confusions and controversies about Asperger syndrome. J Child Psychology Psychiatry 45:672–686, 2004. Gillberg C: Chromosomal disorders and autism. J Autism Dev Disord 28:415–425, 1998. Kent L, Evans J, Paul M, et al.: Comorbidity of autistic spectrum disorders in children with Down syndrome. Dev Med Child Neurol 41:152–158, 1999. Miles JH, McCathren RB: Autism overview. Gene Reviews, 2003. http://www.genetests.org Muhle R, Trentacoste SV, Rapin I: The genetics of autism. Pediatrics 113:e472–e486, 2004. National Research Council: Educating children with autism. Washington, DC: National Academy Press, 2001. Prater CD: Autism: a medical primer. Am Fam Physician 66:1667–1674, 2002. Ritvo ER, Jorde LB, Mason-Brothers A, et al.: The UCLA-University of Utah epidemiologic survey of autism: recurrence risk estimates and genetic counseling. Am J Psychiatr 146:1032, 1989. Stokstad E: Development. New hints into the biological basis of autism. Science 294:34–37, 2001. Tuchman R: Autism. Neurol Clin 21:919–932, 2003. Wassink TH, Piven J, Patil SR: Chromosomal abnormalities in a clinic sample of individuals with autistic disorder. Psychiatr Genet 11:57–63, 2001. Wolff DJ, Clifton K, Karr C, et al.: Pilot assessment of the subtelomeric regions of children with autism: detection of a 2q deletion. Genet Med 4:10–14, 2002.
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Fig. 1. A girl (at 4 years and 10 years) with autism. Her chromosome study showed a balanced translocation between the short arm of chromosome 5 and the long arm of the chromosome 10 [t(5;10)(p13;q21)] (karyotype shown). Her parents had normal chromosomes.
Beckwith-Wiedemann Syndrome d. Paternally expressed 11p genes i. IGF2 (the gene for insulin-like growth factor-2): a paternally expressed and maternally imprinted embryonic growth factor. Many sporadic cases show loss of imprinting of IGF2 resulting in biallelic expression ii. KCNQ1OT1 gene (also known as LIT1): the unmethylated paternal allele of KvDMR1 permits transcription of the antisense transcript KCNQ1OT1 and silencing of the KCNQ1 and CDKN1C genes e. Effect of multiple genes: combination of increased expression of paternally expressed growth promoter genes such as IGF2 and loss of maternally expressed growth suppressor genes in some patients with paternal uniparental disomy of 11p15 f. Uniparental disomy (mosaic paternal isodisomy) for the band 11p15.5 (10–20% of sporadic cases) i. Two paternally derived copies of chromosome 11p15 and no maternal contribution for that chromosome region ii. Resulting from postzygotic mitotic recombination and mosaic paternal isodisomy iii. All patients with uniparental disomy exhibit somatic mosaicism
The Beckwith-Wiedemann syndrome (BWS) is the most common and the best-known congenital overgrowth syndrome. It was named after Beckwith who in 1963 described three unrelated patients with exomphalos, hyperplasia of the kidneys and pancreas, and adrenal cytomegaly. Wiedemann in 1964 reported a familial form of omphalocele with macroglossia. The incidence is estimated to be about 1 in 13,700 births.
GENETICS/BASIC DEFECTS 1. Genetics of BWS: complex a. Pedigree data i. Sporadic (85%) ii. Familial (15%): autosomal dominant inheritance with variable expressivity, incomplete penetrance, and preferential maternal transmission b. Karyotypic data i. Chromosome rearrangements influenced by the parent of origin (2%) a) Paternally derived 11p15.5 duplications exhibiting atypical clinical features as well as a significant risk of developmental delay b) Maternally derived translocations and inversions exhibiting typical features of BWS ii. Normal karyotype (98%) c. Molecular data: BWS is caused by alterations in growth regulatory genes on chromosome region 11p15.5, which is subjected to genomic imprinting (an epigenetic mechanism in which gene expression is altered according to the parental origin of the allele) 2. Pathogenesis a. Imprinted genes have been implicated in the pathogenesis of both familial and sporadic BWS b. A subgroup of BWS patients has loss of methylation at a differentially methylated region (KvDMR1) within the KCNQ1 gene centromeric to the IGF2 and H19 genes c. Maternally expressed 11p genes i. P57KIP2 (also known as CDKN1C, a cation-independent cyclase): a candidate for a maternally expressed growth inhibitory gene in BWS a) Germline mutations detected in >40% of familial cases b) Mutations infrequent (<5%) in sporadic cases ii. H19: a maternally expressed gene encoding a biologically active nontranslated mRNA that may function as a tumor suppressor. Deletion of H19 or transposition from its usual position relative to IGF2 disrupts normal imprinting iii. KCNQ1 (also known as KvLQT1): serves as an imprinting center, disruption of which could affect transcription and DNA replication through an effect on chromatin structure
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1. Variable phenotypic expression 2. Prenatal and postnatal overgrowth (gigantism) (cardinal feature) a. Large or above normal size baby at birth b. Eventual somatic gigantism in most cases c. Advanced bone age d. Hemihyperplasia or hemihypertrophy (13%) 3. Performance a. Varying intelligence i. Normal ii. Mild-moderate mental retardation from undetected hypoglycemic episodes during infancy b. Seizures in some cases 4. Craniofacial features a. Macroglossia (cardinal feature) i. Chronic alveolar hypoventilation ii. Anterior open bite b. Ear-lobe grooves or indented ear lesions on the posterior rim of the helix or concha c. Nevus flammeus d. Midfacial hypoplasia e. Prominent occiput 5. Abdominal wall defect a. Omphalocele (cardinal feature) b. Umbilical hernia c. Diastasis recti
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6. Gastointestinal anomalies a. Malrotation anomalies b. Dome-shaped defect of the diaphragm 7. Visceromegaly a. Hepatomegaly (frequent) b. Nephromegaly (frequent) c. Cardiomegaly d. Occasional clitoromegaly e. Hyperplastic pancreas, bladder, uterus, and thymus 8. Neoplasms (7.5%) a. Benign tumors i. Adrenal adenoma ii. Carcinoid tumor iii. Fibroadenoma iv. Fibrous hamartoma v. Ganglioneuroma vi. Myxoma b. Malignant tumors i. Wilms tumor (most frequent) ii. Adrenocortical carcinoma iii. Hepatocellular carcinoma iv. Glioblastoma v. Neuroblastoma vi. Rhabdomyosarcoma vii. Malignant lymphoma viii. Pancreatoblastoma ix. Teratoma 9. Additional features a. Polyhydramnios b. Prematurity c. Enlarged placenta d. Hemangioma e. Other renal anomalies i. Medullary dysplasia ii. Duplicated collecting system iii. Nephrocalcinosis iv. Medullary sponge kidney v. Cystic changes vi. Diverticula 10. Adult phenotype a. Hemihyperplasia b. Prominent jaw c. Enlarge tongue d. Ear creases and pits e. Enlarged kidneys and other abdominal organs f. Normal height
DIAGNOSTIC INVESTIGATIONS 1. Transitory neonatal hypoglycemia (spontaneous regression during the first 4 months of life) (63%) 2. Neonatal polycythemia (20%) 3. Hypercholesterolemia, hyperlipidemia, hypothyroidism, thyroxine-binding globulin deficiency: rare occurrence 4. Periodic abdominal ultrasonography for organomegaly and embryonal tumors, followed by MRI or CT if indicated 5. Radiography a. Advanced bone age b. Chest radiography to rule out rare neural crest tumors such as thoracic neuroblastoma
6. Echocardiography for suspected cardiac abnormality 7. Chromosome analysis (high resolution and FISH studies) a. Normal chromosomes in most patients b. Chromosome abnormalities involving 11p15 in )1% of cases i. Paternally derived 11p15 duplication ii. Maternally derived translocations and inversions 8. Molecular analysis a. Paternal uniparental disomy (UPD) of 11p15 in multiple tissues (10–20%) i. Restriction fragment length polymorphism (RFLP) analysis of multiple 11p15 loci ii. Methylation studies of multiple imprinted genes on 11p15 b. Mutation analysis: P57KIP2 (5–10%) (screen for mutation by heteroduplex/SSCP analysis, followed by sequence of P57KIP2 exons)
GENETIC COUNSELING 1. Recurrence risks a. Probably a low recurrence risk in cases of negative family history, normal karyotype, and absence of identifiable molecular etiology b. Up to 50% of recurrence risk in cases of positive family history and normal karyotype c. Up to 50% recurrence risk in cytogenetically detected maternal 11p15 translocation or inversion d. An undetermined recurrence risk in cytogenetically detected paternal 11p15 duplication e. A very low recurrence risk in cases of paternal 11p15 uniparental disomy as this event arises from a postzygotic somatic recombination f. Up to 50% recurrence risk if a P57KIP2 mutation is present in a parent (usually maternally transmitted) 2. Prenatal diagnosis a. Maternal serum alpha fetoprotein screening: may be elevated in a fetus with omphalocele b. Prenatal Ultrasonography i. Fetal overgrowth (macrosomia) ii. Polyhydramnios iii. Enlarged placenta iv. A long umbilical cord v. Macroglossia vi. Distended abdomen vii. Abdominal wall defects viii. Organomegaly ix. Renal anomalies x. Cardiac anomalies c. Cytogenetic studies i. Possible if a cytogenetic abnormality has been identified in the proband and one parent ii. To identify translocations, inversions, and duplications involving 11p15 d. Molecular analysis i. Uniparental disomy ii. Mutation analysis of P57KIP2 provided the mutation is documented in the previously affected child
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3. Management a. Early detection and close monitoring for hypoglycemia to reduce the risk of central nervous system complications b. Partial tongue resection for cosmetic purpose and to relieve severe airway obstruction c. Surgical risks related to hypoglycemia or difficulty in intubation secondary to macroglossia d. Management of abdominal wall defects, gastrointestinal malformations, and renal anomalies e. Orthopedic follow-up of hemihyperplasia f. Management of structural renal abnormalities g. Management of embryonal neoplasms
REFERENCES Beckwith JB: Extreme cytomegaly of the adrenal fetal cortex, omphalocele, hyperplasia of kidneys and pancreas, and Leydig cell hyperplasia: Another syndrome? Abstract, Western society of Pediatric Research, Los Angels, November 11, 1963. Borer JG, Kaefer M, Barnewolt CE, et al.: Renal findings on radiological followup of patients with Beckwith-Wiedemann syndrome. J Urol 161:235–239, 1999. Chitayat D, Rothchild A, Ling E, et al.: Apparent postnatal onset of some manifestations of the Wiedemann-Beckwith syndrome. Am J Med Genet 36:434–439, 1990. Cohen MM Jr: Overgrowth syndromes: An update. Adv Pediatr 40:441–491, 1999. Elliot M, Maher ER: Beckwith-Wiedemann syndrome. J Med Genet 31:560–564, 1994. Elliott M, Bayly R, Cole T, et al.: Clinical features and natural history of Beckwith-Wiedemann syndrome: presentation of 74 new cases. Clin Genet 46:168–174, 1994. Engel JR, Smallwood A, Harper A, et al.: Epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome. J Med Genet 37:921–926, 2000. Engstrom W, Lindham S, Schofield P: Wiedemann-Beckwith syndrome. Eur J Pediatr 147:450–457, 1988. Everman DB, Shuman C, Dzolganovski B, et al.: Serum alpha-fetoprotein levels in Beckwith-Wiedemann syndrome. J Pediatr 137:123–127, 2000. Ferry RJ Jr, Cohen P: Beckwith-Wiedemann syndrome. Emedicine, 2002. http://www.emedicine.com Hatada I, Mukai T: Genomic imprinting and Beckwith-Wiedemann syndrome. Histol Histopathol 15:309–312, 2000. Hatada I, Ohashi H, Fukushima Y, et al.: An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome. Nat Genet 14:171–173, 1996.
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Joyce JA, Lam WK, Catchpoole DJ, et al.: Imprinting of IGF2 and H19: lack of reciprocity in sporadic Beckwith-Wiedemann syndrome. Hum Mol Genet 6:1543–1548, 1997. Lam WW, Hatada I, Ohishi S, et al.: Analysis of germline CDKN1C (p57KIP2) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel genotype-phenotype correlation. J Med Genet 36:518–523, 1999. Li M, Squire JA, Weksberg R: Molecular genetics of Beckwith-Wiedemann syndrome. Curr Opin Pediatr 9:623–629, 1997. Li M, Squire JA, Weksberg R: Molecular genetics of Wiedemann-Beckwith syndrome. Am J Med Genet 79:253–259, 1998. Maher ER, Reik W: Beckwith-Wiedemann syndrome: imprinting in clusters revisited. J Clin Invest 105:247–252, 2000. Murrell A, Heeson S, Cooper WN, et al.: An association between variants in the IGF2 gene and Beckwith-Wiedemann syndrome: interaction between genotype and epigenotype. Hum Molec Genet 13:247–255, 2004. Norman AM, Read AP, Clayton-Smith J, et al.: Recurrent WiedemannBeckwith syndrome with inversion of chromosome (11) (p11.2p15.5). Am J Med Genet 42:638–641, 1992. Pettenati MJ, Haines JL, Higgins RR, et al.: Wiedemann-Beckwith syndrome: Presentation of clinical and cytogenetic data on 22 new cases and review of the literature. Hum Genet 74:143–154, 1986. Reish O, Lerer I, Amiel A, et al.: Wiedemann-Beckwith syndrome: further prenatal characterization of the condition. Am J Med Genet 107:209–213, 2002. Shuman C, Weksberg R: Beckwith-Wiedemann syndrome. Gene Reviews, January, 2003. http://www.genetests.org Slatter RE, Elliott M, Welham K, et al.: Mosaic uniparental disomy in Beckwith-Wiedemann syndrome. J Med Genet 31:749–753, 1994. Slavotinek A, Gaunt L, Donnai D: Paternally inherited duplications of 11p15.5 and Beckwith-Wiedemann syndrome. J Med Genet 34:819–826, 1997. Waziri M, Patil SR, Hanson JW, et al.: Abnormality of chromosome 11 in patients with features of Beckwith-Wiedemann syndrome. J Pediatr 102:873–876, 1983. Weksberg R, Shuman C: Beckwith-Wiedemann syndrome. In: Cassidy SB, Allanson JE (eds): Management of Genetic Syndromes. New York: Wiley-Liss, 2001. Weng EY, Moeschler JB, Graham JM Jr: Longitudinal observations on 15 children with Wiedemann-Beckwith syndrome. Am J Med Genet 56:366–373, 1995. Weng EY, Mortier GR, Graham JM Jr: Beckwith-Wiedemann syndrome. An update and review for the primary pediatrician. Clin Pediatr 34:317–326, 1995. Wiedemann H-R: Complexe malformatif familial avec hernie ombilicale et macroglossia, un “syndrome nouveau.” J Genet Hum 13:223–232, 1964. Winter SC, Curry CJ, Smith JC, et al.: Prenatal diagnosis of the BeckwithWiedemann syndrome. Am J Med Genet 24:137–141, 1986.
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Fig. 1. Five infants with BWS showing hemangioma, macroglossia and umbilical hernia.
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Fig. 2. An infant with BWS showing macroglossia, ear crease, and umbilical hernia.
Fig. 5. A young adult with BWS showing macroglossia and post-surgical status of umbilical and inguinal hernia repairs.
Fig. 3. An infant with BWS and a large omphalocele requiring surgical intervention.
Fig. 4. An infant with BWS prior to partial glossectomy.
Behcet Disease In 1937, Behçet first described three patients with oral and genital ulceration and hypopyon. It is most common in the Middle and Far East with a prevalence of 7 to 8 per 100,000 people, whereas in the United States the prevalence is estimated at 4 per 1,000,000 people.
GENETICS/BASIC DEFECTS 1. A complex multisystem inflammatory disease of unknown cause 2. Considered a relapsing and remitting vasculitis of the small- to medium-sized vessels with following protean manifestations a. Aphthous stomatitis b. Genital ulceration c. Uveitis d. Synovitis e. Gastrointestinal lesions f. Cutaneous lesions g. Central nervous system lesions h. Cardiac lesions i. Vessel lesions 3. Immunopathogenic aspects of Behcet disease a. Neutrophil activation b. Cellular and humoral immunity c. Antigenic stimuli i. Herpes simplex virus ii. Streptococci and superantigens iii. Heat shock proteins (65 kDa, αβ-crystallin) d. Genetic predisposition to HLA-B51 and antigen presentation e. Retinal-S antigen and HLA-B51 as autoantigens f. Vascular disease and antiendothelial cell antibodies g. Severity and sex: more severe in men
CLINICAL FEATURES 1. Highly variable clinical course with recurrences and remissions 2. Recurrent attacks of oral, genital, ocular, and skin lesions a. Oral aphthous ulcers i. Keystones to diagnosis of Behcet disease according to the classification criteria ii. Often an initial presenting sign iii. Occurring on the buccal mucosa, tongue, gingiva and the soft palate area iv. Minor aphthous ulcers: superficial with a diameter of 2–6 mm, appearing as multiple lesions, and developing within 1–2 days. They heal without scarring within 7–10 days and recur at various frequencies v. Major aphthous ulcers: deeper and painful lesions leaving scars after healing 114
vi. Herpetiform aphthous ulcers: numerous lesions grouped as small ulcers b. Genital ulcers i. Women: located on the vulva, vagina, cervix uteri ii. Men: located on the prepuce and scrotum iii. Lesions resembling the oral aphthae but tend to be deeper and leaving scars iv. Differential diagnosis from other genital ulcers (herpes simplex, syphilis, tropical ulcers, and skin infestations) c. Ocular lesions (70–85%) i. Generally follow the genital and oral ulceration by a few years ii. Characterized by severe vasculitis with arterial and venous occlusions iii. Hypopyon (presence of leukocytes in the anterior chamber of the eye) iv. Uveitis v. Hemorrhagic and exudative retinal lesions (retinitis) vi. Marked vitritis vii. Choroiditis viii. Bilateral nongranulomatous inflammation of the iris and ciliary body ix. Intermittent blurring of vision and loss of vision d. Skin lesions i. Pustular vasculitic cutaneous lesions: may evolve as lesions of small vessel necrotizing vasculitis from a neutrophilic vascular reaction to a lymphocytic perivascular reaction ii. Erythema nodosum-like lesions: usually occurring on the lower extremities but can be seen on the arms, neck, and face iii. Pseudofolliculitis iv. Papulopastular lesions: neutrophil-induced, vesselbased reaction v. Acneiform nodules 3. Articular manifestations a. Recurrent seronegative arthritis i. Common findings ii. A nonspecific synovitis b. Monoarthritis c. Polyarthritis 4. Gastrointestinal manifestations a. Ulcerative lesions most frequently occurring in the terminal ileum, caecum, stomach, and intestine b. Symptoms i. Abdominal pain ii. Diarrhea iii. Melena iv. Perforation 5. CNS manifestations (about 1% of patients) a. Headaches b. Meningitis
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7.
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c. Meningoencephalitis d. Cranial nerve palsies e. Peripheral nerve involvement with vasculitis f. Cerebellar ataxia g. Hemiplegia h. Benign intracranial hypertension i. Neurologic deficits j. Cerebral aneurysm k. Cerebral vasculitis and ischaemic stroke: unusual l. Personality changes and depression m. Dementia n. Hearing and vestibular disturbances Pulmonary manifestations a. Tracheobronchial ulcerations b. Pleurisy c. Embolism d. Pulmonary arterial aneurysms e. Pneumonitis f. Fibrosis Renal involvement: rare a. Glomerulonephritis b. Systemic amyloidosis Cardiac manifestations a. Intracardiac thrombosis b. Myocardial infarction c. Pericarditis d. Endocarditis Vascular manifestations a. Superficial thrombophlebitis b. Deep thrombophlebitis c. Small vessel vasculitis d. Aneurysm Criteria for clinical diagnosis of Behcet disease, proposed by O’Duffy and Goldstein in 1976, require the presence of recurrent oral or genital aphtha along with two additional systemic findings for diagnosis and only one for the diagnosis of the incomplete form a. Criteria i. Aphthous stomatitis ii. Aphthous genital ulceration iii. Uveitis iv. Cutaneous “pustular” vasculitis v. Synovitis vi. Meningoencephalitis b. Diagnosis: at least three criteria present, one being recurrent aphthous ulceration c. Incomplete form: two criteria present, one being recurrent aphthous ulceration d. Exclusion i. Inflammatory bowel disease ii. Systemic lupus erythematosus iii. Reiter’s disease iv. Herpetic infections The International Study Group criteria were published in 1990 to include positive Pathergy test as one of the criteria to establish the diagnosis of Behcet disease: a. Recurrent oral ulceration: minor aphthous, major aphthous, or herpetiform ulceration observed by physician or patient that recurred at least three times in one 12-month period
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b. Plus 2 of the following criteria (findings applicable only in absence of other clinical explanations) i. Recurrent genital ulceration: aphthous ulceration or scarring observed by physician or patient ii. Eye lesions: anterior uveitis, posterior uveitis, or cells in vitreous on slit lamp examination; or retinal vasculitis observed by ophthalmologist iii. Skin lesions: erythema nodosum observed by physician or patient, pseudofolliculitis or papulopustular lesions; or acneiform nodules observed by physician in post-adolescent patients not receiving corticosteroid treatment iv. Pathergy test (a nonspecific pustule that is an inflammatory reaction to needle pricks in approximately 40% of patients, especially during the exacerbation period): Pathergy test is positive when pricking a sterile needle into the patient’s forearm results in an aseptic erythematous nodule or pustule that is more than 2 mm in diameter at 24–48 hours
DIAGNOSTIC INVESTIGATIONS 1. Positive skin pathergy 2. Laboratory findings a. Acute-phase response i. Raised erythrocyte sedimentation rate ii. Increased serum levels of C-reactive protein iii. Elevated plasma complement components, such as C3, C4, C9, and factor B b. Disease exacerbations i. Elevated IgG, IgA, IgM ii. Elevated C-reactive protein iii. Elevated α2-globulin c. Interleukin (IL)-8 as a serological marker 3. HLA typing 4. Fluorescein angiography, color Doppler imaging and fundoscopic examination to detect retinal features 5. MRI and CT scan to detect the neurologic lesions 6. Histopathological features a. Pathergy lesions i. Leucocytoclastic vasculitis ii. Neutrophilic vascular reaction iii. Polymorphonuclear leucocyte infiltration b. Erythema nodosum-like lesions i. Neutrophilic vascular reaction or vasculitis in the dermis and subcutaneous tissue ii. Perivascular lymphocytic dermal inflammation c. Common histopathological lesions in all organ systems i. Vasculitis ii. Thrombosis iii. Perivascular infiltrates of lymphomononuclear cells iv. Neutrophilic vascular reaction d. Early cutaneous lesions: neutrophilic vascular reaction or leucocytoclastic vasculitis e. Late cutaneous lesions: lymphocytic perivasculitis
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased
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b. Patient’s offspring: not increased 2. Prenatal diagnosis: no prenatal diagnosis reported 3. Management: a. Mucocutaneous lesions i. Topical corticosteroids: useful for oral and genital ulcers ii. Colchicine: beneficial effects on the mucocutaneous symptoms, presumably by inhibiting neutrophil function iii. Treatment with thalidomide: effective for oral and genital ulcers and pseudofolliculitis iv. Systemic corticosteroids : prescribed for erythema nodosum that is refractory to treatment with colchicine b. Ocular lesions i. About 25% of patients eventually develop blindness despite therapeutic intervention ii. Topical mydriatic agents and corticosteroid drops: given for attacks of anterior uveitis iii. Colchicine: prescribed to prevent both anterior and posterior uveitis because of its high degree of efficacy and relatively low toxicity iv. Topical injection of corticosteroids, with systemic administration in some cases: used for acute attacks of posterior uveitis v. Cytotoxic agents (azathioprine, chlorambucil, and cyclophosphamide): help prevent ocular attacks in approximately 50–75% of patients vi. Cyclosporine: beneficial in 70–80% of patients with ocular lesions that have been refractory to the conventional therapies vii. Subcutaneous human recombinant interferon alpha: an effective and fairly well tolerated therapy for Behcet disease viii. Results from therapies: improved vision and decreased pain, saving the individual a potential enucleation c. Arthritis i. Nonsteroidal anti-inflammatory drugs and colchicine: effective for most cases of arthritis ii. Low dose corticosteroids and azathioprine: used in patients whose arthritis is resistant to treatment with nonsteroidal anti-inflammatory drugs, colchicine, or Sulfasalazine iii. Interferon alfa: also highly effective d. Gastrointestinal lesions i. Sulfasalazine and corticosteroids: the principal drugs ii. Bowel rest: obligatory in patients with an acute abdomen and bleeding iii. Surgery: considered for patients with bowel perforation and persistent bleeding e. CNS lesions i. High doses of corticosteroids ii. Supplemented with cytotoxic agents f. Large-vessel lesions i. Treated with a combination of corticosteroids and cytotoxic agents ii. Anticoagulants and antiplatelet agents: used for deep venous thrombosis iii. Surgery for refractory large-vessel disease
REFERENCES Behçet H: Über rezidivierende, aphthöse, durch ein Virus verursachte Geschwüre am Mund, am Auge und an den Genitalien. Dermatol Wschr 105:1152–1157, 1937. Benezra D, Cohen E: Treatment and visual prognosis in Behcet’s disease. Br J Ophthalmol 70:589–592, 1986. Brik R, Shamali H, Bergman R: Successful thalidomide treatment of severe infantile Behçet disease. Pediatr Dermatol 18:143, 2001. Chajek T, Fainaru M: Behcet’s disease: Report of 41 cases and review of the literature. Medicine 54:179–196, 1975. Chen KR, Kawara Y, Miyakawa S et al.: Cutaneous vasculitis in Behçet’s disease. A clinical and histopathological study of 20 patients. J Am Acad Dermatol 36:689–696, 1997. Direskeneli H: Behcet’s disease: infectious aetiology, new autoantigens, and HLA-B51. Ann Rheum Dis 60:996–1002, 2001. Ecker RD, Galiani D, Carney M, et al.: Behcets Disease in an African American man. Am J Emerg Med 18:118–119, 2000. Englin RP, Lehner T, Subak-Sharpe JH: Detection of RNA complementary to herpes simplex virus in mononuclear cells from patients with Behcets syndrome and recurrent oral ulcers. Lancet 2:1356–1361, 1982. Evereklioglu C, Inalöz HS, Kirtak N, et al.: Serum leptin concentration is increased in patients with Behçet’s syndrome and is correlated with disease activity. Br J Dermatol 147:331, 2002. Ghate JV, Jorizzo JL. Behçets disease and complex aphthosis. J Am Acad Dermatol 40:1–18, 1999. George RK, Chan CC, Whitcup SM, et al.: Ocular immunopathology of Behcet’s disease. Surv Ophthalmol 42:157–162, 1997. Georgiou S, Monastirli A, Pasmatzi E, et al.: Efficacy and safety of systemic recombinant interferon-alpha in Behcet’s disease. J Int Med 243:367–372, 1998. Hamuryudan V, Mat C, Saip S, et al.: Thalidomide in the treatment of the mucocutaneous lesions of the Behcet syndrome. A randomized, doubleblind, placebo-controlled trial. Ann Int Med 128:443–450, 1998. International Study Group for Behcet’s Disease: Criteria for diagnosis of Behcet’s Disease. Lancet 335:1078–1080, 1990. Jorizzo JL, Abernethy JL, White WL, et al.: Mucocutaneous criteria for the diagnosis of Behçet’s disease: an analysis of clinicopathologic data from multiple international centers. J Am Acad Dermatol 32:968–976, 1995. Krespi Y, Akman-Demir G, Poyraz M, et al.: Cerebral vasculitis and ischaemic stroke in Behçet’s disease: report of one case and review of the literature. Eur J Neurol 8:719, 2001. Lang B, Laxer R, Thorin P, et al.: Pediatric onset of Behçet’s syndrome with myositis: case report and literature review illustrating unusual features. Arthritis Rheum 33:418–424, 1990. Mangelsdorf HC, White WL, Jorizzo JL: Behçet’s disease: Report of twentyfive patients from United States with prominent mucocutaneous involvement. J Am Acad Dermatol 34:745–750, 1996. Mogulkoc N, Burgess MI, Bishop PW: Intracardiac thrombus in Behcet’s disease: a systemic review. Chest 118:479–487, 2000. O’Duffy JD, Goldstein NP: Neurologic involvement in seven patients with Behcet’s disease. Am J Med 61:17-18, 1976. Önder M, Gürer MA: The multiple faces of Behçet’s disease and its aetiological factors. J Eur Acad Dermatol Venereol 15:126, 2001. Piuetti Pezzi P, Gasparri V, De Liso P, et al.: Prognosis in Behcet’s Disease. Ann Ophthalmol 17:20–25, 1985. Rabinovich CE, Wagner-Weiner L: Behcet syndrome. Emedicine, 2001. http://www.emedicine.com Rizzi R, Bruno S, Dammacco R: Behçet’s disease: an immune-mediated vasculitis involving vessels of all sizes. Int J Clin Lab Res 27:225–232, 1997. Sakane T, Takeno M, Suzuki N, et al.: Behçet’s disease. N Engl J Med 341: 1284–1291, 1999. Serdaroglu P: Behçet’s disease and the nervous system. J Neurol 245:197–205, 1998. Shek LPC, Lee YS, Lehman TJA: Thalidomide responsiveness in an infant with Behçet’s syndrome. Pediatrics 103:1295–1297, 1999. Stratigos A, Laskaris G, Stratigos J: Behçet’s disease. Semin Neurol 12:346–357, 1992. Verity DH, Marr JE, Ohno S, et al.: Behçet’s disease, the Silk Road and HLA-B51: historical and geographical perspectives. Tissue Antigens 54:213–220, 1999. Yazici H: The place of Behcet’s syndrome among the autoimmune diseases. Int Rev Immunol 14:1–10, 1997. Zen-nyoji M, Okamura SI, Kyoko Harada K, et al.: Intestinal Behcet’s disease associated with generalized myositis. Gastrointestinal Endoscopy 51:359–361, 2000.
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Fig. 2. A female patient with Behcet disease showing generalized scars from blisters on the buccal mucosa, trunk, arms, legs, and palms.
Fig. 1. Aphthae on the tongue, buccal mucosa, and gums of a child with Behcet disease.
Fig. 3. A large aphthous ulcer on mucosal membrane of the lower lip of a patient with acute exacerbation of Behcet disease.
Fig. 4. Occluded retinal vessels and retinal hemorrhage with arterial and venous occlusive vasculitis in a patient with Behcet disease.
Bladder Exstrophy Bladder exstrophy is a rare developmental anomaly occurring as an isolated defect in about 1/25,000–1/40,000 births.
GENETICS/BASIC DEFECTS 1. Genetics: usually an isolated defect 2. Basic defects a. Probably failure of fusion of the secondary mesoderm (from the primitive streak) in the midline of the anterior abdominal wall, with subsequent rupture of the thin wall consisting only of ectoderm and endoderm b. Early rupture (5th week) resulting in exstrophy of the cloaca, later rupture (7th week) resulting in exstrophy of the bladder
CLINICAL FEATURES 1. Classical bladder exstrophy a. Diagnosis easily made at birth b. Occupy 60% of the patients with the exstrophy-epispadias complex c. Bladder plate protruding just beneath the umbilical cord d. Posterior bladder wall is exposed through a midline abdominal wall defect e. Inferiorly displaced umbilicus located close to the superior margin of the exstrophic bladder f. Rectus muscles divergent on either side of the bladder i. Leading to the separated pubic bones ii. Separation of the pubic bones caused by an outward rotation of the innominate bones and eversion of the pubic rami g. Male patients i. A short epispadiac phallus with a dorsal urethral plate a) Caused by separation of the pubic bones b) Possibly caused by a true deficiency of corporeal tissue ii. A splayed glans iii. Dorsal chordee h. Female patients i. Genital defect analogous to the male but more easily reconstructed ii. Separated mons pubis (both hemiclitori and labia) (split clitoris and exstrophic vagina) iii. Predisposing to uterine prolapse, especially after pregnancy and delivery, secondary to pelvic floor defect i. Urinary tract abnormalities i. Generally normal upper urinary tract ii. Occasional abnormalities a) Unilateral renal agenesis b) Horseshoe kidney c) Hydronephrosis d) Other renal anomalies 118
j. Internal genitalia: usually normal k. Fertility and childbearing i. Documented in both sexes but less common in the males ii. C-section advised to avoid injury to continence mechanism iii. Postpartum uterine prolapse common because of aggravation of preexisting abnormal pelvic support l. Inguinal hernias i. Incidence: very common a) 56–82% in boys b) 11–15% in girls ii. Incidence of bowel incarceration below one year of age: 10–53% iii. Causes a) Large internal and external inguinal rings b) Lack of obliquity of the inguinal canal m. Anus i. Anteriorly placed ii. Fecal continence adversely affected by the divergence of the pelvic musculature n. Rectal prolapse i. Virtually always disappears after bladder closure or cystectomy ii. Represents an indication for surgical management of the exstrophied bladder o. Spinal abnormalities (6.7%) i. Myelomeningocele ii. Lipomeningocele iii. Scimitar sacrum iv. Posterior laminal defects v. Vertebral fusion vi. Hemivertebrae p. Malignancies i. Rare late complication of bladder exstrophy, especially in untreated patients whose bladders are left exstrophic for many years ii. Types of malignancies a) Adenocarcinoma: the most common type, arising from the precursor cystitis glandularis, a consequence of chronic irritation and inflammation of exposed bladder mucosa b) Squamous cell carcinoma and rhabdomyosarcoma c) Adenocarcinoma developing adjacent to the ureterointestinal anastomoses in patients with urinary diversions that mix the urinary and fecal streams d) The risk of developing colon adenocarcinoma is increased 7000-fold after ureterosigmoidostomy among patients younger than 25 years of age than the general population
BLADDER EXSTROPHY
q. Behavioral, social and school competency problems observed in 70% of adolescents and 33% of school aged children r. 70% of parents express concern about the children’s sexual function or sexual disfigurement s. Consider all patients with exstrophy-epispadias complex to be latex-sensitive 2. Variants of exstrophy a. Pseudo-exstrophy (exstrophic abdominal wall defect without bladder exstrophy) b. Duplicate exstrophy c. Superior vesical fistula and fissure d. Covered exstrophy and visceral sequestration
c.
DIAGNOSTIC INVESTIGATIONS 1. General assessment 2. Cardiopulmonary assessment 3. Renal ultrasound for baseline examination of the kidneys since increased bladder pressure after bladder closure can lead to hydronephrosis and upper urinary tract deterioration 4. Voiding cystourethrogram a. To rule out bilateral vesicoureteral reflux which is present in nearly all patients with classic bladder exstrophy b. Performed in early childhood to assess bladder capacity in preparation for continence reconstruction
d.
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: the risk of recurrence of exstrophy or epispadias in a given family is one of 275 births b. Patient’s offspring: the risk of a parent with exstrophy producing a child with exstrophy or epispadias is up to one of 70 or 500 times the risk of the general population 2. Prenatal diagnosis possible by ultrasonography a. Absence of bladder filling in the presence of normal kidneys (bladder never demonstrated on the ultrasound) (71%) b. A protuberance on the lower abdomen representing the exstrophied bladder (47%) c. A diminutive penis with anteriorly displaced scrotum (57% of the males) d. A low-set umbilical insertion (29%) e. Abnormal widening of the iliac crests (18%) f. Separation of the pubic rami g. Difficulty in ascertaining the sex of the fetus 3. Management a. Supportive management i. Ligate umbilical cord with suture to avoid bladder mucosal damage by an umbilical clamp ii. Protect bladder a) With clear plastic wrap b) Irrigate the bladder surface with sterile saline each time diaper is changed and the wrap replaced iii. Initiate prophylactic antibiotics b. Goals of the reconstruction of bladder exstrophy i. Preservation of the kidney function ii. Creation of urinary continence
e.
f. g.
h.
i.
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iii. Reduction in the urinary tract infections iv. Creation of functionally and cosmetically acceptable external genitalia Initial bladder closure i. Closure of the pelvic ring a) Important for the initial closure b) Important for the eventual attainment of urinary continence ii. Pelvic osteotomy a) Two main approaches: posterior iliac osteotomy and the anterior innominate osteotomy b) Reduce the tension on the suture lines to help securing the bladder closure c) To restore the pelvic anatomy and thus increase the chances of eventual continence and reduce the likelihood of uterine prolapse Epispadias repair i. Usually performed at 2–3 years of age before the continence procedure ii. Contributing significantly to the development of bladder capacity iii. Goals a) Reconstruction of the urethra and glans penis b) Encourage the potential of penile length c) Correction of the dorsal chordee d) Achieving adequate skin coverage iv. Penis is generally reconstructible to cosmetically and functionally acceptable form, despite a short phallus Bladder neck reconstruction i. Usually performed at age of 4–5 years (when toilet training is possible) ii. Require anti-reflux procedure since all exstrophy patients have vesicoureteral reflux iii. Complete urinary drainage achieved with ureteral stents and suprapubic cystostomy tubes Ureteral reimplantation Bladder augmentation and continent diversion for patients who have failed bladder neck reconstruction and have an inadequate bladder capacity Alternatives for exstrophy reconstruction i. For patients with very small bladder plates or hydronephrosis ii. Ureterosigmoidostomies a) Allow children to achieve continence b) Protect upper urinary tracts c) Potential complications: recurrent acute and chronic pyelonephritis, urolithiasis, hyperchloremic hypokalemic metabolic acidosis, ureteral obstruction and the late development of colonic malignancy Repair of inguinal hernias at the time of primary closure of bladder exstrophy
REFERENCES Barth RA, Filly RA, Sondheimer FK: Prenatal sonographic findings in bladder exstrophy. J Ultrasound Med 9:359–361, 1990. Ben-Chaim J, Docimo SG, Jeffs RD, et al.: Bladder exstrophy from childhood into adult life. J R Soc Med 89:39–46, 1996.
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Burbige KA, Hensle TW, Chambers WJ, et al.: Pregnancy and sexual function in women with bladder exstrophy. Urology 28:12–14, 1986. Cacciari A, Pilu GL, Mordenti M, et al.: Prenatal diagnosis of bladder exstrophy: what counseling? J Urol 161:259–261; discussion 262, 1999. Cadeddu JA, Benson JE, Silver RI, et al.: Spinal abnormalities in classic bladder exstrophy. Br J Urol 79:975–978, 1997. Canning DA: Exstrophy of the cloaca and exstrophy of the bladder: two different expressions of a primary development field defect. J Urol 169:1601, 2003. Cerniglia FR, Roth DA, Gouyden ET: Covered exstrophy and visceral sequestration in a male newborn. J Urol 141:903–904, 1989. Diseth TH, Emblem R, Schultz A: Mental health, psychosocial functioning, and quality of life in patients with bladder exstrophy and epispadias-an overview. World J Urol 17:239–248, 1999. Gearhart JP, Ben-Chaim J, Jeffs RD, et al.: Criteria for the prenatal diagnosis of classic bladder exstrophy. Obstet Gynecol 85:961–964, 1995. Goldstein I, Shalev E, Nisman D: The dilemma of prenatal diagnosis of bladder exstrophy: a case report and a review of the literature. Ultrasound Obstet Gynecol 17:357–359, 2001. Grady RW, Carr MC, Mitchell ME: Complete primary closure of bladder exstrophy. Epispadias and bladder exstrophy repair. Urol Clin North Am 26:95–109, 1999. Higgins CC: Exstrophy of the bladder: report of 158 cases. Am Surg 28:99–102, 1962. Ives E, Coffey R, Carter CO: A family study of bladder exstrophy. J Med Genet 17:139–141, 1980.
Krisiloff M, Puchner PJ, Tretter W, et al.: Pregnancy in women with bladder exstrophy. J Urol 119:478–479, 1978. Ledfors GE, Lansing JD, Slate WG, et al: Pregnancy and exstrophy of the urinary bladder. Obstet Gynecol 28:254–257, 1966. Martinez-Frias ML, Bermejo E, Rodriguez-Pinilla E, et al.: Exstrophy of the cloaca and exstrophy of the bladder: two different expressions of a primary developmental field defect. Am J Med Genet 99:261–269, 2001. Megalli M, Lattimer JK: Review of the management of 140 cases of exstrophy of the bladder. J Urol 109:246–248, 1973. Mesrobian HG, Kelalis PP, Kramer SA: Long-term followup of 103 patients with bladder exstrophy. J Urol 139:719–722, 1988. Messelink EJ, Aronson DC, Knuist M, et al.: Four cases of bladder exstrophy in two families. J Med Genet 31:490–492, 1994. Mildenberger H, Kluth D, Dziuba M: Embryology of bladder exstrophy. J Pediatr Surg 23:166–170, 1988. Shapiro E, Lepor H, Jeffs RD: The inheritance of exstrophy-epispadias complex. J Urol 132:308, 1980. Stein R, Thuroff JW: Hypospadias and bladder exstrophy. Curr Opin Urol 12:195–200, 2002. Stjernqvist K, Kockum CC: Bladder exstrophy: psychological impact during childhood. J Urol 162:2125–2129, 1999. White P, Lebowitz RL: Exstrophy of the bladder. Radiol Clin North Am 15:93–107, 1977. Yerkes EB, Rink RC: Exstrophy and epispadias. Emedicine, 2002. http://www.emedicine.com
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Fig. 1. A newborn male with classic bladder exstrophy showing low insertion of the umbilical cord, a bulging mass of exstrophic bladder, and grossly abnormal external genitalia.
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Body Stalk Anomaly Body stalk anomaly, sometimes also called limb body wall complex, is a rare abdominal wall defect due to failure of the development of the body stalk. Prevalence is estimated to be 0.32 per 10,000 births.
4. Pathogenesis a. The umbilical cord, derived from a small mass of mesoderm (body stalk), attaches the embryo to the wall of the blastocysts b. Abnormal development of the body stalk resulting in an absent or rudimentary umbilical cord c. Consequences i. Direct attachment of fetus to the placenta ii. Abdominal viscera lying in a sac outside the abdominal cavity covered by amnion
GENETICS/BASIC DEFECTS 1. Sporadic occurrence in most cases, although concordance in twins has been reported 2. Failure in body folding in cranial, caudal and lateral axes during the embryonic stage of development a. Abnormalities of cranial folding leading to pentalogy of Cantrell consisting of the following: i. Cardiac abnormalities ii. Sternal cleft iii. Upper abdominal defect iv. Anterior diaphragmatic hernia v. Deficiency of the diaphragmatic pericardium b. Abnormalities of caudal folding leading to the following: i. Cloacal exstrophy ii. Hypogastric omphalocele iii. Imperforate anus iv. Partial colonic agenesis v. Agenesis of one umbilical artery c. Abnormalities of lateral folding leading to midline omphalocele d. Abnormalities of folding along all three axes resulting in a body stalk anomaly i. Failure to obliterate the extraembryonic cavity that continues to communicate with the intraembryonic cavity ii. Creation of a large ventral wall defect that is covered by an amnioperitoneal membrane which contains the abdominal viscera and inserts directly into the chorionic plate iii. The fetus appearing to be directly attached to the placenta as the umbilical cord is significantly shortened or absent iv. Frequent kyphoscoliosis owing to limited truncal flexion 3. Possible causes of the anomaly a. Early amnion rupture before obliteration of the extraembryonic coelom b. Abnormal splitting of the embryo at the fourth gestational week c. Disturbance of the blood flow due to vascular rupture, as described in cocaine users d. A special situation in monozygotic twins e. Maternal uniparental disomy of chromosome 16 in a fetus with body stalk anomaly suggesting placental insufficiency or imprinting effects as cause of this anomaly
CLINICAL FEATURES 1. A large anterior abdominal wall defect with a large omphalocele a. Outside the abdominal cavity containing thoracic and/or abdominal organs b. Covered by amnion c. Appears continuous with (adherent to) the placental membranes 2. Absent, rudimentary, or extremely short umbilical cord. A severe type of short umbilical cord syndrome may be a variant of the body stalk anomaly 3. Two-vessel cord 4. Severe kyphoscoliosis 5. Placenta directly attached to the amnioperitoneal sac 6. Extensive associated anomalies a. Hypoplasia of the lungs b. Anal atresia (imperforate anus) c. Agenesis of the colon d. Intestinal atresia e. Exstrophy of the cloaca f. Vaginal atresia g. Agenesis of uterus and gonads h. Absence of external genitalia i. Hypoplastic kidneys j. Absence of diaphragm k. Diaphragmatic hernia l. Spina bifida m. Dysplastic thorax n. Occasional coexistence of the syndrome with limb malformations (mostly lower extremities) and amniotic bands 7. Fetal death caused by abruptio placentae 8. Liveborn infant die shortly afterward
DIAGNOSTIC INVESTIGATIONS
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1. Radiography to document skeletal anomalies 2. Cytogenetic analysis a. No specific anomaly b. Placental karyotyping: report of a case with placental trisomy 16 and maternal uniparental disomy (UPD)
BODY STALK ANOMALY
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: not surviving to reproductive age 2. Prenatal diagnosis a. High maternal serum alpha fetoprotein b. Ultrasonography i. Can be diagnosed as early as the first trimester by transvaginal sonography ii. A large abdominal anterior wall defect with abdominal organs in a sac outside the abdominal cavity in apparent continuity with (adherent to) the placental membranes iii. An extremely short or absent umbilical cord iv. Severe kyphoscoliosis v. Polyhydramnios vi. Oligohydramnios vii. Two vessel cord viii. Sonographic signs alone expect an unequivocal poor prognosis c. Amniocentesis i. Elevated amniotic fluid alpha feto-protein level ii. Abnormal acetylcholinesterase iii. Normal chromosomes 3. Management: newborn with the body stalk anomaly, uniformly fatal
REFERENCES Becker R, Runkel S, Entezami M: Prenatal diagnosis of body stalk anomaly at 9 weeks of gestation. Fetal Diagn Ther 15:301–303, 2000. Blackburn W, Cooley NR: Short umbilical cord syndrome: An anomaly complex recognizable during the prenatal period. Clin Res 32:884, 1984. Cantrell JR, Haller JA, Ravith MM: A syndrome of congenital defects involving the abdominal wall, sternum, diaphragm, pericardium, and heart. Surg Gynecol Obstet 107:602–607, 1958. Chan Y, Silverman N, Jackson L, et al.: Maternal uniparental disomy of chromosome 16 and body stalk anomaly. Am J Med Genet 94:284–286, 2000.
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Craven CM, Carey JC, Ward K: Umbilical cord agenesis in limb body wall defect. Am J Med Genet 71:97–105, 1997. Dakalakis JG, Sebire NJ, Jurkovic D, et al.: Body stalk anomaly at 10–14 weeks of gestation. Ultrasound Obstet Gynecol 10:416–418, 1997. Daskalakis GJ ,Nicolaides KH: Monozygotic twins discordant for body stalk anomaly. Ultrasound Obstet Gynecol 20:79–81, 2002. de Silva MV, Senanayake H, Siriwardana KD: Body stalk anomaly. Ceylon Med J 46:68, 2001. Giacoia GP: Body stalk anomaly: Congenital absence of the umbilical cord. Obstet Gynecol 80:527–529, 1992. Ginsberg NE, Cadkin A, Strom C: Prenatal diagnosis of body stalk anomaly in the first trimester of pregnancy. Ultrasound Obstet Gynecol 10:419–421, 1997. Goldstein I, Winn HN, Hobbins JC: Prenatal diagnostic criteria for body stalk anomaly. Am J Perinatol 6:84,85, 1989. Hiett AK, Devoe LD, Falls DG, et al.: Ultrasound diagnosis of a twin gestation with concordant body stalk anomaly: A case report. J Reprod Med 37:944–946, 1992. Jauniaux E, Vyas S, Finlayson C, et al.: Early sonographic diagnosis of body stalk anomaly. Prenat Diagn 10:127–132, 1990. Lockwood C, Scission A, Hobbins J: Congenital absence of the umbilical cord resulting from maldevelopment of embryonic body folding. Am J Obstet Gynecol 155:1049–1051, 1986. Martinez JM, Fortuny A, Comas C, et al.: Body stalk anomaly associated with maternal cocaine abuse. Prenat Diagn 14:669–672, 1994. Martínez-Frías ML, Bermejo E, Rodríguez-Pinilla E: Body stalk defects, body wall defects, amniotic bands with and without body wall defects, and gastroschisis: Comparative epidemiology. Am J Med Genet 92:13–18, 2000. Paul C, Zosmer N, Jurkovic D, et al.: A case of body stalk anomaly at 10 weeks of gestation. Ultrasound Obstet Gynecol 17:157–159, 2001. Shalev E, Eliyahu S, Battino S, et al.: First trimester transvaginal sonographic diagnosis of body stalk anatomy. J Ultrasound Med 14:641–642, 1995. Shih JC, Shyu MK, Hwa SL, et al.: Concordant body stalk anomaly in monozygotic twinning-early embryo cleavage disorder. Prenat Diagn 16:467–470, 1996. Smrcek JM, Germer U, Krokowski M, et al.: Prenatal ultrasound diagnosis and management of body stalk anomaly: analysis of nine singleton and two multiple pregnancies. Ultrasound Obstet Gynecol 21:322–328, 2003. Takeuchi K, Fujita I, Nakajima K, et al.: Body stalk anomaly: prenatal diagnosis. Int J Gynaecol Obstet 51:49–52, 1995. Van Allen M, Curry C, Gallagher I: Limb body wall complex. I. Pathogenesis. Am J Med Genet 28:529–548, 1987.
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Fig. 1. An extremely premature neonate with body stalk anomaly. Short umbilical cord (7.5 cm with 5 cm fused with placenta) and a large amnioperitoneal sac between the abdomen and the placenta are evident. The sac was filled with internal viscera. In addition, there were anal and urethral atresia, rectovesical fistula, left renal agenesis, lumbosacral meningomyelocele, severe scoliosis, and lumbosacral hypoplasia.
Fig. 2. An infant with body stalk anomaly showing Potter facies, severe kyphoscoliosis, and a large amnioperitoneal sac outside the body. The sac contained abdominal organs. The umbilical cord was absent. Limb and vertebral defects illustrated in the radiographs.
BODY STALK ANOMALY
Fig. 3. Another infant with body stalk anomaly showing anterior abdominal wall defect with a large sac containing abdominal organs, exstrophy of the bladder, and clubfeet.
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Branchial Cleft Anomalies Abnormal persistence of branchial apparatus remnants results in branchial anomalies.
GENETICS/BASIC DEFECTS 1. Embryology of the fetal branchial apparatus a. A derivative of a foregut, developed during the second fetal week b. Consisting of five paired pharyngeal arches, separated internally by four endodermal pouches and externally by four ectodermal clefts 2. Embryology of the branchial clefts a. First branchial cleft i. Giving rise to the Eustachian tube, tympanic cavity, and mastoid antrum ii. Contributing to the formation of the tympanic membrane iii. The only cleft to contribute to the adult structure is the external auditory canal. b. Second, third, and fourth branchial clefts i. Known as the cervical sinus of His (part of an ectodermally lined depression) ii. Obliteration of the cervical sinus as the second and fifth branchial clefts merge c. Second branchial pouch i. Lined by ectoderm ii. Contributing to the palatine tonsil and tonsillar fossa d. Third branchial pouch: forming the following structures i. Inferior parathyroid gland ii. Thymus iii. Pyriform sinus e. Fourth branchial pouch: forming the following structures i. Superior parathyroid gland ii. Apex of the pyriform sinus 3. Pathogenesis of branchial cleft anomalies: remains controversial a. Arising from incomplete obliteration of the cervical sinus of His b. Arising from buried epithelial cell rests 4. Genetics: autosomal dominant inheritance in some families
CLINICAL FEATURES (KOELLER, 1999) 1. Manifestation of branchial cleft anomalies a. Cyst i. An epithelial-lined structure without an external opening ii. Most common branchial cleft anomalies (75%)
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b. Sinus i. A blind tract with an opening externally through the skin on the side of the neck representing persistence of a branchial groove ii. A blind tract with an opening internally into the foregut representing persistence of a branchial pouch c. Fistula i. A tract communicating between the skin externally (a patent abnormal canal opening externally on the neck surface) and the foregut internally (within the pharyngeal mucosa) ii. Representing persistence of a branchial groove with its corresponding pouch and without branchial membrane between them d. Skin tag: a branchial remnant presenting in the lateral neck e. Bilateral branchial cleft anomalies i. Occurring in 2–3% of cases ii. Often familial 2. First branchial cleft cyst a. Accounting for only 5–8% of all branchial cleft defects b. Most commonly seen in middle-aged women c. Usually manifesting as recurrent abscesses or other inflammation (sinus tract) either around the ear or at the angle of the mandible d. History of recurrent parotid abscesses unresponsive to antibiotics and drainage e. Cystic drainage into the external auditory canal i. Aural fistulas ii. Auricular swelling iii. Otitis iv. Otorrhea v. A cervical skin tag at birth f. Occasional sinus tract extending to the hyoid bone g. Cyst related to the parotid gland i. Forming abscess and produce parotitis ii. May be associated with facial nerve palsy 3. Second branchial cleft cyst a. Most common developmental anomalies arising from the branchial apparatus b. Cysts i. Accounting for at least three-fourths of branchial cleft anomalies ii. Typically occurring between 10 and 40 years of age c. Location of the cysts i. Most commonly in the submandibular space ii. Anywhere along a line from the oropharyngeal tonsillar fossa to the supraclavicular region of the neck d. Signs and symptoms of second branchial cleft cyst i. Usually appearing as painless, fluctuant masses in the lateral portion of the neck adjacent to the
BRANCHIAL CLEFT ANOMALIES
anteromedial border of the sternocleidomastoid muscle at the mandibular angle ii. Enlarge slowly over time iii. Painful and tender if secondarily infected iv. Highly suggestive in a young patient with a history of recurrent inflammation in the region of the mandibular angle v. Ostium usually noted at birth just above the clavicle in the anterior neck if a fistula is present e. Fistulas and sinuses i. Almost always present at birth ii. With a small pinpoint external opening iii. May go unnoticed for years if there is no drainage iv. Symptoms consisting of continuous or intermittent mucoid drainage and recurrent attacks of inflammation that often follow mild trauma or an infection of the upper respiratory tract v. Occasional formation of cellulitis and abscess vi. Probing of the track producing irritation of the vagus nerve vii. Usually unilateral viii. Found in several members of the same family 4. Third branchial cleft cyst a. Extremely rare b. Most cysts located in the posterior cervical space posterior to the sternocleidomastoid muscle c. Constituting the second most common congenital lesion of the posterior cervical space of the neck after cystic hygroma d. Usually manifesting as a painless, fluctuant mass in the posterior triangle area of the neck e. Mass usually distending during a viral infection of the upper respiratory tract 5. Fourth branchial cleft cyst a. Extremely rare b. Usually manifesting as a sinus tract rather than a cyst or fistula c. Majority of the lesions occurring on the left side
DIAGNOSTIC INVESTIGATIONS 1. CT scans/MRI imagings a. First branchial cleft cyst i. Appearing as a cystic mass either within, superficial to, or deep to the parotid gland ii. Variable wall thickness and enhancement: increase with recurrent infections iii. Difficult to differentiate from other cystic mass of the parotid gland b. Second branchial cleft cyst i. Typically well-circumscribed, homogeneously hypoattenuated masses surrounded by a uniformly thin wall ii. Increased mural thickness after infection iii. “Beaked sign” (a curved rim of tissue or “beak” pointing medially between the internal and external carotid arteries) considered a pathognomonic imaging feature of a second branchial cleft cyst
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c. Third branchial cleft cyst i. Most commonly appearing as a unilocular cystic mass centered in the posterior cervical space ii. Cyst fluid varying in signal intensity on T1weighted images depending on the protein concentration and is typically hyperintense relative to muscle on T2-weighted images d. Fourth branchial cleft cysts i. Connected with the pyriform sinus ii. Appearing similar to an external or mixed laryngocele 2. Ultrasonography a. A fluctuant, compressible, anechoic or hypoechoic mass b. May have fine internal debris 3. Sinogram or fistulogram with radiopaque dye a. To help confirming the diagnosis b. To identify length and location of the fistulous tract c. To identify an associated cyst
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Not increased in de novo case ii. 50% recurrence risk if a parent is affected with an autosomal dominant disorder b. Patient’s offspring: 50% in autosomal dominant inheritance 2. Prenatal diagnosis by ultrasonography possible by demonstrating a cystic neck mass in the fetus with differential diagnosis including hemangioma, dermoid cyst, neuroblastoma, congenital cystic hygroma, teratoma, epignathus, esophageal duplication, goiter, and laryngocele 3. Management a. First branchial cleft cyst: complete surgical excision (only curative therapy) b. Second and third branchial cleft cysts: surgical excision recommended because of increased frequency of secondary infection c. Recurrence risk uncommon after surgical excision d. Antibiotics required for treating infections or abscess
REFERENCES Anand TS, Anand CS, Chaurasia BD: Seven cases of branchial cyst and sinuses in four generations. Hum Hered 29:213–216, 1979. Agaton-Bonilla FC, Gay-Escoda C: Diagnosis and treatment of branchial cleft cysts and fistulae. A retrospective study of 183 patients. Int J Oral Maxillofac Surg 25:449–452, 1996. Arndal H, Bonding P: First branchial cleft anomaly. Clin Otolaryngol 21:203–207, 1996. Benson MT, Dalen K, Mancuso AA, et al.: Congenital anomalies of the branchial apparatus: embryology and pathologic anatomy. Radiographics 12:943, 1992. Chandler JR, Mitchell B: Branchial cleft cysts, sinuses, and fistulas. Ophthalmol Clin N Am 14:175–186, 1981. Choi SS, Zalzal GH: Branchial anomalies: A review of 52 cases. Laryngoscope 105:909–913, 1995. Clevens RA, Weimert TA: Familial bilateral branchial cleft cysts. Ear Nose Throat J 74:419–421, 1995. Doi O, Hutson JM, Myers NA, et al.: Branchial remnants: A review of 58 cases. J Pediatr Surg 23:789–792, 1988.
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Ford GR, Balakrishnan A, Evans JN, et al.: Branchial cleft and pouch anomalies. J Laryngol Otol 106:137–143, 1992. Howie AJ, Proops DW: The definition of branchial cysts, sinuses and fistulae. Clin Otolaryngol 7:51–57, 1982. Koeller KK, Alamo L, Adair CF, et al.: Congenital cystic masses of the neck: radiologic-pathologic correlation. Radiographics 19:121–146, 1999. Lev S, Lev MH: Imaging of cystic lesions. Radiol Clin North Am 38:1013–1027, 2000. Mandell DL: Head and neck anomalies related to the branchial apparatus. Ophthalmol Clin N Am 33:1309–1332, 2000. Maran AGD, Buchanan DR: Branchial cysts, sinuses and fistulae. Clin Otolaryngol 3:77–92, 1978. Muckle TJ: Hereditary branchial defects in a Hampshire family. Brit Med J 1:1297–1299, 1961.
Nicollas R, Guelfucci B, Roman S, et al.: Congenital cysts and fistulas of the neck. Int J Pediatr Otorhinolaryngol 55:117–124, 2000. Palacios E, Valvassori G: Branchial cleft cyst. Ear Nose Throat J 80:302, 2001. Ramirez-Camacho R, Garcia Berrocal JR, Borrego P: Radiology quiz case 2. Second branchial cleft cyst and fistula. Arch Otolaryngol Head Neck Surg 127:1395–1396, 2001. Robichaud J, Papsin BC, Forte V: Third branchial cleft anomaly detected in utero. J Otolaryngol 29:185–187, 2000. Triglia JM, Nicollas R, Ducroz V, et al.: First branchial cleft anomalies: a study of 39 cases and a review of the literature. Arch Otolaryngol Head Neck Surg 124:291–295, 1998. Wheeler CE, Shaw RF, Cawley E P: Branchial anomalies in three generations of one family. Arch Derm 77:715–719, 1958.
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Fig. 1. A branchial cleft cyst in the left side of the neck.
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Campomelic Dysplasia Campomelic dysplasia is a rare, often lethal congenital osteochondrodysplasias associated with skeletal malformations and sex-reversal. The term “campomelia” derives from Greek, meaning bent or curved limb. The incidence of campomelic dysplasia is reported to be 0.05–0.9 per 10,000 births.
GENETICS/BASIC DEFECTS
2.
1. Inheritance: autosomal dominant 2. Etiology a. Assignment of a locus CMPD1 to 17q24.3-q25.1 was based on characterization of three independent de novo chromosome 17 translocations in campomelic dysplasia patients b. XY sex reversal of two of these translocation patients placed an autosomal sex-determining locus, SRA1, in the same region c. SOX9, a gene related to the mammalian Y chromosome sex-determining gene SRY, was mapped to this region and found to be near the translocation breakpoint of a sex-reversed campomelic dysplasia patient. d. Subsequent identification of de novo mutations in sex-reversed campomelic patients demonstrated that SOX9 is the gene responsible for both campomelic dysplasia and autosomal sex reversal e. SOX9 mutations i. Disrupt skeletogenesis and chondrocytic differentiation ii. Produce defective testicular development often resulting in sex reversal with female phenotype in chromosomal XY males f. Proof of SOX9 being responsible for both campomelic dysplasia and XY sex reversal: demonstration of de novo heterozygous loss-of-function mutations within the SOX9 coding region in nontranslocation campomelic dysplasia patients g. Isolation of the SOX9 gene on chromosome 17q by positional cloning in combination with positional candidate information from the vicinity of breakpoints in campomelic dysplasia patients with reciprocal de novo translocations
3. 4.
5.
CLINICAL FEATURES 1. Clinically a heterogeneous disorder a. Long-limbed variety i. Bent bones of normal thickness, may be slightly shortened ii. Rarely involves the upper limbs b. Short-limbed variety i. Bent bones are short and wide ii. Two skull types a) Craniosynostotic type with cloverleaf skull b) Normocephalic type 131
6.
c. Acampomelic campomelic dysplasia i. The eponymous feature ‘campomelia’ (the bending of the long bones): not an obligatory feature of the syndrome ii. Absence of campomelia in about 10% of campomelic dysplasia cases Prenatal history a. Polyhydramnios (30% of cases) in the 3rd trimester common b. Growth retardation Extreme hypotonia at birth Characteristic craniofacial features a. Frequent macrodolichocephaly b. Cloverleaf skull c. Wide fontanel d. Short, narrow, and upslanted palpebral fissures e. Ocular hypertelorism f. Flat nasal bridge g. Long philtrum h. Micrognathia (Pierre Robin sequence) i. Cleft palate in 2/3rd of the cases j. Low-set and posteriorly rotated ears k. Prominent nuchal folds l. Hearing loss (deaf) in survivors Prominent and characteristic musculoskeletal features a. Congenital bowed lower limbs (anterior bowing of the tibiae) with pretibial skin dimples. Pretibial dimples appear to result from the loss of subcutaneous tissue secondary to marked stretching of the skin overlying the apexes of the bony curvatures during fetal life b. Short limbs c. Short neck d. Pterygium coli e. Narrow thorax f. Kyphoscoliosis g. Talipes equinovarus h. Hand anomalies i. Brachydactyly ii. Clinodactyly iii. Camptodactyly i. Congenital dislocation of the hips j. Winging of the scapula k. Fewer ribs Genitalia a. Genotypic XY males (3/4th of karyotypic males with sex reversal) i. External genitalia: range from unambiguous female external genitalia to hypospadias with a bifid scrotum and an enlarged clitoris ii. Internal genitalia: various combinations of internal Mullerian and Wolffian duct structures b. Genotypic XX females: remain phenotypic female
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7. CNS a. Mental retardation in survivors b. Large brain c. Hydrocephalus (25%) d. Polygyria e. Absent olfactory bulbs and/or tracts f. Dysgenesis of the corpus callosum g. Gross cellular disorganization, especially of cerebral peduncle, thalamus, and caudate nucleus 8. Respiratory insufficiency secondary to a. Robin sequence b. Narrow airways due to laryngotracheobronchomalacia (the most characteristic finding) c. Hypoplastic lungs d. A small bell-shaped thorax 9. Occasional abnormalities a. Congenital heart diseases i. Patent ductus arteriosus ii. Ventricular septal defects iii. Coarctation of the aorta iv. Tetralogy of Fallot b. Renal anomalies i. Hydronephrosis ii. Hydroureter iii. Renal hypoplasia iv. Renal cortical and medullary cysts c. Ear anomalies i. Hypoplastic cochlea and semicircular canals ii. Anomalies in incus and stapes 10. Cause of death a. Usually due to respiratory insufficiency i. Primarily owing to airway and pulmonary defects, lack of laryngotracheobroanchial cartilages and hypotonia ii. Resulting in apneic spells, atelectasis, aspiration, and pneumonia b. A high rate of neonatal death i. Most deaths occurring neonatally (77%) ii. 90% of deaths before 2 years 11. Life expectancy varies depending on the severity of the phenotype a. Young infants who survive i. Feeding difficulties ii. Stridor iii. Retractions iv. Frequent otitis media v. Bronchitis vi. Poor growth b. Infants who survive several years i. May be mentally retarded ii. May show variable breakpoints within the vicinity of chromosome 17 (q21-q25) iii. Oldest reported survivor: 17 years of age with an IQ of 45 c. Complications of survivors of campomelic dysplasia i. Recurrent apnea ii. Upper respiratory infections iii. Progressive kyphoscoliosis iv. Mild to moderate learning difficulties
v. Short stature vi. Dislocation of the hips d. Possible explanations for the survival of patients with campomelic dysplasia i. Mosaicism of the SOX9 mutations ii. Chromosomal rearrangements involving chromosome 17q (q23.3-q25.1) shown to cause campomelic dysplasia without disrupting the SOX9 gene, resulting in a milder phenotype
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Affected infants i. Tubular bones a) Bowed femora and tibiae b) Short fibulae c) Radioulnar dislocation ii. Thorax a) Severe hypoplastic, bladeless scapulae b) Thin short clavicles c) Nonmineralized sternum d) Small thoracic cage with slender and/or decreased number of ribs (usually 11 pairs) iii. Spine a) Abnormal cervical vertebrae b) Kyphoscoliosis c) Non-mineralized thoracic pedicles iv. Pelvis a) Dislocation of the hips b) Narrow iliac wings c) Poorly developed ischiopubic rami d) Coxa vara v. Hands and feet a) Short first metacarpal bone b) Talipes equinovarus vi. Skeletal maturation a) Delayed bone age b) Delayed ossification of proximal tibial and distal femoral epiphysis and talus b. Survivors i. Hypoplastic scapulae ii. Defective ischiopubic ossification iii. Absent or hypoplastic patellae iv. Spinal dysraphism c. Considerable radiographic overlap with ischiopubicpatella syndrome 2. Gonadal histology a. Similar to XY gonadal dysgenesis b. Ranging from dysplastic testicular tissue to poorly differentiated ovarian tissue with a few primordial follicles 3. Histology of growth plate: unremarkable epiphyseal resting cartilage 4. Cytogenetic analysis a. Identification of the sex reversal b. Identification of the chromosomal rearrangement involving 17q 5. Molecular analysis of SOX9 mutation
CAMPOMELIC DYSPLASIA
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless gonadal mosaicism in one of the parent b. Patient’s offspring: 50% if the patient can survive to the reproductive age 2. Prenatal diagnosis a. Possible by ultrasonography as early as 18 weeks of gestation i. Ultrasonographic findings a) Symmetrical anterior bowing of femurs and tibias b) Hypoplastic or absent scapulae c) Small thorax compared to the abdomen d) Bilateral talipes equinovarus e) External genitalia not compatible with 46,XY karyotype f) Polyhydramnios g) Fetal growth retardation h) Large head with internal hydrocephalus i) Sagittal scan of the face showing a flat nasal bridge, elongated philtrum, and micrognathia ii. Major differential diagnosis of ultrasonographic features a) Osteogenesis imperfecta b) Hypophosphatasia c) Unclassifiable varieties of congenital bowing of the long bones b. Amniocentesis result of 46,XY with ultrasonographic finding of a female external genitalia c. Identification of SOX9 mutation in the fetus 3. Management a. Supportive medical care b. Orthopedic treatment of the musculoskeletal malformations to prevent additional morbidity i. Hip dislocation ii. Bracing or spinal fusion for spinal deformity iii. Serial casting or surgical correction for foot deformity c. Gonadodectomy advocated in surviving phenotypic females with Y chromosome fragments owing to the increased risk of gonadoblastoma
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REFERENCES Argaman Z, Hammerman CA, Kaplan M, et al.: Picture of the month. Campomelic dysplasia. Am J Dis Child 147:205–206, 1993. Cordone M, Lituania M, Zampatti C, et al.: In utero ultrasonographic features of campomelic dysplasia. Prenat Diagn 9:745–750, 1989. Foster, JW, Dominguez-Steglich MA, Guioli S, et al.: Campomelic dysplasia and autosomal sex-reversal caused by mutations in an SRY-related gene. Nature 372:525–530, 1994. Hall BD, Springer JW: Campomelic dysplasia: Further elucidation of a distinct entity. Am J Dis Child 134:285–289, 1980. Hoefnagel D et al.: Camptomelic dwarfism associated with XY-gonadal dysgenesis and chromosome anomalies. Clin Genet 13:489–499, 1978. Houston CS, Opitz J, Spranger J, et al.: The campomelic syndrome: Review, report of 17 cases, and follow-up on the currently 17-year-old boy first reported by Maroteaux et al. in 1971. Am J Med Genet 15:3–28, 1983. Iravani S, Debich-Spicer D, Gilbert-Barness E: Pathological case of the month. Arch Pediatr Adolesc Med 154:747–748, 2000. Khajavi A et al.: Heterogeneity in the camptomelic syndromes: Long and short bone varieties. Radiology 120:641–647, 1976. Khoshhal K, Letts RM: Orthopaedic manifestations of campomelic dysplasia. Clin Orthop Rel Res 401:65–74, 2002. Kwok C, Weller PA, Guioli S, et al.: Mutations in SOX-9, the gene responsible for campomelic dysplasia and sex reversal. Am J Hum Genet 57:1028–1036, 1995. Lynch SA, Gaunt ML, Minford AM: Campomelic dysplasia: evidence of autosomal dominant inheritance. J Med Genet 30:683–686, 1993. Mansour S, Hall CM, Pembrey ME, et al.: A clinical and genetic study of campomelic dysplasia. J Med Genet 32:415–420, 1995. Mansour S, Offiah AC, McDowall S, et al.: The phenotype of survivors of campomelic dysplasia. J Med Genet 39:597–602, 2002. Savarirayan R, Robertson SP, Bankier A, et al.: Variable expression of campomelic dysplasia in a father and his 46,XY daughter. Pediatr Pathol Mol Med 22:37–46, 2003. Schafer AJ: Campomelic dysplasia/autosomal sex reversal/SOX9. In Scriver CR, Beaudet al., Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001. Thurmon TF et al.: Familial campomelic dwarfism. J Pediatr 83:841–843, 1973. Tommerup N, Schempp E, Meinecke P, et al.: Assignment of an autosomal sex reversal locus (SRA1) and compomelic dysplasia (CMPD1) to 17q24.3-q25.1. Nature Genet 4:170–173, 1993. Tongsong T, Wanapirak C, Pongsatha S: Prenatal diagnosis of campomelic dysplasia. Ultrasound Obstet Gynecol 15:428–430, 2000. Wagner T, Wirth J, Meyer J, et al.: Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 79:1111–1120, 1994. Yang S, Gilbert-Barness E: Skeletal system. In: Gilbert-Barness E (ed): Potter’s Pathology of the Fetus and Infant. 1st ed. St Louis, Mo: Mosby-Year Book Inc; 1997, 1452–1476.
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Fig. 1. Radiograph of an infant with campomelic dysplasia showing bowed femurs.
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Fig. 2. An infant with campomelic dysplasia showing bowing of the limbs with pretibial skin dimples, hypoplasia of cervical vertebra and scapula, 11 pairs of ribs, non-mineralized pedicles, vertical/narrow iliac wings, and bowing of femurs.
Fig. 3. A neonate with campomelic dysplasia showing large head, flat face, flat nasal bridge, low-set ears, micrognathia, and bowed lower legs with pretibial dimples. The radiographs show bowing of the femora, tibia, and fibulas.
Cat Eye Syndrome Cat-eye syndrome is a clinically recognizable congenital malformation syndrome consisting primarily of colobomas, anal anomalies, pre-auricular anomalies, cardiac and renal defects, and mild to moderate mental retardation. The name “cat eye” was introduced because of iris colobomas resembling the pupils of the cat.
GENETICS/BASIC DEFECTS 1. Historic background a. In 1965, an extra bisatellited marker chromosome was described in patients with cat-eye syndrome phenotype b. Later in 1981, the marker was determined to be an inverted dicentric duplication of a part of chromosome 22 [inv dup(22)(pter→q11::q11→pter)] 2. Molecular and cytogenetic bases a. Associated with the presence of three copies (trisomy) or four copies (tetrasomy) of a segment of chromosome22q11.2, usually in the form of a bisatellited, isodicentric supernumerary chromosome b. Formation of transient or unstable dic r(22) during early fetal development, which subsequently are lost from most cells, resulting in cat eye syndrome features c. The minimal common duplication required to produce features of cat eye syndrome (the cat eye syndrome critical region): defined by the dic r(22) patient, breakpoints between proximal locus ATP6E and distal locus D22S57, and covering approximately 2 Mb of 22q11.2 d. Maternal origin of the supernumerary chromosome in cases studied e. Direct correlations between the extent of duplicated chromosome 22 material and the severity of the cat eye syndrome remain difficult. f. Human homolog of insect-derived growth factor, CECR1: a candidate gene for features of cat-eye syndrome
CLINICAL FEATURES 1. Marked phenotypic variability 2. Major features a. Preauricular skin tags and/or pits: most consistent features b. Ocular coloboma c. Congenital heart defect i. Ventricular septal defect ii. Total anomalous pulmonary venous connection iii. Atrial septal defect iv. Patent ductus arteriosus v. Pulmonary stenosis vi. Aortic malformation vii. Tricuspid atresia viii. Hypoplastic left heart syndrome 136
d. Anorectal malformations i. Anal atresia or imperforate anus ii. Anal stenosis iii. Anorectal atresia iv. Ectopic anus v. Associated rectal fistulas e. Urogenital malformations i. Male external genital malformation ii. Renal agenesis/hypoplasia iii. Hydro(uretero) nephrosis iv. Vesicoureteral reflux v. Female genital malformation vi. Renal dysplasia or polycystic kidney vii. Bladder defects viii. Renal cystic malformation ix. Ectopic/horseshoe kidney 3. Minor features a. Craniofacial abnormalities i. Microcephaly ii. Ocular abnormalities a) Downslanting palpebral fissures b) Hypertelorism c) Ocular motility defect d) Epicanthal folds e) Microphthalmia iii. Oral abnormalities a) Micrognathia b) Cleft palate or absent uvula iv. Low-set or dysplastic ears b. Skeletal abnormalities i. Arm or hand deformity ii. Leg or foot deformity iii. Scoliosis or chest deformity iv. Vertebral anomaly v. Congenital dislocation of the hip vi. Rib or sternal anomaly c. Abdominal abnormalities i. Umbilical hernia ii. Malrotation of the gut iii. Hirschsprung or megacolon iv. Biliary atresia or choledochal cyst v. Volvulus vi. Meckel diverticulum 4. Neurodevelopmental outcome a. Growth and development i. Short stature ii. Mental development: markedly variable a) Normal-borderline normal b) Mild-moderate retardation c) Severe mental retardation b. Neurological abnormalities i. Dysregulation of muscle tone ii. Visual defect
CAT EYE SYNDROME
iii. iv. v. vi. vii. viii. ix. x. xi.
Hearing impairment Ventricular dilatation Abnormal slow EEG Seizures Spasticity Cerebral or cerebellar atrophy Hyperactive behavior Ataxia Facial nerve palsy
DIAGNOSTIC INVESTIGATIONS 1. Chromosome analysis from blood and other tissues a. Conventional b. FISH 2. Radiography for limb defect 3. Echocardiography for congenital heart defects 4. Renal ultrasonography for renal anomalies 5. Developmental evaluation
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: a small recurrence risk because of possible presence of germline mosaicism b. Patient’s offspring i. Patients with an inv dup(22): 50% ii. Patients with mosaic form of an inv dup(22): lower than 50%, depends on the percentage of the marker chromosomes 2. Prenatal diagnosis by amniocentesis or CVS a. Presence of a bisatellited, dicentric supernumerary chromosome b. FISH with a chromosome 22-specific cosmid probe to identify chromosome 22 3. Management a. Supportive b. Surgery i. Congenital heart defect ii. Anorectal anomalies iii. Urogenital anomalies iv. Gastrointestinal anomalies v. Skeletal anomalies c. Potential anesthetic risks i. Potential difficult airway management ii. Congenital heart disease iii. Renal and hepatic dysfunction
REFERENCES Beeser SL, Donnenfeld AE, Miller RC, et al.: Prenatal diagnosis of the derivative chromosome 22 associated with cat eye syndrome by fluorescence in situ hybridization. Prenat Diagn 14:1029–1034, 1994. Berends MJ, Tan-Sindhunata G, Leegte B, et al.: Phenotypic variability of CatEye syndrome. Genet Couns 12:23–34, 2001. Bofinger MK ,Soukup SW: Cat eye syndrome. Partial trisomy 22 due to translocation in the mother. Am J Dis Child 131:893–897, 1977. Bühler EM, Mehes K, Muller H, et al.: Cat-eye syndrome, a partial trisomy 22. Humangenetik 15:150–162, 1972. Cory CC ,Jamison DL: The cat eye syndrome. Arch Ophthalmol 92:259–262, 1974.
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Crolla JA, Howard P, Mitchell C, et al.: A molecular and FISH approach to determining karyotype and phenotype correlations in six patients with supernumerary marker (22) chromosomes. Am J Med Genet 72:440–447, 1997. Devavaram P, Seefelder C ,Lillehei CW: Anaesthetic management of Cat Eye Syndrome. Paediatr Anaesth 11:746–748, 2001. Duncan AM, Rosenfeld W ,Verma RS: Re-evaluation of the supernumerary chromosome in an individual with cat eye syndrome. Am J Med Genet 27:225–227, 1987. El-Shanti H, Hulseberg D, Murray JC, et al.: A three generation minute supernumerary ring 22: association with cat eye syndrome. Am J Hum Genet 53(suppl):A126, 1993. Freedom RM ,Gerald PS: Congenital cardiac disease and the “cat eye” syndrome. Am J Dis Child 126:16–18, 1973. Guanti G: The aetiology of the cat eye syndrome reconsidered. J Med Genet 18:108–118, 1981. Hoo JJ: DA/DAPI pattern of marker chromosome: cytogenetics of cat eye syndrome. Clin Genet 29:265–267, 1986. Hoo JJ, Robertson A, Fowlow SB, et al.: Inverted duplication of 22pter— q11.21 in cat-eye syndrome. Am J Med Genet 24:543–545, 1986. Hsu LYF, Hirschhorn K: The trisomy 22 syndrome and the cat eye syndrome. In Yunis JJ (ed): New Chromosomal Syndromes. New York, Academic Press, 1977, 339–368. Johnson A, Minoshima S, Asakawa S, et al.: A 1.5-Mb contig within the cat eye syndrome critical region at human chromosome 22q11.2. Genomics 57:306–309, 1999. Kolvraa S, Koch J, Gregersen N, et al.: Application of fluorescence in situ hybridization techniques in clinical genetics: use of two alphoid repeat probes detecting the centromeres of chromosomes 13 and 21 or chromosome 14 and 22, respectively. [erratum appears in Clin Genet 40:474 –475, 1991]. Clin Genet 39:278–286, 1991. Liehr T, Pfeiffer RA ,Trautmann U: Typical and partial cat eye syndrome: identification of the marker chromosome by FISH. Clin Genet 42:91–96, 1992. Magenis RE, Sheehy RR, Brown MG, et al.: Parental origin of the extra chromosome in the cat eye syndrome: evidence from heteromorphism and in situ hybridization analysis. Am J Med Genet 29:9–19, 1988. McDermid HE, Duncan AM, Brasch KR, et al.: Characterization of the supernumerary chromosome in cat eye syndrome. Science 232:646–648, 1986. McTaggart KE, Budarf ML, Driscoll DA, et al.: Cat eye syndrome chromosome breakpoint clustering: identification of two intervals also associated with 22q11 deletion syndrome breakpoints. Cytogenet Cell Genet 81: 222–228, 1998. Mears AJ, Duncan AM, Budarf ML, et al.: Molecular characterization of the marker chromosome associated with cat eye syndrome. Am J Hum Genet 55:134–142, 1994. Mears AJ, el-Shanti H, Murray JC, et al.: Minute supernumerary ring chromosome 22 associated with cat eye syndrome: further delineation of the critical region. Am J Hum Genet 57:667–673, 1995. Reeser SL, Donnenfeld AE, Miller RC, et al.: Prenatal diagnosis of the derivative chromosome 22 associated with cat eye syndrome by fluorescence in situ hybridization. Prenat Diagn 14:1029–1034, 1994. Riazi MA, Brinkman-Mills P, Nguyen T, et al.: The human homolog of insectderived growth factor, CECR1, is a candidate gene for features of cat eye syndrome. Genomics 64:277–285, 2000. Rosias PR, Sijstermans JM, Theunissen PM, et al.: Phenotypic variability of the cat eye syndrome. Case report and review of the literature. Genet Couns 12:273–282, 2001. Schachenmann G, Schmid W, Fraccaro M, et al.: Chromosomes in coloboma and anal atresia. Lancet 290, 1965. Schinzel A, Schmid W, Fraccaro M, et al.: The “cat eye syndrome”: Dicentric small marker chromosome probably derived from a N° 22 (tetrasomy 22pter ≥ q11) associated with a characteristic phenotype. Report of 11 patients and delineation of the clinical picture. Hum Genet 57:148–158, 1981. Urioste M, Visedo G, Sanchis A, et al.: Dynamic mosaicism involving an unstable supernumerary der(22) chromosome in cat eye syndrome. Am J Med Genet 49:77–82, 1994. Wilson GN, Baker DL, Schau J, et al.: Cat eye syndrome owing to tetrasomy 22pter→q11. J Med Genet 21:60–63, 1984.
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Fig. 1. A boy with cat eye syndrome showing ocular coloboma and bilateral club hands with missing thumbs. The radiographs shows bilateral radial aplasia/hypoplasia with missing thumbs. The patient has a supernumerary marker chromosome 22, illustrated by the chromosome spread.
Cerebro-Costo-Mandibular Syndrome In 1966, Smith et al. described a rare disorder characterized mainly by growth retardation, dysmorphic chest, mandibular hypoplasia, glossoptosis and variable palatal abnormalities.
GENETICS/PATHOGENESIS 1. Inheritance a. Sporadic in majority of cases b. Familial occurrence in a few instances i. Autosomal recessive pattern ii. Autosomal dominant pattern 2. Pathogenesis of the rib gaps a. Not well understood b. Rib abnormality results from a lack of fusion between two mesenchymal tissues derived from the somatic mesoderm (posteriorly) and the lateral plate mesoderm (anteriorly) c. Defective organization of the somite results in discontinuities of the ribs
5. 6. 7. 8. 9. 10.
11. 12. 13. 14.
15. 16.
CLINICAL FEATURES 1. Variable inter- and intra-familial expression 2. Cardinal signs a. Rib abnormalities i. Posterior rib gaps a) Present in almost all affected newborn infants b) Showing great variability in severity c) Disappear in time d) Sometimes replaced by callus or pseudoarthroses ii. Segmentation defects and rudimentary rib development, fusion of most ribs to the vertebrae, and absence of any normal costovertebral articulations iii. Thin ribs iv. Agenetic ribs b. Micrognathia/Pierre Robin anomaly c. Cerebral abnormalities i. Microcephaly ii. Agenesis of the corpus callosum iii. Dilated lateral ventricles iv. Porencephalic cyst v. Variable degree of mental retardation probably secondary to hypoxia following respiratory distress 3. Other skeletal anomalies a. Vertebral anomalies including hemivertebrae b. Hip dislocation c. Subluxation of the elbows d. Pectus carinatum e. Hypoplasia of the sternum, clavicles, and pubic rami f. Epiphyseal stippling g. Abnormal phalanges and toes h. Clubfoot 4. Intrauterine growth retardation
Postnatal growth deficiency Respiratory distress Feeding difficulties Language delay Conductive deafness Palatal defect a. Short soft palate b. Cleft palate Dental defects Laryngeal and tracheal abnormalities Pterygium coli Renal anomalies a. Renal cysts b. Ectopia Congenital heart defects Prognosis a. Mental retardation often among the late survivors b. High mortality (40% in the first year of life, 50% in the first month of life) mostly due to respiratory insufficiency secondary to rib abnormalities and flail chest
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Rib malformations i. Multiple gaps consisting of fibrous or cartilaginous tissue ii. Thin ribs iii. Agenetic ribs b. Vertebral anomalies c. Other associated skeletal anomalies d. Micrognathia 2. Cranial ultrasonography for cerebral abnormalities 3. Histology of rib gaps: undifferentiated fibrous connective tissue and muscles, instead of cartilage and bone
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1. Recurrence risk a. Patient’s sib i. Not increased in sporadic cases and in a fresh mutation case of an autosomal dominant disorder ii. 25% in an autosomal recessive disorder b. Patient’s offspring: not increased unless the patient survives and is affected with an autosomal dominant disorder in which case there is a 50% risk of having an affected child 2. Prenatal diagnosis by ultrasonography: difficult to establish a. Small mandible b. A narrow short chest c. Defective ribs d. Growth retardation e. Vertebral anomalies f. Limb anomalies
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g. Increased nuchal translucency h. Cystic hygroma i. Polyhydramnios 3. Management a. Treatment of respiratory distress b. Nasogastric tube feeding c. Tracheostomy may be required d. Surgery for cleft palate e. Early intervention and multidisciplinary team approach f. Orthopedic care for skeletal anomalies
REFERENCES Clarke EA, Nguyen VD: Cerebro-costo-mandibular syndrome with consanguinity. Pediatr Radiol 15:264–266, 1985. Drossou-Agakidou V, Andreou V, Soubassi-Griva V, et al.: Cerebro-costomandibular syndrome in four sibs, two pairs of twins. J Med Genet 28:704–707, 1991. Flodmark P, Wattsgård C: Cerebro-costo-mandibular syndrome. Pediatr Radiol 31:36–37, 2001. Hennekam RCM, Beemer FA, Huijbers WAR, et al.: The Cerebro-costomandibular syndrome: Third, report of familial occurrence. Clin Genet 28:118–121, 1985. Hennekam RCM, Goldschmeding R: Complete absence of rib ossification, micrognathia and ear anomalies: Extreme expression of Cerebro-costomandibular syndrome? Eur J Hum Genet 6:71–74, 1998. Hosalkar HS: The Cerebro-costo-mandibular syndrome: 9-year follow-up of a case. J Postgrad Med 46:268–271, 2000. Ibba RM, Corda A, Zoppi MA, et al.: Cerebro-costo-mandibular syndrome: early sonographic prenatal diagnosis. Ultrasound Obstet Gynecol 10:142–144, 1997. Kang YK, Lee SK, Chi JG: Maxillo-mandibular development in cerebro-costomandibular syndrome. Pediatr Pathol 12:717–724, 1992. Kirk EPE, Arbuckle S, Ramm PL, et al.: Severe micrognathia, cleft palate, absent olfactory tract, and abnormal rib development: Cerebro-costo-mandibular syndrome or a new syndrome? Am J Med Genet 84:120–124, 1999. Kuhn JP, Lee SB, Jockin H, et al.: Cerebro-costo-mandibular syndrome. A case with cardiac anomaly. J Pediatr 86:243–244, 1975. Leroy JG, Devos EA, Vanden Bulcke LJ, et al.: Cerebro-costo-mandibular syndrome with autosomal dominant inheritance. J Pediatr 99:441–443, 1981.
McNicholl B, Egan-Mitchell B, Murray JP, et al.: Cerebro-costo-mandibular syndrome: a new familial developmental disorder. Arch Dis Child 45:421–424, 1970. Megier P, Ayeva-Derman M, Esperandieu O, et al.: Prenatal Ultrasonographic diagnosis of the Cerebro-costo-mandibular syndrome: case report and review of the literature. Prenat Diagn 18:1294–1299, 1998. Merlob P, Schonfeld A, Grunebaum M, et al.: Autosomal dominant cerebrocosto-mandibular syndrome. Ultrasonographic and clinical findings. Am J Med Genet 26:195–202, 1987. Miller KE, Parker Allen R, Davis WMS: Rib gap defects with micrognathia. The Cerebro-costo-mandibular syndrome-a Pierre Robin-like syndrome with rib dysplasia. Am J Roentgenol 114:253–256, 1972. Mohan M, Mandalm KR: Cerebro-costo-mandibular syndrome. Indian Pediatr 19:97–98, 1982. Morin G, Gekas J, Naepels P, et al.: Cerebro-costo-mandibular syndrome in a father and a female fetus: early prenatal ultrasonographic diagnosis and autosomal dominant transmission. Prenat Diagn 21:890–893, 2001. Plötz FB, van Essen AJ, Bosschaart AN, et al.: Cerebro-costo-mandibular syndrome. Am J Med Genet 62:286–292, 1998. Schroer RJ, Meyer LC: Cerebro-costo-mandibular syndrome. Proc Greenwood Genet Ctr 4:55–59, 1984. Seno T: An experimental study of the formation of the body wall in the chick. Acta Anat 45:60–82, 1961. Silverman FN, Strefling AM, Stevenson DK, et al.: Cerebro-costo-mandibular syndrome. J Pediatr 97: 406–416, 1980. Smith DW, Theiler K, Schachenmann G: Rib-gap defect with micrognathia, malformed tracheal cartilages, and redundant skin: a new pattern of defective development. J Pediatr 69:799–803, 1966. Straus WL, Jr, Rawles ME: An experimental study of the origin of the trunk musculature and ribs in the chick. Am J Anat 92:471–509, 1953. Tachibana K, Yamamoto Y, Osaki E, et al.: Cerebro-costo-mandibular syndrome. A case report and review of the literature. Hum Genet 54:283–286, 1980. Trautman MS, Schelley SL, Stevenson DK: Cerebro-costo-mandibular syndrome. A familial case consistent with autosomal recessive inheritance. J Pediatr 107:990–991, 1985. Van den Ende JJ, Schrander-Stumpel C, et al.: The Cerebro-costo-mandibular syndrome: Seven patients and review of the literature. Clin Dysmorphol 7:87–95, 1998. Williams HJ, Sane SM: Cerebro-costo-mandibular syndrome: long-term follow-up of a patient and review of the literature. Am J Roentgenol 126:1223–1228, 1976.
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Fig. 1. An infant with cerebro-costo-mandibular syndrome (at birth and 12 weeks of age) showing severe micro/retrognathia and malformations of the ribs with multiple gaps and segmentation defects.
Charcot-Marie-Tooth Disease 5. X-linked dominant form of CMT (CMT1X) a. Accounting for 10–20% of CMT (the second most common form of inherited demyelinating neuropathy, next to CMT1A) b. Caused by mutations in the gene for the gap junction protein 1 (GJB1) or connexin 32 (Cx32) on Xq13.1 c. An identical clinical phenotype caused by mutations within all regions of the Cx32 gene coding sequence 6. Dejerine-Sottas syndrome (DSS) a. Also called hereditary motor and sensory neuropathy type III (HMSN III) b. A severe demyelinating neuropathy c. Autosomal dominant new mutations (PMP22 mutations) d. Clinical symptoms overlapping with CMT1: these two disorders may represent a spectrum of related clinical phenotypes that can arise from allelic missense point mutations in the PMP22 gene e. Allelic mutations in the MPZ gene similarly identified in sporadic patients with DSS, also implying that CMT type 1 and DSS constitute a spectrum of peripheral neuropathy phenotypes with common genetic bases 7. Hereditary neuropathy with liability to pressure palsies (HNPP) a. Characterized by recurrent episodes of nerve palsies b. Associated with apparent reciprocal deletion of 1.5-Mb at 17p11.2–p12, which implicates decreased dosage and expression of the PMP22 gene as a possible cause of HNPP 8. Problems in classification of inherited neuropathies a. PMP22 deletion causes HNPP b. PMP22 duplication causes CMT1A c. Deletion and duplication of PMP22 causes HNPP and CMT1A, respectively, establishing a singular genetic mechanism as the cause of the two most common inherited neuropathies d. PMP22 mutations cause DSS, CMT1A, and HNPP e. MPZ mutations cause DSS, CMT1B, and a CMT2like phenotype f. GJB1 mutations cause CMT1X g. EGR2 mutations cause CMT1 and DSS
Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy. It is a pathologically heterogeneous group of hereditary motor and sensory neuropathies, characterized by slowly progressive weakness and atrophy, primarily in the distal leg muscles. The incidence is estimated to be approximately 1 in 2500.
GENETICS/BASIC DEFECTS 1. Charcot-Marie-Tooth disease type 1 (CMT1) a. Also called hereditary motor and sensory neuropathy type I (HMSN I) b. The most common subtype (accounting for about 50% of CMT) c. A demyelinating neuropathy d. Autosomal dominant form i. CMT1A: caused by a 1.5-Mb tandem duplication of the chromosomal region 17p11.2, which contains the peripheral myelin protein 22 (PMP 22) gene (90% of CMT1 patients) ii. CMT1B: caused by mutations of the myelin protein zero (MPZ) gene (1q22) (5–10%) iii. CMT1C: caused by mutations of LITAF gene (16p13.1-p12.3) iv. CMT1D: caused by mutations of early growth response gene 2 (EGR2) gene (10q21.1-q22.1) 2. Charcot-Marie-Tooth disease type 2 (CMT2) a. Also called hereditary motor and sensory neuropathy type II (HMSN II) b. An axonal neuropathy c. Autosomal dominant inheritance d. Accounting for 20–40% of CMT e. Disease gene loci for CMT2 i. CMT2A: 1p36.2 (KIF1Bβ) ii. ΧΜΤ2Β: 3q21 (RAB7) iii ΧΜΤ2Χ: 12q23-q24 iv. ΧΜΤ2D: 7p15 v. ΧΜΤ2Ε: 8p21 (NEFL) vi. ΧΜΤ2F: 7q11-21ΧΜΤ2Γ: 3q13.1 3. Intermediate form of autosomal dominant CMT (rare) a. Autosomal dominant inheritance b. Combination of myelinopathy and axonopathy in individual patients c. At least two chromosome loci (10q24.1-25 and 19p12-13.2) identified by linkage analysis 4. Autosomal recessive form of CMT (CMT4) (rare) a. CMT4A: The first locus identified: 8q13-q21.1 (corresponding gene, GDAP1) b. CMT4B1: 11q22 (MTMR2) c. CMT4B2: 11p15 (CMT4B2) d. CMT4C: 5q32 e. CMT4D: 8q24.3 (NDRG1) f. CMT4E: 10q21.1-q22.1 (EGR2) g. CMT4F: 19q13.1-q13.2 (PRX)
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1. Clinical phenotype of all forms of CMT a. Generally similar b. Clinical presentation with distal leg weakness and atrophy c. Followed by hand involvement 2. Presence of a wide range of variation and severity of symptoms in the affected areas and in the rate of progression of symptoms 3. CMT1A
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a. Accounting for 90% of CMT1 patients b. A wide range of variation in clinical presentation and severity among affected members of large families with CMT1A c. CMT1A PMP22 duplication i. Asymptomatic patients a) Observed in some family members in large pedigrees b) No symptoms c) Normal neurologic examination including ability to walk on their heels and normal stretch reflexes d) Slow MNCV e) Duplication of PMP22 confirming the diagnosis of CMT1A ii. Symptomatic patients a) Onset: first decade or early in the second decade b) Presenting symptoms in infants and children: walking on their toes and have severe tightness of the heel cord c) Occasional patients born with foot deformities including clubfeet d) Other symptoms: abnormal gait, foot deformities, or loss of balance e) Muscle weakness starting in the feet and legs f) Frequently trip over objects on the floor and sprain ankles as a result of weakness of the dorsiflexor muscles of the feet, innervated by the peroneal nerves g) Difficulty or inability to walk on heels h) Tight heel cords i) Foot drops with each step, forcing the patient to flex the hip, giving the steppage or equine gait j) Pes cavus deformity developing with age k) Atrophy of the legs, due to wasting of the peroneal muscles giving the stork legs or ‘inverted champagne bottle’ appearance l) Weakness of the intrinsic hand muscles usually occurring late in the course of the disease m) Claw hands n) Mild sensory loss to pricking pain in the legs in some patients o) Frequently decreased vibratory sense iii. Associated symptoms a) Enlarged (auricular, ulnar, and peroneal) nerves in 20–25% of the patients, not related to the age of the patient or the severity of the disease b) Tremor in 40% of the patients c) Hip dysplasia with hip pain and a limp d) Restrictive lung disease usually not a major problem in patients with CMT1 e) Other associated features: spastic paraparesis, deafness, optic atrophy, Marfan-like appearance, and absence of eyebrows f) Exacerbation of the weakness in 50% of the patients with early onset disease during pregnancy and delivery
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g) Certain medication and neurotoxic substances may aggravate the neuropathy in patients with CMT. d. CMT1A point mutations in PMP22 i. Show severe disease in childhood ii. Found in patients that have been diagnosed with the Dejerine-Sottas syndrome 4. CMT1B a. Accounting for less than 10% of CMT1 patients b. MPZ mutations identified in CMT1B, DDS, or congenital hypomyelination phenotype c. Differentiating from CMT1A i. An earlier onset of the symptoms manifested by delayed ability to walk ii. Proximal leg weakness without decreasing ambulation iii. Slower motor NCVs 5. CMT2 a. Neuronal type (a progressive peripheral motor and sensory neuropathy) b. Clinical phenotype similar to the type 1 CMT i. Symptoms a) Tingling b) Numb feeling c) Pain d) Muscle cramp e) Loss of muscle strength: distal weakness with feet involvement first f) Walking instability g) Increased loss of strength h) Increased sensory loss ii. Signs a) Atrophied hands b) Atrophied legs c) Postural tremors d) Fasciculations e) Pes cavus f) Claw toes g) Steppage gait h) Leg atrophy i) Short calf muscles j) Abnormal Romberg sign k) Absent biceps, triceps, knee, and ankle jerks c. Other characteristics i. Generally a later onset of the symptoms than seen in the type 1 ii. Pes cavus and short calf muscles: predominantly present in patients with early-onset disease iii. Less involvement of the hand muscles iv. No clinical evidence of palpable enlarged nerves v. No sensory deterioration vi. Normal or slightly diminished motor nerve conduction velocities 6. Autosomal recessive CMT (CMT4) a. Progressive motor and sensory neuropathy b. Rare heterogeneous forms with a broad spectrum of clinical severity c. Presentation of symptoms in infancy by delay in walking d. Early and rapidly progressive deformities of the feet and spine
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e. A high incidence of associated features such as sensorineural hearing loss f. Weakness beginning in the feet but affecting both distal and proximal muscles g. No enlargement of superficial nerves h. Presence of three pathologic forms 7. X-linked CMT (CMTX) a. Inheritance i. Dominant form in 90% of cases ii. Recessive form in 10% of cases b. A disease-causing mutation and a family pedigree consistent with X-linked dominant inheritance i. Presence of a disease-causing mutation in the GJB1 (Cx32) gene ii. Lack male to male transmission c. Males and females with peripheral motor and sensory neuropathy i. Affected males a) More severe phenotype than the affected females b) More severe progressive peripheral motor and sensory neuropathy than that seen in CMT1A c) Moderately slow median nerve MNCV: 34.5 ± 6.2 m/sec d) Reduced motor and sensory nerve amplitudes (median nerve CMAP): 3.7 ± 3.7 mV ii. Affected females a) Normal, or mild to moderate signs and symptoms b) Moderately slow MNCV: 45.8 ± 7.3 m/sec c) Reduced motor and sensory nerve amplitudes (median nerve CMAP): 7.8 ± 3.4 mV d. Signs and symptoms i. Typical presenting symptom: weakness of the feet and ankles ii. Initial physical findings: depressed or absent tendon reflexes with weakness of foot dorsiflexion at the ankle iii. Typical adult patients a) Bilateral foot drop b) Symmetrical atrophy of muscles below the knee with stork leg appearance c) Pes cavus d) Atrophy of intrinsic hand muscles especially the thenar muscles of the thumb e) Absent tendon reflexes in both upper and lower extremities f) Proximal muscles usually remain strong. g) Mild to moderate sensory loss (deficits of position, vibration, and pain/temperature) commonly occurring in the feet e. Other characteristics i. Symptoms typically develop between ages 5 and 25 years ii. Onset commonly within the first decade in males iii. Earlier onset with delayed walking in infancy as well as later onset beyond the 4th decades possible iv. Mild symptoms may be overlooked by patient and physician
v. Severe motor slowing in most families, consistent with a demyelinating form of the disease vi. A predominant axonal type also been described 8. Dejerine-Sottas syndrome (DSS) a. The syndrome still used to define the rare cases of severe hypo-demyelinating neuropathy of early onset b. Criteria for diagnosis i. Early onset of the disease by age 2 years with delayed motor milestones ii. Severe motor, sensory, and skeletal muscle deficits, frequently extending to proximal muscles. Sensory ataxia and scoliosis also present. iii. Very low conduction velocities, usually <12 m/s iv. Nerve biopsy reveals severe hypomyelination and basal lamina reduplication, with multiple onion bulb formation v. Presence of the enlarged nerves c. De novo point mutations in either MPZ or PMP22 found in most DSS cases d. May be a variant of CMT1A or CMT1B 9. Congenital hypomyelination (CH) a. An ill-defined and extremely rare disease merging into Dejerine-Sottas disease b. A clinical syndrome characterized by infantile hypotonia due to distal muscle weakness, areflexia and very slow NCVs. Severe weakness may lead to early death c. Severe contractures of joints or arthrogryposis multiplex congenita in severe cases d. Mutation analysis showing MPZ mutations, suggesting some of the DSS and CH are part of a spectrum of the demyelinating form of CMT1B 10. Hereditary neuropathy with liability to pressure palsies (HNPP) a. Also called familial recurrent polyneuropathy or tomaculous neuropathy b. Clinical manifestations i. Periodic/transient//recurrent episodes of numbness, muscular weakness, and atrophy ii. Palsies after relatively minor compression or trauma of the peripheral nerves (the axillary, median, radial, ulnar, and peroneal nerves) c. Nerve conduction abnormalities mainly localized at common entrapment sites d. Nerve biopsy: occurrence of focal myelin thickenings (tomacula) in several fibers e. Commonly associated with deletion of PMP22 gene
DIAGNOSTIC INVESTIGATIONS 1. Two types of CMT, currently distinguishable by the value of motor nerve conduction velocity (MNCV) of median nerve on electrophysiologic examination and nerve biopsy findings a. Demyelinating form (CMT1) i. Slowing of MNCV (15–30 m/sec) ii. Hypertrophy of peripheral nerves with onion bulb formation and segmental demyelination b. Axonal form (CMT2) i. Normal or mildly slow MNCV (>40 m/sec) ii. Normal size nerves iii. No evidence of segmental demyelinations
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2. Motor nerve conduction velocity of the median nerve (MNCV) a. Uniform conduction slowing i. CMT1A ii. CMT1B iii. CMT4 iv. Dejerine-Sottas syndrome b. Multifocal conduction slowing i. CMTX ii. Hereditary neuropathy with liability to pressure palsies (HNPP) c. Incompletely characterized electrophysiology i. PMP22 point mutations ii. MPZ point mutations iii. EGR2 mutations d. Usually normal in CMT2 3. EMG testing: evidence of an axonal neuropathy in CMT2 a. Positive waves b. Polyphasic potentials c. Fibrillations d. Reduced amplitudes of evoked motor and sensory responses 4. Compound motor action potentials (CMAP): greatly reduced in CMT2 5. Nerve biopsy a. CMT1A i. Regression of onion bulb ii. Significantly increased ratio of axon diameter/total fiber diameter, indicating arrestedremyelination b. CMT1B i. Demyelinating process with onion bulb formation (sural nerve biopsy) ii. Ultrastructural finding of uncompacted myelin is consistent with the accepted function Po as a homophilic adhesion molecule c. CMT2 i. No histological evidence of well-formed onion bulbs on the nerve biopsies ii. Loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments d. Autosomal recessive demyelinating CMT with three pathologic forms: i. Classical onion bulbs ii. Basal laminar onion bulbs iii. Focally folded myelin sheaths e. CMTX i. Nerve hypertrophy or onion bulb formation: rare ii. A primary axonal neuropathy with axonal sprouting in most affected individuals iii. Prominent demyelination consistent with a CMT1 phenotype in some cases f. Congenital hypomyelination: hypomyelination (few thin myelin lamella) without active myelin breakdown products and early onion bulb formations g. Hereditary neuropathy with liability to pressure palsies (HNPP): demyelination and remyelination with tomacula or sausage-like thickening on the myelin sheath
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6. Molecular genetic testing a. CMT1 i. CMT1A a) Sequence analysis for point mutations in the PMP22 gene b) Mutation scanning for point mutations in the PMP22 gene ii. CMT1B a) Sequence analysis for point mutations in the MPZ gene b) Mutation scanning for point mutations in the MPZ gene iii. CMT1C: direct DNA/linkage analysis for point mutation in LITAF iv. CMT1D a) Sequence analysis for point mutations in the EGR2 gene b) Mutation scanning for point mutations in the EGR2 gene b. CMT2E: sequence analysis for mutations in NEFL c. CMT4 i. CMT4E: molecular genetic testing for EGR2 ii. CMT4F: molecular genetic testing for PRX d. CMTX: sequence analysis to detect mutations in the GJB1 coding region (accounting for about 90% of mutations in patients with CMTX) e. Molecular genetic testing approach i. In cases of HNPP a) Test for the PMP22 deletion (since this is by far the major cause) b) If negative, then sequence PMP22 ii. In CMT patients with uniform slowing of motor NCVs between 10–35 ms a) Test for the PMP22 duplication (since this is the major cause of CMT1) b) If negative, sequence PMP22, MPZ, GJB1, and EGR2 iii. In DSS with appropriately slowed NCVs a) Test for the duplication: usually negative b) Sequence PMP22, MPZ, GJB1, EGR2, and PRX genes iv. In cases where CMT1X is the most likely diagnosis (based on intermediate slowing of NCVs, no male-to-male transmission) a) Sequence GJB1 alone: the appropriate initial test b) If negative, sequence MPZ and NEFL v. In cases of suspected CMT2 a) Probably premature to test for MPZ and NFEL mutations alone (the only commercially available tests) b) Await a comprehensive battery in the future
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal dominant CMT a) Majority of CMT1 patients carry the PMP22 duplication and represent de novo mutation
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cases: recurrence risk to sib not increased unless a parent is affected, in which case the recurrence risk is 50% b) Patients with de novo MPZ mutation: recurrence risk to sibs not increased unless a parent is affected, in which case the recurrence risk is 50% ii. Autosomal recessive CMT: 25% iii. X-linked dominant CMT (patients with Cx32 mutation) a) A carrier mother has a 50% risk of transmitting the disease-causing mutation with each pregnancy. Sons who inherit the mutation will be affected. Daughters who inherit the mutation will be carriers and may or may not be affected b) A noncarrier mother: recurrence risk to sibs low but not zero since the risk of germline mosaicism in mothers is not known b. Patient’s offspring i. Autosomal dominant CMT: Patients with PMP22 duplication, PMP22 deletion, or MPZ mutation will have a 50% risk of transmitting the disease to the offspring ii. Autosomal recessive CMT: not increased unless the spouse is a carrier or affected iii. X-linked dominant CMT (patients with Cx32 mutation) a) All the daughters of an affected male inherit the mutation but may or may not have symptoms b) None of his sons will be affected 2. Prenatal diagnosis available to pregnancies at risk for CMT1A, CMT1B, CMT2E, CMT4E, CMT4F, and CMTX a. Identify the disease-causing allele of an affected family member before prenatal diagnosis b. Mutation analysis of fetal DNA obtained from amniocentesis or CVS c. CMT1 i. Prenatal diagnosis of CMT1A by FISH a) Parental blood samples studied to confirmed to be duplicated for PMP22 by FISH b) Interphase FISH assay performed on amniotic fluid specimens and chorionic villus samples to detect a submicroscopic 17p12 duplication in the fetus with CMT1A ii. Preimplantation diagnosis for CMT1A: selection of healthy embryos is made based on the presence of the nonduplicated haplotype and heterozygosity of a marker d. CMT2E: molecular genetic testing of DNA extracted from fetal cells obtained from amniocentesis or CVS for testing of NEFL mutation when both diseasecausing alleles of an affected family member are identified e. CMT4E and CMT4F: molecular genetic testing of DNA extracted from fetal cells obtained by amniocentesis or CVS for testing of EGR2 and PRX mutations respectively when both disease-causing alleles of an affected family member are identified
f. CMTX i. Prenatal diagnosis available to pregnancies of women who are heterozygotes for a diseasecausing GJB1 mutation that has been identified in an affected family member ii. Amniocentesis or CVS a) Determination of the fetal sex b) DNA extracted from cells from male fetuses tested to determine if a disease-causing mutation is present 3. Management a. No specific treatment to reverse or slow the natural disease process b. Supportive care i. Daily heel cord stretching exercises ii. Special shoes to support ankle iii. Ankle/foot orthoses to correct foot drop and aid walking iv. Orthopedic surgery to correct severe pes cavus deformity v. Forearm crutches or canes for gait stability vi. Wheelchairs required for less than 5% of patients c. Avoid medications known to cause nerve damage i. Vincristine ii. Taxol iii. Cisplatin iv. Isoniazid v. Nitrofurantoin d. Acetaminophen or nonsteroidal anti-inflammatory agents for musculoskeletal pain e. Tricyclic antidepressants, carbamazepine, or gabapentin for neuropathic pain
REFERENCES Auer-Grumbach M, Wagner K, Strasser-Fuchs S, et al.: Clinical predominance of proximal upper limb weakness in CMT1A syndrome. Muscle Nerve 23:1243–1249, 2000. Auer-Grumbach M, De Jonghe P, Verhoeven K, et al.: Autosomal dominant inherited neuropathies with prominent sensory loss and mutilations. A review. Arch Neurol 60:329–334, 2003. Baas F: Genetic diagnosis of Charcot-Marie-Tooth disease. Methods Mol Biol 217:177–184, 2003. Berger P, Young P, Suter U: Molecular cell biology of Charcot-Marie-Tooth disease. Neurogenetics 4:1–15, 2002. Birouk N, Azzedine H, Dubourg O, et al.: Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1 gene. Arch Neurol 60:598–604, 2003. Bird TD: Hereditary motor-sensory neuropathies. Charcot-Marie-Tooth syndrome. Neurol Clin 7:9–23, 1989. Bird TD: Charcot-Marie-Tooth hereditary neuropathy. Overview, type 1, type 2, type 4, type X. Gene Reviews, 2003. http://www.genetests.org Bird TD, Kraft GH: Charcot-Marie-Tooth disease: data for genetic counseling relating age to risk. Clin Genet 14:43–49, 1978. De Jonghe P, Nelis E, Timmerman V, et al.: Molecular diagnostic testing in Charcot-Marie-Tooth disease and related disorders. Approaches and results. Ann N Y Acad Sci 883:389–396, 1999. De Jonghe P, Timmerman V, Nelis E, et al.: Charcot-Marie-Tooth disease and related peripheral neuropathies. J Peripher Nerv Syst 2:370–387, 1997. De Vos A, Sermon K, De Rijcke M, et al.: Preimplantation genetic diagnosis for Charcot-Marie-Tooth disease type 1A. Mol Hum Reprod 9:429–435, 2003. De Vos A, Sermon K, Van de Velde H, et al.: Pregnancy after preimplantation genetic diagnosis for Charcot-Marie-Tooth disease type 1A. Mol Hum Reprod 4:978–984, 1998.
CHARCOT-MARIE-TOOTH DISEASE Dubourg O, Tardieu S, Birouk N, et al.: Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked CharcotMarie-Tooth disease. Brain 124:1958–1967, 2001. Ericson U, Ansved T, Borg K: Charcot-Marie-Tooth disease—muscle biopsy findings in relation to neurophysiology. Neuromuscul Disord 8:175–181, 1998. Garcia CA: A clinical review of Charcot-Marie-Tooth. Ann N Y Acad Sci 883:69–76, 1999. Hahn AF, Bolton CF, White CM, et al.: Genotype/phenotype correlations in Xlinked dominant Charcot-Marie-Tooth disease. Ann N Y Acad Sci 883:366–382, 1999. Humberstone PM: Nerve conduction studies in Charcot-Marie-Tooth disease. Acta Neurol Scand 48:176–190, 1972. Ionasescu VV, Ionasescu R, Searby C: Screening of dominantly inherited Charcot-Marie-Tooth neuropathies. Muscle Nerve 16:1232–1238, 1993. Kashork CD, Chen KS, Lupski JR, et al.: Prenatal diagnosis of Charcot-MarieTooth disease type 1A. Ann N Y Acad Sci 883:457–459, 1999. Kashork CD, Lupski JR, Shaffer LG: Prenatal diagnosis of Charcot-MarieTooth disease type 1A by interphase fluorescence in situ hybridization. Prenat Diagn 19:446–449, 1999. Kleopa KA, Scherer SS: Inherited neuropathies. Neurol Clin 20:679–708, 2002. Lebo RV: Prenatal diagnosis of Charcot-Marie-Tooth disease. Prenat Diagn 18:169–172, 1998. Lebo RV, Martelli L, Su Y, et al.: Prenatal diagnosis of Charcot-Marie-Tooth disease type 1A by multicolor in situ hybridization. Am J Med Genet 47:441–450, 1993. Lewis RA: The challenge of CMTX and connexin 32 mutations. Muscle & Nerve 23:147–149, 2000. Lewis RA, Sumner AJ, Shy ME: Electrophysiological features of inherited demyelinating neuropathies: a reappraisal in the era of molecular diagnosis. Muscle Nerve 23:1472–1487, 2000. Löfgren A, De Vos A, Sermon K, et al.: Preimplantation diagnosis for CharcotMarie-Tooth type 1A. Ann N Y Acad Sci 883:460–462, 1999.
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Low PA, McLeod JG, Prineas JW: Hypertrophic Charcot-Marie-Tooth disease. Light and electron microscope studies of the sural nerve. J Neurol Sci 35:93–115, 1978. Lupski JR: DNA diagnostics for Charcot-Marie-Tooth disease and related inherited neuropathies. Clin Chem 42:995–998, 1996. Lupski JR: Charcot-Marie-Tooth disease: lessons in genetic mechanisms. Mol Med 4:3–11, 1998. Lupski JR: Recessive Charcot-Marie-tooth disease. Ann Neurol 47:6–8, 2000. Lupski JR, Garcia CA: Molecular genetics and neuropathology of CharcotMarie-Tooth disease type 1A. Brain Pathol 2:337–349, 1992. Lupski JR, Wise CA, Kuwano A, et al.: Gene dosage is a mechanism for Charcot-Marie-Tooth disease type 1A. Nat Genet 1:29–33, 1992. Murakami T, Garcia CA, Reiter LT, et al.: Charcot-Marie-Tooth disease and related inherited neuropathies. Medicine (Baltimore) 75:233–250, 1996. Pareyson D: Charcot-Marie-Tooth disease and related neuropathies: molecular basis for distinction and diagnosis. Muscle Nerve 22:1498–1509, 1999. Pleasure DE: Genetics of Charcot-Marie-Tooth disease. Arch Neurol 60:481–482, 2003. Roa BB, Lupski JR: Molecular genetics of Charcot-Marie-Tooth neuropathy. Adv Hum Genet 22:117–152, 1994. Rudnik-Schoneborn S, Rohrig D, Nicholson G, et al.: Pregnancy and delivery in Charcot-Marie-Tooth disease type 1. Neurology 43:2011–2016, 1993. Teunissen LL, Notermans NC, Franssen H, et al.: Disease course of CharcotMarie-Tooth disease type 2. Arch Neurol 60:823–828, 2003. Thomas PK: Overview of Charcot-Marie-Tooth disease type 1A. Ann N Y Acad Sci 883:1–5, 1999. Vance JM: Charcot-Marie-Tooth disease type 2. Ann N Y Acad Sci 883: 42–46, 1999. Vance JM: The many faces of Charcot-Marie-Tooth disease. Arch Neurol 57:638–640, 2000.
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Fig. 1. Two patients with Charcot-Marie-Tooth disease showing storklike legs and pes cavus deformities. Fig. 2. A 23-year-old female with Charcot-Marie-Tooth disease showing stork legs with muscle wasting, pes cavus deformities and foot drop. She has absent deep tendon reflexes. Her onset of disease began in the third grade with a history of tripping, falling, and clumsiness. Family history revealed affected individuals in three generation.
CHARGE Association CHARGE association is a nonrandom occurrence of congenital malformations including Coloboma, Heart disease, Atresia of choana, Retarded growth and/or CNS anomalies, Genitourinary defects and/or hypogonadism, and Ear anomalies and/or deafness. The association was first reported by Hall in 1979 in 17 children with multiple congenital anomalies who were ascertained because of choanal atresia. However, the acronym was coined by Pagon in 1981. The prevalence is estimated to be 1 in 10,000.
GENETICS/BASIC DEFECTS 1. Sporadic in most cases 2. Possible polytropic developmental field defect involving neural crest cells or the neural tube itself 3. A possible genetic causation a. Increased paternal age b. Rare familial cases c. A high concordance rate in monozygotic twins d. A de novo gene mutation e. Parent-to-child transmission suggesting autosomal dominant inheritance f. Recurrences among siblings to normal parents suggesting possible germ cell line mosaicism g. Submicroscopic chromosome anomaly i. Different chromosome anomalies reported in patients with a pattern of malformations reminiscent of CHARGE association ii. Recently, de novo overlapping microdeletions were identified in 8q12 in patients with CHARGE syndrome by array-based comparative genomic hybridization 4. Sequence analysis of genes residing within 8q12 critical region revealed mutations in the CHD7 gene (a novel member of the chromodomain gene family) in a number of CHARGE patients without microdeletions
CLINICAL FEATURES 1. Major criteria a. Eye anomalies i. Coloboma (80–90%) of the iris, choroid disc and optic nerve ii. Microphthalmia/anophthalmia iii. Secondary retinal detachments and cataracts iv. Total or partial vision loss v. Superior palpebral ptosis, epicanthus, and telecanthus b. Choanal Atresia (50–60%) c. Ear anomalies/deafness (90%) i. External ears a) Asymmetry b) Posteriorly rotated c) Dystopia 149
d) e) f) g) h) i)
Prominent Increased width Decreased height Cup-shaped ‘Snipped-off’ helical fold Prominent antihelix discontinuous with the antitragus j) Triangular concha k) Small or absent lobes ii. Middle ears a) Chronic serous otitis media approaching 100% b) Eustachian tube anomalies associated with choanal atresia or palatal cleft c) Ossicular malformations d) Conductive hearing loss iii. Inner ears a) Cochlear defects b) Sensorineural hearing loss iv. Temporal bone malformations d. Cranial nerve dysfunction (70–90%) i. Cranial nerve I: anosmia ii. Cranial nerve VII: unilateral or bilateral facial palsy iii. Cranial nerve VIII: sensorineural deafness and vestibular problems iv. Cranial nerves IX and/or X: velopharyngeal incoordination and swallowing problems 2. Minor criteria a. Heart disease (cardiovascular malformations) (75–85%) i. Conotruncal defects (e.g., tetralogy of Fallot) ii. AV canal defects iii. Aortic arch anomalies iv. Others b. Growth and mental Retardation (70–100%) i. Growth deficiency ii. Short stature iii. Delayed motor milestones iv. Hypotonia v. Mental retardation c. Genital anomaly (70–80%) i. Males: micropenis, cryptorchidism, delayed/ incomplete pubertal development ii. Females: hypoplastic labia, delayed/incomplete pubertal development d. Orofacial cleft i. Cleft lip/palate (15–20%) ii. Laryngeal cleft e. Tracheoesophageal fistula/esophageal atresia (15–20%) f. Distinctive face (70–80%) i. Broad forehead ii. Square face iii. Facial asymmetry
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iv. v. vi. vii. viii. ix. x. xi. xii. xiii.
Ptosis Arched eyebrows Shallow supraorbital ridges Iris coloboma High nasal bridge Full nasal tip Microretrognathia Cleft lip/palate Laterally protruding ears Prognathism, prominent mandibular mentum, and generalized facial narrowing with advancing age xiv. Occasional broad or webbed neck with sloping shoulders 3. Occasional findings a. Thymic/parathyroid hypoplasia: DiGeorge sequence without chromosome 22q11 deletion (rare) b. Renal anomalies (15–25%) i. Dysgenesis ii. Horseshoe/ectopic kidney iii. Hydronephrosis c. Hand anomalies i. Polydactyly, ectrodactyly, thumb hypoplasia (rare) ii. Altered palmar flexion creases (50%) d. General appearance i. Webbed neck (rare) ii. Sloping shoulders (occasional) iii. Accessory or hypoplastic nipples (rare) e. Abdominal defects i. Omphalocele (rare) ii. Umbilical hernia (15%) f. Spine anomalies (rare) i. Scoliosis ii. Hemivertebrae g. CNS malformations i. Midline defects (corpus callosum agenesis, arhinencephaly, septal agenesis, meningoencephalocele, partial vermis agenesis) (22%) ii. Asymmetry (cerebral, ventricular, cerebellar) (18%) iii. Hindbrain anomalies (brain stem hypotrophy demonstrated by CT scan or MRI, vermian agenesis) (14%)
DIAGNOSTIC INVESTIGATIONS 1. Audiology, tympanometry, BAER, and CT of temporal bones for evaluation of hearing loss 2. Dilated fundoscopic exam for colobomas 3. Nasal pharyngeal feeding tube passage and CT scan of upper airway for evaluation of choanal atresia 4. Echocardiography for cardiovascular malformations 5. Ultrasound for renal anomalies 6. CT scan and/or MRI for brain malformations 7. Chromosome analysis for associated chromosomal anomalies 8. Molecular genetic analysis for CHD7 gene mutation
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected with autosomal dominant disorder b. Patient’s offspring: not increased unless the patient has an autosomal dominant disorder 2. Prenatal diagnosis a. Ultrasonography: difficult unless in the pregnancy at risk b. CHD7 gene mutation analysis of fetal cells obtained from CVS and amniocentesis for the family at risk may be available clinically in the near future 3. Management a. Feeding problems/failure to thrive i. Use of antispasmodics ii. Nissen fundoplication iii. Gastrostomy tube for feeding b. Developmental delay/mental retardation i. Early infant intervention ii. Special education c. Respiratory problems: may require tracheostomy for aspiration of secretions d. Choanal stenosis/atresia i. Airway stabilization and circulatory support ii. Requires surgical opening for the posterior choanae by placing stents to keep the nasal passages open if there is obstructed breathing iii. Choanoplasty e. Congenital heart defects: corrective surgery when indicated f. Colobomas: requires ophthalmologic care g. External ear anomalies/hearing loss i. Hearing aids for deafness ii. Surgery for ear canal and temporal bone abnormalities h. Management of other associated anomalies
REFERENCES Amiel J, Attié-Bitach T, Marianowski R, et al.: Temporal bone anomaly proposed as a major criteria for diagnosis of CHARGE syndrome. Am J Med Genet 99:124–127, 2001. Awrich PD, Flannery DB, Robertson L, et al.: CHARGE association anomalies in siblings [abstract]. Am J Med Genet 34:80A, 1982. Blake KD, Davenport SL, hall BD, et al.: CHARGE association: an update and review for the primary pediatrician. Clin Pediatr 37:159–173, 1998. Chestler RJ, France TD: Ocular findings in CHARGE syndrome. Six case reports and a review. Ophthalmology 95:1613–1619, 1988. Clementi M, Tenconi R, Turolla L, et al.: Apparent CHARGE association and chromosome anomaly: chance or contiguous gene syndrome. Am J Med Genet 41:246–250, 1991. De Krijger RR, Mooy CM, Van Hemel JO, et al.: CHARGE association-related ocular pathology in a newborn with partial trisomy 19q and partial monosomy 21q, from a maternal translocation (19;21)(q13.1;q22.3). Pediatr Dev Pathol 2:577–581, 1999. Dhooge L, Lemmerling M, Lagache M, et al.: Otological manifestations of CHARGE association. Ann Otol Rhinol Laryngol 107(pt 1):935–941, 1998. Edwards BM, Van Riper LA, Kileny Pr: Clinical manifestations of CHARGE association. Int J Pediatr Otorhinolaryngol 33:23–42, 1995. Edwards BM, Kileny PR, Van Riper LA: CHARGE syndrome: a window of opportunity for audiologic intervention. Pediatrics 110:119–126, 2002. Graham JM Jr: A recognizable syndrome within CHARGE association: HallHittner syndrome. Am J Med Genet 99:120–123, 2001.
CHARGE ASSOCIATION Hall BD: Choanal atresia and associated multiple anomalies. J Pediatr 95:395–398, 1979. Harris J, ‘Robert E, Kallen B: Epidemiology of Choanal atresia with special reference to the CHARGE association. Pediatrics 99:363–367, 1997. Hittner HM, Hirsch NJ, Kreh GM, et al.: Colobomatous microphthalmia, heart disease, hearing loss, and mental retardation—a syndrome. J Pediatr Ophthalmol Strabismus 16:122–128, 1979. Hurst JA, Meinecke P, Baraitser M: Balanced t(6;8)(6p8p6q8q) and the CHARGE association. J Med Genet 28:54–55, 1991. Kaplan LC: Choanal atresia and its associated anomalies. Further support for the CHARGE association. Int J Pediatr Otorhinolaryngol 8:237–242, 1985. Lubinsky MS: Properties of associations: identity, nature, and clinical criteria, with a commentary on why CHARGE and Goldenhar are not associations. Am J Med Genet 49:21–25, 1994. Metlay LA, Smythe PS, Miller ME: Familial CHARGE association: clinical report with autopsy findings. Am J Med Genet 26:577–581, 1999. Mitchell JA, Giangiacomo J, Hefner MA, et al.: Dominant CHARGE association. Ophthalmol Paediatr Genet 6:271–276, 1985. Morgan DW, Bailey CM, Phelps P, et al.: Ear-nose-throat abnormalities in the CHARGE association. Arch Otolaryngol Head Neck Surg 119:49–54, 1993. Murofoshi T, Ouvrier RA, Parker GD, et al.: Vestibular anomalies in CHARGE association. Ann Otol Rhinol Laryngol 106:129–134, 1997. North KN, Wu BL, Cao BN, et al.: CHARGE association in a child with de novo inverted duplication (14)(q22>q24.3). Am J Med Genet 57:610–614, 1995. Pagon RA, Graham JM Jr, Zonana J, et al.: Coloboma, congenital heart disease, and Choanal atresia with multiple anomalies: CHARGE association. J Pediatr 99:223–227, 1981.
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Russell-Eggitt JM, Blake KD, Taylor DSL, et al.: The eye in CHARGE association. Br J Ophthalmol 74:421–426, 1990. Sanlaville D, Romana SP, Lapierre JM, et al.: A CGH study of 27 patients with CHARGE association. Clin Genet 62:135–138, 2002. Siebert JR, Graham JM, MacDonald C: pathological features of the CHARGE association: support for involvement of the neural crest. Teratology 31:331–336, 1985. Tellier AL, Lyonnet S, Cormier-Daire V, et al.: Increased paternal age in CHARGE association. Clin Genet 50:548–550, 1996. Tellier AL, Theopile D, Bonner D, et al.: CHARGE association: report of 47 cases with genotypic analysis of chromosomes 7q36 and 22q11. Am J Hum Genet 59 (suppl):100A, 1996. Telllier AL, Cormier-Daire V, Abadie V, et al.: CHARGE association: report of 47 cases and review. Am J Med Genet 76:402–409, 1998. Tellier AL, Amiel J, Delezoide AL, et al.: Expression of the PAX2 gene in human embryos and exclusion in the CHARGE syndrome. Am J Med Genet 93:85–88, 2000. Thelin JW, Mitchell JA, Hefner MA: CHARGE syndrome: part II. Hearing loss. Int J Pediatr Otorhinolaryngol 12:145–163, 1986. Vissers LELM, van Ravenswaaij CMA, Admiraal R, et al.: Mutations in a novel member of the chromodomain gene family cause CHARGE syndrome. American Society of Human Genetics 54th Annual Meeting, Abstract #1, 2004. Warburg M: Ocular colobomata and multiple congenital anomalies: the CHARGE association. Ophthalmol Paediatr Genet 6:31–36, 1983. Wiener-Vacher SR, Amanou L, Denixe P, et al.: Vestibular function in children with the CHARGE association. Arch Otolaryngol Head Neck Surg 125:342–347, 1999.
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Fig. 1. A boy with typical CHARGE association at ages 11 (front view) and 15 (lateral view). The patient had bilateral colobomas, choanal atresias, growth and mental retardation, hypogonadism, and ear anomalies with hearing loss.
Cherubism In 1933, Jones first described familial occurrence of painless enlargement of the jaws in three siblings. Jones later in 1938 reported observations on the same family under the title “familial multilocular cystic disease of the jaws” and coined the term “cherubism” after the cherubs of Renaissance art for the full round cheeks and the upward cast of the eyes giving the children a peculiarly grotesque, cherubic appearance.
GENETICS/BASIC DEFECTS
6. 7.
1. Inheritance a. Autosomal dominant b. Familial in 80% of cases c. Males affected twice as often as females d. 80% overall penetrance i. 100% in males ii. 50–70% in females e. Variable expressivity 2. Cause a. Caused by mutations in the gene encoding c-Ablbinding protein SH3BP2 b. Gene for cherubism mapped to chromosome region 4p16.3
8.
9.
CLINICAL FEATURES 1. Variable size of the jaw lesions in cherubism a. Minor lesions of both jaws b. Massive involvement of both jaws 2. Natural history: a. Classically normal at birth b. Onset usually between 14 months and 5 years. However, the severe cases are evident at birth c. Progresses until puberty d. Usually progression stops after puberty e. Regression of the bone lesions (involution of the disease) without treatment in some cases f. Rapidly growing and extensively deforming lesions of the maxilla and the mandible including the coronoids and condyles in severely affected individuals 3. Characteristic ‘eyes raised to heaven’ cherubic appearance: an appearance of the cherubs portrayed in Renaissance art a. Fullness of the lower half of the face (cheeks and jaw) b. Retraction of the lower lids by the stretched skin over the cheeks pulling down the lower eyelids. Consequently, a thin line of sclera is exposed beneath the iris and the eyes appear to be raised heavenward in a manner reminiscent of a “the cherubs in Renaissance paintings” 4. Painless hard enlargement of the jaws 5. Exclusively affecting maxilla and mandible a. Mandible usually involved b. Involvement of the maxilla in 60% of cases
10.
11.
12. 13.
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c. Painless lesions d. Bilateral enlargement with loss of bone in the jaws and its replacement with large amount of fibrous tissue e. Dental effect by bone lesion i. Premature loss of deciduous teeth ii. Displacement of permanent dentition f. Swelling usually abates by the third decade, whereas radiographic changes commonly persist into the fourth decade Submandibular lymph node enlargement in 45% of cases Ocular manifestations a. Lower lid retraction b. Proptosis c. Diplopia d. Globe displacement e. Visual loss due to optic nerve atrophy f. Rare extension of lesion into the orbits Rare upper airway involvement a. Displaced tongue affecting speech, mastication, swallowing, and respiration b. Obstructive apnea Extremely rare extrafacial skeletal involvement a. Upper humerus b. Bilateral triquetral bones c. Anterior ribs d. Upper femoral necks Rare associated syndromes a. Noonan syndrome (Addante, 1996) b. Ramon syndrome i. Cherubism ii. Short stature iii. Mental retardation iv. Gingival fibromatosis v. Epilepsy c. Fragile X syndrome d. Craniosynostosis Functional impairment a. Mastication problems b. Speech difficulty c. Tooth alteration d. Loss of normal vision Psychological consequences Differential diagnosis a. Four main types of fibrous dysplasia i. Monostotic fibrous dysplasia: only one bone is affected ii. Polyostotic: multiple bones are affected iii. McCune-Albright syndrome a) Polyostotic form b) Accompanied by pigmentary lesions c) Endocrine dysfunction presenting as precocious puberty in females iv. Craniofacial form of fibrous dysplasia
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a) Only bones of the craniofacial complex are affected b) Onset in the second decade in majority of patients c) Generally unilateral lesions, tend to become static once skeletal maturity is reached d) Clinically difficult to differentiate from cherubism if the skeletal abnormalities are localized to the jaws e) Molecularly different from cherubism b. Infantile cortical hyperostosis i. Diagnosed in the first 6 months of life ii. Radiographically does not produce cystic areas iii. Characterized by thickening of the mandibular lower border iv. Does not have bilateral expression c. Osteitis fibrosa cystica secondary to hyperparathyroidism i. Increased serum alkaline phosphatase ii. Increased serum calcium iii. Decreased serum phosphorus iv. Increased urinary phosphorus d. Various tumors of the jaws
DIAGNOSTIC INVESTIGATIONS 1. Serum alkaline phosphatase levels may be elevated 2. Radiography a. Extensive involvement of the mandible and the maxilla b. Multilocular radiolucent areas in the mandible and maxilla with expansion of the bony cortex i. Often very extensive ii. With a few irregular bony septa iii. Multilocular rarefactions replaced by sclerosis with progressive calcification in the adult c. Absent and displaced teeth in the involved areas 3. CT scan a. Superior in making the diagnosis b. Determining the degree of severity 4. Histological changes in cherubism a. Replacement of the normal bony architecture with proliferating fibrous tissue containing numerous giant cells b. Mononuclear fibroblastic stroma i. Nonneoplastic fibrous lesions rich in multinucleated giant cells identified as osteoclasts ii. Irregular bone formation c. A peculiar perivascular cuffing of collagen: considered by some to be pathognomonic for the condition d. Histological resemblance to the following disorders: i. Giant cell tumor ii. Giant cell granulomas iii. Ossifying fibroma iv. Fibrous dysplasia of the jaw v. Paget disease of bone 5. Molecular genetic analysis: detection of a SH3BP2 gene mutation by sequencing of select exons or entire coding region is available clinically
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected b. Patient’s offspring: 50% 2. Prenatal diagnosis a. Ultrasonography: not possible since the lesion is postnatal in nature b. Molecular analysis possible on fetal DNA obtained by amniocentesis or CVS if the disease-causing mutation is identified in an affected family member 3. Management a. Observation i. Generally self-limiting lesions and subside with age ii. Surgical intervention required only in cases with esthetic or functional problems b. Tracheostomy to secure the airway for upper airway obstruction c. Teeth extraction from the sites of fibrous changes d. Curettage alone or in combination with surgical contouring: considered the treatment of choice e. Resection of the orbital lesions may be required to improve visual impairment f. Prompt recurrence likely if surgery is performed at an early age g. Radiation therapy ineffective and contraindicated in view of the following risks: i. Osteoradionecrosis ii. Interference with dentofacial growth and development iii. Affect on future surgical procedures h. Experimental use of calcitonin to treat cherubism described recently
REFERENCES Ayoub AF, El-Mofty SS: Cherubism: report of an aggressive case and review of the literature. J Oral Maxillofac Surg 51:702–705, 1993. Battaglia A, Merati A, Magit A: Cherubism and upper airway obstruction. Otolaryngol Head Neck Surg 122:573–574, 2000. Bianchi SD, Boccardi A, Mela F, et al.: The computed tomographic appearances of cherubism. Skeletal Radiol 16:6–10, 1987. Caballero Herrera R, Vinals Iglesias H: Cherubism: a study of three generations. Medicina Oral 3:163–171, 1998. Caffey J, Williams JL: Familial fibrous swelling of the jaws. Radiology 56: 1–5, 1951. Carroll AL, Sullivan TJ: Orbital involvement in cherubism. Clin Experiment Ophthalmol 29:38–40, 2001. Colombo F, Cursiefen C, Neukam FW, et al.: Orbital involvement in cherubism. Ophthalmology 108:1884–1888, 2001. Dunlap C, Neville B, Vickers RA, et al.: The Noonan syndrome/cherubism association. Oral Surg Oral Med Oral Pathol 67:698–705, 1989. Faircloth WJ, Edwards RC, Farhood VW: Cherubism involving a mother and daughter: case reports and review of the literature. J Oral Maxillofac Surg 49:535–542, 1991. Hart W, Schweitzer DH, Slootweg PJ, et al.: Een man met cherubisme. Ned Tijdschr Geneeskd 144:34–38, 2000. Hitomi G, Nishide N, Mitsui K: Cherubism: diagnostic imaging and review of the literature in Japan. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81:623–628, 1996.
CHERUBISM Imai Y, Kanno K, Moriya T, et al.: A missense mutation in the SH3BP2 gene on chromosome 4p16.3 found in a case of nonfamilial cherubism. Cleft Palate Craniofac J 40:632–638, 2003. Jones WA: Familial multilocular cystic disease of the jaws. Am J Cancer 17:946–950, 1933. Jones WA: Cherubism. Oral Surg 20:648–653, 1965. Jones WA: Further observations regarding familial multilocular cystic disease of the jaws. Br J Radiol 11:227–240, 1938. Jones WA, Gerrie J, Pritchard J (1950). Cherubism-familial fibrous displasia of the jaws. J Bone Joint Surg Br 32b:334–347, 1950. Katz JO, Dunlap CL, Ennis RLJ (1992). Cherubism: report of a case showing regression without treatment. J Oral Maxillofac Surg 50:301–303, 1992. Kaugars GE, Niamtu III J, Svirsky JA: Cherubism: diagnosis, treatment, and comparison with central giant cell granulomas and giant cell tumors. Oral Surg Oral Med Oral Pathol 73:369–374, 1992. Khosla VM, Korobkin M: Cherubism. Am J Dis Child 120:458–461, 1970. Kozakiewicz M, Perczynska-Partyka W, Kobos J: Cherubism-clinical picture and treatment. Oral Dis 7:123–130, 2001. Lo B, Faiyaz-Ul-Haque M, Kennedy S, et al.: Novel mutation in the gene encoding c-Abl-binding protein SH3BP2 causes cherubism. Am J Med Genet 121A:37–40, 2003. Mangion J, Rahman N, Edkins S, et al.: The gene for cherubism maps to chromosome 4p16.3. Am J Hum Genet 65:151–157, 1999.
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Mangion J, Edkins S, Goss AN, et al.: Familial craniofacial fibrous dysplasia: absence of linkage to GNAS1 and the gene for cherubism. J Med Genet 37:E37, 2000. Peters WJN: Cherubism: a study of twenty cases from one family. Oral Surg 47:307–311, 1979. Ramon Y, Engelberg IS: An unusually extensive case of cherubism. J Oral Maxillofac Surg 44:325–328, 1986. Silver EC, de Souza PEA, Barreto DC, et al.: An extreme case of cherubism. Br J Oral Maxillofac Surg 40:45–48, 2002. Southgate J, Sarma U, Townend JV, et al.: Study of the cell biology and biochemistry of cherubism. J Clin Pathol 51:831–837, 1998. Tiziani V, Reichenberger E, Buzzo CL, et al.: The gene for cherubism maps to chromosome 4p16. Am J Hum Genet 65:158–166, 1999. Ueki Y, Tiziani V, Santanna C, et al.: Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism. Nature Genet 28:125–126, 2001. Wada S, Udagawa N, Nagata N, et al.: Calcitonin receptor down-regulation relates to calcitonin resistance in mature mouse osteoclast. Endocrinology 137:1042–1048, 1996. Zachariades N, Papanicolaou S, Xypolyta A, et al.: Cherubism. Int J Oral Surg 14:138–145, 1985. Zohar Y, Grausbord R, Shabtai F, et al.: Fibrous dysplasia and cherubism as an hereditary familial disease: follow-up of four generations. J Craniomaxillofac Surg 17:340–344, 1989.
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Fig. 1. A boy with cherubism showing full cheeks and jaw and the retraction of the lower eyelids with symmetrical augmentation on both mandibular angles.
Chiari Malformation In 1891, Chiari first described a dysplasia of the nervous system consisting of herniation of the cerebellar tonsils into foramen magnum. There are three types of Chiari malformation. The commonest ones are type I and type II, the latter has been named the Arnold-Chiari malformation. (De Reuck, 1976)
GENETICS/BASIC DEFECTS
c.
d.
1. Classification of Chiari malformations according to the severity a. Type I (the milder malformation) i. Ectopia of the cerebellar tonsils (caudal herniation of the cerebellar tonsils and inferior cerebellum through the foramen magnum) ii. Usually an isolated feature encountered in adults b. Type II (the more severe malformation) i. Downward displacement of the cerebellar medulla and fourth ventricle into the spinal canal ii. Almost always associated with meningomyelocele iii. May be associated with polygyria, cortical heterotopia, and dysgenesis of the corpus callosum c. Type III (the most severe malformation) i. Downward displacement of most of the cerebellum into a high cervical/low occipital encephalocele ii. Malformation consisting of anatomical anomalies typical of Chiari type II malformation with those of a high cervical/occipital encephalocele 2. Acquired Chiari I malformation caused by conditions leading to increased intracranial pressure a. Head injury b. Hydrocephalus c. Craniosynostosis 3. Brainstem dysfunction, sensory disturbance, and motor loss caused by impaction of the tonsils against the cervicomedullary structures
e.
f.
CLINICAL FEATURES 1. Patients with Chiari I malformation a. Asymptomatic in majority of patients b. General symptoms i. Headache ii. Fatigue iii. Memory loss iv. Pressure on the neck v. Back pain vi. Insomnia vii. Poor circulation viii. Nausea ix. Menstrual problems x. Sexual alterations xi. Hypothermia xii. Bronchial aspirations
g.
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xiii. Respiratory alterations xiv. Drop attacks xv. Rare reports of sudden death Ocular symptoms i. Loss of vision ii. Intolerance of bright light iii. Diplopia Otolaryngologic symptoms i. Vestibular manifestations a) Imbalance b) Swaying c) Dizziness d) Positional vertigo e) Spontaneous vertigo f) Nystagmus g) Hearing loss h) Tinnitus ii. Alterations of cranial pairs a) Dysphagia b) Dysphonia c) Alterations in tongue mobility d) Loss of smell e) Facial hyposthesia iii. Sleep apnea Cerebellum compression symptoms i. Ataxia ii. Nystagmus iii. Gait difficulties iv. Opisthotonos v. Horner’s syndrome vi. Paralysis of the last cranial nerves vii. Hypotonia viii. Trembling ix. Dysarthria x. Dysmetria Associated CNS anomalies i. Stenosis of the aqueduct of Silvia ii. Meningomyelocele iii. Syringomyelia (cystic dilation of the spinal cord) Symptoms associated with syringomeyelia i. Known to accompany 50% to 70% of patients with Chiari I malformations ii. Obstructed cerebrospinal fluid at the site of cerebellar tonsillar herniation shows perivascular movement of CSF from the spinal subarachnoid space into the spinal cord with each Valsalva maneuver and cause syringomyelia iii. Tingling, hyposthesia, and burning sensation in the extremities iv. Thermalgesic anesthesia v. Alteration in muscular reflexes vi. Areflexia vii. Alteration of kinesthesia
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viii. Motor skill dysfunction ix. Headache or nonradicular pain in the shoulder, back, and limbs x. Headache usually suboccipital and upper cervical in location and is exacerbated by Valsalva maneuvers xi. Associated with the development of a painful, rapidly progressive, or left-curving scoliosis xii. Recent reports of spontaneous radiographic improvement of childhood Chiari malformations and syringomyelia 2. Chiari I malformation in children and adolescents a. Natural history of an asymptomatic Chiari I malformation in children i. Not well understood ii. Rarely reported to resolve spontaneously iii. Asymptomatic at the time of diagnosis in many children iv. Degree of tonsillar ectopia correlating well with the presence of neurologic signs and symptoms v. Rare reports of sudden death b. Group I (asymptomatic) i. Age at diagnosis: 3 months to 17 years ii. Associated conditions a) Hydrocephalus b) Craniofacial syndromes c) Epilepsy d) Occult spinal dysraphism c. Group II (brain stem compression) i. Age at diagnosis: 7 months to 26 years ii. Associated conditions a) Craniofacial syndromes b) Hydrocephalus c) Precocious puberty iii. Symptoms a) Neck pain b) Vertigo c) Headache d) Numbness e) Swallowing difficulties f) Apnea g) Opisthotonos h) Brachialgia i) Hyposthenia j) Spasticity k) Hemifacial pain d. Group III (presence of syringomyelia). Symptoms are: i. Numbness ii. Sensory loss iii. Neck pain iv. Vertigo v. Scoliosis vi. Hyposthenia vii. Headache viii. Muscle hypotrophy ix. Swallowing difficulties x. Limb pain 3. Patients with Chiari II malformation
a. Almost invariably associated with myelomeningocele (90%) b. Brain stem signs in 20% of patients with Chiari II malformation in children and adolescence i. Vertigo ii. Bioccipital headache iii. Cerebellar dysfunction iv. Progressive paresis of the arms 4. Patients with Chiari III malformation a. Rarest of the Chiari malformations b. Associated with a high cervical or occipital encephalocele c. Prognosis for nearly all reported patients i. Various degree of developmental delay ii. Epilepsy iii. Hypotonia iv. Spasticity v. Upper and/or lower motor neuron deficits vi. Lower cranial nerve dysfunction d. CNS anomalies usually observed in an occipital encephalocele i. A small cranial fossa ii. Caudal displacement of cerebellar tonsils and vermis iii. Medullary kinking iv. Tectal beaking v. Obvious hydrocephalus
DIAGNOSTIC INVESTIGATIONS 1. CT or MRI a. Chiari I malformation i. Incidental detection in asymptomatic individuals ii. Herniation of the tonsils >5 mm below the foramen magnum on MRI considered diagnostic b. Chiari II malformation i. Caudal cerebellum (100%) ii. Kinking of medulla on spinal cord (79%) iii. Elongation of brainstem and low medulla, stretched aqueduct and fourth ventricle (75%) iv. Beaking of quadrigeminal plate (60%) v. Large massa intermedia (55%) vi. Large fourth ventricle (25%) vii. Hydromyelia (15%) c. Chiari III malformation i. An occipitocervical meningoencephalo-cele protruding through a bony defect involving the lower occipital squama and/or the posterior arch of the first cervical vertebrae ii. A small posterior cranial fossa with low tentorial attachment iii. Scalloping of the clivus iv. Massive herniation of the hypoplastic cerebellar structures into the malformation v. Beaking of the tectal plate vi. Dysgenesis of the corpus callosum vii. Severe ventricular dilatation (hydrocephalus) 2. Brainstem auditory evoked potentials (BAEP)
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a. Consistently abnormal in symptomatic Chiari II malformation b. Showing a positive predictive value of 88% in predicting central neurologic sequelae in newborns and infants
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: not increased 2. Prenatal diagnosis a. Prenatal ultrasonography i. Classic ‘lemon and banana’ signs, the gold standard in the early screening of Chiari II malformation ii. Clivus-supraocciput angle below 5th centile of nomogram in cases of Chiari II malformation b. Prenatal MRI: Chiari III malformation diagnosed during third trimester using single shot fast spin echo sequence to avoid motion artifact 3. Management a. Chiari I malformation i. Conservative treatment for asymptomatic patients ii. Main treatment consisting of decompressing the structures trapped in the foramen magnum a) Suboccipital craniectomy with or without dural patch grafting and cervical laminectomies: the most often used procedure b) Syringosubarachnoid shunt when indicated iii. Shunting of hydrocephalus iv. Major preexisting sensory or motor deficits: poor prognosticators for functional recovery b. Chiari II (Arnold-Chiari) malformation i. Seen most often in children with myelomeningocele ii. Shunting of hydrocephalus often resolves brainstem symptoms and surgical decompression may not be necessary iii. Surgical decompression of posterior fossa and upper cervical spine may be required if brainstem compression symptoms remain after shunting iv. Surgical intervention indicated to prevent further deterioration of the motor function and to diminish the progress of spasticity and scoliosis from tethered cord syndrome c. Chiari III malformation i. Primary closure of the malformation: usually the treatment of choice ii. CSF shunting of the associated hydrocephalus postponed to a later phase iii. Neonates often require intensive care treatment for the associated severe respiratory distress
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REFERENCES Aribal ME, Gurcan F, Aslan B: Chiari III malformation: MRI. Neuroradiology 38:184–186, 1996. Bindal AK, Dunsker SB, Tew JM: Chiari I malformation: classification and management. Neurosurgery 37:1069–1074, 1995. Caldarelli M, Rea G, Cincu R, et al.: Chiari type III malformation. Childs Nerv Syst 18:207–210, 2002. Cama A, Tortori-Donati P, Piattelli GL, et al.: Chiari complex in children. Neuroradiological diagnosis, neurosurgical treatment and proposal of a new classification. Eur J Pediatr Surg 5 (Suppl):35–38, 1995. Castillo M, Quencer RM, Dominquez R: Chiari III malformation: imaging features. AJNR 13:107–113, 1992. D’Addario V, Pinto V, Del Bianco A, et al.: The clivus-supraocciput angle: a useful measurement to evaluate the shape and size of the fetal posterior fossa and to diagnose Chiari II malformation. Ultrasound Obstet Gynecol 18:146–149, 2001. Dauser RC, Dipietro MA, Venes JL: Symptomatic Chiari I malformation in childhood: a report of 7 cases. Pediatr Neurosci 14:184–190, 1988. De Barros MC, Farias W, Ataide L, et al.: Basilar impression and Arnold Chiari malformation. A study of 66 cases. J Neurol Neurosurg Psychiatry 31: 596–605, 1968. De Reuck J, Theinpont L: Fetal Chiari’s type III malformation. Child’s Brain 2:85–91, 1976. Dure LS, Percy AK, Cheek WR, et al.: Chiari type I malformation in children. J Pediatr 115:573–576, 1989. Dyste GN, Menezes AH, Van Gildrer JC: Symptomatic Chiari malformations. J Neurosurg 71:159–168, 1989. Elster AD, Chen MYM: Chiari I malformations: clinical and radiologic reappraisal. Radiology 183:347–353, 1992. Gálvez MJN, Rodrigo JJF, Liesa RF, et al.: Otorhinolaryngologic manifestations in Chiari malformation. Am J Otolaryngol 23:99–104, 2002. Gammal TE, Mark EK, Brooks BS: MR imaging of Chiari II malformation. AJNR Am J Neuroradiol 35:1037–1044, 1987. Genitori L, Peretta P, Nurisso C, et al.: Chiari type I anomalies in children and adolescents: minimally invasive management in a series of 53 cases. Childs Nerv Syst 16:707–718, 2000. Häberle J, H¸lskamp G, Harms E, et al.: Cervical encephalocele in a newborn—Chiari III malformation. Case report and review of the literature. Childs Nerv Syst 17:373–375, 2001. Koehler J, Schwarz M, Urban PP, et al.: Masseter reflex and blink reflex abnormalities in Chiari II malformation. Muscle Nerve 24:425–427, 2001. Lee R, Tai K, Cheng P, et al.: Chiari III Malformation: Antenatal MRI Diagnosis. Clin Radiol 57:759, 2002. Milhorat TH, Chou MW, Trinidad EM et al.: Chiari I malformation redefined: clinical and radiographic findings for 364 symptomatic patients. Neurosurgery 44:1005–1017, 1999. Mohr PD, Strang FA, Sambrook MA, et al.: The clinical and surgical features in 40 patients with primary cerebellar ectopia (adult Chiari malformation). Q J Med 46:85–96, 1977. Nagib MG: An approach to symptomatic children (ages 4–14 years) with Chiari type I malformation. Pediatr Neurosurg 21:31–35, 1994 Naidich TP: Cranial CT signs of the Chiari II malformation. J Neuroradiol 8:207–227, 1981. Naya Galvez MJ, Fraile Rodrigo JJ, Liesa RF, et al.: Otorhinolaryngologic manifestations in Chiari malformation. Am J Otolaryngol 23:99–104, 2002. Paul KS, Lye RH, Strang FA, et al.: Arnold-Chiari malformation. Review of 71 cases. J Neurosurg 58:183–187, 1983. Rauzzino M, Oakes WJ: Chiari II malformation and syringomyelia. Neurosurg Clin N Am 6:293–309, 1995. Ventureyra EC, Aziz HA, Vassilyadi M: The role of cine flow MRI in children with Chiari I malformation. Childs Nerv Syst 19:109–113, 2003. Weinberg JS, Freed DL, Sadock J, et al.: Headache and Chiari I malformation in the pediatric population. Pediatr Neurosurg 29:14–18, 1998.
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Fig. 1. Sagittal section of a neonate with a large ruptured lumbar meningomyelocele. Arnold-Chiari malformation is evident: the brain stem and lower portion of cerebellum herniate through the foramen magnum and overlap the cervical cord which is severely flattened. The brain shows hydrocephalus.
Fig. 3. A 28-year-old female with Chiari I malformation with normal phenotype but complaining headache, dizziness, and neck pain worsen by pregnancy.
Fig. 2. A patient with multiple congenital anomalies (mental retardation, flat facial plane, epicanthus inversus, blepharophimosis, cataracts, nystagmus, elbow flexion contractures, and vertical talus) with Chiari I malformation (MRI of the brain).
Chondrodysplasia Punctata Chondrodysplasia punctata refers to punctate calcifications, due to abnormal calcium deposition in the areas of enchondral bone formation, described in a variety of chondrodysplasias.
GENETICS/BASIC DEFECTS 1. Genetic heterogeneity of chondrodysplasia punctata a. Rhizomelic chondrodysplasia punctata type I (RCDP1) i. Autosomal recessive disorder ii. Caused by mutations in PEX7, mapped at 6q22-q24, which encodes the cytosolic peroxisomal targeting signal type 2 (PTS2)-receptor protein peroxin 7 iii. Genotype–phenotype correlations a) Classic RCDP1: all patients with homozygous for the L292X mutation b) Phenotype determined by the other allele if the patients are compound heterozygotes for L292X and another mutation c) A milder phenotype associated with several PEX7 alleles b. Rhizomelic chondrodysplasia punctata type 2 (RCDP2) i. Autosomal recessive disorder ii. Caused by mutations in the gene that encodes peroxisomal dihydroxyacetone phosphate acyltransferase (DHAPAT) c. Rhizomelic chondrodysplasia punctata type 3 (RCDP3) i. Autosomal recessive disorder ii. Caused by mutations in the gene (mapped at 2q31) that encodes peroxisomal alkyl-dihdroxyacetone phosphate synthase (ADHAPS) d. Relatively mild autosomal dominant ConradiHünermann syndrome i. Chondrodysplasia punctata, tibia-metacarpal type ii. Chondrodysplasia punctata, humero-metacarpal type e. X-linked dominant type only in females (ConradiHünermann-Happle syndrome) (CDPX2) i. Lethal in males ii. Caused by mutations of the 3β-hydroxysteroidΔ8-Δ7-isomerase (also called emopamil-binding protein, EBP) iii. The gene encoding EBP mapped to Xp11.22p11.23 iv. EBP: catalyzes an intermediate step in the conversion of lanosterol to cholesterol v. Presence of gonadal and somatic mosaicism in CDPX2 f. X-linked recessive type with a deletion of the short arm of the X chromosome (CDPX1) i. Caused by defects in arysulfatase E, a vitamin K-dependent enzyme 161
ii. The locus of the disease identified through the characterization of patients with chromosomal abnormalities involving the Xp22.3 region iii. The gene of CDPX1, named ARSE, encoding a new sulfatase (arylsulfatase E), showing a high sequence homology to steroid sulfatase iv. Point mutations of the ARSE gene detected in the DNA of karyotypically normal patients with chondrodysplasia punctata 2. Causes of stippled cartilaginous calcifications a. Peroxisomal disorders i. Zellweger syndrome a) A peroxisomal disorder b) An autosomal recessive inheritance c) Associated stippled calcifications of the epiphyses, particularly common in the patella d) Severe hypotonia e) Characteristic facies with a high forehead, hypertelorism, epicanthal folds, Brushfield spots, and shallow supraorbital ridges f) Club foot deformity g) The affected infants usually die early in infancy h) Involvement of other organ systems, especially the brain (migrational disorders) and kidneys (cortical cystic disease of the kidneys) ii. Rhizomelic chondrodysplasia punctata b. Genetic disorders i. Conradi-Hunermann chondrodysplasia punctata ii. X-linked dominant chondrodysplasia punctata iii. Smith-Lemli-Opitz syndrome iv. Greenberg dysplasia (cholesterol biosynthesis disorder) a) An autosomal recessive disorder b) Appears to be caused by an error of sterol metabolism at the level of 3β-hydroxysteroidΔ14 reductase c) Nonimmune hydrops fetalis d) Mid-face hypoplasia e) Micrognathia f) Rhizo-mesomelic dwarfism with relatively long and broad hands and feet g) Narrow thorax h) Protuberant abdomen i) Radiographic findings of grossly irregular and deficient ossification of the short tubular bones, fragmented ossification at the ends of the long tubular bones, small pelvic bones with irregular “moth-eaten” contours, platyspondyly with multiple ossification centers of the ver-
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v.
vi.
vii. viii.
ix. x. xi. xii. xiii. xiv. xv.
xvi. xvii. xviii. xix. xx.
xxi.
tebral bodies, and deficient ossification of the calvaria CHILD syndrome a) Congenital hemidysplasia b) Ichthyosiform erythroderma c) Limb defects (unilateral hypomelia with ipsilateral epiphyseal stippling) Dappled diaphyseal dysplasia (lethal shortlimbed dysplasia, type Carty) a) An autosomal recessive disorder b) All cases were stillborn or died in utero c) Fetal hydrops d) Polyhydramnios e) Short limbs with relatively long hands and feet f) Small thorax g) Protuberant abdomen h) Radiographic findings of fragmented appearance of the ribs, small islands of ossification from disruption of the facial bones, axial and appendicular skeleton (multifocal or dappled ossification of long bones), and absent ossification of the calvaria Acrodysostosis De Barsy syndrome a) Cutis laxa b) Corneal clouding c) Mental retardation d) Stippled epiphysis GM1 gangliosidosis Galactosialidosis Fibrochondrogenesis Mucolipidosis II De Lange syndrome X-linked ichthyosis Keutel syndrome a) Stippled epiphysis (knees, elbows) b) Brachytelephalangism c) Pulmonary stenosis Hypothyroidism Chromosome translocation Trisomy 21 and 18 Turner syndrome Brachytelephalangic chondrodysplasia punctata a) An X-linked recessive disorder b) Male infants affected with a very small nose, anteverted and grooved nares c) Benign type of chondrodysplasia punctata d) Also observed in a patient with Xp terminal deletion with ichthyosis and mental retardation e) Distal phalangeal hypoplasia: the most characteristic radiological sign of this form Chondrodysplasia punctata, metacarpal type a) Including tibial-metacarpal type and humeralmetacarpal type b) An autosomal dominant disorder c) Named for a specific long bone but with overlap in the long bone involved d) All have short metacarpals.
e) Affected children with a hypoplastic midface, a depressed nasal bridge, small mouth, micrognathia, short neck, and short limbs f) Radiographically, with short metacarpals associated with short tibias in the tibiametacarpal type and short humeri in humerometacarpal type xxii. Sheffield-type chondrodysplasia punctata a) Heterogeneous group of patients with punctate epiphyses, particularly in the calcaneus and spine b) A benign course c) Distal phalangeal hypoplasia d) Probably not a specific entity but rather a heterogeneous group of disorders that can be included in other entities xxiii. Pacman dysplasia a) A single case report with peculiar bone dysplasia, stippling in many areas, short bowed bones, and periosteal cloaking b) Osteoclasts with an unusual appearance reminiscent of the Pacman figures in computer games on bone histology c) The entire coccygeal and sacral regions replaced by stippling d) Dense stippling also observed in the thoracic region e) Considerable stippling also observed in the epiphyses of the proximal femur, talus, calcaneus, cuboid, and the bones of the hand f) Wide periosteal cloaking of many bones and poor ossification g) Bowed femora h) Superior inferior sagittal clefting in the AP views in the upper spine c. Vitamin K disorders i. Warfarin embryopathy a) Associated with maternal use of warfarin sodium b) Consistent features: saddle nose deformity, hypertelorism, frontal bossing, high-arched palate, short neck, and short stature c) Other features: rhizomelia, micromelia, flexion contractures, optic atrophy, psychomotor retardation, cataracts, congenital heart disease, and renal anomalies ii. Vitamin K epoxide reductase deficiency d. Acquired in utero i. Fetal alcohol syndrome ii. Phenacetin intoxication iii. Fetal hydantoin syndrome iv. Femoral hypoplasia unusual facies syndrome v. Maternal diabetes vi. Maternal systemic lupus erythematosis vii. Febrile illness e. Other conditions involving unusual calcification that may be confused with puncta i. Amelia and other absence deficiency ii. Cerebrocostomandibular syndrome
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iii. Dysplasia epiphysealis hemimelica iv. Calcifying arthritis v. Metachondromatosis
CLINICAL FEATURES 1. Recessive rhizomelic form a. Classic RCDP1 i. Skeletal abnormalities a) Severe symmetric shortening of the proximal limb segments (more severe in humeri than femora) b) Stippled (punctate) epiphyses involving knees, hips, elbows, shoulders, hyoid bone, larynx, sternum, and ribs ii. Peripheral calcifications iii. Facial dysmorphism a) Frontal bossing b) A short, saddle nose iv. Ocular features a) Cataracts: the most common ocular defect developing in virtually all patients: usually present at birth or appear in the first few months of life and are progressive b) Optic atrophy c) Posterior embryotoxon d) Strabismus e) Adhesions between iris and cornea in the ring of Schwabe v. Severe failure to thrive with profound postnatal growth deficiency vi. Gross developmental retardation vii. Contractures and stiff, painful joints, causing irritability in infancy viii. Other complications a) Seizures b) Recurrent respiratory tract infections caused by neurological compromise, aspiration, immobility, and a small chest with restricted expansion c) Spastic quadriplegia d) Ichthyotic skin changes e) Cleft soft palate f) Cervical spine stenosis g) Congenital heart disease h) Ureteropelvic junction obstruction ix. A high mortality a) About 60% survive the first year b) About 39% survive the second year c) Only a few survive beyond age ten years b. Mild RCDP1 i. Only a few patients reported ii. Consistent features a) Chondrodysplasia b) Cataracts iii. Variable expression a) Punctate calcifications b) Rhizomelia c) Mental and growth deficiency 2. X-linked dominant form (CDPX2)
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a. Phenotype i. Usually a mild form of the disease identified in adult females ii. May be a stillborn iii. Occurring almost only in females iv. Presumably lethal in males, although a few affected males have been reported b. Lyonization (skewed X-chromosome inactivation) in females resulting in phenotypic variability and asymmetric findings c. Showing increased disease expression in successive generations (anticipation): another striking clinical feature of CDPX2 that may be associated with skewed methylation d. Skin lesions i. The hallmark of the X-linked dominant form ii. Congenital ichthyosiform erythroderma, distributed in a linear or blotchy pattern iii. Systematized atrophoderma mainly involving the fair follicles iv. Circumscribed alopecia v. Sparse eyebrows and lashes vi. Nails: flattened and split into layers e. Epiphyseal calcification in the first year of life f. Limb shortening i. Rhizomesomelic ii. Usually asymmetric iii. Severely affected infants with bilateral findings resembling those of RDCP1 g. Other later signs i. Palmoplantar keratosis ii. Follicular atrophoderma iii. Segmental cataracts iv. Tooth and bone abnormalities 3. X-linked recessive chondrodysplasia punctata, brachytelephalangic type (CDPX1) a. Clinical reports available so far are mainly those of patients who are nullisomic for Xp22.3 in which chondrodysplasia punctata is part of a complex phenotype due to a “contiguous gene syndrome” b. Wide spectrum of manifestations, ranging from aborted fetus, neonatal death, midfacial hypoplasia, and brachytelephalangy c. Facial anomalies with severe nasal hypoplasia d. Short stature e. Cardinal manifestations i. Epiphyseal stippling ii. Hypoplasia of the distal phalanges f. Abnormalities of proximal and middle phalanges after healing of the punctate calcifications: typical diagnostic signs g. Without limb shortening or cataracts h. Presence of ichthyosis attributed to the involvement of the STS gene in the patients with Xp deletion i. Mild ichthyosis that improves with age: may be part of the CDPX phenotype 4. Chondrodysplasia punctata, tibia-metacarpal type a. Symmetrical rhizomelic shortness of the upper limbs b. Punctate epiphyseal calcifications noted at birth
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c. d. e. f.
Abnormal face (flattened mid-face and nose) Short hands Normal height Normal mentation
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Classic RCDP1 i. Bilateral shortening of the humerus and to a lesser degree the femur ii. Punctate calcifications in the epiphyseal cartilage at the knee, hip, elbow, shoulder, hyoid bone, larynx, sternum, and ribs iii. Radiolucent coronal clefts of the vertebral bodies that represent unossified cartilage iv. Abnormal epiphyses and flared and irregular metaphyses secondary to resolved punctate calcification after age one to three years b. Tibia-metacarpal type i. Shortened and bowed tibia and radii ii. Overgrowth of the fibulae iii. Ulnar hypoplasia iv. Calcific stippling of the proximal bones v. Punctate calcifications of the trachea, thyroid cartilage, entire spine, and sacrum vi. Clefting (coronal and/or sagittal) of the vertebral bodies vii. Symmetrical brachymetacarpy: shortened 2nd, 3rd, and 4th metacarpals viii. Shortened radial head ix. Patella dislocation 2. Biochemical/molecular studies a. RCDP1 i. Deficiency of red blood cell plasmalogens ii. Increased plasma concentration of phytanic acid iii. Deficiencies in plasmalogen biosynthesis and phytanic acid hydroxylation in cultured skin fibroblasts iv. PEX7 receptor defect in RCDP1 predicted by the following: a) Deficiency of plasmalogens in red blood cells b) Increased plasma concentration of phytanic acid c) Normal plasma concentration of very long chain fatty acids v. Molecular genetic analysis: PEX7 gene mutation analysis and sequencing b. RCDP2 i. Deficiency of the peroxisomal enzyme dihydroxyacetone phosphate acyltransferase (DHAPRT) in cultured skin fibroblasts ii. DHAPRT gene mutation analysis by sequencing of coding regions c. RCDP3 i. Deficiency of the peroxisomal enzyme, akkyldihydroxyacetone phosphate synthase (ADHAPS) in cultured skin fibroblasts ii. ADHAPS gene mutation analysis d. X-linked dominant form (CDPX2)
i. Diagnosis confirmed by measuring the plasma concentration of sterols which show accumulation of precursors, 8(9)-cholesterol and 8-dehydrocholesterol ii. Identify molecular defect in human EBP in CDPX2 patients e. X-linked recessive form (CDPX1): ARSE gene mutation analysis
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal recessive RCDP1: 25% ii. Autosomal dominant form: not increased unless one of the parents is affected iii. X-linked recessive form: 50% of brothers affected when the mother is a carrier iv. X-linked dominant form a) 50% of sisters and brothers (lethal) affected when the mother is a carrier b) Possibility of an apparently normal mother being a carrier to be considered when examining seemingly sporadic cases b. Patient’s offspring i. Autosomal recessive RCDP1: do not reproduce ii. Autosomal dominant form: 50% iii. X-linked recessive form: 50% risk of daughters to be carriers; none of sons will be affected iv. X-linked dominant form: affected mother: 50% of sons affected (lethal in male); 50% of daughters affected 2. Prenatal diagnosis a. Radiography i. Stippling of the bones of the extremities and pelvis ii. Abnormalities of the vertebral bodies b. Ultrasonography i. Rhizomelic form a) Severe rhizomelic limb shortening b) Punctuate epiphyseal calcifications c) Associated sonographic findings: profound hypoplasia of the humeri, metaphyseal flaring, a flattened midface, joint contracture, clubfoot deformity, and hydramnios ii. Nonrhizomelic form a) Asymmetric, variable limb shortening without a clear pattern of rhizomelia or mesomelia b) Calcifications in the long bone epiphyses, which may be recognizable in the second trimester or may not be recognizable even in the third trimester c) Other sonographic findings: spinal deformities, frontal bossing, a depressed nasal bridge, ascites, and polyhydramnios iii. X-linked dominant form a) Growth retardation b) Skeletal asymmetry c) Polyhydramnios
CHONDRODYSPLASIA PUNCTATA
c. Assays of plasmalogen biosynthesis in cultured chorionic villi or amniocytes for pregnancies at 25% risk for RCDP1 d. Enzyme activity of alkyl-dihydroxyacetone phosphate synthase (ADHAPS) and subcellular localization of peroxisomal thiolase performed on uncultured chorionic villi e. Molecular prenatal diagnosis in X-linked dominant chondrodysplasia punctata to identify disease-causing EBP mutation in the fetus 3. Management a. Mainly supportive b. G-tube placement for poor feeding and recurrent aspiration c. Cataract extraction to preserve vision d. Orthopedic procedures to correct contractures to improve function e. X-linked dominant form i. Emollients for ichthyosis ii. Splinting for clubbed feet iii. Surgery for polydactyly iv. Ophthalmological care for cataracts
REFERENCES Argo KM, Toriello HV, Jelsema RD, et al.: Prenatal findings in chondrodysplasia punctata, tibia-metacarpal type. Ultrasound Obstet Gynecol 8:350–354, 1996. Aughton DJ, Kelley RI, Metzenberg A, et al.: X-linked dominant chondrodysplasia punctata (CDPX2) caused by single gene mosaicism in a male. Am J Med Genet 116A:255–260, 2003. Barr DG, Kirk JM, al Howasi M, et al.: Rhizomelic chondrodysplasia punctata with isolated DHAP-AT deficiency. Arch Dis Child 68:415–417, 1993. Becker K, Csikós M, Horv·th A, et al.: Identification of a novel mutation in 3βhydroxysteroid-Δ8-Δ7-isomerase in a case of Conradi-HünermannHapple syndrome. Exp Dermatol 10:286–289, 2001. Borochowitz Z: Generalized chondrodysplasia punctata with shortness of humeri and brachymetacarpy: humero-metacarpal (HM) type: variation or heterogeneity? Am J Med Genet 41:417–422, 1991. Braverman N, Steel G, Obie C, et al.: Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nat Genet 15:369–376, 1997. Braverman N, Lin P, Moebius FF, et al.: Mutations in the gene encoding 3βhydroxysteroid-Δ8-Δ7-isomerase cause X-linked dominant ConradiHünermann syndrome. Nature Genet 22:291–294, 1999. Braverman NE, Moser AB, Steinberg SJ: Rhizomelic chondrodysplasia punctata type I. Gene Reviews. 2004. http://www.genetests.org Braverman N, Chen L, Lin P, et al.: Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype. Hum Mutat 20:284–297, 2002. Brites P, Motley A, Hogenhout E, et al.: Molecular basis of rhizomelic chondrodysplasia punctata type I: high frequency of the Leu-292 stop mutation in 38 patients. J Inherit Metab Dis 21:306–308, 1998. Brookhyser KM, Lipson MH, Moser AB, et al.: Prenatal diagnosis of rhizomelic chondrodysplasia punctata due to isolated alkyldihydroacetonephosphate acyltransferase synthase deficiency. Prenat Diagn 19:383–385, 1999.
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Brunetti-Pierri N, Andreucci MV, Tuzzi R, et al.: X-linked recessive chondrodysplasia punctata: spectrum of arylsulfatase E gene mutations and expanded clinical variability. Am J Med Genet 117A:164–168, 2003. Carty H: Dappled diaphyseal dysplasias. Rofo 150:228–229, 1989. Collins P, Olufs R, Karvitz H, et al.: Relationship of maternal warfarin therapy in pregnancy to chondrodysplasia punctata: report of a case. Am J Obstet Gynecol 127:444–446, 1977. Derry JMJ, Gormally E, Means GD, et al.: Mutations in a Δ8-Δ7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. Nature Genet 22:286–290, 1999. DiPreta EA, Smith KJ, Skelton H: Cholesterol metabolism defect associated with Conradi-Hunerman-Happle syndrome. Int J Dermatol 39:846–858, 2000. Happle R: X-linked dominant chondrodysplasia punctata. Review of literature and report of a case. Hum Genet 53:65–73, 1979. Happle R: Cataracts as a marker of genetic heterogeneity in chondrodysplasia punctata. Clin Genet 19:64–66, 1981. Has C, Bruckner-Tuderman L, Müller D, et al.: The Conradi-H¸nermannHapple syndrome (CDPX2) and emopamil binding protein: novel mutations, and somatic and gonadal mosaicism. Hum Mol Genet 9:1951–1955, 2000. Herman GE, Kelley RI, Pureza V, et al.: Characterization of mutations in 22 females with X-linked dominant chondrodysplasia punctata (Happle syndrome). Genet Med 4:434–438, 2002. Ikegawa S, Ohashi H, Ogata T, et al.: Novel and recurrent EBP mutations in Xlinked dominant chondrodysplasia punctata. Am J Med Genet 94: 300–305, 2000. Kelley RI, Wilcox WG, Smith M, et al.: Abnormal sterol metabolism in patients with Conradi-Hunermann-Happle syndrome and sporadic lethal chondrodysplasia punctata. Am J Med Genet 83:213–219, 1999. Kozlowski K, Bates EH, Young LW, et al.: Radiological case of the month. Dominant X-linked chondrodysplasia punctata. Am J Dis Child 142: 1233, 1988. Motley AM, Brites P, Gerez L, et al.: Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1. Am J Hum Genet 70:612–624, 2002. Parenti G, Buttitta P, Meroni G, et al.: X-linked recessive chondrodysplasia punctata due to a new point mutation of the ARSE gene. Am J Med Genet 73:139–143, 1997. Pauli RM, Lian JB, Mosher DF, et al.: Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of warfarin embryopathy: Clues to the mechanism of teratogenicity of Coumadin derivatives. Am J Hum Genet 41:566–583, 1987. Poznanski AK: Punctate epiphyses: a radiological sign not a disease. Pediatr Radiol 24:418–424, 1994. Pradhan GM, Chaubal NG, Chaubal JN, et al.: Second-trimester sonographic diagnosis of nonrhizomelic chondrodysplasia punctata. J Ultrasound Med 21:345–349, 2002. Shirahama S, Miyahara A, Kitoh H, et al.: Skewed X-chromosome inactivation) causes intra-familial phenotypic variation of an EBP mutation in a family with X-linked dominant chondrodysplasia punctata. Hum Genet 112:78–83, 2003. Spranger JW, Brill PW, Poznanski A: Bone Dysplasias. An Atlas of Genetic Disorders of Skeletal Development. 2nd ed. Oxford: Oxford University Press.2002. pp 57–79. White AL, Modaff P, Holland-Morris F, et al.: Natural history of rhizomelic chondrodysplasia punctata. Am J Med Genet 118A:332–342, 2003. Whittock NV, Izatt L, Simpson-Dent SL, et al.: Molecular prenatal diagnosis in a case of an X-linked dominant chondrodysplasia punctata. Prenat Diagn 23:701–704, 2003.
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Fig. 2. FISH (patient 1) with a SHOX (short stature homeobox containing gene) probe for Xp22.3 (a pink signal) and Yp11.3 (a pink signal) showing a deleted pink Xp22.3 signal. The pink signal in the X chromosome is an X peri-centromere probe (SXZ1) and the green signal is a Yq12 probe (DXZ1).
Fig. 1. Patient 1 (a Japanese newborn boy) with X-linked recessive form of chondrodysplasia punctata. Radiographs show paravertebral and calcaneus punctate calcification.
Fig 3. The mother of patient 1 is a carrier of del(X)(p22.3p22.3) (SHOX-). Her FISH showed that a red signal (a probe for Xp22.3; SHOX gene) is deleted in one of her X chromosome.
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Fig. 5. Radiograph of another neonate with rhizomelic form of chondrodysplasia punctata, showing similar radiographic features.
Fig. 4. A neonate with rhizomelic form of chondrodysplasia punctata, showing short humeri and punctate calcifications in the shoulder and/or elbow joints illustrated by radiograph. Fig. 6. Another neonate with chondrodysplasia punctata showing depressed nasal bridge and under-developed nasal cartilage. The infant has punctate calcifications in the proximal femoral heads.
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Fig. 7. Radiographs of a child with an autosomal dominant chondrodysplasia punctata showing punctate calcifications in the knees.
Chromosome Abnormalities in Pediatric Solid Tumors Consistent chromosome abnormalities have been described in many pediatric solid tumors. These findings led to direct molecular investigation and a better understanding of tumor pathogenesis. Clinical correlation often produced useful prognostic information.
GENETICS/BASIC DEFECTS 1. Somatic mutation theory of cancer a. Resulting from the accumulation of specific genetic changes b. Several lines of evidence i. Monoclonal origin of most tumors, suggesting that they derive from a single progenitor cell ii. Several tumors occurring not only sporadically but also as familial hereditary traits iii. Mutagenic nature of most carcinogenic agents, at least in experimental systems iv. Acquired genetic changes in the tumor cells, many of which are detectable at the chromosome level and several of these mutations have been shown to be tumorigenic in experimental animals 2. Chromosome abnormalities in neoplastic cells a. Technical improvement in basic cytogenetic techniques i. Use of colchicine to arrest dividing cells in metaphase and hypotonic solutions to improve spreading of the chromosomes a) Description of the correct chromosome number in humans b) The first specifically neoplasia-associated chromosome aberration: the Ph1 chromosome in chronic myeloid leukemia ii. Introduction of chromosome banding techniques a) Possible to identify individual chromosome pairs b) To detect and characterize even subtle rearrangements b. Clonal chromosome aberrations in neoplasms i. Primary aberrations a) Nonrandomly associated with particular tumor types b) Sometimes observed as the sole karyotypic deviation c) Thought to constitute early and essential events in carcinogenesis d) Increased genomic instability thought to be one of the consequences of the acquisition of a primary cancer chromosome rearrangement e) Many primary aberrations affect cellular oncogenes, often fusing them with other genes to encode hybrid proteins or disrupting the normal control sequences of the oncogene, causing its inappropriate expression 169
ii. Secondary aberrations a) Occurrence of new abnormalities facilitated by primary aberrations b) Nonrandom c) Distribution of the secondary aberrations dependent on both the primary abnormality and the tumor type in which they occur iii. Cytogenetic noise a) Resulting from acquired instability b) Random changes with little or no selective value 3. Mechanisms by which chromosomal aberrations arise a. Aberrations that lead to aneuploidy i. Polyploidy ii. Aneuploidy iii. Reciprocal translocation iv. Nonreciprocal translocation v. Amplification (double minutes) vi. Amplification (HSR) vii. Amplification (distributed insertions) b. Aberrations that leave the chromosome apparently intact i. Loss of heterozygosity (LOH) (somatic recombination) ii. Loss of heterozygosity (duplication/loss) 4. Identification of specific chromosome rearrangements in neoplasms a. Leukemia and lymphoma i. Crucial for more detailed studies utilizing molecular genetic techniques ii. Possible to compare cytogenetic findings with morphologic, immunologic, and clinical parameters such as the response to therapy and survival iii. Diagnostic and prognostic implications of karyotyping b. Solid tumors i. In general, more complex karyotypes observed in solid tumors ii. Have distinct patterns of primary and secondary aberrations closely associated with histopathologic entities iii. Identification of only a few genes as a consequence of recurrent structural rearrangements iv. Fusion of transcription factor gene with other loci, a common feature v. Tumor suppressor genes a) Important in solid tumors b) Thought to encode inhibitors of unrestrained growth c) Behave in a recessive manner at the cellular level (i.e., loss or structural disruption of both wild-type alleles is required to unleash a neoplastic phenotype)
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5. Retinoblastoma (RB) a. A prototype tumor for understanding basic concepts in cancer genetics b. Genetics of retinoblastoma i. Thought to be a single gene disorder caused by mutation of the RB1 gene ii. Sporadic, nonhereditary form in most cases a) Unilateral or unifocal retinoblastoma b) A mutation in the RB1 locus occurred later in embryogenesis iii. Hereditary form (1/3rd of tumors) a) Bilateral or multifocal retinoblastoma b) Predisposition inherited as an autosomal dominant trait c) Mutations inherited from a carrier parent in 25% of the cases d) A new mutation occurring very early in embryogenesis in 75% of cases e) Overall estimates of the penetrance of the trait: 85–95% c. Retinoblastoma gene, RB1 i. The first cancer-predisposition gene to be cloned ii. Chromosome map: 13q14 iii. More than 100 different mutations reported to date a) Missense mutations b) Nonsense mutations c) Splice-site mutations d) Small and large deletions d. Knudson’s “two-hit hypothesis” of tumorigenesis i. In the unaffected individual, both RB1 genes are intact and serve as guardians of the retina ii. Retinoblastoma develops as a result of two separate mutations iii. Sporadic tumors: two separate mutations occurring somatically in the same retinal cell iv. Heritable retinoblastoma: The first mutation is germinal and the second somatic e. Inherited form of retinoblastoma i. Critical gene for retinoblastoma located in band 13q14, suggested by cytogenetic analyses of tumor cells and lymphocytes ii. Homozygous loss of DNA markers from 13q14 in tumor cells from individuals with familial retinoblastoma vs heterozygous loss of these DNA markers in normal cells, suggested by molecular genetic investigations 6. Neuroblastoma (NB) a. A malignant tumor derived from undifferentiated neural crest cells that are committed to differentiate into the sympathetic nervous system b. Inheritance i. Sporadic in most cases ii. A few clustered familial cases reported indicating an autosomal dominant inheritance with incomplete penetrance c. Molecular biology i. The amplification (i.e., increased number of DNA copies) of the oncogene MYCN (N-myc) and changes in the normal diploid chromosomal content
a) Both are correlated with disease prognosis and disease recurrence b) The amplification can be in the form of the double minute chromosomes, which are extragenomic segments of DNA, or in homogeneously staining chromosomal regions ii. Variable DNA content of neuroblastoma a) Near-triploid DNA index regardless of any clinical or biologic features predicts a smaller risk of progression to higher-stage diseases b) Diploid/tetraploid index tends to predict higher risk of progression or multiple relapses iii. Other molecular markers (receptors for nerve growth factors) associated with neuroblastoma a) Trk A: associated with favorable neuroblastomas b) Trk B: expressed in unfavorable neuroblastomas 7. Wilms tumor (WT) a. Biological pathways leading to the development of Wilms tumor i. Complex ii. Involvement of several genetic loci a) Two genes on chromosome 11p; one on chromosome 11p13 (the Wilms tumor suppressor gene, WT1) and the other on chromosome 11p15 (the putative Wilms tumor suppressor gene, WT2) b) Loci at 1p, 7p, 16q, 17p (the p53 tumor suppressor gene), and 19q (the putative familial Wilms tumor gene, FWT2) b. Inheritance i. Sporadic in majority of cases (>95%) ii. Familial predisposition to Wilms tumor is rare, affecting only1.5% of patients with Wilms tumor c. Association with specific genetic disorders or recognizable syndromes i. WAGR syndrome a) Large constitutional deletions of chromosome 11p13 b) Tumor suppressor gene: WT1 c) Mechanism of gene inactivation: hemizygous deletion d) Wilms tumor incidence: >30% e) Associated features: aniridia, genitourinary abnormalities f) Mental retardation g) Associated aniridia: caused by deletion of the PAX6 gene in the 11p13 region in close proximity to WT1 gene ii. Denys-Drash syndrome a) Chromosomal loss: 11p13 b) Tumor suppressor gene: WT1 c) Mechanism of gene inactivation: mutation (DNA binding domain) d) Wilms tumor incidence: >90% e) Associated features: pseudohermaphroditism, mesangeal sclerosis, renal failure
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iii. Beckwith-Weidemann syndrome a) Chromosomal loss: 11p15 b) Tumor suppressor gene: (WT2/BWS?) c) Mechanism of gene inactivation: unknown d) Wilms tumor incidence: 5% e) Associated features: organomegaly, hemihypertrophy, umbilical hernia, neonatal hypoglycemia, other tumors such as hepatoblastoma iv. Perlman syndrome a) Renal dysplasia b) Multiple congenital anomalies c) Gigantism d) Wilms’ tumor v. X-linked Simpson-Golabi-Behmel syndrome a) Overgrowth disorder b) Caused by mutations in the GPC3 gene located on Xq26 c) Overlapping physical features with BeckwithWiedemann syndrome d) Wilms’ tumor and other embryonal tumors 8. Primary tumors of the central nervous system a. Primitive neuroectodermal tumors (PNETs) i. Homozygous inactivation of the TP53 gene, a tumor-suppressor gene located in 17p, secondary to i(17p): implicated in the development of several tumor types ii. Molecular analyses indicating the existence of a second tumor-suppressor gene, distinct from and distal to the TP53 locus that might be pathogenetically involved in a subset of primitive neuroectodermal tumors b. Gliomas i. A tumor-suppressor gene in 22q implicated as an essential event in the genesis of a number of neurogenic neoplasms ii. A candidate for such a role: is NF2, thought to be mutated in neurofibromatosis type 2, a dominantly inherited disorder predisposing for gliomas, neurinomas, and meningiomas
CLINICAL FEATURES 1. Only retinoblastoma, neuroblastoma, and Wilms tumor will be discussed here 2. Retinoblastoma a. A rare malignant tumor arising from cells of the embryonal neural retina b. Develops only in infants and young children c. Unifocal retinoblastoma: presence of a single retinoblastoma d. Multifocal retinoblastoma: presence of more than one tumor i. Unilateral: occurrence of multiple RB tumors in one eye ii. Bilateral: occurrence of RB tumors in both eyes iii. “Trilateral” retinoblastoma: occurrence of bilateral retinoblastoma plus a pinealoma e. Presenting signs
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i. White papillary reflex (leukocoria): the most common presenting sign ii. Strabismus: the second most common presenting sign iii. Less common signs a) Poor vision b) Orbital swelling c) Unilateral mydriasis d) Heterochromia iridis e) Glaucoma f) Orbital cellulitis g) Uveitis h) Hyphema or vitreous hemorrhage i) Nystagmus f. Retinoma-associated eye lesions ranging from retinal scars to calcified phthisical eyes resulting from spontaneous regression of retinoblastoma (include benign retinal tumors called retinocytoma or retinoma) g. Patients with germline RB1 mutations: at an increased risk of developing tumors outside the eye i. Pinealomas ii. Osteosarcomas iii. Soft tissue sarcomas iv. Melanomas 3. Neuroblastoma a. The most frequently occurring solid tumor in children b. Responsible for 8–10% of all cancers in children and approximately 15% of all pediatric cancer deaths c. 40% of cases diagnosed in children under 1 year of age who have a very good prognosis d. 60% in older children and young adult who have a poor prognosis despite advanced medical and surgical management e. Amplification of MYCN gene found in neuroblastomas: i. A powerful prognostic indicator ii. Associated with: a) Advanced stages of disease b) Rapid tumor progression c) Poor outcome f. Clinical presentation i. Variable presentation a) Localized disease (1/3rd to 1/4th of cases) b) Metastatic disease (2/3rd to 3/4th of cases) c) Asymptomatic in small number of patients ii. Retroperitoneal and abdominal tumors (62–65%) a) A palpable mass b) Abdominal pain (34%) c) Weight loss (21%) d) Anorexia e) Vomiting f) Symptoms related to mass effect iii. Thoracic tumors (14%) a) Dysphagia b) Cough c) Respiratory distress iv. Pelvis (5%) and paraspinal tumors that compress the spinal cord
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a) Urinary dysfunction b) Constipation c) Fetal incontinence d) Lower extremity weakness v. Neck tumors a) Horner syndrome: present in patients with lesions in the cervical or upper thoracic sympathetic ganglia (1.7%) b) Airway distress vi. Liver metastasis a) Hepatomegaly b) Jaundice c) Abnormal liver function tests d) Abdominal pain vii. Bone metastases and bone marrow involvement a) Bone pain b) Palpable bony nodules c) Anemia d) Purpura viii. Fever (28%) ix. Lymph node metastases: palpable lymphadenopathy x. Retrobulbar and orbital metastases: periorbital ecchymoses xi. Severe diarrhea refractory to standard treatment due to production of vasoactive intestinal peptide by tumor cells (4%) xii. Acute cerebellar encephalopathy (2%) a) Cerebellar ataxia b) “Dancing eyes and dancing feet syndrome” (involuntary eye fluttering and muscle jerking) xiii. Symptoms related to high catecholamine levels (0.2%) a) Hypertension b) Palpitations c) Flushing d) Sweating e) Malaise f) Headache 4. Wilms’ tumor a. The most common kidney cancer in childhood b. Represents about 6% of all childhood cancers in the United States c. Clinical presentation i. Presence of an asymptomatic abdominal mass: the most common presentation a) Usually affects one kidney with multiple tumor foci in 8% of cases b) Bilateral in 6% of cases ii. Hypertension, gross hematuria, and fever observed in 5–30% of patients iii. Hypotension, anemia, and fever in a small number of patients who have hemorrhaged into their tumor iv. Rare respiratory symptoms related to the presence of lung metastases in patients with advancedstage disease d. Association with congenital malformations i. Found in 60% of the bilateral cases and 4% of the unilateral cases
ii. WAGR iii. Denys-Drash syndrome iv. Beckwith-Wiedemann syndrome v. Perlman syndrome vi. Beckwith-Wiedemann syndrome vii. X-linked Simpson-Golabi Behmel syndrome e. Likelihood of developing Wilms’ tumor in aniridia patients i. Aniridia patients without other anomalies: 1–2% ii. Aniridia patients with WAGR syndrome: 25–40%
DIAGNOSTIC INVESTIGATIONS 1. Cytogenetic and molecular genetic techniques used in analyzing tumor materials from patients a. Conventional and molecular cytogenetic techniques most commonly used i. Metaphase cytogenetics or karyotyping (G-, Q-, and R-bandings): a) Protein digestion and/or special dye generating banding pattern specific for each chromosome b) Identification of numerical and structural chromosomal anomalies ii. Fluorescence in situ hybridization (FISH) a) A small, labeled DNA fragment used as a probe to search for homologous target sequences in chromosome or chromatin DNA b) Identification of the presence, number of copies per cell, and localization of probe DNA c) Applicable to interphase cells iii. Comparative genomic hybridization (CGH) a) Comparative hybridization of differentially labeled total genomic tumor DNA and normal reference DNA to normal human metaphases used as templates b) Detection of variant DNA copy numbers at the chromosome level c) Applicable to fresh or preserved specimens iv. Multicolor karyotyping (M-FISH, SKY) a) Hybridization with 24 differentially labeled, chromosome-specific probes allowing the painting of every human chromosome in a distinct color b) Detection of rearrangements involving one or more chromosomes within individual metaphase spreads c) Accurate origin identification of all segments in complex rearrangements d) Clarification of marker chromosomes b. Other techniques i. Flow cytometry ii. Reverse transcriptase-polymerase chain reaction (RT-PCR) iii. Quantitative PCR iv. Southern blot analysis of gene rearrangements v. Loss of heterozygosity analysis (LOH) vi. Restriction landmark genome scanning vii. Representational difference analysis viii. cDNA gene expression microarrays
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ix. Proteomic methods a) Matrix Assisted Laser Desorption ionization Time of Flight (MALDI-TOF) b) Surface Enhanced Laser Desorption Ionization Time of Flight (SELDI-TOF) 2. Cytogenetic studies in retinoblastoma a. Cytogenetically visible changes of 13q14: infrequent in retinoblastoma b. Deletions or unbalanced translocations leading to loss of 13q14 band (10%) c. Monosomy 13 (10%) d. i(6p), mostly detected as a supernumerary isochromosome (1/3rd of cases) e. Gain of 1q material (1/3rd of cases) f. Cytogenetic aberrations in retinoblastoma i. Secondary to RB1 mutations ii. More related to tumor progression than to tumor establishment 3. Other studies for retinoblastoma a. Indirect ophthalmoscopy to examine the fundus of the eye to detect retinomas, preferably by a retinal specialist b. Imaging studies (CT, MRI, ultrasonography) to support the diagnosis and stage the tumor c. Histopathological examination to confirm the diagnosis d. Direct DNA testing of the RB1 gene in WBC DNA i. Identify a germline mutation in about 80% of individuals with a hereditary predisposition to retinoblastoma ii. Probability of detection of the RB1 gene mutation in an index case dependent on the following: a) Whether the tumor is unifocal or multifocal b) Whether the family history is positive or negative c) The sensitivity of the testing methodology 4. Cytogenetic studies in neuroblastoma a. Identification of multiple cytogenetic abnormalities in neuroblastoma i. Allelic losses on chromosomes 1p (particularly 1p36), 11q, 14q, 7q, 2q, 3p, and 19q ii. Allelic gains on chromosomes 17q, 18q, 1q, 7q, and 5q b. Hyodiploid, triploid or “near triploid”, or “neartetraploid” in modal chromosome number i. Majority (55%) with triploid or “near-triploid” (a chromosome number between 58–80) ii. Remainder with “near-diploid” (35 to 57 chromosomes) or “near-tetraploid” (81–103 chromosomes) c. Frequent partial 1p monosomy (70–80% of cases) with most commonly deleted region being between 1p32 and 1p36 d. Gain on the long arm of chromosome 17 (17q) i. Probably the most common genetic abnormality in neuroblastomas ii. Occurring in approximately 75% of primary tumors iii. Most often resulting from an unbalanced translocation of this region to other chromosomal sites, most frequently 1p or 11q iv. A powerful independent finding of adverse outcome
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e. Deletions of the long arms of chromosomes 11 (11q) and 14 (14q) i. Appears to be common in neuroblastomas ii. Both inversely related to MYCN amplification f. Frequent presence of extrachromosomal double minute chromatin bodies (DMs) or homogneously staining regions (HSRs) i. Cytogenetic evidence of gene amplification ii. Amplified region derived from the distal short arm of chromosome 2 (2p24) that contains the MYCN proto-oncogene 5. Other studies for neuroblastoma a. Imaging studies i. Chest radiography ii. Ultrasound iii. CT iv. MRI v. Radionucleotide bone scan b. Blood tests i. Elevated urinary and serum catecholamine metabolites a) Homovanillic acid (HVA) b) Vanillylmandelic acid (VMA) ii. Abnormal liver function tests 6. Cytogenetic studies in Wilms’ tumor a. A near-diploid chromosome count b. Triploid-tetraploid karyotypes in a few cases with tendency to have an anaplastic morphology c. Numerical aberrations i. Mainly involving gains of chromosomes a) Trisomy 12: particularly frequent b) Followed by trisomies 8, 6, 7, 13, 20, and 17 d. Structural rearrangements i. Involve all chromosomes except the Y chromosome ii. Recombinations of 11p (>20%) a) Vast majority of the breakpoints assigned to 11p13 and 11p15, indicating these loci are important in sporadic Wilms tumor b) Loss of heterozygosity studies indicating that alleles from 11p13 and 11p15 are often lost in Wilms’ tumor iii. Loss of the long arm of chromosome 16 occurring in about 20% of Wilms’ tumors: associated with poor prognosis independent of stage or tumor histology 7. Other studies in Wilms’ tumor a. Renal ultrasound to monitor Wilms’ tumor b. Abdominal CT scanning to determine the tumor’s origin, lymph node involvement, bilateral kidney involvement, and invasion into major vessels (e.g., inferior vena cava or liver metastases) c. Chest radiography to detect lung metastases d. Histopathological examination to confirm the diagnosis e. Further studies of certain patients with either Wilms tumor or associated anomalies i. Hemihypertrophy/Beckwith-Wiedemann syndrome: uniparental disomy studies to evaluate constitutional or somatic alterations of 11p15 ii. WAGR syndrome: molecular evaluation of the 11p13 region if chromosomal studies do not reveal a deletion
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a) Fluorescence in-situ hybridization (FISH) b) Pulsed-field electrophoresis iii. Denys-Drash syndrome: molecular evaluation of WT1 to determine whether the patient indeed carries a constitutional mutation. If the mutation is present, family members need to be screened iv. Aniridia a) Cytogenetic analysis and molecular evaluation of the WAGR region by FISH or pulsed field to rule out contiguous deletion of Pax6 and WT1 b) No further screening for Wilms tumor if Pax6 mutation is identified in isolated cases of aniridia 8. Cytogenetic studies of primary tumors of the central nervous system a. Primitive neuroectodermal tumors i. Near-diploid in most tumors ii. I(17q): the most consistent rearrangement b. Gliomas i. Mostly astrocytomas and ependymomas ii. No specific structural rearrangement found iii. Loss of 1p and gain of 1q found in a subset of tumors iv. Loss of chromosome 22 common in childhood gliomas v. Loss of material from chromosome 22, either numeric or structural aberrations, found recurrently in rhabdoid tumors, meningiomas, and neurinomas 9. Cytogenetic studies in hepatoblastoma a. Trisomy 2 or duplications of part of 2q: detected in half of the cases b. Trisomy 20 c. Duplication of 8q through either i(8q) formation or trisomy 8 10. Cytogenetic studies in sarcomas a. Ewing sarcoma/primitive neuroectodermal tumor i. Reciprocal translocation t(11;22)(q24;q12) a) Characteristic primary rearrangement b) Found in nearly 90% of the tumors c) Causing a fusion of the transcription factor gene FLI1 on chromosome 11 with EWS on chromosome 22 (FLI1-EWS, a fusion transcript). Only the chimeric gene expresses on the derivative chromosome 22 which contains a sequence encoding a DNA-binding domain from FLI1 ii. t(21;22)(q22;q12), ERG-EWS iii. t(7;22)(p22;q12), ETV1-EWS iv. t(17;22)(q12;q12), E1AF-EWS v. t(2;22)(q33;q12), FEV-EWS b. Additional chromosome changes i. Trisomy 8 ii. Der(16)t(1;16)(a10-q21;q10-13), leading to gain of 1q and loss of 16q c. Congenital or infantile fibrosarcoma i. t(12;15)(p13;q25), ETV6-NTRK3 ii. Hyperdiploid with few or no structural rearrangements
iii. Nonrandom numerical changes a) Trisomies 11 and 20, the most frequent changes, followed by: b) Trisomies 17 and 8 d. Osteosarcomas i. Highly complex karyotypes in the majority of cases ii. Chromosome number in the triploid-tetraploid range iii. Most common numeric aberrations involving −3, −10, −13, and −15 iv. Structural rearrangements involving chromosome arms 1p, 1q, 3p, 3q, 7q, 11p, 17p, and 22q v. Presence of many undefined chromosome markers e. Rhabdomyosarcoma i. The most common soft tissue sarcoma in childhood ii. Alveolar subtype a) t(2;13)(q35-37;q14), shown to juxtapose the PAX3 gene on chromosome 2 with the FKHR gene on chromosome 13, leading to the formation of a hybrid transcription factor (PAX3-FKHR) b) Found in about 70% of the alveolar tumors c) Only occasionally described in other subtypes iii. Embryonal subtype: numerical changes with +2, +8, +11, and +20, found in 35–50% of cases 11. Other common, recurrent translocation in solid and soft tissue tumors of childhood a. Alveolar soft part sarcoma: t(X;17)((p11;q25), ASPLTFE3 b. Inflammatory myofibroblastic tumor: 2p23 translocations, ALK-TPM3 c. Desmoplastic small round cell tumor i. t(11;22)(p13;q12), WT1-EWS ii. t(11;22)(q24;q12), FLI1-EWS, ERG-EWS d. Synovial sarcoma i. t(X;18)(p11.23;q11.2), SSX1-SSXT ii. t(X;18)(p11.21;q11), SSX2-SSXT e. Malignant melanoma of soft part (clear cell sarcoma): t(12;22)(q13;q12), ATF1-EWS f. Myxoid liposarcoma i. t(12;16)(q13;p11), CHOP-TLS(FUS) ii. t(12;22)(q13;q12), CHOP-EWS g. Extraskeletal myxoid chondrosarcoma: t(9;22)(q22;q12), CSMF-EWS h. Dermatofibrosarcoma protuberans and giant cell fibroblastoma: t(17;22)(q22;q13), COL1A1-PDGFB i. Lipomas: t(var;12)(var;q13-15), var, HMGI-C j. Leiomyomas: t(12;14)(q13;15), HMGI-C,? 12. Other primary chromosome changes in solid tumors a. Benign tumors i. Meningioma and acoustic neuroma a) −22 b) 22q− ii. Mixed tumors of salivary glands a) t(3;8)(p21;q12) b) t(9;12)(p13-22;q13–15) iii. Colonic adenomas
CHROMOSOME ABNORMALITIES IN PEDIATRIC SOLID TUMORS
a) 12q− and/or +7 b) 12q− and/or +8 iv. Cortical adenoma of the kidney (+7, +7, +17, −Y) b. Adenocarcinomas i. Bladder a) i(5p) b) +7 c) −9/9q− d) 11p− ii. Prostate: del(10)(q24) iii. Lungs (small cell carcinoma): del(3)(p14p23) iv. Colon a) 12q− b) +7 c) +8 d) +12 e) 17(q11) f) 17p− v. Kidney: del(3)(p11p21) vi. Uterus: 1q− vii. Ovary a) 6q− b) t(6;14)(q21;q24) viii. Endometrium a) Trisomy 1q b) +10 c. Embryonal and other tumors i. Testicular (germ cell tumors): i(12p) ii. Malignant melanoma a) Del(6)(q11q27) b) i(6p) c) Del(1)(p11p22) d) t(1;19)(q12;q13) iii. Mesothelioma: del(3)(p13p23) iv. Glioma: −22 13. Potential prognostic markers of neoplastic disease a. Breast cancer: allelic loss at 1p22–p31 (lymph node metastasis and tumor size >2 cm) b. Bladder cancer i. LOH RB (high grade/muscle invasion) ii. Genomic alterations (2q−, 5p+, 5q−, 6q−, 8p−, 10q−, 18q−, 20q+) (higher grade) c. Cervical carcinoma: LOH on chromosome (advanced stage) d. Colorectal cancer i. LOH at 18q21 or p53 expression (recurrence/ poor survival) ii. MSI (microsatellite instability) and K-ras mutations in normal appearing colonic mucosa (predictive of colorectal cancer) iii. P16-hypermethylation (shorter survival in Stage T3N0M0 tumors) e. Gastric cancer i. LOH p53 (invasive disease) ii. LOH of 7q (D7S95) (poor prognosis (in Stage III/IV)) f. Glioma: chromosome 22q loss (astrocytomas progression) g. Head and neck squamous cell carcinoma
h. i.
j. k.
l.
m. n.
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i. LOH of 14q (poor outcome) ii. LOH on 2q (poor prognosis) iii. LOH on 17p (chemoresistance) Melanoma: LOH in plasma (advanced stage/tumor progression) Neuroblastoma i. N-myc amplification (poor prognosis) ii. TrkA expression (good prognosis) iii. High telomerase expression (aggressive behavior) Neuroblastomas, 4s-: N-myc amplification, 1p deletion, 17q gains, elevated telomerase activity (poor prognosis) Non-small cell lung cancer i. Allelic imbalances on 9p (poor prognosis) ii. LOH 11p (poor prognosis) PNET i. LOH of 17p (metastatic disease) ii. C-myc amplification (poor prognosis) Prostate cancer: LOH on 13q (advanced stage) Retinoblastoma: LOH at RB1 locus (tumoral differentiation, absence of choroidal invasion)
GENETIC COUNSELING 1. Recurrence risk a. Retinoblastoma i. Predisposition to retinoblastoma which is caused by germline mutations in the RB1 gene: transmitted in an autosomal dominant fashion ii. Use RB1 mutation analysis to clarify the genetic status of at-risk sibs and offspring when a previously characterized germline cancer-predisposing mutation is available iii. Use indirect testing using polymorphic loci linked to the RB1 gene in some families to clarify genetic status of at-risk family members if RB1 direct DNA testing is not available or is uninformative iv. Use empiric recurrence risk estimates in all families in which direct DNA testing of RB1 and linkage analysis are unavailable or uninformative v. Risk to patient’s siblings a) When there is an existing family history: a 45% chance for siblings of bilaterally affected cases and a 30% chance for siblings of unilaterally affected cases to develop disease b) When there is absence of any family history: 2% risk for siblings of bilaterally affected cases and 1% for siblings of unilaterally affected cases to develop disease c) There is an additional risk to siblings in the absence of any family history or documented mutation in parental leukocyte DNA because of germline mosaicism. If neither parent has the cancer-predisposing RB1 germline†mutation that was identified in the index case, germline mosaicism in one parent is possible and the risk to each sib of having retinoblastoma is 3–5%
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d) If the index case has mosaicism for an RB1 cancer-predisposing mutation (the mutation arose as a post-zygotic event) and that neither parent has an RB1 germline mutation, the risk to the sibs is not increased and thus it is not warranted to test the sibs for the RB1 mutation identified in the index case vi. Risk for patient’s offspring a) About 45% by the age 6 years (consistent with an autosomal dominant inheritance with 90% penetrance) for the offsprings of survivors of hereditary (multifocal, bilateral) retinoblastoma b) About 2.5% for the offsprings of survivors of unilateral retinoblastoma c) The low (~1%), but not negligible, risk to the offspring of index cases with unifocal disease and a negative family history reflects the possibility of a germline RB1 mutation with low penetrance or mutational mosaicism b. Neuroblastoma i. Risk for patient’s sibling: low unless a parent has hereditary form of neuroblastoma ii. Risk for patient’s offspring: 50% c. Wilms’ tumor i. Risk for patient’s sibling: low unless a parent has hereditary form of Wilms tumor ii. Risk for patient’s offspring: 50% 2. Prenatal diagnosis a. Retinoblastoma i. Prenatal testing possible if the germline RB1 mutation in the parent is known or if RB1 linkage analysis is informative in the family ii. Mutation analysis on fetal DNA obtained from amniocentesis or CVS iii. Use prenatal ultrasonography to detect intraocular tumors if the disease-causing RB1 mutation is identified in the fetus b. Adrenal neuroblastoma i. Prenatal diagnosis adrenal neuroblastoma by ultrasonography usually made in the 3rd trimester ii. Sonographic appearance of the adrenal neuroblastoma varies a) Solid b) Purely cystic (50%) c) Mixed echo pattern (related to necrosis, hemorrhage or spontaneous tumoral involution) d) Fetal hydrops e) Hydropic placenta with metastases in the placenta iii. Frequently producing catecholamines and hence maternal symptoms could aid the diagnosis iv. Elevated catecholamines in the amniotic fluid c. Wilms tumor by prenatal ultrasonography i. A solid echogenic mass with a clearly defined capsule ii. Areas of hemorrhage and necrosis may be seen within the mass
3. Management a. Surgeries for most solid tumors b. Determining the genetic changes present in the tumor of an individual patient: becoming increasingly important for managing the oncology patient c. Retinoblastoma i. Goals of treatment: preservation of sight and life ii. Treatment options a) Enucleation b) Cryotherapy c) Photocoagulation d) Photochemistry e) External-beam radiation f) Radiation therapy using episcleral plaques iii. Novel treatment options: systemic chemotherapy combined with local therapy iv. Frequent postoperative follow-up examinations for early detection of new intraocular tumors v. Detection of second nonocular tumors vi. Individuals warrant surveillance for early manifestations of retinoblastoma a) Individuals with retinomas b) Asymptomatic at-risk children d. Neuroblastoma i. Localized, low-risk disease: a) Primary curative surgery b) Minimal therapy: low-dose radiation or chemotherapy c) Supportive care with surveillance ii. Intermediate-risk patients: combination therapy with radiation, chemotherapy, and surgery iii. High-risk patients a) Combination of radiation, myeloablative chemotherapy, and surgery (delayed) b) Autologous bone marrow transplant c) Research protocols e. Wilms tumor: the usual approach in most patients is nephrectomy followed by chemotherapy with or without postoperative radiotherapy
REFERENCES Albertson DG, Collins C, McCormick F, et al.: Chromosome aberrations in solid tumors. Nature Genet 34:369–376, 2003. Barcus ME, Ferreira-Gonzalez A, Buller AM, et al.: Genetic changes in solid tumors. Semin Surg Oncol 18:358–370, 2000. Bennicelli JL, Barr FG: Genetics and the biologic basis of sarcomas. Curr Opin Oncol 11:267–274, 1999. Brodeur GM, Maris JM, Yamashiro DJ, et al.: Biology and genetics of human neuroblastomas. J Pediatr Hematol Oncol 19:93–101, 1997. Carlson EA, Desnick RJ: Mutational mosaicism and genetic counseling in retinoblastoma. Am J Med Genet 4:365–381, 1979. Cavenee WK, Dryja TP, Phillips RA, et al.: Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305:779–784, 1983. Clericuzio CL, Johnson C: Screening for Wilms tumor in high-risk individuals. Hematol Oncol Clin North Am 9:1253–1265, 1995. Cooper CS: Translocations in solid tumours. Curr Opin Genet Dev 6:71–75, 1996. Coppes MJ, Egeler RM: Genetics of Wilms tumor. Semin Urol Oncol 17:2–10, 1999. Draper GJ, Sanders BM, Brownbill PA, et al.: Patterns of risk of hereditary retinoblastoma and applications to genetic counseling. Br J Cancer 66:211–219, 1992. Davidoff AM, Hill DA: Molecular genetic aspects of solid tumors in childhood. Semin Pediatr Surg 10:106–118, 2001.
CHROMOSOME ABNORMALITIES IN PEDIATRIC SOLID TUMORS Heim S, Mitelman R: Primary chromosome abnormalities in human neoplasia. Adv Cancer Res 52:1–43, 1989. Heim S, Mitelman F: Cytogenetics of solid tumours. Recent Adv Histopathol 15:37–66, 1992. Horsthemke B: Genetics and cytogenetics of retinoblastoma. Cancer Genet Cytogenet 63:1–7, 1992. Karnes PS, Tran TN, Cui MY, et al.: Cytogenetic analysis of 39 pediatric central nervous system tumors. Cancer Genet Cytogenet 59:12–19, 1992. Kesrouani A, Duchatel F, Seilanian M, et al.: Prenatal diagnosis of adrenal neuroblastoma by ultrasound: a report of two cases and review of the literature. Ultrasound Obstet Gynecol 13:446–449, 1999. Knudson AG: Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:82–823, 1971. Lee KL, Ma JF, Shortliffe LD: Neuroblastoma: Management, recurrence, and follow-up. Urol Clin N Amer 30:881, 2003. Lohmann DR, Horsthemke B, Bornheld N, et al.: Retinoblastoma. Gene Reviews. 2003. http://www.genetests.org Maris JM, Matthay KK: Molecular biology of neuroblastoma. J Clin Oncol 17:2264–2279, 1999. Mertens F, Mandahl N, Mitelman F, et al.: Cytogenetic analysis in the examination of solid tumors in children. Pediatr Hematol Oncol 11:361–377, 1994. Mitelman Database of Chromosome Aberrations in Cancer: http:// cgap.nci,nih.gov/Chromosomes/Mitelman Pakakasama S, Tomlinson GE: Genetic predisposition and screening in pediatric cancer. Pediatr Clin N Amer 49:1393–1413, 2002.
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Pappo AS, Rodriguez-Galindo C, Dome JS, et al.: Pediatric tumors. In Abeloff: Clinical Oncology, 2nd ed, 2000. Chapter 80, 2346–2401. Paulino AC, Coppes MJ: Wilms tumor. eMedicine. 2003. http://www. emedicien.com Quesnel S, Malkin D: Genetic predisposition to cancer and familial cancer syndromes. Pediatr Clin N Amer 47:791–808, 1997. Rowland JM: Molecular genetic diagnosis of pediatric cancer: current and emerging methods. Pediatr Clin N Amer 49:1415–1435, 2002. Sandberg AA: Chromosomal lesions and solid tumors. Hosp Pract October 15:93–106, 1988. Sandberg AA, Turc-Carel C: The cytogenetics of solid tumors. Relation to diagnosis, classification and pathology. Cancer 59:387–395, 1987. Schwab M, Westermann F, Hero B, et al.: Neuroblastoma: biology and molecular and chromosomal pathology. Lancet Oncol 4:472–480, 2003. Sippel KC, Faioli RE, Smith GD, et al.: Frequency of somatic and germ-line mosaicism in retinoblastoma: implications for genetic counseling. Am J Hum Genet 62:610–619, 1998. Stanbridge EJ: Functional evidence for human tumour suppressor genes: Chromosome and molecular genetic studies. Cancer Surv 12:5–24, 1992. Vadeyar S, Ramsay M, James D, et al.: Prenatal diagnosis of congenital Wilms’ tumor (nephroblastoma) presenting as fetal hydrops. Ultrasound Obstet Gynecol 16:80–83, 2000. Varella-Garcia M: Molecular cytogenetics in solid tumors: laboratorial tool for diagnosis, prognosis, and therapy. The Oncologist 8:45–58, 2003.
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Fig. 1. Notice white firm neoplasm (retinoblastoma) filling the vitreous space of the eye.
Fig. 3. Karyotype of a patient with Wilms tumor showing 46,XY, der(11)(p11.2q13.5)del(11)(p13p15.1).
Fig. 4. Note a lobulated meningioma encroaching the brain at the inferior surface of left frontal lobe.
Fig. 2. Large well circumscribed ovoid Wilms tumor in the upper pole of the kidney. Barely identifiable small areas of hemorrhage and necrosis are present.
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Fig. 7. N-MYC amplification in a patient with neuroblastoma. Gross copy number of the orange signal is noted (LSIÆ N-MYC (2p24.1) SpectrumOrange TM probe).
Fig. 5. Karyotypes of two patients with meningioma showing 46,XX,del(22)(q12) (the first picture) and 44,XX,del(7)(q32q36), −11,der(14)t(11;14)(q12;p11),−22 (the second picture) respectively.
Fig. 6. Neuroblastoma smear. Note the anaplastic neuroblastic cells mixed with blood.
Cleft Lip and/or Cleft Palate Cleft lip and/or palate (CL/CP) is the most common craniofacial malformation with an estimated incidence of approximately 1 in 700 to 1 in 1000 live births among Caucasians. CL/CP may occur as an isolated finding or may be found in association with other congenital malformations.
patients in different populations has a positive family history of CL/CP iii. Isolated CL/CP is considered multifactorial in origin and demonstrates strong familial aggregation with a significant genetic component iv. No evidence of classic Mendelian inheritance attributable to any single gene, although a number of genes or loci have been implicated, including transforming growth factor-alpha, retinoic acid receptor alpha, BCL3, MSX-1 and several regions on chromosome 6p23-24 (OFC1), 2q13 (OFC2), 19q13.2 (OFC3), and other loci such as 4q25-4q31.3 and 17q21
GENETICS/BASIC DEFECTS 1. Environmental agents a. Cleft lip and cleft palate i. Alcohol ii. Anticonvulsants (phenytoin, sodium valproate) iii. Isotretinoin iv. Steroids v. Methotrexate vi. Maternal infections in the first trimester a) Rubella b) Toxoplasmosis vii. Maternal smoking b. Isolated clefts i. Little evidence linking to any single teratogenic agent, except anticonvulsant phenytoin ii. Use of phenytoin during pregnancy is associated with a tenfold increase in the incidence of cleft lip c. Cleft lip: incidence of cleft lip in infants in mothers who smoke during pregnancy is twice that of those born to nonsmoking mothers 2. Genetic factors a. Syndromic clefts associated with malformations involving other developmental regions i. About 25% of neonates with CL/CP show associated malformations, syndromes or aneuploidy ii. Van der Woude syndrome: the most commonly recognized syndrome associated with CL/CP, an autosomal dominant disorder characterized by CL/CP and blind sinuses or pits of the lower lip iii. Microdeletion of chromosome 22q11.2 (velocardiofacial syndrome, DiGeorge syndrome, and conotruncal anomaly face syndrome): currently the most common syndromic diagnoses among patients with clefts of the secondary palate alone iv. Other syndromes associated with clefts of the secondary palate alone: a) Stickler syndrome b) Ectrodactyly-ectodermal clefting (EEC) syndrome c) Popliteal pterygium syndrome b. Nonsyndromic cleft of the lip and/or palate i. An embryopathy derived from failure in fusion of the nasal process and/or palatal shelves ii. Genetic factors play an important role in the etiology of cleft lip and/or palate since one in five
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1. Classification of different types of orofacial clefting a. Cleft lip with or without cleft palate (CL/CP) i. Unilateral cleft lip ii. Unilateral cleft lip and cleft palate iii. Bilateral cleft lip iv. Bilateral cleft lip and cleft palate b. Cleft palate only i. Cleft palate ii. Submucous cleft palate iii. Velopharyngeal insufficiency iv. Robin sequence and robin complexes c. Median clefts i. Median cleft lip ii. Persistent infranasal furrow iii. Median frenular cleft iv. Median mandibular cleft d. Alveolar clefts (oral-facial-digital syndromes) e. Tessier type clefts including lateral and oblique facial clefts 2. Racial difference in CL/CP a. Whites: approximately 1 in 1000 births b. African Americans: 0.41 per 1000 births c. Asians: approximately twice of whites 3. Sex difference in CL/CP and isolated clefts of the secondary palate a. Children born with CL/CP: 60–80% are males b. Isolated clefts of the secondary palate: more frequently in females 4. Sites of clefts a. Isolated cleft lip: 21% b. CL/CP: 46% c. Clefts of the secondary palate alone: 33% d. Unilateral clefts i. More common in the left than the right (2:1) ii. Much more common than bilateral (9:1) iii. Associated with palatal clefts in 68% of cases
CLEFT LIP AND/OR CLEFT PALATE
e. Bilateral clefts of the lip: associated with palatal clefts in 86% of cases 5. Types of cleft lip a. Microform i. Presence of a vertical groove and vermilion notching ii. Associated with varying degrees of lip shortening b. Unilateral incomplete cleft lip i. Present with varying degrees of lip disruption ii. Associated with an intact nasal sill or Simonart band (a band of fibrous tissue from the edge of the red lip to the nostril floor) c. Complete cleft lip: characterized by disruption of the lip, alveolus, and nasal sill 6. Secondary medical problems with the presence of cleft plate a. Difficulty in sucking b. Inadequate intake of formula c. Aspiration d. Deviated nasal septum (airway obstruction) e. Hearing impairment f. Recurrent ear infections g. Malocclusion h. Abnormal craniofacial growth i. Inability to generate a pressure gradient between the oral and nasal chambers (hinders sucking in most infants) j. Speech dysfunction i. The most serious untoward consequence associated with cleft palate ii. Hypernasality or escape of sound into the nasal cavity associated with the production of many consonant phonemes and vowels in the English language except m, n, and ng k. Cosmetic disfigurement associated with orofacial clefting
DIAGNOSTIC INVESTIGATIONS 1. Speech and hearing evaluation 2. Echocardiography for associated cardiac anomalies 3. Karyotyping if indicated, especially to detect del(22)(q11.2) 4. Molecular genetic analysis for a known mutation in a syndromic CL/CP
GENETIC COUNSELING 1. Recurrence risk a. Recurrence risk for nonsyndromic CL ± CP i. Unaffected parent a) No previously affected child: about 0.1% (general population risk) b) With one previously affected child: about 4% c) With two previously affected children: about 14% ii. One affected parent a) No previously affected child: about 4% b) With one previously affected child: about 12% c) With two previously affected children: about 25%
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iii. Two affected parents a) No previously affected child: about 35% b) With one previously affected child: about 45% c) With two previously affected children: about 50% b. Recurrence risk for nonsyndromic CP i. Unaffected parent a) No previously affected child: about 0.04% (general population risk) b) With one previously affected child: about 3.5% c) With two previously affected children: about 13% ii. One affected parent a) No previously affected child: about 3.5% b) With one previously affected child: about 10% c) With two previously affected children: about 24% iii. Two affected parents a) No previously affected child: about 2.5% b) With one previously affected child: about 40% c) With two previously affected children: about 45% c. Presence of a microform such as a form fruste cleft lip, submucous cleft palate, or bifid uvula suggest genetic factors within the family, which would alter the inheritance risks (e.g., striking association with lower-lip pits in the van der Woude syndrome) d. Recurrence risk for CL/CP with associated anomalies i. Mendelian diseases and syndromes a) Autosomal dominant inheritance (e.g., Apert syndrome) b) Autosomal recessive inheritance (e.g., Smith-Lemli-Opitz syndrome) c) X-linked inheritance (e.g., oto-palato-digital syndrome) ii. Chromosome disorders (e.g., trisomy 13) 2. Prenatal diagnosis a. Prenatal ultrasonography i. CL/CP not reliably diagnosed until the soft tissues of the fetal face become distinct by 13–14 weeks by transabdominal (TA) sonography and by transvaginal (TV) sonography slightly earlier ii. Fetal palate best seen in the axial plane iii. Fetal lips optimally visualized in the coronal view iv. To demonstrate isolated CL/CP v. To demonstrate associated anomalies (limb and spine anomalies, most common with 33%; cardiovascular anomalies, 24%) b. Fetal echocardiography in case of fetal cardiac anomalies c. Fetal karyotyping in case of associated fetal anomalies 3. Management a. Medical i. A highly specialized multidisciplinary approach from birth to adulthood ii. Airway management iii. Establishment of feeding iv. Speech, hearing, and language therapies b. Surgical
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i. Primary surgery on the lip: usually carried out around the age of 3 months followed by palatal repair at around 6 months ii. Preventative and restorative dental care iii. Orthodontics iv. Secondary surgery in the form of alveolar bone grafting v. Pharyngeal flap or sphincter pharyngoplasty for velopharyngeal incompetence c. Psychological issues i. Parental stress ii. Parent-child relationship iii. Behavioral and emotional adjustment iv. Self-concept and personality v. Cosmetic disfigurement vi. Social functioning vii. Congnitive development and adjustment viii. Cleft Lip and Palate Association (CLAPA), a helpful source of support and information for both families and professionals d. Recent observation suggests beneficial effects of folic acid supplementation during pregnancy in the prevention of facial clefting
REFERENCES Bergé SJ, Plath H, Van de Vondel PT, et al.: Fetal cleft lip and palate: sonographic diagnosis, chromosomal abnormalities, associated anomalies and postnatal outcome in 70 fetuses. Ultrasound Obstet Gynecol 18:422–431, 2001. Bonaiti-Pellié C, Briand ML, Feingold J, et al.: An epidemiological and genetic study of facial clefting in France. I. Epidemiological and frequency in relatives. J Med Genet 11:374–377, 1982. Burdi AR: Epidemiology, etiology, and pathogenesis of cleft lip and palate. Cleft Palate J 14:14:262–269, 1977. Carinci F, Pezzetti F, Scapoli L, et al.: Genetics of nonsyndromic cleft lip and palate: a review of international studies and data regarding the Italian population. Cleft Palate Craniofac J 37:33–40, 2000. Chen H: Medical Genetics Handbook. St Louis: Warren H Green, 1988, pp 320–321. Cockell A, Lees M: Prenatal diagnosis and management of orofacial clefts. Prenat Diagn 20:149–151, 2000. Cohen MM Jr: Craniofacial disorders. In Rimoin DL, Connor JM, Pyeritz RE, Korf BR (eds): Emery and Rimoin’s Principles and Practice of Medical Genetics. 4th ed, London, Churchill Livingstone, 2002, Chapter 142, pp3689–3727. Curtis E, Fraser F, Warburton D: Congenital cleft lip and palate: risk figures for counselling. Am J Dis Child 102:853–857, 1961. De La Pedraja J, Erbella J, McDonald WS, et al.: Approaches to cleft lip and palate repair. J Craniofac Surg 11:562–571, 2000. Endrica MC, Kapp-Simon KA: Psychological issues in craniofacial care: state of the art. Cleft Palate-Craniofac J 36:3–11, 1999.
Farrall M, Holder S: Familial recurrence-pattern analysis of cleft lip with or without cleft palate. Am J Hum Genetics 50:270–277, 1992. Fraser FC: The genetics of cleft lip and palate. Am J Hum Genet 22:336–352, 1970. Fraser GR, Calnan GS: Cleft lip and palate: Seasonal incidence, birth weight, birth rank, sex, site, etc. Arch Dis Child 36:420, 1961. Habib Z: Factors determining occurrence of cleft lip and cleft palate. Surg Gynecol Obstet 146:105–110, 1978. Habib Z: Genetic counseling and genetics of cleft lip and palate. Obstet Gynecol Surv 33:441–447, 1978. Hartridge T: The role of folic acid in oral clefting. Br J Orthodontics 26:115–120, 1999. Hibbert SA, Field JK: Molecular basis of familial cleft lip and palate. Oral Dis 2:238–241, 1996. Kirschner RE, LaRossa D: Cleft lip and palate. Otolaryngol Clin N Amer 33:1191–1215, 2000. Lee W, Kirk JS, Shaheen KW, et al.: Fetal cleft lip and palate detection by three-dimensional ultrasonography. Ultrasound Obstet Gynecol 16: 314–320, 2000. Lynch HAT, Kimberling WJ: Genetic counseling in cleft lip and cleft palate. Plast Reconstr Surg 68:800–815, 1981. Matthews MS, Cohen M, Viglione M, et al.: Prenatal counseling for cleft lip and palate. Plast Reconstr Surg 101:1–5, 1998. Melnick M, Bixler D, Fogh-Anderson P, et al.: Cleft ± cleft palate: an overview of the literature and an analysis of Danish cases born between 1941 and 1968. Am J Med Genet 6:83–97, 1980. Milerad J, Larson O, Hagberg C, et al.: Associated malformations in infants with cleft lip and palate: a prospective, population-based study. Pediatrics 100:180–186, 1997. Mitchell LE, Risch N: Mode of inheritance of nonsyndromic cleft lip with or without cleft palate: a reanalysis. Am J Hum Genetics 51:323–332, 1992. Mulliken JB, Benacerraf BR: Prenatal diagnosis of cleft lip. What the sinologist needs to tell the surgeon. J Ultrasound Med 20:1159–1164, 2001. Murray JC: Gene/environment causes of cleft lip and/or palate. Clin Genet 61:248–256, 2002. Nyberg D, Sickler G, Hegge F, et al.: Fetal cleft lip with and without cleft palate: US classification and correlation with outcome. Radiology 195: 677–684, 1995. Prescott NJ, Winter RM, Malcolm S: Nonsyndromic cleft lip and palate: complex genetics and environmental effects. Ann Hum Genet 65:505–515, 2001. Stark RB: The pathogenesis of harelip and cleft palate. Plast Reconstr Surg 13:20–39, 1954. Stein J, Mullikan JB, Stal S, et al.: Nonsyndromic cleft lip with or without cleft palate: Evidence of linkage to BCL3 in 17 mutigenerational families. Am J Hum Genet 57:257–272, 1995. Tolarova M, Harris J: Reduced occurrence of orofacial clefts after periconceptional supplementation with high-dose folic acid and multivitamins. Teratology 51:71–78, 1995. Tolarova M, Cervenka J: Classification and birth prevalence of orofacial clefts. Am J Med Genet 75:126–137, 1998. Wyszynski DF, Beaty TH: Review of the role of potential teratogens in the origin of human non-syndromic oral clefts. Teratology 53:309–317, 1996. Wyszynski DF, Beaty TH, Maestri N: Genetics of nonsyndromic oral clefts revisited. Cleft Palate Craniofac J 33:406–417, 1996.
CLEFT LIP AND/OR CLEFT PALATE
Fig. 3. An infant and a boy with cleft palate. Fig. 1. Two infants with bilateral cleft lips and cleft palate.
Fig. 4. A boy with high-arched palate. Fig. 2. An infant with unilateral cleft lip and cleft palate.
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Fig. 5. An infant with bilateral CL/CP associated with trisomy 13.
Fig. 6. A stillborn with CL/CP and other multiple congenital anomalies including massive cystic hygroma.
Cleidocranial Dysplasia Cleidocranial dysplasia is a generalized skeletal dysplasia affecting not only the clavicles but almost the entire skeletal system. It is characterized by aplasia or hypoplasia of the clavicles, enlarged calvaria with frontal bossing, multiple Wormian bones, delayed tooth eruption, supernumerary unerupted teeth, distal phalanges with abnormally pointed tufts, hypoplasia of the pelvis, and numerous other abnormalities.
3.
GENETICS/BIRTH DEFECTS 1. Inheritance: autosomal dominant 2. Cause a. Caused by mutations in CBFA1 (RUNX2) gene resulting in haploinsufficiency. Types of mutations identified are: i. Deletion ii. Insertion iii. Missense iv. Nonsense b. The gene for cleidocranial dysplasia: called corebinding factor A1 (CBFA1) (a member of the runt family of transcription factors), mapped to 6p21. The alternative gene name is called RUNX2 c. CBFA1 encodes a transcription factor that activates osteoblast differentiation and plays a role in differentiation of chondrocytes 3. No significant genotype/phenotype correlations observed
4.
5.
6.
7.
CLINICAL FEATURES 1. Significant intra- and inter-familial variability of phenotypic expression 2. Abnormal craniofacial growth a. Head i. A large brachycephalic head ii. A broad forehead with frontal bossing iii. Delayed closure of the fontanelles and sutures iv. Poorly developed midfrontal area showing a frontal groove owing to incomplete ossification of the metopic suture v. Soft skull in infancy b. Face i. Frontal and parietal bossings, separated by a metopic groove ii. A depressed nasal bridge iii. Hypertelorism with possible exophthalmos iv. A small, flattened facial appearance (midface hypoplasia) with mandibular prognathism v. An anatomic pattern of dentofacial deformity consistent with the diagnosis of vertical maxillary deficiency (short face syndrome, type 2) c. Oral/dental i. High arched palate ii. Clefts involving soft and hard palates
8.
iii. Persistence of the deciduous dentition with delayed eruption of the permanent teeth: a relatively constant finding iv. Impaction of supernumerary permanent teeth v. Crowding/malocclusion vi. Dentigerous cysts Shoulders and thorax a. Ability to bring shoulders together b. Dimplings in the skin secondary to mild hypoplasia of the clavicles c. Sloping, almost absent shoulders secondary to severe hypoplasia or absence of the clavicles d. Narrow thorax: may lead to respiratory distress during early infancy Mildly disproportionate short stature with short limbs comparing to the trunk and more apparent in the upper limbs than the lower Spine a. Scoliosis b. Kyphosis Hands a. Brachydactyly b. Short distal phalanges c. Tapering fingers d. Nail dysplasia/hypoplasia e. Short, broad thumbs f. Clinodactyly of the 5th fingers Other abnormalities a. Hearing loss b. Abnormal gait c. Joint hypermobility d. Muscular hypotonia Cesarean section often required in the pregnant female due to dysplastic pelvis
DIAGNOSTIC INVESTIGATIONS
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1. Molecular genetic studies of mutations involving PEBP2αA/CBFA1 2. Radiographic findings: generalized failure of midline ossification a. Skull i. Delayed closure of the anterior fontanelle (open fontanelle) and sagittal and metopic sutures, often for life ii. Unossified areas of the skull becoming smaller with increasing age iii. Multiple Wormian bones formation, particularly around the lambdoid suture iv. Small or absent nasal bones v. Segmental calvarial thickening vi. Underdeveloped maxilla vii. Delayed union of the mandibular symphysis viii. Platybasia
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b.
c.
d.
e.
f.
g.
ix. Small cranial base x. A large foramen magnum xi. Hypoplastic sinuses (paranasal, frontal, mastoid) Clavicles i. Absent clavicles: rare ii. Pseudarthrosis of one or both clavicles iii. Hypoplasia of the acromial end: common iv. Two separate fragments v. Absent sternal end with presence of the acromial end vi. Bilaterality is the rule but not always the case Chest i. Small bell-shaped thoracic cage ii. Short, oblique ribs iii. Presence of cervical ribs iv. Scapula often hypoplastic with deficient supraspinatus fossae and acromial facets v. Associated deficiency in musculature Pelvis i. Widened pubis symphysis resulting from delay in ossification during adulthood ii. Hypoplasia and anterior rotation of the iliac wings iii. Wide sacroiliac joints iv. Delayed ossification of the pubic bone v. Large femoral epiphyses vi. Unusual shape of femoral head reminiscent of a ‘chef’s hat’ vii. Broad femoral necks viii. Frequent coxa vara Spine i. Hemivertebrae ii. Posterior wedging iii. Spondylolysis and spondylolisthesis iv. Syringomyelia v. Spina bifida occulta of the cervical, thoracic, or lumbar region Tubular bones i. Presence of both proximal and distal epiphyses in the second metacarpals and metatarsals leading to excessive growth and length ii. Frequent cone-shaped epiphyses and premature closure of epiphyseal growth plates leading to shortening of bones iii. Wide epiphyses iv. Unusually short distal phalanges and the middle phalanges of the second and fifth fingers v. Poorly developed terminal phalanges giving a tapered appearance to the digit vi. Occasional hypoplasia, dysplasia, and aplasia of nails Dentition: impacted, supernumerary teeth
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected with the disorder or has germ line mosaicism b. Patient’s offspring: 50%
2. Prenatal diagnosis a. Ultrasonography i. Hypoplastic clavicles ii. Less calcified cranium than expected for gestational age iii. Other skeletal anomalies b. Direct DNA testing possible for those families with a known mutation in the CBFA1 3. Management a. Hearing evaluation b. Evaluate the presence of submucous cleft palate c. Evaluation of obstructive sleep apnea d. Medical and surgical therapy for upper airway obstruction, recurrent and chronic sinusitis and otitis e. Monitor skeletal and orthopedic complications f. Early surgical and orthodontic intervention of unerupted permanent teeth to induce eruption g. Orthognathic surgery to correct mid-face hypoplasia to reduce or correct significant upper respiratory complications and malocclusions h. Surgical and orthodontic management of vertical maxillary deficiency i. Women with cleidocranial dysplasia at risk for a Cesarean section delivery
REFERENCES Aktas S, Wheeler D, Sussman MD: The ‘chef’s hat’ appearance of the femoral head in cleidocranial dysplasia. J Bone Joint Surg Br 82:404–408, 2000. Chitayat D, Hodgkinson KA, Azouz EM: Intrafamilial variability in cleidocranial dysplasia: a three generation family. Am J Med Genet 42:298–303, 1992. Cohen MM Jr: RUNX genes, neoplasia, and cleidocranial dysplasia. Am J Med Genet 104:185–188, 2001. Cole WR, Levine S: Cleidocranial dysplasia. Br J Radiol 24:549–555, 1951. Cooper SC, Flaitz CM, Johnston DA, et al.: A natural history of cleidocranial dysplasia. Am J Med Genet 104:1–6, 2001. Dann JJ III, Crump P, Ringenberg QM: Vertical maxillary deficiency with cleidocranial dysplasia. Diagnostic findings and surgical-orthodontic correction. Am J Orthod 78:564–574, 1980. Dhooge I, Lantsoght B, Lemmerling M, et al.: Hearing loss as a presenting symptom of cleidocranial dysplasia. Otol Neurotol 22:855–857, 2001. Ducy P: Cbfa1: a molecular switch in osteoblast biology. Dev Dynamics 219:461–471, 2000. Farrar EL, Van Sickels JE: Early surgical management of cleidocranial dysplasia: a preliminary report. J Oral Maxillofac Surg 41:527–529, 1983. Feldman GJ, Robin NH, Brueton LA, et al.: A gene for cleidocranial dysplasia maps to the short arm of chromosome 6. Am J Hum Genet 56:938–943, 1995. Gelb BD, Cooper E, Shevell M, et al.: Genetic mapping of the cleidocranial dysplasia (CCD) locus on chromosome band 6p21 to include a microdeletion. Am J Med Genet 58:200–205, 1995. Golan I, Baumert U, Held P, et al.: Radiological findings and molecular genetic confirmation of cleidocranial dysplasia. Clin Radiol 57:525–529, 2002. Golan I, Preising M, Wagener H, et al.: A novel missense mutation of the CBFA1 gene in a family with cleidocranial dysplasia (CCD) and variable expressivity. J Craniofac Genet Dev Biol 20:113–120, 2000. Hamner LH III, Fabbri EL, Browne PC: Prenatal diagnosis of cleidocranial dysostosis. Obstet Gynecol 83:856–857, 1994. Hassan J, Sepulveda W, Teixeira J, et al.: Prenatal sonographic diagnosis of cleidocranial dysostosis. Prenat Diagn 17:770–772, 1997. International Working Group on Constitutional Diseases of Bone: International nomenclature and classification of the osteochondrodysplasias (1997). Am J Med Genet 79:376–382, 1998. Jarvis JL, Keats TE: Cleidocranial dysplasia. A review of 40 new cases. AJR 121:5–16, 1974.
CLEIDOCRANIAL DYSPLASIA Jensen BL: Somatic development in cleidocranial dysplasia. Am J Med Genet 35:69–74, 1990. Jensen BL, Kreiborg S: Development of the dentition in cleidocranial dysplasia. J Oral Pathol Med 19:89–93, 1990. Jensen BL, Kreiborg S: Development of the skull in infants with cleidocranial dysplasia. J Craniofac Genet Dev Biol 13:89–97, 1993. Jensen BL, Kreiborg S: Craniofacial abnormalities in 52 school-age and adult patients with cleidocranial dysplasia. J Craniofac Genet Dev Biol 13:98–108, 1993. Jensen BL, Kreiborg S: Craniofacial growth in cleidocranial dysplasia. A roentgenocephalometric study. J Craniofac Genet Dev Biol 15:35–43, 1995. Komori T, Yagi H, Nomura S, et al.: Targeted disruption of CBFA1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89:755–764, 1997. Kreiborg S, Jenson BL, Larsen P, et al.: Anomalies of craniofacial skeleton and teeth in cleidocranial dysplasia. J Craniofac Genet Dev Biol 19:75–79, 1999. Lee B, Thirunsvukkarasu K, Zhou I, et al.: Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/ CBFA1. Nat Genet 16:307–310, 1997. Mundlos S: Cleidocranial dysplasia: clinical and molecular genetics. J Med Genet 36:177–182, 1999. Mundlos S, Otto F, Mundlos C, et al.: Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89:773–779, 1997.
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Narahara K, Tsuji K, Yokoyama Y, et al.: Cleidocranial dysplasia associated with a t(6;18)(p12;q24) translocation. Am J Med Genet 56:119–120, 1995. Nienhaus H, Mau U, Zang KD, et al.: Pericentric inversion of chromosome 6 in a patient with cleidocranial dysplasia. Am J Med Genet 46:630–631, 1993. Otto F, Thornell AP, Crompton T, et al.: CBFA1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89:765–771, 1997. Quack I, Vonderstrass B, Stock M, et al.: Mutation analysis of core binding factor A1 in patients with cleidocranial dysplasia. Am J Hum Genet 65: 1268–1278, 1999. Stewart PA, Wallerstein R, Moran E, et al.: Early prenatal ultrasound diagnosis of cleidocranial dysplasia. Ultrasound Obstet Gynecol 15:154–156, 2000. Tesa A, Salvi S, Casali C, et al.: Six novel mutations of the RUNX2 gene in Italian patients with cleidocranial dysplasia. Hum Mutat mutation in Brief #626, 2003 online. Zackai EH, Robin NH, McDonald-McGinn DM: Sibs with cleidocranial dysplasia born to normal parents: germ line mosaicism? Am J Med Genet 69:348–351, 1997. Zhang YW, Yasui N, Kakazu N, et al.: PEBP2alphaA/CBFA1 mutations in Japanese cleidocranial dysplasia patients. Gene 244:21–28, 2000. Zhou G, Chen Y, Zhou L, et al.: CBFA1 mutation analysis and functional correlation with phenotypic variability in cleidocranial dysplasia. Hum Mol Genet 8:2311–2316, 1999.
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Fig. 2. A child with cleidocranial dysplasia showing prominent forehead, wide anterior fontanel and cranial sutures, wide eyes, depressed nasal bridge, and easily proximated shoulders. Radiographs show poorly ossified skull, wide fontanels, cone-shaped thorax, and absence of clavicles. Fig. 1. An infant and a child with cleidocranial dysplasia showing a large brachycephalic skull, frontal bossing, a large anterior fontanel, widely spaced eyes, flat nasal bridge, and easily proximated shoulders.
CLEIDOCRANIAL DYSPLASIA
Fig. 3. A girl with cleidocranial dysplasia at different ages showing short stature, frontal bossing, wide cranial sutures, wide set eyes, depressed nasal bridge, and sloping and easily proximated shoulders.
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Fig. 4. An adult with cleidocranial dysplasia showing widened cranial sutures, a characteristic face, and sloping and easily proximated shoulders. Radiograph showed a cone-shaped thorax with absent clavicles.
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Fig. 5. A father and a son with cleidocranial dysplasia showing characteristic clinical findings and a dysplastic left clavicle presenting as two separate fragments, illustrated by radiograph.
Cloacal Exstrophy Cloacal exstrophy is a rare congenital malformation resulting in exstrophy of the urinary, intestinal and genital systems and is associated with anomalies of other organ systems. The term OEIS complex (omphalocele, exstrophy of the bladder, imperforate anus, and spinal defects) are used to describe the spectrum of malformations in cloacal exstrophy. The incidence of cloacal exstrophy is estimated to be 1/200,000–1/400,000 live births.
CLINICAL FEATURES
GENETICS/BASIC DEFECTS 1. Genetics a. Recurrence of OEIS complex in siblings can be explained by the following mechanisms: i. Autosomal recessive inheritance ii. Multifactorial determination iii. Gonadal mosaicism for a dominant mutation iv. Environmental factors v. Subclinical maternal disorder b. Higher incidence of OEIS complex in monozygotic twins than in dizygotic twins suggests a possible genetic contribution to the occurrence of these defects 2. Basic defects of OEIS complex a. Resulting from a single localized defect in the early caudal mesoderm at approximately 29 days of development b. Resulting in the following sequence of events: i. Failure of cloacal septation leading to a persistence of the cloaca with a rudimentary mid-gut and imperforate anus ii. Failure of break down of the cloacal membrane leading to exstrophy of the cloaca, omphalocele, and lack of fusion of the pubic rami iii. The lumbosacral somites giving rise to abnormal vertebrae in which there is protrusion of the dilated spinal cord (hydromyelia) and a cystic, skin-covered mass in the lumbosacral region 3. Cloaca and cloacal exstrophy a. Cloaca i. A transient embryological structures ii. The term ‘cloaca’ literally means ‘sewer’ in Latin iii. The term used to represent the emptying of the gastrointestinal and urogenital tracts into a common sinus iv. Defined as a common chamber (orifice) in the perineum into which the urinary, genital and intestinal tract drain b. Cloacal exstrophy: the common orifice empties onto the anterior abdominal wall
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1. Classic exstrophy of the cloaca a. Lower abdominal defect b. Exposure of intestinal and bladder mucosa c. Accompanied by the following anomalies i. Omphalocele ii. Imperforate anus iii. Urogenital anomalies 2. Gastrointestinal malformations a. Omphalocele b. Imperforate anus c. Rectovestibular/rectovesical fistula d. Small bowel anomalies i. Foreshortened small bowel ii. Rotational anomalies e. Meckel diverticulum f. Inguinal hernias 3. CNS malformations a. Spina bifida: the most common CNS malformation i. Leptomeningocele ii. Myelomeningocele iii. Meningocele iv. Spina bifida occulta v. Cord tethering b. Craniosynostosis 4. Skeletal malformations a. Vertebral anomalies i. Presence of extra vertebrae ii. Hemivertebrae and associated scoliosis iii. Absent vertebrae b. Pubic diastasis c. Lower extremity anomalies i. Clubfoot deformities ii. Limb deficiencies 5. Genitourinary malformations a. Bladder anomaly i. Open ii. Separated into 2 halves iii. Flanking the exposed interior of the cecum iv. Openings to the remainder of the hindgut v. Prolapse of the terminal ileum as a “trunk” of bowel onto the cecal plate b. Renal anomalies i. A single kidney ii. Rudimentary kidney iii. Pelvic ectopic kidney iv. Ureteropelvic junction obstruction v. Malrotation vi. Crossed renal ectopia
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c. Ureteral anomalies i. Duplication ii. Ectopic insertion iii. Distal stricture and megaureter d. Male genitalia anomalies i. Small and bifid penis ii. Hemiglans located caudal to each hemibladder e. Female genitalia anomalies i. Bifid clitoris ii. Uterine duplication iii. Vaginal duplication iv. Vaginal agenesis 6. Prognosis a. Used to be uniformly fatal malformation in its worst form b. Currently with an 80–100% survival rate due to early surgical repair but accompanied by lifelong severe morbidity
DIAGNOSTIC INVESTIGATIONS 1. Evaluation of associated malformations 2. Karyotyping for genetic sex 3. Renal ultrasonography for renal and upper urinary tract anomalies 4. Voiding cystourethrography to assess bladder capacity in early childhood in preparation for continence reconstruction 5. Radiographic studies to demonstrate spinal dysraphism a. Plain spinal radiographs b. Myelography c. CT d. CT myelography e. Spinal MRI to identify occult abnormalities that predispose to symptomatic spinal cord tethering
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: recurrence in subsequent pregnancies noted in one report b. Patient’s offspring: Lack of offspring from patients with cloacal exstrophy making the determination of inheritance difficult 2. Prenatal diagnosis by ultrasonography a. Elevated maternal serum α-fetoprotein (AFP) in OEIS complex. The open ventral wall defect likely results in AFP leakage b. Ultrasonography i. Major ultrasound criteria a) Nonvisualization of the bladder (91%) b) A large midline infraumbilical anterior wall defect or cystic anterior wall structure (persistent cloacal membrane) (82%) c) Omphalocele (77%) d) Lumbosacral myelomeningocele (68%) ii. Minor (less frequent) ultrasound criteria a) Lower limb defects (23%) b) Renal anomalies (23%) c) Ascites (14%) d) Widened pubic arches (18%) e) A narrow thorax (9%)
f) Hydrocephalus (9%) g) A single umbilical artery (9%) 3. Management a. Appropriate parental counseling and referral to a center with significant expertise in the management of cloacal exstrophy when prenatal diagnosis is made b. Medical stabilization of the infant i. Fluid and electrolyte replacement ii. Parenteral nutrition iii. Moisten the exstrophied bladder and bowel with saline and cover them with a protective plastic dressing iv. Daily prophylactic antibiotics c. Gender assignment i. Evaluation of the genitalia ii. Decision limited to the genetic male patients with cloacal exstrophy a) Male gender assignment appropriate for male patients with adequate bilateral or unilateral phallic structures b) Male neonates with minimal phallic structures: appropriate to raise as female subjects with early excision of the gonads c) Appropriate hormonal manipulation to improve psychosexual dysfunction d) Improvements in phallic reconstruction eventually allow most genetic male patients to be assigned male gender iii. Initial sexual reassignment to be done in conjunction with extensive family counseling as well as continued counseling for the parents and children d. Management of gastrointestinal malformations i. Closure of omphalocele ii. Combined with gastrointestinal diversion or reconstruction a) Ileostomy with resection of the hindgut remnant b) Colostomy e. Management of genitourinary malformations i. Bladder closure ii. Initial bladder excision and urinary diversion iii. Further augmentation or urinary diversions to achieve continence f. Management of CNS malformations i. Closure of myelomeningocele ii. Cord untethering iii. Spinal fusion iv. Cranial expansion for craniosynostosis g. Management of orthopedic malformations i. Manage myelodysplasia ii. Pelvic osteotomies iii. Various orthopedic devices to assist with ambulation
REFERENCES Austin PF, Homsy YL, Gearhart JP, et al.: The prenatal diagnosis of cloacal exstrophy. J Urol 160:1179–1181, 1998. Baker Towell DM, Towell AD: A preliminary investigation into quality of life, psychological distress and social competence in children with cloacal exstrophy. J Urol 169:1850–1853, 2003.
CLOACAL EXSTROPHY Carey JC, Greenbaum B, Hall Arch Dermatol: The OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects). Birth Defects Orig Artic Ser XIV(6B):253–263, 1978. Chitrit Y, Zorn B, Filidori M, et al.: Cloacal exstrophy in monozygotic twins detected through antenatal ultrasound scanning. J Clin Ultrasound 21:339–342, 1993. Davidoff AM, Hebra A, Balmer D, et al.: Management of the gastrointestinal tract and nutrition in patients with cloacal exstrophy. J Pediatr Surg 31:771–773, 1996. Diamond DA, Jeffs RD: Cloacal exstrophy: a 22-year experience. J Urol 133:779–782, 1985. Dick EA, de Bruyn R, Patel K, et al.: Spinal ultrasound in cloacal exstrophy. Clin Radiol 56:289–294, 2001. Flanigan RC, Casale AJ, McRoberts JW: Cloacal exstrophy. Urology 23:227–233, 1984. Fujiyoshi Y, Nakamura Y, Cho T, et al.: Exstrophy of the cloacal membrane. A pathologic study of four cases. Arch Pathol Lab Med 111:157–160, 1987. Gosden C, Brock DJH: Prenatal diagnosis of exstrophy of the cloaca. JAMA8: 95, 1981. Hurwitz RS, Manzoni GA, Ransley PG, et al.: Cloacal exstrophy: a report of 34 cases. J Urol 138:1060–1064, 1987. Jeffs RD: Exstrophy and cloacal exstrophy. Urol Clin North Am 5:127–140, 1978. Kaya H, Oral B, Dittrich R, et al.: Prenatal diagnosis of cloacal exstrophy before rupture of the cloacal membrane. Arch Gynecol Obstet 263: 142–144, 2000. Kutzner DK, Wilson WG, Hogge WA: OEIS complex (cloacal exstrophy): prenatal diagnosis in the second trimester. Prenat Diagn 8:247–253, 1988.
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Lee DH, Cottrell JR, Sanders RC, et al.: OEIS complex (omphalocele-exstrophyimperforate anus-spinal defects) in monozygotic twins. Am J Med Genet 84:29–33, 1999. Loder RT, Dayioglu MM: Association of congenital vertebral malformations with bladder and cloacal exstrophy. J Pediatr Orthop 10:389–393, 1990. Lund DP, Hendren WH: Cloacal exstrophy: experience with 20 cases. J Pediatr Surg 28:1360–1368; discussion 1368–1369, 1993. Lund DP, Hendren WH: Cloacal exstrophy: a 25-year experience with 50 cases. J Pediatr Surg 36:68–75, 2001. Mathews R, Jeffs RD, Reiner WG, et al.: Cloacal exstrophy-improving the quality of life: the Johns Hopkins experience. J Urol 160:2452–2456, 1998. Meglin AJ, Balotin RJ, Jelinek JS, et al.: Cloacal exstrophy: radiologic findings in 13 patients. AJR Am J Roentgenol 155:1267–1272, 1990. Mitchell ME, Plaire C: Management of cloacal exstrophy. Adv Exp Med Biol 511:267–270; discussion 270–263, 2002. Molenaar JC: Cloacal exstrophy. Semin Pediatr Surg 5:133–135, 1996. Reddy RA, Bharti B, Singhi SC: Cloacal exstrophy. Arch Dis Child 88:277, 2003. Schober JM, Carmichael PA, Hines M, et al.: The ultimate challenge of cloacal exstrophy. J Urol 167:300–304, 2002. Smith NM, Chambers HM, Furness ME, et al.: The OEIS complex (omphaloceleexstrophy-imperforate anus-spinal defects): recurrence in sibs. J Med Genet 29:730–732, 1992. Smith EA, Woodard JR, Broecker BH, et al.: Current urologic management of cloacal exstrophy: experience with 11 patients. J Pediatr Surg 32: 256–261; discussion 261–252, 1997. Yerkes EB, Rink RC: Exstrophy and epispadias. 2002. www.emedicine.com
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Fig. 1. Two infants (A,B;C) with cloacal exstrophy. The schematic diagram (D) illustrates the anatomy of various defects in the second infant (C).
Collodion Baby b. The term “collodion baby” is considered a descriptive term for infants born encased in membrane-like thick scale and includes several heterogeneous conditions c. Several disorders of cornification showing this phenotype at birth d. A mutation of keratinocyte transglutaminase may play a role in lamellar ichthyosis, although lamellar ichthyosis is still considered genetically heterogeneous e. Keratinocytes lacking specific transglutaminase will not cause cross-linked envelopes
Collodion baby is a descriptive term for infants born encased in a membrane-like thick scale resembling oiled parchment or collodion. Neonates born with the features of collodion baby subsequently develop lamellar ichthyosis, ichthyosiform erythroderma, or other forms of ichthyosis. Collodion baby is a rare congenital condition accounting for 1 in 50,000 to 1 in 100,000 deliveries.
GENETICS/BASIC DEFECTS 1. Etiology a. Common severe phenotype (not associated with noncutaneous features) i. Autosomal recessive nonbullous congenital erythrodermic ichthyosis (50% of cases) including harlequin fetus. Harlequin ichthyosis represents the most severe end of the phenotypic spectrum ii. Autosomal recessive lamellar ichthyosis (10%) with mutations in the gene for keratinocyte transglutaminase (TGM1) on chromosome 14q11 in many patients iii. Two self-healing collodion baby siblings observed to have compound heterozygous transglutaminase 1 mutations G278R and D490G iv. Mapping of a second locus for lamellar ichthyosis to chromosome 2q33-q35 v. Rare reports of autosomal dominant lamellar ichthyosis vi. Other clinically indistinguishable cases linked to chromosomes 3 and 19 b. Common milder phenotypes i. Mild form of ichthyosis vulgaris (10%) ii. Recovery without sequaelae (10%) c. Associated congenital ichthyosis i. Trichothiodystrophy ii. Poorly documented true collodion membrane a) Sjogren-Larsson syndrome (ichthyosis, spastic paraplegia, mental retardation, and retinopathy with abnormal levels of fatty aldehyde dehydrogenase activity in cultured fibroblasts) b) Netherton syndrome c) Gaucher disease type II d) Congenital hypothyroidism e) Conradi syndrome f) Dorfman Chanarin syndrome g) Ketoadipiaciduria h) Koraxitrachitic syndrome i) Ichthyosis variegata j) Palmoplantar keratoderma with anogenital leukokeratosis 2. Pathogenesis a. Pathogenesis not yet clarified
CLINICAL FEATURES 1. Major clinical features a. Newborn covered with a taut, shiny membrane resembling plastic wrap b. The membrane often fissured and cracked at birth c. Lamellar exfoliation cracks and peels over the course of several weeks to reveal underlying normal skin or skin with mild scaling that goes on to resolve d. Red/ivory-colored (erythematous) underlying skin e. Persistence of mild ichthyosis in some patients f. Ectropion (eversion of the eyelids) g. Eclabium (eversion of the lips) h. Crumpled pinnae i. Resolved tapered fingertips and partially flexed hands with shedding of the encasing membrane 2. Minor clinical features a. Secondary skin infections in the cracks and fissures b. Scarring in the areas of deep fissuring 3. Complications a. Difficulties in temperature regulation b. Increased insensible water loss predisposing to hypernatremic dehydration c. Secondary infections from gram-positive organisms and Candida albicans d. Septicemia e. Pneumonia secondary to aspiration of squamous material in the amniotic fluid f. Respiratory difficulty due to restricted chest wall movement g. Possible loss of vision caused by corneal damage 4. Prognosis a. Long-term prognosis difficult to address at birth b. Infrequently, a collodion baby may have normal skin after exfoliation of the membranes
DIAGNOSTIC INVESTIGATIONS
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1. Skin biopsy a. Transglutaminase assay b. Conventional and electron microscopy
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i. Hyperkeratosis with thick compact cornified layer (orthokeratoric stratum corneum) ii. Aberrant keratinized/cornified cells iii. Irregularly convoluted horny cells and numerous intercellular Odland bodies (lamellar granules) and nuclear debris in distal layer of the stratum corneum 2. Molecular genetic analysis a. TGM1 sequence analysis: identification of mutation of keratinocyte transglutaminase 1 gene for severe form of autosomal recessive lamellar ichthyosis and self-healing collodion baby b. TGM1 mutations include missense, nonsense, and splice site c. Carrier testing available to at-risk family members on a clinical basis once the mutation in TGM1 has been identified in the proband 3. Studies for other associated conditions a. Polarized light examination of hair and eye brows i. Trichothiodystrophy ii. Netherton syndrome b. Leukocyte lipid inclusions i. Dorfman Chanarin syndrome ii. Neonatal Gaucher disease c. Thyroid hormone level: congenital hypothyroidism d. Skeletal study: Conradi syndrome e. Neurosensory evaluation
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal recessive inheritance: 25% recurrence risk ii. Autosomal dominant inheritance: not increased unless a parent is affected b. Patient’s offspring i. Autosomal recessive inheritance: not increased unless the spouse is a carrier or affected ii. Autosomal dominant inheritance: 50% 2. Prenatal diagnosis: direct mutation analysis of the keratinocyte transglutaminase 1 gene on fetal DNA obtained from amniocentesis or CVS for severe form of autosomal recessive lamellar ichthyosis, provided the mutation in TGM1 has been identified in the proband 3. Management: requiring intensive care a. Maintain skin integrity i. Assess open skin lesions ii. Minimal handling with precaution iii. Prevent secondary infection and avoid prophylactic use of antibiotics b. Maintain body temperature i. Avoid radiant heat ii. Use humidified incubator for dehydration and hypothermia iii. Pre-warm all linen used to absorb weeping
c. Ophthalmological management of ectropion important for the prevention of conjunctivitis and keratitis d. Sedation with opioids indicated for severe pain e. Retinoids in case of delayed shedding of the collodion membrane beyond 3 weeks f. Use keratolytics agents (e.g., alpha-hydroxy acid preparations) to promote peeling and thinning of the stratum corneum as the child becomes older
REFERENCES Akcakus M, Gunes T, Kurtoglu S, et al.: Collodion baby associated with asymmetric crying facies: a case report. Pediatr Dermatol 20:134–136, 2003. Akiyama M: Severe congenital ichthyosis of the neonate. Int J Dermatol 37:722–728, 1998. Akiyama M, Shimizu H, Yoneda K, et al.: Collodion baby: ultrastructure and distribution of cornified cell envelope proteins and keratins. Dermatology 195:164–168, 1997. Akiyama M, Takizawa Y, Kokaji T, et al.: Novel mutations of TGM1 in a child with congenital ichthyosiform erythroderma. Brit J Derm 144: 401–407, 2001. Bale SJ: Autosomal recessive congenital ichthyosis. Gene Reviews, 2003. http://genetests.org Buyse L, Graves C, Marks R, et al.: Collodion baby dehydration: the danger of high transepidermal water loss. Br J Dermatol 129:86–88, 1993. Cserhalmi-Friedman PB, Milstone LM, Christiano AM: Diagnosis of autosomal recessive lamellar ichthyosis with mutations in the TMG1 gene. Br J Dermatol 144:726–730, 2001. Frenk E, de Techtermann F: Self-healing collodion: evidence for autosomal recessive inheritance. Pediatr Dermatol 9:95–97, 1992. Huber M, Rettler I, Bernasconi K, et al.: Mutations of keratinocyte transglutaminase in lamellar ichthyosis. Science 267:525–528, 1995. Jeon S, Djian P, Green H: Inability of keratinocytes lacking specific transglutaminase to form cross-linked envelopes: absence of envelopes as a simple diagnostic test for lamellar ichthyosis. Proc Natl Acad Sci USA 95: 687–690, 1998. Pigg M, Gedde-Dahl T Jr, Cox DW, et al.: Haplotype association and mutation analysis of the transglutaminase 1 gene for prenatal exclusion of lamellar ichthyosis. Prenat Diagn 20:132–137, 2000. Raghunath M, Hennies HC, Ahvazi B, et al.: Self-healing collodion baby: a dynamic phenotype explained by a particular transglutaminase-1 mutation. J Invest Dermatol 120:224–228, 2003. Russell LJ, DiGiovanna JJ, Rogers Genome Res, et al.: Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis. Nat Genet 9:279–283, 1995. Sandler B, Hashimoto K: Collodion baby and lamellar ichthyosis. J Cutan Pathol 25:116–121, 1998. Schorderer DF, Huber M, Laurini RN, et al.: Prenatal diagnosis of lamellar ichthyosis by direct mutational analysis of the keratinocyte transglutaminase gene. Prenat Diagn 17:483–486, 1997. Shareef MJ, Lawlor-Klean P, Kelly KA, et al.: Collodion baby: a case report. J Perinatol 4:267–269, 2000. Stone DL, Carey WF, Christodoulou J, et al.: Type 2 Gaucher disease: the collodion baby phenotype revisited. Arch Dis Child Fetal Neonatal Ed 82:F163–166, 2000. Sybert VP: Disorders of the epidermis. In: Sybert VP (ed): Genetic Skin Disorders. New York, Oxford: Oxford University Press, 1997, pp 23–26. Taïeb A, Labrèze C: Collodion baby: What’s new. J Eur Acad Dermatol Venereol 16:436–437, 2002. Van Gysel D, Lijnen RLP, Moekti S, et al.: Collodion baby: a follow-up study of 17 cases. J Eur Acad Dermatol Venereol 16:472–475, 2002. Williams ML, Elias PM: Genetically transmitted, generalized disorders of cornification: The ichthyosis. Dermatol Clin 5:155–178, 1987.
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Fig 1. A collodion baby wrapped with a taut, shinny membrane over the whole body, red underlying skin, ectropion, crumpled pinnae, and partially flexed hands by encasing membrane.
Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency) 21-hydroxylase deficiency is the most common type of congenital adrenal hyperplasia (CAH). The incidence of classic 21hydroxylase deficiency is estimated to be 1/12,000–1/15,000 births. The nonclassical form of the disease, also called “lateonset” CAH, occurs in approximately 1 in 1000 of the general population depending on the ethnic group and in up to 6% of hirsute women.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Biochemical and molecular basis a. Deficient 21-hydroxylase activity: the most common form (>90% of cases) of CAH b. Caused by mutations of CYP21 (CYP21A2) gene, mapped on the short arm of chromosome 6 (6p21.3): present in duplicate c. A highly homologous pseudogene (CYP21P) i. Located in the same chromosomal region as the active gene ii. Severe mutations of the pseudogene incompatible with coding for a functional enzyme d. About 95% of mutant alleles generated by recombination events between CYP21 and CYP21P e. Relatively common exchange of genetic material between these two homologous genes, the major reason for the high incidence of 21-hydroxylase deficiency compared to other forms of CAH 3. Pathophysiology a. Classic form of 21-hydroxylase deficiency i. Prenatal exposure to potent androgens (testosterone and delta4-androstenedione) at critical stages (8–12 weeks) of sexual differentiation resulting in virilization of the external genitalia in genetic females, resulting in varying degrees of genital ambiguity (female pseudohermaphroditism) at birth ii. Subdivision of classic form a) Simple virilizing form (about 25%) b) Salt-wasting form (>75%) in which aldosterone production is inadequate and at risk of life-threatening salt-wasting crises b. Nonclassic “late onset” form of 21-hydroxylase deficiency i. Has only moderate enzyme deficiency ii. Present postnatally with signs of hyperandrogenism iii. Females with the nonclassic form: not virilized at birth 4. CAH due to 21-hydroxylase deficiency a. 21-hydroxylase i. A microsomal cytochrome P450 enzyme ii. Required to convert: 198
a) 17-hydroxy-progesterone to 11-deoxycortisol b) Progesterone to deoxycorticosterone b. 21-hydroxylase deficiency i. Impairs the metabolism of cholesterol to cortisol, generating excessive level of 17-hydroxyprogesterone ii. Produces androstenedione and other androgens from the precursor (17-hydroxyprogesterone) via an alternative metabolic pathway iii. Aldosterone deficiency a) Inability to synthesize adequate amounts of aldosterone due to severely impaired 21hydroxylation of progesterone in about 75% of patients b) Resulting in sodium loss via the kidney, colon and sweat glands and excrete potassium from the renal tubules c. Cortisol deficiency i. Glucocorticoids a) Increase cardiac contractility b) Increase cardiac output c) Increase cardiac and vasculature sensitivity to the pressor effects of catecholamines and other pressor hormone ii. Absence of glucocorticoids a) Decrease in cardiac output b) Decrease in glomerular filtration leading to an inability to excrete free water and consequently to hyponatremia d. Shock and severe hyponatremia much more likely in 21-hydroxylase deficiency in which both cortisol and aldosterone biosynthesis are affected 5. Phenotype–genotype correlations a. Mutations in CYP21, such as deletions, frameshifts, or nonsense mutations i. Totally ablate enzyme activity ii. Most often associated with salt-wasting b. Mutations mainly consisting of the missense mutation Ile172Asn (Il72N) i. Yielding enzymes with 1–2% normal activity ii. Carried predominantly by patients with simple virilizing disease c. Mutations such as Val281Leu (V281L) and Pro30Leu (P30L) i. Producing enzymes with 20–60% of normal activity ii. Most often associated with the nonclassical disorder d. Two different CYP21 mutations i. Producing compound heterozygotes ii. Most often with a phenotype compatible with that of the less severe gene defects
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e. All patients homozygous or compound heterozygous for large deletions or gene conversions have a saltwasting classic form
CLINICAL FEATURES 1. Classic CAH phenotype a. Simple virilizing form (about 25% of patients) b. Salt wasting form (>75% of patients) i. Adrenal crises present at 1–4 weeks of age in severely affected patients a) Severe dehydration b) Hypotension c) Severe hyponatremia, hyperkalemia, and hyperreninemia d) Progressing to adrenal crisis (azotemia, vascular collapse, hypovolemic shock, and death) if adequate medical care is not provided e) Affected infant boys who are not detected in a newborn screening program are at high risk of a salt-wasting crisis since their normal genitalia fail to alert physicians to the diagnosis of congenital adrenal hyperplasia ii. Nonspecific symptoms a) Poor appetite/feeding b) Vomiting c) Hypotension d) Lethargy e) Failure to gain weight (weight loss) iii. Improved sodium balance and more efficient aldosterone synthesis with age in patients known to have severe slat-wasting episodes in infancy and early childhood iv. Siblings may be discordant for salt wasting v. The degree of salt wasting may vary in individuals carrying identical mutations vi. Patients with 3β-hydroxysteroid hydrogenase deficiency, aldosterone synthase deficiency, or lipoid hyperplasia a) Unable to synthesize aldosterone b) May present with salt-wasting crises c. Children with classic CAH i. Lack sufficient amounts of cortisol to mount a stress response and frequently succumb to minor illnesses ii. Premature closure of the epiphyses resulting in short stature even though these children grow at an accelerated rate when young d. Growth disturbances i. Accelerated skeletal maturation in untreated patients due to high levels of androgen ii. Growth retardation in patients treated with excessive doses of glucocorticoids iii. Final height, despite careful monitoring and good patient compliance, usually averaging one to two standard deviations below the population mean or the target height based on parental heights e. Reproductive problems in affected females
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i. Ambiguous genitalia typically present in the neonatal period a) Clitoromegaly (mild) b) With or without partial fusion of the labioscrotal folds (intermediate) c) Complete fusion of the labioscrotal folds with the appearance of a penile urethra (severe) ii. Internal genitalia a) Normal ovaries, fallopian tubes, and uteri b) Normal upper third of the vagina but urogenital sinus may be present distally with one opening on the perineum iii. Signs of androgen excess in affected females without glucocorticoid replacement therapy a) Clitoral enlargement b) Excessive linear growth c) Advanced bone age d) Acne e) Early onset of pubic and axillary hair f) Hirsutism g) Male pattern baldness h) Menstrual abnormalities i) Reduced fertility iv. Adolescence a) Late menarche in inadequately treated girls b) Sonographic finding of multiple ovarian cysts similar to patients with polycystic ovarian syndrome c) Anovulation d) Irregular bleeding e) Hyperandrogenic symptoms v. Pregnancy and live-birth rates a) Severely reduced in salt-wasting patients b) Mildly reduced in simple virilizing patients c) Normal in nonclassical patients vi. Factors suggested responsible for the impaired fertility a) Adrenal overproduction of androgens and progestins (17-hydroxyprogesterone, progesterone, and androstenedione) b) Ovarian hyperandrogenism c) Polycystic ovary syndrome d) Ovarian adrenal rest tumors e) Neuroendocrine factors f) Genital surgery g) Psychosocial factors (delayed psychosexual development, reduced sexual activity, low maternal feelings) vii. No evidence of an excess of congenital malformations in offspring of women with 21-hydroxylase deficiency viii. Other types of congenital adrenal hyperplasia a) 11β-hydroxylase deficiency: similar to 21hydroxylase deficiency b) 17α-hydroxylase deficiency: remains sexually infantile due to inability to synthesize sex hormones unless supplemented with estrogen c) 3β-hydroxysteroid hydrogenase deficiency: slightly virilized due to high levels of dehydroepiandrosterone
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f. Reproductive function and problems in affected males i. Signs of androgen excess in affected males without glucocorticoid replacement therapy a) Penile enlargement b) Small testes c) Excessive linear growth d) Advanced bone age e) Acne f) Early onset of pubic and axillary hair ii. Ability to father children iii. Testicular adrenal rests a) Most often benign b) Manifest as testicular enlargement c) Seen most often in inadequately treated patients, particularly those with the saltwasting form of 21-hydroxylase deficiency iv. Other types of congenital adrenal hyperplasia a) Men with 11β-hydroxylase deficiency: similar to those with 21-hydroxylase deficiency b) Genetic males with 3β-hydroxysteroid hydrogenase deficiency, 17α-hydroxylase deficiency, or lipoid hyperplasia: usually raised as females and castrated during or before adolescence to prevent malignant transformation of abdominal testes g. Effects on gender role, sexual orientation, and identity i. Gender role a) Referring to gender-stereotyped behaviors such as choice of play toys by young children b) Girls with 21-hydroxylase deficiency may show low interest in maternal behavior, extending from lack of doll play in early childhood to lack of interest in childrearing in women. ii. Sexual orientation a) Referring to homosexual versus heterosexual preferences b) Heterosexuality in most adult women with 21-hydroxylase deficiency c) Homosexuality or bisexuality or increased tendency to homo-erotic fantasies in a small but significant proportion in women with 21-hydroxylase deficiency iii. Gender identity a) Referring to self-identification as male or female b) Self-reassignment to the male sex is unusual in women with 21-hydroxylase deficiency c) Severely virilized females are more likely to be raised as males in cultures that value boys more highly and/or in third world countries in which the diagnosis is likely to be delayed 2. Nonclassic CAH phenotype a. Having only moderate enzyme deficiency b. Nonambiguous external genitalia, with normal or mild clitoromegaly, in females affected with mild, nonclassical form of 21-hydroxylase deficiency c. Signs of androgen excess i. Wide spectrum of symptoms and signs
ii. Asymptomatic in many affected individuals iii. Children: premature pubarche iv. Young women a) Severe cystic acne b) Hirsutism c) Oligomenorrhea d. Signs and symptoms suggesting mild CAH i. Children a) Moderate to severe recurrent sinus or pulmonary infections b) Severe acne c) Hyperpigmentation, especially of the genitalia d) Tall for age e) Early onset of puberty ii. Adults a) Childhood history as described above b) Syncope or near-syncope c) Shortened stature compared with either parent d) Hypotension (21-hydroxylase deficiency) e) Hypertension (11β-hydroxylase deficiency) iii. Women a) Clitoromegaly b) Poorly developed labia c) Premature adrenarche d) Hirsutism e) Menstrual disturbances f) Infertility g) Polycystic ovary syndrome
DIAGNOSTIC INVESTIGATIONS 1. Newborn screening a. Objectives i. Detect a common and potentially fatal childhood disease (classic form of CAH) ii. Prevent serious morbidity and mortality by early recognition and treatment iii. Prevent incorrect male sex assignment of affected female infants with ambiguous genitalia iv. Detect most, but not all, cases of the nonclassic form of 21-hydroxylase deficiency b. Filter-paper blood spot sample i. Markedly elevated 17-hydroxyprogesterone by radioimmunoassay ii. False positives a) Samples taken in the first 24 hours of life (elevated in all infants) b) Variation of weight adjusted cut-off values among newborn screening programs c) Infants with low birth weight or prematurity iii. Second level of screening based on detection of actual mutations on DNA extracted from the same dried blood spots c. Main benefits of newborn screening i. Reduced morbidity and mortality ii. Reduced time to diagnosis of infants with 21hydroxylase deficiency iii. Infants ascertained through screening a) Less severe hyponatremia b) Tend to be hospitalized for shorter periods of time
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2. Diagnosis of CAH a. Female neonates i. With genital ambiguity a) Genital ambiguity highly distressing to the family b) Require urgent expert medical attention c) Need immediate comprehensive evaluation by a multidisciplinary team including specialists from pediatric endocrinology, psychosocial services, pediatric surgery/ urology, and genetics ii. With or without salt loss iii. Presence of elevated concentration of serum 17hydroxyprogesterone a) Only diagnostic of CAH when measured after the 3rd day of life b) Presence of relatively high concentrations in the immediate neonatal period in normal infants iv. Normal internal female genitalia on pelvic ultrasonography v. Normal female karyotype (46,XX) b. Male neonates i. Salt-losing crises ii. Presence of elevated 17-hydroxyprogesterone concentration 3. Clinical chemistry a. Comparison of baseline and cortrosyn stimulated serum concentrations of the steroid precursor 17hydroxyprogesterone (nonclassical) b. Increased serum levels of progesterone, 17-hydroxyprogesterone, and androstenedione in affected males and females with classic 21-hydroxylase deficiency c. Elevated serum levels of testosterone and adrenal androgen precursors in affected girls d. Salt losers i. Low serum bicarbonates, sodium and chloride levels ii. Elevated levels of serum potassium and serum urea nitrogen iii. Hyponatremia and hyperkalemia usually not present before 7 days of age iv. Inappropriately increased urine sodium levels v. Elevated plasma rennin levels vi. Serum aldosterone level inappropriately low for the rennin level 4. Karyotyping or fluorescence in situ hybridization for sex chromosome material a. 46,XX in females with 21-hydroxylase deficiency b. 46,XY in males with 21-hydroxylase deficiency 5. Annual bone age radiography 6. Careful monitoring of linear growth 7. Transabdominal pelvic sonography a. Perform in patients with CAH undergoing vaginal reconstruction b. Provide adequate information about the anatomy of the vagina and urogenital sinus c. Demonstrate presence or absence of a uterus or associated renal anomalies 8. Urogenitogram helpful to define the anatomy of the internal genitalia
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9. Adrenal ultrasonography to detect enlarged, lobulated adrenals with stippled echogenicity invariably associated with CAH 10. Sonography or MRI for testicular adrenal rest tumors 11. Carrier detection a. Carriers: asymptomatic individuals who have one normal allele and one mutant allele b. ACTH stimulation test i. Resulting in slightly elevated serum concentrations of deoxycortisol and 17-hydroxyprogesterone ii. Overlap in serum concentration of 17-hydroxyprogesterone between carriers and noncarriers iii. No longer the preferred method of carrier detection c. Molecular genetic testing i. Molecular genetic testing of the CYP21A2 gene available to at-risk relatives, given that the diseasecausing mutation(s) have been identified in the proband ii. The preferred method of carrier detection 12. Molecular genetic testing a. Molecular genetic analysis for CYP21A2 gene for a panel of 9 common mutations and gene deletions detect about 90–95% of disease-causing alleles in affected individuals and carriers b. Complete gene sequencing detects more rare alleles in affected individuals in whom the panel of nine mutations and deletions reveals only one or neither disease-causing allele c. Applications i. Primarily used in genetic counseling for carrier detection of at-risk relatives and for prenatal diagnosis ii. Can be used for diagnosis in newborns with slight to moderate elevations of 17-hydroxyprogesterone
GENETIC COUNSELING 1. Recurrence risk a. Genetic counseling according to autosomal recessive inheritance i. Most parents: heterozygotes with one normal allele and one mutated allele ii. 1% of probands having only one parent who is heterozygous since 1% of mutations occur de novo iii. In some instances, a parent, who was previously not known to be affected, was found to have the nonclassic form of 21-hydroxylase deficiency b. Patient’s sib i. When the parents of a proband are both obligate heterozygotes a) 25% risk of inheriting both altered alleles and being affected b) 50% risk of inheriting one altered allele and being an unaffected carrier c) 25% risk of inheriting both normal allele and being unaffected d) 2/3rd chance of unaffected sibs of a proband being a carrier
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ii. When a parent of a proband has 21-hydroxylase deficiency and the other is heterozygous a) 50% risk of inheriting both mutant alleles and being affected b) 50% risk of inheriting one mutant allele and being a carrier c. Patient’s offspring for a woman with classic 21hydroxylase deficiency i. When the spouse status is unknown a) Risk of having an infant with the same disorder: approximately 1 in 120 births b) Risk of having an affected female infant: approximately 1 in 240 births c) Risk figures are based on an estimated 1 in 60 incidence of heterozygous individuals with a CYP21 mutation, derived from newborn screening data ii. When the spouse is not a carrier or not affected: risk is not increased iii. Appropriate to offer molecular genetic testing of the CYP21A2 gene to the spouse given the high carrier rate for 21-hydroxylase deficiency d. Patient’s offspring for a woman with nonclassic CAH and are compound heterozygotes with one severe CYP21A2 mutation: risk of having an affected infant with classic CAH is 1 in 4 pregnancies (or 1 in 8 pregnancies for an affected female infant) when the spouse is a known carrier of the severe form of CYP21A2 deficiency 2. Prenatal diagnosis a. Determination of amniotic fluid (AF) hormone levels i. Elevated 17α-hydroxyprogesterone ii. Elevated androstenedione b. Human leukocyte antigen (HLA) typing on cultured chorionic villus cells and cultured AF cells i. Basis for prenatal diagnosis: the gene for 21hydroxylase has been linked to the HLA system on chromosome 6 ii. HLA type a) Fetus with an HLA type identical to that of the proband with 21-hydroxylase deficiency predicted to be affected b) Fetus sharing 1 parental haplotype with the proband predicted to be a heterozygous carrier c) Fetus with both haplotypes different from the index case predicted to be homozygous normal c. Molecular DNA diagnosis i. Molecular genetic testing of the proband and both parents should be undertaken prior to conception: a) To identify the two disease-causing mutations b) To confirm both parents are carriers ii. Analysis of both parents a) To determine the phase of different mutations (whether they lie on the same or opposite alleles) b) To distinguish homozygotes and hemizygotes (individuals who have a mutation on one chromosome and a deletion on the other)
iii. De novo mutations, found in patients with CAH but not in parents, observed in 1% of diseasecausing CYP21B mutations iv. Before 10 weeks of gestation and prior to any prenatal testing, administer dexamethasone to the pregnant mother to suppress excess fetal adrenal androgen secretion and to prevent virilization of an affected female v. Obtain fetal cells to determine fetal sex by chromosome analysis or FISH using Y-chromosome specific probes a) CVS in the 10th–12th week of gestation (preferable because of early result) b) Amniocentesis at 16–18 weeks of gestation vi. If the fetus is a female and if the two CYP21A2 disease-causing mutations have been identified in the proband a) Perform molecular genetic testing to determine whether the fetus has inherited both disease-causing alleles b) Female fetus known to have 21-hydroxylase deficiency by DNA analysis or having an indeterminant status: continue dexamethasone treatment to term vii. If the fetus is a male or unaffected female by DNA analysis: discontinue dexamethasone treatment 3. Management a. Replacement with glucocorticoids (hydrocortisone, prednisone, dexamethasone) i. Indicated in all patients with classic and symptomatic non-classical patients with 21-hydroxylase deficiency ii. To suppress the excessive secretion of CRH and ACTH by the hypothalamus and pituitary iii. To reduce the abnormal blood levels of adrenal sex steroids iv. Situations in which increase hydrocortisone dose is needed in patients with classic 21-hydroxylase deficiency a) Febrile illness b) Surgery under general anesthesia v. Increase does of hydrocortisone or prednisone in pregnancy due to pregnancy-induced alterations in steroid metabolism and clearance vi. Glucocorticoid replacement also required in patients with CAH caused by other enzymatic deficiencies b. Mineralocorticoid replacement i. Mineralocorticoid (fludrohydrocortisone) and sodium chloride supplements required in infants with the salt-wasting form of 21-hydroxylase deficiency ii. Treat patients with simple virilizing form of the disease by fludrohydrocortisone to aid in adrenocortical suppression and reduce the dose of glucocorticoid required to maintain acceptable 17-hydroxyprogesterone levels iii. Signs of over treatment with mineralocorticoid and sodium replacement a) Hypertension b) Tachycardia
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c.
d.
e.
f.
g.
c) Suppressed plasma rennin activity iv. Other indications of fludrohydrocortisone replacement a) 3β-hydroxysteroid hydrogenase deficiency b) Aldosterone synthase deficiency c) Lipoid hyperplasia Other pharmacological approaches i. A novel 4-drug regimen for 21-hydroxylase deficiency a) Consisting of flutamide (an androgen receptor blocking drug), testolactone (an aromatase inhibitor), and low dose of hydrocortisone and fludrocortisone b) Benefit: produce less bone age advancement and attain more appropriate linear growth velocity than standard treatment c) Side effect: occurrence of central precocious puberty requiring treatment with gonadotrophin releasing hormone analog ii. Experimental treatment with carbenoxolone, an inhibitor of 11β-hydroxysteroid dehydrogenase Corrective surgery i. Decision about surgery a) Made by the parents, together with the clinical team b) After disclosure of all relevant clinical information and all available options c) Obtain informed consent ii. Objectives a) Genital appearance compatible with gender b) Unobstructed urinary emptying without incontinence or infections c) Good adult sexual and reproductive function iii. Clitoroplasty, rather than clitoridectomy, done in infancy iv. Vaginal reconstruction a) Often postponed until the age of expected sexual activity b) Single-stage corrective surgery in children Adrenalectomy i. Questionable therapeutic alternative ii. Likely to be used, if at all, in patients with severe 21-hydroxylase deficiency refractory to standard medical management Management of testicular adrenal rests i. Effective adrenal suppression with dexamethasone since many of these tumors are ACTHresponsive ii. Testis-sparing surgery for cases unresponsive to dexamethasone after imaging the tumor by sonography and/or MRI Management of adolescence with classical and nonclassical CAH i. Psychological assessment and support of the patient ii. Counseling a) Sexual function b) Future surgeries c) Gender role d) Issues related to living with a chronic disorder
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e) Low risk of women with CAH or nonclassic CAH having an affected fetus h. Management of pregnancy in women with classic 21hydroxylase deficiency i. Factors contributing to lower fertility rates a) Masculinization of the external genitalia b) An inadequate introitus c) Factors relating to genital reconstructive surgery (poor surgical repair, vaginal stenosis, and clitoral dysfunction) d) Hormonal factors (increased levels of adrenal androgens and progestational steroid, and ovarian hyperandrogenism) ii. Recent improvement of fertility prognosis a) Earlier detection and treatment of 21hydroxylase deficiency b) Surgical advances in genital reconstruction c) Higher patient compliance rates iii. Preconception issues for all women with classic 21-hydroxylase deficiency who desire pregnancy a) Need for glucocorticoid treatment b) Careful endocrine monitoring throughout gestation c) Ovulation induction with clomiphene citrate or gonadotropin therapy or in vitro fertilization for patients who do not achieve normal ovulatory cycles and fertility despite effective glucocorticoid therapy d) Most pregnancies are successful in carrying to term with a healthy outcome e) Preconceptional counseling about the risk of having a child affected with 21-hydroxylase deficiency iv. Gestational management a) Regular assessment of maternal clinical status, serum electrolytes, and circulating adrenal androgen levels during gestation to determine the need for increased glucocorticoid or mineralocorticoid therapy b) Signs of adrenal steroid insufficiency (excessive nausea, slat craving, and poor weight gain) c) Monitor hypertension and fluid retention in patients receiving mineralocorticoid therapy, particularly in the third trimester v. Labor and delivery a) Require stress doses of glucocorticoid therapy during labor and delivery b) Elective cesarean section considered for pregnant women with virilizing CAH, for cephalopelvic disproportion due to android pelvic characteristics and especially for those who have had reconstructive surgery of the external genitalia vi. Evaluation of the infant a) Clinical signs of adrenal suppression (hypotension, hypoglycemia), particularly in cases in which dexamethasone was administered during pregnancy b) Sign of ambiguous external genitalia
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c) Female pseudohermaphroditism secondary to either maternal hyperandrogenism or fetal 21hydroxylase deficiency (if the father is a carrier) i. Prenatal therapy i. Inclusion criteria a) A previously affected sibling or first-degree relative with known mutations causing classic CAH, proven by DNA analysis b) Reasonable expectation that the father is the same as the father of the proband c) Availability of rapid, high-quality genetic analysis d) Therapy started less than 9 weeks after the last menstrual period e) No plans for therapeutic abortion f) Reasonable expectation of patient compliance ii. Dexamethasone a) No salt-retaining activity b) Not significantly metabolized by placental 11β-hydroxysteroid dehydrogenase c) Able to cross the placenta iii. Administer dexamethasone to the mother in pregnancies at risk for a female child affected with virilizing adrenal hyperplasia a) To suppress fetal adrenal androgen production, beginning before the 7–8th week of gestation, to prevent ambiguity of the external genitalia in the female fetus with classic CAH b) To prevent progression of virilization on therapy after 7–8th week of gestation iv. Outcome of prenatally treated females a) Approximately 70% born with normal or only slightly virilized genitalia with clitoromegaly, partial labial fusion, or both b) Approximately 30% born with marked genital virilization v. Disadvantage: 7 out of 8 fetuses unnecessarily treated since CAH is inherited as an autosomal recessive disease and only affected girls benefit from the treatment vi. Prompt discontinuation of dexamethasone therapy to minimize potential risks of glucocorticoid toxicity if: a) Male sex determination by prenatal genetic diagnosis b) CYP21 genotype indicating that the fetus is unaffected vii. Refer patient to centers with expertise in the prenatal management of pregnancies at risk for CAH viii. Long-term follow-up studies still needed for prenatally treated children ix. Side effects of women treated to term (10%) a) Features of Cushing syndrome (excessive weight gain, severe striae, hypertension, hyperglycemia) b) Resolved when the treatment is discontinued x. Side effects of women treated for a shorter time (10–20%) a) Edema b) Gastrointestinal upset
c) Mood fluctuations d) Acne e) Hirsutism xi. Similar therapeutic approaches: effective in families at risk for 11β-hydroxylase deficiency, in which affected female fetuses may also suffer severe prenatal virilization xii. Prenatal therapy not appropriate for nonclassic CAH xiii. Parents of affected girls a) Many opting for prenatal medical treatment because of severe psychological impact of ambiguous genitalia on the child and on the family b) Obtain informed consent as to the potential fetal and maternal risks, some of which may yet to be recognized
REFERENCES Al-Alwan I, Navarro O, Daneman D, et al.: Clinical utility of adrenal ultrasonography in the diagnosis of congenital adrenal hyperplasia. J Pediatr 135:71–75, 1999. American Academy of Pediatrics Ad Hoc Writing Committee, 2000-2001: Technical Report: congenital adrenal hyperplasia. Pediatrics 106: 1511–1518, 2000. Bose HS, Sugawara T, Strauss JF III, et al.: The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Enl J Med 355:1970–1978, 1996. Chen H: Genetic disorders. In Paul I Liu (ed): Blue Book of Diagnostic Tests. Philadelphia, W. B. Saunders co., 1986, pp 421–462. Chertin B, Hadas-Halpern I, Fridmans A, et al.: Transabdominal pelvic sonography in the preoperative evaluation of patients with congenital adrenal hyperplasia. J Clin Ultrasound 28:122–124, 2000. Cutler GB Jr, Laue L: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med 323:1806–1813, 1990. David M, Forest MG: Prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency. J Pediatr 105:799–803, 1984. Deaton MA, Glorioso JE, Mclean DB: Congenital adrenal hyperplasia: not really a zebra. Am Fam Physician 59:1190–1196, 1999. Deneux C, Tardy V, Dib A, et al.: Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 86:207–213, 2001. Forest MG, Morel Y, David MP: Prenatal treatment of congenital adrenal hyperplasia. Trends Endocrinol Metab 9:284–289, 1998. Garner PR: Congenital adrenal hyperplasia in pregnancy. Semin Perinatol 22:446–456, 1998. Hall CM, Jones JA, Meyer-Bahlburg HF, et al.: Behavioral and physical masculinization are related to genotype in girls with congenital adrenal hyperplasia. J Clin Endocrinol Metab 89:419–424, 2004. Hoffman WH, Shin MY, Donohoue PA, et al.: Phenotypic evolution of classic 21-hydroxylase deficiency. Clin Endocrinol 45:103–109, 1996, Hughes IA: Clinical aspects of congenital adrenal hyperplasia: early diagnosis and prognosis. J Inher Metab Dis 9 (Suppl 1):115–123, 1986. Hughes IA: Management of congenital adrenal hyperplasia. Arch Dis Child 63:1399–1404, 1988. Hughes IA: Congenital adrenal hyperplasia: 21-hydroxylase deficiency in the newborn and during infancy. Semin Reprod Med 20:229–242, 2002. Hughes IA: Congenital adrenal hyperplasia: phenotype and genotype. J Pediatr Endocrinol Metab 15 (Suppl 5):1329–1340, 2002. Hughes IA: Intersex. BJU International 90:769–776, 2002. Joint LWPES/ESPE CAH Working Group, Writing Committee: Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. J Clin Endocrinol Metab 87:4098–4053, 2002. Kuttenn F, Couillin P, Girard F, et al.: Late-onset adrenal hyperplasia in hirsutism. N Engl J Med 313:224–231, 1985. Lajic S, Wedell A, Bui TH, et al.: Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. Trends Endocr Metab 9:284–289, 1998.
CONGENITAL ADRENAL HYPERPLASIA Levine LS: Congenital adrenal hyperplasia. Pediatr Rev 21:159–170, 2000. Lo JC, Grumbach MM: Pregnancy outcomes in women with congenital virilizing adrenal hyperplasia. Endocrinol Metab Clin North Am 30:207–229, 2001. Merke DP, Cutler GB: New approaches to the treatment of congenital adrenal hyperplasia. JAMA 277:1073–1076, 1997. Meyer-Bahlburg HF: Gender and sexuality in classic congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 30:155–171, 2001. Miller WL: Molecular biology of steroid hormone synthesis. Endocr Rev 9:295–318, 1998. Miller WL: Congenital adrenal hyperplasia in the adult patient. Adv Intern Med 44:155–173, 1999. New MI: Steroid 21-hydroxylase deficiency (congenital adrenal hyperplasia). Am J Med 98:2S–8S, 1995. New MI: Antenatal diagnosis and treatment of congenital adrenal hyperplasia. Curr Urol Rep 2:11–18, 2001. New MI: Prenatal treatment of congenital adrenal hyperplasia. The United States experience. Endocrinol Metab Clin North Am 30:1–13, 2001. New MI, Putnam A: 21-hydroxylase deficiency. Gene Reviews, 2002. http://www.genetests.org New MI, Wilson RC: Genetic Disorders of the Adrenal Gland. In Rimoin DL, Connor JM, Pyeritz RE, Korf BR (eds): Emery and Rimoin’s Principles and Practice of Medical Genetics, 4th ed, Vol 2, Chapter 84, pp 2277–2314, 2002. New MI, Carlson A, Obeid J, et al.: Extensive personal experience. Prenatal diagnosis for congenital adrenal hyperplasia. J Clin Endocrinol Metab 86:5651–5657, 2001. Pang S: Congenital adrenal hyperplasia. Endocrinol Metab Clin 26: 853–891, 1997. Pang S, Shook MK: Current status of neonatal screening for congenital adrenal hyperplasia. Curr Opin Pediatr 9:419–423, 1997. Pang S, Wallace MA, Hofman L, et al.: Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics 81:866–874, 1988. Ritzén EM: Prenatal treatment of congenital adrenal hyperplasia: a commentary. Trends Endocr Metab 9:293–295, 1998. Ritzén EM: Prenatal dexamethasone treatment of fetuses at risk for congenital adrenal hyperplasia: benefits and concerns. Semin Neonatol 6:357–362, 2001.
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Schnitzer JJ, Donahoe PK: Surgical treatment of congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 30:137–154, 2001. Speiser PW: Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Endocrinol Metab Clin North Am 30:31–59, 2001. Speiser PW, New MI: Prenatal diagnosis and management of congenital adrenal hyperplasia. Clin Perinatol 21:631–645, 1994. Speiser PW, White PC: Congenital adrenal hyperplasia. N Engl J Med 349:776–788, 2003. Speiser PW, Dupont B, Rubinstein P, et al.: High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet 37:650–667, 1985. Stikkelbroeck NM, Hermus AR, Braat DD, et al.: Fertility in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Obstet Gynecol Surv 58:275–284, 2003. Therrell BL: Newborn screening for congenital adrenal hyperplasia. Endocrinol Metab Clin 30:15–30, 2001. Therrell BLJ, Berenbaum SA, Manter-Kapanke V, et al.: Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics 101:583–590, 1998. Wedell A: Molecular approaches for the diagnosis of 21-hydroxylase deficiency and congenital adrenal hyperplasia. Clin Lab Med 16:125–137, 1996. Wedell A: Molecular genetics of congenital adrenal hyperplasia (21-hydroxylase deficiency): implications for diagnosis, prognosis and treatment. Acta Paediatr 87:159–164, 1998. White PC: Congenital adrenal hyperplasias. Best Pract Res Clin Endocrinol Metab 15:17–41, 2001. White PC, Speiser PW: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 21:245–291, 2000. White PC, New MI, Dupont B: Congenital adrenal hyperplasia. (first of two parts). N Engl J Med 316:1519–1524, 1987. White PC, New MI, Dupont B: Congenital adrenal hyperplasia (second of two parts). N Engl J Med 316:1580–1586, 1987. Wilson T: Congenital adrenal hyperplasia. Emedicine, 2004. http://www. emedicine.com Woelfle J, Hoepffner W, Sippell WG, et al.: Complete virilization in congenital adrenal hyperplasia: clinical course, medical management and diseaserelated complications. Clin Endocrinol 56:231–238, 2002.
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Fig. 2. A newborn with congenital adrenal hyperplasia showing ambiguous genitalia. Newborn screening from filter paper showed total 17OHP of >240 ng/mL (normal <33). Pair of intron 2 mutations were detected by PCR.
Fig. 1. Three female infants (46,XX) with classic form of CAH showing varying degree of virilization.
Congenital Cutis Laxa Congenital cutis laxa is a rare inherited connective tissue disorder manifested by inelastic, loose, pendulous skin, giving the appearance of premature aging.
GENETICS/BASIC DEFECTS 1. Genetic heterogeneity a. Autosomal recessive cutis laxa: the most common type i. Type I autosomal recessive cutis laxa: less frequent than type II ii. Type II autosomal recessive cutis laxa b. Autosomal dominant cutis laxa c. X-liked recessive cutis laxa i. Previously called occipital horn syndrome ii. At present, best termed as Ehlers-Danlos syndrome type IX 2. Biochemical and molecular defects a. Autosomal recessive cutis laxa type I: molecular studies in a large consanguineous Turkish family demonstrated the presence of a homozygous missense mutation (T998C) in the fibulin-5 (FBLN5) gene, resulting in a serine-to-proline (S227P) substitution in the fourth calcium-binding epidermal growth factor-like domain of fibulin-5 protein b. Autosomal dominant cutis laxa i. Can be caused by mutations in the elastin gene ii. Molecular heterogeneity cannot be excluded c. X-linked recessive cutis laxa i. Caused by mutations in the ATP7A gene ii. Characterized by diminished activity of lysyl oxidase in the skin from affected males iii. Reduced serum copper and ceruloplasmin in affected males, suggesting that the lysyl oxidase deficiency may be secondary to a defect in copper metabolism iv. Now known to be allelic to Menkes disease
CLINICAL FEATURES 1. Autosomal recessive cutis laxa a. More common than the autosomal dominant form b. Autosomal recessive cutis laxa type I i. The poorest prognosis ii. Pulmonary emphysema iii. Umbilical and inguinal hernias iv. Gastrointestinal and vesicourinary tract diverticuli c. Autosomal recessive cutis laxa type II, also called cutis laxa with joint laxity and developmental delay d. Characteristic facies i. Appearing aged due to accentuation of skin folds ii. Downward slanting palpebral fissures iii. Blepharochalasis and, at times, ectropion, adding to the aged appearance 207
iv. A broad flat nose v. Sagging cheeks vi. Long upper lip vii. Short columella viii. Large ears e. Skin i. Prominent skin folds (loose skin) around the knees, abdomen, and thighs ii. No hyperelasticity, fragility, or difficulty in wound healing f. Skeletal muscular abnormalities i. Dislocation of the hips ii. Joint hyperextensibility iii. Hernia iv. Osteoporosis g. Cardiopulmonary abnormalities i. Severe pulmonary emphysema resulting from generalized elastolysis a) Tachypnea b) Pneumonitis c) Airway obstruction d) Severe hypoxia e) Respiratory failure ii. Cardiac abnormalities a) Right ventricular enlargement b) Cor pulmonale c) Bundle branch block d) Pulmonary artery hypoplasia and stenosis e) Dilated and tortuous carotid, vertebral, and pulmonary arteries f) Aortic aneurysm h. Other abnormalities i. Hernias a) Inguinal b) Diaphragmatic c) Ventral d) Inguinal ii. Hollow viscus (pharynx, esophagus, and rectum) diverticula iii. Oral abnormalities a) Deep and resonant voice secondary to lax vocal cords b) Loose oral and pharyngeal mucosa iv. Genitourinary abnormalities a) Bladder diverticula b) Vaginal prolapse v. Dental caries i. A shorter life span 2. Autosomal dominant cutis laxa a. A relatively benign disorder and less common than the autosomal recessive form b. Cutaneous laxity c. Clinical features presenting in infancy
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i. ii. iii. iv.
Intrauterine growth retardation Delayed fontanelle closure Ligamental laxity Episodes of edema may precede the skin changes, usually within the first 2 months of life v. Aging appearance by the end of the second year vi. Pulmonary emphysema common due to a loss of elastic tissue in the lungs d. Skin changes presenting in adulthood i. Usually no internal defects ii. Having a normal life expectancy e. Aging appearance i. Drooping of eyelids ii. Sagging facial skin iii. Accentuation of the nasolabial and other facial folds iv. Often hooked nose with everted nostrils v. Long philtrum f. Few complications i. Hoarseness ii. Pulmonary artery stenosis iii. Mitral valve prolapse iv. Hernia v. Bronchiectasis vi. Joint dislocations vii. Tortuosity and dilatation of carotid arteries and aorta viii. Dilatation of sinuses of Valsalva ix. Coarctation of the aorta g. Normal life span 3. X-linked recessive cutis laxa a. Long and thin face, neck, and trunk b. Mild hyperelastic (but not lax) and bruisable skin with resultant atrophic scars c. Musculoskeletal abnormalities i. Inferior cranial spurs (occipital horns) a) A constant feature b) May be palpated c) May become larger with age d) May represent ectopic bone formation within the trapezius and sternocleidomastoid aponeuroses ii. Skeletal dysplasia most prominent at the wrists and elbows iii. Limitation of extension of the elbows, shoulders, knees iv. Hypermobility of the finger joints v. Pes planus vi. Genu valga vii. Pectus excavatum or carinatum (40%) d. Obstructive uropathy secondary to bladder diverticula with bladder neck obstruction (60–70%) e. Various hernias (hiatal, femoral, and inguinal) (35%) f. Chronic diarrhea (40%) 4. Differential diagnosis a. Wrinkling skin syndrome i. A rare autosomal recessive disorder of the connective tissue ii. Wrinkled skin over abdomen and on the dorsum of the hands and feet
iii. Poor skin elasticity in affected areas iv. Increased palmar and plantar creases v. A prominent venous pattern on the chest vi. Mental retardation vii. Microcephaly viii. Hypotonia ix. Musculoskeletal abnormalities b. De Barsey syndrome i. Cutis laxa (wrinkled atrophic skin) ii. Retarded psychomotor development iii. Corneal clouding due to degeneration of the tunica elastica of the cornea iv. Intrauterine growth retardation v. Pseudoathetoid movement vi. Muscular hypotonia vii. Hypermobility of small joints c. Costello syndrome i. Nasal papillomata ii. Coarse facies iii. Mental retardation iv. Growth retardation v. Cutis laxa d. SCARF syndrome i. An X-linked recessive disorder ii. Skeletal abnormalities a) Craniostenosis b) Enamel hypoplasia, hypocalcification of the teeth c) Short sternum d) Pectus carinatum e) Abnormally shaped vertebrae f) Abnormal modeling of long tubular bones iii. Cutaneous abnormalities a) Cutis laxa b) Wide-spaced nipples c) Diastasis recti d) Umbilical hernia iv. Ambiguous genitalia a) Micropenis b) Perineal hypospadias v. Retardation: mild to moderate psychomotor retardation vi. Facial abnormalities a) Multiple hairwhorls b) Epicanthal folds c) Ptosis d) High and broad nasal root e) Low-set and posteriorly rotated ears f) Small chin
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Autosomal recessive cutis laxa i. Presence of a variety of hernias a) Femoral b) Inguinal c) Obturator d) Hiatal ii. Eventrations of the diaphragm
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iii. Rectal and uterine prolapse iv. Common intrathoracic abnormalities a) Hyperexpansion of the lungs b) Emphysema which may lead to cor pulmonale and death in childhood c) Upper airway obstruction caused by excessively lax vocal cords, leading to congestive heart failure d) Frequent peripheral pulmonary artery stenosis and aortic dilatation v. Diverticula involving the entire bowel but no functional significance vi. Diverticula of the urinary tract predisposing to infection or causing obstruction vii. Arteriographic changes a) Peripheral pulmonary stenosis b) Dilatation and tortuosity of the aorta c) A peculiar corkscrew appearance of the peripheral systemic arteries, similar to the arterial changes seen in Menkes syndrome b. X-linked recessive cutis laxa i. Occipital exostosis (horns) symmetrically located on each side of the foramen magnum ii. Short clavicles with a widened medullary cavity iii. Hammer-shaped distal extremities iv. Focal hyperostosis of the femora at sites of tendon and ligament insertion v. Carpal fusion involving capitate-hamate and trapezium-trapezoid coalescence (over 50%) vi. Deformation of humerus, radius, ulna, tibia, fibula (90%) vii. Osteoporosis (70%) viii. Narrowing of rib cage (65%) ix. Dislocation of radial head (40%) x. Mild platyspondyly xi. Coxa valga xii. Flattening of acetabular rooofs 2. Histopathological abnormality: fragmentation and paucity of elastic fibers in the skin 3. X-linked cutis laxa a. Non-molecular testing i. Low serum copper concentration ii. Low serum ceruloplasmin concentration iii. Copper transport studies in cultured fibroblasts: impaired cellular copper exodus demonstrated by increased cellular copper retention in pulsechase experiments with radiolabelled copper iv. Plasma and CSF catecholamine analysis: abnormal levels reflecting partial deficiency of dopamine-beta-hydroxylase, a copper-dependent enzyme critical for catecholamine biosynthesis v. Low activity of a copper-dependent enzyme, lysyl oxidase b. Molecular genetic testing i. Mutation analysis: multiplex PCR analysis, available on a clinical basis, to detect large ATP7A deletions ii. Sequence analysis: direct sequence analysis of the ATP7A coding region and flanking intron sequences, available on a clinical basis
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iii. Mutation scanning: heteroduplex analysis, available on a clinical basis, to detect small mutations
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal recessive cutis laxa: 25% ii. Autosomal dominant cutis laxa: not increased unless a parent is affected iii. X-linked recessive cutis laxa: a) When the mother is a carrier: 50% risk of brother will be affected and 50% of sisters carriers b) When mother is not a carrier: the recurrence risk is low but greater than that for the general population because the risk of germline mosaicism in mother is not known b. Patient’s offspring i. Autosomal recessive cutis laxa: not increased unless the spouse is a carrier or affected ii. Autosomal dominant cutis laxa: 50% iii. X-linked recessive cutis laxa: Males with occipital horn syndrome will pass the disease-causing gene to all of their daughters and none of their sons 2. Prenatal diagnosis a. DNA-based analysis on fetal DNA obtained from amniocentesis or CVS for the previously characterized disease-causing mutation b. Fetal sex determination for X-linked recessive cutis laxa (occipital horn syndrome) 3. Management a. Supportive therapy: antibiotic prophylaxis for bladder infection b. Surgery for bladder diverticula c. Plastic surgery to improve aging appearance i. Serial excisions of the skin ii. Blepharoplasty iii. Rhytidectomy iv. Rhinoplasty v. Shortening of the upper lip vi. Earlobe reduction vii. Neck lift viii. Correction of lower eyelid laxity, epiphora, and upper eyelid ptosis
REFERENCES Agha A, Sakati NO, Higginbottom MC, et al.: Two forms of cutis laxa presenting in the newborn period. Acta Paediatr Scand 67:775–780, 1978. Allanson J, Austin W, Hecht F: Congenital cutis laxa with retardation of growth and motor development: a recessive disorder of connective tissue with male lethality. Clin Genet 29:133–136, 1986. Andiran N, Sarikayalar F, Saraclar M, et al.: Autosomal recessive form of congenital cutis laxa: more than the clinical appearance. Pediatr Dermatol 19:412–414, 2002. Baldwin L, Kumrah L, Thoppuram P, et al.: Congenital cutis laxa (dermatochalasia) with cardiac valvular disease. Pediatr Dermatol 18:365–366, 2001. Banks ND, Redett RJ, Mofid MZ, et al.: Cutis laxa: clinical experience and outcomes. Plast Reconstr Surg 111:2434–2442; discussion 2443–2434, 2003. Beighton P: The dominant and recessive forms of cutis laxa. J Med Genet 9:216–221, 1972.
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Beighton P: Cutis laxa—a heterogeneous disorder. Birth Defects Orig Artic Ser 10:126–131, 1974. Beighton P, Bull JC, Edgerton MT: Plastic surgery in cutis laxa. Br J Plast Surg 23:285–290, 1970. Boente MDC, Winik BC, Asial RA: Wrinkly skin syndrome: ultrastructural alterations of the elastic fibers. Pediatr Dermatol 16:113–117, 1999. Brown FR, 3rd, Holbrook KA, Byers PH, et al.: Cutis laxa. Johns Hopkins Med J 150:148–153, 1982. Byers PH, Narayanan AS, Bornstein P, et al.: An X-linked form of cutis laxa due to deficiency of lysyl oxidase. Birth Defects Orig Artic Ser 12:293–298, 1976. Byers PH, Siegel RC, Holbrook KA, et al.: X-linked cutis laxa: defective cross-link formation in collagen due to decreased lysyl oxidase activity. N Engl J Med 303:61–65, 1980. Damkier A, Brandrup F, Starklint H: Cutis laxa: autosomal dominant inheritance in five generations. Clin Genet 39:321–329, 1991. Das S, Levinson B, Vulpe C, et al.: Similar splicing mutations of the Menkes/mottled copper-transporting ATPase-gene in occipital horn syndrome and the blotchy mouse. Am J Hum Genet 56:570–576, 1995. Davies SJ, Hughes HE: Costello syndrome: natural history and differential diagnosis of cutis laxa. J Med Genet 31:486–489, 1994. Di Ferrante N, Leachman RD, Angelini P, et al.: Lysyl oxidase deficiency in Ehlers-Danlos syndrome type V. Connect Tissue Res 3:49–53, 1975. Di Ferrante N, Leachman RD, Angelini P, et al.: Ehlers-Danlos type V (Xlinked form): a lysyl oxidase deficiency. Birth Defects Orig Artic Ser 11:31–37, 1975. Dingman RO, Grabb WC, Oneal RM: Cutis laxa congenita—generalized elastosis. Plast Reconstr Surg 44:431–435, 1969. Fitzsimmons JS, Fitzsimmons EM, Guibert PR, et al.: Variable clinical presentation of cutis laxa. Clin Genet 28:284–295, 1985. Goltz RW, Hult AM, Goldfarb M, et al.: Cutis laxa. A manifestation of generalized elastolysis. Arch Dermatol 92:373–387, 1965. Gorlin RJ, Cohen MM Jr: Craniofacial manifestations of Ehlers-Danlos syndromes, cutis laxa syndromes, and cutis laxa-like syndromes. Birth Defects Orig Artic Ser 25(4):39–71, 1990. Harris RB, Heaphy MR, Perry HO: Generalized elastolysis (cutis laxa). Am J Med 65:815–822, 1978.
Hashimoto K, Kanzaki T: Cutis laxa. Ultrastructural and biochemical studies. Arch Dermatol 111:861–873, 1975. Hurvitz SA, Baumgarten A, Goodman RM: The wrinkly skin syndrome: a report of a case and review of the literature. Clin Genet 38:307–313, 1990. Kaler SG: ATP7A-related copper transport disorders. Gene Reviews, 2003. http://www.genetests.org Khakoo A, Thomas R, Trompeter R, et al.: Congenital cutis laxa and lysyl oxidase deficiency. Clin Genet 51:109–114, 1997. Koppe R, Kaplan P, Hunter A, et al.: Ambiguous genitalia associated with skeletal abnormalities, cutis laxa, craniostenosis, psychomotor retardation, and facial abnormalities (SCARF syndrome). Am J Med Genet 34:305–312, 1989. Lally JF, Gohel VK, Dalinka MK, et al.: The roentgenographic manifestations of cutis laxa (generalized elastolysis). Radiology 113:605–606, 1974. Loeys B, Van Maldergem L, Mortier G, et al.: Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum Mol Genet 11:2113–2118, 2002. Markova D, Zou Y, Ringpfeil F, et al.: Genetic heterogeneity of cutis laxa: a heterozygous tandem duplication within the fibulin-5 (FBLN5) gene. Am J Hum Genet 72:998–1004, 2003. Mehregan AH, Lee SC, Nabai H: Cutis laxa (generalized elastolysis). A report of four cases with autopsy findings. J Cutan Pathol 5:116–126, 1978. Meine F, Grossman H, Forman W, et al.: The radiographic findings in congenital cutis laxa. Radiology 113:687–690, 1974. Nahas FX, Sterman S, Gemperli R, et al.: The role of plastic surgery in congenital cutis laxa: a 10-year follow-up. Plast Reconstr Surg 104:1174–1178, 1999. Patton MA, Tolmie J, Ruthnum P, et al.: Congenital cutis laxa with retardation of growth and development. J Med Genet 24:556–561, 1987. Strohecker B: Cutis laxa: etiology, pathophysiology, characteristics, and management. Plastic Surgical Nursing 15:201–203, 1995. Van Malfergem L, Varmos E, Liebaers, et al.: Severe congenital cutis laxa with pulmonary emphysema: a family with three affected sibs. Am J Med Genet 31:455–464, 1988. Zhang M-C, He L, Giro M, et al.: Cutis laxa arising from frameshift mutations in exon 30 of the elastin gene (ELN). J Biol Chem 274:981–986, 1999.
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Fig. 3. A 10-year-old girl with cutis laxa showing redundancy of the skin, sagging of the upper lids, short columella, long philtrum, and sagging skin folds over trunk.
Fig. 1. An infant with cutis laxa showing redundancy of skin folds and bilateral hernias.
Fig. 2. A young girl with cutis laxa showing redundancy of the skin folds, short columella, long philtrum, and sagging of the lower chin and prominent loose skin folds of the trunk.
Congenital Cytomegalovirus Infection Congenital cytomegalovirus infection is the most common congenital infection in neonates in the US, affecting approximately 0.5–1.5% of all live births and 30,000–40,000 newborns annually. Congenital infections result from transplacental transmission of cytomegalovirus (CMV).
8. Congenitally infected newborns: may shed the virus for many years 9. Perinatal CMV infection acquired during birth or from mother’s milk: not associated with newborn illness or CNS sequelae, except perhaps in very preterm newborns who have very low levels of passively acquired CMV antibody at the time of infection
GENETICS/BASIC DEFECTS 1. Human cytomegalovirus a. A DNA virus belonging to the herpesvirus group (herpes simplex, varicella zoster, Epsein-Barr) b. Ability of the virus i. To destroy host cells (lytic infection) ii. To infect a wide range of cells and tissues iii. To evade and interfere with host defense mechanisms iv. To persist indefinitely in the host v. To infect and destroy cells during productive infection (with release of progeny virus) 2. Transmission of CMV a. Horizontal transmission: close intimate contact with another person shedding the virus in body fluids (saliva, blood, cervical secretions, semen, urine, or respiratory droplets) b. Vertical transmission: from mother to infant i. In utero by transplacental passage of maternal bloodborne virus ii. At birth by passage through an infected maternal genital tract iii. Postnatally by ingestion of CMV-positive human milk from seropositive mothers c. Infected organ or bone marrow transplantation d. Infected blood transfusion from CMV-seropositive donors 3. Primary sources of CMV infection for women of childbearing age a. Young children b. Sexual contacts 4. Types of CMV infection a. Primary (first experience) b. Secondary (recurrent) i. Reactivation of the original endogenous CMV ii. Reinfection with a new strain of CMV c. Latent infection: sites at kidney, bone marrow, monocytes 5. The most common vertically transmitted viral infection from mother to fetus in pregnancy a. Recurrent infection: 1% risk of vertical transmission b. Primary infection: 1–4% risk of vertical transmission 6. Symptomatic congenital infections observed primarily among women undergoing a primary infection 7. Greatest risk occurring with infection during the first 22 weeks of gestation
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1. Symptomatic at birth in 5–10% of congenital CMV infections a. Approximately 20% of these will die b. 90% of survivors will develop major neurological sequelae 2. Asymptomatic or “silent” congenital infections at birth in vast majority (85–90%) of cases. 10–15% of the asymptomatic newborns will be afflicted by late sequelae such as mental retardation, deafness or hearing defects, usually during the first 2 years of life 3. Nonneurologic symptoms at birth a. Petechiae (most common nonneurologic symptom) b. Thrombocytopenia c. Purpura d. Ecchymoses e. Splenomegaly f. Hepatomegaly g. Jaundice h. Intrauterine growth retardation i. Chorioretinitis j. Pneumonitis k. Anemia l. Nonimmune hydrops 4. Neurologic symptoms at birth a. Hypotonia b. Lethargy c. Jitteriness d. Split sutures e. Immature primitive reflexes f. Feeding difficulties g. Microcephaly: the most specific predictor of mental retardation and major motor disability h. Seizures 5. Eye manifestations a. Chorioretinitis resulting in a chorioretinal scar b. Corneal opacities c. Bilateral anterior polar cataracts d. Optic nerve hypoplasia and optic nerve coloboma e. Cyclopia and anophthalmia 6. Later neurologic symptoms a. Sensorineural hearing loss b. Learning disability c. Mental retardation d. Cerebral palsy
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7. Prognosis a. Neonatal clinical abnormalities expected to resolve spontaneously within weeks, except for those involving the CNS and hearing b. A leading cause of mental retardation and sensory impairment (50–90% of symptomatic newborns) and sensorineural hearing loss (7–15% of asymptomatic infants) c. An important cause of cerebral palsy and retinal damage 8. Maternal primary CMV infection a. Asymptomatic: vast majority of pregnant women b. Symptomatic (mononucleosis-like syndrome) in approximately 10% of infected pregnant patients i. Fever ii. Fatigue/malaise iii. Myalgia iv. Pharyngitis v. Cough vi. Nausea vii. Headache
DIAGNOSTIC INVESTIGATIONS 1. Children with symptomatic congenital CMV infection a. Cytomegalic inclusion bodies in the urine b. Elevated alanine aminotransferase (ALT >80 IU/mL) c. Thrombocytopenia (<100,000/mcL) d. Conjugated hyperbilirubinemia (direct bilirubin >2 mg/dL) e. Anemia f. Elevated CSF protein (>120 mg/dL) g. Abnormal CT scan (most common neurologic sign and the most sensitive predictor for mental retardation) i. White matter lucencies ii. Ventriculomegaly iii. Intracranial calcifications (usually periventricular) iv. Destructive encephalopathy v. Brain atrophy vi. Neuronal migration disorders 2. Evidence of infection with CMV a. 4-fold rise in antiCMV IgG titers b. Seroconversion from negative to positive c. Sensitivity of the CMV IgM assays (50–90%). The IgM titers may not become positive during acute infection 3. Viral isolation a. The most sensitive method to diagnose CMV infection b. Culture of CMV from virtually all body fluids, including saliva and urine of the newborn, semen, and cervicovaginal secretions c. Detection of CMV within the first 3 weeks of life: considered proof of congenital CMV infection 4. Identification of CMV DNA through PCR (sensitivity of 75–100%)
GENETIC COUNSELING 1. Recurrence risk a. Preconceptional immunity to CMV provides substantial protection against intrauterine transmission and severe fetal infection
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b. Presence of maternal humoral antibody: conferring no fetal protection in subsequent reinfection or reactivation 2. Prenatal diagnosis a. Prenatal ultrasonography i. Intrauterine growth retardation ii. Microcephaly iii. Ventriculomegaly iv. Periventricular calcifications v. Intrahepatic calcifications vi. Nonimmune hydrops vii. Fetal Ascites viii. Pericardial effusion ix. Hepatosplenomegaly x. Echogenic bowel xi. Cardiomegaly xii. Oligohydramnios xiii. Placentomegaly b. Prenatal diagnosis of congenital CMV infection by combined detection of CMV-DNA and CMV-IgM in fetal blood or by combined testing of AF and fetal blood for CMV-DNA and IgM antibodies (sensitivity of 100%) c. Negative results of CMV culture or PCR in the amniotic fluid cannot formally exclude intra-uterine infection d. Prenatal diagnosis of CMV infection remains a ‘longstanding problem still seeking a solution’ as long as no assistance (treatment or prevention) can be offered to the pregnant women 3. Management a. Prevention i. Complicated because both primary and secondary maternal infections give rise to disease in the offspring and absence of characteristic symptoms in CMV-infected mothers excludes clinical recognition of at-risk pregnancies ii. Routine screening of pregnant patients for CMV status: not currently recommended because no effective antiviral therapy is available during gestation and also there is no means to predict the outcome in an infected fetus iii. Risk to CMV infection for women in high-risk environments (day-care centers, nurseries, elementary schools, or health care facilities) iv. Strict hygiene practices for seronegative women to reduce the risk for the infection b. No pharmaceutic regimens available for treatment of maternal and fetal CMV infections. Treatment with antiviral agents (ganciclovir, foscarnet) is limited to severe infections (CMV retinitis) in immunocomromised patients and not currently used in pregnancy c. A live attenuated CMV vaccine i. Live vaccines may bear a serious risk when transmittable to the fetus ii. Concerns for reactivation (reinfection), viral shedding in breast milk and cervix, and oncogenesis
REFERENCES Ahlfors K, Ivarsson S-A, Harris S: Report on a long-term study of maternal and congenital cytomegalovirus infection in Sweden. Review of prospective studies available in the literature. Scand J Infect Dis 31:443–457, 1999.
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American Academy of Pediatrics Report of the Committee on Infectious Diseases: Toxoplasmosis. Red Book 2000, pp 583–586. Bale JF Jr, Blackman JA, Sato Y: Outcome in children with symptomatic congenital cytomegalovirus infection. J Child Neurol 5:131–136, 1990. Beksaç MS, Saygan-Karamürsel B, Ustaçelebi S, et al.: Prenatal diagnosis of intrauterine cytomegalovirus infection in a fetus with non-immune Hydrops fetalis. Acta Obstet Gynecol Scand 80:762–765, 2001. Berenberg W, Nankervis G: Long-term follow-up of congenital cytomegalovirus disease of infancy. Pediatrics 46:403–410, 1970. Bodéus M, Hubinont C, Bernard P, et al.: Prenatal diagnosis of human cytomegalovirus by culture and polymerase chain reaction: 98 pregnancies leading to congenital infection. Prenat Diagn 19:314–317, 1999. Boppana SB, Pass RF, Britt WJ, et al.: Symptomatic congenital cytomegalovirus infection: neonatal morbidity and mortality. Pediatr Infect Dis J 11:93–99, 1992. Boppana SB, Fowler KB, Vaid Y, et al.: Neuroradiographic findings in the newborn period and long-term outcome in children with symptomatic congenital cytomegalovirus infection. Pediatrics 99:409–414, 1997. Boppana SB, Fowler KB, Britt WJ, et al.: Symptomatic congenital cytomegalovirus infection in infants born to mothers with preexisting immunity to cytomegalovirus. Pediatrics 104:55–60, 1999. Brown HL, Abernathy MP: Cytomegalovirus infection. Semin Perinatol 22: 260–266, 1998. Byrne PJ, Silver MM, Gilbert JM, et al.: Cyclopia and congenital cytomegalovirus infection. Am J Med Genet 28:61–65, 1987. Casteels A, Naessens A, Gordts F, et al.: Neonatal screening for congenital cytomegalovirus infections. J Perinat Med 27:116–121, 1999. Cline MK, Bailey-Dorton C, Cayelli M: Maternal infections. Diagnosis and management. Primary Care: Clin Offic Pract 27:13–33, 2000. Coats DK, Demmler GJ, Paysse EA, et al.: Ophthalmologic findings in children with congenital cytomegalovirus infection. Am Assoc Pediatr Ophthalmol Strabism 4:110–116, 2000. Conboy TJ, Pass RF, Stagno S, et al.: Early clinical manifestations and intellectual outcome in children with symptomatic congenital cytomegalovirus infection. J Pediatr 111:342–348, 1987. Demmler GJ. Infectious Disease Society of America and Centers for Disease Control: summary of a workshop on surveillance for congenital cytomegalovirus disease. Rev Infect Dis 13:315–329, 1991. Demmler GJ: Congenital cytomegalovirus infection and disease. Adv Pediatr Infect Dis 11:135–162, 1996. Enders G, Bäder U, Lindemann L, et al.: Prenatal diagnosis of congenital cytomegalovirus infection in 189 pregnancies with known outcome. Prenat Diagn 21:362–377, 2001. Fowler KB, Stagno S, pass RF, et al.: The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N Enl J Med 326:663–667, 1992. Fowler KB, McCollister FP, Dahle AJ, et al.: Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus infection. J Pediatr 130:624–630, 1997. Gaytant MA, Steegers EAP, Semmekrot BA, et al.: Congenital cytomegalovirus infection: review of the epidemiology and outcome. Obstet Gynecol Surv 57:245–256, 2002. Guerra B, Lazzarotto T, Quarta S, et al.: Prenatal diagnosis of symptomatic congenital cytomegalovirus infection. Am J Obstet Gynecol 183:476–482, 2000.
Guyton TB, Ehrlich F, Blanc WA, et al.: New observations in generalized cytomegalic-inclusion disease of the newborn: report of a case with chorioretinitis. N Engl J Med 257:803–807, 1957. Hicks T, Fowler K, Richardson M, et al.: Congenital cytomegalovirus infection and neonatal auditory screening. J Pediatr 123:779–782, 1993. Istas AS, Demmler GJ, Dobbins JG, and the National Congenital Cytomegalovirus Disease Registry Collaborating Group Surveillance for congenital cytomegalovirus disease: a report from the National Congenital Cytomegalovirus Disease registry. Clin Infect Dis 20:665–670, 1995. Kuhlmann RS, Autry AM: An approach to nonbacterial infections in pregnancy. Clin Fam Pract 3(2): June 2001. Lazzarotto T, Varani S, Guerra B, et al.: Prenatal indicators of congenital cytomegalovirus infection. J Pediatr 137:90–95, 2000. Liesnard C, Donner C, Brancart F, et al.: Prenatal diagnosis of congenital cytomegalovirus infection: prospective study of 237 pregnancies at risk. Obstet Gynecol 95:881–888, 2000. McCracken GH Jr, Shinefield HR, Cobb K, et al.: Congenital cytomegalovirus infection disease: a longitudinal study of 20 patients. Am J Dis Child 117:522–539, 1969. Metz MB: Eye manifestations of intrauterine infections. Ophthalmol Clin N Am 14:521–531, 2001. Miklos G, Orban T: Ophthalmic lesions due to cytomegalic inclusion disease. Ophthalmologica 148:98–106, 1964. Nelson CT, Demmler GJ, Istas AS, et al.: Early prediction of neurodevelopmental outcome in symptomatic congenital cytomegalovirus (CMV) infection. Pediatr Res 39:180A, 1993. Noyola DE, Demmler GJ, Griesser C, et al.: Early predictors of neurodevelopmental outcome in symptomatic . J Pediatr 138:325–331, 2001. Pass RF: Cytomegalovirus infection. Pediatrics in Review 23:163–169, 2002. Pass RF, Stagno S, Myers GJ, Alford CA: Outcome of symptomatic congenital cytomegalovirus infection: results of long-term longitudinal follow-up. Pediatrics 66:758–762, 1980. Perlman JM, Argyle C: Lethal cytomegalovirus infection in preterm infants: Clinical, radiological, and neuropathological findings. Ann Neurol 31:64–68, 1992. Ramsy MEB, Miller E, Peckhan CS: Outcome of confirmed symptomatic congenital cytomegalovirus infection. Arch Dis Child 66:1068–1069, 1991. Roach ES, Sumner TE, Volverg FM, et al.: Radiological case of the month. Am J Dis Child 137:799, 1983. Stagno S: Cytomegalovirus. In Remington JS, Klein JO (eds): Infectious Diseases of the Fetus & newborn Infant. Philadelphia, WB Saunders, 312–353, 1995. Stagno S, Pass RF, Dworsky ME, et al.: Congenital cytomegalovirus infection: The relative importance of primary and recurrent maternal infection. N Engl J Med 306:945–949, 1982. Stagno S, Pass RF, Cloud G, et al.: Primary cytomegalovirus infection in pregnancy. Incidence, transmission to fetus and clinical outcome. JAMA 256:1904–1908, 1986. Williamson WD, Desmond MM, LaFevers N, et al.: Symptomatic congenital cytomegalovirus infection, disorders of language, learning, and hearing. Am J Dis Child 136:902–905, 1982. Yow MD, Williamson DW, Leeds LJ, et al.: Epidemiologic characteristics of cytomegalovirus infection in mothers and their infants. Am J Obstet Gynecol 158:1189–1195, 1988.
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Fig. 2. Photomicrograph of the kidney (macerated fetus, 16 weeks gestation). Even though the tissue is macerated, many cytomegalic inclusion bodies are demonstrable. Coronal section of the brain (frontal lobe) showing ventricular hemorrhage and focal encephalomalacia (chalky white discoloration) due to cytomegalovirus infection.
Fig. 1. A neonate with blue berry muffin skin lesions (generalized purpura) due to cytomegalovirus infection. He died 20 hours after birth. CMV inclusions were noted in kidneys, lungs, liver, pancreas, thyroid, brain and eyes, and also in the urine. Photomicrograph of the kidney shows many tubular epithelial cells containing large cytomegalic inclusion bodies.
Fig. 3. Photomicrograph of premature lung of a different patient showing a single large cytomegalic inclusion body.
Fig. 4. One cytomegalic inclusion body in the urine sediment in another patient.
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Fig. 7. Skull radiographs of another patient with congenital CMV infection showing microcephaly and typical intracranial ventricular subependymal calcifications.
Fig. 5. A macerated stillborn with hydrops fetalis from congenital CMV infection.
Fig. 6. An infant with CNS involvement and chorioretinitis from congenital CMV infection.
Fig. 8. An adult with congenital CMV infection showing mental retardation and intracranial calcifications by CT scan.
Congenital Generalized Lipodystrophy Congenital generalized lipodystrophy (CGL), also called Berardinelli-Seip syndrome (BSCL), is an extremely rare genetic disorder characterized by extreme paucity of adipose tissue from birth, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis, and early onset of diabetes. Its prevalence is estimated to be less than 1 in 12 million people.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Existence of two loci in a gene for congenital generalized lipodystrophy (Berardinelli-Seip congenital lipodystrophy) a. Congenital generalized lipodystrophy type 1 i. Identification of the aberrant gene, 1-acylglycerol3-phosphate O-acyltransferase 2 (AGPAT2) in patients from several pedigrees in which the lipodystrophy was linked to chromosome 9q34 ii. Several homozygous or compound heterozygous mutations in the AGPAT2 gene identified in affected patients iii. AGPAT2 (1-acylglycerol-3-phosphate O-acyltransferase 2) a) Encodes the enzyme AGPAT2 that is responsible for the production of an important intermediate in the synthesis of triglycerides or fat b) Mutations of AGPAT2: may cause CGL by inhibiting the fat synthesis and storage in adipocytes (fat cells) b. Congenital generalized lipodystrophy type 2 i. Identification of another disease locus (BSCL2) which is mapped to chromosome 11q13 ii. Identification of mutations of BSCL2 gene in all families linked to 11q13 iii. BSCL2 (Seipin) gene a) Highly expressive in the brain and testis b) Encodes a protein whose function remains unknown 3. Several other genes are responsible for different types of inherited lipodystrophies: a. Lamin A/C (LMNA) gene in familial partial lipodystrophy Dunnigan variety (autosomal dominant familial partial lipodystrophy) mapped to 1q21–22 b. PPAR-γ (peroxisome proliferator-activated receptor-γ) gene in autosomal dominant familial partial lipodystrophy 4. Cause a. CGL is caused by mutations in BSCL2, AGPAT2, and other as yet unmapped genes b. This genetic heterogeneity is also accompanied by phenotypic heterogeneity 5. Proposed pathogenesis: genetic defect results in poor growth and development of metabolically active adipose tissue with preservation of mechanical disposition of the adipose tissue
CLINICAL FEATURES 1. Extreme paucity (near complete absence) of adipose tissue from birth, resulting in a generalized muscular appearance (an essential diagnostic criterion) 2. Characteristic features during early childhood a. Accerated linear growth b. Voracious appetite c. Increased basal metabolic rate (hypermetabolism) d. Advanced bone age 3. Acanthosis nigricans (dark velvety pigmentation of the skin) a. Common occurrence b. Usually appears by age 8 c. May be widespread, involving the neck, axillae, groin, and trunk d. Can eventually cause skin tag formation 4. Umbilical hernia: common 5. Hepatosplenomegaly a. Almost universal presence of hepatomegaly from fatty liver, ultimately leading to cirrhosis b. Splenomegaly common 6. Acromegaloid appearance a. Enlarged hands and feet b. Prominent mandible 7. Premature thelarche and adrenarche 8. Affected women a. Virilization (clitoromegaly and hirsutism) b. Oligo-amenorrhea c. Polycystic ovaries in postpubertal female patients d. Successful pregnancy rare 9. Affected males with normal reproductive potential 10. Multiple focal lytic lesions in the appendicular bones in postpubertal patients 11. Severe fasting and postprandial hyperinsulinemia and marked hypertriglyceridemia resulting in chylomicronemia, eruptive xanthomas, acute pancreatitis and predisposing to premature atherosclerosis 12. Abnormal glucose intolerance and diabetes mellitus develop during puberty or early adolescence. Diabetic nephropathy and nephropathy may develop during adulthood 13. Rare hypertrophic cardiomyopathy 14. Mental retardation in a few patients
DIAGNOSTIC INVESTIGATIONS
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1. Clinical laboratory work-up a. Marked insulin resistance b. Severe hyperinsulinemia c. Nonketotic insulin-resistant diabetes mellitus d. Hypertriglyceridemia with low serum high-density lipoprotein (HDL) and cholesterol concentration e. Chylomicronemia f. Markedly low plasma leptin levels
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2. MRI (confirmatory) and necropsy a. An extreme paucity of subcutaneous and intermuscular fat i. Intraabdominal sites (omental, mesenteric, and retroperitoneal areas) ii. Thoracic cavity (retrosternal, epicardial, and superior mediastinal areas) iii. Bone marrow iv. Parathyroid glands b. In contrast, a peculiar distribution of normal amounts of adipose tissue over whole body i. Orbits ii. Crista galli iii. Palms iv. Soles v. Scalp vi. Perineum vii. Vulva viii. Epidural area ix. Pericalyceal regions of the kidney x. Periarticular regions (knee, hip, shoulder, elbow, wrist, and ankle joints) xi. Some fat localizes in breasts, tongue, and buccal region 3. Skeletal radiography: multiple focal lytic lesions appear in appendicular skeletons after puberty 4. Echocardiography to detect hypertrophic cardiomyopathy 5. Molecular genetic analysis of mutations in BSCL2 (Seipin) gene and AGPAT2 gene
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased unless the spouse is a carrier or affected 2. Prenatal diagnosis: not reported 3. Management (Garg, 2004) a. Cosmetic management i. Facial reconstruction with free flaps, transposition of facial muscle, and silicone or other implants in the cheeks ii. Liposuction or lipectomy for removal of excessive facial or neck fat iii. Etretinate and fish oil may improve acanthosis in some patients b. Diet i. Avoidance of weight gain to reduce the risk of developing diabetes and dyslipidemia ii. Need sufficient energy to allow for growth and maturation in childhood c. Hypoglycemic drugs i. Require rigorous glycemic control ii. Require large dose of insulin to control hyperglycemia and prevent long-term complications of diabetes, such as nephropathy, retinopathy, neuropathy, and possibly atherosclerosis d. Lipid-lowering drugs i. Fibrates and, if needed, n-3 polyunstaurated fatty acids
ii. Avoid estrogens for oral contraception or postmenopausal hormone replacement therapy in women because it can accentuate hypertriglyceridemia e. Clinical trial of adipocytes hormone leptin-replacement therapy has shown a marked reduction in the blood glucose and lipids and reverse hepatic steatosis, allowing discontinuation of several medications
REFERENCES Afifi AK, Mire-Salman J, Najjar S: The myopathology of congenital generalized lipodystrophy light and electron microscopic observations. Johns Hopkins Med J (Suppl) 139:61–68, 1976. Agarwal AK, Arioglu E, De Almeida S, et al.: AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet 31:21–23, 2002. Agarwal AK, Barnes RI, Garg A: Genetic basis of congenital generalized lipodystrophy. Int J Obes Relat Metab Disord 2003. Agarwal AK, Garg A: Congenital generalized lipodystrophy: significance of triglyceride biosynthetic pathways. Trends Endocrinol Metab 14: 214–221, 2003. Agarwal AK, Simha V, Oral EA, et al.: Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab 88:4840–4847, 2003. Berardinelli W: An undiagnosed endocrinometabolic syndrome: report of 2 cases. J Clin Endocrinol Metab 14:193–204, 1954. Brunzell JD, Shankle SW, Bethune JE: Congenital generalized lipodystrophy accompanied by cystic angiomatosis. Ann Intern Med 69:501–516, 1968. Cao H, Hegele R: Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet 9:109–112, 2000. Chandalia M, Garg A, Vuitch F, et al.: Postmortem findings in congenital generalized lipodystrophy. J Clin Endocrinol Metab 80:3077–3081, 1995. Downes GB, Copeland NG, Jenkins NA, et al.: Structure and mapping of the G protein gamma3 subunit gene and divergently transcribed novel gene, gng3lg. Genomics 53:220–230, 1998. Fleckenstein JL, Garg A, Bonte FJ, et al.: The skeleton in congenital generalized lipodystrophy: evaluation using whole-body radiographic surveys, magnetic resonance imaging and technetium-99m bone scintigraphy. Skel Radiol 21:381–386, 1992. Garg A: Peculiar distribution of adipose tissue in patients with congenital generalized lipodystrophy. J Clin Endocrinol Metab 75:358–361, 1992. Garg A: Lipodystrophies. Am J Med 108:143–152, 2000. Garg A: Acquired and inherited lipodystrophies. N Engl J Med 350:1220–1234, 2004. Garg A, Wilson R, Barnes R, et al.: A gene for congenital generalized lipodystrophy maps to human chromosome 9q34. J Clin Endocrinol Metab 84:3390–3394, 1999. Gomes KB, Fernandes AP, Ferreira ACS, et al.: Mutations in the Seipin and AGPAT2 genes clustering in consanguineous families with BerardinelliSeip congenital lipodystrophy from two separate geographical regions of Brazil. J Clin Endocrinol Metab 89:357–361, 2004. Guell-Gonzales JR, De Acosta OM, Alavez-Matin E, et al.: Bone lesions in congenital generalized lipodystrophy. Lancet 2:104–105, 1971. Heathcote K, Rajab A, Magré J, et al.: Molecular analysis of Berardinelli-Seip congenital lipodystrophy in Oman. Evidence for multiple loci. Diabetes 51:1291–1293, 2002. Helm TN: Lipodystrophy. Cutis 67:163–164, 2001. Huseman CA, Johanson AJ, Varma MM, et al.: Congenital lipodystrophy. II. Association with polycystic ovarian disease. J Pediatr 95:72–74, 1979. Magré J, Delepine M, Khallouf E, et al.: Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 28:365–370, 2001. Magré J, Delépine M, Van Maldergem L, et al.: Prevalence of mutations in AGPAT2 among human lipodystrophies. Diabetes 52:1573–1578, 2003. McLean RH, Hoefnagel D: Partial lipodystrophy and familiar C3 deficiency. Hum Hered 30:149–154, 1980. Oral EA, Simha V, Ruiz E, et al.: Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570–578, 2002.
CONGENITAL GENERALIZED LIPODYSTROPHY Petersen KF, Oral EA, Dufour S, et al.: Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 109:1345–1350, 2002. Premkumar A, Chow C, Bhandarkar P, et al.: Lipoatrophic-lipodystrophic syndromes. AJR 178:311–318, 2002. Rajab A, Heathcote K, Joshi S, et al.: Heterogeneity for congenital generalized lipodystrophy in seventeen patients from Oman. Am J Med Genet 110:219–225, 2002. Reed WB, Dexter R, Corley C, et al.: Congenital lipodystrophic diabetes with acanthosis nigricans. Arch Dermatol 91:326–334, 1965. Rheuban KS, Blizzard RM, Parker MA, et al.: Hypertrophic cardiomyopathy in total lipodystrophy. J Pediatr 109:301–302, 1986. Savage DB, O’Rahilly S: Leptin: a novel therapeutic role in lipodystrophy. J Clin Invest 109:1285–1286, 2002. Seip M: Lipodystrophy and gigantism with associated endocrine manifestations: a new diencephalic syndrome? Acta Paediatr Scand 48:555–574, 1959.
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Seip M, Tryqstad O: Generalised lipodystrophy. Arch Dis Child 38: 447–453, 1963. Seip M, Trygstad O: Generalized lipodystrophy, congenital and acquired (lipoatrophy). Acta Paediatr Suppl 413:2–28, 1996. Senior B, Gellis SS: Syndromes of total lipodystrophy and of partial lipodystrophy. Pediatrics 33:593–612, 1964. Shackleton S. Lloyd DJ, Jackson SNJ: LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet 24:153–156, 2000. Van Maldergem L, Magré J, Khallouf TE, et al.: Genotype–phenotype relationships in Berardinelli-Seip congenital lipodystrophy. J Med Genet 39:722–733, 2002. Westvik J: Radiological features in generalized lipodystrophy. Acta Paediatr (Suppl) 413:44–51, 1996. Wilson TA, Alford BA, Morris L: Cerebral computed tomography in lipodystrophy. Arch Neurol 39:733, 1982.
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Fig. 1. An infant with congenital generalized lipodystrophy showing extreme paucity (near complete absence) of adipose tissue from birth, resulting in a generalized prominent muscular appearance
Congenital Hydrocephalus Hydrocephalus is one of the most common CNS developmental disorders. The incidence of congenital hydrocephalus is estimated as 3 per 1000 live births. Hydrocephalus is defined as an increase in the cerebral spinal fluid (CSF) volume within the ventricular system independent of the actual head circumference.
GENETICS/BASIC DEFECTS 1. Physiology of CSF production and absorption a. Production of CSF: by choroid plexus of lateral ventricles b. Pathway of CSF flow i. From lateral ventricles to third ventricle through foramen of Monro ii. From third ventricle to fourth ventricle through aqueduct of Sylvius iii. Out of the ventricular system: from fourth ventricle to spinal subarachnoid spaces through foramen of Magendie or to the basal cisterns through two lateral foramina of Luschka c. Site of CSF resorption into venous system: primarily through superior sagittal sinus via arachnoid granulations 2. Types and causes of hydrocephalus a. Overproduction of CSF: usually caused by choroid plexus tumors (very rare) b. Noncommunicating hydrocephalus i. Mechanical obstruction within the ventricular system causing impaired CSF absorption a) Foramen of Monro b) Aqueduct of Sylvius c) The fourth ventricle and its outlet channels ii. Causes a) Tumors b) Cysts c) Inflammatory scarring d) Intraventricular hemorrhage e) Rarely genetic disorders c. Communicating hydrocephalus i. Obstruction distally at the arachnoid granulations causing impaired absorption into blood stream ii. Causes a) Meningitis b) Trauma c) Intraventricular hemorrhage 3. Etiology of congenital hydrocephalus a. Tumors blocking CSF pathway i. Benign tumors such as choroid plexus papilloma ii. Malignant tumors b. CNS malformations/syndromes i. Congenital atresia of the foramina of Monro, Magendie or Luschka ii. Dandy-Walker syndrome 221
a) b) c) d)
Atresia of the foramina of the 4th ventricle Dilation of 4th ventricle Extreme Dolichocephaly Sac formation at the caudal end of the cerebellum filling the posterior cranial fossa iii. Aqueductal stenosis iv. X-linked hydrocephalus: Bickers-Adams syndrome characterized by: a) Stenosis of the aqueduct of Sylvius b) Severe mental retardation c) An adduction-flexion deformity of the thumb v. Chiari II malformation vi. Cerebellar agenesis vii. Neural tube defects a) Meningomyelocele b) Encephalocele viii. Other Mendelian conditions with congenital hydrocephalus a) Walker-Warburg syndrome b) Hydrolethalus syndrome c) Meckel syndrome d) Smith-Lemli-Opitz syndrome c. Chromosome abnormalities i. Trisomy 13 ii. Trisomy 18 iii. Trisomy 9 and 9p (mosaic) iv. Triploidy v. Other aneuploidies d. Skeletal dysplasias i. Achondroplasia ii. Craniosynostosis syndromes such as Crouzon syndrome or Apert syndrome iii. Fanconi anemia iv. Hurler or Hunter syndromes e. Infections i. Congenital CMV infection ii. Congenital toxoplasmosis iii. Congenital rubella infections iv. Congenital syphilis v. Meningitis vi. Ventriculitis vii. Abscess f. Vascular malformation g. In utero intraventricular hemorrhage h. Birth trauma i. Destructive lesions i. Hydranencephaly ii. Porencephaly iii. Perinatal leukomalacia 4. Familial (X-linked) aqueductal stenosis (HSAS: hydrocephalus-stenosis of the aqueduct of Sylvius sequence) a. X-linked recessive inheritance b. Linked to chromosome Xq28
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c. Mutations in L1-CAM, the major gene for X-linked hydrocephalus (accounting for 7–27% of all male cases) d. L1-CAM, a neuronal surface glycoprotein, has been implicated in neuronal migration and axon fasciculation 5. Traits known to be due to allelic mutations of L1-CAM a. HSAS b. MASA i. Mental retardation ii. Aphasia iii. Shuffling gait iv. Adducted thumbs c. SP1 (complicated spastic paraparesis, type 1) d. MR-CT (mental retardation-clasped thumbs) e. ACC-DCC (agenesis or dysgenesis of the corpus callosum) 6. Pathogenesis of hydrocephalus-induced brain dysfunction: complex a. Chronic ischemia in white matter related to changes in intracranial pressure and in the vasculature b. Physical damage to periventricular axons with disconnection of neurons c. Alterations in the extracellular chemical environment of neurons
CLINICAL FEATURES 1. Children <2 years a. Relatively benign course because infants can expand their cranium b. Early signs i. Increased head circumference (macrocephaly) ii. Full anterior fontanelle iii. Split cranial sutures iv. Prominent scalp veins v. Poor feeding vi. Vomiting vii. Irritability viii. Reduced activity ix. Delay or loss of developmental milestones x. Hypertonia xi. Hyperreflexia c. Late signs i. Lethargy ii. Sixth cranial nerve palsy iii. Limitation of upgaze resulting in a chronic downward deviation of the eyes (sunsetting sign) 2. Children >2 years a. Symptoms and signs more related to increased intracranial pressure due to inability of cranium to expand sufficiently to offset the mounting volume of CSF b. Headaches c. Nausea d. Vomiting e. Lethargy f. Loss of milestones g. School performance and behavioral change h. Sunsetting of the eyes i. Sixth cranial nerve palsy j. Papilledema
3. Natural history of untreated childhood hydrocephalus: poor. Handicaps resulting directly from hydrocephalus include the following: a. Disturbances in motor abilities, particularly gait b. Impaired cognitive development c. Hypothalamic dysfunction with delayed growth and short stature 4. X-linked neurological syndromes a. HSAS (hydrocephalus-stenosis of the aqueduct of Sylvius sequence) i. Hydrocephalus ii. Macrocephaly iii. Adducted thumbs iv. Spasticity v. Agenesis of the corpus callosum vi. Mental retardation b. MASA syndrome i. Mental retardation ii. Aphasia iii. Shuffling gait iv. Adducted thumbs v. Hydrocephalus
DIAGNOSTIC INVESTIGATIONS 1. Fundoscopic examination a. Bilateral papilledema secondary to high intracranial pressure b. Normal finding in some cases of acute hydrocephalus 2. Lumbar puncture for measuring intracranial pressure a. Avoid if an increase in intracranial pressure is suspected due to obstruction since relief of pressure may cause herniation of the brainstem b. Perform only after imaging studies ruling out an obstruction 3. TORCH titers on the infant and mother if intrauterine infection is suspected 4. Chromosome analysis in cases of associated multiple congenital anomalies 5. Cranial sonography (provided anterior fontanelle is still open) a. Ventriculomegaly b. Intraventricular hemorrhage 6. CT scans a. Ventriculomegaly b. Cerebral edema c. Mass lesions i. Colloid cyst of the third ventricle ii. Thalamic tumor iii. Pontine tumor 7. MRI a. Ventriculomegaly b. Mass lesions c. Associated brain anomalies i. Agenesis of the corpus callosum ii. Chiari malformations iii. Disorders of neuronal migration iv. Vascular malformations 8. Molecular genetic diagnosis to identify L1CAM mutations, identified in 22.4% (15/67) of sporadic cases of clinically or prenatally suspected L1-disease
CONGENITAL HYDROCEPHALUS
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Sporadic: low (4%) ii. Multifactorial trait (e.g., neural tube defect or in female infants with congenital hydrocephalus due to stenosis of the aqueduct of Sylvius): low recurrence risk (5%) for subsequent sibling; 10% risk if there are two affected siblings iii. Autosomal recessive traits (e.g., Dandy-Walker syndrome): 25% affected; 50% carriers; 25% normal iv. X-linked hydrocephalus: 50% of brothers affected and 50% of sisters carriers if the mother is a carrier; negligible in males with “sporadic” hydrocephalus representing a new X-linked mutation b. Patient’s offspring i. Sporadic: low (4%) ii. Multifactorial trait: 3–4.5% recurrence risk iii. Autosomal recessive traits: not increased unless the spouse is a carrier or affected iv. X-linked hydrocephalus: all daughters will be carriers in case of an affected father 2. Prenatal diagnosis a. Ultrasonography i. Fetal ventriculomegaly ii. Additional CNS malformations iii. Extracerebral malformations b. Sonographic findings in HSAS or MASA syndromes i. Male fetus ii. Hydrocephalus iii. Hypoplasia or agenesis of the corpus callosum iv. Bilateral adducted thumbs c. Amniocentesis i. α-fetoprotein and cholinesterase determination from amniotic fluid for neural tube defects ii. Chromosome analysis for suspected chromosomal disorder d. Molecular genetic diagnosis i. DNA diagnosis often requested in families with ‘isolated’ hydrocephalus case due to high rate of de novo mutations, small family size, and the improved sensitivity of prenatal ultrasound scanning ii. Molecular diagnosis of prenatally suspected L1 spectrum disorders, even in cases without positive family history 3. Management a. Folic acid intake before and during the first trimester reduces the incidence of neural tube defects, thereby the incidence of hydrocephalus b. Shunting CSF from the ventricles i. Ventriculoperitoneal shunting (VP) devices with pressure-controlled valves under the scalp close to the burr hole ii. Ventriculopleural shunt iii. Ventriculoatrial shunt iv. Frontal or parietal ventriculostomy v. Does not completely reverse the pathologic alterations in the brain and, unfortunately, treatment
223
by shunting is associated with frequent complications c. Major complication associated with shunt treatment: 81% of children with shunts suffer at least one and usually several malfunctions necessitating hospitalization i. Shunt obstruction ii. Valve malfunction iii. Disconnection iv. Hematoma v. Overdrainage vi. Outgrown shunt vii. Shunt fracture viii. Shunt-related infections, most often caused by staphylococcus aureus, with unexplained fever or frank meningitis ix. Signs of increased intracranial pressure with headache, lethargy, and vomiting x. Abdominal complications a) Peritonitis b) Perforation of an abdominal organ c) Peritoneal cysts d) Development of hydroceles in boys xi. Seizures xii. Allergic reaction to material
REFERENCES Aronyk KE: The history and classification of hydrocephalus. Nerosurg Clin North Am 4:599–609, 1993. Barkovich AJ, Edwards MS: Applications of neuroimaging in hydrocephalus. Pediatr Neurosurg 18:65–83, 1992. Bradley WG Jr: Diagnostic tools in hydrocephalus. Nerosurg Clin North Am 12:661–684, 2001. Burton BK: Recurrence risks for congenital hydrocephalus. Clin Genet 16:47–53, 1979. Del Bigio MR: Future directions for therapy of childhood hydrocephalus: a view from the laboratory. Pediatr Neurosurg 34:172–181, 2001. Del Bigio MR: Pathophysiologic consequences of hydrocephalus. Nerosurg Clin North Am 12:639–649, 2001. Dias MS, Li V: Pediatric surgery for the primary care pediatrician, Part II. Pediatric neurosurgical disease. Pediatr Clin N Amer 45:1539–1578, 1998. Epstein F: How to keep shunts functioning, or ‘the impossible dream’. Clin Neurosurg 32:608–631, 1985. Fernell E, Uvebrant P, von Wendt L: Overt hydrocephalus at birth-origin and outcome. Childs Nerv Syst 3:350–353, 1987. Finckh U, Gal A: Prenatal molecular diagnosis of L1-spectrum disorders. Prenat Diagn 20:744–745, 2000. Futagi Y, Suzuki Y, Toribe Y, et al.: Neurodevelopmental outcome in children with fetal hydrocephalus. Pediatr Neurol 27:111–116, 2002. Golden JA, Bonnemann CG: Developmental Structural Disorders. In Goetz (ed): Textbook of Clinical Neurology. 1st Ed. WB Saunders, 1999, Ch 28, pp 510–537. Habib Z: Genetics and genetic counselling in neonatal hydrocephalus. Obstet Gynecol Surv 36:529–534, 1981. Hamid RKA, Newfield P: Pediatric neuroanesthesia. Hydrocephalus. Anesthesiol Clin North Am 19:207–218, 2001. Harrod MJE, Friedman JM, Santos-Ramos R, et al.: Etiologic heterogeneity of fetal hydrocephalus diagnosed by ultrasound. Am J Obstet Gynecol 150:38–40, 1984. Hord E-D: Hydrocephalus. E-Med J, 2002. Hudgins RJ, Edwards MS, Goldstein R, et al.: Natural history of fetal ventriculomegaly. Pediatrics 82:692–697, 1988. Jouet M, Rosenthal A, Armstrong G, et al.: X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat Genet 7:402–407, 1994. Kanev PM, Park TS: The treatment of hydrocephalus. Nerosurg Clin North Am 4:611–619, 1993.
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Kestle JRW: Pediatric hydrocephalus: current management. Neurol Clin 21:883–895, 2003. Kirpatrick M, Engleman H, Minns RA: Symptoms and signs of progressive hydrocephalus. Arch Dis Child 64:124–128, 1989. Milhorat T: Hydrocephalus: Pathophysiology and clinical features. Neurosurgery 3:3625–3632, 1996. Pattisapu JV: Etiology and clinical course of hydrocephalus. Nerosurg Clin North Am 12:651–659, 2001. Pomili G, Donti GV, Carrozza LA, et al.: MASA syndrome: ultrasonographic evidence in a male fetus. Prenat Diagn 20:1012–1014, 2000. Pudenz RH: The surgical treatment of hydrocephalus—an historical review. Surg Neurol 15:15–26, 1981. Rickert CH, Paulus W: Tumors of the choroid plexus. Microscopy Res Technique 52:104–111, 2001. Rosseau GL, McCullough DC, Joseph AL: Current prognosis in fetal ventriculomegaly. J Neurosurg 77:551–555, 1992. Sahrakar K, Pang D: Hydrocephalus. E-Med J, 2002.
Schrander-Stumpel C, Fryns J-P: Congenital hydrocephalus: nosology and guidelines for clinical approach and genetic counselling. Eur J Pediatr 157:355–362, 1998. Senat MV, Bernard JP, Delezoide A, et al.: Prenatal diagnosis of hydrocephalusstenosis of the aqueduct of Sylvius by ultrasound in the first trimester of pregnancy. Report of two cases. Prenat Diagn 21:1129–1132, 2001. Sztriha L, Vos YJ, Verlind E, et al.: X-linked hydrocephalus: a novel missense mutation in the L1CAM gene. Pediatr Neurol 27:293–296, 2002. Thompson NM, Fletcher JM, Chapieski L, et al.: Cognitive and motor abilities in preschool hydrocephalics. J Clin Exp Neuropsychol 13:245–258, 1991. Váradi V, Tóth Z, Török O, et al.: Heterogeneity and recurrence risk for congenital hydrocephalus (ventriculomegaly): a prospective study. Am J Med Genet 29:305–310, 1988. Weller S, Gärtner J: Genetic and clinical aspects of X-linked hydrocephalus (L1 disease): Mutations in the L1CAM gene. Hum Mutat 18:1–12, 2001.
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Fig. 3. Prenatal ultrasound at 33 weeks showing markedly dilated lateral ventricles Fig. 1. A child with hydrocephalus which was shunted.
Fig. 4. CT scan of the head of a patient showing ventriculomegaly with congenital hydrocephalus.
Fig. 5. CT scan of the head of a patient after ventriculoperitoneal shunt. Fig. 2. An adult with severe congenital hydrocephalus and mental retardation.
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Fig. 6. MRI of the brain of a patient showing hydrocephalus due to aqueduct stenosis.
Fig. 7. CT scans of the brain of a patient showing dilatation of the lateral ventricles with stretching of corpus callosum and cortical atrophy.
Congenital Hypothyroidism All forms of congenital hypothyroidism occur in 1 in 4000 live births worldwide. The dysgenetic form affects twice as many females as males. It is the most prevalent congenital endocrine disease. The incidence is approximately 1 in 32,000 in Blacks and 1 in 2000 in Hispanics.
GENETICS/BASIC DEFECTS 1. Inheritance a. Thyroid dysgenesis i. The most frequent cause of congenital hypothyroidism (85% of cases) ii. Morphological classification a) Ectopic thyroid gland: the most frequent malformation, observed most frequently at the base of the tongue b) Athyreosis (absence of any detectable thyroid tissue) c) Hypoplasia (partially absent thyroid) iii. Sporadic in most cases iv. Genetic factors contributing to the development of thyroid dysgenesis in 2% of cases with a positive familial history v. Molecular defects clarified only in few cases of thyroid dysgenesis a) TSH-receptor gene (thyroid hypoplasia, “apparent athyrosis”) b) Transcription factors: TTF-1 (hypothyroidism, chorea, choreoathetosis, respiratory distress), TTF-2 (thyroid hypoplasia, cleft palate, choanal atresia, curly hair, developmental delay), PAX-8 (thyroid hypoplasia, ectopy) c) NKX2A (athyrosis, hypoplasia, normally developed gland, choreoathetosis, pulmonary problems, mental retardation, pituitary abnormalities) b. Autosomal recessive defects of thyroid hormone biosynthesis with identification of the following candidate genes for congenital hypothyroidism i. Thyroid peroxidase (TPO) gene a) A hemoprotein responsible for tyrosine iodination and coupling b) Intriguing role of TPO mutations in the development of thyroid tumor ii. Sodium-iodide symporter gene iii. Thyroglobulin (Tg) gene iv. Pendrin gene c. Autosomal dominant transmission of congenital hypoplasia due to loss-of-function mutation of PAX-8 2. Etiology of thyroidal congenital hypothyroidism a. Disorders in development of the thyroid gland (85% of cases with congenital hypothyroidism) 227
3.
4.
5.
6.
i. Absent thyroid ii. Under-development with migration failure iii. Under-development with normal migration b. Disorders in thyroid hormone synthesis (10–20%) i. TSH hypo-responsiveness (TSH receptor abnormalities) ii. Defects in iodide transport from circulation into the thyroid cells iii. Defects in iodide transport from the thyroid cell to the follicular lumen, often combined with inner ear deafness (Pendred syndrome, sensorineural hearing loss and goiter) iv. Defects in the synthesis of hydrogen peroxide v. Defects in the oxidation of iodide, iodination and iodothyronine synthesis vi. Defects in processes involved in the synthesis or degradation of thyroglobulin vii. Defects in iodine recycling Etiology of central (hypothalamic or pituitary) congenital hypothyroidism a. Disorders in development and/or function of the hypothalamus b. Disorders in development and/or function of the pituitary glands c. Disorders in development and/or function of the hypothalamus and pituitary glands Transient form of primary congenital hypothyroidism a. Occurs in 5–10% of infants detected by newborn screening b. Represents about 5% of cases with congenital hypothyroidism c. Etiology i. Mothers with chronic autoimmune thyroiditis: transplacental passage of maternal TSH-receptor blocking antibodies leading to inhibition of TSH action on the infant’s thyroid gland until the maternal antibodies disappear ii. Antithyroid drugs taken by pregnant women with thyroid autoimmune disease iii. Maternal dietary iodide deficiency iv. Maternal dietary goitrogen ingestion v. Exposure to excess iodine in the perinatal period a) Use of iodinated disinfectants b) Use of contrast agents Down syndrome: congenital hypothyroidism occurs approximately 28 times more common among infants with Down syndrome than in the general population with an incidence of 1% detected by newborn screening Pathogenesis of mental retardation in congenital hypothyroidism: due to the central role of thyroid hormones in brain development, which takes place during fetal life and early postnatal life up to the 2nd or 3rd year of age
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CLINICAL FEATURES 1. Most newborn are asymptomatic 2. Severe dysgenetic and athyrotic hypothyroidism a. Early symptoms i. Feeding problems ii. Constipation iii. Growth failure iv. Hoarse cry b. Signs and symptoms in infants and toddlers i. Delayed linear growth ii. Hypotonia iii. Decreased activity iv. Lethargy v. Prolonged jaundice vi. Bradycardia vii. Hypothermia viii. Cold to touch ix. Dry/puffy/thick skin x. Sparse hair xi. Characteristic craniofacial appearance a) Coarse facial feature b) Puffy eyes c) Myxedematous facies d) Large fontanelles e) A broad, flat nose f) Pseudohypertelorism g) Large, protruding tongue xii. Delayed tooth eruption xiii. Occasional cardiomegaly xiv. Protuberant abdomen with umbilical hernia xv. Constipation xvi. Poor nail growth xvii. Delayed return of the deep tendon reflexes xviii. Irreversible growth failure and mental retardation
3. 4. 5.
DIAGNOSTIC INVESTIGATIONS 1. Newborn screening a. Successful identification of infants with congenital hypothyroidism b. Enables early diagnosis and treatment of infants and prevention of mental retardation c. Newborn screening measures either TSH or T4 in neonatal blood placed on filter paper d. Confirmation with a serum sample if the filter paper result is abnormal i. Primary congenital hypothyroidism a) Low serum T4 levels b) Elevated serum TSH ii. Hypopituitary hypothyroidism a) Low total T4 levels b) Low or normal TSH iii. Thyroxine-binding globulin (TBG) deficiency a) Low total T4 but normal serum free T4 levels b) Normal TSH 2. Laboratory diagnosis a. Thyroid function tests i. Elevated serum TSH ii. Low serum T4 levels b. Determine antithyroglobulin and antithyroid peroxidase antibodies if indicated
6. 7.
c. Determine TBG levels for suspected TBG deficiency Radiography for bone age Ultrasonography, considered as the best noninvasive method for the anatomical assessment of the thyroid gland Radionuclide scan (thyroid scintigraphy) using 99mTc or 123I a. To demonstrate the presence of ectopic thyroid tissue or thyroid aplasia b. Iodide transport defect i. Low or absent uptake of 123I ii. Response to therapeutic doses of potassium iodide c. Defective organification of iodide i. Rapid uptake of 123I ii. Marked decrease in thyroid radioactivity when perchlorate or thiocyanate is administered 2 hours after administering radioiodine iii. Occasional sensorineural hearing loss (Pendred syndrome) d. Iodotyrosine-coupling defect i. Rapid uptake of 123I ii. No discharge by perchlorate iii. Very high thyroid gland content of monoiodotyrosine (MIT) and diiodotyrosine (DIT) iv. Virtually undetectable T4 and T3 v. Adequately iodinated thyroglobulin e. Defects in thyroglobulin gene expression and thyroglobulin secretion i. Elevated uptake of 123I ii. No discharge by perchlorate iii. Abnormal serum iodoproteins iv. Elevated protein-bound/ T4 iodine ratio v. Low or borderline serum thyroglobulin f. Iodotyrosine deiodinase defect i. Rapid uptake and turnover of 123I ii. Elevated serum and urinary iodotyrosines (MIT, DIT) iii. Response to iodine supplementation Intelligence quotient (IQ) measurement for testing neuropsychological progress and outcome Molecular genetic diagnosis by sequencing of select exons to identify mutations
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Sporadic cases: low recurrence risk ii. Autosomal recessive inheritance: 25% iii. Autosomal dominant inheritance: low recurrence risk unless a parent is affected b. Patient’s offspring i. Sporadic cases: low recurrence risk ii. Autosomal recessive inheritance: low recurrence risk unless the spouse carries the recessive gene iii. Autosomal dominant inheritance: 50% 2. Prenatal diagnosis a. Ultrasonography and percutaneous fetal blood sampling i. Detection of fetal goiter a) A rare yet potentially dangerous condition b) A large goiter may cause hyperextension of the neck of the fetus caused by a large goi-
CONGENITAL HYPOTHYROIDISM
ter, resulting in malpresentation and complicate labor and delivery c) Possibility of compressing the trachea and asphyxiating the neonate after birth ii. Fetal blood sample a) Elevated TSH b) Low T4 b. Amniocentesis i. Determination of TSH concentration (markedly elevated TSH level) in amniotic fluid in the second trimester for the offspring of a couple both known to have an iodide (iodothyronine synthesis) enzymatic organification defect ii. Affected fetus with markedly increased TSH level in the amniotic fluid sample for the trimester c. Molecular genetic diagnosis possible by sequencing of select exons on fetal DNA for previously identified mutations in a research laboratory 3. Management a. Sodium L-thyroxine i. The treatment of choice ii. Early therapy (within 14 days) with appropriate doses of thyroxine (about 10 mcg/kg/day) will prevent any brain damage even in case of evidence of fetal hypothyroidism, since thyroxine of maternal origin will reach and protect the fetus iii. Avoid over treatment to prevent the following adverse effects a) Premature cranial suture fusion b) Acceleration of growth and skeletal maturation c) Problems with temperament and behavior b. X-linked dominant thyroxine-binding globulin deficiency (causing a low total T4 but normal free T4): no need for thyroid hormone replacement c. Intrauterine treatment of fetus with a large goiter i. Indicated because of the morbidity associated with compression of the trachea and mechanical interferences during delivery ii. Intra-amniotic administration of levothyroxine presents the least invasive approach to fetal treatment a) Rapid decrease in the fetal goiter size b) Normalization of fetal thyroid function d. Intrauterine treatment of fetus affected with iodide organification defect with synthroid
REFERENCES American Academy of Pediatrics AAP Section on Endocrinology and Committee on Genetics, and American Thyroid Association Committee on Public Health: Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics 91:1203–1209, 1993. Abuhamad AZ, Fisher DA, Worsof SL, et al.: Antenatal diagnosis and treatment of fetal goitrous hypothyroidism: case report and review of the literature. Ultrasound Obstet Gynecol 6:368–371, 1995. Abramowicz MJ, Duprez L, Parma J, et al.: Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland. J Clin Invest 99:3018–3024, 1997. Abramowicz MJ, Vassart G, Refetoff S: Probing the cause of thyroid dysgenesis. Thyroid 7:325–336, 1997. Agrawal P, Ogilvy-Stuart A, Lees C: Intrauterine diagnosis and management of congenital goitrous hypothyroidism. Ultrasound Obstet Gynecol 19:501–505, 2002.
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Ambrugger P, Stoeva I, Biebermann H, et al.: Novel mutations of the thyroid peroxidase gene in patients with permanent congenital hypothyroidism. Eur J Endocrinol 145:19–24, 2001. Bargagna S, Canepa G, Costagli C, et al.: Neuropsychological follow-up in early-treated congenital hypothyroidism: a problem-oriented approach. Thyroid 10:243–249, 2000. Beltroy E, Umpaichitra V, Gordon S, et al.: Two infants who have coarse facial features and growth and developmental delay. Pediatr Rev 24:16–21, 2003. Biebermann H, Liesenkotter KP, Emeis M, et al.: Severe congenital hypothyroidism due to a homozygous mutation of the betaTSH gene. Pediatr Res 46:170–173, 1999. Bourgeois MJ, Varma S: Congenital hypothyroidism. http://www. emedicine.com Castanet M, Polak M, Bonaiti-Pellie C, et al.: Nineteen years of national screening for congenital hypothyroidism: familial cases with thyroid dysgenesis suggest the involvement of genetic factors. J Clin Endocrinol Metab 86:2009–2014, 2001. Clifton-Blight RJ, Wentworth J, Heinz P, et al.: Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat Genet 18:399–401, 1998. Coyle B, Reardon W, Herbrick JA, et al.: Molecular analysis of the PDS gene in Pendred syndrome. Hum Mol Genet 7:1105–1112, 1998. Davidson KM, Richards DA, Schatz DA, et al.: Successful in utero treatment of fetal goiter and hypothyroidism. N Engl J Med 234:543–546, 1991. Delange F: Neonatal screening for congenital hypothyroidism: results and perspectives. Horm Res 48:51–61, 1997. De Vijlder JJM: Primary congenital hypothyroidism: defects in iodine pathways. Eur J Endocrinol 149:247–256, 2003. Fisher DA: Fetal thyroid function diagnosis and management of fetal thyroid disorders. Cog 40:16–31, 1997. Grüters A, Jenner A, Krude H: Long-term consequences of congenital hypothyroidism in the era of screening programmes. Best Pract Res Clin Endocrinol Metab 16:369–382, 2002. Hirsch M, Josefsberg Z, Schoenfeld A, et al.: Congenital hereditary hypothyroidism—prenatal diagnosis and treatment. Prenat Diagn 10:491–496, 1990. Kohn LD, Suzuki K, Hoffman WH, et al.: Characterization of monoclonal thyroid-stimulating and thyrotropin binding-inhibiting autoantibodies from a Hashimoto’s patients whose children had intrauterine and neonatal thyroid disease. J Clin Endocr Metab 82:3998–4004, 1997. Kopp P: Perspective: genetic defects in the etiology of congenital hypothyroidism. Endocrinology 143:2019–2024, 2002. Kreisner E, Camargo-Neto E, Maia CR, et al.: Accuracy of ultrasonography to establish the diagnosis and aetiology of permanent primary congenital hypothyroidism. Clin Endocrinol (Oxf) 59:361–365, 2003. LaFranchi S: Congenital hypothyroidism: etiologies, diagnosis, and management. Thyroid 9:735–740, 1999. Macchia PE: Recent advances in understanding the molecular basis of primary congenital hypothyroidism. Mol Med Today 6:36–42, 2000. Macchia PE, De Felice M, Di Lauro R: Molecular genetics of congenital hypothyroidism. Curr Opin Genet Dev 9:289–294, 1999. Macchia PE, Lapi P, Krude H, et al.: PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet 19:83–86, 1998. Medeiros-Neto G, Bunduki V, Tomimori E, et al.: Prenatal diagnosis and treatment of dyshormonogenetic fetal goiter due to defective thryoglobulin synthesis. J Clin Endocrinol Metab 82:4239–4242, 1997. Noia G, De Santis M, Tocci A, et al.: Early prenatal diagnosis and therapy of fetal hypothyroid goiter. Fetal Diagn Ther 7:138–143, 1992. Perelman AH, Johnson RL, Clemons RD, et al.: Intrauterine diagnosis and treatment of fetal goitrous hypothyroidism. J Clin Endocrinol Metab 71:618–621, 1990. Schwingshandl J, Donaghue K, Luttrell B, et al.: Transient congenital hypothyroidism due to maternal thyrotrophin binding inhibiting immunoglobulin. J Paediatr Child Health 29:315–318, 1993. Smith DW, Klein AM, Henderson JR, et al.: Congenital hypothyroidism—signs and symptoms in the newborn period. J Pediatr 87:958–962, 1975. Van Naarden Braun K, Yeargin-Allsopp M, Schendel D, et al.: Long-term developmental outcomes of children identified through a newborn screening program with a metabolic or endocrine disorder: a population-based approach. J Pediatr 143:236–242, 2003. Vilain C, Rydlewski C, Duprez L, et al.: Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8. J Clin Endocrinol Metab 86:2345–238, 2001.
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Fig. 1. A neonate with congenital hypothyroidism showing coarse facial features, hypotonia and umbilical hernia.
Fig. 2. A twin affected with congenital hypothyroidism (left) shows coarse facial features. The normal co-twin is on the right.
Congenital Muscular Dystrophy (POMGnT1) gene which is mapped to chromosome 1p32-p34 b) Sharing features with Fukuyama CMD c) Milder phenotype with survival ranging from early childhood to the seventh decade iii. Walker-Warburg syndrome a) Caused by mutation in the protein O-mannosyltransferase-1 (POMT1) gene b) Similar to muscle-eye-brain disease c) Comparatively more severe leading to death in the first few months of life iv. Other CMD with neuronal migration defects
Congenital muscular dystrophy (CMD) refers to a group of genetic disorders in which weakness and an abnormal muscle biopsy are present at birth.
GENETICS/BASIC DEFECTS 1. Inheritance a. Genetic heterogeneity b. Autosomal recessive in general 2. Classification a. Merosin—negative (laminin α2 deficient) CMD (complete or partial) i. Chromosome locus: 6q22–q23 ii. Caused by mutations of the laminin α2-chain (LAMA2) gene iii. “Classical CMD”: deficient in merosin, the α2 chain of laminin-2, a major constituent of the basal lamina of skeletal muscle fibers linking the extracellular matrix to the dystrophin-associated proteins and integrins iv. A milder phenotype caused by partial deficiency of merosin b. Merosin-positive CMD consisting of a genetically more heterogeneous group i. Rigid spine syndrome a) Caused by mutations in the selenoprotein N1 (SEPN1) gene which is mapped to chromosome 1p35–p36 b) Early onset of hypotonia c) Rigidity of the spine d) Scoliosis ii. Ullrich syndrome: congenital muscular dystrophy with proximal joint contractures and distal joint laxity iii. Pure CMD: either with normal or deficient levels of laminin-α2 (merosin) iv. Other merosin-positive CMD a) Merosin-positive CMD with mental retardation b) Merosin-positive CMD with cerebellar hypoplasia c. Merosin-positive CMD with mental retardation and neuronal migration disorders i. Fukuyama CMD a) Chromosome locus: 9q31–q33 b) FCMD gene encodes fukutin c) Fukutin gene defect represents a novel mutation with a retrotransposal insertion of tandemly repeated sequences on chromosome 9q31-q33 ii. Muscle-eye-brain disease a) Caused by mutation in the protein O-mannoside N-acetylglucosaminyltransferase-1
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1. Typical features a. Floppy infant b. Low muscle tone c. Contractures d. Muscle weakness i. Tends to be stable over time ii. Complications of dystrophy becoming more sever with time 2. Merosin-negative CMD a. Demonstrating clinical homogeneity i. Severe hypotonia ii. Multiple contractures iii. Delayed developmental milestones iv. Normal mentation v. Variable degrees of central hypomyelination seen on neuroimaging b. Patients with complete merosin deficiency i. Typically presenting as floppy infants ii. May or may not require ventilatory assistance iii. Most patients stabilize and able to continue developing without mechanical ventilation iv. Feeding difficulty leading to recurrent aspiration and poor nutrition in some patients v. The best motor milestone achieved: standing with support vi. Unable to ambulate vii. Cognitive development a) Generally normal b) Mental retardation in patients with brain anomalies viii. Epilepsy c. Patients with partial merosin deficiency i. Wide clinical spectrum a) Marked hypotonia at birth, contractures, and severely delayed motor milestones b) Limb-girdle muscular dystrophy-like presentation in the teen
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c) An adult-onset proximal limb-girdle weakness with elevated CK concentration ii. White matter abnormalities by MRI in all patients with documented merosin gene mutations 3. Merosin-positive CMD a. Rigid spine disease i. Onset in infancy ii. Axial muscle weakness iii. Early rigidity of the spine iv. Prominent nasal voice v. Nocturnal respiratory insufficiency vi. Early respiratory failure b. Ullrich disease i. Proximal contractures ii. Distal joint laxity iii. Delayed motor milestones a) Ability to walk in some cases b) Wheelchair dependent in majority of cases iv. Normal intelligence c. Pure CMD i. Normal intelligence ii. Normal brain imaging d. Other merosin-positive CMD 4. Merosin-positive CMD with mental retardation and neuronal migration defects a. Fukuyama CMD i. An autosomal recessive disorder ii. Prevalent in Japan iii. Early onset (before nine months) iv. Muscle weakness v. Accompanied by joint contractures vi. Hypotonia/hypokinesia vii. Severe mental retardation viii. Epilepsy ix. Eye anomalies a) Myopia b) Congenital nystagmus c) Cortical blindness d) Optic atrophy e) Choreoretinal degeneration x. Brain anomalies (cobblestone lissencephaly; type 2 lissencephaly) a) Micropolygyria b) Pachygyria c) White matter lucency d) Minor cerebellar alterations (cortical dysplasia b. Muscle-eye-brain disease i. An autosomal recessive disorder ii. Mimics Walker-Warburg syndrome but overall changes tend to be much milder iii. Present as a floppy infant with suspected blindness iv. Severe mental retardation v. Extensive neuronal migration disorder a) Pachygyria and polymicrogyria b) Brain stem hypoplasia c) Cerebellar dysgenesis d) Hydrocephalus
vi. Muscle involvement: typical features of muscular dystrophy with ongoing de- and regeneration vii. Normal expression of laminin α2 c. Walker-Warburg syndrome i. An autosomal recessive disorder ii. Type II lissencephaly a) Micropolygyric ‘cobblestone’ cortex b) Extensive white matter abnormalities c) Hydrocephaly with enlarged ventricles d) Brainstem hypoplasia e) Hypoplasia of the cerebellum, particularly the cerebellar vermis iii. Ocular dysgenesis a) Megacornea b) Buphthalmos c) Corneal clouding d) Cataracts e) Abnormal vitreous f) Retinal hypopigmentation g) Hypoplasia of the optic nerve h) Clinically blind iv. Muscular dystrophy a) Variable in severity: ranges from myopathy with increased variation of fiber size to severe, end-stage muscular dystrophy b) Well preserved expression of laminin α2 v. Complete lack of psychomotor development (severe mental retardation) for those who survive for some years
DIAGNOSTIC INVESTIGATIONS 1. Elevated serum creatine kinase (CPK) levels 2. Brain MRI with variety of findings a. Pachygyria (with normal cognitive function) b. Cerebellar hypoplasia (with normal cognitive function but delay of speech development) c. Cerebellar cysts (in connection with pure CMD) d. Abnormal white matter signal (in connection with pure CMD of merosin-deficient type) e. Large lissencephalic changes f. Hydrocephalus 3. EMG: the motor units show myopathy with small amplitude and duration 4. Muscle biopsy a. Dystrophic or myopathic pattern b. Varying degrees of muscle fiber degeneration and replacement of muscle fibers by connective tissue and fat c. In the severe merosin-deficient form of CMD: very few muscle fibers left d. Immunohistochemic staining for merosin i. Normal in most of the subgroups of CMD ii. Deficient or totally lacking in CMD with merosin deficiency iii. Merosin is deficient in 5% of patients with Fukuyama type CMD 5. Molecular genetic analyses a. Fukuyama CMD: sequencing of entire coding region or select exons of FCMD gene
CONGENITAL MUSCULAR DYSTROPHY
b. Muscle-eye-brain disease: sequencing of entire coding region or select exons or targeted mutation analysis of POMGnT1 gene c. Walker-Warburg syndrome: sequencing of entire coding region or select exons or mutation scanning of POMT1 gene
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% (autosomal recessive) b. Patient’s offspring: i. Many individuals not living long enough to reproduce ii. All offspring are carriers iii. Recurrence risk to offspring probably less than 1% 2. Prenatal diagnosis a. Available for pregnancies at 25% risk for complete merosin deficiency by linkage analysis, provided complete merosin deficiency has been documented in the muscle of the proband b. Prenatal diagnosis by DNA mutation analysis is available for pregnancies at increased risk of Fukuyama MD, muscle-eye-brain disease, or Walker-Warburg MD by analysis of fetal DNA, obtained by amniocentesis or CVS, provided both disease-causing alleles of an affected family member have been identified 3. Management a. No definitive treatment available b. General approaches i. Weight control to avoid obesity ii. Physical therapy and stretching exercises a) To promote mobility b) To prevent contractures iii. Using mechanical devices to help ambulation and mobility iv. Surgical interventions for scoliosis and foot deformity v. Medications for seizure control vi. Respiratory aids as needed vii. Social and emotional support
REFERENCES Aida N: Fukuyama congenital muscular dystrophy: a neuroradiologic review. J Magn Reson Imaging 8:317–326, 1998. Allamand V, Guicheney P: Merosin-deficient congenital muscular dystrophy, autosomal recessive (MDC1A, MIM#156225, LAMA2 gene coding for alpha2 chain of laminin). Eur J Hum Genet 10:91–94, 2002. Brockington M, Sewry CA, Herrmann R, et al.: Assignment of a form of congenital muscular dystrophy with secondary merosin deficiency to chromosome 1q42. Am J Hum Genet 66:428–435, 2000. Brockington M, Blake DJ, Prandini P, et al.: Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am J Hum Genet 69:1198–1209, 2001. Brockington M, Yuva Y, Prandini P, et al.: Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. Hum Mol Genet 10:2851–2859, 2001. Caro PA, Scavina M, Hoffman E, et al.: MR imaging findings in children with merosin-deficient congenital muscular dystrophy. AJNR Am J Neuroradiol 20:324–326, 1999.
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Chijiiwa T, Nishimura M, Inomata H, et al.: Ocular manifestations of congenital muscular dystrophy (Fukuyama type). Ann Ophthalmol 15:921–923, 926–928, 1983. Cormand B, Avela K, Pihko H, et al.: Assignment of the muscle-eye-brain disease gene to 1p32–p34 by linkage analysis and Homozygosity mapping. Am J Hum Genet 64:126–135, 1999. Cormand B, Pihko H, Bayés M, et al.: Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease. Neurology 56:1059–1069, 2001. De Stefano N, Dotti MT, Villanova M, et al.: Merosin positive congenital muscular dystrophy with severe involvement of the central nervous system. Brain Dev 18:323–326, 1996. Donner M, Rapola J, Somer H: Congenital muscular dystrophy: a clinicopathological and follow-up study of 15 patients. Neuropadiatrie 6:239–258, 1975. Dubowitz V: 68th ENMC international workshop (5th international workshop): On congenital muscular dystrophy, 9–11 April 1999, Naarden, The Netherlands. Neuromuscul Disord 9:446–454, 1999. Dubowitz V: Congenital muscular dystrophy: an expanding clinical syndrome. Ann Neurol 47:143–144, 2000. Echenne B: Congenital muscular dystrophy of a non-Fukuyama type. Brain Dev 10:397, 1988. Eeg-Olofsson KE: Congenital muscular dystrophy. Care of children and families. Scand J Rehabil Med Suppl 39:53–57, 1999. Farina L, Morandi L, Milanesi I, et al.: Congenital muscular dystrophy with merosin deficiency: MRI findings in five patients. Neuroradiology 40:807–811, 1998. Flanigan KM, Kerr L, Bromberg MB, et al.: Congenital muscular dystrophy with rigid spine syndrome: a clinical, pathological, radiological, and genetic study. Ann Neurol 47:152–161, 2000. Fukuyama Y, Ohsawa M: A genetic study of the Fukuyama type congenital muscular dystrophy. Brain Dev 6:373–390, 1984. Fukuyama Y, Osawa M, Suzuki H: Congenital progressive muscular dystrophy of the Fukuyama type-clinical, genetic and pathological considerations. Brain Dev 3:1–29, 1981. Gordon E, Hoffman EP, Pegoraro E: Congenital muscular dystrophy overview. Gene Reviews 2004. (http://www.genetests.org) Guicheney P, Vignier N, Helbling-Leclerc A, et al.: Genetics of laminin alpha 2 chain (or merosin) deficient congenital muscular dystrophy: from identification of mutations to prenatal diagnosis. Neuromuscul Disord 7:180–186, 1997. Guicheney P, Vignier N, Zhang X, et al.: PCR based mutation screening of the laminin alpha2 chain gene (LAMA2): application to prenatal diagnosis and search for founder effects in congenital muscular dystrophy. J Med Genet 35:211–217, 1998. Helbling-Leclerc A, Zhang X, Topaloglu H, et al.: Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy. Nat Genet 11:216–218, 1995. Hillaire D, Leclerc A, Faure S, et al.: Localization of merosin-negative congenital muscular dystrophy to chromosome 6q2 by homozygosity mapping. Hum Mol Genet 3:1657–1661, 1994. Jones R, Khan R, Hughes S, et al.: Congenital muscular dystrophy: the importance of early diagnosis and orthopaedic management in the long-term prognosis. J Bone Joint Surg Br 61:13–17, 1979. Kobayashi O, Hayashi Y, Arahata K, et al.: Congenital muscular dystrophy: Clinical and pathologic study of 50 patients with the classical (Occidental) merosin-positive form. Neurology 46:815–818, 1996. Kondo E, Saito K, Toda T, et al.: Prenatal diagnosis of Fukuyama type congenital muscular dystrophy by polymorphism analysis. Am J Med Genet 66:169–174, 1996. Kondo-Iida E, Kobayashi K, Watanabe M, et al.: Novel mutations and genotypephenotype relationships in 107 families with Fukuyama-type congenital muscular dystrophy (FCMD). Hum Mol Genet 8:2303–2309, 1999. Kondo-Iida E, Saito K, Tanaka H, et al.: Molecular genetic evidence of clinical heterogeneity in Fukuyama-type congenital muscular dystrophy. Hum Genet 99:427–432, 1997. Leyten QH, Gabreels FJ, Joosten EM, et al.: An autosomal dominant type of congenital muscular dystrophy. Brain Dev 8:533–537, 1986. Leyten QH, Gabreels FJ, Renier WO, et al.: Congenital muscular dystrophy: a review of the literature. Clin Neurol Neurosurg 98:267–280, 1996. Leyten QH, Gabreels FJ, Renier WO, et al.: Congenital muscular dystrophy. J Pediatr 115:214–221, 1989.
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Lopate G: Congenital muscular dystrophy. EMedicine (www.emedicien.com) McMenamin JB, Becker LE, Murphy EG: Congenital muscular dystrophy: a clinicopathologic report of 24 cases. J Pediatr 100:692–697, 1982. Mendell JR: Congenital muscular dystrophy: searching for a definition after 98 years. Neurology 56:993–994, 2001. Misugi N: Light and electron microscopic studies of congenital muscular dystrophy. Brain Dev 2:191–199, 1980. Moghadaszadeh B, Desguerre I, Topaloglu H, et al.: Identification of a new locus for a peculiar form of congenital muscular dystrophy with early rigidity of the spine, on chromosome 1p35–36. Am J Hum Genet 62:1439–1445, 1998. Muntoni F, Guicheney P: 85th ENMC International Workshop on Congenital Muscular Dystrophy. 6th International CMD Workshop. 1st Workshop of the Myo-Cluster Project ‘GENRE’. 27–28th October 2000, Naarden, The Netherlands. Neuromuscul Disord 12:69–78, 2002. Naom I, Sewry C, D’Alessandro M, et al.: Prenatal diagnosis in merosin-deficient congenital muscular dystrophy. Neuromuscul Disord 7:176–179, 1997. Nass D, Goldberg I, Sadeh M: Laminin alpha2 deficient congenital muscular dystrophy: prenatal diagnosis. Early Hum Dev 55:19–24, 1999. Nissinen M, Helbling-Leclerc A, Zhang X, et al.: Substitution of a conserved cysteine-996 in a cysteine-rich motif of the laminin alpha2-chain in congenital muscular dystrophy with partial deficiency of the protein. Am J Hum Genet 58:1177–1184, 1996.
Philpot J, Sewry C, Pennock J, et al.: Clinical phenotype in congenital muscular dystrophy: correlation with expression of merosin in skeletal muscle. Neuromuscul Disord 5:301–305, 1995. Santavuori P, Leisti J, Kruus S: Muscle, eye, and brain disease: a new syndrome. Neuropaediatrie 8(suppl):553–558, 1977. Sombekke BH, Molenaar WM, van Essen AJ, et al.: Lethal congenital muscular dystrophy with arthrogryposis multiplex congenita: three new cases and review of the literature. Pediatr Pathol 14:277–285, 1994. Takai Y, Tsutsumi O, Harada I, et al.: Prenatal diagnosis of Fukuyama-type congenital muscular dystrophy by microsatellite analysis. Hum Reprod 13:320–323, 1998. Toda T, Segawa M, Nomura Y, et al.: Localization of a gene for Fukuyama type congenital muscular dystrophy to chromosome 9q31–33. Nat Genet 5:283–286, 1993. Toda T, Kobayashi K, Kondo-Iida E, et al.: The Fukuyama congenital muscular dystrophy story. Neuromuscular Dis 10:153–159, 2000. Tomé FM, Evangelista T, Leclerc A, et al.: Congenital muscular dystrophy with merosin deficiency. C R Acad Sci III 317:351–357, 1994. Topaloglu H, Renda Y, Yalaz K, et al.: Classification of congenital muscular dystrophy. J Pediatr 117:166–167, 1990. Voit T: Congenital muscular dystrophies: 1997 update. Brain Dev 20:65–74, 1998. Yoshioka M, Kuroki S: Clinical spectrum and genetic studies of Fukuyama congenital muscular dystrophy. Am J Med Genet 53:245–250, 1994.
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Fig. 1. An infant with congenital muscular dystrophy showing hypotonic frog-leg posture, the chest deformity due to weakness of the intercostal muscles, and contractures of joints.
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Congenital Toxoplasmosis Acute infection in a pregnant woman with Toxoplasma gondii can result in an infected infant. In the United States, the incidence of congenital toxoplasmosis is estimated to be 1 in 1000 to 1 in 10,000 births and approximately 400–4000 cases of congenital toxoplasmosis occur each year.
7.
GENETICS/BASIC DEFECTS
9.
1. Toxoplasma gondii a. A protozoan parasite b. The causative agent of toxoplasmosis, a common infection throughout the world with estimated 1 billion people infected worldwide c. Life cycle: exists in three forms i. The oocysts, or soil form ii. The tachyzoite, or active infectious form iii. The tissue cyst, or latent form 2. Hosts a. Cats i. The primary host ii. Maintain the intestinal-epithelial sexual cycle of toxoplasma development with the production of oocysts b. All other animals (humans, birds, rodents, and domestic animals) i. The intermediate or secondary hosts ii. Have an extraintestinal asexual cycle with resultant parasitemia and the production of tissue cysts 3. Routes by which Toxoplasma is transmitted to humans a. Principal routes i. Acquired a) Ingestion of raw or inadequately cooked infected meat (beef, pork, or lamb) b) Ingestion of oocysts, an environmentally resistant form of the organism that cats pass in their feces and human exposure to cat litter or contaminated soil (from gardening or unwashed fruits or vegetables) ii. Congenital: transplacental infection of unborn fetus by the newly infected mother b. Rare routes i. Blood and blood product transfusion ii. Organ transplant iii. Laboratory accident c. No evidence of direct human to human transmission other than from mother to fetus 4. 70% of the obstetric population with negative antibodies: at risk for transmission to the fetus 5. Congenital toxoplasmosis usually occurs as a result of primary maternal infection 6. Maternal-fetal transmission rate depends on gestational age at the time of maternal infection a. <5% before 5th week of gestation b. 25% in the first trimester
8.
10.
c. 75% in the third trimester d. >90% in the last few weeks of pregnancy Severity of the fetal infection inversely related to gestational age: the earlier infections being the most severe Untreated maternal infections: about 50% of cases transmit to the fetus An immunocompetent woman previously infected are considered immune and will not transmit T. gondii to her offspring. Toxoplasma infection leads to life-long immunity with the presence of T. gondii-specific IgG antibodies. Acute toxoplasmosis in the adult is often asymptomatic and usually does not result in complications Reactivation can occur in immunocompromised pregnant woman (i.e., HIV) leading to parasitemia and fetal infection
CLINICAL FEATURES
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1. Unpredictable manifestations in the fetus and in the newborn 2. Maternal infections a. Generally asymptomatic in immunocompetent mothers b. Subtle symptoms in about 15–20% of infected mothers i. Cervical lymphadenopathy: the most common clinical manifestation ii. Fatigue iii. Flu-like symptoms c. In immunocompromised mothers i. Chorioretinitis ii. Encephalitis iii. Pneumonitis iv. Myocarditis d. Maternal infections early in pregnancy i. Less likely to be transmitted to the fetus than infections later in pregnancy ii. More likely to be severe than later infections 3. Fetal infections a. Usually resulting from a primary maternal infection with risk of developing congenital abnormalities. Reactivation of T. gondii in an immunocompromised patient can render the fetus susceptible to infection b. Infectivity: The incidence and severity of the fetal infection depend on the gestational age at the time of the maternal infection. The later the gestation, the higher the infectivity. However, the postnatal sequelae is severer when infection occurs early in gestation 4. Natural history of congenital toxoplasmosis a. Free of symptoms at birth in vast majority of cases with congenital infection (70–90% of cases) b. About 15% of the infected children with signs or symptoms at birth or neonatal period i. Maculopapular rash ii. Generalized lymphadenopathy iii. Hepatosplenomegaly iv. Jaundice
CONGENITAL TOXOPLASMOSIS
v. Thrombocytopenia vi. Consequences of intrauterine meningoencephalitis a) CSF abnormalities b) Hydrocephalus c) Microcephaly d) Chorioretinitis e) Seizures vii. Signs of the “classic triad” (hydrocephalus, intracranial calcifications, and chorioretinitis) without systemic signs of disease c. Sequelae during childhood or early adult life in 50–90% of cases i. Learning disability ii. Visual impairment iii. Chorioretinitis: the most frequent congenital manifestation and is progressive in >80% of patients by 20 years of age iv. Mental retardation v. Hearing loss d. Eye manifestations i. Strabismus (33%) ii. Nystagmus (27%) iii. Microphthalmia (13%) iv. Phthisis (4%) v. Microcornea (19%) vi. Cataract (10%) vii. Active vitritis (11%) viii. Active retinitis (11%) ix. Chorioretinal scars (79%) x. Optic atrophy (20%) e. Severely affected congenital infection i. Die in utero ii. Die within a few days of life
DIAGNOSTIC INVESTIGATIONS 1. Serological testing a. IgM antibodies i. Produced one to two weeks after an infection ii. Levels detectable for years after the acute infection b. IgG antibodies i. Levels peak approximately 2 months after the initial infection ii. Remain positive for life c. IgA antibodies i. Parallels IgM production ii. Peak levels occur approximately 2 months after the initial infection and then rapidly decline d. IgE antibodies i. Detected early after an acute infection ii. Usually present for 4–8 months iii. May provide useful information regarding the timing of an acute infection 2. Detection of antibodies to toxoplasmosis in the neonatal period a. Specific T. gondii IgM antibody i. A positive IgM antibody in the newborn: diagnostic of congenital toxoplasmosis ii. A negative IgM antibody in the newborn does not exclude the diagnosis and may be due to the following reasons:
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a) Lack of production of IgM b) Waning of the IgM response by the time of birth c) Insensitivity of the assay iii. A positive IgM antibody in the mother a) Associated with recent maternal infection b) Would support the diagnosis of congenital toxoplasmosis b. Specific T. gondii IgA antibody: more sensitive test than IgM antibodies c. Neonatal screening with IgM or IgA antibodies fails to detect majority of children with congenital toxoplasmosis when the maternal infection occurred before the 20 weeks of pregnancy 3. Definitive postnatal diagnosis of congenital toxoplasmosis a. Detection of parasites in material collected from the newborn (blood, cerebrospinal fluid, or other clinical material) by inoculation into mice or tissue culture b. Detection of persisting specific IgG antibodies at the age of 1 year c. Reappearance of specific IgG antibodies in the child after cessation of postnatal antibiotic therapy d. Diffuse cerebral calcifications and hydrocephalus detected by radiography, ultrasonography, CT scan, or MRI of the brain 4. Other diagnostic evaluation of the infants a. Physical examination b. Dilated retinal examination c. Examination of the cerebrospinal fluid i. Protein ii. Glucose iii. Cell count iv. Antibody determination d. Audiologic screen e. Examination of the placenta i. Evidence of infection, although the gross appearance may not parallel the severity of fetal disease ii. Inoculation of the placental tissue into mice or tissue culture to attempt isolation of the parasite
GENETIC COUNSELING 1. Recurrence risk: women with previous infection not at risk for delivering a fetus with congenital toxoplasmosis unless immunosuppressed 2. Prenatal diagnosis a. Seroconversion during pregnancy i. Absence of specific Toxoplasma gondii IgG antibodies in the first serum sample obtained during gestation ii. Detection of specific IgG and IgM antibodies in the follow-up sample at a later prenatal visit or at birth b. Suggestive but not diagnostic signs by prenatal ultrasonography i. Ventriculomegaly: the most common sonographic finding in utero ii. Intracranial calcifications iii. Hydrops iv. Microcephaly v. Choroid plexus cysts
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vi. Growth retardation vii. Hepatomegaly viii. Splenomegaly ix. Ascites x. A thickened placenta c. Prenatal diagnosis of acute infection in the fetus i. Amniocentesis or cordocentesis a) Detection of parasites in amniotic fluid or in fetal blood by inoculation into tissue culture or mice b) Detection of anti-Toxoplasma gondii IgM, IgA, and IgE antibodies in the fetal blood. The diagnosis of fetal T. gondii infection before 22 weeks using cordocentesis is not possible because fetal IgM or IgA may not be produced before 22 weeks’ gestation. c) Detection of T. gondii DNA (B1 gene) by gene amplification in amniotic fluid: more accurate and faster diagnosis of congenital toxoplasmosis ii. Chorionic villus sampling not helpful because it will show placental but not fetal infection 3. Management a. Prevention of toxoplasma infection i. Cook meat to a safe temperature to kill toxoplasma ii. Peel or thoroughly wash fruits and vegetables before eating iii. Clean cooking surfaces and utensils after they have contacted raw meat, poultry, seafood, or unwashed fruits or vegetables iv. Avoid changing cat litter during pregnancy or use gloves and wash hands thoroughly v. Do not feed raw or undercooked meat to cats and keep cats inside to prevent acquisition of Toxoplasma by eating infected prey vi. Avoid risk factors for T. gondii infection including careful adherence to simple hygienic measures during pregnancy (decrease Toxoplasma infection by 60%) b. Treat Toxoplasma infection with spiramycin, pyrimethamine, sulfonamides, and folinic acid i. Reduce sequelae of congenital infection by treating the mother as soon as possible after the serologic screening program identifies the infection ii. Treat infected neonates: sooner the treatment, the better the outcome c. Newborn screening for Toxoplasma-specific IgM allows the identification and treatment of subclinical cases so that the sequelae of infection with toxoplasmosis may be prevented or attenuated
REFERENCES Alford CA Jr, Stagno S, Reynolds DW: Congenital toxoplasmosis: clinical, laboratory, and therapeutic considerations with special reference to subclinical disease. Bull NY Acad Med 50:160–181, 1974.
American Academy of Pediatrics Report of the Committee on Infectious Diseases: Toxoplasmosis. Red Book 2000, pp 583–586. Antsaklis A, Daskalakis G, Papantoniou N, et al.: Prenatal diagnosis of congenital toxoplasmosis. Prenat Diagn 22:1107–1111, 2002. Bale JF Jr: Congenital infections. Neurol Clin 20:1039–1060, 2002. Beasley DM, Egerman RS: Toxoplasmosis. Semin Perinatol 22:332–338, 1998. Black MW, Boothroyd JC: Lytic cycle of Toxoplasma gondii. Microbiol Mole Biol Rev 64:607–623, 2000. Daffos F, Forestier F, Capella-Pavlovsky M, et al.: Prenatal management of 746 pregnancies at risk for congenital toxoplasmosis. N Engl J Med 318:271–275, 1988. Desmonts G, Couvreur J: Congenital toxoplasmosis: A prospective study of 378 pregnancies. N Engl J Med 290:1110–1116, 1974. Foulon W, Pinon J-M, Stray-Pedersen B, et al.: Prenatal diagnosis of congenital Toxoplasmosis: a multicenter evaluation of different diagnostic parameter. Am J Obstet Gynecol 181: 1999. Foulon W, Villena I, Stray-Pedersen B, et al.: Treatment of toxoplasmosis during pregnancy: a multicenter study of impact on fetal transmission and children’s sequelae at age 1 year. Am J Obstet Gynecol 190:410–415, 1999. Fricker-Hidalgo H, Pelloux H, Muet F, et al.: Prenatal diagnosis of congenital toxoplasmosis: comparative value of fetal blood and amniotic fluid using serological techniques and cultures. Prenat Diagn 17:831–835, 1997. Guerina NG, Hsu H-W, Meissner HC, et al.: Neonatal serologic screening and early treatment for congenital Toxoplasma Gondii infection. N Engl J Med 330:1858–1863, 1994. Hall SM: Congenital toxoplasmosis. Brit Med J 305:291–297, 1992. Hezard N, Marx-Chemla C, Foudrinier F, et al.: Prenatal diagnosis of congenital toxoplasmosis in 261 pregnancies. Prenat Diagn 17:1047–1054, 1997. Hohlfeld P, Daffos F, Thulliez P, et al.: Fetal toxoplasmosis: outcome of pregnancy and infant follow-up after in utero treatment. J Pediatr 115:765–769, 1989. Hohlfeld P, Dafos F, Costa JM, et al.: Prenatal diagnosis of congenital toxoplasmosis with a polymerase-chain-reaction test on amniotic fluid. N Engl J Med 331:695–699, 1994. Hovakimyan A, Cunningham ET Jr: Ocular toxoplasmosis. Ophthalmol Clin N Amer 15:327–332, 2002. Jones J, Lopez A, Wilson M: Congenital toxoplasmosis. Am Fam Physician 67:2131–2138, 2000. Kuhlmann RS, Autry AM: An approach to nonbacterial infections Lopez A, Dietz VJ, Wilson M, et al.: Preventing congenital toxoplasmosis. Morbidity Mortality Weekly Report 49(RR-2):57, 2000. Lopez A, Dietz VJ, Wilson M, et al.: Preventing congenital toxoplasmosis. Morbidity Mortality Weekly Report 49(RR-2), 2000. Lynfield R, Eaton RB: Teratogen update: congenital toxoplasmosis. Teratology 52:176–180, 1995. Metz MB: Eye manifestations of intrauterine infections. Ophthalmol Clin N Am 14:521–531, 2001. Naessens A, Jenum PA, Pollak A, et al.: Diagnosis of congenital toxoplasmosis in the neonatal period: a multicenter evaluation. J Pediatr 135:714–719, 1999. Pataki, Meszner Z, Todorova R: Congenital toxoplasmosis. Int Pediatr 15:33–36, 2000. Patel DV, Holfels EM, Vogel NP, et al.: Resolution of intracranial calcifications in infants with treated congenital toxoplasmosis. Radiology 199:433–440, 1996. Remington JS: Toxoplasmosis in the adult. Bull N Y Acad Med 50:211–227, 1974. Roizen N, Swisher CN, Stein MA, et al.: Neurologic and developmental outcome in treated congenital toxoplasmosis. Pediatrics 95:11–20, 1995. Sever JL, Ellenberg JH, Ley AC, et al.: Toxoplasmosis: Maternal and pediatric findings in 23,000 pregnancies. Pediatrics 82:181–192, 1988. Wilson CB, Remington JS: What can be done to prevent congenital toxoplasmosis? Am J Obstet Gynecol 138:357–363, 1980.
CONGENITAL TOXOPLASMOSIS
Fig. 1. A newborn died of congenital generalized toxoplasma infection. The heart showed myocarditis with presence of toxoplasma cyst (arrow) (H & E, ×400)
Fig. 2. Toxoplasma cyst seen in high magnification (arrow) (H & E, ×1000)
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Fig. 4. A small area of resolving acute toxoplasmic retinochoroiditis adjacent to a larger area of healed congenital toxoplasmosis scar.
Fig. 5. Satelitte lesions of acute exacerbation of toxoplasmic retinochoroiditis adjacent to a larger scar of healed congenital ocular toxoplasmosis.
Fig. 3. Mild acute chorionitis associated with toxoplasma infection. A toxoplasma cyst was found in chorionic plate of the placental disc (H & E, ×1000) Fig. 6. Diffusely scattered punctate cerebral calcifications secondary to congenitally acquired toxoplasmosis
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Fig. 7. An adult with congenital toxoplasmosis who had mental retardation, seizures, and chorioretinitis. CT of the brain showed scattered multiple foci of intracerebral calcifications.
Conjoined Twins Conjoined twins are incompletely separated monozygotic twins. They have long fascinated both medical profession and lay public. Such events are rare and occur in 1/50,000 to 1/100,000 births and one in 400 sets of monozygotic twins. It is a complication of monochorionic twinning at 13 to 15 days after conception.
GENETICS/BASIC DEFECTS 1. Conjoined twins a. Rare variants of monozygotic, monochorionic twins b. Two theories of con-joined twin formation i. Resulting from the secondary union of two originally separate monovular embryonic discs ii. Resulting from an incomplete separation of the inner cell mass at around 13–15 days of gestation of the monovular twins c. Twins can be conjoined at any site from the cranium downward to the sacrococcygeal region d. Approximately 60% are stillborn e. Female predominance: approximately 3:1 female-tomale ratio 2. Embryologic classification of conjoined twins a. Ventral (87%) i. Rostral (48%) a) Cephalopagus 11% b) Thoracopagus 19% c) Omphalopagus 18% ii. Caudal (11%) (ischiopagus) iii. Lateral (28%) (parapagus) b. Dorsal (13%) i. Craniopagus (5%) ii. Rachipagus(2%) iii. Pygopagus (6%) 3. Anatomic classifications of conjoined twins, based on how the body axes of the twins are mutually oriented in the embryonic disc a. Notochordal axes facing each other i. Ventro-ventral a) Thoracopagus b) Xiphopagus c) Omphalopagus ii. Cranial ventro-vental (cephalothoracopagus) iii. Caudal ventro-ventral (ischiopagus) iv. Cranial end-to-end (craniopagus) v. Caudal end-to-end (pygopagus) b. Notochordal axes facing side-by-side i. Dicephalus ii. Diprosopus 4. Anatomic classifications of conjoined twins, based on how the subsequent events of migration, growth, and body folding result in different types of conjoined twins a. Dipygus b. Fetus-in-fetu 241
i. A fetiform mass located within a basically normal fetus ii. Inclusion of a monozygotic diamniotic twin within the bearer is the best explanation 5. Duplicitas symmetros (symmetrical conjoined twins resulting from incomplete fission of the uniovum) a. Terata Katadidyma (twins joined at the lower part of the body and double above) i. Dicephalus (twins with 2 separate heads and necks side by side with 1 body; lateral conjugation) ii. Diprosopus (twins with 2 faces side by side, 1 head, and 1 body) iii. Ischiopagus (twins joined by the inferior margins of the coccyx and sacrum with 2 completely separate spinal columns; caudal conjugation) iv. Pygopagus (twins joined by posterior surfaces of the coccyx and sacrum, back to back; posterior conjugation) v. Craniothoracopagus vi. Ileothoracopagus b. Terata anadidyma (twins joined at the upper part of the body and double below) i. Craniopagus (twins joined at the top of cranial vaults; cephalic conjugation) ii. Dipygus (twins with 1 head, 1 thorax, 1 abdomen, and double pelvis with or without 2 sets of external genitalia and up to 4 legs; lateral conjugation) iii. Syncephalus (twins joined by the face; the faces turn laterally) c. Tera anakatadidyma (twins joined by the midportion of the body) i. Omphalopaus (twins joined from the umbilicus to xiphoid cartilage; anterior conjugation) ii. Xiphopagus (twins joined at xiphoid process) iii. Rachipagus (twins joint by the vertebral column; back to back) iv. Thoracopagus (twins joined at the chest wall; anterior conjugation) 6. Duplicatas asymmetros (asymmetrical conjoined twins resulting from unequal and incomplete fission of the uniovum and unequal placental circulation to twins) a. Cephalic conjugation i. Craniopagus parasiticus ii. Janus parasiticus iii. Epignathus heteropagus b. Anterior conjugation i. Thoracopagus parasiticus ii. Epigastrius c. Posterior conjugation i. Ischiopagus parasiticus ii. Pyopagus parasiticus iii. Sacral parasiticus
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CONJOINED TWINS
CLINICAL FEATURES 1. Thoracopagus twins a. Represents 40% of conjoined twins b. Conjoined at the thoracic region c. Face to face d. Associated congenital heart defects i. Present in 75% of cases ii. Presence of varying degree of pericardial sac fusion iii. A conjoined heart with two ventricles and a varying number of atria (most frequent abnormality) iv. Ventricular septal defect in virtually all patients 2. Omphalopagus twins (fused umbilical region)/Xiphopagus twins (fused xiphoid process of sternum) a. Constitutes one third of all types of conjoined twins b. The most readily separable conjoined twins since their union may involve only skin and portions of the liver, occasionally including portions of the sternum c. Most omphalopagus twins joined by a skin bridge that contains liver and bowel d. Conjoined liver in 81% e. Conjoined sternal cartilage in 26% f. Conjoined diaphragm in 17% g. Conjoined genitourinary tract in 3% h. Malformations of the abdominal wall (usually omphalocele) in at least one of the twins in 33% i. Congenital heart defects in at least one of the twins in 25% i. Ventricular septal defects ii. Tetralogy of Fallot j. Concordant congenital heart defects in only one out of 9 sets of twins 3. Pygopagus twins a. Constitutes 19% of conjoined twins b. Conjoined at sacrum (buttocks and lower spine) c. Most commonly back-to-back (face away from each other) d. May share part of the sacral spinal canal e. May share common rectum and anus f. Often with fused genitalia 4. Ischiopagus twins a. Constitutes 6% of conjoined twins b. Conjoined back-to-back at the coccyx c. Often with a common large pelvic ring formed by the union of the two pelvic girdles d. May have 4 legs (ischiopagus tetrapus) e. May have three legs (ischiopagus tripus) f. Frequently share the lower gastrointestinal tract i. Intestines joined at the terminal ileum ii. Emptying into a single colon g. May have a single bladder and urethra h. Displaced anus i. Common vaginal anomalies j. Common rectovaginal communications 5. Craniopagus twins (fused at the cranial vault) (2%) a. Classification according to the area of junction i. Frontal craniopagus ii. Parietal craniopagus (most common)
6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
16.
17.
18.
iii. Temporal craniopagus iv. Occipital craniopagus b. Classification based on surgical and prognostic purposes i. Partial type (brains separated by bone or dura with each brain having separate leptomeninges) ii. Complete type (presence of cerebral connection) Rachiopagus twins (fused upper spinal column; back to back) Pygodidymus twins (fused cephalothoracic region; duplicate pelves and lower extremities) Pygopagus twins/pygomelus twins (joined back-to-back at the sacrum; additional limb or limbs at or near buttock) Iniopagus twins/craniopagus occipitalis twins (fused head, at parasitic occipital region) Epicomus twins/craniopagus parasiticus twins (smaller, parasitic twin joined to larger autosite at occiput) Monocephalus twins (single head with 2 bodies) Diprosopus twins (single body with 2 faces) Dicephalus twins (symmetric body with 2 heads) Dipygus parasiticus twins (head and thorax completely merged; pelvis and lower extremities duplicated) Cephalopagus conjoined twins a. The rarest type of conjoined twins b. Fused from the top of the head to the umbilicus c. Presence of two faces on the opposite sides of the head with one face usually being rudimentary d. Separation of the lower abdomen e. With 4 arms and 4 legs f. Prognosis dismal dependent on the following factors i. Presence of associated anomalies ii. Degree of fusion of the intracranial, intrathoracic and/or intra-abdominal structures iii. Extent of venous connections Epigastric heteropagus twins a. A rare type of conjoined twinning b. Resulting from an ischemic atrophy of one fetus at an early stage of gestation c. Pelvis and lower limbs of the ischemic fetus (incomplete parasitic twin; heteropagus) attached to the epigastrium of the well-developed fetus (the autosite) Fetus in fetu a. The parasites embodied in the autosite, usually within cranial, thoracic, and abdominal cavities during the developmental process of the asymmetrical conjoined twins b. Most likely arise from inclusion of a monochorionic, diamniotic, monozygotic twin within the bearer due to anastomoses of vitillene circulation Prognosis a. A high mortality rate i. Nearly 40% are stillborn ii. 1/3 die within 24 hours of birth iii. No prospect of survival when complex cardiac union is present b. Causes of death i. Severely abnormal conjoined heart ii. Pulmonary hypoplasia due to distortion of fused thoracic cages
CONJOINED TWINS
19. Examples of historically famous conjoined twins a. So-called Biddenden Maids (1100–1134) in England i. Probably pyopagus twins ii. Their famous image imprinted on the “cakes” iii. Walks with their arms around each other b. Chang and Eng Bunker (1811–1874) from Bangkok and settled in the USA (“Siamese twins”) i. Later married to twin girls ii. Fathered 22 children c. Blazˇek sisters (1878–1922) from Bohemia i. 2 heads ii. 4 arms iii. 4 legs iv. Partially fused torso v. Combined reproductive organs vi. Delivered an infant through a single vagina but the gestation had occurred in the uterus of one of the twins
DIAGNOSTIC INVESTIGATIONS 1. Prenatal echocardiography a. Presence and extent of cardiac conjunction b. Associated cardiac defects 2. Prenatal radiography 3. Prenatal ultrasonography (including transvaginal twodimensional sonography), especially three-dimensional sonographic examinations (The surface-rendered image of the conjoined twin and its demonstration on an axially rotating cine loop facilitates explanation of the precise nature of the abnormalities, especially in the case of cephalothoracopagus conjoining) 4. CAT scan and MRI of the abdomen and the chest a. Anatomy of the heart b. Anatomy of the livers c. Anatomy of the genitourinary systems 5. Gastrointestinal contrast studies to demonstrate the presence and level of conjunction of the intestinal tract 6. Ventrally fused conjoined twins a. Prenatal radiography/ultrasonography i. Fetal body parts on the same level ii. Constant relative fetal position iii. Fetal extremities in unusual proximity iv. Face-to-face fetal position v. Bibreech, less commonly bicephalic presentation vi. Hyperextension of one or both cervical spines b. Prenatal ultrasonography i. Nonseparable continuous external skin contour ii. Single heart sound by Doppler iii. Solitary large liver and heart iv. Multiple shared omenta v. Solitary umbilical cord with >3 vessels 7. Cephalothoracopagus a. Prenatal radiographic criteria i. Both fetal heads at the same level ii. Backward fusion of the cervical spines iii. A narrow space between lower cervical and upper thoracic spines iv. No change in fetal relative positions after maternal movement
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b. Prenatal sonographic criteria i. Fusion of the skulls, face, thorax, and upper abdomen ii. Fetal body parts at the same level iii. Constant relative fetal motion iv. Fetal extremities in unusual positions v. Breech position vi. Hyperextension of both cervical spines vii. Nonseparable external skin contour viii. A solitary umbilical cord with multiple vessels ix. Polyhydramnios x. Two actively beating hearts xi. Two sets of pelves, limbs and spine
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not higher according to family study b. Patient’s offspring: report of delivery of a healthy male infant to the pygopagus Blazˇek sisters 2. Prenatal diagnosis a. Radiography b. 2D/3D ultrasonography: prenatal diagnosis made as early as 10–12 weeks’ gestation c. Transcervical embryoscopy for first trimester embryonic evaluation of conjoined twins after a missed abortion 3. Management a. Early prenatal diagnosis: highly desirable, given the extremely poor prognosis of some types of conjoined twins b. Psychological and prognosis counseling c. Accurate preoperative investigation d. A team approach e. Previous experience f. Meticulous operative and postoperative management g. Substantial mortality rate related to the underlying conditions h. High likelihood of success if major associated anomalies are absent i. Options of obstetrical management i. Continue the vaginal delivery and deliver the twins intact ii. Deliver the twins vaginally after intrauterine separation or a destructive procedure iii. Cesarean section and deliver the twins intact iv. Cesarean section and deliver the twins after intrauterine separation or destruction j. Anesthetic management for separating operations i. Extensive cross circulation a) Through a liver bridge b) Common cerebral venous sinus ii. Mechanical problems a) One anesthetist required for each infant b) A third anesthetist to look after intravenous infusions and monitors c) A fourth anesthetist to look after massive blood loss, circulatory collapse or other catastrophic occurrence iii. Anticipate complex congenital heart defects that was not diagnosed preoperatively
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REFERENCES Awashi M, Narlawar R, Hira P, et al.: Fetus in fetu. Rare cause of a lump in an adult’s abdomen. Aust Radiol 45:354–356, 2001. Bega G, Wapner R, Lev-Toaff A, et al.: Diagnosis of conjoined twins at 10 weeks using three-dimensional ultrasound: a case report. Ultrasound Obstet Gynecol 16:388–390, 2000. Benirschke K, Temple WW, Bloor CM: Conjoined twin: nosologic and congenital malformation Birth Defects 15:179–192, 1978. Benirschke K: Sonographic diagnosis of conjoined twinning. Ultrasound Obstet Gynecol 1:241, 1998. Biswas A, Chia D, Wong YC: Three-dimensional sonographic diagnosis of cephalothoracopagus janiceps twins at 13 weeks. Ultrasound Obstet Gynecol 18:289, 2001. Bonilla-Musoles F, Machado LE, Osborne Nat Genet, et al.: Two-dimensional and three-dimensional sonography of conjoined twins. J Clin Ultrasound 30:68–75, 2002. Chen C-P, Lee C-C, Liu F-F, et al.: Prenatal diagnosis of cephalothoracopagus janiceps monosymmetros. Prenat Diagn 17:384–388, 1997. Chou SY, Liang SJ, Wu CF, et al.: Sacral parasite conjoined twin. Obstet Gynecol 98:938–940, 2001. Edmonds LD, Layde PM: Conjoined twins in the United States. 1970–1977. Teratology 25:301–308, 1982. Gilbert-Barness E, Debich-Spicer D, Opitz JM: Conjoined twins: morphogenesis of the heart and a review. Am J Med Genet 120A:568–582, 2003. Gore RM, Filly RA, Parer JT: Sonographic antepartum diagnosis of conjoined twins. Its impact on obstetric management. JAMA 247:3351–3353, 1982. Guttmacher AF: Biographical notes on some famous conjoined twins. Birth Defects Original Article Series III(1):10–17, 1967. Guttmacher AF, Nichols BL: Teratology of conjoined twins. Birth Defects Orig Artic Ser 3(1):3–9, 1967. Harper RG, Kenigsberg K, Sia CG, et al.: Xiphopagus conjoined twin: a 300year review of the obstetric, morphopathologic, neonatal, and surgical parameters. Am J Obstet Gynecol 137:617–629, 1980. Herbert WNP, Cefalo RC, Koontz WL: Perinatal management of conjoined twins. Am J Perinatal 1:58–63, 1983. Keats AS, Cave PE, Slataper EL, et al.: Conjoined twins-A review of anesthetic management for separating operations. Birth Defects Original Article Series III(1):80–88, 1967. Knox JS, Webb AJ: The clinical features and treatment of fetus in fetu: two case reports and review of literature. J Pediatr Surg 10:483–489, 1975. Kuroda K, Kamei Y, Kozuma S, et al.: Prenatal evaluation of cephalopagus conjoined twins by means of three-dimensional ultrasound at 13 weeks of pregnancy. Ultrasound Obstet Gynecol 16:264–266, 2000. Lam YH, Sin SY, Lam C, et al.: Prenatal sonographic diagnosis of conjoined twins in the first trimester: two case reports. Ultrasound Obstet Gynecol 11:289–291, 1998.
Maymon R, Halperin R, Weinraub Z, et al.: Three-dimensional transvaginal sonography of conjoined twins at 10 weeks: a case report. Ultrasound Obstet Gynecol 11:292–294, 1998. Machin GA: Multiple pregnancies and conjoined twins. In Gilbert-Barness E (ed.): Potter’s Pathology of the Fetus and Infant. St. Louis, Mosby, 1997, Ch 9, pp 281–321. Nastanski F, Downey EC: Fetus in fetu: a rare cause of a neonatal mass. Ultrasound Obstet Gynecol 18:72–75, 2001. Petit T, Raynal P, Ravasse P, et al.: Prenatal sonographic diagnosis of a twinning Epigastric heteropagus. Ultrasound Obstet Gynecol 17:534–535, 2001. Rudolph AJ, Michaels JP, Nichols BL: Obstetric management of conjoined twins. Birth Defects Original Article Series III(1):28–37, 1967. Sanders SP, Chin AJ, Parness IA, et al.: Prenatal diagnosis of congenital heart defects in thoracoabdominally conjoined twins. N Engl J Med 313:370–374, 1985. Sills ES, Vrbikova J, Kastratovic-Kotlica B: Conjoined twins, conception, pregnancy, and delivery: A reproductive history of the pygopagus Blazˇek sisters (1878–1922). Am J Obstet Gynecol 185:1396–1402, 2001. Spencer R: Anatomic description of conjoined twins: a plea for standardized terminology. J Pediatr Surg 31:941944, 1996. Spencer R: Theoretical and analytical embryology of conjoined twins: Part I: Embryogenesis. Clin Anat 13:36–53, 2000. Spencer R: Theoretical and analytical embryology of conjoined twins: Part II: Adjustments to union. Clin Anat 13:97–120, 2000. Spencer R: Parasitic conjoined twins: external, internal (fetuses in fetu and teratomas), and detached (acardiacs). Clin Anat 14:428–444, 2001. Spitz L, Kiely EM: Experience in the management of conjoined twins. Brit J Surg 89:1188–1192, 2002. Tan A, Lee S-L: Prenatal diagnosis of parasitic twins using three-dimensional ultrasound: a case report. Ultrasound Obstet Gynecol 20:192–193, 2002. Tongsong T, Chanprapaph P, Pongsatha S: First-trimester diagnosis of conjoined twins: a report of three cases. Ultrasound Obstet Gynecol 14:434–437, 1999. Van Den Brand SF, Nijhuis JG, Van Dongen PW: Prenatal ultrasound diagnosis of conjoined twins. Obstet Gynecol Surv 49:656–662, 1994. Weingast GR, Johnson ML, Pretorius DH, et al.: Difficulty in sonographic diagnosis of cephalothoracopagus. J Ultrasound Med 3:421–423, 1984. Wilcox DT, Quinn FM, Spitz L, et al.: Urological problems in conjoined twins. Brit J Urol 81:905–910, 1998. Yin CS, Chen W-H, Wei RY-C, et al.: Transcervical embryoscopic diagnosis of conjoined twins in a ten-week missed abortion. Prenat Diagn 18:626–628, 1998. Zimmermann AA: Embryological and anatomic considerations of conjoined twins. Birth Defects 3:18–27, 1967.
CONJOINED TWINS
Fig. 1. The conjoined twins are joined at the level of abdomen from umbilicus to the xiphoid cartilage (xiphoomphalopagus). This type of conjoined twins is the one most amenable to successful surgical correction because the incidence of complex anatomical anomalies is low. Left twin was successfully separated from the right twin who succumbed shortly after surgery to multiple congenital anomalies including exstrophy of the cloaca, left Bochdalek hernia, hypoplastic kidney, hypoplastic lungs, imperforate anus, and a large sacral meningomyelocele.
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Fig. 3. These twins are thoraco-omphalopagus, connected at the thorax and upper abdomen. The heart showed complex anomalies with a common atrium and a single ventricle. Therefore, separation of the twins was not attempted.
Fig. 4. The radiograph of the twins in Fig. 3 showing the connection at the thorax and the upper abdomen.
Fig. 2. Prenatal ultrasound (A) detected the above conjoined twins with a shared liver (CAB) and separate hearts, stomach, pelvis, and extremities. One fetus was noted to have a meningomyelocele (M). The magnified view (B) shows part of the shared liver and meningomyelocele.
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Fig. 5. Dicephalic conjoined twins. Two separate heads, two separate necks, and only one body are evident. The twins shared a common pericardium with complex cardiac anomalies, a common aorta at the level of iliac arteries, a common small intestine and other GI tract distally, a common bladder and urethra drained from a single kidney from each twin, and single normal female genitalia with normally placed fallopian tubes and ovaries. Surgical separation of the twins was deemed impossible and was not attempted.
Fig. 7. A stillbirth with dicephalic conjoined twins.
Fig. 8. A set of dicephalic conjoined twin embryos at 6–7 weeks of gestation.
Fig. 6. The radiograph of the above-conjoined twins showing separate heads, vertebrae, and upper GI tract. There is one pericardium sac and a fused liver.
Corpus Callosum Agenesis/Dysgenesis Agenesis/dysgenesis of the corpus callosum is among the most common brain developmental malformation with a wide spectrum of associated clinical and pathologic abnormalities. The prevalence and clinical significance are uncertain. It is estimated to be 0.3–0.7% in the general population and 2–3% in the developmentally disabled.
GENETICS/BASIC DEFECTS 1. Markedly heterogeneous etiology of agenesis/dysgenesis of the corpus callosum a. Sporadic in most cases b. Environmental factors i. Alcoholism ii. Maternal rubella iii. Maternal diabetes c. A multifactorial trait d. As a part of autosomal dominant syndrome i. Agenesis/dysgenesis of the corpus callosum ii. Apert syndrome iii. Basal cell nevus syndrome iv. Miller-Dieker syndrome v. Rubinstein-Taybi syndrome vi. Tuberous sclerosis e. As a part of autosomal recessive syndrome i. Agenesis/dysgenesis of the corpus callosum ii. Agenesis/dysgenesis of the corpus callosum with thrombocytopenia iii. Acrocallosal syndrome iv. Andermann syndrome a) Agenesis/dysgenesis of the corpus callosum with peripheral neuropathy b) Mapping of the gene to a 5-cm region in chromosome 15q13-15 v. Cerebro-oculo-facio-skeletal (COFS) syndrome vi. Cogan syndrome (ocular motor apraxia) vii. Craniotelencephalic dysplasia viii. Dincsoy syndrome a) Multiple midline malformations b) Limb abnormalities c) Hypopituitarism ix. Fukuyama congenital muscular dystrophy x. Hydrolethalis syndrome xi. Joubert syndrome (cerebellar vermis agenesis) xii. Leprechaunism xiii. Lowry-Wood syndrome a) Epiphyseal dysplasia b) Microcephaly c) Nystagmus xiv. Meckel-Gruber syndrome xv. Microcephalic osteodysplastic primordial dwarfism type I/III xvi. Neu-Laxova syndrome 247
xvii. Opitz G syndrome xviii. Peters plus syndrome a) Peters anomaly b) Short-limb dwarfism xix. Shapiro syndrome (recurrent hypothermia) xx. Smith-Lemli-Opitz syndrome xxi. Toriello-Carey syndrome a) Agenesis/dysgenesis of the corpus callosum b) Facial anomalies c) Robin sequence xxii. Vici syndrome a) Agenesis/dysgenesis of the corpus callosum b) Immunodeficiency c) Cleft lip/palate d) Cataract e) Hypopigmentation xxiii. Walker-Warburg syndrome a) Hydrocephalus b) Agyria c) Retinal dysplasia xxiv. Warburg micro syndrome a) Microcephaly b) Microphthalmia c) Cerebral malformations d) Other anomalies f. As a part of X-linked syndrome i. Agenesis/dysgenesis of the corpus callosum ii. Agenesis/dysgenesis of the corpus callosum with Hirschsprung disease iii. Agenesis/dysgenesis of the corpus callosum with hypohidrotic ectodermal dysplasia iv. Aicardi syndrome (retinovertebral anomalies in females) v. ATR-X syndrome (X-linked alpha thalassemia mental retardation syndrome) vi. Craniofrontonasal syndrome vii. Curatolo syndrome a) Agenesis/dysgenesis of the corpus callosum b) Chorioretinal abnormality viii. FG syndrome a) Mental retardation b) Large head c) Imperforate anus d) Congenital Hypotonia e) Partial agenesis/dysgenesis of the corpus callosum ix. HSAS syndrome (hydrocephalus due to congenital stenosis of aqueduct of Sylvius) x. Lenz dysplasia a) Microphthalmia/anophthalmia b) Associated anomalies xi. Lujan-Fryns syndrome
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a) X-linked mental retardation b) Marfanoid habitus xii. MASA syndrome a) Mental retardation b) Aphasia c) Shuffling gait d) Adducted thumbs xiii. MLS syndrome a) Microphthalmia b) Linear skin defects xiv. Opitz G syndrome xv. OFD I xvi. Proud syndrome a) X-linked syndrome b) Seizures c) Acquired micrencephaly d) Agenesis/dysgenesis of the corpus callosum xvii. XLIS syndrome (X-linked lissencephaly) g. As a part of unknown-genesis syndrome i. Calloso-genital dysplasia ii. Delleman (oculocerebrocutaneous) syndrome iii. Frontonasal dysplasia iv. Opitz C trigonocephaly syndrome v. Sebaceous nevus syndrome h. As a part of metabolic disorders i. Adenylosuccinase deficiency ii. Adipsic hypernatremia iii. β-hydroxyisobutyryl coenzyme A deacyclase deficiency iv. Glutaric aciduria type II v. Histidinemia vi. Hurler syndrome vii. Leigh syndrome viii. Menkes syndrome ix. Neonatal adrenoleukodystrophy x. Nonketotic hyperglycinemia xi. Pyruvate dehydrogenase deficiency xii. Zellweger syndrome i. Associated chromosome abnormalities i. Trisomy 18 ii. Trisomy 8 iii. Trisomy 21 iv. Trisomy 22 v. Other trisomies vi. Deletions vii. Translocations viii. Duplications j. Agenesis of the corpus callosum with interhemispheric cyst: a heterogeneous group of disorders that have in common callosal agenesis and extraparenchymal cysts, both of which are among the commonest CNS malformations k. Incidental finding in normal individuals (isolated dysgenesis of the corpus callosum) 2. Embryogenesis of the corpus callosum a. Development of the corpus callosum i. A late event in cerebral ontogenesis ii. Taking place between 12–18 weeks of gestation b. An important brain commissure connecting the cerebral hemispheres
c. Essential for efficient cognitive function d. Failure of development of the commissural fibers connecting the cerebral hemispheres produces dysgenesis or agenesis of the corpus callosum e. Diagnosis of agenesis: a challenge even for expert sonologists, particularly prior to 20 weeks of gestation 3. Types of agenesis a. Complete agenesis: commonly regarded as a malformation deriving from faulty embryogenesis b. Type I agenesis i. Not associated with other disorder ii. Usually absent or associated with mild neurologic manifestations c. Type II agenesis i. Associated with other migrational, genetic, and chromosomal disorders ii. Usually associated with severe neurologic manifestations d. Partial agenesis i. Referred to as dysgenesis ii. Either a true malformation or a disruptive event occurring at any time during pregnancy iii. Missing caudad portion (splenium and body) to varying degrees 4. Agenesis/dysgenesis of the corpus callosum a. Without other associated brain anomalies b. Frequently associated with other brain anomalies i. Defects of septum pellucidum and fornix ii. Hydrocephalus iii. Dandy-Walker malformation iv. Interhemispheric cyst v. Holoprosencephaly vi. Porencephaly vii. Polymicrogyria viii. Macrogyria ix. Cortical heterotopia and atrophy x. Lipoma xi. Encephalocele xii. Hypoplasia of cerebellum c. Frequently associated other anatomical anomalies i. Congenital heart defects ii. Costovertebral defects iii. Gastrointestinal anomalies iv. Genitourinary anomalies
CLINICAL FEATURES 1. Craniofacial abnormalities a. Microcephaly b. Macrocephaly 2. Developmental anomalies a. Nonspecific mental retardation b. Developmental delay c. Learning disabilities d. Behavioral disorder e. Mental retardation f. Failure to thrive 3. Infantile spasms/seizures 4. Signs and symptoms related to type I and type II agenesis a. Type I
CORPUS CALLOSUM AGENESIS/DYSGENESIS
i. Variable intelligence: normal to mild or moderate mental retardation ii. Seizure disorder iii. Impaired visual, motor, and/or bimanual coordination iv. Mild impairment of crossed tactile localization and skills requiring matching of visual patterns b. Type II i. Mental retardation ii. Seizures iii. Hydrocephaly iv. Microcephaly v. Hemiparesis vi. Diplegia vii. Spasticity viii. Failure to thrive
DIAGNOSTIC INVESTIGATIONS 1. Psychometric tests a. Difficulties in motor coordination b. Difficulties in inter-hemispheric transfer of tactile information c. Difficulties in some areas of memory d. A marked difference in verbal IQ and performance IQ in children 2. EEG for seizure activities 3. CT and/or ultrasound of the brain a. Absence of the corpus callosum b. Absence of septum pellucidum c. Increased separation of the lateral ventricles d. Marked separation of the slit-like anterior horns of the lateral ventricles and dilatation of the occipital horns creating the typical ‘rabbit’s ear’ or ‘tear drop’ appearance e. Upward displacement of the third ventricle f. Evidence of other migration disorders 4. Coronal radiographs showing a pathognomonic bat-wing ventricular pattern 5. Karyotyping for underlying chromosomal disorder 6. Metabolic studies for underlying inborn error of metabolism
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: depending on the etiology and the mode of inheritance i. Isolated Agenesis/dysgenesis of the corpus callosum: recurrence risk not increased ii. Environmental factor: recurrence risk not increased by avoiding the environmental factor iii. Autosomal recessive inheritance: 25% of siblings affected, 50% siblings carriers, and 25% of siblings normal iv. Autosomal dominant inheritance: recurrence risk not increased unless a parent is affected in which case the recurrence risk is 50% v. X-linked recessive inheritance a) Carrier mother (50% of brothers affected; 50% of sisters carriers)
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b) Affected father (all brothers normal, all sisters carriers) vi. X-linked dominant inheritance a) Affected mother (50% of brothers and sisters affected) b) Affected father (all brothers normal; all sisters affected) vii. Chromosomal disorder: recurrence risk increased, especially if a parent carries a balanced translocation b. Patient’s offspring i. Environmental factor: recurrence risk not increased by avoiding the environmental factor ii. Autosomal recessive inheritance: recurrence risk not increased unless the spouse is also a carrier in which case the recurrence risk is 50% iii. Autosomal dominant inheritance: 50% iv. X-linked recessive inheritance a) Carrier female (50% of sons affected, 50% of daughters carriers) b) Affected male (all sons normal, all daughters carriers) v. X-linked dominant inheritance a) Affected female (50% of sons and daughters affected) b) Affected male (all sons normal, all daughters affected) vi. Chromosomal disorder: recurrence risk increased, especially if a parent carries a balanced translocation 2. Prenatal diagnosis a. Ultrasonography i. Prenatal detection of the agenesis of the corpus callosum usually not possible before 22 weeks of gestations ii. Direct demonstration of the absence or partial absence of the corpus callosum iii. Failure to visualize the cavum septum pellucidum iv. Third ventricle lying between widely separated lateral ventricles due to absent corpus callosum v. Lateral ventricles more parallel to the midline than usual vi. A cyst arising from the superior aspect of the third ventricle communicating with the lateral ventricles vii. Vertical orientation of the gyri with agenesis instead of normal horizontal alignment viii. Colpocephaly (locally dilated occipital horns of the lateral ventricle) forming an appearance on axial views similar to bulls’ horns ix. Absence of pericallosal artery x. Up to 50% of cases with other associated anatomic defects xi. Variable developmental outcome on prenatal detection of an isolated agenesis of the corpus callosum b. MRI i. Allows more detailed visualization of the fetal brain than ultrasonography
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ii. Constitutes a useful additional procedure after ultrasonographic diagnosis or suspicion of corpus callosum agenesis c. Amniocentesis recommended for karyotyping as there is 10–20% risk of aneuploidy associated with the agenesis of the corpus callosum d. Prenatal counselling for ultrasonically diagnosed fetal agenesis of the corpus callosum remains very difficult, as giving precise information on outcome is impossible. The following observation, however, may be of help in prenatal counseling: i. Isolated agenesis/dysgenesis of the corpus callosum (in the absence of other sonographically detectable anomalies) carrying apparent excellent prognosis a) 85% chance of a normal developmental outcome b) 15% risk of handicap ii. Agenesis/dysgenesis of the corpus callosum with other associated anomalies: poor outcome 3. Management a. Identification of actual deficits resulting from the absence of such a major structure (corpus callosum): clearly an issue b. Multidisciplinary team approach to intervention programs c. Anticonvulsants for seizures d. Management based on the underlying etiology
REFERENCES Achiron R, Achiron A: Development of the human fetal corpus callosum: a high-resolution, cross-sectional sonographic study. Ultrasound Obstet Gynecol 18:343–347, 2001.
Barkovich AJ, Simon EM, Walsh CA: Callosal agenesis with cyst. A better understanding and new classification. Neurology 56:220–227, 2001. Bennett GL, Bromley B, Benacerraf BR: Agenesis of the corpus callosum: prenatal detection usually is not possible before 22 weeks of gestation. Radiology 199:447–450, 1996. Casaubon LK, Melanson M, Lopes-Cendes I, et al.: The gene responsible for a severe form of peripheral neuropathy and agenesis of the corpus callosum maps to chromosome 15q. Am J Hum Genet 58:28–34, 1996. da-Silva EO: Callosal defect, microcephaly, severe mental retardation, and other anomalies in three sibs. Am J Med Genet 29:837–843, 1988. D’Ercole C, Girard N, Cravello L, et al.: Prenatal diagnosis of fetal corpus callosum agenesis by ultrasonography and magnetic resonance imaging. Prenat Diagn 18:247–253, 1998. Dobyns WB: Absence makes the search grow longer. (Editorial) Am J Hum Genet 58:7–16, 1996. Finlay DC, Peto T, Payling J, et al.: A study of three cases of familial related agenesis of the corpus callosum. J Clin Exp Neuropsychol 22:731–742, 2000. Gupta JK, Lilford RJ: Assessment and management of fetal agenesis of the corpus callosum. Prenat Diagn 15:301–312, 1995. Lacey, DJ: Agenesis of the corpus callosum. Clinical features in 40 children. Am J Dis Child 139:953–955, 1985. Loeser JD, Alvord EC: Agenesis of the corpus callosum. Brain 91:553–570, 1968. Moutard M-L, Kieffer V, Feingold J, et al.: Agenesis of corpus callosum: prenatal diagnosis and prognosis. Child Nerv Syst 19:471–476, 2003. Pilu G, Hobbins JC: Sonography of fetal cerebrospinal anomalies. Prenat Diagn 22:321–330, 2002. Pilu GL, Sandri F, Perolo A, et al.: Sonography of fetal agenesis of the corpus callosum: a survey of 35 cases. Ultrasound Obstet Gynecol 3:318–329, 1993. Probst FP: Agenesis of the corpus callosum. Acta Radiol 331 (Suppl):1–150, 1973. Serur D, Jeret JS, Wisniewski K, et al.: Agenesis of the corpus callosum: clinical, neuroradiological and cytogenetic studies. Neuropediatrics 19: 87–91, 1988. Vergani P, Ghidini A, Strobelt N, et al.: Prognostic indicators in the prenatal diagnosis of agenesis of the corpus callosum. Am J Obstet Gynecol 170:753–758, 1994.
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Fig. 1. An infant (ages 3 months and 16 months) with agenesis of the corpus callosum and interhemispheric cyst, illustrated by MRI.
Craniometaphyseal Dysplasia Craniometaphyseal dysplasia (CMD) is a rare craniotubular bone dysplasia in which sclerosis of the skull is associated with abnormal modeling of the metaphyses of the long bones.
GENETICS/BASIC DEFECTS 1. Genetic heterogeneity a. Autosomal dominant form [also called CMD, Jackson type (CMDJ)]: i. CMDJ locus mapped to 5p15.2–p14.1 within a region harboring the human homolog (ANKH) of the mouse progressive ankylosis (ank) gene ii. ANK protein: spans the outer cell membrane and shuttles inorganic pyrophosphate, a major inhibitor of physiologic and pathologic calcification, bone mineralization and bone resorption b. Autosomal recessive form i. Rare ii. Ill-defined iii. Probably heterogeneous iv. Often difficult to diagnose with precision v. Autosomal recessive CMD locus mapped to 6q21–22 2. Basic defects a. Autosomal dominant form: caused by mutations in the human homolog of the mouse progressive ankylosis gene (ANKH) b. Autosomal recessive form i. May involve dysfunctional osteoclasts because reported metabolic responses of affected children to therapy with calcitonin and clacitrol ii. Osteoclast-like cells derived from the bone marrow shown to lack expression of the osteoclast vacuolar proton pump
CLINICAL FEATURES 1. Autosomal dominant form a. General features i. Good general health ii. Normal intelligence iii. Normal stature b. Bony overgrowth of the facial bone resulting in the typical facies: i. Frontal bossing ii. Hypertelorism iii. Paranasal bossing (30% of cases in childhood) a) May be present during infancy b) Tends to regress with age c) Virtually absent by adolescence and early adulthood d) May be associated with some degree of nasal obstruction and frequent mouth breathing 252
iv. Mild to moderate mandibular prognathism v. An open mouth secondary to bony encroachment of the nasal passages vi. Malalignment of the teeth vii. Grotesque hyperostosis of the facial bones viii. Decreased facial movement c. Bony overgrowth of the cranial foramina resulting in the following features: i. Cranial nerve paralysis ii. Nystagmus iii. Optic atrophy iv. Facial palsy (30% of cases) a) Common but variable b) May be unilateral or bilateral c) May occur at any age d) The involvement often fluctuant in early childhood e) May be permanent in adulthood v. Deafness (50% of cases) a) Due to compromised auditory nerve and inner ear by bone overgrowth b) May be unilateral or bilateral c) Often “mixed” in type due to chronic otitis media and upper respiratory tract infection secondary to minor anatomical abnormalities of the airway and sinuses d) Usually partial and rarely profound vi. Less commonly reported conditions a) Compression of the cerebellar tonsils and medulla secondary to a narrowed foramen magnum b) Obstruction of Eustachian tube c) Obstruction of nasolacrimal duct d) Obstruction of nasal passages e) Raised intracranial pressure: rare instances of a potentially lethal rise in intracranial pressure due to hyperostosis of the calvarium d. Abnormal modeling of the metaphyses of the long bones i. Metaphyseal widening of the long and short tubular bones ii. Thin cortical layer iii. Coarse trabeculations e. Clinical and radiographic features improved in later childhood in the dominant form 2. Autosomal recessive form a. Similar to, but more severe than, those seen in the dominant form b. An increasing severity with age c. Progressive overgrowth and craniofacial deformity i. Very severe facial distortion ii. A thick bony wedge over the bridge of the nose iii. Dystopia canthorum
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iv. Ocular hypertelorism v. Enlarged malar prominences and mandible (marked prognathism) vi. Wide alveolar ridge vii. Narrowed nasal passages leading to mouth breathing viii. Dental abnormalities d. Abnormal modeling of the metaphyses of the long bones i. Gradual, club-shaped widening of the metaphyses ii. Thin cortex and undermineralized medullary bone 3. Differential diagnosis a. Pyle disease (metaphyseal dysplasia) i. Frequently confused with craniometaphyseal dysplasia. In Pyle disease, metaphyseal flaring occurs but there is minimal involvement of the skull ii. Autosomal recessive inheritance b. Craniodiaphyseal dysplasia i. Most severe thickening, distortion, and enlargement of the craniofacial region ii. Characterized by diaphyseal endostosis iii. Does not exhibit metaphyseal flaring iv. Inheritance likely autosomal recessive c. Frontometaphyseal dysplasia i. A pronounced bony supra-orbital ridge ii. Hirsutism iii. Long-bone alterations iv. Conductive deafness d. Camurati-Engelmann disease (progressive diaphyseal dysplasia) i. Presence of excess subperiosteal bone in the diaphyses of the long bone ii. Normal metaphyses iii. Rare craniofacial involvement e. Van Buchem disease (hyperostosis corticalis generalisata) i. Dense and thickened craniofacial skeleton ii. Generalized cortical thickening of the long bones mainly due to endosteal bone apposition
DIAGNOSTIC INVESTIGATIONS 1. Normal serum calcium, phosphorous and alkaline phosphatase 2. Radiographic features a. Autosomal dominant form: age-related radiographic features i. Characteristic hyperostosis and sclerosis of the skull ii. Paranasal bony bossing, most evident in early childhood iii. May be present with prognathism and asymmetry iv. Characteristic nonsclerotic widening of the metaphyses of the tubular bones: a major radiographic feature a) Most obvious at the lower end of the femur b) An “Erlenmeyer flask” configuration in childhood
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c) A “club” shape in adulthood b. Autosomal recessive form: severe radiographic manifestations i. Increasing severity with age ii. Sclerosis and hyperostosis of the calvarium, the base of the skull, and the facial bones and mandible iii. Increased bone deposition on the walls of the paranasal sinuses iv. Underpneumatization of mastoid cells v. Gradual, club-shaped widening of the metaphyses vi. Thin cortex and undermineralized medullary bone 3. Gross pathological features a. Thickened “ivory-hard” facial and cranial bones b. Narrow cranial foramina c. Narrowing of the nasal chambers and posterior choanae 4. Histological features a. Compact laminar cortical bone with dilated Haversian canals containing osteoblasts b. No osteoclasts identified in the periosteal or endosteal layers c. An increased amount of ground substance and excessive formation of subperiosteal and subendosteal bone 5. Molecular genetic analysis for mutations in the human homolog of the mouse progressive ankylosis gene (ANKH)
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal dominant form: 50% risk if one parent is affected, otherwise risk not increased ii. Autosomal recessive form: 25% b. Patient’s offspring i. Autosomal dominant form: 50% ii. Autosomal recessive form: not increased unless the spouse is also a carrier in which case there is 50% recurrence risk 2. Prenatal diagnosis: has not been reported 3. Management a. Medical treatment attempted with the following two hormones i. Calcitonin: has an inhibitory effect on bone formation ii. Calcitriol a) Stimulates resorption of bone by promoting osteoclast formation b) Partial resolution of facial nerve paralysis, increased size of the cranial nerve foramina, and demineralization of the cranial base during treatment of one patient with high doses of calcitriol b. Hearing aids for hearing loss c. Psychological support for facial disfigurement
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d. Surgical treatment with mixed results i. Resection of dysplastic bone arduous because it is highly mineralized with a consistency like thick ivory ii. Craniofacial reduction performed with some difficulty iii. Optic canal decompression for progressive visual loss iv. Facial nerve decompression v. Middle ear exploration and implantation of total ossicular replacement prosthesis for conductive hearing loss vi. Foramen magnum decompression for cervicomedullary encroachment
REFERENCES Beighton P: Craniometaphyseal dysplasia (CMD), autosomal dominant form. J Med Genet 32:370–374, 1995. Beighton P, Hamersma H, Horan F: Craniometaphyseal dysplasia—variability of expression within a large family. Clin Genet 15:252–258, 1979. Boltshauser E, Schmitt B, Wichmann W, et al.: Cerebellomedullary compression in recessive craniometaphyseal dysplasia. Neuroradiology 38 Suppl 1:S193–S195, 1996. Bricker SL, Langlais RP, van Dis ML: Dominant craniometaphyseal dysplasia. Literature review and case report. Dentomaxillofac Radiol 12:95–100, 1983. Carnevale A, Grether P, del Castillo V, et al.: Autosomal dominant craniometaphyseal dysplasia. Clinical variability. Clin Genet 23:17–22, 1983. Chandler D, Tinschert S, Lohan K, et al.: Refinement of the chromosome 5p locus for craniometaphyseal dysplasia. Hum Genet 108:394–397, 2001. Cheung VG, Boechat MI, Barrett CT: Bilateral choanal narrowing as a presentation of craniometaphyseal dysplasia. J Perinatol 17:241–243, 1997. Cole DE, Cohen MM Jr: a new look at craniometaphyseal dysplasia. J Pediatr 112:577–579, 1988. Cooper JC: Craniometaphyseal dysplasia: a case report and review of the literature. Br J Oral Surg 12:196–204, 1974. Day RA, Park TS, Ojemann JG, et al.: Foramen magnum decompression for cervicomedullary encroachment in craniometaphyseal dysplasia: case report. Neurosurgery 41:960–964, 1997. Fanconi S, Fischer JA, Wieland P, et al.: Craniometaphyseal dysplasia with increased bone turnover and secondary hyperparathyroidism: therapeutic effect of calcitonin. J Pediatr 112:587–591, 1988.
Gorlin RJ, Spranger J, Koszalka MF: Genetic craniotubular bone dysplasias and hyperostoses: a critical analysis. Birth Defects Orig Art Ser V(4):79–95, 1969. Gorlin RJ, Koszalka MF, Spranger J: Pyle’s disease (familial metaphyseal dysplasia). A presentation of two cases and argument for its separation from craniometaphyseal dysplasia. J Bone Joint Surg Am 52:347–354, 1970. Iughetti P, Alonso LG, Wilcox W, et al.: Mapping of the autosomal recessive (AR) craniometaphyseal dysplasia locus to chromosome region 6q21–22 and confirmation of genetic heterogeneity for mild AR spondylocostal dysplasia. Am J Med Genet 95:482–491, 2000. Jackson WPU, Albright F, Drewry G, et al.: Metaphyseal dysplasia, epiphyseal dysplasia, diaphyseal dysplasia, and related conditions. I. Familial metaphyseal dysplasia and craniometaphyseal dysplasia: their relation to leontiasis ossea and osteopetrosis: disorders of ‘bone remodeling’. Arch Intern Med 94:871–885, 1954. Key LL Jr, Volberg F, Baron R, et al.: Treatment of craniometaphyseal dysplasia with calcitriol. J Pediatr 112:583–587, 1988. Kietzer G, Paparella MM: Otolaryngological disorders in craniometaphyseal dysplasia. Laryngoscope 79:921–941, 1969. Martin FW: Otorhinological aspects of craniometaphyseal dysplasia. Clin Otolaryngol 4:67–76, 1979. Millard DR Jr, Maisels DO, Batstone JH, et al.: Craniofacial surgery in craniometaphyseal dysplasia. Am J Surg 113:615–621, 1967. Nürnberg P, Thiele H, Chandler D, et al.: Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia. Nat Genet 28:37–41, 2001. Nürnberg P, Tinschert S, Mrug M, et al.: The gene for autosomal dominant craniometaphyseal dysplasia maps to chromosome 5p and is distinct from the growth hormone-receptor gene. Am J Hum Genet 61:918–923, 1997. Penchaszadeh VB, Gutierrez ER, Figueroa E: Autosomal recessive craniometaphyseal dysplasia. Am J Med Genet 5:43–55, 1980. Puri P, Chan J: Craniometaphyseal dysplasia: ophthalmic features and management. J Pediatr Ophthalmol Strabismus 40:228–231, 2003. Reichenberger E, Tiziani V, Watanabe S, et al.: Autosomal dominant craniometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK. Am J Hum Genet 68:1321–1326, 2001. Shea J, Gerbe R, Ayani N: Craniometaphyseal dysplasia: the first successful surgical treatment for associated hearing loss. Laryngoscope 91:1369–1374, 1981. Yamamoto T, Kurihara N, Yamaoka K, et al.: Bone marrow-derived osteoclastlike cells from a patient with craniometaphyseal dysplasia lack expression of osteoclast-reactive vacuolar proton pump. J Clin Invest 91:362–367, 1993.
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Fig. 1. A girl with craniometaphyseal dysplasia showing characteristic craniofacial features consisting of hypertelorism, broadening nasal base with paranasal bossing, short nose, and prominent facial bones.
Cri-Du-Chat Syndrome Cri-du-chat syndrome is a chromosome 5p deletion syndrome first describe by Lejeune et al. in 1963. The incidence is estimated to be approximately 1 in 15,000–50,000 births. The prevalence among mentally retarded individuals is approximately 1.5 in 1000.
GENETICS/BASIC DEFECTS 1. Cause a. Caused by deletion of short arm of chromosome 5 (5p15.2–15.3) i. De novo deletion (80%): paternally derived deletions in 80% of cases ii. Familial rearrangement (12%) iii. Mosaicism (3%) iv. Rings (2.4%) v. De novo translocation (3%) b. A high-resolution physical and transcription map generated a 3.5-Mb region of 5p15.2 that is associated with the Cri du chat syndrome region 2. Genotype–phenotype correlation a. Deletion of 5p15.3 results in a cat-like cry and speech delay b. Deletion of 5p15.2 results in the distinct facial features associated with the syndrome as well as the severe mental and developmental delay 3. Hemizygosity of δ-catenin (CTNND2, mapped to 5p15.2), reported to be associated with severe mental retardation in cri-du-chat syndrome 4. Deletion of the telomerase reverse transcriptase (TERT) gene (mapped at 5p15.33) and haploinsufficiency of telomere maintenance is probably a genetic element contributing to the phenotypic changes in cri-du-chat syndrome
CLINICAL FEATURES 1. Characteristic mewing cry a. A high-pitched monochromatic cry with subtle dysmorphism and neonatal complications: commonly observed in infants with this syndrome b. Observed in many infants with Cri-du-chat syndrome c. Not associated with other aneuploidies d. Usually considered diagnostic e. Loss of the characteristic cry by age 2 years in one third of children 2. Clinical findings during infancy a. Low birth weight b. Hypotonia c. Microcephaly d. Poor sucking/swallowing difficulties e. Need for incubator care f. Respiratory distress 256
g. h. i. j. k. l. m.
Jaundice Pneumonia Dehydration Failure to thrive/growth retardation Early ear infections Severe cognitive, speech and motor delays Facial features i. Round face with full cheek ii. Hypertelorism iii. Epicanthal folds iv. Down-slanting palpebral fissures v. Strabismus vi. Flat nasal bridge vii. Down-turned mouth viii. Micrognathia ix. Low-set ears n. Cardiac defects i. VSD ii. ASD iii. PDA iv. Tetralogy of Fallot o. Short fingers p. Single palmar creases q. Less frequent features i. Cleft lip and palate ii. Preauricular tags and fistulas iii. Thymic dysplasia iv. Gut malrotation v. Megacolon vi. Inguinal hernia vii. Dislocated hips viii. Cryptorchidism ix. Hypospadias x. Rare renal malformations a) Horseshoe kidneys b) Renal ectopia or agenesis c) Hydronephrosis xi. Clinodactyly of the fifth fingers xii. Talipes equinovarus xiii. Pes planus xiv. Syndactyly of the second and third fingers and toes xv. Oligosyndactyly xvi. Hyperextensible joints 3. Clinical findings in childhood a. Severe mental retardation b. Developmental delay c. Microcephaly d. Hypertonicity e. Premature graying of the hair f. Small, narrow and often asymmetric face g. Dropped-jaw h. Open-mouth expression secondary to facial laxity
CRI-DU-CHAT SYNDROME
i. j. k. l. m.
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Short philtrum Malocclusion of the teeth Scoliosis Short third-fifth metacarpals Chronic medical problems i. Upper respiratory tract infections ii. Otitis media iii. Severe constipation iv. Hyperactivity Clinical findings in late childhood and adolescence a. Coarsening of facial features b. Prominent supraorbital ridges c. Deep-set eyes d. Hypoplastic nasal bridge e. Affected females reaching puberty and developing secondary sex characteristics and menstruate at the usual time f. Small testis and normal spermatogenesis in males Dermatoglyphics a. Transverse flexion creases b. Distal axial triradius c. Increased whorls and arches on digits Behavioral profile a. Hyperactivity b. Aggression c. Tantrums d. Stereotypic and self-injurious behavior e. Repetitive movements f. Hypersensitivity to sound g. Clumsiness h. Obsessive attachments to objects i. Able to communicate needs and interact socially with others j. Autistic-like features and social withdrawal: more characteristic of individuals who have a 5p deletion as the result of an unbalanced segregation of a parental translocation Prognosis a. Ability of many children to develop some language and motor skills b. Ability of these children to attain developmental and social skills observed in 5- to 6-year-old children, although their linguistic abilities are seldom as advanced c. Older, home-reared children i. Usually ambulatory ii. Able to communicate verbally or through gestural sign language iii. Independent in self-care skills.
DIAGNOSTIC INVESTIGATIONS 1. Conventional cytogenetic studies. The size of the 5p deletion may vary from the entire short arm to only 5p15. A small deletion of 5p may be missed by a conventional cytogenetic technique 2. High-resolution cytogenetic studies are required for a smaller 5p deletion 3. Molecular cytogenetic studies using fluorescent in situ hybridization (FISH)
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a. Allow the diagnosis to be made in the patients with very small deletions b. Use genetic markers that have been precisely localized to the area of interest c. The absence of a fluorescent signal from either the maternal or paternal chromosome 5p regions: indicative of monosomy for that chromosomal region Skeletal radiographs a. Microcephaly b. Retromicrognathia c. Cranial base malformations i. Reduced cranial base angle ii. Malformed sella turcica and clivus d. Disproportionately short third, fourth, and fifth metacarpals and disproportionately long second, third, fourth, and fifth proximal phalanges (frequent) Echocardiography to rule out structural cardiac malformations MRI of the brain a. Atrophic brainstem, middle cerebellar peduncles and cerebellar white matter b. Possible hypoplasia of cerebellar vermis with enlargement of the cisterna magna and 4th ventricle Swallowing study for feeding difficulty Comprehensive evaluation for receptive and expressive language. Most children have better receptive language than expressive language Developmental testing and referral to early intervention and appropriate school placement
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Recurrence risk for a de novo case is 1% or less ii. Rare recurrences in chromosomally normal parents: most likely the result of gonadal mosaicism for the 5p deletion in one of the parents iii. The risk is substantially high if a parent is a balanced carrier of a structural rearrangement. Risk should be assessed based on the type of structural rearrangement and its pattern of segregation b. Patient’s offspring: female patients are fertile and can deliver viable affected offspring, with an estimated recurrence risk of 50% 2. Prenatal diagnosis by amniocentesis, CVS, and PUBS for chromosome analysis to detect 5p deletion 3. Management a. Supportive care. No treatment exists for the underlying disorder b. Appropriate treatment for chronic medical problems i. Upper respiratory tract infections ii. Otitis media iii. Severe constipation c. Using the relatively good receptive skills to encourage language and communicative development rather than relying on traditional verbal methods d. Early intervention programs i. Physical therapy ii. Occupational therapy iii. Speech therapy
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e. Introduction to sign language, an effective means of developing communication skills (50% of children are able to use sign language to communicate) f. Behavior modification programs to successfully managing hyperactivity, short attention span, low threshold for frustration, and self-stimulatory behaviors (eg, head-banging, hand-waving) g. Surgical interventions i. Correction of congenital heart defects if indicated ii. Medical problems involving minor malformations such as strabismus and clubfoot iii. Gastrostomy in infancy to protect airway of patients with major feeding difficulties iv. Orchiopexy for undescended testes v. Issues important to anesthetic plan a) Anatomical abnormalities of the airway b) Congenital heart disease c) Hypotonia d) Mental retardation e) Temperature maintenance
REFERENCES Aoki S, Hata T, Hata K, et al.: Antenatal sonographic features of cri-du-chat syndrome. Ultrasound Obstet Gynecol 13:216–217, 1999. Baccichetti SE, Lenzini L, Artifoni D, et al.: Terminal deletion of the short arm of chromosome 5. Clin Genet 34:219–223, 1988. Brislin RP, Stayer SA, Schwartz RE: Anaesthetic considerations for the patient with cri du chat syndrome. Paediatr Anaesth 5: 139–141, 1995. Cerruti Mainardi P, Guala A, Pastore G, et al.: Psychomotor development in Cri du Chat Syndrome. Clin Genet 57:459–461, 2000. Chen H: Cri-du-chat syndrome. http://www.emedicine.com Church DM, Bengtsson U, Nielsen KV, et al.: Molecular definition of deletions of different segments of distal 5p that results in distinct phenotypic features. Am J Hum Genet 56:1162–1172, 1995. Church DM, Yang J, Bocian M, et al.: A high-resolution physical and transcript map of the Cri du Chat region of human chromosome 5p. Genome Res 7:787–801, 1997. Clarke DJ, Boer H: Problem behaviors associated with deletion Prader-Willi, Smith-Magenis, and Cri du chat syndrome. Am J Ment Retard 103: 264–271, 1998. Collins MS, Cornish K: A survey of the prevalence of stereotypy, self-injury and aggression in children and young adults with Cri du Chat syndrome. J Intellect Disabil Res 46:133–140, 2002. Cornish KM, Munir F: Receptive and expressive language skills in children with cri-du-chat syndrome. J Commun Disord 31:73–80; quiz 80–81, 1998. Cornish KM, Pigram J: Developmental and behavioural characteristics of cri du chat syndrome. Arch Dis Child 75:448–450, 1996. Dykens EM, Clark DJ: Correlates of maladaptive behavior in individuals with 5p- (cri du chat) syndrome. Dev Med Child Neurol 39:752–756, 1997. Fengen K, Niebuhr E: Measurements of hand radiographs from 32 Cri-du-chat probands. Radiology 1978; 129:137–141. Fankhauser L, Brundler AM, Dahoun S: Cri-du-chat syndrome diagnosed by amniocentesis performed due to abnormal maternal serum test. Prenat Diagn 18:1099–1100, 1998.
Gersh M, Goodart SA, Pasztor LM: Evidence for a distinct region causing a cat-like cry in patients with 5p deletions. Am J Hum Genet 56: 1404–1410, 1995. Gersh M, Grady D, Rojas K: Development of diagnostic tools for the analysis of 5p deletions using interphase FISH. Cytogenet Cell Genet 77: 246–251, 1997. Goodart SA, Simmons Arch Dermatol, Grady D, et al.: A yeast artificial chromosome contig of the critical region for cri-du-chat syndrome. Genomics 24:63–68, 1994. Hodapp RM, Wijma CA, Masino LL: Families of children with 5p- (cri du chat) syndrome: familial stress and sibling reactions. Dev Med Child Neurol 39:757–761, 1997. Kjaer I, Niebuhr E: Studies of the cranial base in 23 patients with cri-du-chat syndrome suggest a cranial developmental field involved in the condition. Am J Med Genet 82:6–14, 1999. Manning KP: The larynx in the cri du chat syndrome. J Laryngol Otol 91:887892, 1977. Mainardi PC, Perfumo C, Cali A, et al.: Clinical and molecular characterization of 80 patients with 5p deletion: genotype-phenotype correlation. J Med Genet 38:151–158, 2001. Marinescu RC, Johnson EI, Dykens EM, et al.: No relationship between the size of the deletion and the level of developmental delay in Cri-Du-Chat syndrome. Am J Med Genet 86:66–70, 1999. Marinescu RC, Johnson EI, Grady D, et al.: FISH analysis of terminal deletions in patients diagnosed with cri-du-chat syndrome. Clin Genet 56:282–288, 1999. Martinez JE, Tuck-Muller CM, Superneau D: Fertility and the cri du chat syndrome. Clin Genet 43:212–214, 1993. Medina M, Marinescu RC, Overhauser J, et al.: Hemizygosity of δ-catenin (CTNND2) is associated with severe mental retardation in cri-du-chat syndrome. Genomics 63:157–164, 2000. Niebuhr E: The cat cry syndrome (5p-) in adolescents and adults. J Ment Defic Res 15 Pt 4:277–291, 1971. Niebuhr E: The Cri du Chat syndrome: epidemiology, cytogenetics, and clinical features. Hum Genet 44: 227–275, 1978. Overhauser J, McMahon J, Oberlender S: Parental origin of chromosome 5 deletions in the cri-du-chat syndrome. Am J Med Genet 37: 83–86, 1990. Overhauser J, Huang X, Gersh M: Molecular and phenotypic mapping of the short arm of chromosome 5: sublocalization of the critical region for the cri-du-chat syndrome. Hum Mol Genet 3:247–252, 1994. Perfumo C, Mainardi PC, Cali A, et al.: The first three mosaic cri du chat syndrome patients with two rearranged cell lines. J Med Genet 37:967–972, 2000. Romano C, Ragusa RM, Scillato F, et al.: Phenotypic and phoniatric findings in mosaic cri du chat syndrome. Am J Med Genet 39:391–395, 1991. Saito N, Ebara S, Fukushima Y, et al.: Progressive scoliosis in cri-du-chat syndrome over a 20-year follow-up period: a case report. Spine 26:835–837, 2001. Stefanou EG, Hanna G, Foakes A, et al.: Prenatal diagnosis of cri du chat (5p-) syndrome in association with isolated moderate bilateral ventriculomegaly. Prenat Diagn 22:64–66, 2002. Tullu MS, Muranjan MN, Sharma SV, et al.: Cri-du-chat syndrome: clinical profile and prenatal diagnosis. J Postgrad Med 44:101–104, 1998. Van Buggenhout GJ, Pijkels E, Holvoet M, et al.: Cri du chat syndrome: changing phenotype in older patients. Am J Med Genet 90:203–215, 2000. Wilkins LE, Brown JA, Wolf B: Psychomotor development in 65 home-reared children with cri-du-chat syndrome. J Pediatr 97:401–405, 1980. Wilkins LE, Brown JA, Nance WE: Clinical heterogeneity in 80 home-reared children with cri du chat syndrome. J Pediatr 102: 528–533, 1983. Zhang A, Zheng C, Hou M, et al.: Deletion of the telomerase reverse transcriptase gene and haploinsufficiency of telomere maintenance in Cri du chat syndrome. Am J Hum Genet 72:940–948, 2003.
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Fig. 2. Cri-du-chat syndrome in an older child and a teenager showing a long and narrow face.
Fig. 1. Two infants with cri-du-chat syndrome. Note a round face with full cheeks, hypertelorism, epicanthal folds, and apparently low-set ears.
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Fig. 3. G-banded karyotypes with 5p deletion in two children with cri-du-chat syndrome.
Fig. 4. FISH of an interphase cell and a metaphase spread with two orange signals (LSI SpectrumOrange, D5S721) and one green signal (LSI SpectrumGreen, D5S23 chromosome 5p15.2-specific probe) indicating deletion of 5p15.2.
Crouzon Syndrome In 1912, Crouzon described the hereditary syndrome of craniofacial dysostosis in a mother and son. He described the triad of calvarial deformities, facial anomalies, and exophthalmos. Crouzon syndrome is characterized by premature closure of calvarial and cranial base sutures as well as those of the orbit and maxillary complex (craniosynostosis). Other clinical features include hypertelorism, exophthalmos, strabismus, beaked nose, short upper lip, hypoplastic maxilla, and relative mandibular prognathism. Prevalence is 1 per 60,000 (approximately 16.5 per 1,000,000) live births. Crouzon syndrome makes up approximately 4.8% of all cases of craniosynostosis.
iv. Maxillary hypoplasia v. Occasional upper airway obstruction
CLINICAL FEATURES
GENETICS/BASIC DEFECTS 1. Inheritance a. An autosomal dominant disorder with i. Complete penetrance ii. Variable expressivity b. Sporadic in 50% of patients resulting from new mutations 2. Cause a. Mutations in the fibroblast growth factor receptor-2 (FGFR2) gene which is mapped to 10q25–q26 b. Mutations reported in the third immunoglobulins-like domain c. Different mutations detected in both exon IIIa and exon IIIc. Most of these mutations are missense, although several different mutations leading to alternative splicing have been recognized d. Crouzon syndrome exhibits locus heterogeneity with causal mutations in FGFR2 and FGFR3 in different affected individuals e. Crouzon syndrome with acanthosis nigricans: always due to an Ala391Glu mutation within the transmembrane region of the FGFR3 gene 3. Pathophysiology a. Premature synostosis of the coronal, sagittal, and occasional lambdoidal sutures i. Begins in the first year of life ii. Completed by the second or third year b. Degree of deformity and disability determined by the order and rate of suture fusion c. After fusion of a suture i. Growth perpendicular to that suture becoming restricted ii. Fused bones acting as a single bony structure d. Compensatory growth occurring at the remaining open sutures to allow continued brain growth e. Multiple sutural synostoses often extend to premature fusion of the skull base sutures causing the following effects i. Midfacial hypoplasia ii. Shallow orbit iii. A foreshortened nasal dorsum 261
1. History a. Presence of mildly affected individuals in the family b. Craniofacial abnormalities often present at birth and may progress with time c. Decreased mental function in approximately 12% of the patients d. Headaches (29%) and failing vision due to elevated intracranial pressure e. Visual disturbance results from corneal injury due to exposed conjunctivitis and keratitis f. Conductive deafness common due to ear canal stenosis or atresia g. Causes of upper airway obstruction i. Septal deviation ii. Mid-nasal abnormalities iii. Choanal abnormalities iv. Nasopharyngeal narrowing h. Meniere disease i. Seizures (12%) 2. Skull and face a. Craniosynostosis i. Onset: commonly seen during the first year ii. Usually completing by the second or third year iii. Coronal suture most commonly involved iv. Acrocephaly v. Brachycephaly vi. Turricephaly vii. Oxycephaly viii. Flat occiput ix. High prominent forehead with or without frontal bossing x. Ridging of the skull usually palpable b. Cloverleaf skull i. Rare ii. Occurring in most severely affected individuals iii. Flattened sphenoid bone iv. Shallow orbits v. Hydrocephalus (progressive in 30%) vi. Midface (maxillary) hypoplasia 3. Eyes a. Exophthalmos (proptosis) (100%) secondary to shallow orbits resulting in frequent exposure conjunctivitis or keratitis b. Ocular hypertelorism (100%) c. Divergent strabismus d. Rare occurrence i. Nystagmus ii. Iris coloboma
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iii. Aniridia iv. Anisocoria v. Microcornea vi. Megalocornea vii. Cataract viii. Ectopia lentis ix. Blue sclera x. Glaucoma xi. Luxation of the eye globes xii. Blindness from optic atrophy Nose a. Beaked appearance (parrot-like nose) b. Compressed nasal passage c. Choanal atresia or stenosis d. Deviated nasal septum Mouth a. Mandibular prognathism b. Overcrowding of upper teeth c. Malocclusions d. V-shaped maxillary dental arch e. Narrow, high, or cleft palate and bifid uvula f. Oligodonti g. Macrodontia h. Peg-shaped i. Widely spaced teeth Ears a. Narrow or absent ear canals b. Deformed middle ears c. Mild to moderate hearing losses Other skeletal a. Cervical fusion (18%), C2-C3 and C5-C6 b. Block fusions involving multiple vertebrae c. Subluxation of the radial heads d. Ankylosis of the elbows Acanthosis nigricans (5%) a. Detectable after infancy b. The hallmark of these lesions i. A darkened, thickened skin with accentuated markings ii. A velvety feel CNS a. Chronic tonsillar herniation (approximately 73%). Of these, 47% have progressive hydrocephalus b. Syringomyelia c. Mental retardation (3%)
DIAGNOSTIC INVESTIGATIONS 1. Skull radiographs a. Synostosis: the coronal, sagittal, lambdoidal, and metopic sutures may be involved b. Craniofacial deformities c. Digital markings of skull d. Basilar kyphosis e. Widening of hypophyseal fossa f. Small paranasal sinuses g. Maxillary hypoplasia with shallow orbits 2. Cervical radiographs a. Butterfly vertebrae b. Fusions of the vertebral bodies and the posterior elements
3.
4.
5. 6.
i. Cervical fusions in approximately 18% of patients ii. C2-C3 and C5-C6 affected equally iii. Block fusions may involve multiple vertebrae Limb radiographs a. Metacarpophalangeal analysis b. Subluxation of the radial head Computed tomography (CT) scan: comparative 3dimensional reconstruction analysis of the calvaria and cranial bases to precisely define the pathologic anatomy and to permit specific operative planning Magnetic resonance imaging (MRI) Used to demonstrate occasional corpus callosum agenesis and optic atrophy Molecular analysis a. FGFR2 mutations in more than 50% of patients (FGFR2 mutations also observed in Apert syndrome, Pfeiffer syndrome, and Jackson-Weiss syndrome) b. FGFR3 ala391-to-glu mutation in all patients with associated acanthosis nigricans
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected or with germinal mosaicism b. Patient’s offspring: 50% 2. Prenatal diagnosis a. Prenatal ultrasonography i. Exophthalmos ii. Ocular hypertelorism b. Identification of the disease-causing FGFR2 mutation using i. CVS in the first trimester ii. Amniocentesis in the second trimester iii. Preimplantation genetic diagnosis 3. Management a. Medical care i. No specific medical therapy available ii. Nasal continuous positive airway pressure device to relieve airway obstruction iii. Management of speech b. Surgical care i. Stage reconstruction to coincide with facial growth patterns, visceral function, and psychosocial development ii. Early craniectomy with frontal bone advancement most often indicated to prevent or treat increased intracranial pressure because newborns with Crouzon syndrome develop multiple suture synostosis and fused synchondrosis iii. Fronto-orbital and midfacial advancements to help in the cosmetic reconstruction of facial dysmorphisms iv. A new technique, craniofacial disjunction, followed by gradual bone distraction (Ilizarov procedure) has been reported to produce complete correction of exophthalmos and improvement in the functional and aesthetic aspects of the middle third of the face without the need for bone graft in patients aged 6–11 years v. Shunting procedures for hydrocephalus
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vi. Tracheostomy for airway compromise vii. Myringotomy to drain middle ear secretions secondary to distorted nasopharynx viii. Orthodontic management
REFERENCES Anderson PJ, Evans RD: Metacarpophalangeal analysis in Crouzon syndrome. Am J Med Genet 80:439, 1998. Anderson PJ et al.: Hand anomalies in Crouzon syndrome. Skeletal Radiol 26:113–115, 1997 Anderson PJ, Hall C, Evans RD: The cervical spine in Crouzon syndrome. Spine 22:402–405, 1997. Beck R, Sertie AL, Brik R, et al.: Crouzon syndrome: association with absent pulmonary valve syndrome and severe tracheobronchomalacia. Pediatr Pulmonol 34:478–481, 2002. Bresnick S, Schendel S: Crouzon’s disease correlates with low fibroblastic growth factor receptor activity in stenosed cranial sutures. J Craniofac Surg 6:245–248, 1995. Cinalli G, Renier D, Sebag G: Chronic tonsillar herniation in Crouzon’s and Apert’s syndromes: the role of premature synostosis of the lambdoid suture. J Neurosurg 83:575–782, 1995. Cohen MM: An etiologic and nosologic overview of craniosynostosis syndromes. BDOAS 11(2):137, 1975. Cohen MM Jr: Craniosynostosis: Diagnosis, Evaluation, and Management. New York, Raven Press, 1986. Cohen MM Jr: Craniosynostoses: phenotypic/molecular correlations [editorial] [see comments]. Am J Med Genet 56:334–339, 1995. Cohen MM Jr: An etiologic and nosologic overview of craniosynostosis syndromes. Birth Defects Orig Artic Ser ?(2):137–189, 1975. Cohen MM Jr: Craniosynostosis update 1987. Am J Med Genet Suppl 4:99–148, 1988. Cohen MM Jr, Kreiborg S: Birth prevalence studies of the Crouzon syndrome: comparison of direct and indirect methods. Clin Genet 41:12–15, 1992. Cohen MM Jr, MacLean RE: Craniosynostosis: Diagnosis, Evaluation, and Management. 2nd ed., Oxford University Press, New York, 1999. Crouzon O: Dysostose cranio-faciale hereditaire. Bull Mem Soc Med Hosp Paris 33:545–555, 1912 David DJ, Sheen R: Surgical correction of Crouzon syndrome. Plast Reconstr Surg 85:344–3, 1990. Dodge HW, et al.: Craniofacial dysostosis: Crouzon’s disease. Pediatrics 23:98–106, 1959. Glaser RL et al.: Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. Am. J. Hum. Genet. 66: 768–777, 2000 Golabi M, et al.: Radiographic abnormalities of Crouzon syndrome. A survey of 23 cases Proc Greenwood Genet Ctr 3:102, 1984. Gorry MC, Preston RA, White GJ: Crouzon syndrome: mutations in two splice forms of FGFR2 and a common point mutation shared with JacksonWeiss syndrome. Hum Mol Genet 4:1387–1390, 1995. Harper JC, Wells D, Piyamongkol W, et al.: Preimplantation genetic diagnosis for single gene disorders: experience with five single gene disorders. Prenat Diagn 22:525–533, 2002. Hollway GE, Suthers GK, Haan EA: Mutation detection in FGFR2 craniosynostosis syndromes. Hum Genet 99:251–255, 1997.
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Jabs EW, Li X, Scott AF: Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2 [published erratum appears in Nat Genet 9:451, 1995]. Nat Genet 8:275–279, 1994. Jarund M, Lauritzen C: Craniofacial dysostosis: airway obstruction and craniofacial surgery. Scand J Plast Reconstr Surg Hand Surg 30:275–279, 1996. Kaler SG. et al.: Radiologic hand abnormalities in fifteen cases of Crouzon syndrome. J Cranio Genet Dev Biol 2:205–214, 1982. Kreiborg S: Crouzon syndrome: a clinical and roentgencephalometric study. Scan J Plast Reconstr Surg Suppl 18, 1–198, 1981. Leo MV, Suslak L, Ganesh VL, et al.: Crouzon syndrome: prenatal ultrasound diagnosis by binocular diameters. Obstet Gynecol 78:906–908, 1991. Liptak GS, Serletti JM: Pediatric approach to craniosynostosis [published erratum appears in Pediatr Rev 20:20, 1999.]. Pediatr Rev 19:352; quiz 359, 1998. Menashe Y, et al.: Exophthalmus-prenatal ultrasonic features for diagnosis of Crouzon syndrome. Prenatal Diagn 9:805–808, 1989. Meyers GA, Day D, Goldberg R: FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative RNA splicing. Am J Hum Genet 58:491–498, 1996. Meyers GA, Orlow SJ, Munro IR: Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nat Genet 11:462–464, 1995. Meyers GA, et al.: Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nature Genet 11:462–464, 1995. Navarrete C, et al.: Germinal mosaicism in Crouzon syndrome. A family with three affected siblings of normal parents. Clin Genet 40:29–34, 1991. Oldridge M et al.: Mutations in the third immunoglobulin domain of the fibroblast growth factor receptor-2 gene in Crouzon syndrome. Hum Mol Genet 4 (6): 1077–1082, 1995 Park WJ, Meyers GA, Li X: Novel FGFR2 mutations in Crouzon and JacksonWeiss syndromes show allelic heterogeneity and phenotypic variability. Hum Mol Genet 4:1229–1233, 1995. Preston RA et al.: A gene for Crouzon craniofacial dysostosis maps to the long arm of chromosome 10. Nature Genet 7:149–153, 1994. Reardon W, Winter RM, Rutland P: Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet 8:98–103, 1994. Bobertson MM, Reynolds HT: Crouzon’s disease (craniofacial dysostosis). A neuropsychiatric presentation. S Afr Med J 49:7–10, 1975. Rollnick BR et al.: Germinal mosaicism in Crouzon syndrome. Clin Genet 33:145–150, 1988. Rutland P, Pulleyn LJ, Reardon W: Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes [see comments]. Nat Genet 9:173–176, 1995. Schwartz M, Kreiborg S, Skovby F: First-trimester prenatal diagnosis of Crouzon syndrome. Prenat Diagn 16:155–158, 1996. Tessier P: The definitive plastic surgical treatment of the severe facial deformities of craniofacial dysostosis: Crouzon’s and Apert’s disease. Plast Reconst Surg 48:419–442, 1971. Turvy TA, et al.: Multidisciplinary management of Crouzon syndrome. J Am Dent Assoc 99:205–209, 1979. Wilkes D, Rutland P, Pulleyn LJ: A recurrent mutation, ala391glu, in the transmembrane region of FGFR3 causes Crouzon syndrome and acanthosis nigricans. J Med Genet 33:744–748, 1996. Wilkie AO, Slaney SF, Oldridge M: Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome [see comments]. Nat Genet 9:165–172, 1995.
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Fig. 2. A neonate with Crouzon syndrome showing typical craniofacial features with tracheostomy in place for the respiratory problem.
Fig. 1. Two children with Crouzon syndrome showing proptosis secondary to shallow obits and hypertelorism.
Fig. 3. A father and a daughter with Crouzon syndrome showing characteristic craniofacial features.
Cystic Fibrosis Cystic fibrosis (CF) is the most common Caucasian lethal genetic disorder (with gene frequency of 1 in 25) in the United States, where 4–5% of population have at least one CF allele. CF affects approximately 1 in 2500 live births among Caucasians, 1 in 17,000 among African-Americans, and 1 in 90,000 among Asians.
CLINICAL FEATURES
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal recessive b. CF gene mapped to chromosome 7q31.2 2. Molecular defect a. Caused by a single gene defect on chromosome 7 that encodes a cAMP-regulated chloride channel known as the cystic fibrosis transmembrane conductance regulator (CFTR) i. CFTR usually resides in the apical membrane of epithelial cells lining the airway, biliary tree, intestines, vas deferens, sweat ducts, and pancreatic ducts. ii. Insufficient fluid secretion secondary to inability of CFTR to transport chloride ion at the above sites causes higher viscidity of the protein portions of the secretions and obstructing the ducts, leading to plugging and dysfunction at the organ level iii. CFTR also regulates the activity of other proteins that conduct ions and affects intracellular regulatory processes at the cellular level b. Presence of close to 1000 different disease-causing mutations of the CFTR gene i. Deletion mutations including delta F508 which, observed in over 70% of patients with CF, have a deletion of three contiguous base pairs resulting in the loss of a single amino acid, phenylalanine at codon 508) ii. Missense mutation (single base pair exchange within a normal length CFTR protein) iii. Nonsense mutations (exchange of a single base pair resulting in premature termination of the protein) iv. Frameshift mutations (the deletions or insertion of a single base pair) c. Genotype–phenotype correlations i. Phenotypic presentation of the disease: probably related to the underlying genetic abnormality ii. Patients with homozygous delta F508 typically have respiratory distress and malabsorption iii. Patients with less severe variations of the disease or typical CF with borderline normal sweat tests may have other haplotypes
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1. Classic clinical triad a. Exocrine pancreatic insufficiency b. Chronic obstructive pulmonary disease c. Elevation of sodium and chloride concentration in sweat 2. Chronic sino-pulmonary disease a. Varying widely in age of onset and rate of progression b. Clinical course i. Newborn with CF with histologically normal respiratory systems ii. First few months of age a) Epithelial chloride channel defect, leading to abnormal respiratory secretions, bronchopulmonary infections, and airway obstruction b) Clinical manifestations including cough, wheezing, retractions, and tachypnea c. Persistent endobronchial infection and inflammation with typical CF pathogens i. Staphylococcus aureus a) Responsible for the majority of lung disease when CF was first described b) Commonly isolated in the first year of life from the sputum of patients with CF c) Typically controlled by antibiotic therapy d) Currently only 10% of adult patients with CF are chronically colonized by the pathogen ii. Mucoid and non-mucoid pseudomonas aeruginosa a) The most prevalent of the pathogens in CF, causing chronic infection in up to 90% of adults and 80% of children b) Initial colonization with nonmucoid forms c) Subsequent conversion to mucoid variants iii. Hemophilus influenzae a) Commonly seen in babies b) Rarely encountered in the adults iv. Other pulmonary pathogens a) Burkholderia cepacia b) Aspergillus c) Mycobacteria d) Respiratory viruses d. Upper airway disease i. Opacified or maldeveloped sinuses ii. Nasal polyps (up to 26% of patients) iii. Sinusitis a) Facial pain b) Swelling c) Tenderness d) Air-fluid levels on radiograph
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e. Pulmonary exacerbations i. Persistent cough and sputum production ii. Increased dyspnea iii. Reduction in pulmonary function iv. Increased hemoptysis: a life-threatening complication but fatal hemoptysis is rare v. Digital clubbing vi. Changes in chest radiographic findings vii. Bronchiolitis viii. Increased rales or rhonchi ix. Decreased air exchange x. Increased use of accessory muscles of respiration xi. Spontaneous pneumothorax (5–8%), a lifethreatening complication xii. Obstructive airway disease, leading to respiratory insufficiency associated with bronchiectasis 3. Gastrointestinal abnormalities a. Intestine i. Meconium ileus at birth a) An obstruction of the distal ileum or proximal colon with thickened, viscous meconium in 15–20% of CF patients developed in utero in the second trimester b) Virtually diagnostic of CF ii. Meconium peritonitis (rupture of the intestine secondary to complete obstruction) iii. Meconium plug syndrome in the newborn infants, a more benign condition characterized by blockage of the colon iv. Distal intestinal obstruction syndrome later in childhood, adolescence, or adulthood (10%), presenting as crampy abdominal pain, usually with decreased stooling v. Rectal prolapse occurring in less than 1% of patients but may be the presenting symptom, particularly in infants vi. Occasional intussusception vii. Gastroesophageal reflux b. Pancreas i. Pancreatic exocrine insufficiency a) Failure of the pancreas to produce sufficient digestive enzymes to allow breakdown and absorption of fats and protein b) Obstruction of the pancreatic duct in utero with resultant progressive loss of exocrine pancreatic acini and their function c) A hallmark of the disease, occurring in 90% of patients by 1 year of age d) Leads to frequent, bulky, foul-smelling, oily stools e) Steatorrhea (presence of excessive undigested fat in the stool) f) Failure to thrive is commonly in the patients with CF ii. Recurrent pancreatitis in few patients iii. CF-related diabetes mellitus, rare before 10 years of age c. Liver i. Prolonged obstructive jaundice in a few affected infants, presumably secondary to obstruction of
4.
5.
6.
7.
8.
extrahepatic bile ducts by thick bile along with intrahepatic bile stasis ii. Chronic hepatic disease manifested by clinical or histologic evidence of focal biliary cirrhosis or multi-lobular cirrhosis Genitourinary manifestations a. Congenital bilateral absence of the vas deferens in most males i. Leading to azoospermia ii. A significant cause of infertility b. Infertility common in women i. Due to increased amounts of thick mucus in the cervical canal ii. An increased incidence of amenorrhea iii. Occasional patients carrying pregnancies to term without significant respiratory deterioration Skeletal manifestations a. Hypertrophic pulmonary osteoarthropathy i. Rarely seen in children with CF ii. Increasing frequency with increasing age and severity of disease b. Triad of skeletal manifestations i. Clubbing of fingers and toes ii. Arthritis iii. Periosteal new bone formation Nutritional abnormalities a. Failure to thrive, a common manifestation during infancy and beyond b. Poor appetite c. Weight loss d. Fatigue e. Prone to heat prostration f. Hypoproteinemia with or without edema, anemia, and deficient fat-soluble vitamins A, D, E, and K g. Peripheral neuropathy secondary to deficient vitamin E h. Delayed puberty largely due to nutritional factors i. Potentially lethal protein-energy malnutrition in some infants j. Development of some degree of malabsorption by 4 years of age in roughly 85% of patients Salt losing syndromes a. Acute salt depletion b. Chronic hypochloremic or hyponatremic alkalosis c. Excessive salt loss in the sweat potentially fatal for patients exposed to moderate heat or during prolonged hot weather Prognosis a. Respiratory failure: the leading cause of death in CF and occurs eventually in nearly all patients b. Current median survival: approximately 35 years in the United States c. Current data suggesting a lifespan exceeding 50 years for those diagnosed and treated early
DIAGNOSTIC INVESTIGATIONS 1. Newborn screening a. Measuring blood immunoreactive trypsinogen in dried blood spots i. Elevated levels in most CF infants (85–90% sensitive)
CYSTIC FIBROSIS
ii. Associated with a relatively large number of false positive results iii. Diagnosis must be confirmed by sweat tests or genotyping (CF multimutational analysis) b. Use DNA-based testing on dried blood spots by CFTR multimutational analysis 2. Sweat test a. The traditional method of CF diagnosis b. Reliably identifies the vast majority of patients with CF who have multiorgan involvement including the lungs and pancreas c. Using pilocarpine iontophoresis technique to produce sweat for chloride analysis d. Sweat chloride concentrations i. >60 mEq/L, observed in: a) CF patients with clinical manifestation of chronic pulmonary disease and/or pancreatic insufficiency b) CF patients with positive family history c) Untreated Addison disease d) Ectodermal dysplasia e) Certain types of glycogen storage diseases f) Untreated hypothyroidism g) A few normal adults ii. <60 mEq/L, observed in: a) Very few patients with CF (fewer than 1% of CF patients when they are well) b) CF patients with malnutrition and edema 3. Indications for sweat testing a. Meconium ileus or peritonitis (neonate) b. Jaundice (infancy) c. Hypochloremic alkalosis (infancy) d. Heat prostration (infancy or adulthood in males) e. Failure to thrive (infancy to childhood) f. Rectal prolapse (childhood) g. Nasal polyposis (childhood to adulthood) h. Panopacification of sinuses or pansinusitis (childhood) i. Pancreatitis (late childhood to early adulthood) j. Unexplained cirrhosis (childhood to adolescence) k. Gallstones (late childhood to early adulthood) l. Congenital bilateral absence of the vas deferens or azoospermia (any age but more obvious in adults) m. Recurrent or persistent pneumonia (any age) n. Staphylococcal pneumonia (any age but especially infants) o. Mucoid Pseudomonas in lung (any age) p. Bronchiectasis (any age) q. Positive family history in siblings or first cousins (any age) 4. Other clinical laboratory tests a. Prolonged prothrombin time secondary to deficient vitamin K b. Shortened red blood cell survival time secondary to deficient vitamin E c. Hypochloremic alkalosis secondary to high salt loss d. Isolation of organisms from the respiratory tract i. Pseudomonas aeruginosa ii. Burkholderia cepacia iii. Staphylococcus aureus e. Oxygen saturation
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5. Radiographic findings a. Chest X-ray i. Earliest finding: hyperinflation often with right upper lobe mucus retention ii. Progression to widespread bronchial dilatation, cysts, linear shadows, and infiltrates b. Sinuses X-ray: nearly universal presence of pansinusitis c. Abdominal X-ray i. Uncomplicated meconium ileus: multiple loops of dilated small bowel ii. Meconium peritonitis a) Calcifications within the abdominal cavity or even within the scrotum b) Resulting from an in utero perforation or complicated meconium ileus associated with volvulus d. Skeletal X-ray i. Arthritis ii. Periostitis in the diaphysis of the tubular bones 6. CT scan, especially high-resolution CT scan a. Readily identify air-trapping in the expiratory phase b. Mosaic perfusion, a secondary sign of small airway abnormality c. Centilobular nodule characterized by a cluster of illdefined nodules corresponding to branching terminal airways filled with secretions d. Classic findings of CF of progressive bronchiectasis involving the large airways i. Thick parallel bronchial walls seen as linear shadows or tram-line tracts ii. Ring shadows representing dilated thick-walled bronchi iii. Multiple nodular densities representing mucus plugging 7. Pulmonary function test 8. Molecular testing a. More than 1000 different mutations described to date b. ΔF508 mutation (deletion of a phenylalanine residue at position 508 in the 1480 amino acid protein) i. Present in about 70% of CF alleles in the U.S. ii. Homozygous ΔF508 mutation in about 50% of American CF patients c. Higher frequencies of certain mutations in different ethnic groups i. A455E mutation in Dutch CF patients ii. W1282X mutation in Ashkenazi Jewish CF patients d. Presence of two alleles with CF causing mutations confirms the diagnosis e. Conventional commercial genotyping testing for about 80 specific mutations in CFTR (including ΔF508 mutation) identifies about 95% of all CF alleles 9. Carrier testing available for family members of known patients or for couples without a family history
GENETIC COUNSELING 1. Recurrence risk a. Both parents carrying at least one abnormal copy of the CF gene
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b. Patient’s siblings i. 25% with CF disease ii. 50% with CF carrier c. Patient’s offspring: low recurrence risk unless the spouse is affected or a carrier of CF mutation 2. Prenatal diagnosis a. Ultrasonography i. Hyperechogenic fetal bowel suggestive of intestinal obstruction: perform carrier testing for CF gene mutations in the parents a) Diagnosis of CF highly likely in the fetus if both parents are carriers of a CF mutation b) Confirmed CF diagnosis by direct mutation analysis of amniotic fluid cells ii. Meconium peritonitis secondary to small bowel perforation in utero a) Associated with CF in only 7% of cases b) Presence of abdominal calcification usually associated with causes of meconium peritonitis other than CF c) Absence of abdominal calcifications favors the diagnosis of CF, to be confirmed by parental CF carrier testing and mutation analysis of fetal cells in at-risk couples b. Molecular genetic analysis i. Prenatal diagnosis accomplished in most families with an affected member by mutation analysis from fetal cells obtained from CVS (10 weeks) or amniocentesis (15–18 weeks) ii. Preimplantation genetic diagnosis to screen embryos before implantation, an alternative for at-risk couples a) A cleavage stage biopsy of embryo on day two or three after in vitro fertilization b) Removal of one or two cells for genetic analysis by nested polymerase chain reaction and heteroduplex formation c) Transfer of normal or carrier embryos to establish pregnancy d) Followed by CVS or amniocentesis to confirm the original diagnosis c. Postnatal sweat testing mandatory in all cases in which the diagnosis of CF has been made or excluded on the basis of prenatal DNA analysis 3. Management a. Antibiotic treatment of acute respiratory infections and exacerbations of chronic endobronchial infections i. Purpose a) To improve pulmonary function b) To improve exercise tolerance c) To improve quality of life ii. Short term oral ciprofloxacin for mild exacerbations by pseudomonas agent with caution in the younger pediatric age patients iii. Intravenous antibiotics, a mainstay of treatment of acute exacerbations of pulmonary disease a) Aminoglycoside (usually tobramycin) and β-lactam antibiotics b) Implanted central lines or peripheral vein catheters to maintain IV access iv. Aerosol (inhaled) antibiotics such as tobramycin v. Other aerosol antibiotics such as colistin
b. Airway clearance and exercise i. Percussion and postural drainage in an attempt to keep the airways free of infected and obstructive secretions ii. Positive expiratory pressure (PEP) devices to promote mucous clearance by preventing airway closure and increase collateral ventilation iii. Therapy vest, a chest wall compression and oscillation system comprising a fitted vest coupled to a pneumatic compressor iv. Flutter valve vibrating devices v. Directed exhalation techniques c. Sodium cromolyn (IntalTM) or nedocromil (TiladeTM) beneficial in some patients d. Use of inhaled (aerosolized) bronchodilators such as β-adrenergics e. Use of inhaled alpha dornase (DNase) (PulmozymeTM) to reduce sputum viscosity by cleaving extracellular neutrophil-derived DNA and brings about sustained improvement in pulmonary function in many patients with CF f. Avoid cough depressants g. Oxygen therapy if indicated h. Anti-inflammatory therapies i. Glucocorticoids: useful in selected patients ii. Ibuprofen i. Nutritional support to prevent malnutrition i. Provide pancreatic enzyme supplements and vitamins to correct malabsorption ii. Provide normal or high-fat diets with essential fatty acids necessary for growth and development iii. Provide fat-soluble vitamin supplements j. Management of gastrointestinal obstructive complications i. Gastrograffin enema for treatment of fecal impaction with distal intestinal obstruction syndrome ii. Surgery for intussusception if indicated iii. Surgery necessary to correct obstruction due to meconium ileus in most newborns k. Management of biliary tract disease i. Treatment of severe focal or multi-lobular biliary cirrhosis, portal hypertension, and hypersplenism a) Sclerosing of esophageal varices b) Hepatic shunt procedures c) Liver transplantation ii. Cholecystectomy for gallstones iii. Urodeoxycholic acid for selected cases of liver dysfunction l. Management of CF-associated diabetes mellitus i. Dietary management ii. Oral hypoglycemic agents for some patients iii. Insulin often required m. Management of pneumothorax i. Chest tube drainage ii. Followed by simple surgical oversewing of blebs if the initial air leak does not resolve iii. Followed by definitive pleural ablation if necessary
CYSTIC FIBROSIS
n. Management of hemoptysis i. Reassurance in most cases ii. Additional vitamin K iii. Discontinue drugs that may interfere clotting iv. Bronchial artery embolization by interventional radiologic techniques in unusual cases o. Management of respiratory failure i. Oxygen administration ii. Tracheal intubation and mechanical ventilation in terminally ill patients on the lung transplant waiting list iii. Lung transplantation, the ultimate approach to irreversible respiratory failure iv. Heart-lung and lung transplantation successfully applied to patients with end-stage CF patients p. Gene therapy in CF patients by in vivo gene transfers (targeted lung delivery of aerosolized gene vectors)
REFERENCES Boat TF, et al.: The diagnosis of cystic fibrosis: Consensus Statement, Consensus Conferences: Concepts of Care; 1996, Vol Vii, Section 1. Clinical Practice Guidelines for CF, CF Foundation, Bethesda, Md. Bye MR, Ewig JM, Quittel LM: Cystic fibrosis. Lung 172:251–270, 1994. Corteville JE, Gray DL, Langer JC: Bowel abnormalities in the fetus—correlation of prenatal ultrasonographic findings with outcome. Am J Obstet Gynecol 175:724–729, 1996. Cystic Fibrosis Genetic Analysis Consortium: Population variation of common cystic fibrosis mutations. Hum Mutat 4:167–177, 1994. Cystic Fibrosis Foundation. Cystic Fibrosis Foundation patient Registry Annual Data Report 1998. Bethesda, Md, 1999. Davis PB: Cystic fibrosis. Pediatr Rev 22:257–264, 2001. Davis PB, Drumm ML, Konstan MW: State of the art: cystic fibrosis. Am J Crit Care Med 154:1229–1256, 1996. Edenborough FP, Mackenzie WE, Stableforth DE: The outcome of 72 pregnancies in 55 women with cystic fibrosis in the United Kingdom 1977–1996. Brit J Obstet Gynecol 107:254–261, 2000. Estroff JA, Parad RB, Benacerraf BR: Prevalence of cystic fibrosis in fetuses with dilated bowel. Radiology 183:677–680, 1992. Farrell PM: Improving the health of patients with cystic fibrosis through newborn screening. Adv Pediatr 47:79–115, 2000. Farrell PM, Fost NF: Prenatal screening for cystic fibrosis: where are we now? J Pediatr 141:758–763, 2002. Farrell PM, Mischler EH: Newborn screening for cystic fibrosis. Adv Pediatr 39:31–64, 1992. Farrell MH, Farrell PM: Newborn screening for cystic fibrosis: ensuring more good than harm. J Pediatr 143:707–712, 2003. Fiel SB (ed): Cystic fibrosis. Clin Chest Med 19:423–567, 1998. Gan KH, Veeze HJ, van den Ouweland AM, et al.: A cystic fibrosis mutation associated with mild lung disease. N Engl J Med 333:95–99, 1995. Gilljam M, Antoniou M, Shin J, et al.: Pregnancy in cystic fibrosis: fetal and maternal outcome. Chest 118:85–91, 2000.
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Grody WW: Cystic fibrosis: molecular diagnosis, population screening, and public policy. Arch Pathol Lab Med 123:1041–1046, 1999. Hammond KB, Abman SH, Sokol RJ, et al.: Efficacy of statewide neonatal screening for cystic fibrosis by assay of trypsinogen concentrations. N Engl J Med 325:769–774, 1991. Kerem BEK: The molecular basis for disease variability in cystic fibrosis. Eur J Hum Genet 4:65–73, 1996. LeGrys VA: Sweat testing for the diagnosis of cystic fibrosis: practical considerations. J Pediatr 129:892–897, 1996. Macek M Jr, Mackova A, Hamosh A, et al.: Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%. Am J Hum Genet 60:1122–1127, 1997. Marshall BC, Samuelson WM: Basic therapies in cystic fibrosis. Does standard therapy work? Clin Chest Med 19:487–504, 1998. Mickle JE, Cutting Genome Res: Clinical implications of cystic fibrosis transmembrane conductance regulator mutations. Chest Med 19:443–458, 1998. Muller F, Simon-Bouy B, Girodon E, et al.: Predicting the risk of cystic fibrosis with abnormal ultrasound signs of fetal bowel: results of a French molecular collaborative study based on 641 prospective cases. Am J Med Genet 110:109–115, 2002. Orenstein DM, Winnie GB, Altman H: Cystic fibrosis: A 2002 update. J Pediatr 140:156–164, 2002. Pollitt RG: Screening for cystic fibrosis. Semin Neonatol 3:9–15, 1998. Riodan J, Rommens J, Kerem B-S, et al.: Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245:1066–1073, 1989. Rosenstein BJ: What is a cystic fibrosis diagnosis? Clin Chest Med 19:423–441, 1998. Rosenstein BJ, Cutting GR: The diagnosis of cystic fibrosis: a consensus statement. Cystic Fibrosis Foundation Consensus Panel. J Pediatr 132: 589–595, 1998. Ruzal-Shapiro C: Cystic fibrosis: An overview. Radiol Clin North Am 36: 143–161, 1998. Shalon LB, Adelson JW: Cystic fibrosis. Gastrointestinal complications and gene therapy. Pediatr Clin N Amer 43:157–196, 1996. Sharer N, Schwarz M, Malone G, et al.: Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 339:645–652, 1998. Strom CM, Ginsberg N, Rechitsky S, et al.: Three births after preimplantation genetic diagnosis for cystic fibrosis with sequential first and second polar body analysis. Am J Obstet Gynecol 178:1298–1306, 1998. Tait JF, Gibson RL, Marshall SG, et al.: Cystic fibrosis. Rene Reviews, 2001. http://www.genetests.org Tsui L-C, Buchwald M: Biochemical and molecular genetics of cystic fibrosis. Adv Hum Genet 20:153–266, 1991. Wall J, Cai S, Chehab FF: A 31-mutation assay for cystic fibrosis testing in the clinical molecular diagnostics laboratory. Hum Mutat 5:333–338, 1995. Welsh MJ, Ramsey BW, Accurso F, et al.: Cystic fibrosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, 8 ed. McGraw-Hill, New York, 2001, pp 5121–5188 Wilson RD, Davies G, Desilets V, et al.: Cystic fibrosis carrier testing in pregnancy in Canada. J Obstet Gynaecol Can 24:644–651, 2002. Yankaskas JR, Mallory GB Jr: Lung transplantation in cystic fibrosis. Consensus Conference Statement. Chest 113:217–226, 1998. Zielenski J, Tsui LC: Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet 29:777–807, 1995.
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Fig. 1. This 5-month-old infant has history of failure to thrive, foul smelling stools and excessive spitting. The patient is positive for two copies of the ΔF508 mutation.
Fig. 2. A 16-year-old boy with cystic fibrosis showing an emaciate chest, club fingers, and a honeycomb-like chest with air trapping illustrated by chest radiographs.
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Fig. 5. Fragment size separation of CFTR mutations using capillary gel electrophoresis (ABI 310 genetic analyzer, Applied Biosystems). A mutation in ΔF508 is noted in red.
Fig. 3. Photomicrograph of the pancreas of a 16-year-old male who died of bronchiectasis and bronchopneumonia. In the top photomicrograph, the exocrine glands (acini) are mostly absent. Irregularly dilated exocrine ductules are lined by flattened atrophic epithelium. Many unaffected islets of Langerhans are present at left lower corner. In the lower photomicrograph with higher magnified, there are many islets of Langerhans but normal exocrine glands and ductules are absent.
Fig. 4. Photomicrograph of the duodenum of the same patient. The Brunner’s glands in the submucosa are distended by inspissated secretion. Three mucosal crypts are also slightly dilated.
Dandy-Walker Malformation c. d. e. f. g.
Diaphragmatic hernia Omphalocele Polycystic kidneys Spinal defects Limb defects i. Polydactyly ii. Syndactyly 6. Common presenting signs and symptoms a. Macrocrania b. Bulging fontanel c. Upward gaze palsy d. Hypertelorism e. Strabismus f. Hypotonia g. Headache and vomiting h. Seizures i. Hemiparesis j. Facial palsy k. Palpebral ptosis l. Pyramidal signs m. Cerebellar dysfunction n. Motor dysfunction o. Mental retardation: subnormal intelligence reported in 40–70% of cases 7. Prognosis a. Grim but not uniformly fatal b. Worst prognosis when there are associated anomalies and chromosome abnormalities c. Better chance of normal outcome for isolated DandyWalker variant
In 1954, Benda introduced the term Dandy-Walker syndrome to indicate the association of (1) ventriculomegaly of variable degree, (2) a large cisterna magna, and (3) a defect in the cerebellar vermis through which the cyst communicates with the fourth ventricle. Currently, the following findings are included in the Dandy-Walker syndrome or malformation: (4) cystic dilatation of the fourth ventricle, (5) dysgenesis of the cerebellar vermis, and (6) a high position of the tentorium. The Dandy-Walker malformation has prevalence of about 1 in 30,000 live births and found in 4–12% of infantile hydrocephalus.
GENETICS/BASIC DEFECTS 1. Heterogeneous etiology a. Isolated b. A part of a Mendelian disorder c. A part of a chromosome disorder i. Trisomy 18 ii. Triploidy iii. Trisomy 13 d. Environmental factors 2. Uncertain significance of Dandy-Walker variant and mega-cisterna magna
CLINICAL FEATURES 1. Maternal polyhydramnios/oligohydramnios 2. Fetal anomalies a. Echogenic bowel b. Effusions/hydrops c. Single umbilical artery d. Growth restriction e. Abundant nuchal folds f. Cystic hygroma 3. Neuropathologic triad a. Cystic dilatation of the fourth ventricle b. Hypoplasia of the cerebellar vermis c. Hydrocephalus 4. Associated intracranial anomalies (70% of cases) a. An enlarged posterior fossa b. Ventriculomegaly c. Atresia of the foramina of Magendie and Luschka d. Midline anomalies i. Agenesis of the corpus callosum ii. Holoprosencephaly iii. Occipital meningocele and encephalocele e. Porencephalic cyst f. Migrational disorder g. Gyral abnormalities h. Microcephaly 5. Non-CNS associated malformations a. Facial clefting b. Cardiovascular defects
DIAGNOSTIC INVESTIGATIONS 1. Sonography a. Sonographic diagnosis of classic Dandy-Walker malformation: straightforward from mid-gestation b. Detection of Dandy-Walker malformation as early as 14 weeks using vaginal sonography c. In the transcerebellar view i. An enlarged cisterna magna connected to the area of the fourth ventricle through a defect in the cerebellar vermis ii. Presence of borderline-to-overt ventriculomegaly iii. Frequent association of other neural and extraneural malformation 2. CT and MRI of the brain a. Large median posterior fossa cyst widely communicating with the fourth ventricle b. Cystic enlargement of the fourth ventricle c. Cerebellar vermis dysgenesis d. An upwardly displaced tentorium e. Hydrocecphalus f. Atresia of the foramina of Magendie and Luschka 273
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g. Frequently associated CNS anomalies i. Agenesis of corpus callosum ii. Occipital encephalocele iii. Porencephalic cyst iv. Holoprosencephaly v. Others
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: a low recurrence risk in the order of 1–5% unless the Dandy-Walker malformation is a part of a mendelian disorder or associated with chromosome anomaly b. Patient’s offspring: not surviving to reproductive age because of severe neurologic deficits associated with major malformations 2. Prenatal diagnosis a. Ultrasonography for detecting unique previously described CNS malformations b. MRI of the fetal CNS c. Prenatal amniocentesis for fetal karyotyping 3. Management a. Ventriculoperitoneal shunt b. Cyst-peritoneal shunt c. Ventriculocystoperitoneal shunt d. Posterior fossa craniectomy with cyst fenestration
REFERENCES Achiron R, Achiron A: transvaginal ultrasonic assessment of the early fetal brain. Ultrasound Obstet Gynecol 1:336–342, 1991. Almeida GM, Matushita H, Mattosinho-França LC, et al.: Dandy-Walker syndrome: posterior fossa craniectomy and cyst fenestration after several shunt revisions. Child’s Nerv Syst 6:335–337, 1990. Babcock CJ, Chong BW, Salamat MS, et al.: Sonographic anatomy of the developing cerebellum: normal embryology can resemble pathology. Am J Roentgenol 166:427–433, 1996. Benda CE: The Dandy-Walker syndrome or the so-called atresia of the foramen Magendie. J Neuropathol Exp Neurol 13:14–27, 1954. Bromley B, Nadel AS, Pauker S, et al.: Closure of the cerebellar vermis: evaluation with second trimester US. Radiology 193:761–763, 1994.
Ecker JL, Shipp TD, Bromley B, et al.: The sonographic diagnosis of DandyWalker and Dandy-Walker variant: associated findings and outcomes. Prenat Diagn 20:328–332, 2000. Estroff JA, Scott MR, Benacerraf BR: Dandy-Walker variant: prenatal sonographic features and clinical outcome. Radiology 185:755–758, 1992. Hart MN, Malamud N, Ellis W: The Dandy-Walker syndrome: a clinicopathological study based on 28 cases. Neurology 22:771–780, 1972. Hirsch JF, Pierre-Kahn A, Reiner D, et al.: The Dandy-Walker malformation. A review of 40 cases. J Neurosurg 61:515–522, 1984. Incesu L, Khosla A: Dandy-Walker malformation. Emedicine, 2003. http://www.emedicine.com Klein O, Pierre-Kahn A, Boddaert N, et al.: Dandy-Walker malformation: prenatal diagnosis and prognosis. Childs Nerv Syst 19:484–489, 2003. Kölble N, Wisser J, Kurmanavicius J, et al.: Dandy-Walker malformation: prenatal diagnosis and outcome. Prenat Diagn 20:318–327, 2000. Kumar R, Jain MK, Chhabra DK: Dandy-Walker syndrome: different modalities of treatment and outcome in 42 cases. Child’s Nerv Syst 17:348–352, 2001. Laing FC, Frates MC, Brown DL, et al.: Sonography of the fetal posterior fossa: false appearance of mega-cisterna magna and Dandy-Walker variant. Radiology 192:247–251, 1994. Mahony BS, Callen PW, Filly RA, et al.: The fetal cisterna magna. Radiology 153:773–776, 1984. Maria BL, Zinrech SJ, Carson BC, et al.: Dandy-Walker syndrome revisited. Pediatr Neurosci 13:45–48, 1987. Murray JC, Johnson JA, Bird TD: Dandy-Walker syndrome: etiologic heterogeneity and empiric recurrence risks. Clin Genet 28:272–283, 1985. Nyberg DA, Mahony BS, Hegge FN, et al.: Enlarged cisterna magna and the Dandy-Walker malformation: factors associated with chromosome abnormalities. Obstet Gynecol 71:436–442, 1991. Osenbach RK, Menezes AH: Diagnosis and management of the Dandy-Walker malformation: 30 years of experience. Pediatr Neurosurg 18:179–189, 1992. Pascual-Castroviejo I, Velez A, Pascual-Pascual SI, et al.: Dandy-Walker malformation: analysis of 38 cases. Child’s Nerv Syst 7:88–97, 1991. Pilu G, Hobbins JC: Sonography of fetal cerebrospinal anomalies. Prenat Diagn 22:321–330, 2002. Pilu GL, Goldstein I, Reece EA, et al.: Sonography of fetal Dandy-Walker malformation: a reappraisal. Ultrasound Obstet Gynecol 2:151–156, 1992. Sawaya R, McLaurin RL: Dandy-Walker syndrome: Clinical analysis of 23 cases. J Neurosurg 55:89–98, 1981. Tsao K, Chuang NA, Filly RA, et al.: Entrapped fourth ventricle. Another pitfall in the prenatal diagnosis of Dandy-Walker malformations. J Ultrasound Med 21:91–96, 2002. Udvarhelyi GB, Epstein MH: The so-called Dandy-Walker syndrome: Analysis of 12 operated cases. Child’s Brain 1:158–182, 1975.
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Fig. 2. MRI of the brain of the patient in Fig. 1 shows Dandy-Walker malformation with a large posterior fossa cyst which communicates with dilated 4th ventricle. In addition, this patient also has agenesis of corpus callosum, hydrocephalus, and vermis dysgenesis.
Fig. 1. An 8-month-old patient with Dandy-Walker malformation associated with multiple congenital anomalies including facial dysmorphism, skin tags (pseudotails) on the cheek, and limb anomalies.
De Lange Syndrome In 1933, Cornelia de Lange reported two nonfamilial infant girls with severe mental retardation and multiple abnormalities of the skull, face, and extremities. Earlier in 1916, Brachmann had described a child with similar features. The syndrome is also called Brachmann-de Lange syndrome or Cornelia de Lange syndrome. The prevalence is estimated to be 1 in 10,000 births.
GENETICS/BASIC DEFECTS 1. A heterogeneous clinical entity a. Sporadic in vast majority of cases (99%) b. Striking concordance in MZ twins c. Rare familial occurrences i. Autosomal dominant inheritance ii. Autosomal recessive inheritance: unlikely 2. Both missense and protein-truncating mutations in NIPBL, the human homolog of the Drosophila melangaster Nipped-B gene, have recently been reported to cause de Lange syndrome 3. Inconsistent chromosome abnormalities occasionally associated with de Lange phenotype
CLINICAL FEATURES 1. Marked clinical variability 2. General history a. Prenatal and/or postnatal growth deficiency b. Prematurity c. Diminished sucking and swallowing ability d. Low pitched cry (74%) in the newborn period and in the early infancy but may disappear in the late infancy e. Global developmental delay f. Initial hypertonicity g. Recurrent respiratory tract infections h. Gastroesophageal reflux i. Failure to thrive 3. Growth a. Prenatal onset growth retardation b. Short stature 4. Skin a. Hypertrichosis (hirsutism) (78%): often with hairy whorls over the shoulders, lower back, and extremities b. Cutis marmorata (60%) c. Periorbital “cyanosis” 5. Characteristic craniofacial appearance a. Microcephaly (98%) b. Brachycephaly c. Hairy (low hairline) forehead d. Mask like (grim, devoid of expression) facies e. Hypertelorism f. Antimongoloid slant of palpebral fissures g. Synophrys (prominent bushy, confluent eyebrows joining at the nose) (99%) h. Long and curly eyelashes (99%) 276
i. Depressed nasal bridge (83%) j. Small nose k. Anteverted nares (88%) l. Micrognathia (84%) m. Long bulging, prominent philtrum (94%) n. Thin upper lip (94%) o. Central depression below lower lip p. Down turned corners of the mouth (94%) q. Late eruption of teeth r. Widely spaced teeth (86%) s. High arched palate (86%) t. Low set, malformed, and hairy ears (70%) u. Low posterior hairline (92%) v. Short neck (66%) 6. Eye abnormalities (57%) a. Strabismus b. Nystagmus (37%) c. Myopia (60%) d. Ptosis (45%) e. Microcornea f. Astigmatism g. Optic atrophy h. Coloboma of the optic nerve i. Eccentric pupils j. Microphthalmia k. Blue sclerae 7. Limb abnormalities a. Upper extremities i. Micromelia (shortened limbs) (93%) ii. Ectrodactyly/oligodactyly/phocomelia (27%) iii. Clinodactyly of the 5th fingers (74%) iv. Small hands v. Proximally placed thumbs vi. Camptodactyly vii. Webbings of fingers viii. Brachydactyly ix. Flexion contractures of the elbows common (64%) x. Restriction of supination and pronations xi. Subluxation or dislocation of the radial head b. Lower extremities i. Small feet ii. Cutaneous syndactyly of the second and third toes (86%) iii. Tight Achilles tendon (equines deformity) iv. Pes planus v. Valgus heel vi. Flexion contractures of the knees 8. CNS anomalies a. Variable mental retardation to near-normal intellect b. Seizures (23%) c. Abnormal speech development d. Hearing deficits (60–100%)
DE LANGE SYNDROME
e. Hypoplasia of the vermis f. Hypertonia/hypotonia 9. Behavior disorder a. Sleep disturbance (55%) b. Aggression (49%) c. Self-destructive tendencies (44%) d. Hyperactivity (40%) e. Low-pitched growling sound rather than cry f. Infrequent facial expressions of emotion g. Severe language delay h. Autistic-like behavior i. Repetitive stereotypic movement j. Eliciting pleasurable responses by vestibular stimulation or vigorous movement 10. Other anomalies a. Small hypoplastic nipples (55%) b. Small hypoplastic umbilicus (53%) c. Cardiovascular anomalies (15–20%) i. Ventricular septal defect ii. Atrial septal defect iii. Patent ductus arteriosus iv. Aortic valve anomaly v. Hypoplasia of the aorta vi. Persistent left superior vena cava vii. Pulmonary stenosis viii. Endocardial cushion defect ix. Tetralogy of Fallot d. Gastrointestinal anomalies i. Inguinal hernia ii. Hiatus hernia iii. Congenital diaphragmatic hernia iv. Gut duplication v. Malrotation of colon vi. Pyloric stenosis e. Genitourinary anomalies i. Hypoplastic, dysplastic, or cystic kidneys ii. Hypoplastic external genitalia, cryptorchidism or hypospadias in males iii. Small labia majora, bicornuate or septate uterus in females f. Abnormal dermatoglyphics i. Transverse palmar creases (51%) ii. Increased atd angle iii. Hypoplastic finger ridge patterns
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Skull i. Microcephaly: frequent ii. Brachycephaly: frequent iii. Trigonocephaly with orbital hypotelorism iv. Parietal foramina v. Micrognathia vi. High-arched palate vii. Cleft palate b. Spine i. Kyphoscoliosis ii. Platyspondyly iii. Scheuermann disease
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iv. Spina bifida v. Square vertebrae vi. Coxa valga c. Chest i. Aspiration pneumonia: frequent ii. Thin ribs iii. Short clavicles iv. Short hypoplastic sternum with reduced number of ossification centers v. Abnormal sternal angle vi. Cervical ribs vii. Hypoplasia of the first rib viii. Chronic pneumonia ix. Bronchiolitis d. Congenital heart diseases e. Gastrointestinal tract i. Swallowing dysfunction: frequent ii. Bowel rotation anomalies with bands: frequent iii. Hiatal hernia iv. Hypertrophic pyloric stenosis v. Duodenal stenosis vi. Colon duplication vii. Inguinal hernia viii. Umbilical hernia f. Genitourinary tract i. Incomplete rotation of the kidneys ii. Renal duplication iii. Polycystic kidneys iv. Chronic pyelonephritis v. Abnormal renal function with poor visualization on excretory urography vi. Vesicoureteral reflux vii. Divided uterine canal with septate vagina g. Limbs i. Micromelia: frequent ii. Short humerus and/or forearm bones: frequent iii. Elongated humeral neck (similar to femoral neck): frequent iv. Subluxation or dislocation of malformed radius and/or ulna at elbow with fixation in flexion v. Absent or hypoplastic ulna: frequent vi. Retarded bone maturation with abnormal sequence of appearance of ossification centers: frequent vii. Absent carpals, metacarpals, and fingers (ectrodactyly/oligodactyly): frequent viii. Short, broad metacarpals, particularly 1 and 5: frequent ix. Hypoplastic phalanges particularly middle 5th (curved) and middle second fingers: frequent x. Cutaneous syndactyly of second and third toes or other toes and fingers: frequent xi. Cutis valgus xii. Absent or hypoplastic radius xiii. Lunate and triquetral fusion xiv. Aplastic or hypoplastic ulnar styloid xv. Double distal phalanges of thumbs and/or great toes xvi. Congenital dislocated hips xvii. Aseptic necrosis of femoral head
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2. 3. 4. 5. 6. 7.
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xviii. Broad ischial bones xix. Large obturator foramina xx. Short broad femoral necks xxi. Absent tibia with deformed fibula xxii. Fusion of phalanges of fifth toe xxiii. Rocker-bottom foot xxiv. Metatarsus adductus xxv. Planovalgoid foot xxvi. Talipes equinovarus xxvii. Shortening of femur and/or leg bones xxviii. Wide gap between first and second toes xxix. Osteoporosis Endocrinologic studies in patients with severe growth retardation Echocardiography for evaluation of congenital heart defects Abdominal ultrasonography for GU anomalies EEG for seizures High resolution chromosome analysis for associated chromosome anomaly DNA mutation analysis of NIPBL (positive in 47%)
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: an empiric risk of about 1–4% b. Patient’s offspring: 50% in case of an autosomal dominant inheritance 2. Prenatal diagnosis by ultrasonography a. Intrauterine growth retardation b. Characteristic facies i. A small bulging nose ii. Long bulging philtrum iii. Protruding and overhanging upper lip iv. Micrognathia c. Limb defects i. Micromelia ii. Monodactyly iii. Ulnar agenesis d. Diaphragmatic hernia 3. Management a. Adequate caloric intake b. Treat gastroesophageal reflux with thickened feeds in an upright position and pharmacotherapy c. Fitting of hearing aids and early consistent training for hearing impaired children d. Early intervention and special education programs for psychomotor delay e. Behavioral modification f. Correction of refractory errors with glasses g. Anticonvulsants for seizures h. Surgical repairs i. Fundoplication and gastrostomy feedings necessary in patients with severe esophagitis and progressive failure to thrive despite conservative intervention ii. Diaphragmatic hernia iii. Cardiac defect iv. Severe skeletal deformities v. Renal malformations vi. Ptosis obstructing the visual axis vii. Orchiplexy
REFERENCES Aberfeld DC, Pourfar M: De Lange’s Amsterdam dwarfs syndrome. Report of two cases. Dev Med Child Neurol 7:35–41, 1965. Abraham JM, Russell A: De Lange syndrome. A study of nine examples. Acta Paediatr Scand 57:339–353, 1968. Ackerman J, Gilbert-Barnes E: Brachmann-de Lange syndrome. Am J Med Genet 68:367–368, 1997. Beck B: Epidemiology of Cornelia de Lange’s syndrome. Acta Paediatr Scand 65:631–638, 1976. Beck B: Psycho-social assessment of 36 de Lange patients. J Ment Defic Res 31:251–257, 1987. Beratis NG, Hsu LY, Hirschhorn K: Familial de Lange syndrome. Report of three cases in a sibship. Clin Genet 2:170–176, 1971. Berney TP, Ireland M, Burn J: Behavioural phenotype of Cornelia de Lange syndrome. Arch Dis Child 81:333–336, 1999. Brachmann W: Ein Fall von symmetrischer Monodaktylie durch Ulnadefekt, mit symmetrischer Flughautbildung in den Ellenbeugen, sowie anderen Abnormalitaten. Jahr Kinderheiklunde 84:225–235, 1916. Braddock Skelet Radiol, Lachman RS, Stoppenhagen CC,et al.: Radiological features in Brachmann-de Lange syndrome. Am J Med Genet 47:1006–1013, 1993. Breslau EJ, Disteche C, hall JG, et al.: Prometaphase chromosomes in five patients with the Brachmann-de Lange syndrome. Am J Med Genet 10:179–186, 1981. Bryson Y, Sakati N, Nyhan WL, et al.: Self-mutilative behavior in the Cornelia de Lange syndrome. Am J Ment Defic 76:319–324, 1971. Chrzanowska KH, Janniger CK: de Lange syndrome. Emedicine, 2002. http://www.emedicine.com De Lange C: Sur un type nouveau de dégénération (typus amstelodamensis). Arch med Enfants 36:713–719, 1933. Filippi G: The de Lange syndrome. Report of 15 cases. Clin Genet 35:343–363, 1989. Gadoth N, Lerman M, Garty B-Z, et al.: Normal intelligence in the Cornelia de Lange syndrome. Johns Hop Med J 150:70–72, 1982. Gillis LA, McCallum J, Kaur M, et al.: NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype–phenotype correlations. Am J Hum Genet 75:610–623, 2004. Goodban MT: Survey of speech and language skills with prognostic indicators in 116 patients with Cornelia de Lange syndrome. Am J Med Genet 47:1059–1063, 1993. Goolsby LM, McNamara MF, Andeson CF, et al.: Diagnosis: Brachmann-de Lange syndrome. J Ultrasound Med 14:325–336, 1995. Greenberg F, Robinson LK: Mild Brachmann-de Lange syndrome: changes of phenotype with age. Am J Med Genet 32:90–92, 1989. Halal F, Preus M: The hand profile in de Lange syndrome: diagnostic criteria. Am J Med Genet 3:317–323, 1979. Hawley PD, Jackson LG, Kurnit DM: Sixty-four patients with Brachmann-de Lange syndrome: A survey Am J Med genet 20:453–459, 1985. Ireland M: Cornelia de Lange syndrome. In: Cassidy SB, Allanson JE (eds): Management of Genetic Syndromes. New York: Wiley-Liss, 2001. Ireland M, Donnai D, Burn J: Brachmann-de Lange syndrome. Delineation of the clinical phenotype. Am J Med Genet 47:959–964, 1993. Jackson L, Kline AD, Barr MA,et al.: de Lange syndrome: a clinical review of 310 individuals. Am J Med Genet 47:940–946, 1993. Jervis GA, Stimson CW: de Lange syndrome. The “Amsterdam type” of mental defect with congenital malformation. J Pediatr 63:634–645, 1963. Johnson Hum Genet, Ekman P, Friesen W: A behavioral phenotype in the de Lange syndrome. Pediatr Res 10:843–850, 1976. Joubin J, Pettrone CF, Pettrone FA: Cornelia de Lange’s syndrome. A review article (with emphasis on orthopedic significance). Clin Orthop Relat Res171:180–185, 1982. Kousseff BG, Newkirk P, Root AW: Brachmann-de Lange syndrome. 1994 update. Arch Pediatr Adolesc Med 148:749–755, 1994. Kurlander GJ, DeMyer W: Roentgenology of the Brachmann-de Lange syndrome. Radiology 88:101–110, 1967. Lee FA, Kenny FM: Skeletal changes in the Cornelia de Lange syndrome. Am J Roentgenol 100:27–39, 1967. Marino T, Wheeler PG, Simpson LL, et al.: Fetal diaphragmatic hernia and upper limb anomalies suggest Brachmann-de Lange syndrome. Prenat Diagn 22:144–147, 2002. McArthur RG, Edwards JH: DeLange syndrome: Report of 20 cases. Can Med Assoc J 96:1185–1198, 1967.
DE LANGE SYNDROME Motl ML, Opitz JM: Studies of malformation syndromes XXVA. Phenotypic and genetic studies of the Brachmann-de Lange syndrome. Hum Hered 21:1–16, 1971. Opitz JM: Editorial comment: the Brachmann-de Lange syndrome. Am J Med Genet 22:89–102, 1985. Opitz JM: Brachmann-de Lange syndrome: a continuing enigma. Arch Pediatr Adolesc Med 148:1206–1208, 1994. Pashayan H: Variability of the de Lange syndrome: report of three cases and genetic analysis of 54 families. J Pediatr 75:853–858, 1969. Pashayan Hum Mutat, Fraser FC, Pruzansky S: Variable limb malformations in the Brachmann-de Lange syndrome. Birth Defects Original Article Series 11(5):147–156, 1975. Preus M, Rex AP: Definition and diagnosis of the Brachmann-de Lange syndrome. Am J Med Genet 16:301–312, 1983.
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Ptacek LJ, Opitz JM, Smith DW, et al.: The Cornelia de Lange syndrome. J Pediatr 63:1000–1020, 1963. Russell KL, Ming JE, Patel K, et al.: Dominant paternal transmission of Cornelia de Lange syndrome: a new case and review of 25 previously reported familial recurrences. Am J Med Genet 104:267–276, 2001. Silver HK: The de Lange syndrome. Typus Amstelodamensis. Am J Dis Child 108:523–529, 1964. Tekin M, Bodurtha J: Cornelia de Lange syndrome. Emedicine, 2002. http://www.emedicine.com Van Allen MI, Filippi G, Siegel-Bartelt J, et al.: Clinical variability within Brachmann-de Lange syndrome: a proposed classification system. Am J Med Genet 47:947–958, 1993.
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Fig. 1. A neonate and a child with de Lange syndrome showing characteristic facies, oligodactyly, and severe hirsutism.
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Fig 3. A 46,XX male with de Lange phenotype.
Fig 2. Four patients with classic De Lange syndrome of different ages showing typical facial appearance (synophrys, coarse eyebrows, long curly eyelashes, depressed nasal bridge with anteverted nares, long thin upper lip, down-turned angles of the mouth, and widely spaced teeth) and ectrodactyly/oligodactyly in the first two cases.
Fig 4. Two adults with de Lange syndrome showing hirsutism and mental retardation.
Del(22q11.2) Syndromes The 22q11.2 deletion syndromes are a group of conditions with a deletion in the long arm of chromosome 22. They share a characteristic spectrum of congenital cardiac defects with wide ranging noncardiac congenital anomalies (immune deficiencies secondary to aplasia or hypoplasia of the thymus, hypocalcemia due to small or absent parathyroid glands, palatal and speech abnormalities, and congnitive difficulties). The occurrence is approximately 1 in 4000 live births. Historic overviews of the syndromes associated with 22q11.2 deletion: 1. Congenital thymic hypoplasia associated with hypocalcemia (1959) 2. DiGeorge syndrome (DGS) (1972) a. Congenital thymic hypoplasia b. Hypocalcemia c. T-cell dysfunction d. Typical facial anomalies e. Typical cardiac anomalies 3. Takao syndrome (conotruncal anomaly face syndrome) (1976) a. Conotruncal cardiac anomalies b. Typical facial appearance c. Velopharyngeal insufficiency d. Learning disability 4. Velocardiofacial syndrome (VCFS) (Shprintzen syndrome) (1978) a. Velophalangeal abnormalities b. Cardiac abnormalities c. Facial abnormalities d. The birth incidence of 1/1800–1/400, making VCFS the second most common cause of congenital heart disease after Down syndrome 5. DiGeorge syndrome speculatively linked to chromosome 22 (1981) 6. Partial monosomy of chromosome 22 (1982) 7. “CATCH-22 syndrome” (1989): not a preferred term a. Cardiac disease b. Abnormal facies c. Thymic hypoplasia d. Cleft palate e. Hypocalcemia f. Associated with a deletion in chromosome-22 8. Cayler craniofacial syndrome associated with del(22q11.2) (1994) a. Asymmetric crying facies b. Phenotypic spectrum expanded to include extracardiac anomalies c. Associated with del(22q11.2) 9. Some cases of autosomal dominant Opitz G/BBB syndrome (1995) a. Hypertelorism b. Laryngotracheoesophageal cleft c. Cleft palate
d. e. f. g.
Swallowing difficulty Genitourinary defects Mental retardation Congenital heart defects
GENETICS/BASIC DEFECTS
282
1. Inheritance a. De novo deletions in the majority of cases (93%) b. The deletion can be transmitted as an autosomal dominant trait c. Familial deletions identified in 7% of probands 2. Cause: hemizygous deletion of 22q11.2 a. Deletions inherited from an affected parent (<14%) b. Up to 89% of patients show a typical phenotype of DiGeorge syndrome c. Occupy roughly 15% of the patients with congenital heart disease d. Microdeletions detected by fluorescence in situ hybridization (FISH) probes 3. Molecular/cytogenetic basis a. DiGeorge critical region (300–600 kbp containing approximately 25 to 30 candidate genes), mapped to 22q11.2 b. Candidate genes i. Ubiquitin-fusion-degradation-1-like (UFD1L) gene, located in the DiGeorge critical region, which is most consistently deleted in patients with DGS (88%) or VCFS (76%). A significant percentage of cardiac patients with conotruncal cardiac malformations have a 22q11.2 deletion ii. TBX1 gene (belongs to the T-box family of transcription factors): TBX1 haploinsufficiency is likely the major determinant of aortic arch defects in patients with 22q11.2 deletion syndrome 4. Cardiac embryogenesis and branchial arch abnormalities a. Cardiac structures (derived from the cardiogenic cord in the embryonic mesoderm during very early embryogenesis) b. Conotruncus (outflow structures of the heart, derived from branchial arches IV and VI, which differentiate into aorta and pulmonary artery respectively). Malalignment of these structures and incomplete septation give rise to the following diverse congenital heart disease associated with DiGeorge syndrome: i. Arch abnormalities (interrupted aortic arch, aortic coarctation) ii. Conotruncal abnormalities (truncus arteriosus, pulmonary artery atresia) iii. Malalignment of the interventricular septum with the conotruncus (VSD, ASD, Tetralogy of Fallot, DORV) iv. Valvular or myocardium abnormalities (unusual)
DEL(22Q11.2) SYNDROMES
c. Branchial arches are also the embryological origin of the anterior facial structures, thyroid, thymus, and parathyroids. Their abnormalities are the phenotypic hallmark of the DiGeorge syndrome groups 5. Heterogeneous etiology of congenital heart defects a. Deletion 22q11.2 (the 2nd most common chromosomal cause of significant congenital heart disease) b. Aneuploidy (trisomy 21 remains the most common chromosomal cause of significant congenital heart disease) c. Single gene disorder d. Multifactorial trait e. Maternal disease such as diabetes mellitus f. Teratogen exposure
CLINICAL FEATURES 1. Marked variability of phenotype 2. Endocrine abnormalities: common in patients with a 22q11.2 deletion a. Hypocalcemia (30%) i. Invariably due to hypoparathyroidism, documented by aplasia or hypoplasia of the parathyroid glands at surgery or autopsy ii. Symptoms of hypocalcemia most likely manifest in the neonatal period, because maternal calcium supply by fetal circulation is abruptly interrupted at birth and the calcium intake within the first few days of life is usually insufficient a) Seizures b) Tremors c) Tetany iii. Other signs of hypocalcemia a) Paresthesias b) Muscle cramps c) Rigidity iv. Prevalence of hypocalcemia by phenotypic characteristics a) DiGeorge syndrome (69–72%) b) Velocardiofacial syndrome (13–22%) c) Conotruncal anomaly face syndrome (10%) d) 22q11.2 deletion (49–60%) v. Autoimmune enteropathies b. Growth disorders i. Growth hormone deficiency ii. Short stature c. Thyroid disorders i. Congenital hypothyroidism a) Noted in 7% of patients with VCFS b) Noted in 5% of patients with DGS ii. Hyperthyroidism due to Graves disease 3. Immunodeficiency (highly variable) (77%) a. Primary T-cell dysfunction (decreased production of T cells caused by impaired formation of thymic tissue) (67%) b. Secondary T-cell functional defects (19%) c. Humoral immune deficits (23%) d. IgA deficiency (13%) e. Associated autoimmune disease i. Polyarticular juvenile rheumatoid arthritis, a frequency 150 times that of the general population rate ii. Autoimmune hemolytic anemia
283
iii. Idiopathic thrombocytopenic purpura iv. Autoimmune enteropathies (celiac disease) v. Vitiligo 4. Cardiovascular malformations (75%, the most common structural anomaly) a. Conotruncal heart defects i. Tetralogy of Fallot (the most common heart anomaly) ii. Pulmonary atresia with ventricular septal defect iii. Truncus arteriosus (25%) iv. Interrupted aortic arch type B (30%) v. Atrial septal defect b. Right-sided, cervical, or double aortic arch/aberrant subclavian artery c. Pulmonary artery abnormalities i. Discontinuity of the pulmonary arteries ii. Diffuse hypoplasia iii. Discrete stenosis iv. Defect of arborization v. Major aortopulmonary collateral arteries d. Infundibulum abnormalities i. Malaligned ii. Hypoplastic iii. Absent e. Semilunar valve abnormalities i. Bicuspid ii. Severely dysplastic iii. insufficient iv. Stenotic 5. Craniofacial features a. Palate i. Velopharyngeal incompetence (27%) ii. Submucous cleft palate (16%) iii. Overt cleft palate (11%) iv. Bifid uvula (5%) v. Cleft lip/palate (2%) vi. Suspected velopharyngeal incompetence vii. Normal b. Ears i. Low-set ears ii. Overfolded helices iii. Squared off helices iv. Cupped, microtic, and protuberant ears v. Preauricular pits/tags vi. Narrow canals vii. Chronic otitis media viii. Conductive hearing loss c. Nose i. Prominent nasal root ii. Bulbous nasal tip iii. Hypoplastic alae nasae iv. Nasal dimple/bifid nasal tip v. Chronic sinusitis d. Throat i. Stridor caused by a vascular ring ii. Laryngomalacia iii. Laryngeal webs e. Eyes i. Tortuous retinal vessels (58%) ii. Posterior embryotoxon (69%)
284
6.
7.
8.
9.
10.
11.
DEL(22Q11.2) SYNDROMES
iii. Hooding of the upper and/or lower lid (47%) iv. Ptosis (9%) v. Epicanthal folds (3%) vi. Distichiasis (3%) Skeletal abnormalities a. Vertebral anomalies (19%) i. Coronal clefts ii. Hemivertebrae iii. Butterfly vertebrae iv. Scoliosis b. Rib anomalies including supernumerary ribs (19%) c. Hypoplastic scapulae d. Upper limb anomalies including pre/postaxial polydactyly (6%) e. Lower limb anomalies (15%) i. Postaxial polydactyly ii. Club foot iii. Overfolded toes iv. 2, 3 syndactyly f. Craniosynostosis Renal abnormalities (37%) a. Calculi b. Single kidney c. Small kidneys d. Echogenic kidney e. Horseshoe kidney f. Bladder wall thickening g. Multicystic dysplastic kidney h. Duplicated collecting system i. Renal tubular acidosis Neuromuscular development a. Developmental delays b. Hypotonia c. Feeding disorders CNS manifestations a. Mental retardation b. Seizures (with or without hypocalcemia) c. Asymmetric crying facies d. Ataxia e. Cerebellar hypoplasia f. Enlarged Sylvian fissures g. Pituitary abnormalities h. Polymicrogyria i. Mega cisterna magna j. Neural tube defects Behavior phenotype a. Attention deficit/hyperactivity disorder b. Autism spectrum disorder c. Nonverbal learning disability d. Language deficits e. Social-emotional concern f. Schizophrenia Adult phenotype a. Lower rates of congenital heart defects b. Higher rates of palate anomalies, learning disabilities/mental retardation, and psychiatric disorders
DIAGNOSTIC INVESTIGATIONS 1. Cytogenetic studies a. High resolution chromosome analysis to detect del(22q11.2)
2. 3. 4.
5. 6.
7. 8.
b. Fluorescence in situ hybridization (FISH) for the chromosome region 22q11 to detect submicroscopic deletion Molecular analysis: polymerase chain reaction (PCR)based assays for detection of deletions of 22q11.2 Echocardiography for cardiovascular anomalies Chest X-ray a. Presence of a heart defect b. Absence of thymus shadow Renal ultrasound examination at irregular intervals for the development of renal stones MRI of the brain: detects high prevalence of brain abnormalities that are most likely neurodevelopmental and may partially explain the high prevalence of learning disability and psychiatric disorder a. Cerebellar atrophy b. Agenesis of the corpus callosum c. White matter hyperintensities d. Cavum septum pellucidum e. Cerebral atrophy f. Widespread differences in white matter bilaterally g. Regional specific differences in grey matter in the left cerebellum, insula, and frontal and right temporal lobes Blood calcium levels Immunological studies a. Impaired formation of thymic tissue b. Decreased production of T cells c. Secondary T-cell functional defects, humoral deficits, or both
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Low recurrence risk, provided parents are phenotypically normal and neither one is a carrier of del(22q11.2) ii. High recurrence risk in case of a parent with germline mosaicism for a microdeletion syndrome b. Patient’s offspring: 50% affected 2. Prenatal diagnosis a. Indications for prenatal testing for the 22q11.2 deletion i. A previous child with a 22q11.2 deletion or DiGeorge/velocardiofacial syndrome ii. An affected parent with a 22q11.2 deletion iii. In utero detection of a fetus with a conotruncal cardiac defect b. Prenatal ultrasonography and fetal echocardiography for a fetus at risk for the 22q11.2 deletion i. Conotruncal cardiac defect with associated anomalies ii. Conotruncal cardiac defect without associated anomalies iii. Aplasia or hypoplasia of the fetal thymus in the presence of conotruncal cardiac anomalies: very specific for deletion 22q11.2 iv. Cardiac lesions with the deletion a) Interrupted aortic arch (50-80%) b) Truncus arteriosus (35%)
DEL(22Q11.2) SYNDROMES
c) Tetralogy of Fallot (15%) d) Rare in double outlet right ventricle and transposition of the great vessels v. Sensitivity of different sonographic features allowing discrimination of a subgroup likely to be associated with microdeletion 22q11.2 a) Nuchal translucency (12%) b) Polyhydramnios (20%) c) IUGR (8%) d) Extra-cardiac anomalies (36%) c. Prenatal diagnosis of 21q11.2 deletion by amniocentesis or CVS i. Fluorescence in situ hybridization (FISH) analysis with probes from the DiGeorge chromosomal region (DGCR) ii. Preimplantation genetic diagnosis by FISH reported in an at-risk mother with a 22q11.2 deletion iii. Occasional detection of an unbalanced translocation or an interstitial deletion of 22q11.2 by cytogenetic analysis iv. Molecular genetic analysis a) Demonstrate failure to inherit a parental allele or hemizygosity in the deleted region b) Restriction fragment length polymorphism (RFLP) analysis and quantitative hybridization c) PCR assays using short tandem repeat polymorphisms (STRs) within the DGCR v. Limitations of prenatal testing for the 22q11.2 deletion a) DGS/VCFS, a heterogeneous disorder in which 10–15% of patients do not have the deletion. Therefore, FISH analysis is of limited value in couples who have had a previously affected child without a deletion b) Atypical deletions of 22q11.2, unbalanced chromosomal translocations, deletions involving other chromosomes have not been detected by FISH using commercially available probes c) Consider other causes of congenital heart defects such as aneuploidy, single gene defects, maternal diseases such as diabetes, and exposure to teratogens d) Inability to predict accurately the phenotype prenatally 3. Management a. Medical care i. Manage the feeding problems a) Modification of spoon placement when eating b) Treat gastroesophageal reflux with acid blockade, prokinetic agents, postural therapy, and medication to treat gastrointestinal dysmotility and to facilitate bowel evacuation ii. Hypocalcemia a) Asymptomatic hypocalcemia: treat with oral calcium supplements b) Severe symptomatic hypocalcemia: treat with prompt administration of parenteral calcium
285
c) Goal of treatment: maintain calcium in the low-normal range (8–9 mg/dL) to minimize hypercalcinuria iii. Thyroid hormone for hypothyroidism iv. Growth hormone therapy in growth hormone deficient children with a 22q11.2: associated with sustained improvements in height and growth velocity v. Early intervention programs including speech therapy for developmental delay vi. Management of psychiatric disorder b. Surgical care i. Congenital heart diseases a) Palliative operation b) Corrective operation ii. Velopharyngeal dysfunction a) Pharyngoplasty b) Plastic surgery of cleft lip/palate iii. Surgery a) Gastrointestinal anomalies b) Renal anomalies c) Musculoskeletal anomalies
REFERENCES Akiba T, Odake A, Shirahata E, et al.: Three patients with different phenotypes in a family with chromosome 22q11.2 deletions. Pediatr Int 42:183–185, 2000. Amati F, Conti E, Novelli A, et al.: Atypical deletions suggest five 22q11.2 critical regions related to the DiGeorge/velo-cardio-facial syndrome. Eur J Hum Genet 7:903–909, 1999. Ardinger R, Ardinger H: Velocardiofacial syndrome. Emedicine, 2001. http://www.emedicine.com Boudjemline Y, Fermont L, Le Bidois J, et al.: Can we predict 22q11 status of fetuses with Tetralogy of Fallot? Prenat Diagn 22:231–234, 2002. Burn J: Closing time for CATCH22. J Med Genet 36:737–738, 1999. Burn J, Takao A, Wilson D, et al.: Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11. J Med Genet 30:822–824, 1993. Carlson C, Sirotkin H, Pandita R, et al.: Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. Am J Hum Genet 61:620–629, 1997. Chaoui R, Korner H, Bommer C, et al.: Fetal thymus and the 22q11.2 deletion. Prenat Diagn 22:839–840, 2002. Cohen E, Chow EWC, Weksberg R, et al.: Phenotype of adults with the 22q11 deletion syndrome: a review. Am J Med Genet 86:359–365, 1999. Cuneo BF: 22q11.2 deletion syndrome: DiGeorge, velocardiofacial, and conotruncal anomaly face syndrome. Curr Opin Pediatr 13:465–472, 2001. De Decker HP, Lawrenson JB: The 22q11.2 deletion: from diversity to a single gene theory. Genet Med 3:2–5, 2001. De la Chapelle A, Herva R, Koivisto M, et al.: A deletion in chromosome 22 can cause DiGeorge syndrome. Hum Genet 57:253–256, 1981. Di Rocco M, Buocompagni A, Picco P, et al.: Spectrum of clinical features associated with interstitial chromosome 22q11 deletion. J Med Genet 35:346, 1998. Driscoll DA: Genetic basis of DiGeorge and velocardiofacial syndromes. Curr Opin Pediatr 6:702–706, 1994. Driscoll DA: Prenatal diagnosis of the 22q11.2 deletion syndrome. Genet Med 3:14–18, 2001. Driscoll DA, Spinner NB, Budarf ML, et al.: Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genet 44:261–268, 1992. Emanuel BS, McDonald-McGinn D, Saitta SC, et al.: The 22q11.2 deletion syndrome. Adv Pediatr 48:39–73, 2001. Giannotti A, Digilio MC, Marino B, et al.: Cayler cardiofacial syndrome and del22q11: part of the CATCH 22 phenotype. Am J Med Genet 53:303–304, 1994. Goldberg R, Motzkin B, Marion R, et al.: Velo-cardio-facial syndrome: A review of 120 patients. Am J Med Genet 45:313–319, 1993.
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Goldmuntz E, Driscoll D, Budarf ML, et al.: DiGeorge syndrome with isolated aortic coarctation and isolated ventricular septal defect in three sibs with a 22q11 deletion of maternal origin. J Med Genet 30:807–812, 1993. Goodship J, Cross I, LiLing J, et al.: A population study of chromosome 22q11 deletions in infancy. Arch Dis Child 79:348–351, 1998. Hall JG: CATCH 22. J Med Genet 30:801–802, 1993. Iwarsson E, Ahrlund-Richter KL, Inzunza J, et al.: Preimplantation genetic diagnosis f DiGeorge syndrome. Mol Hum Reprod 4:871–875, 1998. Johnson MC, Strauss AW, Dowton SB, et al.: Deletion within chromosome 22 is common in patients with absent pulmonary valve syndrome. Am J Cardiol 76:66–69, 1995. Kornfeld SJ, Zeffren B, Christodoulou CS, et al.: DiGeorge anomaly: A comparative study of the clinical and immunologic characteristics of patients positive and negative by fluorescence in situ hybridization. J Allergy Clin Imm 105:983–987, 2000. Machlitt A, Tennstedt C, Korner H, et al.: Prenatal diagnosis of 22q11.2 microdeletion in an early second trimester fetus with conotruncal anomaly presenting with increased nuchal translucency and bilateral echogenic foci. Ultrasound Obstet Gynecol 19:510–513, 2002. Marino B, Digilio MC, Toscano A, et al.: Anatomic patterns of conotruncal defects associated with deletion 22q11. Genet Med 3:45–48, 2001. Matsuoka R, Kimura M, Scambler PJ, et al.: Molecular and clinical study of 183 patients with conotruncal anomaly face syndrome. Hum Genet103: 70–80, 1998. McDermid HE, Morrow BE: Genomic disorders on 22q11. Am J Hum Genet 70:1077–1088, 2002. McDonald-McGinn DM, Driscoll DA, Bason L, et al.: Autosomal dominant Opitz GBBB syndrome due to a 22q11.2 deletion. Am J Med Genet 59:103–113, 1995. McDonald-McGinn DM, Kirschner R, Goldmuntz E, et al.: The Philadelphia story: the 22q11.2 deletion: report on 250 patients. Genet Couns 10:11–24, 1999. McDonald-McGinn DM, Tonnesen MK, Laufer-Cahana A, et al.: Phenotype of the 22q11.2 deletion in individuals identified through an affected relative: cast a wide FISHing net! Genet Med 3:23–29, 2001. McDonald-McGinn DM, Emanuel BS, Zackai EH: 22q11.2 deletion syndrome. Gene Reviews, 2003. http://www.genetests.org
Momma K, Kondo C, Matsuoka R, et al.: Cardiac anomalies associated with a chromosome 22q11 deletion in patients with conotruncal anomaly face syndrome. Am J Cardiol 78:591–594, 1996. Motzkin B, Marion R, Goldberg R, et al.: Variable phenotypes in velocardiofacial syndrome with chromosomal deletion. J Pediatr 123:406– 410, 1993. Ryan AK, Goodship JA, Wilson DI, et al.: Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet 34:798–804, 1997. Shprintzen RJ: Velocardiofacial syndrome. Otolarngol Clin N Amer 33:1217–1240, 2000. Smith CA, Driscoll DA, Emanuel BS, et al.: Increased prevalence of immunoglobulin A deficiency in patients with the chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin Diagn Lab Immunol 5:415–417, 1998. Sullivan KE, Jawad AF, Randall P, et al.: Lack of correlation between impaired T cell production, immunodeficiency, and other phenotypic features in chromosome 22q11.2 deletion syndromes. Clin Immunol Immunopathol 86:141–146, 1998. Thomas JA, Graham JM, Jr.: Chromosomes 22q11 deletion syndrome: an update and review for the primary pediatrician. Clin Pediatr (Phila) 36:253–266, 1997. Van Amelsvoort T, Daly E, Robertson D, et al.: Structural brain abnormalities associated with deletion at chromosome 22q11. Brit J Psychiatry 178:412–419, 2001. Weinzimer SA: Endocrine aspects of the22q11.2 deletion syndrome. Genet Med 3:19–22, 2001. Wilson DI, Cross IE, Goodship JA, et al.: DiGeorge syndrome with isolated aortic coarctation and isolated ventricular septal defect in three sibs with a 22q11 deletion of maternal origin. Br Heart J 66:308–312, 1991. Wilson DI, Goodship JA, Burn J, et al.: Deletions within chromosome 22q11 in familial congenital heart disease. Lancet 340:573–575, 1992. Woodin M, Wang PP, Aleman D, et al.: Neuropsychological profile of children and adolescents with the 22q11.2 microdeletion. Genet Med 3:34–39, 2001.22, 2001. Yamagishi H: The 22q11.2 deletion syndrome. Keio J Med 51:77–88, 2002.
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Fig. 1. An infant (A) with DiGeorge syndrome. The deletion of 22q11.2 was shown by partial karyotype with ideogram (B) and FISH with DiGeorge cosmid probe (C). The FISH in D is a control.
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Fig. 4. A 16-year-old boy with tetralogy of Fallot, inguinal hernia, developmental delay, bilateral conductive hearing loss (late onset at 15 years of age), and del(22q11.2) shown in the next figure.
Fig. 2. A newborn infant with conotruncal anomaly facies syndrome. The radiograph shows a conotruncal heart anomaly and absent thymus.
Fig. 5. FISH of the patient in the Fig. 4. showing two green signals (a probe for 22q13 ARSA) and only one red signal (a probe for 22q11.2; TUPLE1) demonstrating del(22q11.2).
Fig. 3. A 4-year-6-month old girl with tetralogy of Fallot, growth retardation, developmental delay, and del(22q11.2).
Fig. 6. A mother and daughter both have deletion 22q11.2.
Diabetic Embryopathy Maternal diabetes adversely affects the fetus during pregnancy. The risk of developing congenital malformations has been well documented. The frequency of congenital anomalies among insulin-dependent diabetic offspring is estimated at 3–6% of all infants at birth, representing a two- to three-fold increase, when compared with nondiabetics.
GENETICS/BASIC DEFECTS 1. Teratogenicity of maternal diabetes mellitus in human a. Occurring during embryogenesis at the end of blastogenesis and organogenesis between 3rd and 7th weeks of gestation b. Leading to a spectrum of malformations known as diabetic embryopathy 2. Diabetic fetopathy a. Occur during fetal development (after the 10th week of gestation) b. Not associated with malformations c. Fetal hyperinsulinism: the cause of macrosomia and numerous other postnatal complications 3. Potential pathogenetic mechanisms of diabetic embryopathy: most likely multifactorial a. Oxidant stress b. Perturbed biosynthesis of prostaglandins and DNA c. Altered expression of some of the morphogenetic regulatory molecules i. Extracellular matrix (ECM) proteins ii. Transcription factors iii. Proto-oncogen
CLINICAL FEATURES 1. General features of infants of diabetic mothers a. Higher rate of congenital malformations b. Signs of diabetic fetopathy i. Macrosomia (increase in adipose tissue and organomegaly) a) Classic appearance: a large, ruddy, puffy, fat, and often limp infant, with legs held in a flexed and abducted position b) Presence of prominent fat pads over the upper back and around the lower jaw to produce the image of a round cherubic face c) A predisposing factor for the occurrence of a variety of birth trauma-related injuries ii. Birth trauma-related injuries due to difficult vaginal delivery secondary to shoulder dystocia a) Cephalohematoma b) Subdural hemorrhage c) Clavicular fracture d) Cranial nerve palsies e) Brachial plexopathy (palsy) 289
iii. iv. v. vi. vii. viii.
Hypoglycemia (hyperinsulinemia) Polycythemia Hypomagnesemia Hyperbilirubinemias (jaundice) Hypocalcemia Cardiomyopathy (thickened interventricular septum) ix. Renal vein thrombosis c. Other features i. Large for gestational age ii. Higher fetal death rate iii. Fetal growth retardation in diabetic women with vasculopathy iv. Higher risk of respiratory distress (hyaline membrane disease) v. Asphyxia vi. Acidosis vii. Apneic spells viii. Sepsis ix. Intracranial bleeding x. Neuromuscular excitability xi. Single umbilical artery xii. Small left colon syndrome xiii. Transient hematuria xiv. Abnormal vernix caseosa xv. Hirsutism 2. Spectrum of diabetic embryopathy: malformations vary in extent and severity a. CNS abnormalities i. Neural tube defects: a higher incidence of 19.5 per 1000 in the diabetic gestation, compared with 1–2 per 1000 in the general population ii. Anencephaly a) The most common anomaly affecting the CNS b) An incidence of 0.57% in the diabetic pregnancy, representing a 3-fold increase over the general population iii. Holoprosencephaly iv. Hydrocephalus v. Absent corpus callosum vi. Arnold-Chiari anomaly vii. Schizencephaly viii. Microcephaly ix. Macrocephaly x. Agenesis of olfactory tracts xi. Intracranial lipoma xii. Facial nerve palsy xiii. Calcified falx cerebi xiv. Bizarre undergrowth or overgrowth of the brain xv. Postnatal developmental delay
290
DIABETIC EMBRYOPATHY
b. Facial features (85%) i. Hemifacial microsomia (oculoauriculovertebral anomalies) ii. Macrostomia/lateral facial cleft iii. Cleft lip/palate iv. Micrognathia v. Branchial cleft cyst vi. Frontonasal dysplasia vii. Choanal atresia viii. Short nose ix. Nasal milia x. Fat pad across nose xi. Facial skin tags c. Eye anomalies (48%) i. Lens opacity ii. Cataracts iii. Microophthalmia/optic nerve hypoplasia iv. Colobomas of iris or chorioretina v. Anterior chamber dysgenesis vi. Epibulbar dermoid/oculolipoma vii. Laterally displaced inner canthi viii. Tear duct obstruction d. Ear anomalies (95%) i. Microtia ii. Sensorineural/conductive hearing loss iii. Preauricular tags iv. Anotia v. Atretic ear canal vi. Additional ear malformations e. Cardiovascular anomalies i. Complex transposition of the great vessels ii. Single ventricle iii. Hypoplastic left heart iv. Tricuspid atresia v. Tetralogy of Fallot vi. Ventricular septal defect vii. Atrial septal defect viii. Double outflow right ventricle ix. Pulmonary atresia x. Coarctation of the aorta xi. Subaortic stenosis xii. Right aortic arch xiii. Tricuspid regurgitation xiv. Cleft mitral valve xv. Symmetric hypertrophy of interventricular septum xvi. Hypertrophic cardiomyopathy f. Gastointestinal anomalies i. Situs inversus ii. Pyloric stenosis iii. Duodenal atresia iv. Small bowel atresias v. Small left colon (microcolon) syndrome vi. Rectal atresia vii. Anal atresia (imperforate anus) viii. Meckel diverticulum ix. Diaphragmatic hernia x. Omphalo-enteric cyst/fistula g. Genitourinary anomalies (19%) i. Renal agenesis ii. Cystic kidneys
iii. Ectopic kidney iv. Hydronephrosis v. Ureteral duplication vi. Ureterocele vii. Ambiguous genitalia viii. Hypospadias ix. Micropenis x. Cryptorchidism xi. Uterine agenesis xii. Hypoplastic vagina h. Skeletal anomalies (52%) i. Hand anomalies (limb reduction defects) a) Radial clubbing b) Bifid thumbs c) Hypoplastic/absent thumb d) Radial hypoplasia ii. Polysyndactyly iii. Contractures iv. Costovertebral anomalies a) Fused cervical vertebrae b) Hemivertebrae c) Torticolis d) Bifid/fused ribs v. Hip dislocation vi. Femoral hypoplasia vii. Caudal regression (sirenomelia): very rare but it is one of the most unique and commonly associated lesion with maternal diabetes (occurring in 0.2–0.5% of infants of diabetic pregnancies, a 200-fold increase over the general population) a) Agenesis of sacrum and lumbar spine b) Hypoplasia of the lower extremities c) Phocomelia viii. Craniosynostosis i. Skin anomalies i. Aplasia cutis ii. Cutaneous vascular dysplasia
DIAGNOSTIC INVESTIGATIONS 1. Diagnostic investigations of the infants of diabetic mothers a. Complete blood cell count to detect polycythemia b. Serum or whole blood glucose concentration to detect neonatal hypoglycemia c. Serum magnesium concentration (ionized or total levels) to detect hypomagnesemia d. Serum calcium concentration to detect hypocalcemia e. Serum bilirubin level (total and unconjugated) to detect hyperbilirubinemia f. Arterial blood gas to assess oxygenation and ventilation with evidence of respiratory distress g. Radiography for cardiopulmonary distress and skeletal and vertebral anomalies h. Echocardiography for detecting cardiomyopathy and congenital heart defects i. Renal ultrasonography for renal anomalies
GENETIC COUNSELING 1. Risk of congenital malformation in infants of mothers with insulin-dependent diabetes
DIABETIC EMBRYOPATHY
a. Relative risk (per 100 live births) i. Major malformations: 7.9 ii. Major CNS malformations: 15.5 iii. Cardiovascular malformations: 18.0 b. Absolute risks (per 100 live births) i. Major malformations: 18.4 ii. Major CNS malformations: 5.3 iii. Major cardiovascular malformations: 8.5 2. Risk of congenital malformation in infants of mothers with gestational diabetes mellitus who required insulin during the third trimester of pregnancy a. Relative risk: 20.6 times more likely to have major cardiovascular system defects than infants of nondiabetic mothers b. Absolute risk: 9.7% 3. Prenatal diagnosis a. Determination of glycosylated hemoglobin (HbA1c) of the diabetic mother during the first trimester. There is a significantly higher incidence of major congenital anomalies in the offspring of diabetic women with elevated first trimester HbA1c values (>8%) b. Maternal serum α-fetoprotein determination for the presence of associated neural tube defect c. Prenatal ultrasonography i. Estimation of gestational age ii. Evaluation of congenital malformations a) Cardiac anomalies b) Skeletal anomalies c) CNS anomalies d) Renal anomalies e) Other anomalies iii. Evaluation of fetal growth a) Macrosomia b) Intrauterine growth retardation iv. Assessment of fetal status v. Maternal hydramnios d. Fetal echocardiography for congenital heart defects 4. Management a. To reduce the rate of congenital malformations in offspring of mothers with diabetes mellitus i. Preconceptional care and counseling ii. Prepregnant glycemic control to provide endocrine milieu necessary for normal embryogenesis b. Plan of delivery i. Deliver newborn infant of the diabetic mother between 35th to 37th week of gestation ii. Anticipate Cesarean section with identification of the macrosomic fetus c. Management of respiratory distress d. Management of hypoglycemia, hypocalcemia, and hypomagnesemia e. Management of cardiomyopathy and heart failure f. Management of congenital anomalies
REFERENCES Agrawal RK, Lui K, Gupta JM: Neonatal hypoglycaemia in infants of diabetic mothers. J Paediatr Child Health 36:354–356, 2000. Assemany SR, Muzzo S, Gardner LI: Syndrome of phocomelic diabetic embryopathy (caudal dysplasia). Am J Dis Child 123:489–491, 1972.
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Becerra JE, Khoury MJ, Cordero JF, et al.: Diabetes mellitus during pregnancy and the risks for specific birth defects: a population-based case-control study. Pediatrics 85:1, 1990. Chang TI, Loeken MR: Genotoxicity and diabetic embryopathy: impaired expression of developmental control genes as a cause of defective morphogenesis. Semin Reprod Endocrinol 17:153–165, 1999. Chugh SS, Wallner EI, Kanwar YS: Renal development in high-glucose ambience and diabetic embryopathy. Semin Nephrol 23:583–592, 2003. Cowett RM, Schwartz R: The infant of the diabetic mother. Pediatr Clin N Amer 29:1213–1231, 1982. Dhanasekaran N, Wu YK, Reece EA: Signaling pathways and diabetic embryopathy. Semin Reprod Endocrinol 17:167–174, 1999. Eriksson UJ, Simán CM, Gittenberger-De Groot A, et al.: More on the diabetic embryopathy. Teratology 63:114–115, 2001. Ewart-Toland A, Yankowitz J, Winder A, et al.: oculoauriculovertebral abnormalities in children of diabetic mothers. Am J Med Genet 90:303–309, 2000. Farrell T, Neale L, Cundy T: Congenital anomalies in the offspring of women with type 1, type 2 and gestational diabetes. Diabetic Med 19:322–326, 2002. Feigenbaum A, Chitayat D, Robinson B, et al.: The expanding clinical phenotype of the tRNA Leu(UUR) A→G mutation at np 3243 of mitochondrial DNA: Diabetic embryopathy associated with mitochondrial cytopathy. Am J Med Genet 62:404–409, 1996. Fischer AE: Management of the newborn infant of the diabetic mother. N Y State J Med 61:292–296, 1961. Graber AL, Christman BG, Alogan MT, et al.: Evaluation of diabetes patient education programs. Diabetes 26:61, 1977. Greene MF: Diabetic embryopathy 2001: moving beyond the “diabetic milieu”. Teratology 63:116–118, 2001. Greene MF: Association between maternal diabetes mellitus and major malformations in the offspring: a reply to Dr. Kalter. [Letter] Teratology 65:100–101, 2002. Grix A, Curry C, Hall BD: Patterns of multiple malformations in infants of diabetic mothers. Birth Defects Original Article Series 18:55–77, 1982. Grix A: Invited editorial comment: Malformations in infants of diabetic mothers. Am J Med Genet 13:131–137, 1982. Hajianpour MJ: Infants of diabetic mothers (IDM). The Genetic Letter 3(3):1, 4, 1993. Hare JW, White P: Gestational diabetes and the White classification. Diabetes Care 3:394, 1980. Hsu-Hage BH-H, Yang X: Gestational diabetes mellitus and its complications. Asia Pacific J Clin Nutr 8:82–89, 1999. Johnson JP, Carey JC, Gooch WM, et al.: Femoral hypoplasia-unusual facies syndrome in infants of diabetic mothers. J Pediatr 102:866–872, 1983. Johnson JP, Fineman RM: Branchial arch malformations in infants of diabetic mother: two case reports and a review. Am J Med Genet 13:125–130, 1982. Kalter H: Hyperglycemia and congenital malformations in insulin-dependent diabetes mellitus: a brief summary and evaluation. Teratology 65:97–99, 2002. Khoury MJ, Becerra JE, Cordero JF, et al.: Clinical-epidemiologic assessment of patterns of birth defects associated with human teratogens: application to diabetic embryopathy. Pediatrics 84:658–665, 1989. Kicklighter SD: Infant of diabetic mother. Emedicine, 2001. http://www. emedicine.com Kucˆera J: Rate and type of congenital anomalies among offspring of diabetic women. J Reprod Med 7:61–70, 1971. Kousseff BG: Gestational diabetes mellitus (Class A): a human teratogen? Am J Med Genet 83:402–408, 1999. Kousseff BG: Diabetic embryopathy. Curr Opin Pediatr 11:348–352, 1999. Loffredo CA, Wilson PD, Ferencz C: Maternal diabetes: an independent risk factor for major cardiovascular malformations with increased mortality of affected infants. Teratology 64:98–106, 2001. Miller E, hare JW, Cloherty JP, et al.: Elevated maternal HbA1c in early pregnancy and major congenital anomalies in infants of diabetic mothers. N Engl J Med 304:1331, 1981. Mills JL: Malformations in infants of diabetic mothers. Teratology 25:385, 1982. Mills JL, Baker L, Goldman AS: Malformations in infants of diabetic mothers occur before the seventh gestation week. Diabetes 28:292, 1979. Mølsted-Pedersen L, Tygstrup I, Pedersen J: Congenital malformations in newborn infants of diabetic women. Lancet 1:1124, 1964. More TR, Zurawin RK: Diabetes mellitus and pregnancy. Emedicine, 2002. http://www.emedicine.com
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Reece EA, Hobbins JC: Diabetic embryopathy: pathogenesis, prenatal diagnosis and prevention. Obstet Gynecol Surv 41:325–335, 1986. Reece EA, Homko CJ, Hagay Z: Prenatal diagnosis and prevention of diabetic embryopathy. Obstet Gynecol Clin North Am 23:11–28, 1996. Reece EA, Homko CJ, Wu Y-K: Multifactorial basis of the syndrome of diabetic embryopathy. Teratology 54:171–182, 1996.
Ter Braak EWMT, Evers IM, Erkelens DW, et al.: Maternal hypoglycemia during pregnancy in type I diabetes: maternal and fetal consequences. Diabetes/Metabol Res Rev 18:96–105, 2002. Tyrala EE: The infant of the diabetic mother. Diabetes Preg 23:220–241, 1996. Wong SF, Chan FY, Cincotta RB, et al.: Routine ultrasound screening in diabetic pregnancies. Ultrasound Obstet Gynecol 19:171–176, 2002.
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Fig. 1. A 2-year-9-month old girl with diabetic embryopathy showing left club hand with hypoplastic thumb and sacral agenesis with contractures of knees illustrated by radiographs.
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Fig. 3. A newborn with diabetic embryopathy showing cleft lip/palate, caudal regression, femoral hypoplasia, and polydactyly.
Fig. 2. A newborn with diabetic embryopathy showing a large head due to hydrocephalus, depressed nasal bridge, short nose, micrognathia, microtia, right club hand, hemivertebrae, and caudal dysgenesis.
Fig. 4. An infant born to the diabetic mother showing cystic hygroma with multiple contractures and multiple pterygia.
Down Syndrome In 1866, Down described clinical characteristics of the syndrome that now bears his name. In 1959, Lejeune and Jacobs et al. independently determined that Down syndrome is caused by trisomy 21. Down syndrome is by far the most common and best-known chromosome disorder in humans. Mental retardation, dysmorphic facial features and other distinctive phenotypic traits characterize the syndrome. Frequency is estimated to be 1 in 800 live births. Approximately 6000 children are born with Down syndrome annually in the US.
GENETICS/BASIC DEFECTS 1. Caused by an extra chromosome 21 a. Affect almost every organ system b. Result in a wide spectrum of phenotypic consequences i. Life-threatening complications ii. Significant alteration of life course (e.g., mental retardation) iii. Dysmorphic physical features iv. Decreased prenatal viability v. Increased prenatal and postnatal morbidity 2. Typical physical phenotype due to an extra copy of the proximal part of 21q22.3 a. Mental retardation b. Characteristic facial features c. Hand anomalies d. Congenital heart defects 3. 21q22.1-q22.3 region containing the gene(s) responsible for the congenital heart disease observed in Down syndrome 4. The new gene (DSCR1), identified from region 21q22.1q22.2 is highly expressed in the brain and the heart and is a candidate for involvement in the pathogenesis 5. Types of trisomy 21 a. Full trisomy 21 (94%) b. Mosaicism (2.4%) c. Translocations (3.3%) i. De novo (75%) ii. Familial translocation (25%) d. Isochromosome 21 6. Origin of nondisjunction: maternal nondisjunction in the first meiotic division (75%, most common) 7. Well-documented risk factor for maternal meiotic nondisjunction: advanced maternal age 8. Majority of mosaic cases result from a trisomic zygote with mitotic loss of one chromosome 21
CLINICAL FEATURES 1. Growth and development a. Short stature b. Hypotonia which improves with age 295
c. Moderate-to-severe mental retardation with IQ range of 20–85 (mean IQ is approximately 50) d. Articulatory problems e. Sleep apnea occurring when inspiratory airflow from the upper airway to the lungs is impeded for 10 seconds or more, often resulting in hypoxemia or hypercarbia f. Seizure disorder (5–10%) i. Infantile spasms (most common type of seizures seen in infancy) ii. Tonic–clonic seizures (most commonly seen in older patients) g. Visual and hearing impairments in addition to the presence of mental retardation further limiting the child’s overall function and may prevent the child from participating in significant learning processes and obtaining appropriate language development and interpersonal skills h. Obesity during adolescence i. Premature aging i. Decrease in skin tone ii. Early graying or loss of hair iii. Hypogonadism iv. Cataracts v. Hearing loss vi. Age-related increase in hypothyroidism vii. Seizures viii. Neoplasms ix. Degenerative vascular disease x. Loss of adaptive abilities xi. Increased risk of senile dementia of Alzheimer type 2. Behavior a. Natural spontaneity b. Genuine warmth c. Cheerful d. Gentleness e. Patience f. Tolerance g. Anxiety h. Stubbornness 3. Psychiatric disorders a. Prevalence among children (17.6%) b. Prevalence among adults (27.1%) c. Children and adolescents at a higher risk for i. Autism ii. Attention deficit hyperactivity disorder iii. Conduct disorder iv. Obsessive-compulsive disorder v. Tourette syndrome vi. Depressive disorder during the transition from adolescence to adulthood 4. Skull a. Brachycephaly b. Microcephaly
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c. Sloping forehead d. Vertical creases on the forehead when crying (“Woolley” sign, named after the late mentor, Dr. Woolley) e. Flat occiput f. Large fontanels with late closure g. Patent metopic suture h. Absence of frontal and sphenoid sinuses i. Hypoplasia of the maxillary sinuses Eyes a. Up-slanting palpebral fissures b. Bilateral epicanthal folds c. Brushfield spots (speckled iris) d. Refractive errors (50%) e. Strabismus (44%) f. Nystagmus (20%) g. Blepharitis (33%) h. Conjunctivitis i. Tearing from stenotic nasolacrimal ducts j. Congenital cataracts (3%) k. Pseudopapilledema l. Spasm nutans m. Acquired lens opacity (30–60%) n. Keratoconus Nose a. Hypoplastic nasal bone b. Flat nasal bridge Mouth a. Open mouth b. Tendency of tongue protrusion c. Fissured and furrowed tongue d. Mouth breathing e. Drooling f. Chapped lower lip g. Angular cheilitis Teeth a. Partial anodontia (50%) b. Tooth agenesis c. Malformed teeth d. Delayed eruption e. Microdontia (35–50%) in both the primary and secondary dentition f. Hypoplastic and hypocalcified teeth g. Malocclusion h. Taurodontism (0.54–5.6%) i. Increased periodontal destruction Ears a. Small b. Over-folded helix c. Chronic otitis media d. Hearing loss common. Between 66–89% of children have hearing loss of greater than 15–20 dB in at least one ear by auditory brainstem response Neck a. Atlantoaxial instability (14%) resulting from laxity of transverse ligaments that ordinarily hold the odontoid process close to the anterior arch of the atlas b. Laxity causing backward displacement of the odontoid process, leading to spinal cord compression
11. Chest a. Narrow chest b. Decreased internipple distance 12. Congenital heart defects a. Common (40–50%) b. Frequently seen in hospitalized Down syndrome patients (62%) c. Common cause of death in the first two years of life d. Endocardial cushion defect/atrioventricular canal (43%, most common type): About 70% of all endocardial cushion defects are associated with Down syndrome e. Ventricular septal defect (32%) f. Secundum atrial septal defect (10%) g. Tetralogy of Fallot (6%) h. Isolated patent ductus arteriosus (4%) i. Multiple cardiac defects (30%) The most common associated lesions are patent ductus arteriosus (16%) and pulmonic stenosis (9%) 13. Abdomen a. Diastasis recti b. Umbilical hernia 14. Gastrointestinal (12%) a. Duodenal atresia or stenosis b. Hirschsprung disease (less than 1%) c. TE fistula d. Meckel diverticulum e. Imperforate anus f. Omphalocele 15. Genitourinary a. Renal malformations b. Hypospadias c. Micropenis d. Cryptorchidism 16. Skeletal a. Atlantoaxial (and atlantooccipital) instability i. Occurring in approximately 15% of individuals (<21 year old) ii. Mildest asymptomatic form iii. Severe symptomatic subluxation or dislocation at the atlantoaxial joint may injure the spinal cord. Neurologic manifestations include: a) Easy fatigability b) Difficulties in walking c) Abnormal gait d) Neck pain e) Limited neck mobility f) Torticollis (head tilt) g) Incoordination and clumsiness h) Sensory deficits i) Spasticity j) Hyperreflexia k) Clonus l) Extensor-plantar reflex m) Other upper motor neuron and posterior column signs and symptoms n) Rarely progressing to paraplegia, hemiplegia, quadriplegia, or death b. Short and broad hands c. Clinodactyly of the fifth fingers with a single flexion crease (20%)
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d. Hyperextensible finger joints e. Increased space between the great toe and the second toe f. Acquired hip dislocation (6%) Endocrine a. Thyroid disease i. Primarily autoimmune disorder with a lifetime prevalence of 13–63% ii. Congenital hypothyroidism: about 28 times more common among infants with Down syndrome than in the general population with an incidence of 1% detected by newborn screening a) 0.7% permanent congenital hypothyroidism b) 0.3% transient congenital hypothyroidism iii. Hypothyroidism in 16–20% of young patients b. Diabetes c. Decreased fertility i. Almost invariably infertile in males ii. Decreased fertility in females Hematologic a. Neonatal leukemoid reactions (i.e., pseudoleukemia) common and distinguishing this from true leukemia is frequently a diagnostic challenge b. 10- to 15-fold increased risk of developing leukemia in children with Down syndrome. Approximately 1 in 150 patients develops leukemia c. Uniquely predisposed to clonal disorders affecting the megakaryocyte lineage in children with Down syndrome i. Transient myeloproliferative disorder (also known as transient leukemia) c) Resolves spontaneously in most cases d) Develops acute megakaryoblastic leukemia in up to 30% of cases ii. Acute megakaryoblastic leukemia d. An increased risk of hepatitis B carrier status if previously institutionalized Immunodeficiency: patients have about 12-fold increased risk of developing infectious diseases, especially pneumonia, secondary to impaired cellular immunity Upper airway obstruction a. Causes i. Large tonsils and adenoids ii. Lingual tonsils iii. Choanal stenosis iv. Glossoptosis b. Consequences i. Serous otitis media ii. Alveolar hypoventilation iii. Arterial hypoxemia iv. Cerebral hypoxia v. Pulmonary artery hypertension vi. Cor pulmonale vii. Heart failure Skin a. Xerosis b. Localized hyperkeratotic lesions c. Elastosis serpiginosa d. Alopecia areata (up to 10%) e. Vitiligo
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f. Folliculitis g. Abscess formation h. Recurrent skin infections 7. Dermatoglyphics a. Distal axial triradius in the palms b. Transverse palmar creases c. A single flexion crease in the fifth finger d. Ulnar loops (often 10) in the digital patterns e. A pattern present in hypothenar and interdigital III regions 8. Significant health problems observed in adults with Down syndrome a. Untreated congenital heart anomalies b. Acquired cardiac disease c. Pulmonary hypertension d. Recurrent respiratory infections/aspiration leading to chronic pulmonary interstitial changes e. Presenile dementia/Alzheimer-type disease f. Adult-onset epilepsy g. Osteoarthritic degeneration of the spine h. Osteoporosis with resultant fractures of the long bones or vertebral bodies i. Untreated atlantooccipital instability j. Acquired sensory deficits k. Loss of vision due to early onset of adult cataracts, recurrent keratitis or keratoconus l. Significant hearing loss m. Behavioral problems 9. Prognosis a. Life expectancy i. Approximately 75% of conceptuses die in embryonic or fetal stage ii. Approximately 85% of infants survive to 1 year iii. About 50% can be expected to live beyond the age 50 years b. Mobility and mortality i. Presence of congenital heart disease (most significant factor that determines survival) ii. Esophageal atresia with or without TE fistula, Hirschsprung disease, duodenal atresia, infection, and leukemia adding to mortality iii. Higher mortality rate later in life secondary to premature aging c. Phenotype of mosaic individuals: depends on the frequency and distribution of trisomic cells, with typical Down syndrome as the worst phenotype
DIAGNOSTIC INVESTIGATIONS 1. Serum triple screen a. α-fetoprotein b. Unconjugated estriol c. Human chorionic gonadotrophin 2. Cytogenetic studies a. Clinical diagnosis should be confirmed with cytogenetic studies b. Karyotyping is essential for determination of recurrence risk i. Free trisomy 21 (93–96%) ii. Robertsonian translocation (2–5%)
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iii. Reciprocal translocation (<1%) iv. Isochromosome (<1%) v. Mosaicism (2–4%) c. In translocation or isochromosome Down syndrome, karyotyping of the parents and other relatives is required for proper genetic counseling Interphase fluorescence in situ hybridization (FISH) a. Used for rapid diagnosis b. Successfully applied to both prenatal diagnosis and diagnosis in the newborn period Extraction of fetal cells from maternal circulation: after fetal nucleated red blood cells have been sorted using different cell transferrin and glycophorin-A receptors on the cell surface, interphase FISH can determine chromosome constitution. Chromosome-specific probes for X, Y, 13, 18, and 21 permit diagnosis. The FISH finding should be confirmed by standard cytogenetic techniques Thyroid function tests: TSH and T4 should be obtained at birth and annually thereafter Measurement of IgG a. Used to identify deficiency of IgG subclass 2 and 4 b. A significant correlation between decreased IgG subclass 4 and bacterial infections c. Cellular immunity deficits documented in individuals with gingivitis and periodontal disease Skeletal radiography a. Craniofacial anomalies include i. Brachycephalic microcephaly ii. Hypoplastic facial bones and sinuses b. Cervical spine x-rays (lateral flexion and extension views) c. Required to measure the atlanto-dens distance for excluding atlantoaxial instability at 3 years of age d. Used prior to anesthesia if there are signs suggesting spinal cord compression e. Reduced iliac and acetabular angles in the young infant f. Short hands with shortened digits and clinodactyly due to hypoplastic middle phalanx of the fifth finger Echocardiography: this test should be performed on all infants with Down syndrome for identification of congenital heart disease, regardless of findings on physical examination Auditory brainstem response (ABR), also known as brainstem auditory evoked response (BAER), to demonstrate hearing loss. Evaluation of ABR in 47 unselected children with Down syndrome, age between 2 months and 3 1/2 years, demonstrated some degree of hearing loss in 66% of the children examined (28% unilateral, 38% bilateral) Speech evaluation Pediatric vision screening for ophthalmologic disorders Modified Denver Developmental Screening Test chart for noninstitutionalized children for assessing the developmental milestones Growth charts available for children with Down syndrome Prenatal ultrasonography a. Thickened nuchal fold (major marker) b. Cystic hygroma
c. d. e. f. g. h.
Slightly shortened femora Hyperechogenic bowel Pyelectasis Echogenic intracardiac focus Wider lateral flare of the iliac bones Other subtle sonographic signs i. Short ears ii. Hypoplasia of the middle phalanx of the 5th fingers (clinodactyly) iii. Choroid plexus cyst iv. Delayed fusion of the amnion and chorion v. Simian crease of the hand vi. Separation of the great toe (‘sandal gap foot’)
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Nondisjunction type: 1% or less ii. De novo Robertsonian translocation type: 2–3% b. Familial Robertsonian translocation type i. Theoretical recurrence risk for a Robertsonian carrier parent to have a liveborn Down syndrome offspring: 1 in 3 ii. The actual risks to future offspring depend on parental sex: a) Mother with rob(Dq;21q): 10–11% b) Father with rob(Dq;21q): 2.4% c) Mother with rob(21q;22q): 14% d) Father with rob(21q;22q): 1–2% c. A carrier parent with a 21q21q translocation or isochromosome: a 100% recurrence risk d. Gonadal mosaicism postulated for having more than one trisomic child in the family with apparently normal parents e. Patient’s offspring i. Affected individuals rarely reproduce ii. Females with trisomy 21: about 15–30% are fertile and have a 50% risk of having an affected child iii. Males with trisomy 21: no evidence of fathering a child 2. Prenatal screening a. Advanced maternal age i. The first prenatal diagnosis of Down syndrome made in 1968 ii. Gradual introduction of screening women on the basis of advanced maternal age with amniocentesis into medical practice b. Maternal serum biochemical markers i. Low maternal serum alpha-fetoprotein (MSAFP) shown to be associated with Down syndrome in 1983 ii. Later, elevated human chorionic gonadotropin (hCG) and low unconjugated estriol (uE3) found to be the additional markers for Down syndrome iii. By 1988, the three biochemical markers, together with maternal age were accepted as a method of prenatal screening for Down syndrome in the general population
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iv. Estimated detection rate when ultrasound is used to estimate gestational age: 20% when using only the MSAFP test, 59% using the double test (MSAFP and hCG), and 69% using the triple test (MSAFP, hCG, uE3). The false positive rate is 5%. Other factors for adjustment are maternal age and weight, insulin-dependent diabetes mellitus, multiple pregnancy, ethnic origin, previous Down syndrome pregnancy, and first or repeat test in a pregnancy. A positive screening test suggests only an increased risk for having a Down syndrome fetus and that definitive testing by amniocentesis with chromosome analysis is indicated c. First-trimester free beta-hCG and pregnancy-associated plasma protein A retrospective screening study achieved rates as high as those associated with MSAFP, hCG or uE3 in the second trimester. Prospective studies are needed to further assess firsttrimester screening 3. Prenatal diagnosis a. Ultrasonography i. Nuchal fold thickening identifies 75% of Down syndrome fetuses ii. Shortened humerus or femur length detect 31% of cases iii. Cystic hygroma iv. Duodenal atresia or stenosis (double-bubble sign) v. Cardiac defects a) Endocardial cushion defect with atrial and ventricular septal defects b) Abnormal mitral and tricuspid valves vi. Echogenic bowel vii. Renal pyelectasis b. Amniocentesis, CVS, or fetal blood sampling i. FISH analysis of interphase cells or metaphase spreads ii. Chromosome analysis 4. Management a. Medical care i. Early intervention programs a) Physical therapy b) Occupational therapy c) Speech therapy d) Special education programs ii. Hearing evaluation iii. Thyroid hormone for hypothyroidism iv. Medical management of congenital heart defects a) Digitalis and diuretics usually required b) Subacute bacterial endocarditis prophylaxis v. Prompt treatment of respiratory tract infections and otitis media vi. Pneumococcal and influenza vaccines for children with chronic cardiac and respiratory disease vii. Anticonvulsants for seizures viii. Provide pharmacologic agents, behavioral therapy, and psychotherapy for behavioral/psychiatric disorders ix. Treat skin disorders a) Weight reduction b) Proper hygiene
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c) Frequent baths d) Application of antibiotic ointment e) Systemic antibiotics therapy x. Prevent dental caries and periodontal disease a) Appropriate dental hygiene b) Fluoride treatments c) Good dietary habits d) Restorative care xi. Megadoses of vitamins and minerals supplemented with zinc and/or selenium: have not shown benefits in a number of well-controlled studies b. Surgical care i. Presence of Down syndrome alone does not adversely affect the outcome of surgery in the absence of pulmonary hypertension ii. Timely surgery of cardiac anomalies necessary to prevent serious complications iii. Prompt surgical repair of the following gastrointestinal anomalies: a) TE fistula b) Pyloric stenosis c) Duodenal atresia d) Annular pancreas e) Aganglionic megacolon f) Imperforate anus iv. Adenotonsillectomies may be required for obstructive sleep apnea v. Surgical intervention may be necessary to reduce the atlantoaxial subluxation and to stabilize the upper segment of the cervical spine if neurologic deficits are significant vi. Extract congenital cataracts, which occur in about 3% of children, soon after birth with subsequent correction with glasses or contact lenses to assure adequate vision vii. Anesthetic airway management a) Adequate evaluation of the airway and neurological status b) Cervical spine radiography (flexion and extension views) when any neurologic deficits suggest spinal cord compression c) Avoid hyperextension of the head during laryngoscopy and intubation d) Prescribe anticholinergics to control airway hypersecretion e) Aware of other airway complications (subglottic stenosis and obstructive apnea resulting from a relatively large tongue, enlarged adenoids, and midfacial hypoplasia)
REFERENCES Ahmed M, Sternberg A, Hall G, et al.: Natural history of GATA1 mutations in Down syndrome. Blood published online Dec 4, 2003. American Academy of Pediatrics Committee on Genetics: Health supervision for children with Down syndrome. Pediatrics 93:855–859, 1994. American Academy of Pediatrics Committee on sports Medicine and Fitness: Atlantoaxial instability in Down syndrome: subject review. Pediatrics 96:151–154, 1995. American Journal of Medical Genetics: Trisomy 21 (Down syndrome). (Suppl 7): 1–323, 1990.
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Carey JC: Health supervision and anticipatory guidance for children with genetic disorders (including specific recommendations for trisomy 21, trisomy 18, and neurofibromatosis I. Pediatr Clin North Am 39:25–53, 1992. Chen H, Woolley PV Jr: A developmental assessment chart for non-institutionalized Down syndrome children. Growth 42:157–165, 1978. Chen H, Espiritu C, Casquejo C, et al.: Inter-nipple distance in normal children from birth to 14 years, and in children with Turner’s, Noonan’s, Down’s and other aneuploides. Growth 38:421–436, 1974. Chen H, Mu X, Sonoda T, et al.: FGFR3 gene mutation (Gly380Arg) with achondroplasia and i(21q) Down syndrome: phenotype-genotype correlation. South Med J 93:622–624, 2000. Cohen WI (ed): Health care guidelines for individuals with Down syndrome. Down Syndrome Quarterly 1(2), June, 1996. Cronk C, Crocker AC, Pueschel SM: Growth charts for children with Down syndrome: 1 month to 18 years of age. Pediatrics 81:102–110, 1988. Desai SS: Down syndrome: a review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontics 84:279–285, 1997. Epstein CJ: Down syndrome (trisomy 21). In Scriver CR, Beaudet AL, Sly WS, et al. (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed., Pediatr Pathol 1223–1256, 2001. Findlay I, Toth T, Matthews P: Rapid trisomy diagnosis (21, 18, and 13) using fluorescent PCR and short tandem repeats: applications for prenatal diagnosis and preimplantation genetic diagnosis. J Assist Reprod Genet 15:266–275, 1998. Fuentes J-J, Pritchard MA, Planas AM: A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart. Hum Mol Genet 4:1935–1944, 1995. Gross SJ, Bombard AT: Screening for the aneuploid fetus. Obstet Gynecol Clin 25:573–595, 1998. Halliday JL, Watson LF, Lumley J, et al.: New estimates of Down syndrome risks at chorionic villus sampling, amniocentesis, and livebirth in women of advanced maternal age from uniquely defined population. Prenat Diagn 15:455–465, 1995. Hardy O, Worley G, Lee MM, et al.: Hypothyroidism in Down syndrome: screening guidelines and testing methodology. Am J Med Genet 124A:436–437, 2004. Hines S, Bennett F: Effectiveness of early intervention for children with Down syndrome. In Roizen NJ (ed): Down syndrome. Ment Retard Dev Disab Res Rev 2:96–101, 1996.
Korenberg JR, Bradley C, Disteche CM: Down syndrome: molecular mapping of the congenital heart disease and duodenal stenosis. Am J Hum Genet 50:294–302, 1992. Krantz DA, Larsen JW, Buchanan PD: First-trimester Down syndrome screening: free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A. Am J Obstet Gynecol 174:612–616, 1996. Lin YC: Cervical spine disease and Down syndrome in pediatric anesthesia. Anesth Clin North Amer 16:911–923, 1998. Nyberg DA, Souter VL: Sonographic markers of fetal trisomies. J Ultrasound Med 20:655–674, 2001. Opitz JM, Gilbert-Barness EF: Reflections on the pathogenesis of Down syndrome. Am J Med Genet (Suppl 7):38–51, 1990. Pueschel SM: Clinical aspects of Down syndrome from infancy to adulthood. Am J Med Genet Suppl 7:52–56, 1990. Pueschel SM: Young people with Down syndrome: transition from childhood to adulthood. In Roizen NJ (ed): Down syndrome. Ment Retard Dev Disab Res Rev 2:90–95, 1996. Pueschel SM, Rynders JE: Down Syndrome: Advances in Biomedicine and the Behavioral Sciences. Cambridge: The Ware Press 1982. Roizen NJ: Down syndrome and associated medical disorders. In Roizen NJ (ed): Down syndrome. Ment Retard Dev Disab Res Rev 2:85–89, 1996. Roizen NJ, Wolters C, Nicol T: Hearing loss in children with Down syndrome. J Pediatr 123:S9–S12, 1993. Rose NC: Pregnancy screening and prenatal diagnosis of fetal Down syndrome. In Roizen NJ (ed): Down syndrome. Ment Retard Dev Disab Res Rev 2:80–84, 1996. U.S. Preventive Services Task Force: Screening for Down syndrome. In: Guide to clinical preventive services. Baltimore: Williams & Wilkins 1996 Jan; 2nd ed., pp 449–465. Van Allen MI, Fung J, Jurenka SB: Health care concerns and guidelines for adults with Down syndrome. Am J Med Genet (Semin Med Genet) 89:100–110, 1999. Wald NJ, Kennard A, Hackshaw A: Antenatal screening for Down’s syndrome [published erratum appears in J Med Screen 5:110, 1998 and 5:166, 1998]. J Med Screen 4:181–246, 1997. Zigman W, Silverman W, Wisniewski HM: Aging and Alzheimer’s disease in Down syndrome: Clinical and pathological changes. In Roizen NJ (ed): Down syndrome. Ment Retard Dev Disab Res Rev 2:73–79, 1996.
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Fig. 2. An infant with Down syndrome showing microcephaly, sloping forehead, upslanting palpebral fissure, and “Woolley” sign
Fig. 1. An infant with Down syndrome showing sloping forehead, upslanting palpebral fissures, “Woolley” sign, flat nasal bridge, small mouth, protruding tongue, narrow chest, and decreased internipple distance.
Fig. 3. Two infants with Down syndrome showing severe hypotonia in the neck and back (gibbus).
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Fig. 4. An infant with Down syndrome showing lymphedema in the cheeks and thickened nuchal fold.
Fig. 5. Two children with Down syndrome showing Brushfield spots of the iris.
Fig. 6. Two infants with Down syndrome showing typical small ear with overfolded helix.
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Fig. 9. An adult patient with Down syndrome showing upslanting palpebral fissure and severe midfacial hypoplasia.
Fig. 7. Two infants with Down syndrome showing small hands, small fingers, Clinodactyly of the 5th finger with a single crease, and a transverse palmar crease.
Fig. 10. An adult patient with mosaic Down syndrome showing relatively mild phenotype.
Fig. 8. Two infants with Down syndrome showing a widened space between the 1st and the 2nd toes (‘sandal gap foot’).
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Fig. 11. A brother and a sister with non-disjunction type of trisomy 21. Fig. 14. A G-banded karyotype showing a t(14q;21q) carrier.
Fig. 12. A G-banded karyotype showing trisomy 21. Fig. 15. FISH using a probe cocktail for chromosomes 13 (green) and 21 (orange) on interphase cells. Three copies of the orange/chromosome 21 signal are seen with only two copies of the green signal/chromosome 13 (AneuVysion LSI 13/21, Vysis/Abbott).
Fig. 13. A G-banded karyotype showing i(21q) type of trisomy 21.
Dyschondrosteosis (Leri-Weill Syndrome) and Langer Mesomelic Dysplasia 3. Langer mesomelic dwarfism a. A homozygous state of dyschondrosteosis gene b. Caused by deletion of both SHOX alleles (complete SHOX deficiency)
Dyschondrosteosis is an autosomal dominant form of mesomelic dysplasia, first described by Leri and Weill in 1929.
GENETICS/BASIC DEFECTS 1. Inheritance a. Dyschondrosteosis: autosomal dominant b. Langer mesomelic dysplasia: autosomal recessive 2. Molecular basis a. Caused by mutations and deletion of SHOX (short stature homeobox-containing) gene i. The SHOX gene is mapped to Xp22.3, based on the observation of unbalanced translocation involving the pseudoautosomal region of the short arm of the X and Y chromosomes (PAR1) in dyschondrosteosis patients and of some degree of Madelung deformity in Turner syndrome patients ii. The Xp22.3 region encompasses the pseudoautosomal SHOX gene, which encodes isoforms of a homeo-domain transcription factor expressed in developing human limbs iii. The gene in the Xp22.3 region escapes X-inactivation in females and participates in obligate recombination during male meiosis. Consequently, dyschondrosteosis segregates as an apparently “autosomal” dominant disorder b. Haploinsufficiency of the SHOX gene, implicated in the following disorders: i. Turner syndrome: SHOX is haploinsufficient in females with 45,X Turner syndrome, accounting for approximately 2/3 of the characteristic growth deficit ii. Idiopathic short stature: Observation that a point mutation that cosegregates with idiopathic short stature suggests that SHOX haploinsufficiency may also cause growth failure in the patients with normal karyotype. SHOX mutations have been found in 2–3% of patients with idiopathic short stature iii. Leri-Weill dyschondrosteosis (including homozygous form of Langer mesomelic dysplasia) c. Identification of large-scale deletions or mutations in the SHOX gene in the majority of the cases d. SHOX mutations: causative for mesomelic growth retardation and Madelung deformity in LeriWeill dyschondrosteosis and Langer mesomelic dysplasia e. Leri-Weill syndrome as a part of contiguous gene syndrome with deletion of Xp22.3
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1. Dyschondrosteosis a. Mesomelic dwarfism (disproportionate short stature) b. Phenotypic inter- and intra-familial heterogeneity, a frequent finding c. Much more common and less severe than Langer mesomelic dysplasia d. Females more commonly and more severely affected (more severe Madelung deformity) than males e. Intelligence: normal f. Limbs i. Mesomelia (disproportionate forelimb shortening) a) Shortened forearms b) Shortened forelegs ii. A Madelung deformity of the forearms and wrists secondary to bowing of the radius and dorsal subluxations of the distal ulna iii. Reduced radiocarpal motion iv. Limited elbow and wrist pronation and supernation v. Genu varum 2. Langer mesomelic dysplasia a. The homozygous form of Leri-Weill syndrome b. Severe disproportionate short stature with marked mesomelic and rhizomelic limb shortening c. Parents of some children with Langer mesomelic dysplasia have features of the more common dominantly inherited mesomelic skeletal dysplasia Leri-Weill dyschondrosteosis d. Intelligence: normal e. Limb malformations i. Aplasia or severe hypoplasia of the ulna and fibula ii. Thickened and curved radius and tibia f. Hypoplasia of the mandible g. A variable degree of Madelung deformity and mesomelic shortening in both parents 3. Prognosis a. Minimal disability from the Madelung deformities of the wrists b. Secondary arthrosis of the radiocarpal joint c. Osteoarthritis of the large joints d. Langer mesomelic dysplasia: much more severe phenotype than dyschondrosteosis
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DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Mesomelic dysplasia b. Madelung deformity of the wrists i. Short forearm ii. Bowed radius iii. Bowed ulna iv. Premature fusion of the ulnar half of the radial epiphysis v. A V-shaped deformity of the wrist with slanting at the distal radial contour and dorsal dislocation of the ulna vi. Wedging of the carpal bones between the deformed radius and protruding ulna, resulting in a triangular configuration with the lunate at the apex vii. Cubitus valgus c. Coxa valga d. Lateral subluxation of the patella e. Short tibia f. Exostosis of the proximal medial tibia g. Langer mesomelic dysplasia i. Aplasia or severe hypoplasia of the ulna and fibula ii. Thickened and curved radius and tibia 2. Molecular genetic analysis a. SHOX deletions detected by FISH analysis using cosmid probe for SHOX b. SHOX mutations by direct sequencing of genomic PCR products
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sibs i. Not increased if neither parent is affected ii. 50% if one parent is affected iii. 50% affected with dyschondrosteosis and 25% affected with Langer mesomelic dysplasia if both parents are affected with dyschondrosteosis b. Patient’s offspring i. 50% if the spouse is normal ii. 50% affected with dyschondrosteosis and 25% affected with Langer mesomelic dysplasia if the spouse is also affected with dyschondrosteosis 2. Prenatal diagnosis possible for at-risk families a. Prenatal ultrasonography of skeletal features compatible with mesomelic dwarfism b. Molecular analysis of previously identified diseasecausing SHOX mutations in the proband or a parent from the fetal DNA obtained from amniocentesis or CVS 3. Management a. Medical therapy of Madelung deformity i. May be helpful in skeletally mature individuals with Madelung deformity who have mild-tomoderate short-term wrist pain ii. Splints to relief joint pain iii. Decrease manual activity levels to manage symptoms without surgery
b. Surgical therapy of Madelung deformity i. Primary goals: pain relief and cosmetic improvement of Madelung deformity a) Minimal improvement of range of motion, especially in pronation and supination b) Release of the Vickers ligament alone or in combination with an osteotomy ii. Osteotomy of radius iii. Radioulnar length adjustment iv. Ulnar resection c. Tibial osteotomy and lengthening combined with epiphyseodesis of the distal fibular epiphysis for the tibio-fibular disproportion d. Ongoing clinical trial with growth hormone therapy in patients with short stature due to SHOX mutations
REFERENCES Anton JI, Reitz GB, Spiegel MB: Madelung’s deformity. Ann Surg 108:411–439, 1938. Balci S, Zafer Y, Unsal M: Two female siblings from Turkey with Langer mesomelic dysplasia (homozygous Leri-Weill dyschondrosteosis syndrome). Turk J Pediatr 41:531–539, 1999. Beals RK, Lovrien EW: Dyschondrosteosis and Madelung’s deformity. Report of three kindreds and review of the literature. Clin Orthop 116: 24–28, 1976. Belin V, Cusin V, Viot G, et al.: SHOX mutations in dyschondrosteosis (LeriWeill syndrome). Nature Genet 19:67–69, 1998. Blaschke RJ, Monaghan Adv Pediatr, Schiller S, et al.: SHOT, a SHOX-related homeobox gene is implicated in craniofacial, brain, heart, and limb development. Proc Natl Acad Sci USA 95:2406–2411, 1998. Calabrese G, Fischetto R, Stuppia L, et al.: X/Y translocation in a family with Leri-Weill dyschondrosteosis. Hum Genet 105:367–368, 1999. Carter AR, Currey HLF: Dyschondrosteosis (mesomelic dwarfism): a family study. Brit J Radiol 47:634–640, 1974. Dawe C, Wynne-Davies R, Fulford GE: Clinical variation in dyschondrosteosis: a report on 13 individuals in 8 families. J Bone Joint Surg 64B:377–381, 1982. Espiritu C, Chen H, Woolley PV Jr: Mesomelic dwarfism as the homozygous expression of dyschondrosteosis. Am J Dis Child 129:375–377, 1975. Espiritu CE, Chen H, Woolley PV Jr: Probable homozygosity for the dyschondrosteosis genes. Birth Defects Orig Artic Ser 11:127–132, 1975. Felman AH, Kirkpatrick JA Jr: Madelung’s deformity: observations in 17 patients. Radiology 93:1037–1042, 1969. Felman AH, Kirkpatrick JA Jr: Dyschondrosteose: mesomelic dwarfism of Leri and Weill. Am J Dis Child 120:329–331, 1970. Flanagan SF, Munns CFJ, Hayes M, et al.: Prevalence of mutations in the short stature homeobox containing gene (SHOX) in Madelung deformity of childhood. J Med Genet 39:758–763, 2002. Fryns JP, Van den Berghe H: Langer type of mesomelic dwarfism as the possible homozygous expression of dyschondrosteosis. Hum Genet 46:21–27, 1979. Goepp CE, Jackson LG, Barr MA: Dyschondrosteosis: a family showing maleto-male transmission in 5 generations. (Abstract) Am J Hum Genet 30:52A only, 1978. Guichet A, Briault S. Le Merrer M, et al.: Are t(X;Y)(p22;q11) translocations in females frequently associated with Madelung deformity? Clin Dysmorphol 6:341–345, 1997. Herdman RC, Langer LO Jr, Good RA: Dyschondrosteosis, the most common cause of Madelung’s deformity. J Pediatr 68:432–441, 1966. Huber C, Cusin V, Le Merrer M, et al.: SHOX point mutations in dyschondrosteosis. J Med Genet 38:281–284, 2001. Kunze J, Klemm T: Mesomelic dysplasia, type Langer—a homozygous state for dyschondrosteosis. Europ J Pediatr 134:269–272, 1980. Lamberti PM, Light TR: Madelung deformity. Emedicine, 2002. http://www.emedicine.com Langer LO Jr: Dyschondrosteosis, a heritable bone dysplasia with characteristic roentgenographic features. Am J Roentgen 95:178–188, 1965. Langer LO Jr: Mesomelic dwarfism of the hypoplastic ulna, fibula, mandible type. Radiology 89:654–880, 1967.
DYSCHONDROSTEOSIS AND LANGER MESOMELIC DYSPLASIA Léri A, Weill J: Une affection congénitale et symétrique du développement osseux: la dyschondostéose. Bull Mém Soc Med Hosp 35:1491–1494, 1929. Lichtenstein JR, Sundaram M, Burdge R: Sex-influenced expression of Madelung’s deformity in a family with dyschondrosteosis. J Med Genet 17:41–43, 1980. Palka G, Stuppia L, Guanciali Franchi P, et al.: Short arm rearrangements of sex chromosomes with haploinsufficiency of the SHOX gene are associated with Leri-Weill dyschondrosteosis. Clin Genet 57:449–453, 2000. Rao E, Weiss B, Fukami M, et al.: Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 16:54–62, 1997. Rao E, Blaschke RJ, Marchini A, et al.: The Leri-Weill and Turner syndrome homeobox gene SHOX encodes a cell-type specific transcriptional activator. Hum Mol Genet 10:3083–3091, 2001. Rappold GA, Fukami M, Niesler B, et al.: Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature. J Clin Endocrinol Metab 87:1402–1406, 2002. Robertson SP, Shears DJ, Oei P, et al.: Homozygous deletion of SHOX in a mentally retarded male with Langer mesomelic dysplasia. J Med Genet 37:959–964, 2000.
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Ross JL, Scott C Jr, Marttila P, et al.: Phenotypes associated with SHOX deficiency. J Clin Endocrinol Metab 86(12): December, 2001. Schiller S, Spranger S, Scheshinger B, et al.: Phenotypic variation and genetic heterogeneity in Leri-Weill syndrome. Eur J Hum Genet 8:54–62, 2000. Shears DJ, Vassal HJ, Goodman FR, et al.: Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. Nature Genet 19:70–73, 1998. Shears DJ, Guillen-Navarro E, Sempere-Miralles M, et al.: Pseudodominant inheritance of Langer mesomelic dysplasia caused by a SHOX homeobox missense mutation. Am J Med Genet 110:153–157, 2002. Spranger S, Schiller S, Jauch A, et al.: Léri-Weill syndrome as part of a contiguous gene syndrome at Xp22.3. Am J Med Genet 83:367–371, 1999. Stuppia L, Calabrese G, Borrelli P, et al.: Loss of the SHOX gene associated with Leri-Weill dyschondrosteosis in a 45,X male. J Med Genet 36:711–713, 1999. Zinn AR, Wei F, Zhang L, et al.: Complete SHOX deficiency causes Langer mesomelic dysplasia. Am J Med Genet 110:158–163, 2002. Zumkeller W, Wieacker P: Short stature homeobox-containing gene (SHOX): genotype and phenotype. J Endocr Genet 2:141–150, 2001.
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Fig. 2. A young lady with Leri-Weill syndrome with short forearms and Madelung deformity demonstrated by radiographs
Fig. 1. A young lady with Leri-Weill syndrome showing disproportionate short stature, short forearms and legs, and Madelung deformity of the wrists. Radiographs illustrate typical Madelung deformity (curved radius and ulna with triangular configuration) corrected by surgery
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Fig. 3. A young lady with Leri-Weill syndrome showing disproportionate short stature, short forearms and legs, and Mesomelic deformity illustrated by radiographs
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Fig. 5. Radiograph of the mother of above two children showing typical Madelung deformity
Fig. 4. 2 sibs with Langer mesomelic dysplasia showing severe mesomelic dwarfism, Madelung deformities, and radiographic features of bowed and foreshortened radius and ulna, hypoplastic/aplastic fibula, and short and thick tibia. Both parents have dyschondrosteosis.
Dysmelia (Limb Deficiency/Reduction) Dysmelia is a widely accepted term used to define a group of malformations in which there is hypoplasia, and partial or total aplasia of the tubular bones of the extremities, ranging from isolated peripheral hypoplasia to complete loss of the extremity. The condition is commonly known as limb deficiency or limb reduction defect. The prevalence rate for all types of limb deficiency is 0.69 per 1000.
GENETICS/BASIC DEFECTS 1. Causes: heterogeneous a. Known syndromes i. Holt-Oram syndrome ii. Fanconi syndrome iii. Split hand deformity iv. EEC syndrome v. Thrombocytopenia-radial hypoplasia b. Chromosome abnormalities c. Teratogens i. Thalidomide a) A hypnosedative drug, introduced and marketed as Contergan in Germany in the 1950s b) Promoted as a safe sedative and was found to be useful as an antiemetic during pregnancy, resulting in its widespread use throughout Europe in late 1960 c) Has been used in the past few decades in a variety of dermatologic conditions (e.g., erythema nodosum leprosum, prurigo nodularis, actinic prurigo, discoid lupus erythematosus, aphthous stomatitis, Behcet syndrome, and graft-versus-host disease) d) Side effects: teratogenicity and peripheral neuropathy e) Producing a symmetrical pattern of deficiency (or polydactyly) on the preaxial side of both arms and legs ii. Misoprostol (prostaglandin E1 analog) a) Asymmetrical digit loss b) Constriction rings c) Syndactyly d. Fetal constraint i. Ectopic tubal gestation ii. Uterine structural anomalies iii. Early amnion rupture e. Vascular disruption i. Early chorionic villous sampling a) Symmetrical digit loss b) Constriction rings c) Syndactyly ii. Dilation and curettage iii. Exposure to ergotamine iv. Trauma to the abdomen and placenta f. Unknown causes 312
2. The pattern of malformation in dysmelia (Henkel and Willert, 1969) a. A diminution of skeletal material b. Disturbance of maturation of remaining skeletal elements c. Relationship of the malformed extremities to each other 3. A diminution of skeletal material: common to all malformations of dysmelia a. Reduction tendencies of individual bones: the reduction of the skeletal material of the individual bone follows a certain direction and sequence i. Thumb: the reduction tendency of the thumb directs from proximal to distal a) Hypoplastic tubular bones of the thumb and the first metacarpal in the mildest cases b) Reduction of skeletal material beginning at the base of the first metacarpal in the more severe cases c) The shaft of the thumb becomes aplastic with increasing severity d) The last remnant of the first metacarpal is its head, followed by defective proximal phalanx e) Preservation of the terminal phalanx until, in total aplasia, all bones of the thumb disappear ii. Big toe and first metatarsal: the reduction tendency same as the thumb iii. Radius and tibia: the reduction tendency directs from distal to proximal a) Hypoplasia: the mildest degree of malformation of the radius or the tibia b) A defect seen in the distal part of the metaphysis with increasing severity, extending in a proximal direction with more severe deformities c) The head disappears last, before the radius or tibia becomes totally aplastic iv. Humerus and femur: The reduction tendency directs from proximal to distal a) Hypoplastic: the mildest cases of the axial form of ectromelia b) A defect of bone at the proximal end (just distal to the head of the humerus or in the region of the neck and the trochanter in the femur) in more pronounced cases c) Distal epiphysis represents the last part of the humerus or the femur until it disappears in total aplasia b. Reduction tendency of the limb as a whole i. Upper limb a) Mild manifestations of the deformity restricted to the radial ray of the hand
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b) With increasing severity, the radius becomes involved and only after the radius is either completely absent or its remnants have fused with ulna is the humerus affected ii. Lower limb a) Impairment of the tibia and the tibial ray in mild cases b) The tibia need not be totally absent and its remnants need not be fused before the femur shows signs of reduction c) The isolated malformations of the femur have been observed without impairment of the distal part of the limb iii. Coincidental impairment of the shoulder and pelvic girdles with the reduction of the limb mass a) The degree of the impairment dependents on the severity of the humeral or femoral defect b) Most pronounced in phocomelia and amelia iv. Reduction of the hand and fingers a) Strictly dependent on the severity of the defect of the skeleton of the arm b) A decrease in the number of remaining fingers as the defect of the skeleton of the arm increases c) Radial hypoplasia: all fingers may be present, their number is reduced to 4 or even 3 in the axial types and very often to one in phocomelia d) The reduction of the hand starting at the thumb and progressing from the radial to the ulnar side, so that with increasing severity of the arm deficiency, the index, middle, and ring fingers are absent v. Reduction of foot in dysmelia a) Reduction progresses from the tibial to the fibular rays b) Isolated malformations of the tibial ray: extremely rare in dysmelia c. The axis of malformation in dysmelia i. Combination of the humerus, radius and radial ray of the hand in an axis of malformation within the skeleton of the upper extremity, sparing the ulnar ii. Same combination seen in the lower extremity, where the axis is formed by the femur, the tibia and the tibial ray of the foot, sparing the fibula iii. In the short axial types, the ulna or the fibula is the only long bone of the extremity still exists d. Fusion of the adjacent bones i. The skeletal elements undergoing fusion: always hypoplastic or partially aplastic ii. Fusion occurring in parallel bones (carpals, tarsals, metacarpals, metatarsals, radius and ulna) or in bones arranged longitudinally (phalanges, humerus and ulna) iii. Tendency towards synostosis in the lower extremity appears to be limited to the bones of the foot 4. Disturbance of maturation of remaining skeletal elements a. Retardation of cartilage ossification in bones not directly involved in the defect
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b. Ossification centers far away from the part directly involved tend to ossify in a delayed manner 5. Relationship of the malformed extremities to each other a. Bilateral and symmetrical in manifestation in most cases of amelia b. Presence of lower limbs is observed in most patients with dysmelia of the upper extremity, even if the arms are phocomelic or amelic
CLINICAL FEATURES 1. Classification of dysmelia (Henkel and Willert, 1969) a. Ectromelia: i. Definition: used to include those dysmelia in which the radius and the tibia with their peripheral rays and the humerus or the femur are involved ii. Classification (Henkel and Willert, 1969): there is a need to subdivide into the distal, axial and proximal forms of ectromelia because there are differences in manifestation and severity of skeletal abnormality and in some cases, synostosis occurs as well as reduction a) Distal form of ectromelia b) Axial form of ectromelia c) Proximal form of ectromelia b. Phocomelia: i. Definitions a) Used to include those dysmelia in which no remnants of long bones are seen between the limb girdle and the peripheral part (hands and foot) b) Used to describe the congenital anomaly in which a limb is represented by a flipper-like appendage ii. Classification (Frantz and O’Rahilly, 1961) a) Type I: complete phocomelia (hand or digits attached directly to trunk) b) Type II: proximal phocomelia (Forearm bones between hand and trunk) c) Type III: distal phocomelia (hand attached directly to humerus) iii. Unclassifiable limbs (Tytherleigh-Strong and Hooper, 2003) a) Type A: an abnormal humerus with an abnormal single forearm bone b) Type B: an abnormal humerus with abnormal radius and ulna c) Type C: an abnormal humerus fused to a forearm bone or bones c. Amelia: used to include the most severe degree of dysmelia in which there is total loss of an extremity 2. Distal form of ectromelia a. Confined to the distal part of the extremity b. Involving the radial ray of the hand and the radius only i. Thumb type: the mildest degree of dysmelia, affecting the first ray of the hand only with the following two different manifestations a) Triphalangism of the thumb b) Hypoplasia of the thumb ii. Radial type: sparing the ulnar a) Hypoplasia of the radius
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b) Hypoplasia of the radius with radioulnar synostosis c) Partial aplasia of the radius d) Partial aplasia of the radius with radioulnar synostosis e) Total aplasia of the radius c. Involving the tibial ray of the foot and the tibia only i. Big toe type a) Triphalangism of the big toe b) Duplication of the big toe ii. Tibial type: sparing the fibula a) Hypoplasia of the tibia b) Partial aplasia of the tibia c) Total aplasia of the tibia 3. Axial form of ectromelia a. Involvement of the distal as well as the proximal part of the limb i. Involving the radius, the radial ray of the hand and the humerus a) Sparing the ulnar b) The malformed radius: hypoplastic, partly aplastic or totally aplastic c) The remnants of the radius in partial aplasia: regularly fused with the ulna, presenting as radioulnar synostosis ii. Involving the tibia, the tibial ray of the foot and the femur a) Sparing the fibula b) The remnant of the tibia not showing tendency towards synostosis b. The different degrees of reduction of the humerus or the femur leading to the upper and lower limb types i. Upper limb type a) Long axial type of the arm: hypoplasia or partial aplasia of the humerus with partial aplasia of the radius and radioulnar synostosis or with total aplasia of the radius b) Intermediate axial type of the arm: subtotal aplasia of the humerus with partial aplasia of the radius and radioulnar synostosis or with total aplasia of the radius c) Short axial type of the arm: total aplasia of the humerus with partial aplasia of the radius and radioulnar synostosis or with total aplasia of the radius ii. Lower limb type a) Long axial type of the leg: hypoplasia or partial aplasia of the femur with partial or total aplasia of the tibia b) Intermediate axial type of the leg: subtotal aplasia of the femur with partial or total aplasia of the tibia c) Short axial type of the leg: total aplasia of the femur with partial or total aplasia of the tibia 4. Proximal form of ectromelia a. Can be found only in the lower limb b. No parallel defect in the upper limb c. Only involves the proximal part of the lower limb, the femur, which can display all different degrees of reduction, leading to the following subtypes:
i. Long proximal type: hypoplasia of the femur, coxa vara or partial aplasia of the femur without impairment of the distal part of the limb ii. Intermediate proximal type: subtotal aplasia of the femur without impairment of the distal part of the limb iii. Short proximal type: total aplasia of the femur without impairment of the distal part of the limb 5. Phocomelia a. Absent humerus, radius and ulna or femur, tibia and fibula b. Remainder of the extremity i. Consisting of a malformed hand formed by one, two or three ulnar finger rays and ulnar parts of the carpus or of a similarly affected foot ii. Directly attached to a hypoplastic shoulder girdle or to a misshapen pelvis 6. Amelia a. The most severe form of dysmelia b. Total absence of the arm or the leg c. Shoulder girdles: hypoplastic in the absence of the arms d. Pelvis: deformed in a box-like shape in the absence of the legs 7. Differential diagnosis a. Transverse limb defects i. Adam-Oliver syndrome ii. Amniotic band sequence iii. Oro-mandibular limb hypogenesis syndrome iv. Poland anomaly v. Fetuses with homozygous α-thalassemia b. Preaxial limb defects i. Chromosome syndromes ii. Facio-radial syndromes (e.g., Nager syndrome) iii. Hemato-radial syndromes a) Aase syndrome b) Fanconi anemia c) TAR syndrome iv. Holt-Oram syndrome v. Poland anomaly vi. Roberts syndrome vii. VATER association c. Central limb defects i. EEC syndrome ii. Poland anomaly d. Postaxial limb defects i. Cornelia de Lange syndrome ii. Facio-ulnar syndromes (e.g., Miller syndrome) iii. Femur-fibula-ulna complex iv. Ulnar mammary syndrome e. Amniotic band syndrome and other mechanical and constraint problems i. Digital constrictions and amputations ii. Transverse amputations of the distal and proximal limbs, with a normal limb above the amputation iii. Amelia f. Vascular compression, disruption thrombosis, embolization i. Transverse amputations ii. Postaxial and preaxial limb reduction defect
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iii. Femoral hypoplasia iv. Digital amputation or hypoplasia v. Poland anomaly g. Genetic diseases i. Many dominant and recessive syndromes a) Bilateral and unilateral limb reduction defect of preaxial or postaxial type b) Ectrodactyly c) Monodactyly ii. Limb reduction defects as features of many different genetic disorders, such as absent radius with absence/hypoplasia of the thumb h. Cytogenetic abnormalities (e.g., del(13q) syndrome and trisomy 18 syndrome) i. Severe limb hypoplasia ii. Polydactyly iii. Absent thumb iv. Absent radius v. Other multiple congenital anomalies i. Thalidomide embryopathy i. Deformities of the upper and lower extremities: grossly symmetric, although opposite limbs are often unequally affected to some degree a) Amelia b) Phocomelia c) Bone hypoplasia d) Absence of bones ii. Abnormalities of the external ears a) Anotia b) Micro pinna c) Small or absent auditory canals iii. Abnormalities of the eyes a) Anophthalmia b) Microphthamos c) Coloboma d) Cataracts iv. Face a) Hypoplastic nasal bridge b) Choanal atresia v. CNS malformations a) Facial nerve paralysis b) Deafness c) Marcus Gunn or jaw-winking phenomenon d) Crocodile-tear syndrome e) Seizure disorder vi. Respiratory tract anomalies a) Laryngeal and tracheal abnormalities b) Abnormal lobulation of the lungs vii. Cardiovascular anomalies a) Capillary hemangioma, extending from dorsum of the nose to the philtrum in the midline b) Congenital heart diseases (conotruncal defects) viii. Gastrointestinal anomalies a) Upper intestinal atresia b) Congenital absence of the gall bladder and the appendix c) Anal stenosis d) Inguinal hernias
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ix. Renal anomalies a) Abnormal rotation of the kidney b) Pelvic position of the kidneys c) Horseshoe kidney d) Hydronephrosis e) Double ureter x. Genital anomalies a) Double vagina b) Vaginal atresia c) Rectovaginal fistula d) Cryptorchidism xi. Mortality: 40% at or shortly after birth j. Warfarin and diphenylhydantoin i. Digital hypoplasia a) Usually mild b) Can be severe ii. Limb hypoplasia due to chronic exposure throughout gestation, usually very mild k. Maternal diabetes i. Femoral hypoplasia ii. Sacral agenesis
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Evaluate limb defects b. Evaluate nonlimb skeletal defects 2. Diagnostic protocol for preaxial defects a. Blood count including thrombocytes b. Hb F (electrophoresis) c. Urine sediment d. Renal sonography e. Echocardiography f. Chromosome analysis g. Audiologic evaluation h. Ophthalmologic evaluation
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Genetic syndromes: depending on the inheritance pattern of the disorder ii. Chromosome abnormalities: about 1% unless the parent carries a translocation iii. Environmental factors: not increased unless the mother exposes to the teratogen during pregnancy iv. Nonsyndromic nonfamilial reduction defects of one limb a) Transversal: <1% b) Postaxial: <1% c) Preaxial: Low d) Central: low v. Nonsyndromic nonfamilial reduction defects of more than one limb a) Transversal: probably low b) Postaxial: probably low c) Preaxial: unknown d) Central: unknown b. Patient’s offspring i. Genetic syndromes: depending on the inheritance pattern of the disorder
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ii. Chromosome abnormalities: patients usually not surviving to reproduction iii. Environmental factors: not increased unless patient exposes to the same teratogen during pregnancy iv. Nonsyndromic nonfamilial reduction defects of one limb a) Transversal: <1% b) Postaxial: <1% c) Preaxial: probably low d) Central: probably low v. Nonsyndromic nonfamilial reduction defects of more than one limb a) Transversal: possibly low b) Postaxial: possibly low c) Preaxial: unknown d) Central: autosomal dominant 2. Prenatal diagnosis a. Transvaginal sonography: an important element in the evaluation of any first trimester limb deficiencies b. Second trimester ultrasonography to detect limb deficiencies and other associated anomalies c. Chromosome analysis from amniocentesis or CVS to rule out chromosome anomaly 3. Management a. Avoid using teratogenic agents during pregnancy b. Management of malformation of the upper extremities i. Bilateral upper extremity: amelia and/or phocomelia a) Good prosthetic fitting of children based primarily on relating prosthetic function to the functional needs of the patient to be fitted b) Satisfactory foot function, a prerequisite to the prosthetic habilitation of the severe bilateral upper limb problem in children c) Compensatory prehension patterns developed by the feet helpful, particularly in total toilet care and total dressing and undressing ii. Upper extremity: paraxial hemimelica a) Passive stretching b) Application of splints to stabilize the wrists iii. Bilateral transverse hemimelia: fit with standard prostheses with hooks as terminal devices c. Management of malformation of the lower extremities i. Lower extremity phocomelia a) Fit with a special bucket on a pair of short skis to develop balance b) Prostheses to help walking ii. Bilateral transverse lower hemimelia: fit with conventional appliances d. Occupational therapy: exercise and other treatment of the upper extremities to increase strength and dexterity to prepare to operate prostheses e. Prosthetic training of the children f. Parents’ contribution i. Observation of the child’s training session ii. Parent to learn to:
a) Put on and remove prostheses b) Care and encourage use of the prostheses c) Cleanse the stump g. Prosthetic devices i. Every effort to be made to develop a prosthesis that will compensate for the absence of functions and restore independence to the greatest possible degree ii. Main objectives a) To assist the child to develop a normal body image b) To construct a prosthesis based on sound anatomical principles which has an adequate range of motion c) To fit the prosthesis early so that, at a few months of age, the child unconsciously accepts it as a part of his body h. Psychosocial counseling i. To assist parents to cope with the situation ii. To explain the plan of treatment to parents iii. Overall success of a given family in accepting and adjusting to a congenital deformity: related to its educational level and the usual pattern of behavior of its members under stress
REFERENCES Armstrong AP, Page RE: Intrauterine vascular deficiency of the upper limb. J Hand Surg [Br] 22:607–611, 1997 Atken GT: Management of severe bilateral upper limb deficiencies. Clin Orthop 37:53–56, 1964. Boyd PA, Keeling JW, Selinger M, et al.: Limb reduction and chorion villus sampling. Prenat Diagn 10:437–441, 1990. Brent RL, Holmes LB: Clinical and basic science lessons from the thalidomide tragedy: what have we learned about the causes of limb defects? Teratology 38:241–251, 1988. Cobben JM, Hiemstra S, Robinson PH: Genetic counseling in limb reduction defects. Genet Couns 5:243–248, 1994. Curran B, Hambrey R: The prosthetic treatment of upper limb deficiency. Prosthet Orthot Int 15:82–87, 1991. Christianson AL, Nelson MM: Four cases of trisomy 18 syndrome with limb reduction malformations. J Med Genet 21:293–297, 1984. Cobben JM, Hiemstra S, Robinson PH: Genetic counseling in limb reduction defects. Genet Couns 5:243–248, 1994. Frantz CH, O’Rahilly R: Congenital skeletal limb deficiencies. J Bone Joint Surg 43A:1202–1224, 1961. Graham JM Jr: Causes of limb reduction defects: the contribution of fetal constraint and/or vascular disruption. Teratology 13:575–591, 1986. Graham JM Jr: Causes of limb reduction defects: the contribution of fetal constraint and/or vascular disruption. Clin Perinatol 13:575–591, 1986. Graham JM, Miller ME, Stephan MJ, et al.: Limb reduction anomalies and early in utero limb compression. J Pediatr 96:1052–1056, 1980. Hall BD: Vascular abnormalities at the site of limb deficiency. Am J Med Genet 43:619–620, 1992. Henkel L, Willert H-G: Dysmelia. A classification and a pattern of malformation in a group of congenital defects of the limbs. J Bone Joint Surg 51B:399–414, 1969. Hirons RR, Williams KB, Amor RF, et al.: The prosthetic treatment of lower limb deficiency. Prosthet Orthot Int 15:112–116, 1991. Hoon A, Hall JG: Familial limb deficiency. Clin Genet 34:141–142, 1988. Hoyme HE, Jones KL, Van Allen MI, et al.: Vascular pathogenesis of transverse limb reduction defects. J Pediatr 101:839–843, 1982. Lamb DW, Simpson DC, Pirie RB: The management of lower limb phocomelia. J Bone Joint Surg Br 52:688–691, 1970. Lam YH, Tang MHY, Sin SY, et al.: Limb reduction defects in fetuses with homozygous α-thalassaemia-1. Prenat Diagn 17:1143–1146, 1997. McGuirk CK, Westgate M-N, Holmes LB: Limb deficiencies in newborn infants. Pediatrics 108:64, 2001.
DYSMELIA Mongeau M, Gingras G, Sherman ED, et al.: Medical and psychosocial aspects of the habilitation of thalidomide children. Canad Med Assoc J 95:390–395, 1966. Newman CGH: The thalidomide syndrome: risks of exposure and spectrum of malformations. Clin Perinatol 13:555–573, 1986. Radomsky CL, Levine N: Thalidomide. Dermatol Clin 19:87–103, 2001. Rijhsinghani A, Yankowitz J, Mazursky J, et al.: Prenatal ultrasound diagnosis of amelia. Prenat Diagn 15:655–659, 1995.
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Tseng S, Pak G, Washenik K, et al.: Rediscovering thalidomide: a review of its mechanism of action, side effects, and potential uses. J Am Acad Dermatol 35:969–979, 1996. Tytherleigh-Strong G ,Hooper G: The classification of phocomelia. J Hand Surg [Br] 28:215–217, 2003.
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Fig. 2. Radiographs of ectrodactyly (two hands and a foot) in three patients showing different type of ectrodactyly.
Fig. 1. Ectrodactyly of hands and feet in three patients showing symmetric and asymmetric anomalies.
Fig. 3. An infant with transverse reduction of the lower extremities.
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Fig. 5. An embryo with phocomelia showing deficient limbs, illustrated by radiograph. Fig. 4. An infant with unilateral transverse reduction of left upper extremities (intrauterine amputation), constriction ring of the left big toe, and syndactyly of the toes of both feet, secondary to amniotic band syndrome.
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Fig. 7. A newborn with phocomelia showing absence of the upper extremities and reduction of the lower extremities.
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Fig. 8. A child with phocomelia showing complete absence of upper extremities.
Fig. 10. A patient with amelia of the upper extremities. He is intelligent, uses his chin and shoulder to write, and drives a car by using one foot to turn the driving wheel and one foot to pedal the accelerator and brake.
Fig. 9. A girl and a lady with phocomelia showing flipper-like hands.
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Fig. 11. A neonate with del(13q) syndrome showing hypoplastic thumbs, syndactyly of toes, in addition to multiple congenital anomalies. The karyotype shows the deletion of 15q.
Fig. 6. A macerated stillborn with phocomelia. Her upper extremities consist of hands attached to the shoulders with absence of the long bones. Her left lower extremity consists of a foot attached via thin twisted skin to the pelvic area with absence of the long bones. Right lower extremity was completely absent. There were severe dysplastic vertebrae, fusions of ribs, and absence of pelvic bones. In addition, the infant had blind vagina, absent right kidney, rudimentary left kidney, hypoplastic lungs, and microphthalmia.
Fig. 12. Radiograph of another neonate with del(13q) syndrome showing limb reduction anomalies of the upper extremities.
Fig. 13. A neonate with trisomy 18 syndrome showing limb reduction defects of the upper extremities in addition to multiple congenital anomalies.
Dysplasia Epiphysealis Hemimelica Dysplasia epiphysealis hemimelica is a rare osteocarilaginous overgrowth involving one or multiple epiphyses or ossification centers, usually in the lower extremity on one side of the body. In 1926, Mouchet and Belot described a condition called tarsomegaly, which Trevor, later in 1950, called tarso-epiphyseal aclasis. As the tarsal bones are not the only bones involved, Fairbank used the term dysplasia epiphysealis hemimelica.
GENETICS/BASIC DEFECTS 1. Inheritance: a. No known hereditary factor, except a report of a single family with seven members affected by different combinations of dysplasia epiphysealis hemimelica, intracapsular chondroma, extraskeletal osteochondroma, and typical osteochondroma b. Male to female ratio: 3:1 2. Etiology and pathogenesis a. Etiology unknown b. A congenital disorder becoming clinically evident in the course of the development of the epiphyses c. Basic pathologic process: an abnormal proliferation of cartilage in an epiphysis, similar to osteochondroma 5.
CLINICAL FEATURES 1. Most frequent presentation: ages 2–14 years (birth to 63 years of age) 2. Chief clinical signs a. Unilateral asymmetric bony hard swelling on the extremities b. Usually on the inner or outer aspect of the knee and/or ankle c. With or without pain d. With or without restriction of motion e. Slow progression 3. Apparent deformity a. Varus or valgus deformity depending on the site of involvement b. Genu valgum or varum depending on the site of involvement c. Flexion contracture d. Pes planus e. Pes equinus 4. Sites of involvement a. Lower extremities, more commonly affected than the upper extremities i. Talus (most common) ii. Distal femoral epiphysis iii. Distal tibial epiphysis iv. Proximal tibial epiphysis v. Distal fibula epiphysis vi. Tarsal navicular vii. First cuneiform 323
6. 7.
8.
viii. Calcaneus ix. Middle and lateral cuneiforms x. Metatarsals xi. Phalanges b. Upper extremities i. Carpal bones a) Scaphoid b) Lunate c) Capitate d) Hamate e) Trapezium f) Trapezoid ii. Metacarpals iii. Phalanges iv. Proximal radius v. Proximal and distal ulna vi. Proximal and distal humerus vii. Glenoid cavity viii. Coracoid process of the scapula c. Pelvis i. Acetabulum ii. Pubic bone iii. Iliac bone Affected limb a. May be longer than the unaffected one due to: i. The enlargement of several ossification centers ii. Increased diaphyseal length b. May be shorter due to focal early closure of the epiphyseal plate Quiescent following epiphyseal plate fusion Prognosis a. Relatively benign condition b. Malignant degeneration has not been reported Classification based on degrees of involvement (Azouz et al., 1985) a. Localized form i. Usually affecting the bones of the hindfoot or ankle ii. Also may affect an epiphysis b. Classical form i. Characteristic hemimelic distribution seen in more than one area in a single lower extremity (2/3rd of the reported cases), particularly: a) Talus b) Distal femoral epiphyses c) Distal tibial epiphyses ii. Lesion localized to the ankle and foot, called Mouchet and Belot type c. Generalized or severe form i. Involving a whole lower extremity from the pelvis to the foot or ankle ii. Involving femoral head, symphysis pubis or triradiate cartilage of the acetabulum
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DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Skeletal survey to look for sites of involvement b. Earliest radiographic sign i. Appearance of secondary centers of ossification adjacent to an epiphysis ii. Slow enlargement of these centers eventually merging with each other and then with the epiphysis c. Asymmetric hemimelic distribution of overgrowth of one side of epiphysis with irregular contour and ossification i. Generally only half or part (either the medial or lateral half) of an epiphysis or ossification center affected ii. Rarely involving the entire epiphysis d. Overgrowth of adjacent bones e. Adjacent (probably secondary) metaphyseal and growth plate involvement i. Exhibiting widening and streak-like metaphysis (as in Ollier disease) ii. Spur formation (as in osteochondroma) f. Mature lesions showing enlargement of one side of an epiphysis, simulating as osteochondromatous mass or enlargement of one side of an ossification center g. Epiphysis irregularly calcified and ossified h. Joints usually deformed i. Advanced bone age in unaffected epiphyses j. Less common findings i. Loose bodies in affected joints ii. Osteochondral fractures k. Bilateral involvement extremely rare 2. CT of the lesions a. Improving diagnostic accuracy in the growing skeleton b. Demonstration of the anatomic relationship of the involved structures c. Visualization of the soft tissues, bones, and tumorous mass d. Evaluation of the condition of the articular surfaces 3. MRI imaging a. To identify a definite plane of separation between the pathologic osteochondromatous mass and the normal epiphysis b. To accurately identify bony and cartilaginous structural abnormalities in multiple planes noninvasively without ionizing radiation c. To identify secondary changes in menisci, tendons, ligaments, and muscles 4. Histopathology a. Osteocartilaginous exostosis (with cartilaginous cap) arising from an epiphysis, apophysis, or round bone (Oates) b. Nests of cartilage cells showing active proliferation during growth of the lesions c. Diminishing amount and activity of the cartilage as the lesions mature d. Increased size of lesions in adults showing areas of actively proliferating cartilage e. Infrequently with an area of necrosis, presumably caused by inadequate nutrition
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: not increased 2. Prenatal diagnosis: not been reported 3. Management a. Observation b. Surgical excision of the mass or corrective osteotomy generally recommended for the following lesions: i. Causing disabling pain ii. Interfering function iii. Increasing deformity of the involved joint c. Simple excision indicated if the cartilaginous overgrowth is not in the weight-bearing articular surface d. Extraarticular osteotomy indicated for correction of varus/valgus deformities if the arthrogram shows the smooth joint surface e. Anticipate recurrence of the angular deformity after the corrective osteotomy if the growth plate at the affected joint is open and active
REFERENCES Azouz EM: MRI of dysplasia epiphysealis hemimelica. Pediatr Radiol 26: 904, 1996. Azouz EM, Slomic AM, Archambault H: Upper extremity involvement in Trevor disease. J Can Assoc Radiol 35:209–211, 1984. Azouz EM, Slomic AM, Marton D, et al.: The variable manifestations of dysplasia epiphysealis hemimelica. Pediatr Radiol 15:44–49, 1985. Boccio JR, Silvani S, Karlin J, et al.: Dysplasia epiphysealis hemimelica. A case report and literature review. J Am Podiatr Med Assoc 75:523–526, 1985. Carlson DH, Wilkinson RH: Variability of unilateral epiphyseal dysplasia (dysplasia epiphysealis hemimelica). Radiology 133:369–373, 1979. Fairbank TJ: Dysplasia epiphysialis hemimelica (tarso-epiphysial aclasis). J Bone Joint Surg 38-B(1):237–257, 1956. Fasting OJ, Bjerkreim I: Dysplasia epiphysealis hemimelica. Acta Orthop Scand 47:217–225, 1976. Gerscovich EO, Greenspan A: Computed tomography in the diagnosis of dysplasia epiphysealis hemimelica. Can Assoc Radiol J 40:313–315, 1989. Heilbronner DM: Asymmetric dysplasia epiphysealis hemimelica. Orthopedics 11:795–797, 1988. Hensinger RN, Cowell HR, Ramsey PL, et al.: Familial dysplasia epiphysealis hemimelica, associated with chondromas and osteochondromas. Report of a kindred with variable presentations. J Bone Joint Surg Am 56:1513–1516, 1974. Iwasawa T, Aida N, Kobayashi N, et al.: MRI findings of dysplasia epiphysealis hemimelica. Pediatr Radiol 26:65–67, 1996. Keret D, Spatz DK, Caro PA, et al.: Dysplasia epiphysealis hemimelica: diagnosis and treatment. J Pediatr Orthop 12:365–372, 1992. Kettelkamp DB, Campbell CJ, Bonfiglio M: Dysplasia epiphysealis hemimelica. A report of fifteen cases and a review of the literature. J Bone Joint Surg 48-A:746–766, 1966. Kuo RS, Bellemore MC, Monsell FP, et al.: Dysplasia epiphysealis hemimelica: clinical features and management. J Pediatr Orthop 18:543–548, 1998. Merzoug V, Wicard P, Dubousset J, et al.: Bilateral dysplasia epiphysealis hemimelica: report of two cases. Pediatr Radiol 32:431–434, 2002. Peduto AJ, Frawley KJ, Bellemore MC, et al.: MR imaging of dysplasia epiphysealis hemimelica: bony and soft-tissue abnormalities. AJR Am J Roentgenol 172:819–823, 1999. Schmidt MB, Lomasney LM: Radiologic case study. Trevor disease: dysplasia epiphysealis hemimelica. Orthopedics 17:645, 649–653, 1994. Silverman FN: Dysplasia epiphysealis hemimelica. Semin Roentgenol 24:246–258, 1989. Trevor D: Tarso-epiphysial aclasis. A congenital error of epiphysial development. J Bone Joint Surg 32-B(2):204–213, 1950. Wiedemann HR, Mann M, von Kreudenstein PS: Dysplasia epiphysealis hemimelica—Trevor disease. Severe manifestations in a child. Eur J Pediatr 136:311–316, 1981.
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Fig. 1. A 9-year-old boy with dysplasia epiphysealis hemimelica showing hard swellings on the inner sides of the knees and the ankle of the right lower extremities. The knee radiographs at 9 years of age show the secondary ossification center merged with the medial side of the epiphyses of the distal femur and that of the proximal tibia. The radiographs of ankles at 4, 5, and 9 years of age show irregularly calcified mass extending from medial malleolus of the distal tibia and involvement of the talus. The patient had bony protuberance of the right knee and right ankle without pain or restriction of motion. The age of onset was about 2 years of age.
Dystonia Dystonia is a diverse movement disorder with a complex but not fully understood pathophysiology. It is characterized by involuntary sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures.
GENETICS/BASIC DEFECTS 1. Genetically defined forms of the primary dystonias and dystonia-plus syndromes: at least 13 different types of dystonia can be distinguished genetically as follows: a. Dystonia type 1 (early onset primary generalized torsion dystonia, Oppenheim dystonia) i. Autosomal dominant inheritance with reduced penetrance of about 30–40% ii. Locus: DYT1 on chromosome 9q34 iii. Mutations a) GAG deletion in the DYT1 gene resulting in loss of Glutamic-acid residues in the Cterminus of a novel ATP-binding protein, torsin A b) 18 base pair deletion resulting in loss of 6 amino acids (F323-Y328del) in a novel ATP-binding protein, torsin A b. Dystonia 2 (autosomal recessive torsion dystonia) i. Autosomal recessive inheritance ii. Locus: DYT2 (chromosome map unknown) c. Dystonia 3 (X-linked dystonia parkinsonism, ‘lubag’) i. X-linked recessive inheritance ii. Locus: DYT3 on chromosome Xq13.1 d. Dystonia 4 (whispering dysphonia) i. Autosomal dominant inheritance ii. Locus: DYT4 (chromosome map unknown) e. Dystonia 5 (dopa-responsive dystonia- parkinsonism) i. Common autosomal dominant inheritance a) Locus: GCH1 on chromosome 14q22.1-q22.2 b) Caused by mutation in the guanosine triphosphate cyclohydrolase I gene, GCH1 ii. Rare autosomal recessive form (Segawa syndrome) a) Associated with mutations in the tyrosine hydroxylase gene, TH b) Locus: TH on chromosome11p15.5 f. Dystonia 6 (adolescent-onset torsion dystonia of mixed type) i. Autosomal dominant inheritance ii. Locus: DYT6 on chromosome 8p21-8q22 g. Dystonia 7 (adult-onset focal torsion dystonia) i. Autosomal dominant inheritance ii. Locus: DYT7 on chromosome 18p h. Dystonia 8 (paroxysmal dystonic choreoathetosis) i. Autosomal dominant inheritance ii. Locus: DYT8 on chromosome 2q33-q25 326
i. Dystonia 9 (paroxysmal choreoathetosis with episodic ataxia and spasticity) i. Autosomal dominant inheritance ii. Locus: DYT9 on chromosome 1p21-p13.3 j. Dystonia 10 (paroxysmal kinesigenic choreoathetosis) i. Locus: DYT10 on chromosome 16p11.2-q12.1 ii. Autosomal dominant inheritance k. Dystonia 11 (myoclonus-dystonia) i. Autosomal dominant inheritance ii. Locus: DYST11 on chromosome 7q21 iii. Caused by mutations in the ε-sarcoglycan gene in most families l. Dystonia 12 (rapid-onset dystonia-parkinsonism) i. Autosomal dominant inheritance ii. Locus: DYT12 on chromosome 19q m. Dystonia 13 (multifocal/segmental dystonia) i. Autosomal dominant inheritance ii. Locus: DYT13 on chromosome 1p36 2. Secondary dystonia a. Association with a number of disorders i. Hepatolenticular degeneration (Wilson disease) a) Dystonia in over a third of the patients b) Associated with lesions in the putamen in 80% of cases ii. Hallervorden-Spatz disease (pantothenate kinaseassociated neurodegeneration) iii. Huntington chorea iv. Lesch-Nyhan disease v. Metachromatic leukodystrophy vi. Methylmalonic acidemia vii. Mitochondrial disorders viii. Ceroid lipofucinosis ix. Gangliosidoses x. Glutaric aciduria xi. Ataxia telangiectasia xii. Niemann-Pick disease type C xiii. Early-onset parkinsonism xiv. Corticobasal degeneration xv. Certain forms of spinocerebellar ataxia a) Spinocerebellar ataxia 3 (Machado-Joseph disease): the severity of the dystonic symptoms is related to the length of the trinucleotide repeat b) Spinocerebellar ataxia 17 (caused by mutations in the thymine-adenine-thymineadenine binding protein: Dystonia may be the presenting sign of the disorder b. Other causes i. Psychogenic ii. Vascular lesions such as carotid occlusive disease and hemorrhagic stroke iii. Anoxic brain injury (cerebral anoxia/hypoxia): a well-known cause of secondary dystonia
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iv. Acute disseminated encephalomyelitis v. Trauma a) Head trauma: dystonia is among the most common movement disorders following severe head injury b) Peripheral trauma causing segmental dystonia vi. Both acute and chronic use of dopamine blocking medications and other medications a) Haloperidol b) Resperidol c) Fluphenazine d) Thioridazine e) Chlorpromazine f) Metoclopramide g) Phenytoin h) Stonatrioran 3. Pathophysiology: a new interpretive hypothesis involving multiple levels of the nervous system a. Spinal cord: increased spinal motor neuron excitability in patients with generalized dystonia due to reduced presynaptic inhibition and compromised supraspinal inhibition systems b. Basal ganglia: disturbed pattern of basal ganglia output neurons c. Thalamus: disorganization of input–output properties and hyperactivity in thalamic neurons in two dystonic cynomolgus monkeys d. Somato-sensory system: increased temporal discrimination thresholds for tactile stimuli e. Sensorimotor integration and motor cortical function i. Abnormal somatotopic arrangement of sensorimotor interaction ii. Abnormal functioning of cortico-subcortical loops causing abnormalities of both intracortical inhibition and cortical excitability 4. Dystonia with unknown etiology
CLINICAL FEATURES 1. Dystonia describes a symptom that may be part of many disorders with a variety of causes a. An abnormal sustained posture that is often writhing or twisting in quality b. Can be rapid or slow c. Often painful 2. Classifications of dystonia a. Classification based on distribution of dystonia i. Primary/generalized dystonia a) Occurs in childhood b) Often begins focally in the legs and progresses to a generalized symptom involving the entire body ii. Focal dystonia a) May occur at any age b) Typically starts in adulthood c) Affects an isolated body area, such as hand and arm (writer’s cramp), neck (cervical dystonia, previously known as spasmodic torticollis), vocal/laryngeal apparatus (dystonic adductor dysphonia or whispering dysphonia), mouth
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(oromandibular dystonia, musician’s cramp), or eyelids (blepharospasm) d) Multifocal dystonia (two or more noncontiguous parts affected) iii. Segmental dystonia a) May occur at any age b) Typically starts in adulthood c) Involves only the right or left side of the body d) Cranial (two or more parts of cranial and neck musculature affected) e) Axial (neck and trunk affected) f) Brachial (one arm and axial; both arms, with or without neck, with or without trunk) g) Crural (one leg and trunk; both legs, with or without trunk) iv. Hemidystonia: affects ipsilateral arm and leg v. Secondary dystonia a) Can be generalized, focal, or segmental b) Induced by a disease or ingested substance c) Can occur at any time d) Treated by identifying the underlying medical disorder or substance b. Classification based on age of onset of dystonia i. Early-onset dystonia a) Often starts in a limb b) Tends to generalize and frequently has a genetic origin ii. Adult-onset dystonia a) Usually spares the lower extremities b) Frequently involves cervical or cranial muscles c) A tendency to remain focal d) Sporadic in most cases 3. Clinical characteristic in genetically defined forms of dystonia and dystonia-plus a. Dystonia type 1 (early onset generalized primary torsion dystonia) i. Early-onset torsion dystonia (onset usually childhood) ii. May present as focal, usually in the limbs iii. Often generalizes to other body parts as the disease progresses b. Dystonia type 2 (autosomal recessive torsion dystonia) i. Early-onset ii. Generalized or segmental torsion dystonia c. Dystonia type 3 (X-linked dystonia parkinsonism, ‘lubag’ meaning ‘twist’ in a local dialect in the Island of Panay in the Philippines) i. Only described in individuals from the Philippines ii. Usually males iii. Onset usually adulthood iv. Usually generalized dystonia v. Parkinsonism (50% of cases) unresponsive to Ldopa vi. Progressive neurodegenerative syndrome d. Dystonia type 4 (whispering dysphonia) i. Described in a single large Australian family ii. Laryngeal and cervical dystonia iii. Age of onset: 13–37 years
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e. Dystonia type 5 (dopa-responsive dystoniaparkinsonism) i. Childhood onset of dystonia ii. Onset of dystonia in a limb, typically a leg, resulting in gait disturbance iii. Gradual progression to generalized dystonia (usually more pronounced in the legs) iv. Dystonia with concurrent or subsequent parkinsonism v. Diurnal worsening of symptoms a) Aggravation of symptoms toward the evening b) Alleviation of symptoms in the morning after sleep vi. A variety of atypical presentations a) Generalized hypotonia b) Proximal weakness c) Gait disturbance d) ‘Atypical cerebral palsy’ vii. A dramatic response to L-dopa f. Dystonia type 6 (adolescent-onset torsion dystonia of mixed type) i. Described in two Mennonite families ii. Adolescent-onset iii. Mostly segmental torsion dystonia iv. Focal or generalized (rare) v. Cranial, cervical or limb dystonia g. Dystonia type 7 (adult-onset focal torsion dystonia) i. Described in a single German family ii. Adult-onset focal dystonia iii. Torticollis iv. Writer’s cramp v. Spasmodic dysphonia vi. Blepharospasm h. Dystonia type 8 (paroxysmal dysphonic choreoathetosis) i. Variable age of onset (early childhood, adolescence or early adulthood) ii. Attacks of dystonia/choreoathetosis iii. Precipitated by stress, hunger, fatigue, alcohol, caffeine, nicotine, and chocolate i. Dystonia type 9 (paroxysmal choreoathetosis with episodic ataxia and spasticity) i. Age of onset: 2–15 years ii. Attacks of dystonia, paresthesias, and double vision iii. Precipitated by exercise, fatigue, stress, alcohol iv. Spastic paraplegia between attacks j. Dystonia type 10 (paroxysmal kinesigenic choreoathetosis) i. Attacks of dystonia/choreoathetosis ii. Precipitated by sudden unexpected movements iii. Respond to anticonvulsant therapy k. Dystonia type 11 (myoclonus-dystonia) i. Onset usually in the first or second decade of life ii. Rapid, jerk-like movements iii. Responsive to alcohol iv. Combined with variable degrees of dystonia l. Dystonia type 12 (rapid-onset dystonia-parkinsonism) i. Acute or subacute onset (develop over hours or weeks) of generalized dystonia ii. In combination with parkinsonism
m. Dystonia type 13 (multifocal/segmental dystonia) i. Described in a single Italian family ii. Juvenile or early adult onset of segmental dystonia iii. With prominent cranial-cervical and upper limb involvement iv. Some focal dystonia, some generalized dystonia
DIAGNOSTIC INVESTIGATIONS 1. Electromyography shows a simultaneous contraction of both agonist and antagonist muscles 2. Neuroimaging a. Lacks signs of structural abnormality b. Inconsistent results of functional imaging studies 3. Dopa-responsive dystonia a. GTPCH1-deficient dopa-responsive dystonia i. Decreased concentration of both total biopterin (BP) and neopterin (NP) in cerebrospinal fluid in patients with GTPCH1 deficiencies ii. Phenylalanine loading test to detect a subclinical defect in phenylalanine metabolism iii. DNA mutation analysis to detect GCH1 mutation b. TH-deficient dopa-responsive dystonia i. Normal BP and NP, and reduced-3-methoxy-4hydroxy-phenylethyleneglycol in CSF ii. DNA mutation analysis to detect TH mutation
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal recessive inheritance: 25% ii. Autosomal dominant inheritance: not increased unless one of the parent carries a mutant allele in which case, there is a 50% risk of having an affected sib iii. X-linked recessive inheritance; 50% of male sib will be affected given the mother is a carrier iv. Secondary dystonias: risk depending on the etiology b. Patient’s offspring i. Autosomal recessive inheritance: not increased (all offspring are carriers) unless the spouse is also a carrier in which case, there is a 50% risk of having an affected offspring ii. Autosomal dominant inheritance: 50% iii. X-linked recessive inheritance: none of the sons will be affected; all of the daughters will be carriers iv. Secondary dystonias: risk depending on the etiology 2. Prenatal diagnosis is possible for some forms of dystonia by DNA analysis of the fetal blood obtained from amniocentesis of CVS provided the disease-causing allele(s) of an affected family member have been identified 3. Management a. Generalized idiopathic dystonia i. Medical therapy a) Anticholinergic agents (trihexyphenidyl): first choice (a moderate response in about 40–50% of dystonia patients)
DYSTONIA
b) Benzodiazepines (diazepam, clonazepam) c) Dopamine depletors (tetrabenazine) d) γ-aminobutyric acidergics (baclofen) e) Atypical neuroleptics (clozapine, olanzapine) ii. Intrathecal baclofen infusion iii. Ablative therapies, reserved for patients in whom medical therapies fail a) Pallidotomy b) Thalamotomy b. Dopa-responsive dystonia i. A dramatic response to small dosages of levodopa (100 mg/day) (confirms the diagnosis) ii. Maintenance with low-dose levodopa for life may improve from severe inability to completely normal function c. Focal dystonias i. Unresponsive to systemic drug treatment in most case ii. Frequently well controlled by periodic botulinum toxin (BTX) injections into the muscles directly involved in the dystonia iii. Try with intrathecal baclofen and surgery if oral medications fail d. Cervical dystonias resistant to BTX: selective peripheral denervation
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REFERENCES Bressman SB, Sabatti C, Raymond D, et al.: The DYT1 mutation and guidelines for diagnostic testing. Neurology 54:1746–1752, 2000. Fahn S, Bressman SB, Marsden CD: Classification of dystonia. Adv Neurol 78:1–10, 1998. Friedman J, Standaert DG: Movement disorders. Neurol Clin 19:681–705, 2001. Furukawa Y: Dopa-responsive dystonia. Gene Reviews, 2004, http:// www.genetests.org Klein C, Ozelius LJ: Dystonia: clinical features, genetics, and treatment. Curr Opin Neurol 15:491–497, 2002. Klein C, Breakefield XO, Ozelius LJ: Genetics of primary dystonia. Semin Neurol 19:271–280, 1999. Krauss JK, Jankovic J: Head injury and posttraumatic movement disorders. Neurosurgery 50:927–939, 2002; discussion 939–940. Müller U, Steinberger D, Nemeth AH: Clinical and molecular genetics of primary dystonias. Neurogenetics 1:165–177, 1998. Németh AH: The genetics of primary dystonias and related disorders. Brain 125(Pt 4):695–721, 2002. Néemeth AH: Dystonia overview. Gene Reviews, 2004. http://www. genetests.org Ozelius L, Kramer P, Moskowitz CB, et al.: Human gene for torsion dystonia located on chromosome 9q32–q34. Neuron 2:1427–1434, 1989. Schlaggar BL, Mink JW: Movement disorders in children. Pediatr Rev 24:39–51, 2003. Trosˇt M: Dystonia update. Curr Opin Neurol 16:495–500, 2003. Valente EM, Bentivoglio AR, Cassetta E, et al.: DYT13, a novel primary torsion dystonia locus, maps to chromosome 1p36.13–36.32 in an Italian family with cranial-cervical or upper limb onset. Ann Neurol 49:362–366, 2001. Vitek JL: Pathophysiology of dystonia: a neuronal model. Mov Disord 17 Suppl 3:S49–S62, 2002.
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Fig. 1. A 7-year-old girl with progressive dystonia showing dystonic posturing with gait locking of the knees and swiveling of the hips to propel the legs forward. She developed normally until age 6 when she started to have loss of balance, falling, unable to get the foot off the ground, stiffing of lower and upper extremities, and slurring of speech. Plasma amino acids, urine organic acids, blood chemistry, lactate/ pyruvate, ceruloplasmin, copper, arsenic, lead, 5-methyltetrahydrofolate, neurotransmitter metabolites/amines, tetrahydrobiopterin/ neopterine, and various lysosomal enzymes were all normal. No mutations were detected on mitochondrial myopathy mtDNA, DYT1, and PANK2. MRI of the brain showed bilateral hyperdense basal ganglia lesions. Use of levodopa/dopamine agonists has at best, been minimally beneficial.
Dystrophinopathies ii. Cloning of the dystrophin gene by positional cloning in the late 1980s constituted the initial proof that deletions in the Xp21 region were associated with the disease iii. The dystrophin gene a) The largest gene of the 30,000 genes that encode proteins in the human genome b) Consisting of 79 exons spanning more than 2.6 million bp of genomic sequence c) Correspond to about 0.1% of the total human genome d) Correspond to about 1.5% of the entire X chromosome iv. Southern blot analysis of affected boys with a complete set of cDNA probes a) Over 60% with detectable deletions b) 6% with duplications c) A number of point mutations described recently v. Consequences of absent dystrophin in skeletal and cardiac muscles in affected patients a) Muscle contraction leading to membrane damage and activation of the inflammatory cascade b) Progressing to muscle necrosis, fibrosis, and loss of function d. The DMD phenotype most frequently due to mutations that cause a disruption in the reading frame 2. BMD a. Inheritance: X-linked recessive (same as DMD) b. Also caused by mutations in the gene for dystrophin at Xp21.1 c. The BMD phenotype most often due to mutations that preserve the open reading frame but in which portions of the protein are deleted. Frame deletions of the long rod segment of the gene are particularly forgiving and produce a mild phenotype.
The dystrophinopathies include a spectrum of muscle disease caused by mutations in the DMD gene that encodes the protein dystrophin. They are characterized by a spectrum of muscle disease that ranges from mild to severe. The mild end of the spectrum includes the phenotypes of asymptomatic increase in serum concentration of creatine phosphokinase (CK) and muscle cramps with myoglobinuria and isolated quadriceps myopathy. The severe end of the spectrum includes progressive muscle diseases that are classified as Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) when skeletal muscle is primarily affected and as X-linked dilated cardiomyopathy (XLDCM) when the heart is primarily affected. In this chapter, I will limit my discussion on DMD and BMD. DMD is one of the most common types of muscular dystrophy in childhood, primarily affecting skeletal and cardiac muscle. It is one of the most common of all clinical genetic disorders. Its incidence is estimated to be approximately 1 in 3500 live male births. BMD is a milder allelic form of dystrophin deficiency, affecting 1 in 30,000 male births.
GENETICS/BASIC DEFECTS 1. DMD a. Inheritance i. X-linked recessive ii. Exceptionally high mutation rate of 10–4 in both sperm and eggs iii. Approximately 1/3 of cases are due to new genetic mutations iv. Approximately 2/3 of cases occurring by inheritance of the disease-causing gene from the carrier mother v. Only males affected (as a rule) b. DMD gene i. Observation of a series of young females affected clinically as Duchenne muscular dystrophy with an X-autosome translocation a) Breakpoint in the X chromosome in the same place (Xp21.1) b) Different autosomes involved for each affected female c) Mapping of dystrophin gene to chromosome Xp21 ii. The largest human gene, covering 2.5 megabases and including 79 exons iii. The enormity of the DMD gene along with the spontaneous mutation rate of each base pair allows a high frequency of novel mutations c. Dystrophin, the product (protein) of the human dystrophin gene (dys) i. Loss of dystrophin at the muscle membrane clearly related to mutations in the gene encoding dystrophin at band Xp21
CLINICAL FEATURES
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1. DMD a. During early infancy i. Asymptomatic ii. Normal motor milestones iii. Rare global developmental delay or delayed achievement of early motor milestones b. 4–5 years of age: onset of symptoms i. A waddling gait ii. Difficulty in climbing stairs due to pelvic weakness iii. Difficulty in running iv. Toe walking resulting from tight Achilles tendon v. Inability to jump vi. Frequent falling vii. Neck flexor weakness with marked head lag when pulling to sit from the supine position
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c. Progressive difficulty in rising from the floor secondary to weakness of proximal pelvic girdle and proximal leg muscle, resulting in the Gower’s maneuver requiring the use of the hands to “climb up the legs” d. Pseudohypertrophy of muscles, especially calf muscles: unusually firm and rubbery consistency on palpation e. Compensatory lumbar lordosis to maintain an upright posture secondary to weakness of hip extensors f. Weakness of the arms (proximal more severely affected than distal) apparent as the disease progresses g. Marked laxity of the shoulder girdle musculature with prominent spontaneous winging of the scapulae h. Inability to walk usually before 13 years of age i. Rapid development of fixed skeletal deformities following loss of ambulation i. Equinovarus deformities of the feet ii. Scoliosis iii. Wheelchair confinement by adolescence j. Unexplained cardiac arrest and/or myoglobinuria: features of malignant hyperthermia during general anesthesia in rare instances k. Progressive and restrictive respiratory deficit with nocturnal hypoventilation in the latter teens to early 20s secondary to weak intercostal muscles l. Eventual respiratory failure requiring assisted ventilation m. Some degree of mental impairment is usually present. Approximately 25% of patients have IQ below 75, presumably due to the lack of dystrophin in the brain n. Natural history i. Progressive and predictable deterioration of muscle function ii. Cause of death: cardiopulmonary insufficiency in the late 2nd or 3rd decade o. Female carriers i. Usually asymptomatic ii. Manifesting female carriers (rare): occasional, slow progressive myopathy of moderate severity with elevated CPK (>1000) and associated symptoms in about 8% of carriers. Following conditions induce expression of the disease phenotype: a) Random X-inactivation: the extent of clinical involvement is dependent in part upon the degree of skewed X-chromosome inactivation in somatic cells b) Turner syndrome having a single X chromosome c) X-autosome translocation that disrupts the dystrophin gene and causes nonrandom inactivation of the normal allele on the other X chromosome 2. BMD a. A more benign and variable presentation with later onset and slower progression b. Onset of symptoms after age 6–12 c. Progressive symmetrical muscle weakness and atrophy i. Proximal greater than distal ii. Often with calf hypertrophy iii. Weakness of quadriceps femoris may be the only sign
d. Activity induced cramping in some patients e. Flexion contractures of the elbows may occur late in the course f. Wheelchair dependency, if present, after 16 years of age g. Preservation of the neck flexor muscle strength in BMD, differentiating it from DMD h. Rare BMD patients not diagnosed until adulthood and never lose ambulation i. A proportion of cases have some degree of mental impairment j. Heart failure from dilated cardiomyopathy, a common cause of morbidity and the most common cause of death, despite the milder skeletal muscle involvement k. Death usually in the 4th or 5th decade l. Female carriers i. Clinical features similar to DMD female carriers ii. About 5–10% of female carriers show some degree of muscle weakness iii. Often with calf hypertrophy iv. May develop dilated cardiomyopathy
DIAGNOSTIC INVESTIGATIONS 1. Determination of serum creatine kinase (CK-MM) a. 50-fold elevation (BMD) to 100-fold elevation (DMD) in affected boys, resulting from leakage of the muscle isoform b. Serum creatine kinase levels: range of values overlapping with the normal range in carrier females, making the test less than definitive 2. Determination of other enzymes: grossly elevated aldolase, SGOT, lactic dehydrogenase, and pyruvate kinase 3. Electrocardiography and echocardiography to detect cardiac involvement a. Electrocardiography i. Abnormalities in the early stage of the disease a) Tall R-wave b) Deep Q-wave ii. Arrhythmias iii. Progressive cardiomyopathy in the mid-teens a) Myocardial dilatation b) Myocardial thickening b. Echocardiography i. Left ventricular dilatation and dysfunction ii. Mitral regurgitation secondary to dilated cardiomyopathy or associated mitral valve prolapse 4. Radiography for scoliosis 5. Pulmonary function testing with negative inspiratory force and forced vital capacity as disease progresses 6. Cytogenetic analysis a. Males affected with DMD and other X-linked disorders such as retinitis pigmentosa, chronic granulomatous disease, McLeod red cell phenotype, glycerol kinase deficiency, and adrenal hypoplasia as part of contiguous gene deletion syndrome i. High resolution chromosome studies a) To detect visible deletions b) To detect chromosome rearrangements involving Xp21.1 ii. FISH analysis with probes covering the GK and NRDB1 genes in addition to exons in the DMD gene
DYSTROPHINOPATHIES
7.
8.
9.
10.
b. Females with classic DMD i. May have X chromosome rearrangement ii. May have deletion involving Xp21.1 iii. May have complete absence of an X chromosome (45,X) iv. May have complete uniparental disomy of the X chromosome v. Warrant high-resolution chromosome studies Electromyography (EMG) to distinguish a myopathic process from a neurogenic disorder a. Not diagnostic b. Demonstrating characteristic myopathy c. Reduction in the duration and amplitude of motor unit action potentials d. An enhanced frequency of polyphasic potentials DNA analyses for diagnostic confirmation a. Deletion of the dystrophin gene in 60% of patients: 98% of all deletions which occur in hotspots within the dystrophin gene can be recognized by multiplex PCR which amplifies 18 to 25 of the gene’s 79 exons from genomic DNA obtained from blood samples b. Duplications (6% of cases): the next most common mutation of the dystrophin gene, also detectable by multiplex PCR amplification c. Point mutations (1/3 of patients) difficult to identify due to the large size of the gene d. Enhanced single-strand conformation polymorphism (SSCP) and heteroduplex analysis: highly sensitive and possible to detect approximately 90% of patients with DMD e. RNA-based methods, such as reverse-transcriptase PCR (RT-PCR) f. Protein truncation test: to rapidly screen the DMD gene for translation terminating mutations Muscle biopsy (needle biopsy vs open biopsy under general anesthesia), frequently performed when a clinically suspected DMD patient does not have a large deletion or duplication by genomic DNA testing a. Histology i. Rounding of muscle fibers ii. Marked variability in muscle fiber size iii. Increased central nucleation iv. Fiber splitting v. Presence of necrotic and regenerating fibers along with large, round hyaline fibers vi. Virtual replacement of muscle fibers by fatty and fibrous tissue in late stage b. Dystrophin determination by Western blot analysis or immunostaining i. Usually little or no detectable dystrophin in patients with DMD ii. Dystrophin reduced in amount or abnormal in size in patients with BMD Carrier testing a. Carrier testing of young girls or genetic testing of siblings of patients with DMD should be delayed until they are old enough to participate in the decisionmaking process b. Appropriate to test the mother who has an affected boy with deletion or duplication identified by stan-
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dard DNA screening, especially if there are other female relatives of childbearing age who are at risk for being carriers c. Possibility of gonadal mosaicism (up to 15%) exists when the mother does not carry the boy’s mutation. i. Her sisters could not have inherited the mutation ii. Her daughter may have inherited the mutations d. Offer linkage analysis to modify risk of carrier status if no mutation is known or if tissue for DNA analysis is not available i. Knowledge of a childhood CPK level in the at risk girl helpful ii. Elevated CPK in an at-risk female is presumptive evidence of her being a carrier e. Muscle biopsy: not a helpful test in determining carrier status
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib given that the mother is a carrier (the carrier mother with one defective gene and one normal gene is usually not affected) i. 50% risk to her son to receive the disease gene and express the disease ii. 50% risk to her daughter to receive the disease gene and become a carrier iii. Mother of a DMD patient, regardless of proven carrier status, has an empiric risk of 10–30% of having an affected male fetus due to presence of maternal germinal mosaicism b. Patient’s offspring i. Males with DMD: patient usually succumb or too debilitated to reproduce ii. Males with BMD a) May reproduce b) None of the sons will inherit the mutation c) All the daughters are carriers 2. Prenatal diagnosis a. In case of a known and readily detectable gene defect i. Amniocentesis and mutation analysis of amniocytes, usually by multiplex PCR ii. Preimplantation diagnosis by single-cell PCR of blastomere or polar body iii. Fetal nucleated erythrocytes from maternal blood analyzed by multiplex PCR b. In case of unknown gene defect i. Fetal sexing, allowing females to proceed to term ii. Linkage analysis iii. Fetal muscle biopsy for quantitative dystrophin analysis may serve as a diagnostic option 3. Management a. Largely supportive i. Physical therapy to eliminate the need for surgical release of contractures a) Night splints with ankle foot orthoses (AFOs) b) Daily stretching c) Crucial to maintain ambulation as long as possible because its loss is associated with
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b.
c.
d.
e. f. g. h.
i.
contractures and scoliosis, and, in turn, associated with restrictive lung disease ii. Regular use of an incentive spirometer at home to prolong pulmonary function iii. Continuous positive airway pressure (CPAP) iv. Bilevel positive airway pressure BiPAP: more physiologic v. Psychological support Treatment of dystrophic cardiomyopathy i. An angiotensin-converting enzyme inhibitor ii. With or without a β-blocker iii. A diuretic Pharmaceutical agents (steroids) shown great promise in delaying the progression of DMD i. Prednisone ii. Deflazacort (not FDA approved but used widely in Europe and Canada) Orthopedic surgery i. Release of joint contractures ii. Spine fusion to minimize painful spinal deformity and secondary pulmonary complications Prescribe wheelchair when dependency becomes inevitable Careful monitoring of pulmonary function Ventilation for respiratory failure Genetic therapies in DMD: use of viral and plasmid vectors to deliver dystrophin to dystrophin–deficient muscle in vivo i. Truncated dystrophin genes (minidystrophin and microdystrophin transgenes): improve force output and other features of the dystrophic mdx phenotype ii. Tissue-specific promoters: targeted transgene expression via muscle-specific promoters, a good platform for vector-mediated therapeutic delivery of dys to dystrophic muscle iii. Plasmid vectors iv. Viral vectors a) Adenoviral vectors b) Adenoassociated vectors c) Retroviral vectors d) Lentiviral vectors e) Other viral vectors including herpes simplex virus, Epstein-Barr virus, and chimeric adeno-retrovirus Corrective gene therapy i. Targeted corrective gene conversion therapies a) Introduction of construct of homologous DNA containing a nonhomologous sequence into mammalian cells in vitro induces specific genetic transformations in the host chromosomal DNA. b) An attractive therapeutic strategy for DMD if the DNA can be delivered to the muscles efficiently ii. Small fragment homologous replacement (SFHR): involves the application of PCR amplicons to correct mutant loci in vitro or in vivo iii. Chimeraplasty with hybrid RNA-DNA molecules (chimeraplasts) that promote gene conversion via intranuclear DNA mismatch repair mechanisms
iv. Gentamicin a) An aminoglycoside antibiotics targeting functional complexes (typically ribosomes) b) Causes a relaxation in codon recognition c) Enables stop-codon read-through of the mdx nonsense mutation (a mutation that produces a stop codon in the transcribed mRNA) in exon 23 of the dystrophin gene in the mdx mouse v. Cell-mediated delivery of dys a) Use cell transplantation to deliver normal (nondystrophic) dys to dystrophic muscle b) Use donor myogenic precursor cells to remodel the dystrophic muscle of the recipient c) Systemic applications of stem-cell subpopulations d) Use autologous cells (as an alternative to donor cells) which can be isolated, genetically engineered, and used to deliver functional dystrophin to the dystrophic muscle vi. Muscle derived precursor cells a) Delivery of normal dystrophin by the transplantation of nondystrophic muscle derived precursor cells b) Resulting in some recovery of normal function in dystrophic muscle c) Greatly compromised by host immune response vii. Nonmuscle stem cells a) Induction of a few systemically injected bone-marrow cells to enter muscle after regeneration induced by injury b) These cells with neuronal, osteogenic, myogenic, and haemopoietic expression profiles may provide alternatives for cell-based delivery of nondystrophic loci to dystrophic muscle. viii. Utrophin a) A 395 kDa ubiquitous protein homologue of dystrophin b) Utrophin expression has a widespread sarcolemmal distribution in human dystrophic muscle. ix. Other alternative approaches that may be useful in the support of functional improvement in dystrophic muscle include: a) α7β1 integrin b) Myoprotective or myoproliferative cytokine factors such as leukemia inhibitory factor and insulin-like growth factor-1 c) Inhibition of myostatin
REFERENCES Altman DJ, Gilchrist JM: Dystrophinopathies. Emedicine, 2002. http://www. emedicine.com Beggs AH, Kunkel LM: Improved diagnosis of Duchenne/Becker muscular dystrophy. J Clin Invest 85:613–619, 1990. Beggs AH, Koenig M, Boyce F, et al.: Detection of 98% of DMD/BMD gene deletions by polymerase chain reaction. Hum Genet 86:45–48, 1990. Biggar WD, Klamut HJ, Demacio PC, et al.: Duchenne muscular dystrophy: Current knowledge, treatment, and future prospects. Clin Orthop Rel Res 401:88–106, 2002.
DYSTROPHINOPATHIES Brooke MH, Griggs RC, Mendell JR, et al.: The natural history of Duchenne muscular dystrophy (DMD): a caveat for therapeutic trials. Trans Am Neurol Assoc 106:195–199, 1981. Cox GF, Kunkel LM: Dystrophies and heart disease. Curr Opin Cardiol 12:329–343, 1997. Eggers S, Pavanello RC, Passos-Bueno MR, et al.: Genetic counseling for childless women at risk for Duchenne muscular dystrophy. Am J Med Genet 86:447–453, 1999. Emery AH: The muscular dystrophies. Lancet 359:687–695, 2002. Gillard EF, Chamberlain JS, Murphy EG, et al.: Molecular and phenotype analysis of patients with deletions within the deletion-rich region of the Duchenne muscular dystrophy (DMD) gene. Am J Hum Genet 45:507–520, 1989. Heckmatt JZ, Moosa A, Hutson C, et al.: Diagnostic needle muscle biopsy, a practical and reliable alternative to open biopsy. Arch Dis Child 59:528–532, 1984. Hoffman EP, Brown RH, Jr., Kunkel LM: Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51:919–928, 1987. Hoffman EP, Fischbeck KH, Brown RH, et al.: Characterization of dystrophin in muscle-biopsy specimens from Duchenne’s and Becker’s muscular dystrophy patients. N Enl J Med 318:1363–1368, 1988. Hoffman EP, Arahata K, Minetti C, et al.: Dystrophinopathy in isolated cases of myopathy in females. Neurology 42:967–975, 1992. Hu XY, Ray PN, Murphy EG, et al.: Duplicational mutation at the Duchenne muscular dystrophy locus: its frequency, distribution, origin, and phenotype genotype correlation. Am J Hum Genet 46:682–695, 1990. Jacobs PA, Hunt PA, Mayer M, et al.: Duchenne muscular dystrophy (DMD) in a female with an X/autosome translocation: further evidence that the DMD locus is at Xp21. Am J Hum Genet 33:513–518, 1981. Kapsa R, Kornberg AJ, Byrne E: Novel therapies for Duchenne muscular dystrophy. Lancet Neurol 2:299–310, 2003. Koenig M, Hoffman EP, Bertelson CJ, et al.: Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic
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organization of the DMD gene in normal and affected individuals. Cell 50:509–517, 1987. Koenig M, Beggs AH, Moyer M, et al.: The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion. Am J Hum Genet 45:498–506, 1989. Korf BR, Darras BT, Urion DK: Dystrophinopathies. Gene Reviews, 2003. http://www.genetests.org Malhortra SB, Hart KA, Klamut HJM, et al.: Frame-shift deletions in patients with Duchenne and Becker muscular dystrophy. Science 242:755–759, 1988. Mathews KD: Muscular dystrophy overview: genetics and diagnosis. Neurol Clin 21:795–816, 2003. Mendell JR, Buzin CH, Feng J, et al.: Diagnosis of Duchenne dystrophy by enhanced detection of small mutations. Neurology 57:645–650, 2001. Muntoni F, Torelli S, Ferlini A: Dystrophin and mutations: one gene, several proteins, multiple phenotypes. Lancet Neurol 2:731–740, 2003. Nevo Y, Shomrat R, Yaron Y, et al.: Fetal muscle biopsy as a diagnostic tool in Duchenne muscular dystrophy. Prenat Diagn 19:921–926, 1999. Perloff JK, Roberts WC, de Leon AC Jr, et al.: The distinctive electrocardiogram of Duchenne’s progressive muscular dystrophy. Am J Med 42:179–188, 1967. Roest PA, Roberts RG, van der Tuijn AC, et al.: Protein truncation test (PTT) to rapidly screen the DMD gene for translation terminating mutations. Neuromuscul Disord 3:391–394, 1993. Roland EH: Muscular dystrophy. Pediatr Rev 21:233–237, 2000. Van Deutekom JC, Van Ommen GJ: Advances in Duchenne muscular dystrophy gene therapy. Nat Rev Genet 4:774–783, 2003. Wagner KR: Genetic diseases of muscle. Neurol Clin 20:675–678, 2002. Worton RG, Thompson MW: Genetics of Duchenne muscular dystrophy. Annu Rev Genet 22:601–629, 1988. Worton RG, Molnar MJ, Brais B, et al.: The muscular dystrophies. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001.
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Fig. 2. A 12-year-old boy with DMD showing moderate calf hypertrophy. He began to fall frequently at school, could not get up from sitting position and had waddling gait, proximal muscle weakness, prominent lordosis, decreased deep tendon reflexes, and mild mental retardation. Muscle biopsy revealed absence of dystrophin.
Fig 3. A 10-year-old boy with DMD starting to use wheelchair for ambulation. He had tip toe walking at age of 6 and markedly elevated CPK at 24,000–26,000. Muscle biopsy of quadriceps femoris muscle showed marked variation in fiber size, moderate number of necrotic fibers, occasional regeneration fibers and hyalinized fibers, mild increase in internal nuclei, a few split fibers and moderate increase in perimysial and endomysial connective tissue. Molecular genetic analysis revealed deletion of exon 45 of the dystrophin gene. Fig 1. A 10-year-old boy with DMD showing Gower sign maneuver. He walked before 16 months of age and had trouble getting up. Radiography showed mild cardiomegaly. Muscle biopsy showed absence of dystrophin. Molecular genetic analysis revealed exons 45–50 deletion of the dystrophin gene.
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Fig. 5. Biopsy of left calf muscle of another patient at age 4 showed widening of perimysium (large arrows) and endomysium with fibrosis; variation of fiber size with presence of large rounded fibers (small arrows). Degenerative fibers were often seen. (H & E, × 400)
Fig. 6. Enzyme histochemical stain showed both type I (dark stained) and type II (light stained) fibers are randomly affected and there is a remarkable variation of fiber size even at the early stage (myosin ATPase at 4.6, × 400)
Fig. 4. A male with DMD at 4-, 10-, and 29-year-old showing the progression of the disease. He has deletion of exons 49–54 of the dystrophin gene.
Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) Syndrome EEC syndrome is an ectodermal dysplasia syndrome associated with ectrodactyly and cleft lip/palate.
GENETICS/BASIC DEFECTS 1. Inheritance a. Familial cases (50%) i. Autosomal dominant inheritance ii. Variable clinical expression and incomplete penetrance (93–98%) b. Sporadic cases (50%): more severe phenotype than the familial cases 2. At least three distinctive EEC loci identified a. EEC1 (7q11.2-q21.3) b. EEC2 (chromosome 19 pericentromeric region) c. EEC3 (3q27) 3. Molecular basis of EEC3 a. Causative mutations for EEC syndrome have only been identified in p63 with identification of heterozygous mutations in the DNA-binding domain of the p63 gene at 3q27 b. The p63 protein i. A member of the p53 family ii. Implicated in apoptosis rather than tumor suppression. Increased susceptibility for cancer development has not been shown in patients with EEC syndrome 4. A genotype–phenotype correlation described for p63 mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand/split foot malformation: a specific pattern of missense mutations exists in EEC syndrome that are not generally found in split hand/foot malformation or limb-mammary syndrome 5. EEC syndrome as a model of apoptosis disturbance a. Split hands and feet are caused by a failure of cell death between fingers and between toes b. Urogenital anomalies are due to abnormal regression of Wolffian or Mullerian duct c. Facial clefts are attributed to the abnormal elimination of excess cells during fusion of the archetypal plate
4. Ectodermal dysplasia (77%): may exhibit the following signs: a. Sparse scalp hair b. Sparse eyebrows and eyelashes c. Thin and brittle nails d. Hypohidrosis e. Thin and dry skin with an increased susceptibility to eczema f. Dental anomalies i. Hypodontia ii. Coniform-shaped teeth iii. Enamel dysplasia 5. Characteristic face a. Bilateral cleft lip and/or palate (68%) b. Maxillary hypoplasia c. Short philtrum d. Broad nasal tip e. Choanal atresia f. Anomalies of the lacrimal ducts resulting in blepharitis, keratitis, and dacryocystitis (59%) 6. Urogenital defects (23%) a. Hydronephrosis b. Hydroureter c. Renal agenesis 7. Conductive hearing loss (14%) 8. Developmental delay 9. Occasional CNS malformations a. Rare growth hormone deficiency secondary to hypothalamic-pituitary insufficiency b. Holoprosencephaly associated with hypogonatdotropic hypogonadism and central diabetes insipidus c. Isolated absent septum pellucidum 10. Phenotype overlapping with split hand/foot malformations
DIAGNOSTIC INVESTIGATIONS 1. 2. 3. 4. 5.
Ophthalmologic evaluation for tear duct obstruction Early audiological assessment Renal ultrasound for associate renal anomalies Radiographic evaluation for ectrodactyly Starch-iodine test (the skin is painted with tincture of iodine, air dried, and sprayed with starch) after sweat stimulation with intradermal injections of pilocarpine to demonstrate hypohidrosis 6. Direct molecular analysis is possible for EEC3 7. Linkage analysis for known EEC2 families
CLINICAL FEATURES 1. Significant intra/interfamilial variability 2. Cardinal signs (triad) a. Ectrodactyly b. Ectodermal dysplasia c. Orofacial clefts 3. Distal limb malformations: highly variable a. Ectrodactyly (84%) i. Also called split hand/foot malformation ii. A central reduction of the hands and feet that is often associated with syndactyly b. Present in all four or any combination of extremities involved or not present at all
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1. Counseling according to autosomal dominant inheritance a. Patient’s sib: i. Recurrence risk of 50% if a parent is affected ii. Recurrence risk not increased if both parents are normal b. Patient’s offspring: recurrence risk of 50%
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c. Dilemmas in counseling due to highly variable clinical expression d. Consider the possibility of nonpenetrance due to gonadal mosaicism 2. Prenatal diagnosis a. Prenatal ultrasonography i. Cleft lip/palate ii. Ectrodactyly iii. Associated anomalies b. Molecular genetic analysis of p63 gene mutation i. On fetal DNA extracted from CVS and amniocytes by direct sequencing and restriction endonucleases digestion (loss of AciI site on mutant allele) ii. Using a preimplantation genetic diagnostic approach 3. Management a. Supportive (multi-disciplinary team approach) i. Artificial tear for tear duct blockage ii. Anticipate recurrent ophthalmologic infections iii. Periodic odontologic management to prevent dental malocclusion and caries iv. Simple emollients for dry skin b. Surgery i. Early surgery for tear duct blockage ii. Surgery for all defects causing functional impairment a) Cleft lip/palate b) Ectrodactyly c) Associated anomalies
REFERENCES Akahoshi K, Sakazume S, Kosaki K, et al.: EEC syndrome type 3 with a heterozygous germline mutation in the P63 gene and B cell lymphoma. Am J Med Genet 120A:370–373, 2003. Annerén G, Andersson T, Lindgren PG, et al.: Ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC): the clinical variation and prenatal diagnosis. Clin Genet 40:257–262, 1991. Barrow LL, van Bokhoven H, Daack-Hirsch S, et al.: Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts. J Med Genet 39:559–566, 2002. Bigatà X, Bielsa I, Artigas M, et al.: The ectrodactyly-ectodermal dysplasiaclefting syndrome (EEC): report of five cases. Pediatr Dermatol 20:113–118, 2003. Bixler D, Spivack J, Bennett J, et al.: The ectrodactyly-ectodermal dysplasiaclefting (EEC) syndrome. Report of 2 cases and review of the literature. Clin Genet 3:43–51, 1972. Bronshtein M, Gershoni-Baruch R: Prenatal transvaginal diagnosis of the ectrodactyly, ectodermal dysplasia, cleft palate (EEC) syndrome. Prenat Diagn 13:519–522, 1993.
Buss FW, Hughes HE, Clarke A: Twenty-four cases of the EEC syndrome: clinical presentation and management. J Med Genet 32:716–723, 1995. Celli J, Duijf P, Hamel BC, et al.: Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 99:143–153, 1999. Crackower MA, Scherer SW, Rommens JM, et al.: Characterization of the split hand/split foot malformation locus SHFM1 at 7q21.3-q22.1 and analysis of a candidate gene for its expression during limb development. Hum Mol Genet 5:571–579, 1996. Kosaki R, Ohashi H, Yoshihashi H, et al.: A de novo mutation (R279C) in the P63 gene in a patient with EEC syndrome. Clin Genet 60:314–315, 2001. Nardi AC, Ferreira U, Netto Junior NR: Urinary tract involvement in EEC syndrome: a clinically study in 25 Brazilian patients. Am J Med Genet 44:803–806, 1992. O’Quinn JR, Hennekam RC, Jorde LB, et al.: Syndromic ectrodactyly with severe limb, ectodermal, urogenital, and palatal defects maps to chromosome 19. Am J Med Genet 62:130–135, 1992. Qumsiyeh MB: EEC syndrome (ectrodactyly, ectodermal dysplasia and left lip/palate) is on 7p11.2-q21.3. Clin Genet 42:101, 1992. Penchaszadeh VB, de Negrotti TC: Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome: dominant inheritance and variable expression. J Med Genet 13:281–284, 1976. Rodini ES, Richieri-Costa A: EEC syndrome: report on 20 new patients, clinical and genetic considerations. Am J Med Genet 37:42–53, 1990. Roelfsema NM, Cobben JM: The EEC syndrome: A literature study. Clin Dysmorphol 5:115–127, 1996. Rollnick BR, Hoo JJ: Genitourinary anomalies are a component manifestation in the ectodermal dysplasia, ectrodactyly, cleft lip/palate (EEC) syndrome. Am J Med Genet 29:131–135, 1998. Rodini ES, Richieri-Costa A: EEC syndrome: report on 20 new patients, clinical and genetic considerations. Am J Med Genet 37:42–53, 1990. Roelfsema NM, Cobben JM: The EEC syndrome: a literature study. Clin Dysmorphol 5:115–127, 1996. Scherer SW, Poorkaj P, Massa H, et al.: Physical mapping of the split hand/split foot locus on chromosome 7 and implication in Syndromic ectrodactyly. Hum Mol Genet 3:1345–1354, 1994. South AP, Ashton GH, Willoughby C, et al.: EEC (Ectrodactyly, Ectodermal dysplasia, Clefting) syndrome: heterozygous mutation in the p63 gene (R279H) and DNA-based prenatal diagnosis. Br J Dermatol 146:216–220, 2002. Tse K, Temple IK, Baraitser M: Dilemmas in counseling: The EC syndrome. J Med Genet 27:752–755, 1990. Van Bolhoven H, Jung M, Smits AP, et al.: Limb mammary syndrome: a new genetic disorder with mammary hypoplasia, ectrodactyly, and other hand/foot anomalies maps to human chromosome 3q27. Am J Hum Genet 64:538–546, 1999. Van Bokhoven H, Hamel BCJ, Bamshad M, et al.: p63 gene mutations in EEC syndrome, Limb-Mammary syndrome, and isolated split hand-split foot malformation suggest a genotype–phenotype correlation. Am J Hum Genet 69:481–492, 2001. Van Maldergem L, Gillerot Y, Vamos E, et al.: Vasopressin and gonadotropin deficiency in a boy with the ectrodactyly-ectodermal dysplasia-clefting syndrome. Acta Paediatr 81:365–367, 1992. Wessagowit V, Mellerio JE, Pembroke AC, et al.: Heterozygous germline missense mutation in the p63 gene underlying EEC syndrome. Clin Exp Dermatol 25:441–443, 2000.
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Fig. 1. A stillborn with severe EEC syndrome.
Fig. 3. An infant with EEC syndrome.
Fig. 2. An infant with EEC syndrome.
Ehlers-Danlos Syndrome Ehlers-Danlos syndrome (EDS) is a heterogeneous hereditary disorder of connective tissue affecting skin, ligaments, joints, blood vessels, and internal organs. EDS is characterized by skin extensibility, joint hpermobility, and tissue fragility. The prevalence of EDS is estimated to be about 1 in 5000 births.
a. Autosomal dominant inheritance b. EDS VIIA caused by mutations in the genes for type I collagen (COL1A1) c. EDS VIIB caused by mutations in the genes for type I collagen (COL1A2), mapped at 7q22.1 6. Dermatospraxis type (EDS type VIIC) a. Autosomal recessive inheritance b. Caused by homozygous mutations in the ADAMTS2 gene (5q23) encoding procollagen I N-terminal peptidase resulting in procollagen peptidase deficiency 7. Other types a. EDS type V i. X-linked recessive inheritance ii. Described in only two families with clinical features similar to EDS II iii. Molecular basis unknown b. EDS type VIII i. A rare type ii. Autosomal dominant inheritance iii. Similar to classic type except the presence of periodontal friability c. EDS type IX i. Previously redefined as occipital horn syndrome (X-linked cutis laxa) ii. An X-linked recessive condition allelic to Menkes syndrome iii. Abnormal copper utilization secondary to defective copper transport resulting in decreased activity of lysyl oxidase, an important copperdependent enzyme required for cross-linking in collagen biosynthesis and elastin fibers d. EDS type X i. Autosomal recessive inheritance ii. Described only in a single family iii. Associated platelet aggregation due to a defect in fibronectin e. EDS type XI i. Termed familial joint hypermobility syndrome ii. Autosomal dominant inheritance iii. Previously removed from the EDS classification
GENETICS/BASIC DEFECTS 1. Classic type (includes EDS type I, gravis type and EDS type II, mitis type) a. Autosomal dominant inheritance b. Mutations in the COL5A1 gene (mapped at 9q34.2q34.3), COL5A2 (mapped at 2q31), and COL1A1 (mapped at 17q21.31-q22) genes result in EDS I c. Mutations in the COL5A1 and COL5A2 genes result in EDS II 2. Hypermobile type (EDS type III) a. Autosomal dominant inheritance in the classic form of type III EDS b. Mutations in COL3A1, typically cause EDS IV, also cause EDS III c. Mutations in the TNXB gene that encodes tenascin-X (neither a collagen nor a collagen-modifying protein) result in a variation of the classic form of the EhlersDanlos syndrome i. Autosomal recessive disorder ii. Clinical findings (joint hypermobility, soft hyperextensible skin, and easy bruising without skin scars) are compatible with Beighton’s description of Ehlers-Danlos syndrome type III or “benign familial hypermobility” 3. Vascular type (EDS type IV, arterial-ecchymotic type) a. Autosomal dominant inheritance b. COL3A1 locus: 2q31 c. Caused by mutations in the gene that encodes type III procollagen (COL3A1), which is the major component of blood vessels, viscera and the uterus. Consequently, individuals with this type often experience life-threatening vascular and gastrointestinal complications 4. Kyphoscoliosis type (EDS type VI, ocular-scoliotic type) a. Autosomal recessive inheritance b. PLOD gene mapped to 1p36.3-p36.2 c. Caused by mutations in the PLOD gene encoding lysyl hydroxylase d. Caused by deficient activity of the enzyme procollagen lysyl hydroxylase e. EDS VIA: reduced activity of lysyl hydroxylase f. EDS VIB: normal enzyme level 5. Arthrochalasis type (EDS types VIIA and VIIB, arthrochalasis multiplex congenita)
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1. Classic type (EDS I and II) a. Major diagnostic criteria: the presence of scars with joint hypermobility suggests the classical type i. Skin hyperextensibility ii. Widened atrophic scars (the hallmark “cigarettepaper” scars, a manifestation of tissue fragility) iii. Joint hypermobility iv. Positive family history b. Minor diagnostic criteria i. Smooth, velvety skin
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ii. Molluscoid pseudotumors a) Fresh lesions associated with scars b) Frequently found over pressure points such as elbows and knees iii. Subcutaneous spheroids a) Small subcutaneous spherical hard bodies b) Frequently mobile and palpable on the forearms and shins c) May be calcified and detectable radiologically iv. Complications of joint hypermobility a) Sprains b) Dislocations c) Recurrent joint subluxations in the shoulder, patella, and temporomandibular joints d) Pes planus v. Muscle hypotonia vi. Delayed gross motor development vii. Easy bruising viii. Manifestations of tissue extensibility and fragility a) Hiatal hernia b) Anal prolapse in childhood c) Cervical insufficiency ix. Surgical complications (postoperative hernias) x. Positive family history c. Other features i. Families with variable severity (mild, moderate, and severe) of the skin manifestations ii. Dyspareunia and sexual dysfunction: occasional complaints iii. Fatigue: a frequent complaint 2. Hypermobile type (EDS III) a. Major diagnostic criteria i. Skin involvement (variable hyperextensibility and/or smooth, velvety skin) ii. Generalized joint hypermobility (dominant clinical feature) b. Minor diagnostic criteria i. Recurrent joint dislocations (particularly shoulder, patella, and temporomandibular joints) ii. Chronic joint/limb pain (early onset, chronic, and possibly debilitating) iii. Positive family history c. Other features i. Early-onset, chronic, and possibly debilitating musculoskeletal pain ii. Aggravation of joint symptoms during pregnancy but a complete return to the former status is possible 3. Vascular type (EDS IV) a. Major diagnostic criteria: the presence of any 2 or more major criteria is highly indicative of diagnosis of EDS IV; biochemical testing is strongly recommended to confirm the diagnosis i. Thin translucent skin (especially noticeable on the chest or abdomen) ii. Arterial/intestinal/uterine fragility or rupture (presenting signs in 70% of adults with vascular type of EDS) a) Spontaneous arterial rupture peaks in the 3rd or 4th decade but may occur earlier, most
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commonly involves midsized arteries, and is the most common cause of sudden death. The sites of arterial rupture are the thorax and abdomen (50%), head and neck (25%), and extremities (25%) b) Intrapartum uterine rupture and pre/postpartum arterial rupture result in 15% mortality. Vaginal and perineal tears may complicate pregnancies during delivery c) Gastrointestinal ruptures occur in about 25% of patients, most common in the sigmoid colon d) Ruptures of the small bowel and stomach are rare. The rupture may present as an acute abdomen iii. Easy bruising a) Life long history b) Spontaneous or with minimal trauma iv. Characteristic facial appearance in some affected patients due to a decrease in the subcutaneous adipose tissue a) Thin lips and philtrum b) Small chin c) Thin nose d) Large eyes v. Family history of the vascular type of EDS b. Minor diagnostic criteria: the presence of one or more minor criteria contribute to the diagnosis of the vascular type of EDS, but are not sufficient to establish the diagnosis i. Acrogeria (an aged appearance of the extremities, particularly the hands) ii. Hypermobility of small joints (usually limited to the digits) iii. Tendon and muscle rupture (knee) iv. Talipes equinovarus (clubfoot) (12%) v. Early-onset varicose veins vi. Arteriovenous, carotid-cavernous sinus fistula vii. Pneumothorax/pneumohemothorax (common in childhood) viii. Chronic joint subluxations/dislocations a) TMJ b) Patella c) Ankles ix. Congenital dislocation of the hips x. Gingival recession xi. A positive family history consistent with autosomal dominant inheritance with sudden death in close relatives c. Other features i. An uncommon subtype: diagnosis often made only after a catastrophic complication or at postmortem examination ii. Acute abdominal and flank pain (diffuse or localized): a common manifestation of arterial or intestinal rupture iii. Subcutaneous venous pattern particularly apparent over the chest and abdomen iv. Hypermobility of large joints and hyperextensibility of the skin: unusual in the vascular type
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v. The teenage boys: at higher risk for arterial rupture possibly due to further weakening of the defective collagen during the prepubertal growth spurt vi. Patients undergoing surgery: prone to have arterial rupture in the postoperative period, possibly due to increased collagenase activity after surgical trauma vii. Aneurysms (if present) resulting from arterial tears with walled-in hematomas or pseudoaneurysms viii. Danger of varicose-vein surgery in unrecognized cases since the extreme fragility of all blood vessels can lead to a loss of a limb or even loss of life 4. EDS V a. An extremely rare X-linked, recessively inherited disorder b. Clinically similar to EDS II i. Joint hyperextensibility ii. Slightly hyperelastic skin iii. Skin subject to mildly abnormal scarring c. Normal life span d. Asymptomatic female carriers 5. Kyphoscoliosis type (EDS VI) a. Major diagnostic criteria: presence of 3 major criteria is suggestive of diagnosis of EDS, kyphoscoliosis type i. Generalized joint laxity (recurrent joint dislocations common in adults) ii. Severe muscle hypotonia at birth iii. Kyphoscoliosis, present at birth or within the first year of life, progressive (adults with severe kyphoscoliosis are at risk for restrictive lung disease and pneumonia) iv. Scleral fragility and rupture of the ocular globe b. Minor diagnostic criteria i. Tissue fragility, including atrophic scars ii. Easy bruising iii. Marfanoid habitus iv. Microcornea (most patients) v. Radiologically considerable osteopenia (osteoporosis) vi. Family history (e.g., affected sibs) c. Other features i. Pronounced muscular hypotonia leading to delayed gross motor development ii. Severe phenotype often results in loss of ambulation in the second or third decade iii. Scleral fragility leading to rupture of the ocular globe after minor trauma iv. Cardiovascular complications a) Vascular rupture: the major life-threatening complication b) Both aortic dilatation/dissection and rupture of medium-sized arteries may occur c) Mitral valve prolapse common v. Differential diagnosis: severe neonatal form of Marfan syndrome 6. Arthrochalasia type (EDS VIIA and VIIB) a. Major diagnostic criteria: i. Severe generalized joint hypermobility, with recurrent subluxations
ii. Congenital bilateral hip dislocation (present in all biochemically proven individuals, may lead to short stature) b. Minor diagnostic criteria: i. Skin hyperextensibility ii. Tissue fragility, including atrophic scars iii. Easy bruising iv. Muscle hypotonia v. Kyphoscoliosis (may lead to short stature) vi. Radiologically mild osteopenia c. Other features i. Short stature resulting from complication of severe kyphoscoliosis and/or hip dislocation ii. Differential diagnosis: Larsen syndrome 7. Dermatosparaxis type (EDS VIIC) a. Major diagnostic criteria: i. Severe skin fragility (wound healing not impaired, scars not atrophic) ii. Sagging, redundant skin (redundancy of the facial skin resulting in an appearance resembling cutis laxa) analogous to the animal disease dermatosparaxia b. Minor diagnostic criteria: i. Soft, doughy skin texture ii. Easy bruising (substantial) iii. Premature rupture of fetal membranes iv. Large hernias (umbilical, inguinal) c. Other features i. Blue sclera ii. Palmar creases iii. Micrognathia iv. Joint laxity without subluxations 8. EDS VIII a. Chronically inflamed, heavily pigmented, discrete, pretibial plaques (granulomatous collagen degeneration) b. Premature periodontal disease c. Premature loss of teeth d. Hypermobile joints e. Thin, soft, hyperextensible skin f. Easy bruising skin g. Skin prone to abnormal scarring h. No consistent biochemical or structural changes detectable 9. Occipital horn syndrome (EDS IX) a. Also called X-linked cutis laxa b. Skeletal dysplasia i. Occipital horns ii. Broad clavicles iii. Deformed radii, ulnae, and humeri iv. Narrow rib cage v. Undercalcified long bones vi. Coxa valga c. Unusual facial appearance d. Hypermobility of finger joints e. Limitation of extension of elbows f. Chronic diarrhea g. Genitourinary abnormalities i. Bladder diverticulae ii. Susceptible to rupture of the bladder
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h. Vascular complications i. Splenic artery aneurysm ii. Hepatic artery aneurysm i. Neuropathologic findings i. Neovascularization and extreme reduplication of the cerebral arteries with cystic medial degeneration ii. Cerebellar hypoplasia iii. Focal cortical dysplasia iv. Cerebellar heterotopias j. Abnormal copper utilization i. Depleted serum copper level ii. Depleted serum ceruloplasmin level 10. Ehlers-Danlos syndrome with fibronectin deficiency (EDS X) a. A mild, recessively inherited variant of Ehlers-Danlos syndrome b. Resembling EDS types II and III c. Thin, fragile, easily scarred skin d. Joint hypermobility e. Excessive bruising f. Abnormal platelet aggregation but correctable with normal fibronectin
DIAGNOSTIC INVESTIGATIONS 1. Classic type a. Ultrastructural studies i. Disturbed collagen fibrillogenesis ii. A characteristic “cauliflower” deformity of collagen fibrils b. Abnormal electrophoretic mobility of the proα1(V) and proα2(V) chains of collagen type V in some patients c. Demonstration of a mutation in COL5A1 and/or COL5A2 genes. Mutations in the COL1A1 are not a major cause of classic EDS. d. Echocardiogram to measure aortic root size 2. Vascular type a. Demonstration of structurally abnormal collagen type III produced by cultured skin fibroblasts b. Demonstration of a mutation in the COL3A1 gene c. Surveillance of aneurysm by MRI or CT scan without contrast material or venous subtraction angiography 3. Kyphoscoliosis type a. Demonstration of deficient activity of the enzyme procollagen lysine hydroxylase in affected individuals, diagnosed by biochemical testing of the urine and enzyme assay of cultured fibroblasts b. Demonstration of an increased ratio of deoxypyridinoline to pyridinoline crosslinks in the urine measured by HPLC, a highly sensitive and specific test c. Demonstration of mutations of the PLOD gene that encodes the enzyme procollagen lysyl hydroxylase d. Echocardiogram to measure aortic root size 4. Arthrochalasis type a. Electrophoretic demonstration of pNα1(I) or pNα2(I) chains extracted from dermal collagen or harvested from cultured skin fibroblasts b. Mutation analysis (complete or partial exon 6 skipping in cDNAs of COL1A1 or COL1A2 respectively) 5. Dermatospraxis type: electrophoretic demonstration of pNα1(I) or pNα2(I) chains from collagen type I extract-
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ed from dermis in the presence of protease inhibitors, or obtained from cultured skin fibroblasts
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal recessive: 25% risk of having an affected sib ii. Autosomal dominant: risk low (1–5%) unless the parent is affected or having somatic mosaicism or germline mosaicism iii. X-linked recessive: 50% risk of having an affected brother if the mother is a carrier b. Patient’s offspring i. Autosomal recessive: risk not increased unless the spouse is a carrier ii. Autosomal dominant: 50% risk of having an affected offspring iii. X-linked recessive: none of the sons will be affected; all daughters will be carriers 2. Prenatal diagnosis a. Possible by demonstrating the disease causing mutation in the fetal cells from CVS or amniocentesis or by linkage analysis for families in which linkage has been established b. Possible by biochemical assay on cultured fetal cells for demonstrating biochemical defect in the specific type of collagen 3. Management a. General approach: conservative and preventive management of most skin and joint problems i. Avoid tension when sutures are applied ii. Leave removable sutures in place for twice the usual time iii. Physical therapy to strengthen the muscles that need to provide support for the loose ligaments b. Classic type i. Medical intervention limited to symptomatic therapy and prophylactic measures ii. Wear protection pads or stocking iii. Avoid contact sports iv. Physiotherapy for children with hypotonia and delayed motor development v. Antimicrobial prophylaxis for patients with mitral valve prolapse vi. Ascorbic acid helps avoid easy bruising but does not change the basic clinical picture c. Kyphoscoliotic type i. Orthopedic management of kyphoscoliosis ii. Physical therapy for older children, adolescents, and adults iii. Antimicrobial prophylaxis for patients with mitral valve prolapse iv. Aggressive control of blood pressure v. Improve with large doses of ascorbic acid because vitamin C is a cofactor for the enzyme that is deficient a) Improve urinary excretion of hydroxylysine b) Improve muscle strength and wound healing
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d. Vascular type i. Prompt recognition of the major complications ii. Difficult to repair ruptured arteries because of the pronounced vascular fragility iii. Avoid elective surgery iv. Rupture of the bowel, a surgical emergency v. Avoid pregnancy because the risk of vascular rupture is especially high during pregnancy vi. Minimize risk of trauma by avoiding contact sport, heavy lifting, and weight training vii. Treat high blood pressure aggressively viii. Patient education a) Possible complications b) Need for close monitoring c) Attention to sudden unexplained pain
REFERENCES Beighton P: The Ehlers-Danlos syndrome. In: Beighton P (ed): McKusick’s Heritable Disorders of Connective Tissue. St Louis: Mosby, 1992:189–251. Beighton P, Curtis D: X-linked Ehlers-Danlos syndrome type V: The next generation. Clin Genet 27:472–478, 1985. Beighton P, De Paepe A, Danks D, et al.: International nosology of heritable disorders of connective tissue, Berlin, 1986, 29:581, 594, 1988. Beighton P, De Paepe A, Steinmann B, et al.: Ehlers-Danlos syndromes: Revised nosology, Villefranche, 1997. Am J Med Genet 77:31–37, 1998. Burrows NP: The molecular genetics of the Ehlers-Danlos syndrome. Clin Exp Dermatol 24:99–106, 1999. Byers PH: Ehlers-Danlos syndrome type IV: a genetic disorder in many guises. J Invest Dermatol 105:311–313, 1995. Byers PH: An exception to the rule. N Engl J Med 345:1203–1204, 2001. Byers PH: Disorders of collagen biosynthesis and structure. In: Scriver CR, Beaudet al., Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. 8th ed. Vol 4. New York: McGraw-Hill, 2001:5241– 5285. Byers PH, Duvic M, Atkinson M, et al.: Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen. Am J Med Genet 72:94–105, 1997. De Paepe A, Nuytinck L, Hausser I, et al.: Mutations in the COL5A1 gene are causal in the Ehlers-Danlos syndromes I and II. Am J Hum Genet 60:547–554, 1997. Giunta C, Superti-Furga A, Spranger S, et al.: Ehlers-Danlos syndrome type VII: clinical features and molecular defects. J Bone Joint Surg Am 81:225–238, 1999. Mao JR, Bristow J: The Ehlers-Danlos syndrome: on beyond collagens. J Clin Invest 107:1063–1069, 2001.
McKusick VA: Heritable Disorders of Connective Tissue. Saint Louis, CV Mosby Co., 1972. Mentzel HJ, Seidel J, Vogt S, et al.: Vascular complications (splenic and hepatic artery aneurysms) in the occipital horn syndrome: report of a patient and review of the literature. Pediatr Radiol 29:19–22, 1999. Michalickova K, Susic M, Willing MC, et al.: Mutations of the alpha2(V) chain of type V collagen impair matrix assembly and produce Ehlers-Danlos syndrome type I. Hum Mol Genet 7:249–255, 1998. Myllyharju J, Kivirikko KI: Collagens and collagen-related disease. Ann Med 33:7–21, 2001. Nuytinck L, Freund M, Lagae L, et al. Classical Ehlers-Danlos syndrome caused by a mutation in type I collagen. Am J Hum Genet 66:1398–1402, 2000. Pepin M, Byers PH: Ehlers-Danlos syndrome, vascular type. Gene Reviews, 2002. http://www.genetests.org Pope FM, Burrow NP: Ehlers-Danlos syndrome has varied molecular mechanisms. J Med Genet 34:400–410, 1997. Pyeritz RE: Ehlers-Danlos syndrome. N Engl J Med 342:730–732, 2000. Schalkwijk J, Zweers MC, Steijlen PM, et al.: A recessive form of the EhlersDanlos syndrome caused by tenascin-X deficiency. N Engl J Med 345:1167–1175, 2001. Smith LT, Wertelecki W, Milstone LM, et al.: Human Dermatosparaxis: a form of Ehlers-Danlos syndrome that results from failure to remove the aminoterminal propeptide of type I procollagen. Am J Hum Genet 51:235–244, 1992. Sorokin Y, Johnson MP, Rogowski N, et al.: Obstetric and gynecologic dysfunction in the Ehlers-Danlos Syndrome. J Reprod Med 39:281–284, 1994. Steinmann B, Royce PM, Superti-Furga A: The Ehlers-Danlos syndrome. In Royce PM, Steinmkann B (eds): Connective Tissue and Its Heritable Disorders. Molecular, Genetic, and Medical Aspects. New York, WileyLiss, 1993:351–408. Tiller GE, Cassidy SB, Wensel C, et al.: Aortic root dilatation in Ehlers-Danlos syndrome types I, II and III. A report of five cases. Clin Genet 53:460–465, 1998. Wenstrup RJ: Ehlers-Danlos syndrome, kyphoscoliotic form. Gene Reviews, 2003. http://www.genetests.org Wenstrup RJ, Paepe AD: Ehlers-Danlos syndrome, Classic type. Gene Reviews, 2003. http://www.genetests.org Wenstrup RJ, Florer JB, Willing MC, et al.: COL5A1 Haploinsufficiency is a common molecular mechanism underlying the classical form of EDS. Am J Hum Genet 66:1766–1776, 2000. Wenstrup RJ, Meyer RA, Lyle JS, et al.: Prevalence of aortic root dilatation in the Ehlers-Danlos syndrome. Genet Med 4:112–117, 2002. Yeowell HN, Pinnell Skelet Radiol: The Ehlers-Danlos syndromes. Semin Dermatol 12:229–240, 1993. Yeowell HN, Walker LC: Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of Ehlers-Danlos syndrome type VI. Mol Genet Metab 71:212–224, 2000.
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Fig. 1. Hyperextensible joints enable a girl and two sisters with EDS to exhibit difficult hyperextensible joint maneuvers.
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Fig. 2. Familial Ehlers-Danlos syndrome in the son (A–D), the daughter (E), and the father (F–H) exhibiting hyperextensible joints and hyperelastic skin. The son also has fascia weakness presenting as a hernia on the lower chin.
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Fig. 4. Typical EDS showing easy bruises and scars of the skin
Fig. 3. A male and a female with EDS showing hyperextensible joints and hyperelastic skin.
Ellis-van Creveld Syndrome In 1940, Ellis and van Creveld described a syndrome, characterized by ectodermal dysplasia, polydactyly, chondrodysplasia, and congenital heart disease. Ellis-van Creveld syndrome, also called chondroectodermal dysplasia, is relatively common in inbred communities, such as the Amish of Lancaster County where it occurs in 1/5000 births compared to 1/60,000 births in the general population.
e) Enamel hypoplasia commonly resulting in abnormally shaped teeth with frequent malocclusion iii. Occasional sparse hair d. Cardiac anomalies (50–60%) i. A single atrium ii. AV canal iii. Ventricular septal defect iv. Atrial septal defect v. Patent ductus arteriosus vi. The major cause of shortened life expectancy 2. Other clinical findings a. Other oral lesions i. A fusion of the anterior portion of the upper lip to the maxillary gingival margin a) Resulting in absence of mucobuccal fold b) Causing the upper lip to present a slight Vnotch in the middle ii. Multiple labiogingival frenula frequent iii. Lower alveolar ridge often serrated b. Musculoskeletal anomalies i. Low-set shoulders ii. A narrow thorax iii. Frequently lead to respiratory difficulties iv. Knock knees (genu valgum) v. Lumbar lordosis vi. Broad hands and feet vii. Sausage-shaped fingers c. Genitourinary anomalies (22%) i. Hypospadias ii. Epispadias iii. Hypoplastic penis iv. Cryptorchidism v. Vulvar atresia vi. Focal renal tubular dilation in medullary region vii. Nephrocalcinosis viii. Renal agenesis ix. Megaureters d. CNS i. Normal intelligence in most patients ii. Occasional CNS anomalies or mental retardation
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal recessive inheritance b. Parental consanguinity in 30% of cases 2. Basic defect a. Generalized dysplasia of endochondral ossification i. Delayed in the primary centers ii. Premature in the secondary centers iii. Leads to short stature with progressive distal shortening of the extremities b. Caused by mutations in a novel gene, EVC, which is mapped to chromosome 4p16.1 c. Caused by mutations in a second gene, called EVC2, that gives rise to the same phenotype of the syndrome d. May be allelic to Weyers acrodental dysostosis
CLINICAL FEATURES 1. A clinical tetrad a. Chondrodystrophy i. The most common feature affecting the tubular bones ii. Disproportionate dwarfism iii. Progressive distal limb shortening a) Symmetrical b) Affects the forearms and lower legs b. Polydactyly i. A constant finding a) Bilateral b) Postaxial ii. Polydactyly of the hands observed in most cases iii. Polydactyly of the feet observed only in 10% of cases c. Ectodermal dysplasia (up to 93%) i. Nails a) Hypoplastic b) Dystrophic c) Friable d) Completely absent in some cases ii. Teeth a) Neonatal teeth b) Partial anodontia c) Small teeth d) Delayed eruption
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1. Radiography a. Essential features i. Postaxial polydactyly ii. Progressively distal shortening of segments (acromesomelia with relative shortening of the distal and middle segment of the limbs and phalanges) iii. Generalized thickness and coarseness of bones
ELLIS-VAN CREVELD SYNDROME
b. Other features depending on disease severity and age i. Curvature of the humerus ii. Enlargement of distal ends of the radii and ulnae iii. Hypoplastic distal phalanges iv. Short, broad middle phalanges v. Fusion of metacarpals vi. Fusion of the hamate and capitate bones of the wrists vii. Supernumerary carpal bone centers viii. Clinodactyly ix. Synostosis x. Wedge-shaped tibial epiphyses xi. Genu valgum with hypoplasia of the upper lateral tibia xii. Fibula disproportionately smaller than the tibia xiii. Pelvic dysplasia with low iliac wings and spurlike downward projections at the medial and lateral aspects of the acetabula xiv. Narrow thorax with short ribs 2. Echocardiography for cardiac malformations 3. Histopathology: disorganization of chondrocytes in the physeal growth zone of the long bones and vertebrae in the prenatal period and retardation of physeal growth zones in the childhood 4. Mutation analysis
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased unless the spouse is a carrier 2. Prenatal diagnosis a. Fetoscopy b. Ultrasonography i. A narrow chest ii. Postaxial polydactyly iii. Short limbs, especially middle and distal segments iv. A single atrium c. Molecular genetic testing i. Using linked microsatellite markers flanking the EVC locus ii. Mutation analysis of EVC gene 3. Management a. Dental cares i. Childhood a) To prevent caries by dietary counseling, plaque control, and oral hygiene instruction b) Crown or composite build-ups for microdonts c) Partial dentures to maintain space and improve mastication, esthetics, and speech because of congenitally missing teeth d) Orthodontic treatment ii. Adulthood: require implants and prosthetic rehabilitation to replace congenitally missing teeth b. Cardiac surgery to correct cardiac anomalies c. Urologic management for genitourinary anomalies
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d. Orthopedic cares i. Polydactyly excision ii. Surgery for genu valgum
REFERENCES Al-Khenaizan S, Al-Sannaa N, Teebi AS: What syndrome is this? Chondroectodermal dysplasia—the Ellis-van Creveld syndrome. Pediatr Dermatol 18:68–70, 2001. Arya L, Mendiratta V, Sharma RC, et al.: Ellis-van Creveld Syndrome: a report of two cases. Pediatr Dermatol 18:485–489, 2001. Bui TH, Marsk L, Eklof O, et al.: Prenatal diagnosis of chondroectodermal dysplasia with fetoscopy. Prenat Diagn 4:155–159, 1984. Caffey J: Chondroectodermal dysplasia (Ellis-Van Creveld disease). Am J Roentgenol Radium Ther Nucl Med 68:875–886, 1952. Cahuana A, Palma C, Gonzales W, et al.: Oral manifestations in Ellis-van Creveld syndrome: report of five cases. Pediatr Dent 26:277–282, 2004. Da Silva EO, Janovitz D, de Albuquerque SC: Ellis-van Creveld syndrome: report of 15 cases in an inbred kindred. J Med Genet 17:349–356, 1980. Douglas WF, Schonholtz GJ, Geppert LJ: Chondroectodermal dysplasia (Ellisvan Creveld syndrome); report of two cases in sibship and review of literature. AMA J Dis Child 97:473–478, 1959. Dugoff L, Thieme G, Hobbins JC: First trimester prenatal diagnosis of chondroectodermal dysplasia (Ellis-van Creveld syndrome) with ultrasound. Ultrasound Obstet Gynecol 17:86–88, 2001. Ellis RWB, van Creveld S: A syndrome characterized by ectodermal dysplasia, polydactyly, chondrodysplasia and congenital morbus cordis: report of three cases. Arch Dis Child 15:65–84, 1940. Galdzicka M, Patnala S, Hirshman MG, et al.: A new gene, EVC2, is mutated in Ellis-van Creveld syndrome. Mol Genet Metab 77:291–295, 2002. George E, DeSilva S, Lieber E, et al.: Ellis van Creveld syndrome (chondroectodermal dysplasia, MIM 22550) in three siblings from a non-consanguineous mating. J Perinat Med 28:425–427, 2000. Giknis FL: Single atrium and the Ellis-van Creveld syndrome. J Pediatr 62:558–564, 1963. Guschmann M, Horn D, Gasiorek-Wiens A, et al.: Ellis-van Creveld syndrome: examination at 15 weeks’ gestation. Prenat Diagn 19:879–883, 1999. Hattab FN, Yassin OM, Sasa IS: Oral manifestations of Ellis-van Creveld syndrome: report of two siblings with unusual dental anomalies. J Clin Pediatr Dent 22:159–165, 1998. Hill RD: Two cases of Ellis-van Creveld syndrome in a small island population. J Med Genet 14:33–36, 1977. Horigome H, Hamada H, Sohda S, et al.: Prenatal ultrasonic diagnosis of a case of Ellis-van Creveld syndrome with a single atrium. Pediatr Radiol 27:942–944, 1997. Hunter ML, Roberts GJ: Oral and dental anomalies in Ellis van Creveld syndrome (chondroectodermal dysplasia): report of a case. Int J Paediatr Dent 8:153–157, 1998. Husson GS, Parkman P: Chondroectodermal dysplasia (Ellis-Van Creveld syndrome) with a complex cardiac malformation. Pediatrics 28:285–292, 1961. Kushnick T, Paya K, Mamunes P: Chondroectodermal dysplasia: Ellis-van Creveld syndrome. Am J Dis Child 103:77–80, 1962. McKusick VA: Ellis-van Creveld syndrome and the Amish. Nat Genet 24:203–204, 2000. McKusick VA, Egeland JA, Eldridge R, et al.: Dwarfism in the Amish I. The Ellis-Van Creveld Syndrome. Bull Johns Hopkins Hosp 115:306–336, 1964. Laufer-Cahana A: Ellis-van Creveld syndrome. Emedicine, 2002. http://www. emedicine.com Polymeropoulos MH, Ide SE, Wright M, et al.: The gene for the Ellis-van Creveld syndrome is located on chromosome 4p16. Genomics 35:1–5, 1996. Qureshi F, Jacques SM, Evans MI, et al.: Skeletal histopathology in fetuses with chondroectodermal dysplasia (Ellis-van Creveld syndrome). Am J Med Genet 45:471–476, 1993. Reddy DV, Madenlioglu M: Chondroectodermal dysplasia (Ellis-van Creveld syndrome). Report of two cases from Saudi Arabia. Clin Pediatr (Phila) 6:51–56, 1967.
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Ruiz-Perez VL, Ide SE, Strom TM, et al.: Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet 24:283–286, 2000. Sajeev CG, Roy TN, Venugopal K: Images in cardiology: common atrium in a child with Ellis-Van Creveld syndrome. Heart 88:142, 2002. Sergi C, Voigtlander T, Zoubaa S, et al.: Ellis-van creveld syndrome: a generalized dysplasia of enchondral ossification. Pediatr Radiol 31:289–293, 2001. Simon MW: Radiological case of the month. Ellis-van Creveld syndrome (chondroectodermal dysplasia). Am J Dis Child 140:665–666, 1986. Susami T, Kuroda T, Yoshimasu H, et al.: Ellis-van Creveld syndrome: craniofacial morphology and multidisciplinary treatment. Cleft Palate Craniofac J 36:345–352, 1999.
Tongsong T ,Chanprapaph P: Prenatal sonographic diagnosis of Ellis-van Creveld syndrome. J Clin Ultrasound 28:38–41, 2000. Torrente I, Mangino M, De Luca A, et al.: First-trimester prenatal diagnosis of Ellis-van Creveld syndrome using linked microsatellite markers. Prenat Diagn 18:504–506, 1998. Tubbs FE, Crevasse L, Green JR, Jr.: Congenital heart disease in an adult with the Ellis-van Creveld syndrome. Ann Intern Med 57:829–834, 1962. Walls WL, Altman DH, Winslow OP: Chondroectodermal dysplasia (Ellis van Creveld syndrome); report of a case and review of the literature. AMA J Dis Child 98:242–248, 1959.
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Fig. 2. Radiograph of a fetus with Ellis-van Creveld syndrome showing short ribs and vertically shortened ilia. The vertebral bodies are unremarkable. Photomicrograph of femoral physeal growth zone shows disorganization of chondrocytes. The physeal growth zone of vertebrae showed better columnization. Fig. 1. A neonate with small chest and short extremities (Perspect Pediatr Pathol 3:1–40, 1976). The fingernails are small and deformed. The baby had 6 fingers on each hand. Radiograph of the chest shows short ribs but the vertebral bodies are normal.
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Fig. 3. A 10-year-old Lebanese girl, a product of a consanguineous parents, with Ellis-van Creveld syndrome showing oligodontia and malformed teeth, severe nail hypoplasia of the hands and feet, and broad hands with bilateral post-axial polydactyly. Radiographs show polydactyly, fusion of metacarpals and carpal centers, cone epiphyses of the middle and distal phalanges, and genu valgum.
Enchondromatosis (Maffucci Syndrome; Ollier Syndrome) Enchondromas are benign cartilaginous growth in the intramedullary region of the bones. When two or more bones are affected with enchondromas, the condition is called multiple enchondromatosis. Maffucci first described the syndrome of multiple enchondromas and subcutaneous hemangiomas in 1881, eighteen years before Ollier described multiple enchondromatosis.
b.
GENETICS/BASIC DEFECTS 1. Inheritance a. Maffucci syndrome i. Not hereditary ii. A congenital disorder b. Ollier syndrome i. Not hereditary ii. A congenital disorder c. Obvious inheritance of enchondromatosis: unusual d. No candidate loci identified e. Ollier syndrome and Maffucci syndrome: possibly a spectrum of the same disease process. The latter condition is complicated by vascular anomalies and hemangiomas 2. Basic defect and pathogenesis a. Enchondromas believed to be a part of a generalized mesodermal dysplasia b. Appearance of enchondromata close to the epiphysis can severely affect the progressive development of a bone, resulting in distortion in the shape and length of the bone c. Osteochondromatosis possibly results from abnormal regulation of proliferation and terminal differentiation of chondrocytes in the adjoining growth plate, since enchondromas are usually present in close proximity to, or in continuity with, growth-plate cartilage i. Parathyroid hormone related protein (PTHRP) delays the hypertrophic differentiation of proliferating chondrocytes ii. Indian hedgehog (IHH) promotes chondrocytes proliferation d. Identification of a mutant PTH/PTHRP type I receptor (PTHR1) in human enchondromatosis that signals abnormally in vitro and causes enchondroma-like lesions in transgenic mice i. The mutant receptor constitutively activates Hedgehog signaling ii. Excessive Hedgehog signaling is sufficient to cause formation of enchondroma-like lesions
c.
d.
CLINICAL FEATURES e. f.
1. Maffucci syndrome a. Age of onset
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i. Bony or soft tissue abnormalities at birth in 27% of cases ii. Average age of onset: 4 years (ranging from birth to 30 years of age) Skeletal lesions: multiple enchondromas i. Can occur anywhere in the body ii. Most commonly in the hands, followed by tibia/fibula, foot, femur, humerus, radius/ulna, ribs, pelvis, scapula, and head iii. Common long bone involvement iv. Kyphoscoliosis caused by direct involvement of the spine v. Progressive skeletal deformities a) Enlarged fingers b) Bowed legs c) Asymmetric limb shortening d) Pathological fractures vi. High incidence (23%) of malignancies, especially chondrosarcomas (15%) which lead to greater tissue destruction vii. Vascular malignancies may occur occasionally Vascular lesions: subcutaneous and sometimes visceral hemangiomas i. Occur anywhere in the body ii. Most commonly in the hands, followed by foot, arm, leg, trunk, and head/neck iii. Hemangiomas also reported in the leptomeninges, eyes, pharynx, tongue, trachea, and intestines iv. Appear as blue subcutaneous nodules that sometimes can be emptied by pressure or by elevating the lesions above the level of the heart v. Unilateral or bilateral lesions vi. Phlebitis often results from thrombi forming within the hemangiomatous vessels vii. Characteristic calcified thrombi viii. Histologic types of hemangiomas a) Venous: most often b) Capillary c) Mixed venous/capillary type ix. Lymphangioma, a rare aspect of the mesodermal dysplasia in Maffucci syndrome x. Spindle cell hamangiomatosis as a component of Maffucci syndrome Neoplastic changes i. Overall malignancy rate: 37% ii. Osteosarcoma (30%): average age of onset is 40 years (ranging from 13 to 69 years of age) iii. Astrocytoma/brain tumor iv. Other neoplasms Normal intelligence Short stature
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g. Minimally affected individuals i. No major functional impairment ii. Unrestricted employment iii. Moderate cosmetic deformity only iv. Reconstructive or corrective surgery, limited to one or two major procedures with acceptable final results v. Ablative surgery, restricted to amputation of a finger or a toe h. Moderately affected individuals i. Significant functional impairment ii. Self supporting and able to work most of the time iii. Ambulatory iv. Reconstructive surgery or amputation and prosthesis helpful v. Ablative surgery restricted to potentially functional (transfemoral or transhumeral) amputation i. Severely affected individuals i. Severe functional impairment ii. Inability to work iii. Chronic invalidism iv. No surgical rehabilitation possible v. Forequarter or hindquarter amputation required 2. Ollier syndrome a. Non-hereditary cartilage dysplasia of bone i. Consisting of multiple, asymmetrically distributed, intraosseous cartilaginous foci and subperiosteal deposition of cartilage, either exclusively or predominantly involving one side of the body ii. Multiple enchondromas as described in Maffucci syndrome iii. Enchondromata in infancy and early childhood a) Quite innocuous b) Appearing as small radiolucent defects iv. Characteristic lesions develop as the skeletal growth progresses: a) Localized asymmetric impairment of growth b) Asymmetric shortening and bowing of extremity parts (especially forearm and/or lower leg) v. No increase in size of the lesions after the cessation of the normal growth b. Taut-elastic skin over hyaline cartilage distensions c. Marked asymmetry of swellings with local growth deficiency d. Firm, indolent, rounded distensions continuous with bone on one or more fingers or toes e. Kyphoscoliosis f. Joint impairment g. Spontaneous fractures in affected area h. Rare malignant (chondrosarcoma) transformation 3. Differential diagnosis a. Other types of enchondromatosis i. Metachondromatosis a) An autosomal dominant disorder b) Development of chondromas and osteochondromas involving the bones of the hands and feet c) Painless swelling of the hands and feet d) Normal intelligence
e) Short stature f) Radiographic features intermediate between exostosis and enchondromatosis ii. Spondyloenchondromatosis: characterized by platyspondyly iii. Spondyloenchondromatosis with basal ganglia calcification iv. Dysspondyloenchondromatosis: characterized by malsegmentation of the spine v. Genochondromatosis I a) Enchondromatosis with celery type of metaphyseal lesions b) Characteristic thickening of the clavicles c) Regressive without any complications vi. Genochondromatosis II a) Enchondromatosis with celery type of metaphyseal lesions b) Moderately severe hand involvement with long dense streaks and more irregular radiolucent channels c) Regress without any complications b. Dysplasia epiphysealis hemimelica (Trevor disease) i. Abnormal cartilage growth and maturation ii. Exostosis of epiphyseal growth centers and their equivalents that grow solely by enchondral ossification with no membranous ossification in the lesions a) Apophyses b) Carpal bones c) Tarsal bones d) Sesamoids including the patella
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Enchondromas i. Lesions usually arise within the medullary cavity, replacing the normal cancellous bone with the abnormal cartilage ii. Lytic lesions initially contain calcifications in a punctate pattern iii. Advanced lesions assume a ground glass appearance iv. Predilection for the metaphysis or diaphysis v. Bone often expands but with intact cortex vi. Often with a scalloped border vii. Pathologic fractures not uncommon viii. Multiple asymmetric enchondromas of long and flat bones (characteristic ovoid or pyramid-shaped, linear translucent defects in metaphyses) b. Massive metaphyseal enlargement in any bones, particularly metacarpals and fingers c. Enchondromatosis with destruction and calcification d. Streaks of unossified cartilage in the metaphyses, sometimes extending into the diaphyses e. Madelung deformity f. Shortening of extremities g. Spinal deformity h. Occasional malignant degeneration
ENCHONDROMATOSIS
2. Bone scan a. Exhibiting intense and increased uptake b. To locate polyostotic lesions 3. CT scan a. To delineate the extent of bone involvement b. A good diagnostic tool to demonstrate the high attenuation coefficient (classic in bone affected by fibrous dysplasia) 4. MRI a. To delineate the extent of bone involvement b. Enchondromas i. Low signal intensity on T1-weighted images ii. High signal intensity on T2-weighted images iii. High signal intensity on gradient recalled echo images similar to articular cartilage 5. Histology a. Lobulated foci of disorganized cartilage in the metaphyses, usually after 2nd year of life, up to sexual maturity. There are focal areas of degeneration and calcification b. No new foci after adolescence c. Hyaline cartilage foci replaced by bony substance
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: not increased unless in rare familial cases 2. Prenatal diagnosis: bone lesions unlikely to manifest in the prenatal period 3. Management a. Relief of symptoms b. Early detection of malignancies i. Suspect malignancy change if skeletal or softtissue lesions enlarge or become painful without antecedent trauma ii. Biopsy c. Operative procedures i. Corrective osteotomy ii. Epiphysiodesis iii. Hemiepiphysiodesis iv. Physeal stapling v. Lengthening of an arm or leg vi. Curettage and packing with bone graft material vii. Sclerotherapy, irradiation, and surgery for the vascular lesions
REFERENCES Allen B: Maffucci’s syndrome. Br J Dermatol 98 (suppl 16):31–33, 1978. Anderson IF: Maffucci’s syndrome: report of a case with a review of the literature. S. Afr. Med J 39:1066–1070, 1965. Ben-Itzhak I, Deolf FA, Versfeld GA, et al.: The Maffucci syndrome. J Pediatr Orthop 8:345–348, 1988. Chen VT, Harrison D: Maffucci’s syndrome. Hand 10:292–298, 1978. Fernández-Aguilar S, Fayt I, Noel JC: Spindle cell vulvar hemangiomatosis associated with enchondromatosis: a rare variant of Maffucci’s syndrome. Int J Gynecol Pathol 23:68–70, 2004. Flach HZ, Ginai AZ, Oosterhuis JW: Maffucci syndrome: radiologic and pathologic findings. RadioGraphics 21:1311–1316, 2001. Freisinger P, Finidori G, Maroteaux P: Dysspondylenchondromatosis. Am J Med Genet 45:460–464, 1993. Hopyan S, Gokgoz N, Poon R, et al.: A mutant PTH/PTHrP type I receptor in enchondromatosis. Nature Genet. 30:306–310, 2002.
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Goto T, Motoi T, Komiya K, et al.: Chondrosarcoma of the hand secondary to multiple enchondromatosis; report of two cases. Arch Orthop Trauma Surg 123:42–47, 2003. Gutman E, McCutcheon S, Garber P: Enchondromatosis with hemangiomas (Maffucci’s syndrome). South Med J 71:466–467, 1978. Johnson TE, Nasr AM, Nalbandian RM, et al.: Enchondromatosis and hemangioma (Maffucci’s syndrome) with orbital involvement. Am J Ophthalmol 110:153–159, 1990. Kaibara N, et al.: Generalized enchondromatosis with unusual complications of soft tissue calcifications and hemangiomas. Follow-up for over a twelveyear period. Skeletal Radiol 8:43–46, 1982. Kaplan RP, et al.: Maffucci’s syndrome: two case reports with a literature review. J Am Acad Dermatol 29:894–899, 1994. Kaufman HJ: Enchondromatosis. Semin Roentgen 8:176–177, 1973. Kozlowski K, Jarret J: Genochondromatosis II. Pediatr Radiol 22:593–595, 1992. Kozlowski K, Brostrom K, Kennedy J, et al.: Dysspondyloenchondromatosis in the newborn. Pediatr Radiol 24:311–315, 1994. Kozlowski KS, Masel J: Distinctive enchondromatosis with spine abnormality, regressive lesions, short stature, and coxa vara: importance of long-term follow-up. Am J Med Genet 107:227–232, 2002. Langenskiöld A: The stages of development of the cartilaginous foci in dyschondroplasia (Ollier’s disease). Acta Orthop Scand 38:174–180, 1967. Le Merrer M, Fressinger P, Maroteaux P: Genochondromatosis. J Med Genet 28:458–489, 1991. Lewis RJ, Ketcham AS: Maffucci’s syndrome. Case report and review of the literature. J Bone Joint Surg 55-A:1465–1479, 1973. Liu J, Hudkins PG, Swee RG, et al.: Bone sarcomas associated with Ollier’s disease. Cancer 59:1376–1385, 1987. Loewinger RJ, Lichtenstein JR, Dodson WE, et al.: Maffucci’s syndrome: a mesenchymal dysplasia and multiple tumour syndrome. Br J Dermatol 96:317–322, 1977. Lowell SH, Mathog RH: Head and neck manifestations of Maffucci’s syndrome. Arch Otolaryngol 105:427–430, 1979. Luedtke LM, Flynn JM, Ganley TJ, et al.: The orthopedists’ perspective. Bone tumors, scoliosis, and trauma. Radiol Clin North Am 39(4): July, 2001. Manizer F, et al.: The variable manifestations of multiple enchondromatosis. Pediatr Radiol 99:377–388, 1971. Margolis J: Ollier’s disease. Arch Intern Med 103:279, 1959. Maroteaux P: La metachondromatose. Z Kinderheilkd 109:246–261, 1971. Mellon CD, Carter JE, Owen DB: Ollier’s disease and Maffucci syndrome distinct entities or a continuum. Case report: enchondromatosis complicated y an intracranial glioma. J Neurol 235:376–378, 1988. Menger H, Kruse K, Spranger J: Spondyloenchondrodysplasia. J Med Genet 26:93–99, 1989. Miller SL, Hoffer FA: Malignant and benign bone tumors. Radiol Clin North Am 39(4): July 2001. Montagne A Jr, Ubilluz H: Maffucci’s syndrome. South Med J 76:264–266, 1983. Oestreich AE, Mitchell CS, Akeson JW: Both Trevor and Ollier disease limited to one upper extremity. Skeletal Radiol 31:230–234, 2002. Phelan EMD, Carty HML, Kalos S: Generalized enchondromatosis associated with haemangiomas, soft-tissue calcifications and hymihypertrophy. Br J Radiol 59:69–74, 1986. Saul RA: Hereditary enchondromatosis. Proc Greenwood Genet Center 6:48–50, 1987. Schorr S. Legum C, Ochshorn M: Spondyloenchondrodysplasia. Radiology 118:133–139, 1976. Schwartz HS, Zimmerman NB, Simon MA, et al.: The malignant potential of enchondromatosis. J Bone Joint Surg 69-A: 269–274, 1987. Shapiro F: Ollier’s disease. An assessment of angular deformity, shortening and pathological fracture in 21 patients. J Bone Joint Surg 64-A:95–108, 1982. Slagsvald JE, Bergsholm PER, Larsen JL: Fibromuscular dysplasia of intracranial arteries in a patient with enchondromas (Ollier disease). Neurology 27:1168–1171, 1977. Spranger J, Kemperdieck H, Bakowski H, et al.: Two peculiar types of enchondromatosis. Pediatr Radiol 7:215–219, 1978. Sun T-C, et al.: Chondrosarcoma in Maffucci’s syndrome. J Bone Joint Surg 67-A:1214–1219, 1985. Suringa DWR, Ackerman AB: Cutaneous lymphangiomas with dyschondroplasia (Maffucci’s syndrome). Arch Dermatol 101:472–474, 1970. Tamimi HK, Bolen JW: Enchondromatosis (Ollier’s disease) and ovarian juvenile granulosa cell tumor. Cancer 53:1605–1608, 1984. Unger EC, Kessler HB, Kowalyshyn MJ, et al.: MR imaging of Maffucci’s syndrome. Am J Roentgenol Am J Roentgenol 150:351–353, 1988.
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Fig. 1. A 4-year-old boy with Ollier syndrome showing short stature, scoliosis, and severe limb deformities. The right limbs were affected by larger lesions with more prominent limb shortening. Marked swellings were evident on the right wrist and fingers. The left hand showed Madelung deformity. The radiographs showed massive metaphyseal enchondromatous lesions in the right upper and lower extremities. Streaks of radiolucency due to the abnormal cartilage extended into the diaphyses. The left femur, tibia, and fibula also showed lytic lesions.
Epidermolysis Bullosa Epidermolysis bullosa (EB) is a rare group of inherited disorders of skin fragility, characterized by a reduced resistance of the skin and mucous membranes to trauma, manifesting as blistering or erosion of the skin and the epithelial lining of other organs. Epidermolysis bullosa can be classified into 3 major types, namely the simplex, the junctional, and the dystrophic types, based on the level of the epidermis or basement membrane zone in which blister is formed.
c. NonHerlitz type i. Caused by mutation in laminin 5 and type XVII collagen genes ii. Generally associated with a good prognosis d. Junctional epidermolysis associated with pyloric atresia i. Caused by mutations in a hemidesmosomal component, α6β4 integrin ii. Currently also classified as a subtype of hemidesmosomal epidermolysis bullosa 3. Dystrophic epidermolysis bullosa a. Inheritance: either autosomal dominant or autosomal recessive b. Caused by mutations in type VII collagen gene. COL7A1 gene mutations have been identified in most cases. Type VII collagen is a major component of the anchoring fibrils that tether the basement membrane structure and overlying epidermis to its dermal foundation c. Severity of the phenotype dictated by missense mutation that alters a glycine residue in dominant dystrophic epidermolysis bullosa versus nonsense or frameshift mutations in recessive dystrophic epidermolysis bullosa
GENETICS/BASIC DEFECTS 1. Epidermolysis bullosa simplex (EBS) a. Autosomal dominant simplex type EB (most common type) i. Caused by mutations in the cytoskeleton structural proteins, keratin 5 (KRT5) and keratin 14 (KRT14), leading to disruption of basal cells and the formation of bullae in the basal and parabasal cell zone ii. Keratins 5 and 14: expressed exclusively in basal cell layer of epidermis keratinocytes and essential for the maintenance of normal structural integrity iii. Disease severity correlates with the location within the keratin gene mutation a) Mutations in highly conserved genetic sequences leading to severe disease b) Mutations in less critical keratin gene regions manifesting as milder, more localized symptoms: Koebner variant (generalized blistering but no mucosal or nail changes) and Weber-Cockayne form (blistering is confined primarily to the easily traumatized palms and soles) b. Autosomal recessive simplex types (rare type) i. EB with muscular dystrophy due to abnormal plectin, a protein involved in hemidesmosome formation (currently also classified as a subtype of hemidesmosomal epidermolysis bullosa) ii. EB without muscular dystrophy in patients homozygous for KRT14 gene abnormalities iii. Skin fragility syndrome (a form of ectodermal dysplasia but can also be classified as acantholytic EB simplex variant) with formation of acantholytic vesicles within the epidermis due to plakophilin 1 (PKP1) gene mutations 2. Junctional epidermolysis bullosa a. Inheritance: autosomal recessive in most cases b. Herlitz type (epidermolysis bullosa letalis) i. Cause by mutations in laminin 5 gene ii. Associated with premature death
CLINICAL FEATURES
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1. Epidermolysis bullosa simplex a. General characteristics i. The most common heritable blistering process ii. Intraepidermal blistering at the level of the basal cell iii. Typical healing of blisters without scarring iv. Little involvement of other organ systems v. Extent and severity of disease improves with age b. EBS Koebner type i. Commonly involves hands, feet, and extremities ii. Onset at birth to early infancy iii. Often present with palmar-plantar hyperkeratosis and erosions iv. Mildly involves nails, teeth, and oral mucosa c. EBS Weber-Cockayne type i. Relatively mild variant of EBS ii. Commonly involves palms and soles only after a clearly identifiable traumatic event iii. May not present until adulthood iv. Hyperhidrosis of the palms and soles v. Most common complications involve secondary infections of blistering lesions on the feet d. EBS Dowling-Meara type i. A more severe subtype of EBS ii. Involves a more generalized distribution of blisters occurring at, or shortly after, birth iii. Pronounced inflammation with milia formation in infancy
EPIDERMOLYSIS BULLOSA
iv. Spontaneous blisters occurring in-groups on the trunk and proximal extremities v. Usually healing without scarring later in life vi. Hyperkeratosis may develop at age 6 or 7 years vii. Unlike the previous two subtypes, heat does not appear to exacerbate blistering e. EBS with muscular dystrophy i. Usually present with generalized skin blistering ii. Onset of muscular dystrophy later in life, due to defects of the molecule plectin iii. Dental abnormalities also common 2. Junctional epidermolysis bullosa a. General characteristics i. Blistering at the level of the lamina lucida ii. More severe blistering process iii. Presenting spontaneously or at sites of trauma with generalized blistering b. Herliz or junctional epidermolysis letalis i. The commonest form of JEB formerly known as ‘lethal JEB’ ii. Characterized by generalized blistering at birth iii. Extensive dental enamel hypoplasia iv. Tracheolaryngeal involvement leading to a hoarse cry, cough, and/or other respiratory difficulties v. Gastrointestinal involvement and genitourinary involvement leading to infection and obstructive sequelae vi. Rarely survives beyond 6 months secondary to chronic anemia, failure to thrive, and sepsis vii. Rare survivors: develop exuberant granulation tissue at sites of erosion, especially at the perioral region c. NonHerlitz junctional epidermolysis bullosa i. Early clinical course similar to that found in Herlitz type JEB ii. Often survives infancy iii. May improve clinically with age iv. Rare and mild pulmonary involvement v. Scalp, nail, and tooth abnormalities common vi. Prominent nonhealing periorificial lesions vii. Erosions in the mucous membranes resulting in strictures d. Generalized atrophic benign epidermolysis bullosa i. Generalized cutaneous blistering at birth ii. Blisters heal with a distinctive atrophic appearance iii. Blisters confined to sites of trauma iv. Alopecia v. Dental anomalies vi. Rare severe nail and mucosal involvement e. Junctional epidermolysis associated with pyloric stenosis i. Often with severe skin blistering and extensive multisystem mucosal blistering ii. Presence of pyloric and/or duodenal atresia iii. Often with urologic abnormalities a) Hydronephrosis b) Nephritis iv. Many patients die during infancy
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3. Dystrophic epidermolysis bullosa a. General characteristics i. Characterized by dermolytic blisters in sublamina densa resulting in scarring and milia formations ii. Dystrophic scarring follows cutaneous blistering b. Dominantly inherited dystrophic epidermolysis bullosa i. Mild phenotype ii. Present with generalized blistering at birth or during infancy iii. Blistering at sites of maximal trauma iv. Healing with scarring and small keratinaceous cysts (milia) c. Transient bullous dermolysis of the newborn i. An uncommon variant ii. Blistering at sites of trauma that heals after several months without scarring iii. Variable mucous membrane and nail involvement d. Recessively inherited dystrophic epidermolysis bullosa: Hallopeau-Siemens type (the most severe form) i. Excessive fragile skin leading to blisters with minimal trauma ii. Extensive scarring leading to contractures and fusion of digital web spaces (pseudosyndactyly, “mitten deformities”) that require surgical correction iii. Extremely itching and painful skin iv. Regular mucosal blistering leading to eating and swallowing disorders and ocular abnormalities v. Tendency to growth retardation and anemia vi. Devastating complications unique to recessively inherited dystrophic epidermolysis bullosa a) Increased propensity for cutaneous malignancy at sites of scarring (>40% of patients develop malignancy by age 30 years) b) Aggressive nature of malignancy (squamous cell carcinoma)
DIAGNOSTIC INVESTIGATIONS 1. EM of skin biopsy a. A gold standard of laboratory diagnosis i. To determine the level at which blistering occurs ii. To obtain additional information on the morphology of various basement membrane zone components b. Epidermolysis bullosa simplex i. Cytolysis of the basal cells ii. Distinctive clumping of the keratin tonofilaments c. Junctional epidermolysis bullosa: rudimentary hemidesmosomes d. Dystrophic epidermolysis bullosa: absent or altered anchoring fibrils e. Hemidesmosomal epidermolysis bullosa: separation at the level of hemidesmosome just inside the basal keratinocytes 2. Immunofluorescent microscopy a. Provide additional information on the level of blistering b. Provide important clue to the underlying molecular defects c. Antibodies against intracellular hemidesmosomal component such as BP230 and a lamina densa protein such as type IV collagen
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i. Samples from EBS: both antibodies localized to the floor of the blister ii. Samples from JEB a) Antibodies against BP230 localized to the roof of the blister b) Antibodies against type IV collagen localized to the floor iii. Samples from DEB: both antibodies localized to the roof of the blister d. Samples lacking staining with antibodies specific to laminin 5 support a JEB diagnosis e. Samples lacking staining with antibodies specific to type VII collagen support a DEB diagnosis 3. Linkage analysis of linked markers within or flanking the particular EB gene in families in which the inheritance pattern is known 4. Mutation detection for all forms of epidermolysis bullosa a. Mutation analysis b. Sequence analysis
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal dominant: not increased unless a parent is affected ii. Autosomal recessive: 25% b. Patient’s offspring i. Autosomal dominant: 50% ii. Autosomal recessive: not increased unless the spouse is a carrier or affected 2. Prenatal diagnosis a. Fetal skin biopsy with EM analysis and/or immunohistochemistry with following drawbacks i. Drawbacks a) Fetal biopsy can only be obtained fairly late in gestation (≥17 weeks) b) A relatively high rate of miscarriage c) Fetal status can only be determined by an expert in the ultrastructure of fetal skin who is qualified to make the diagnosis ii. An alternative option for rare families in which mutations cannot be identified and linked markers are not available to be used for prenatal diagnosis b. DNA-based diagnosis on fetal DNA obtained by amniocentesis or CVS for all forms of epidermolysis bullosa c. Linkage analysis by linked markers within or flanking the COL7A1 gene in several DEB families in which the inheritance pattern was known d. Preimplantation genetic diagnosis, an alternative to first-trimester prenatal diagnosis i. Involves in vitro fertilization, usually by intracytoplasmic sperm injection ii. Followed by the biopsy of a single cell from the 8-cell blastocysts (embryo) iii. Using complex polymerase chain reaction analysis to determine whether DNA from the single cell caries the parental mutations
3. Management a. A multidisciplinary team approach, tailored to the severity and extent of skin involvement b. Blister management and dressing technique i. Avoidance of trauma as a primary goal ii. Puncture fresh blisters with a sterile needle and drain blister fluid with the blister roof left in situ so that the blister fluid cannot extend iii. Use white petrolatum-impregnated gauzes, hydrogels, fenestrated silicone dressings or absorbent foam silicone dressings for open wounds iv. Keep intravenous lines in place by using soft roller-gauze bandages v. Avoid dressing with adhesive tapes vi. Prevention and treatment of infections c. Prevention and treatment of complications i. Change dressing regularly a) To control blistering and infection b) To prevent the debilitating contractures secondary to bullae formation in dystrophic EB ii. Physiotherapy a) To maintain mobility b) To decrease contracture formation iii. Corrective surgery recommended for digital fusion (mitten pseudosyndactyly) and contractures iv. Nutritional support v. Gastrointestinal management a) Dilatation of esophageal strictures b) Colonic interposition for advanced cases of strictures c) Gastrostomy tube insertion to provide nutrition d) Laxatives and increased dietary fiber for constipation, anal fissures, and perianal ulceration vi. Care for eye lesions a) Moisture chambers and ocular lubricants b) Treat corneal erosions with antibacterial ointments and use of cycloplegic agents vii. Oral care a) Good oral hygiene b) Gentle cleaning of the mucosal surfaces with normal saline rinses c) Softest brush for regular cleansing d. Pain management i. Acute phase: experience considerable pain and discomfort caused by the expanding and often tense bulla ii. Chronic wounds: experience considerable pain caused by chronic wounds with denuded areas of skin and by therapeutic procedures iii. Analgesics a) Combination of paracetamol and ibuprophen or diclofenac for dressing changes associated with small wounds b) Potent analgesia and sedation required for large dressing changes e. Management of anesthesia and surgery: should be undertaken in specialized centers familiar with the many complex aspects of EB care f. Tumor detection in recessively inherited DEB
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g. Advanced therapy to treat hard to heal wounds i. Cultured keratinocytes ii. Acellular dermal allograft plus ultrathin autografts iii. Living dermal skin substitute iv. Living bilayered skin equivalents a) Composite cultured skin (CCS) b) Graftskin c) Dermagraft
REFERENCES Bello YM, Falabella AF, Schachner LA: Management of epidermolysis bullosa in infants and children. Clin Dermatol 21:278–282, 2003. Chang CH, Perrrin EV, Bove KE: Pyloric atresia associated with epidermolysis bullosa: special reference to pathogenesis. Pediatr Pathol 1:449–457, 1983. Cooper TW, Bauer EA: Epidermolysis bullosa: A review. Pediatr Dermatol 1:181–188, 1983. Dank JP, Kim S, Parisi MA: Outcome after surgical repair of junctional epidermolysis bullosa-pyloric atresia syndrome: a report of 3 cases and review of the literature. Arch Dermatol 135:1243–1247, 1999. De Groot WG, Postuma R, Hunter AGW: Familial pyloric atresia associated with epidermolysis bullosa. J Pediatr 92:429–431, 1978. Eady RA: Epidermolysis bullosa: scientific advances and therapeutic challenges. J Dermatol 28:638–640, 2001. Fine JD, Bauer EA, Briggaman RA: Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa. A consensus report by the Subcommittee on Diagnosis and Classification of the National Epidermolysis Bullosa Registry. J Am Acad Dermatol 24:119–135, 1991. Fine JD, Eady RA, Bauer EA, et al.: Revised classification system for inherited epidermolysis bullosa: report of the Second International Consensus Meeting on diagnosis and classification of epidermolysis bullosa. J Am Acad Dermatol 42:1051–1066, 2000. Fine JD: Inherited epidermolysis bullosa: selected outcomes and a revised classification system. Pediatr Dermatol 17:75–83, 2000. Frieden IJ: Aplasia cutis congenital: a clinical review and proposal for classification. J Am Acad Dermatol 14:646–660, 1986. Hansen SG, Fine JD, levy ML: Three new cases of transient bullous dermolysis of the newborn. J Am Acad Dermatol 40:471, 1999. Hayashi AH, Galliani CA, Gillis DA: Congenital pyloric atresia and Junctional epidermolysis bullosa: a report of long-term survival and a review of the literature. J Pediatr Surg 26:1341–1345, 1991. Herod J, Denyer J, Goldman A, et al.: Epidermolysis bullosa in children: pathophysiology, anaesthesia and pain management. Paediatr Anaesth 12:388–397, 2002. Khavari PA: Gene therapy for genetic skin disease. J Inv Dermatol 110:462, 1998.
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Lestringant GG, Akel SR, Qayed KI: The pyloric atresia-junctional epidermolysis bullosa syndrome. Report of a case and review of the literature. Arch Dermatol 128:1083–1086, 1992. Mallipeddi R: Epidermolysis bullosa and cancer. Clin Exp Dermatol 27:616–623, 2002. McGrath JA, Handyside AH: Preimplantation genetic diagnosis of severe inherited skin diseases. Exp Dermatol 7:65–72, 1998. McGrath JA, McMillian JR, Dunnil MGS: Genetic basis of lethal Junctional epidermolysis bullosa in affected fetus: implication for prenatal diagnosis in one family. Prenat Diagn 15:647–654, 1995. McGrath JA, Kivirikko S, Christiano S, et al.: A homozygous nonsense mutations in the alpha 3 chain gene of laminin 5 (LAMA3) in Herlitz junctional epidermolysis bullosa: prenatal exclusion in a fetus at risk. Genomics 29:282, 1995. Melhem RE, Salem G, Mishalany H: Pyloro-duodenal atresia. A report of three families with several similarly affected children. Pediatr Radiol 3:1–5, 1975. Mitsuhashi Y, Hashimoto I: Genetic abnormalities and clinical classification of epidermolysis bullosa. Arch Dermatol Res 295 (Suppl 1):S29–S33, 2003. Pai S, Marinkovich MP: Epidermolysis bullosa: new and emerging trends. Am J Clin Dermatol 3:371–380, 2002. Paller AS: The genetic basis of hereditary blistering disorders. Curr Opin Pediatr 8:367, 1996. Pearson RW: Clinicopathologic types of epidermolysis bullosa and their nondermatological complications. Arch Dermatol 124:718–725, 1988. Pfendner EG, Nakano A, Pulkkinen L, et al.: Prenatal diagnosis for epidermolysis bullosa: a study of 144 consecutive pregnancies at risk. Prenat Diagn 23:447–456, 2003. Pulkkinen L, Christiano AM, Airenne T: Mutations in the gamma 2 chain gene (LAMC2) of kalinin/laminin 5 in the junctional forms of epidermolysis bullosa. Nature Genet 6:293–297, 1994. Rodeck CH, Eady RA, Gosden CM: Prenatal diagnosis of epidermolysis bullosa letalis. Lancet 1:949–952, 1980. Salas JC, Mellerio JE, Amaya M, et al.: Frameshift mutation in the type VII collagen gene (COL7A1) in five Mexican cousins with recessive dystrophic epidermolysis bullosa. Br J Dermatol 138:852–858, 1998. Sidbury R, Paller AS: Dermatologic clues to inherited disease. Pediatr Clin N Am 47(4), 2000. Smith LT: Ultrastructural findings in epidermolysis bullosa. Arch Dermatol 129:1578–1584, 1993. Sybert VP, Stephens K: Epidermolysis bullosa simplex. Gene Reviews, 2003. http://www.genetests.org Tong L, Hodgkins PR, Denyer J: The eye in epidermolysis bullosa. Br J Ophthalmol 83:323–326, 1999. Vidal F, Aberdam D, Miquel C, et al.: Integrin beta 4 mutations associated with junctional epidermolysis bullosa with pyloric atresia. Nature Genet 10:229–234, 1995. Wojnarowska FT, Eady RA, Wells RS: Dystrophic epidermolysis bullosa presenting with congenital localized absence of skin: report of four cases. Br J Dermatol 108:477–483, 1983.
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Fig. 1. An infant with epidermolysis bullosa showing large blisters on the foot and smaller blisters on other part of the body.
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Fig. 2. A 19-year-old female with recessively inherited dystrophic epidermolysis bullosa (Hallopeau-Siemens type) who was born with generalized blisters involving skin and mucosa, especially blisters and skin sloughing on the fingers and legs (A). She showed excessive fragile skin leading to blisters with minimal trauma, excessive scarring leading to contractures of the right foot and fusion of 1st and 2nd toe on the right foot requiring surgical separation. She also had syndactyly of the 2nd-3rd-4th toes of the left foot. The lesions were extremely itchy and painful and more severe on the lower extremity (B,C). At the time of these photos, the patient still had swallowing difficulty secondary to blistering lesion in the throat.
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Epidermolytic Palmoplantar Keratoderma Epidermolytic palmoplantar keratoderma (EPPK), first described by Vörner in 1901, may be the most common form of diffuse keratoderma and is characterized by keratosis restricted to the palms and soles. The disease is also known as keratosis palmaris et plantaris familiaris.
GENETICS/BASIC DEFECTS 1. Inheritance: a. Autosomal dominant b. Highly penetrant 2. Cause a. Mutations in the keratin 9 gene (KRT9), a type 1 keratin expressed exclusively in the suprabasal keratinocytes of palmoplantar epidermis b. Splice site mutations in keratin 1 gene (KRT1) underlies mild EPPK
CLINICAL FEATURES 1. Characteristic hyperkeratosis a. Early onset: during the first weeks or months after birth b. Diffuse thick yellowish hyperkeratosis, distinctly limited to the palms and soles, with sharply bordered erythematous margins c. Absence of associated features 2. Differential diagnosis (Gruber and Ratnavel, 2003) a. Diffuse hereditary PPK without associated features i. Diffuse nonepidermolytic PPK (NEPPK) a) NEPPK: an autosomal dominant disorder b) Clinically difficult to distinguish between EPPK and NEPPK c) Histologically, EPPK shows epidermolysis of keratinocytes in the suprabasal layers, a characteristic not observed in NEPPK d) In mild cases of EPPK, diagnosis can still be problematic as detection of epidermolysis can be difficult ii. Progressive PPK a) Hyperkeratosis extends onto the dorsa of the hands and the feet with characteristic involvement of the Achilles tendon b) Hyperhidosis common c) Intrafamilial phenotypic variation common d) Course of the disease: worsen during childhood, static after puberty, and improves in the fifth decade of life iii. Gamborg-Nielson PPK a) An autosomal recessive disorder b) Severe form of PPK delineated in 2 families with 6 patients in Sweden c) Thick, diffuse keratoderma with knuckle pads
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d) Occasional keratosis on the dorsa of the hands e) Mutilating changes due to constricting bands surrounding the fingers have been described b. Diffuse hereditary PPK with associated features i. Mal de Meleda a) Described initially in inhabitants of the Adriatic Island of Meleda (Miljet) b) An autosomal recessive disorder c) Diffuse, thick keratoderma with prominent erythematous border extending onto the dorsa of the hands and the feet d) Constricting bands around digits resulting in spontaneous amputation e) Well-circumscribed psoriasis-like plaques or lichenoid patches on the knees and the elbows f) Hyperhidrosis g) Periorbital erythema and hyperkeratosis h) Nail changes (koilonychias, subungual hyperkeratosis) i) Other associated features (lingua plicata, syndactyly, hair on the palms and the soles, high arched palate, left handedness) ii. Vohwinkel PPK mutilans a) An autosomal dominant disorder b) Honeycomb-like keratosis of the palms and soles in infancy c) Progressive constricting fibrous bands on the digits, leading to progressive strangulation and autoamputation d) Starfish-shaped keratosis on the dorsa of the fingers and the knees e) Other associated features (alopecia, deafness, spastic paraplegia, myopathy, ichthyosiform dermatosis, and nail abnormalities) iii. Olmsted mutilating PPK with periorificial keratotic plaques a) An autosomal dominant disorder b) Onset in the first year of life c) Symmetric, sharply defined PPK, surrounded by erythema with flexion deformities of the digits, leading to constriction and spontaneous amputation d) Periorificial keratosis e) Onychodystrophy f) Perianal involvement with variable leukokeratosis iv. PPK with sclerodactyly a) An autosomal dominant disorder b) Sclerodactyly
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c) Diffuse keratoderma more marked on the soles than the palms d) Nail abnormalities e) Hypohidrosis f) Associated with squamous cell carcinoma v. PPK with periodontitis a) An autosomal recessive disorder b) Diffuse trangrediens palmoplantar dermatosis c) Periodontosis, unless treated, results in severe gingivitis and loss of teeth by age 5 years. d) Increased susceptibility to infection e) Scaly, erythematous lesions often observed over the knees, the elbows, and the interphalangeal joints f) Hyperhidrosis with malodor vi. Clouston hidrotic ectodermal dysplasia a) Diffuse, papillomatous PPK b) Nail dystrophy c) Universal sparsity of hair d) Other associated features (sensorineural deafness, polydactyly, syndactyly, fingerclubbing, mental retardation, dwarfism, photophobia, and strabismus) vii. Diffuse NEPPK and sensorineural deafness a) An autosomal dominant disorder b) Diffuse palmoplantar hyperkeratosis c) Associated with a slowly progressive, bilateral, high-frequency hearing loss d) Deafness precedes the skin changes c. Focal (nummular) PPK without associated features i. Focal NEPPK a) An autosomal dominant disorder b) Palmar keratosis with a nummular, linear, membranaceous, fissured, or periungual configuration c) Plantar keratosis with a nummular appearance, localized to pressure points ii. Focal epidermolytic PPK a) An autosomal dominant disorder b) Nummular keratotic lesions, located mainly on plantar pressure points c) Painful lesions iii. Siemens PPK areata/striata a) An autosomal dominant disorder b) Marked variable phenotypic expression c) Marked erythema initially, followed by islands of linear hyperkeratosis d. Focal (nummular) hereditary PPK with associated features i. Oculocutaneous tyrosinemia (tyrosinemia type II) a) Focal, painful PPK b) Bilateral, pseudoherpetic corneal ulceration, leading to corneal scarring and glaucoma c) Mental retardation d) Occasional hyperkeratotic lesions on the elbows, knees, and tongue e) Hyperhidrosis f) Occasional bullous lesions ii. Pachyonychia congenita a) Autosomal recessive disorder
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b) Localized areas of hyperkeratosis on the palms and the soles c) Discoloration and thickening of the nails iii. Keratosis palmaris and plantaris with carcinoma of the esophagus a) Autosomal dominant disorder b) Age of onset: 5–15 years c) Focal PPK d) Increased susceptibility to developing carcinoma of the esophagus (38 fold increase) e) Variable oral leukokeratosis and follicular keratosis iv. Focal palmoplantar and oral mucosa hyperkeratosis a) Autosomal dominant disorder b) Focal PPK, especially on weight-bearing areas c) Oral hyperkeratosis d) Increased severity with age e) Subungual and circumungual hyperkeratosis e. Papular PPK without associated features i. Keratosis palmoplantaris punctata a) Autosomal dominant disorder b) Asymptomatic, tiny hyperkeratotic papules present on the palmoplantar surface c) Absence of associated features in most patients d) Spastic paralysis, ankylosing spondylitis, facial sebaceous hyperplasia reported e) Possible association with gastrointestinal malignancy ii. Acrokeratoelastoidosis a) Autosomal dominant disorder b) Round or oval, yellowish, hyperkeratotic papules that can appear umbilicated c) Distribution of the lesions: along the border of the palms and the soles d) Associated hyperhidrosis iii. Focal acral hyperkeratosis a) Autosomal dominant disorder b) Condition similar to acrokeratoelastoidosis c) Insidious onset in childhood, reaching maximum in early life d) Race: African origin f. Papular PPK with associated features i. Rare single-pedigree syndromes a) Syndrome of cystic eyelids, punctate PPK, hypotrichosis, and hypodontia (SchopfSchulz-Passage syndrome) b) Punctate PPK with ankylosing spondylitis c) Punctate PPK with facial sebaceous hyperplasia d) Punctate PPK with spastic paralysis e) PPK with lipomata ii. Punctate PPK and cancer: g. Acquired palmoplantar keratoderma i. Inflammatory and reactive dermatoses a) Hyperkeratotic eczema b) Psoriasis c) Reiter syndrome
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d) Lichen planus e) Pityriasis rubra pilaris f) Lupus erythematosus g) Callosities h) Darier disease ii. Infective causes a) Dermatophytes b) Viral (human papilloma virus) warts mimicking keratoderma c) AIDS-related psoriasis with discrete keratotic pustular keratoderma d) Late secondary syphilis in patients with HIV with diffuse, symmetric keratoderma or papular PPK e) Yaws f) Leprosy iii. Drugs a) Chronic arsenic exposure with multiple, irregular, warty keratosis b) Lodine: manifestation of drug hypersensitivity iv. Cutaneous features of systemic disease a) Myoedema with hyperkeratosis b) Diabetes with discrete plantar keratosis c) Cutaneous T-cell lymphoma with subungual hyperkeratosis v. Haxthausen keratoderma climactericum a) Onset in the 40s b) Initial lesion: pressure areas on the soles c) Erythema and hyperkeratosis with fissuring making walking painful d) Minimal pruritus e) Discrete and centrally confined palmar involvement vi. Keratoderma associated with internal malignancy a) Keratoderma as a paraneoplastic phenomenon, such as acrokeratosis paraneoplastica of Bazex associated with squamous cell carcinoma of the upper gastrointestinal tract and acanthosis palmaris associated with gastric or pulmonary malignancy in 90% of cases b) Keratoderma as evidence of predisposition to malignancy such as late-onset punctate keratoderma associated with cutaneous and internal malignancy h. Syndromes with PPK as an associated features i. Basal cell nevus syndrome ii. Congenital bullous ichthyosiform erythroderma iii. Congenital nonbullous ichthyosiform erythroderma iv. Darier disease v. Epidermodysplasia verruciformis vi. Epidermolysis bullosa herpetiformis vii. Ichthyosis vulgaris viii. Incontinentia pigmenti ix. Keratitis, ichthyosis, and deafness (KID) syndrome x. Lamellar ichthyosis
DIAGNOSTIC INVESTIGATIONS 1. Histology and ultrastructures: cytolysis of keratinocytes and abnormal aggregation of tonofiilaments in the suprabasal layers of the epidermis 2. Molecular genetic analysis a. KRT9 mutations analysis i. Sequencing of entire coding region ii. Sequencing of select exons iii. Targeted mutations analysis b. KRT1 mutation analysis for patients with no mutations in KRT9
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected in which case there is a 50% risk b. Patient’s offspring: 50% 2. Prenatal diagnosis a. Not usually requested because of mild nature of the disease b. Possible to pregnancy at-risk, provided the diseasecausing mutation has been identified in the proband 3. Management a. Topical keratolytics b. Topical retinoids such as tretinoin
REFERENCES Coleman CM, Munro CS, Smith FJ, et al.: Epidermolytic palmoplantar keratoderma due to a novel type of keratin mutation, a 3-bp insertion in the keratin 9 helix termination motif. Br J Dermatol 140:486–490, 1999. Corden LD, McLean WHI: Human keratin diseases: hereditary fragility of specific epithelial tissues. Exp Dermatol 5:297–307, 1996. Covello SP, Irvine AD, McKenna KE, et al.: Mutations in keratin K9 in kindreds with epidermolytic palmoplantar keratoderma and epidemiology in Northern Ireland. J Invest Dermatol 111:1207–1209, 1998. Christiano AM: Frontiers in keratodermas: pushing the envelope. Trends Genet 13:227–233, 1997. Gruber PC, Ratnavel R: Keratosis palmaris et plantaris. Emedicine, 2003. http://www.emedicine.com Hatsell SJ, Eady RA, Wennerstrand L, et al.: Novel splice site mutation in keratin 1 underlies mild epidermolytic palmoplantar keratoderma in three kindreds. J Invest Dermatol 116:606–609, 2001. He XH, Zhang XN, Mao W, et al.: A novel mutation of keratin 9 in a large Chinese family with epidermolytic palmoplantar keratoderma. Br J Dermatol 150:647–651, 2004. Lucker GP, Van de Kerkhof PC, Steijlen PM: The hereditary palmoplantar keratoses: an updated review and classification. Br J Dermatol 131:1–14, 1994. Navsaria HA, Swensson O, Ratnavel RC, et al.: Ultrastructural changes resulting from keratin-9 gene mutations in two families with epidermolytic palmoplantar keratoderma. J Invest Dermatol 104:425–429, 1995. Ratnavel RC, Griffiths WA: The inherited palmoplantar keratodermas. Br J Dermatol 137:485–490, 1997. Reis A, Kuster W, Eckardt R, et al.: Mapping of a gene for epidermolytic palmoplantar keratoderma to the region of the acidic keratin gene cluster at 17q12-q21. Hum Genet 90:113–116, 1992. Reis A, Hennies HC, Langbein L, et al.: Keratin 9 gene mutations in epidermolytic palmoplantar keratoderma (EPPK). Nat Genet 6:174–179, 1994. Stevens HP, Kelsell DP, Bryant SP, et al.: Linkage of an American pedigree with palmoplantar keratoderma and malignancy (palmoplantar ectodermal dysplasia type III) to 17q24. Literature survey and proposed updated classification of the keratodermas. Arch Dermatol 132:640–651, 1996. Vörner H: Zur Kenntnis des Keratoma hereditarium palmare et plantare. Arch Derm Syph 56:3–31, 1901.
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Fig. 1. A 47-year-old woman with epidermolytic palmoplantar keratoderma showing diffuse keratoderma affecting both the palms and the soles. The keratoderma had erythematous border at the margins of both palms and soles and was completely restricted to the palms and soles. The dorsa of the hands and soles were spared. This patient has multiple affected relatives in several generations.
Facioscapulohumeral Muscular Dystrophy Facioscapulohumeral muscular dystrophy (FSHD) is the third most common neuromuscular disorder after Duchenne muscular dystrophy and myotonic dystrophy. It is characterized by progressive weakness and atrophy of the facial and shoulder girdle muscles. The other muscles are also involved. Its prevalence is estimated to be 1 in 20,000.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant b. Almost complete penetrance (95%) 2. FSHD1 gene a. Mapped to the subtelomeric region of chromosome 4q35 b. Closely linked to the highly polymorphic locus D4F104S1 c. Deletion of 3.3-kb tandemly repeated units within the EcoRI fragment on chromosome 4q35: associated with the disease in 85–95% of FSHD families d. Candidate genes for FSHD not yet elucidated e. Nature of the precise mutation: still unknown f. Approximately 5% of FSHD families fail to exhibit linkage to 4q35, presumably indicating the presence of a second FSHD1 locus 3. Genotype–phenotype correlation a. Patients with a large gene deletion i. Tendency to have a higher chance of exhibiting severe clinical phenotypes ii. Higher chance of central nervous system abnormalities b. Patients with small EcoRI fragments i. Tendency to have earlier-onset disease ii. More rapid progression c. Correlation between the size of the disease-associated 4q35-EcoRI fragment and the following parameters i. Age at onset of symptoms ii. Age at loss of ambulation iii. Muscle strength as measured by quantitative isometric myometry d. De novo mutations i. Association with smaller EcoRI fragments (on average) than those segregating in families ii. Tendency of patients with de novo mutations to have findings the more severe end of the phenotypic spectrum e. Reduced penetrance in females bearing the FSHD small fragment as compared to the penetrance in males with the FSHD small fragment
CLINICAL FEATURES 1. Marked clinical variability a. Age at onset
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i. Usually between the first and second decade ii. Progress gradually over time b. Pattern of muscle involvement i. Progressive weakness and atrophy of the facial and shoulder girdle muscles ii. Other muscles affected in a specific order a) Abdominal muscles involved first b) Followed by foot-extensor and upper arm muscles c) Finally involving pelvic girdle and lower arm muscles c. Intra-familial variability d. Inter-familial variability e. Phenotype ranging from almost asymptomatic forms to more severe wheelchair-bound forms 2. A distinctive distribution of progressive muscular weakness involving the following muscles a. Facial muscles i. Typically involved: a) Obicularis oculi b) Orbicularis oris ii. Clinical signs a) Often asymmetric involvement b) Facial weakness c) Unable to turn up the corners of the mouth when smiling d) Difficulty in whistling e) Unable to purse lips f) Sleeping with eyes partially open, the most common early sign g) Bury eyelashes when attempting to close eyelids tightly h) Sparing of extraocular, eyelid, and bulbar muscles b. Scapular stabilizer muscles i. Affected muscles a) Latissimus dorsi b) Trapezius c) Rhomboids d) Serratus anterior ii. Clinical signs a) Sloping shoulder posture at rest b) Anterior axillary folds c) Straight (horizontally placed) clavicles d) Pectoral muscle atrophy e) Scapular winging, the most common initial finding f) Preferential weakness of the lower trapezius muscle, resulting in characteristic upward movement of the scapula when attempting to flex or abduct the arms
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c. Proximal arm muscles i. Biceps and triceps selectively involved, resulting in atrophy of the upper arm ii. Distal progression of wasting and weakness of upper arm muscles, leading to eventual weakness of wrist and finger extensors iii. Deltoids minimally affected until late in the disease iv. Sparing of the forearm muscles, resulting in so-called “popeye arms” appearance d. Abdominal muscles i. Abdominal muscle weakness resulting in: a) Protuberance of the abdomen b) Exaggerated lumbar lordosis ii. Selective involvement of the lower abdominal muscles, resulting in Beevor’s sign (upward displacement or occasionally downward movement of the umbilicus upon flexion of the neck in a supine position) a) Present in 90% of patients b) Helpful early sign in patients with equivocal findings, as it is rarely found in other muscle disorders e. Lower extremity muscles i. Anterior compartment muscles of the distal leg (anterior tibial and peroneal muscles) a) Usually the first and most severely affected b) Resulting in the typical complaints of a foot slap while walking or frank foot drop c) Frequent tripping or unstable walking, particularly on uneven ground ii. Pelvic girdle muscles a) Less common b) Involving hip flexors and hip abductors c) Resulting in early and relatively severe gait involvement 3. Degree of muscle involvement a. Extremely variable b. Wide range of muscle involvement i. Very mildly affected patients unaware of the disease symptoms ii. Isolated facial weakness iii. Severe generalized weakness iv. Eventually requiring a wheelchair in approximately 20% of patients c. Sex difference in penetrance: males more severely affected than females 4. Clinical course of muscle involvement a. Early involvement of facial and scapular muscles with eventual spreading to pelvic and lower limb muscles b. A slowly progressive course c. A stepwise course with periods of rapid deterioration occurring against a background of stability d. Aggravation of muscle weakness during pregnancy but recover quickly in the puerperium e. Bulbar and pharyngeal muscles, extraocular muscles, and respiratory muscles typically spared 5. Extra muscular involvement (uncommon) a. Coats syndrome i. Neurosensory hearing loss (64%) ii. Retinal vasculopathy (49–75%)
a) Tortuosity of retinal arterioles (microaneurysms) b) Telangiectasia b. Mental impairment c. Cardiac involvement (5%) i. Conduction defects ii. Supraventricular arrhythmia d. Neurologic manifestations i. Preserved sensation ii. Often diminished reflexes 6. Diagnostic criteria include the following 4 main elements: the diagnosis of FSHD often remains a clinical diagnosis a. Onset of disease in the facial or shoulder girdle muscles, sparing the eyes, pharynx, tongue, and heart b. Facial weakness in more than 50% of affected family members c. Autosomal dominant inheritance in familial cases d. Evidence of myopathic disease by electrodiagnostic studies and muscle biopsy in at least one affected family member
DIAGNOSTIC INVESTIGATIONS 1. Serum creatine kinase (CK) a. Normal to elevated levels b. Usually not exceeding 3–5 times the upper limit of the normal range 2. Audiogram for sensorineural hearing loss 3. Fluorescein angiography to demonstrate retinal vasculopathy 4. EMG: nonspecific myopathic features a. Fibrillations b. Positive waves in resting muscle c. Early recruitment of short duration motor unit action potentials 5. Muscle biopsy: nonspecific features a. Underlying process: myopathic and help to exclude the following primary muscle diseases that can present with a FSHD-like phenotype: i. Congenital myopathies a) Nemaline (rod) myopathy b) Centronuclear myopathy ii. Inflammatory myopathies a) Polymyositis b) Inclusion body myositis iii. Other dystrophies a) Scapuloperoneal dystrophy b) Limb-girdle dystrophy iv. Others: desmin-storage myopathy b. Increased variation in fiber size c. Increased internalized nuclei d. Variable degrees of endomysial inflammatory cells e. Angulated “neuropathic-like” myofibers f. Mononuclear inflammatory reaction (75%) 6. Molecular genetic testing a. Mutation analysis i. Detection of the short fragment in affected individuals a) High sensitivity and specificity of the 4q35 deletion for FSHD
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b) Using probe p13E-11 (D4F104S1), which hybridized to 4q35, to detect small EcoRI digestion fragments c) Deletion within the D4Z4 repeat region of chromosome 4q35 (demonstrable short fragment), observed in 95% of patients clinically affected with FSHD, whether familial or sporadic d) Approximately 98% of patients with such a short fragment have clinically demonstrable FSHD e) Confirms the diagnosis with a high degree of certainty ii. Large deletions in the 4q35 region (producing a smaller short fragment) a) Associated with more severe expression of the disease b) Manifest earlier onset of disease c) More severe degree of weakness d) Shorter fragment size generally associated with sporadic cases with an earlier age of onset than with familial cases iii. Variability in fragment size: unable to explain the significant clinical variability sometimes seen within FSHD families, since the deletion size appears to remain stable from generation to generation iv. Findings of a short but less intensively hybridizing p13E-11/EcoRI/BlnI fragment strongly suggest germinal mosaicism. Minor clinical signs in parents may point towards germline mosaicism b. Absence of identifiable D4Z4 deletions in approximately 5% of individuals with FSHD
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. 10% risk for a sib of a de novo case being a carrier. The figure of 10% is based on the observation that both somatic and germinal mosaics are detected, indicating that both types of mutations occur early in embryogenesis and therefore will give rise to a high percentage of mutated germ cells ii. 50% recurrence risk if a parent is affected b. Patient’s offspring: each offspring of an affected individual having a 50% chance of inheriting the deleted region within the D4Z4 repeat motif for FSHD 2. Prenatal diagnosis a. Available for fetuses at 50% risk for FSHD b. Molecular genetic testing: follow a de novo mutation in a subsequent generation by analyzing DNA extracted from fetal cells obtained by: i. CVS ii. Amniocentesis 3. Management a. Lack of effective treatment b. Unpredictability of the clinical course c. Management of pain in the shoulders, back, abdomen, and leg
d. e.
f.
g.
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i. Use of nonsteroidal anti-inflammatory drugs ii. Range-of-motion exercise iii. Gentle stretching through a physical therapy program Physiotherapy Supportive treatment of complications from progressive weakness i. Judicial use of bracing ii. Ankle and foot orthoses to improve mobility and prevent falls in patients with foot drop iii. Surgical fixation of the scapula to the chest wall (thoracoscapular fusion) or to the ribs (scapulocostal fusion) a) Often improving range of motion of the arms b) Short-lived effect in patients with rapidly progressive disease Pharmacologic treatment i. Limited to the use of corticosteroids in patients with evidence of inflammation on muscle biopsy ii. Possible effect of albuterol, a β2 adrenergic agent a) Improvement of lean body mass b) Modest improvement in strength Required assistance in caring the infants after delivery due to weakness in the shoulder girdle
REFERENCES Bakker E, Van der Wielen MJ, Voorhoeve E, et al.: Diagnostic, predictive, and prenatal testing for facioscapulohumeral muscular dystrophy: diagnostic approach for sporadic and familial cases. J Med Genet 33:29– 35, 1996. Dubowitz V: Color Atlas of Muscle Disorders in Childhood. Chicago, Year Book Medical Publishers, 1989. Eggers S, Passos-Bueno MR, Zatz M: Facioscapulohumeral muscular dystrophy: aspects of genetic counselling, acceptance of preclinical diagnosis, and fitness. J Med Genet 30:589–592, 1993. Felice KJ ,Moore SA: Unusual clinical presentations in patients harboring the facioscapulohumeral dystrophy 4q35 deletion. Muscle Nerve 24:352– 356, 2001. Figiewicz DA, Tawil R: Facioscapulohumeral muscular dystrophy. Gene Reviews, 2003. http://www.genetests.org Fitzsimons RB: Facioscapulohumeral muscular dystrophy. Curr Opin Neurol 12:501–511, 1999. International Symposium on Facioscapulohumeral Muscular Dystrophy, Clinical and Molecular Genetic Aspects of the Disease. Kyoto, Japan, July 10, 1994. Muscle Nerve 2:S1–S109, 1995. Kissel JT: Facioscapulohumeral dystrophy. Semin Neurol 19:35–43, 1999. Köhler J, Rupilius B, Otto M, et al.: Germline mosaicism in 4q35 facioscapulohumeral muscular dystrophy (FSHD1A) occurring predominantly in oogenesis. Hum Genet 98:485–490, 1996. Lunt PW, Harper PS: Genetic counseling in facioscapulohumeral muscular dystrophy. J Med Genet 28:655–664, 1991. Lunt PW, Jardine PE, Koch M, et al.: Phenotypic-genotypic correlation will assist genetic counseling in 4q35-facioscapulohumeral muscular dystrophy. Muscle Nerve 2:S103–S109, 1995. Orrell RW, Tawil R, Forrester J, et al.: Definitive molecular diagnosis of facioscapulohumeral dystrophy. Neurology 52:1822–1826, 1999. Padberg GW, Lunt PW, Koch M, et al.: Diagnostic criteria for facioscapulohumeral muscular dystrophy. Neuromusc Disord 4:231–234, 1991. Ricci E, Galluzzi G, Deidda G, et al.: Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q25 locus and clinical phenotype. Ann Neurol 45:751–757, 1999. Rudnik-Schoneborn S, Glauner B, Rohrig D, et al.: Obstetric aspects in women with facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, and congenital myopathies. Arch Neurol 54:888– 894, 1997.
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Sripathi N: Facioscapulohumeral dystrophy. www.emedicine.com Tawil R, Forrester J, Griggs RC, et al.: Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. The FSH-DY Group. Ann Neurol 39:744–748, 1996. Tawil R, Figlewicz DA, Griggs RC, et al.: Facioscapulohumeral dystrophy: a distinct regional myopathy with a novel molecular pathogenesis. FSH Consortium. Ann Neurol 43:279–282, 1998. The FSH-DY Group: A prospective, quantitative study of the natural history of facioscapulohumeral muscular dystrophy (FSHD): implications for therapeutic trials. Neurology 48:38–46, 1997. Upadhyaya M, Cooper DN: Molecular diagnosis of facioscapulohumeral muscular dystrophy. Expert Rev Mol Diagn 2:160–171, 2002.
Upadhyaya M, Maynard J, Osborn M, et al.: Germinal mosaicism in facioscapulohumeral muscular dystrophy (FSHD). Muscle Nerve 2:S45– S49, 1995. Upadhyaya M, MacDonald M, Ravine D: Prenatal diagnosis for facioscapulohumeral muscular dystrophy (FSHD). Prenat Diagn 19:959–965, 1999. van Deutekom JC, Bakker E, Lemmers RJ, et al.: Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: implications for genetic counselling and etiology of FSHD1. Hum Mol Genet 5:1997–2003, 1996. Wijmenga C, Hewitt JE, Sandkuijl LA, et al.: Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat Genet 2:26–23, 1992.
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Fig. 1. A child with FSHD showing periscapular wasting and weakness resulting in scapular winging and inability to abduct the arm above the horizon.
Fig. 2. An adult with FSHD showing scapular winging and wasting of proximal arm muscles.
Fig. 4. A 14-year-old boy with FSHD showing sloping shoulders, inability to raise arms above shoulders, and inability to close his eyelids completely. In addition, he had difficulty in pursing the lips and could not whistle (onset at about 2 years of age). His CPK was 1295 (normal: 0–200 U/L). Molecular genetic analysis revealed FSHD allele 1 of 18 kb and FSHD allele 2 of >48 kb (FSHD deletion, 12–37; marginal, 38–41; no deletion, ≥42). The mother and several other family members are also affected.
Fig. 3. An adult with FSHD showing facial weakness and inability to smile, purse the lips, and whistle.
Familial Adenomatous Polyposis of DNA per cell (aneuploidy): This pathway accounts for: a) All cases of colorectal cancers associated with FAP b) Nearly 85% of sporadic colorectal cancers ii. The pathway of c-myc and β-catenin as downstream targets appears to impact on the kinetochore and microtubule attachment iii. Mutations in APC interfere with the way that epithelial cells divide and distribute their nuclear DNA b. Microsatellite instability i. Produced by defects of the DNA base mismatch repair system ii. This pathway accounts for: a) 15% of sporadic colorectal cancers b) Most cases of hereditary nonpolyposis colorectal cancer 5. Genotype–phenotype correlation a. FAP phenotype expressed in an individual depends in part on the site of the germline APC mutation i. Attenuated familial adenomatous polyposis coli occurs when there is a truncating mutation in the extreme ends of the APC coding sequence ii. Mutations between codons 169 and 1393 resulting in classic FAP iii. Mutations between codons 1250 and 1464, especially around codon 1300, resulting in profuse colorectal polyposis and earlier onset of gastrointestinal polyps iv. Retinal lesions (congenital hypertrophy of the retinal pigment epithelium, a condition present at any age in 60% of FAP families) occur only with mutations between codons 457 and 1444 v. Up to 60% of patients with mutations between codons 1445 and 1580 result in desmoids b. Limited clinical application of genotype–phenotype correlation: considerable phenotypic variability exists even among individuals and families with identical genotypic mutations
Germline mutations in the adenomatous polyposis coli gene (APC) cause the most common form of hereditary polyposis syndromes termed familial adenomatous polyposis (FAP). The incidence is approximately one in 8300 to one in 13,000 live births.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant with high penetrance (80– 100%) b. Spontaneous mutations account for approximately 30% of cases 2. Caused by germline mutations in the adenomatous polyposis coli (APC) gene on chromosome 5q21 a. More than 300 different disease-causing mutations of the APC gene are currently identified b. Nonsense or frameshift mutations that result in a truncated protein in nearly all of the germline mutations in APC c. Nearly 80% of FAP families have identifiable germline mutations in one allele of APC in affected individuals d. Similar high incidence of germline mutations is seen in the FAP variant, Gardner syndrome 3. APC gene a. A large gene consisting of approximately 6 kilobases in length b. A tumor suppressor gene encoding for a 2843-amino acid protein with a putative role in: i. Cell adhesion ii. Signal transduction iii. Transcriptional activation c. The causative germline defect of APC gene predispose to the following conditions: i. FAP ii. Nearly obligatory colorectal cancers d. Loss of second APC allele either by somatic mutation or loss of heterozygosity in the earliest premalignant lesions: i. Dysplastic aberrant crypt foci ii. Small adenomatous polyps e. Adenoma formation i. Beginning with loss of function of the APC tumor suppressor gene ii. Followed by activation of the K-ras oncogene iii. Subsequent loss of function of genes on chromosome 18q and inactivation of p53 ushers in malignant degeneration 4. Colorectal carcinogenesis: involves two principal pathways: a. Chromosomal instability i. Deletion of portions of a chromosome results in loss of specific genes and abnormal amounts
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1. Spectrum of disease activity a. Attenuated FAP (AFAP) i. The number of adenomatous polyps is less than 100 ii. A later age of onset for colorectal cancers b. Fulminant FAP i. With hundreds to thousands of polyps at a young age ii. A nearly 100% risk of developing colorectal cancers by the age of 40
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2. Usually asymptomatic until puberty when colonic polyps begins to develop 3. Average age of onset of polyps: 25 years 4. Presenting symptoms a. Rectal bleeding: the most common symptom b. Diarrhea c. Anemia d. Abdominal pain e. Change in bowel habits occurring approximately 8 years later 5. Congenital hypertrophy of retinal pigment epithelium a. Multiple and bilateral lesions: a sensitive phenotypic marker that can direct clinical screening tests prior to or in lieu of genetic screening in an at-risk member of a FAP kindred b. Generally a benign condition but low-grade adenocarcinoma of the retina has been reported in several individuals with this condition 6. Extracolonic features a. Duodenal or periampullary polyps (5–10% lifetime risk) i. May progress to cancer ii. 5% of these patients develop malignant transformation within 20 years after the onset of polyps b. Other small intestinal tract polyps: rare c. Adenomas of the ileal pouch may follow proctocolectomy d. Pancreatic (2%) and biliary tract cancers: rare e. Adrenal adenomas: rare f. Gastric polyps i. Typically benign fundic gland polyps ii. Adenomatous in rare cases iii. An increased rate of gastric cancer in some kindreds iv. Gastric cancer occur more frequently than duodenal cancer in Japanese FAP kindreds (Opposite is true for FAP kindreds with European Caucasian descent) v. Gastric adenomas occur in 50% of Japanese FAP kindreds g. Papillary thyroid carcinomas i. Affect about 1–2% of patients with FAP ii. One-hundred fold increased risk in the women with FAP iii. Activation of ret/ptc1 oncogene in FAP-associated thyroid papillary carcinomas h. Hepatoblastomas: a 1–3% risk of developing hepatoblastomas from birth until 6 years of age in infants and children who are at risk or known APC mutation carriers i. Brain (medulloblastoma) (<1%) 7. Desmoid tumors a. Also known as mesenteric fibromatosis b. A relatively common complication of FAP i. A lifetime risk for men: 8% ii. A lifetime risk for women: 13% c. No metastatic potential but can be both life-threatening or problematic in treatment when the lesions slowly expand: i. To involve the intra abdominal cavity ii. To surround the nervous or vascular systems
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d. Conditions which may accelerate the growth i. Surgery ii. Estrogen receptor antagonnists iii. Radiation iv. Chemotherapy e. Common recurrence 8. FAP variants a. Gardner syndrome i. Refers to FAP with additional extra intestinal phenotypic manifestations accompanying colonic polyposis a) Osteomas b) Sebaceous cysts c) Lipomas d) Desmoids e) Dental abnormalities ii. Caused by mutations in the APC gene b. Attenuated FAP i. Characterized by the development of significantly fewer colonic adenomas (<100) ii. Typically right-sided polyps iii. 70% of patients develop colorectal cancers by age 65 if polypectomy is not performed iv. Presence of fundic gland polyps, a clue to the possible diagnosis of AFAP c. Turcot syndrome i. Characterized by medulloblastoma in association with colonic polyposis and colorectal cancers ii. Caused by germline APC mutations iii. Variable inter- and intrafamilial phenotypic expression 9. Differential diagnosis with two other main polyposis syndromes and one nonpolyposis syndrome, all of which are associated with an increased risk of GI cancer, especially colorectal cancer a. Juvenile polyposis i. An autosomal dominant disorder ii. Caused by at least two separate genes a) SMAD4/DPC4 in chromosome 18q21 b) BMPR1A/Alk3 in chromosome 10q21-22 iii. Characterized by multiple juvenile polyps of the colorectum iv. Also involves the stomach and the small intestine v. Large polyps a) Commonly lobulated b) Adenomatous dysplasia in 50% of cases, giving rise to the increased risk of colorectal cancer b. Peutz-Jeghers polyposis i. An autosomal dominant disorder ii. Caused by mutations of the LKB1 gene on 19p13.3 iii. Characteristics a) Mucocutaneous melanin pigmentation b) Harmatomatous intestinal polyposis iv. Sites of polyps a) Affect small intestine preferentially b) Also affect stomach and large intestine c. Hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome)
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i. An autosomal dominant disorder ii. Caused by mutations of three DNA mismatch repair genes a) MSH2 (2p21-23) b) MLH1 (3p21) c) MSH6 (2p16) iii. More common than the polyposis syndromes iv. Predominant tumors a) Colorectal cancer b) Endometrial cancer v. Other cancer types: cancers of the stomach, ovary, ureter and renal pelvis, bile ducts, kidney, small intestine, and brain tumors
DIAGNOSTIC INVESTIGATIONS 1. Detection of FAP in known kindreds a. Retinoscopy: presence of more than three pigmented ocular fundic lesions confirms the diagnosis of FAP b. Flexible sigmoidoscopy c. Presymptomatic APC gene testing i. Indications a) Children and siblings of affected individuals with FAP or AFAP: usually delayed until the early teenage years (10 year or older) when screening by flexible sigmoidoscopy would normally commence b) Patients with an unusually high number of colorectal adenomas for their age but not enough to be clinically diagnostic of classical FAP (≥20 cumulative colorectal adenomas, suspected AFAP) c) ≥100 colorectal adenomas ii. Methods a) Protein truncation testing of peripheral blood lymphocytes: detects APC mutation in more than 80–90% of affected families b) Conformation strand gel electrophoresis c) Single-strand conformation polymorphism d) Direct sequencing e) Linkage analysis to markers on chromosome 5q iii. Germline APC testing: the most efficient means for identifying gene carriers within an FAP kindred iv. Direct sequencing targeted at the known region of the APC gene if a mutation has already been detected within one member of a kindred a) Cost effective b) Nearly 90% accurate means of APC testing 2. Screening in FAP a. Colonoscopic examination for at-risk and APC mutation carriers, initiate at 10–12 years of age b. Flexible sigmoidoscopy for at-risk individuals with unknown mutation status i. Annually from age 10–15 ii. Biennially from age 26–35 iii. Every third year from age 36–50 c. Upper GI tract endoscopy for at-risk individuals with colorectal polyps and known gene carriers
d. Annual physical examination to assess thyroid nodules e. Hepatoblastoma screening in children with FAP (atrisk or mutation-positive carriers until age 6) i. Annual screening by liver ultrasonography ii. Annual serum α-fetoprotein levels f. Medulloblastoma screening: brain imaging for symptomatic or known Turcot syndrome kindreds g. Imagings i. CT scan for desmoid tumors of the mesentery ii. MRI to delineate vascular involvement and to predict desmoid growth 3. Screening in AFAP a. Colonoscopy required for individual at risk for AFAP b. Continued screening in the individual with AFAP because of the later age of onset of polyps
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Not increased in a de novo case ii. 50% if a parent is affected b. Patient’s offspring: a 50% risk of inheriting the condition and virtually all children who inherit the condition will develop polyposis 2. Prenatal diagnosis a. Molecular genetic testing of the APC gene on fetal DNA obtained from amniocentesis or CVS for fetuses at 50% risk for FAP if a clinically diagnosed relative has an identified disease-causing APC gene alteration b. Linkage analysis if the family is informative for linked markers 3. Management a. FAP i. Prophylactic surgery remains the best means to minimize the risk of developing colorectal cancers. ii. Consider colectomy a) By late teen years for cancer prophylaxis for both gene carriers and at-risk individuals with polyposis b) Without colectomy, colorectal cancer is inevitable, appearing approximately 10–15 years after the onset of polyposis iii. Specific surgical recommendation a) Proctocolectomy with mucosectomy b) Ileal pouch anal anastomoses c) Ileorectal anastomosis iv. Surgical removal of osteomas for cosmetic reasons v. Treatments for desmoid tumors a) Surgical excision: associated with high rates of recurrence b) Nonsteroidal anti-inflammatory drugs (sulindac, celecoxib) (use before colectomy): remains experimental c) Antiestrogens d) Cytotoxic chemotherapy e) Radiation vi. Celecoxib, a selective cyclooxygenase-2 (prostaglandin synthetase) inhibitor
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a) Reduces by 28% the mean number of polyps in adult patients with FAP b) Potential use of this class of drugs as chemopreventive and therapeutic agents: subject of intense current investigation b. AFAP i. Endoscopy and polypectomy ii. Surgery: ileorectostomy rather than ileal pouch anal anastomosis is recommended because the rectum is relatively spared by polyposis a) For recurrent, numerous polyposis b) For the presence of aggressive histologic features iii. Continued need for annual endoscopic evaluation of the rectal remnant c. Pre- and post-test genetic counseling i. A pretest counseling session covering: a) The nature of the disease itself b) The genetic aspects c) The implications of positive and negative test results on future screenings d) On insurability and family relationships ii. A posttest counseling session a) Disclosure of the results b) Addressing psychological consequences d. Potential consequences of genetic testing for hereditary colorectal cancer (Trimbath and Giardiello, 2002) i. Positive consequences if the result is gene positive (the disease-causing mutation detected) a) Removal of uncertainty b) Early detection of polyps and prevention of cancer c) Greater ability to plan the future including family and career decisions d) Increased compliance with colonic screening/surveillance e) Greater choice of surgical and medical management ii. Negative consequences if the result is gene positive (the disease-causing mutation detected) a) Psychological distress, including anxiety, depression, anger, or denial b) Changes in family psychosocial dynamics c) Stigmatization d) Increased fear about surgery or death e) Children at 50% risk of disease f) Guilt/worry about children g) Colon surgery and possible lifestyle changes iii. Positive consequences if the result is gene negative (truly negative for gene mutation identified in family) a) Removal of uncertainty b) Children not at risk c) Fewer medical exams and costs d) Better insurability iv. Negative consequences if the result is gene negative (truly negative for gene mutation identified in family) a) Survival guilt (guilt about being unaffected when other family members are affected) b) Changes in family psychosocial dynamics
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v. Negative consequences if the result is inconclusive (no pedigree mutation found or variant of unknown significance) a) False sense of security b) Does not rule out risk for disease c) Need for continued screening d) Confusion/anxiety
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Jagelman DG: Extracolonic manifestations of familial polyposis coli. Cancer Genet Cytogenet 27:319–325, 1987. Jagelman DG: Familial Polyposis coli: the clinical spectrum. Prog Clin Biol Res 279:169–175, 1988. Järvinen H: Genetic testing for polyposis: Practical and ethical aspects. Gut 52(Suppl II):ii19–ii22, 2003. Järvinen H, Franssila KO: Familial juvenile polyposis coli; increased risk of colorectal cancer. Gut 25:792–800, 1984. Jones IT, Jagelman DG, Fazio VW, et al.: Desmoid tumors in familial polyposis coli. Ann Surg 204:94–97, 1986. Kim JC, Roh SA, Yu CS, et al.: Familial juvenile polyposis coli with APC gene mutation. Am J Gastroenterol 92:1913–1915, 1997. King JE, Dozois RR, Lindor NM, Ahlquist DA. Care of patients and their families with familial adenomatous polyposis. Mayo Clin Proc 75:57–67, 2000. Klemmer S, Pascoe L, DeCosse J. Occurrence of desmoids in patients with familial adenomatous polyposis of the colon. Am J Med Genet 28:385–392, 1987. Leffall LD Jr, Chung EB, Dewitty RL, et al.: Familial polyposis coli in black patients. Ann Surg 186:324–333, 1977. Leggett B: When is molecular genetic testing for colorectal cancer indicated? J Gastroenterol Hepatol 17:389–393, 2002. Leppert M, Dobbs M, Scambler P, et al.: The gene for familial polyposis coli maps to the long arm of chromosome 5. Science 238:1411–1413, 1987. Lipsky PE: The clinical potential of cyclooxygenase-2-specific inhibitors. Am J Med 106:51S–57S, 1999. Lynch JP, Hoops TC: The genetic pathogenesis of colorectal cancer. Hematol Oncol Clin N Amer 16:775–810, 2002. Lynch HT, Lynch PM, Follett KL, et al.: Familial polyposis coli: heterogeneous polyp expression in 2 kindreds. J Med Genet 16:1–7, 1979. Lynch HT, Boman BM, Fitzgibbons RJ Jr: Familial polyposis coli: genetics, surveillance, and treatment. Nebr Med J 73:329–334, 1988. Murphy EA, Krush AJ: Familial polyposis coli. Prog Med Genet 4:59– 101, 1980.
Matsumoto T, Iida M, Mizuno M, et al.: Serrated adenoma in familial adenomatous polyposis: relation to germline APC gene mutation. Gut 50:401–404, 2002. Nagase H, Miyoshi Y, Horii A, et al.: Correlation between the location of germline mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis. Cancer Res 52:4055–4057, 1992. Nelson RL, Orsay CP, Pearl RK, et al.: The protean manifestations of familial polyposis coli. Dis Colon Rectum 31:699–703, 1988. Nikitin AM, Obukhov VK, Chubarov YY, et al.: Results of a thirty-year study of familial adenomatous polyposis coli. Dis Colon Rectum 40:679–684, 1997. Oving IM, Clevers HC: Molecular causes of colon cancer. Eur J Clin Inv 32:448–457, 2002. Park JG, Han HJ, Kang MS, et al.: Presymptomatic diagnosis of familial adenomatous polyposis coli. Dis Colon Rectum 37:700–707, 1994. Parks TG, Bussey HF, Lockhart-Mummery HE: Familial polyposis coli associated with extracolonic abnormalities. Gut 11:323–329, 1970. Powell SM, Petersen GM, Krush AJ, et al.: Molecular diagnosis of familial adenomatous polyposis. N Engl J Med 329:1982–1987, 1993. Robbins DH, Itzkowitz SH: The molecular and genetic basis of colon cancer. Med Clin North Am 86:1467–1495, 2002. Shepherd NA, Bussey HJR. Polyposis syndromes—an update. Curr Top Pathol 81:323–351, 1990. Soravia C, Berk T, Madlensky L, et al.: Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet 62:1290–1301, 1998. Spirio L, Olschwang S, Groden J, et al.: Alleles of the APC gene: an attenuated form of familial adenomatous polyposis. Cell 75:951–957, 1993. Trimbath JD, Giardiello FM: Review article: genetic testing and counselling for hereditary colorectal cancer. Aliment Pharmacol Ther 16:1843–1857, 2002. Van der Luijt RB, Meera KP, Vasen HF, et al.: Germline mutations in the 3’ part of APC exon 15 do not result in truncated proteins and are associated with attenuated adenomatous polyposis coli. Hum Genet 98:727–734, 1996. Winawer SJ, Fletcher RH, Miller L, et al.: Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 112:594–642, 1997.
FAMILIAL ADENOMATOUS POLYPOSIS
Fig. 1. Colon of an 8-year-old girl with familial adenomatous polyposis. Numerous small polyps were present on the mucosal surface of the entire colon. The polyps measured up to 3 mm in size. Occasional polyps had a slender stalk, up to 2 mm in length. Histologically, the polyps were of tubular (adenomatous) type.
Fig. 2. A segment of colon showing juvenile polyposis. The polyps are large and lobulated. Stalk are present in some of them. The number of polyps is not as numerous as seen in Fig. 1 (AFP).
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Familial Adenomatous Polyposis of DNA per cell (aneuploidy): This pathway accounts for: a) All cases of colorectal cancers associated with FAP b) Nearly 85% of sporadic colorectal cancers ii. The pathway of c-myc and β-catenin as downstream targets appears to impact on the kinetochore and microtubule attachment iii. Mutations in APC interfere with the way that epithelial cells divide and distribute their nuclear DNA b. Microsatellite instability i. Produced by defects of the DNA base mismatch repair system ii. This pathway accounts for: a) 15% of sporadic colorectal cancers b) Most cases of hereditary nonpolyposis colorectal cancer 5. Genotype–phenotype correlation a. FAP phenotype expressed in an individual depends in part on the site of the germline APC mutation i. Attenuated familial adenomatous polyposis coli occurs when there is a truncating mutation in the extreme ends of the APC coding sequence ii. Mutations between codons 169 and 1393 resulting in classic FAP iii. Mutations between codons 1250 and 1464, especially around codon 1300, resulting in profuse colorectal polyposis and earlier onset of gastrointestinal polyps iv. Retinal lesions (congenital hypertrophy of the retinal pigment epithelium, a condition present at any age in 60% of FAP families) occur only with mutations between codons 457 and 1444 v. Up to 60% of patients with mutations between codons 1445 and 1580 result in desmoids b. Limited clinical application of genotype–phenotype correlation: considerable phenotypic variability exists even among individuals and families with identical genotypic mutations
Germline mutations in the adenomatous polyposis coli gene (APC) cause the most common form of hereditary polyposis syndromes termed familial adenomatous polyposis (FAP). The incidence is approximately one in 8300 to one in 13,000 live births.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant with high penetrance (80– 100%) b. Spontaneous mutations account for approximately 30% of cases 2. Caused by germline mutations in the adenomatous polyposis coli (APC) gene on chromosome 5q21 a. More than 300 different disease-causing mutations of the APC gene are currently identified b. Nonsense or frameshift mutations that result in a truncated protein in nearly all of the germline mutations in APC c. Nearly 80% of FAP families have identifiable germline mutations in one allele of APC in affected individuals d. Similar high incidence of germline mutations is seen in the FAP variant, Gardner syndrome 3. APC gene a. A large gene consisting of approximately 6 kilobases in length b. A tumor suppressor gene encoding for a 2843-amino acid protein with a putative role in: i. Cell adhesion ii. Signal transduction iii. Transcriptional activation c. The causative germline defect of APC gene predispose to the following conditions: i. FAP ii. Nearly obligatory colorectal cancers d. Loss of second APC allele either by somatic mutation or loss of heterozygosity in the earliest premalignant lesions: i. Dysplastic aberrant crypt foci ii. Small adenomatous polyps e. Adenoma formation i. Beginning with loss of function of the APC tumor suppressor gene ii. Followed by activation of the K-ras oncogene iii. Subsequent loss of function of genes on chromosome 18q and inactivation of p53 ushers in malignant degeneration 4. Colorectal carcinogenesis: involves two principal pathways: a. Chromosomal instability i. Deletion of portions of a chromosome results in loss of specific genes and abnormal amounts
CLINICAL FEATURES
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1. Spectrum of disease activity a. Attenuated FAP (AFAP) i. The number of adenomatous polyps is less than 100 ii. A later age of onset for colorectal cancers b. Fulminant FAP i. With hundreds to thousands of polyps at a young age ii. A nearly 100% risk of developing colorectal cancers by the age of 40
FAMILIAL ADENOMATOUS POLYPOSIS
2. Usually asymptomatic until puberty when colonic polyps begins to develop 3. Average age of onset of polyps: 25 years 4. Presenting symptoms a. Rectal bleeding: the most common symptom b. Diarrhea c. Anemia d. Abdominal pain e. Change in bowel habits occurring approximately 8 years later 5. Congenital hypertrophy of retinal pigment epithelium a. Multiple and bilateral lesions: a sensitive phenotypic marker that can direct clinical screening tests prior to or in lieu of genetic screening in an at-risk member of a FAP kindred b. Generally a benign condition but low-grade adenocarcinoma of the retina has been reported in several individuals with this condition 6. Extracolonic features a. Duodenal or periampullary polyps (5–10% lifetime risk) i. May progress to cancer ii. 5% of these patients develop malignant transformation within 20 years after the onset of polyps b. Other small intestinal tract polyps: rare c. Adenomas of the ileal pouch may follow proctocolectomy d. Pancreatic (2%) and biliary tract cancers: rare e. Adrenal adenomas: rare f. Gastric polyps i. Typically benign fundic gland polyps ii. Adenomatous in rare cases iii. An increased rate of gastric cancer in some kindreds iv. Gastric cancer occur more frequently than duodenal cancer in Japanese FAP kindreds (Opposite is true for FAP kindreds with European Caucasian descent) v. Gastric adenomas occur in 50% of Japanese FAP kindreds g. Papillary thyroid carcinomas i. Affect about 1–2% of patients with FAP ii. One-hundred fold increased risk in the women with FAP iii. Activation of ret/ptc1 oncogene in FAP-associated thyroid papillary carcinomas h. Hepatoblastomas: a 1–3% risk of developing hepatoblastomas from birth until 6 years of age in infants and children who are at risk or known APC mutation carriers i. Brain (medulloblastoma) (<1%) 7. Desmoid tumors a. Also known as mesenteric fibromatosis b. A relatively common complication of FAP i. A lifetime risk for men: 8% ii. A lifetime risk for women: 13% c. No metastatic potential but can be both life-threatening or problematic in treatment when the lesions slowly expand: i. To involve the intra abdominal cavity ii. To surround the nervous or vascular systems
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d. Conditions which may accelerate the growth i. Surgery ii. Estrogen receptor antagonnists iii. Radiation iv. Chemotherapy e. Common recurrence 8. FAP variants a. Gardner syndrome i. Refers to FAP with additional extra intestinal phenotypic manifestations accompanying colonic polyposis a) Osteomas b) Sebaceous cysts c) Lipomas d) Desmoids e) Dental abnormalities ii. Caused by mutations in the APC gene b. Attenuated FAP i. Characterized by the development of significantly fewer colonic adenomas (<100) ii. Typically right-sided polyps iii. 70% of patients develop colorectal cancers by age 65 if polypectomy is not performed iv. Presence of fundic gland polyps, a clue to the possible diagnosis of AFAP c. Turcot syndrome i. Characterized by medulloblastoma in association with colonic polyposis and colorectal cancers ii. Caused by germline APC mutations iii. Variable inter- and intrafamilial phenotypic expression 9. Differential diagnosis with two other main polyposis syndromes and one nonpolyposis syndrome, all of which are associated with an increased risk of GI cancer, especially colorectal cancer a. Juvenile polyposis i. An autosomal dominant disorder ii. Caused by at least two separate genes a) SMAD4/DPC4 in chromosome 18q21 b) BMPR1A/Alk3 in chromosome 10q21-22 iii. Characterized by multiple juvenile polyps of the colorectum iv. Also involves the stomach and the small intestine v. Large polyps a) Commonly lobulated b) Adenomatous dysplasia in 50% of cases, giving rise to the increased risk of colorectal cancer b. Peutz-Jeghers polyposis i. An autosomal dominant disorder ii. Caused by mutations of the LKB1 gene on 19p13.3 iii. Characteristics a) Mucocutaneous melanin pigmentation b) Harmatomatous intestinal polyposis iv. Sites of polyps a) Affect small intestine preferentially b) Also affect stomach and large intestine c. Hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome)
382
FAMILIAL ADENOMATOUS POLYPOSIS
i. An autosomal dominant disorder ii. Caused by mutations of three DNA mismatch repair genes a) MSH2 (2p21-23) b) MLH1 (3p21) c) MSH6 (2p16) iii. More common than the polyposis syndromes iv. Predominant tumors a) Colorectal cancer b) Endometrial cancer v. Other cancer types: cancers of the stomach, ovary, ureter and renal pelvis, bile ducts, kidney, small intestine, and brain tumors
DIAGNOSTIC INVESTIGATIONS 1. Detection of FAP in known kindreds a. Retinoscopy: presence of more than three pigmented ocular fundic lesions confirms the diagnosis of FAP b. Flexible sigmoidoscopy c. Presymptomatic APC gene testing i. Indications a) Children and siblings of affected individuals with FAP or AFAP: usually delayed until the early teenage years (10 year or older) when screening by flexible sigmoidoscopy would normally commence b) Patients with an unusually high number of colorectal adenomas for their age but not enough to be clinically diagnostic of classical FAP (≥20 cumulative colorectal adenomas, suspected AFAP) c) ≥100 colorectal adenomas ii. Methods a) Protein truncation testing of peripheral blood lymphocytes: detects APC mutation in more than 80–90% of affected families b) Conformation strand gel electrophoresis c) Single-strand conformation polymorphism d) Direct sequencing e) Linkage analysis to markers on chromosome 5q iii. Germline APC testing: the most efficient means for identifying gene carriers within an FAP kindred iv. Direct sequencing targeted at the known region of the APC gene if a mutation has already been detected within one member of a kindred a) Cost effective b) Nearly 90% accurate means of APC testing 2. Screening in FAP a. Colonoscopic examination for at-risk and APC mutation carriers, initiate at 10–12 years of age b. Flexible sigmoidoscopy for at-risk individuals with unknown mutation status i. Annually from age 10–15 ii. Biennially from age 26–35 iii. Every third year from age 36–50 c. Upper GI tract endoscopy for at-risk individuals with colorectal polyps and known gene carriers
d. Annual physical examination to assess thyroid nodules e. Hepatoblastoma screening in children with FAP (atrisk or mutation-positive carriers until age 6) i. Annual screening by liver ultrasonography ii. Annual serum α-fetoprotein levels f. Medulloblastoma screening: brain imaging for symptomatic or known Turcot syndrome kindreds g. Imagings i. CT scan for desmoid tumors of the mesentery ii. MRI to delineate vascular involvement and to predict desmoid growth 3. Screening in AFAP a. Colonoscopy required for individual at risk for AFAP b. Continued screening in the individual with AFAP because of the later age of onset of polyps
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Not increased in a de novo case ii. 50% if a parent is affected b. Patient’s offspring: a 50% risk of inheriting the condition and virtually all children who inherit the condition will develop polyposis 2. Prenatal diagnosis a. Molecular genetic testing of the APC gene on fetal DNA obtained from amniocentesis or CVS for fetuses at 50% risk for FAP if a clinically diagnosed relative has an identified disease-causing APC gene alteration b. Linkage analysis if the family is informative for linked markers 3. Management a. FAP i. Prophylactic surgery remains the best means to minimize the risk of developing colorectal cancers. ii. Consider colectomy a) By late teen years for cancer prophylaxis for both gene carriers and at-risk individuals with polyposis b) Without colectomy, colorectal cancer is inevitable, appearing approximately 10–15 years after the onset of polyposis iii. Specific surgical recommendation a) Proctocolectomy with mucosectomy b) Ileal pouch anal anastomoses c) Ileorectal anastomosis iv. Surgical removal of osteomas for cosmetic reasons v. Treatments for desmoid tumors a) Surgical excision: associated with high rates of recurrence b) Nonsteroidal anti-inflammatory drugs (sulindac, celecoxib) (use before colectomy): remains experimental c) Antiestrogens d) Cytotoxic chemotherapy e) Radiation vi. Celecoxib, a selective cyclooxygenase-2 (prostaglandin synthetase) inhibitor
FAMILIAL ADENOMATOUS POLYPOSIS
a) Reduces by 28% the mean number of polyps in adult patients with FAP b) Potential use of this class of drugs as chemopreventive and therapeutic agents: subject of intense current investigation b. AFAP i. Endoscopy and polypectomy ii. Surgery: ileorectostomy rather than ileal pouch anal anastomosis is recommended because the rectum is relatively spared by polyposis a) For recurrent, numerous polyposis b) For the presence of aggressive histologic features iii. Continued need for annual endoscopic evaluation of the rectal remnant c. Pre- and post-test genetic counseling i. A pretest counseling session covering: a) The nature of the disease itself b) The genetic aspects c) The implications of positive and negative test results on future screenings d) On insurability and family relationships ii. A posttest counseling session a) Disclosure of the results b) Addressing psychological consequences d. Potential consequences of genetic testing for hereditary colorectal cancer (Trimbath and Giardiello, 2002) i. Positive consequences if the result is gene positive (the disease-causing mutation detected) a) Removal of uncertainty b) Early detection of polyps and prevention of cancer c) Greater ability to plan the future including family and career decisions d) Increased compliance with colonic screening/surveillance e) Greater choice of surgical and medical management ii. Negative consequences if the result is gene positive (the disease-causing mutation detected) a) Psychological distress, including anxiety, depression, anger, or denial b) Changes in family psychosocial dynamics c) Stigmatization d) Increased fear about surgery or death e) Children at 50% risk of disease f) Guilt/worry about children g) Colon surgery and possible lifestyle changes iii. Positive consequences if the result is gene negative (truly negative for gene mutation identified in family) a) Removal of uncertainty b) Children not at risk c) Fewer medical exams and costs d) Better insurability iv. Negative consequences if the result is gene negative (truly negative for gene mutation identified in family) a) Survival guilt (guilt about being unaffected when other family members are affected) b) Changes in family psychosocial dynamics
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v. Negative consequences if the result is inconclusive (no pedigree mutation found or variant of unknown significance) a) False sense of security b) Does not rule out risk for disease c) Need for continued screening d) Confusion/anxiety
REFERENCES Aitken RJ, Elliot MS, Torrington M, et al.: Twenty year experience with familial polyposis coli in Cape Town. Br J Surg 73:210–213, 1986. Ao A, Wells D, Handyside AH, et al.: Preimplantation genetic diagnosis of inherited cancer: familial adenomatous polyposis coli. J Assist Reprod Genet 15:140–144, 1998. Bisgaard ML, Fenger K, Bulow S, et al.: Familial adenomatous polyposis (FAP): frequency, penetrance and mutation rate. Hum Mutat 3:121–125, 1994. Bjork J, Akerbant H, Iselius L, et al.: Periampullary adenomas and adenocarcinomas in familial adenomatous polyposis: cumulative risks and APC gene mutations. Gastroenterol 121:1127–1135, 2001. Boardman LA: Heritable colorectal cancer syndromes: recognition and preventive management. Gastroenterol Clin 31:1107–1131, 2002. Bülow S, Holm NV, Hauge M: The incidence and prevalence of familial polyposis coli in Denmark. Scand J Soc Med 14:67–74, 1986. Bülow S, Lauritsen KB, Johansen A, et al.: Gastroduodenal polyps in familial polyposis coli. Dis Colon Rectum 28:90–93, 1985. Bussey HJ: Familial polyposis coli. Pathol Annu 14 Pt 1:61–81, 1979. Bussey HJ: Historical developments in familial polyposis coli. Semin Surg Oncol 3:67–70, 1987. Cetta F, Chiappetta G, Melillo RM, et al.: The ret/ptc 1 oncogene is activated in familial adenomatous polyposis-associated thyroid papillary carcinomas. J Clin Endocrinol Metab 83:1003–1006, 1998. Clark SK, Neale KF, Landgrebe JC, et al.: Desmoid tumours complicating familial adenomatous polyposis. Br J Surg 86:1185–1189, 1999. Cohen SB: Familial polyposis coli and its extracolonic manifestations. J Med Genet 19:193–203, 1982. Corredor J, Wambach J, Barnard J: Gastrointestinal polyps in children: Advances in molecular genetics, diagnosis, and management. J Pediatr 138:621–628, 2001. Cruz-Correa M, Giardiello FM: Diagnosis and management of hereditary colon cancer. Hematol Oncol Clin N Amer 17:537–549, 2003. Eccles DM, Lunt PW, Wallis Y, et al.: An unusually severe phenotype for familial adenomatous polyposis. Arch Dis Child 77:431–435, 1997. Fodde R, Kuipers J, Rosenberg C, et al.: Mutations in the APC tumour suppressor gene cause chromosomal instability. Nature Cell Biol 3:433–438, 2001. Forbes D, Rubin S, Trevenen C, et al.: Familial polyposis coli in childhood. Clin Invest Med 10:5–9, 1987. Gebert HF, Jagelman DG, McGannon E: Familial polyposis coli. Am Fam Physician 33:127–137, 1986. Gebert JF, Dupon C, Kadmon M, et al.: Combined molecular and clinical approaches for the identification of families with familial adenomatous polyposis coli. Ann Surg 229:350–361, 1999. Giardiello FM, Petersen GM, Pintadosi S. APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis. Gut 40:521–525, 1997. Giardiello FM, Yang VW, Hylind LM, et al.: Primary chemoprevention of familial adenomatous polyposis. N Engl J Med 346:1054–1059, 2002. Groden J, Thliveris A, Samowitz W, et al.: Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:589–600, 1991. Hargest R, Eldin A, Williamson R: Gene therapy for familial adenomatous polyposis. Prolonged expression of the adenomatous polyposis coli gene after lipofection into mouse colon in vivo. Adv Exp Med Biol 451:385–391, 1998. Heimann TM, Bolnick K, Aufses AH, Jr.: Results of surgical treatment for familial polyposis coli. Am J Surg 152:276–278, 1986. Herrera-Ornelas L, Elsiah S, Petrelli N, et al.: Causes of death in patients with familial polyposis coli (FPC). Semin Surg Oncol 3:109–117, 1987. Hughes LJ, Michels VV. Risk of hepatoblastoma in familial adenomatous polyposis. Am J Med Genet 43:1023–1025, 1992. Jagelman DG: Familial polyposis coli. Surg Clin North Am 63:117–128, 1983.
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Jagelman DG: Extracolonic manifestations of familial polyposis coli. Cancer Genet Cytogenet 27:319–325, 1987. Jagelman DG: Familial Polyposis coli: the clinical spectrum. Prog Clin Biol Res 279:169–175, 1988. Järvinen H: Genetic testing for polyposis: Practical and ethical aspects. Gut 52(Suppl II):ii19–ii22, 2003. Järvinen H, Franssila KO: Familial juvenile polyposis coli; increased risk of colorectal cancer. Gut 25:792–800, 1984. Jones IT, Jagelman DG, Fazio VW, et al.: Desmoid tumors in familial polyposis coli. Ann Surg 204:94–97, 1986. Kim JC, Roh SA, Yu CS, et al.: Familial juvenile polyposis coli with APC gene mutation. Am J Gastroenterol 92:1913–1915, 1997. King JE, Dozois RR, Lindor NM, Ahlquist DA. Care of patients and their families with familial adenomatous polyposis. Mayo Clin Proc 75:57–67, 2000. Klemmer S, Pascoe L, DeCosse J. Occurrence of desmoids in patients with familial adenomatous polyposis of the colon. Am J Med Genet 28:385–392, 1987. Leffall LD Jr, Chung EB, Dewitty RL, et al.: Familial polyposis coli in black patients. Ann Surg 186:324–333, 1977. Leggett B: When is molecular genetic testing for colorectal cancer indicated? J Gastroenterol Hepatol 17:389–393, 2002. Leppert M, Dobbs M, Scambler P, et al.: The gene for familial polyposis coli maps to the long arm of chromosome 5. Science 238:1411–1413, 1987. Lipsky PE: The clinical potential of cyclooxygenase-2-specific inhibitors. Am J Med 106:51S–57S, 1999. Lynch JP, Hoops TC: The genetic pathogenesis of colorectal cancer. Hematol Oncol Clin N Amer 16:775–810, 2002. Lynch HT, Lynch PM, Follett KL, et al.: Familial polyposis coli: heterogeneous polyp expression in 2 kindreds. J Med Genet 16:1–7, 1979. Lynch HT, Boman BM, Fitzgibbons RJ Jr: Familial polyposis coli: genetics, surveillance, and treatment. Nebr Med J 73:329–334, 1988. Murphy EA, Krush AJ: Familial polyposis coli. Prog Med Genet 4:59– 101, 1980.
Matsumoto T, Iida M, Mizuno M, et al.: Serrated adenoma in familial adenomatous polyposis: relation to germline APC gene mutation. Gut 50:401–404, 2002. Nagase H, Miyoshi Y, Horii A, et al.: Correlation between the location of germline mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis. Cancer Res 52:4055–4057, 1992. Nelson RL, Orsay CP, Pearl RK, et al.: The protean manifestations of familial polyposis coli. Dis Colon Rectum 31:699–703, 1988. Nikitin AM, Obukhov VK, Chubarov YY, et al.: Results of a thirty-year study of familial adenomatous polyposis coli. Dis Colon Rectum 40:679–684, 1997. Oving IM, Clevers HC: Molecular causes of colon cancer. Eur J Clin Inv 32:448–457, 2002. Park JG, Han HJ, Kang MS, et al.: Presymptomatic diagnosis of familial adenomatous polyposis coli. Dis Colon Rectum 37:700–707, 1994. Parks TG, Bussey HF, Lockhart-Mummery HE: Familial polyposis coli associated with extracolonic abnormalities. Gut 11:323–329, 1970. Powell SM, Petersen GM, Krush AJ, et al.: Molecular diagnosis of familial adenomatous polyposis. N Engl J Med 329:1982–1987, 1993. Robbins DH, Itzkowitz SH: The molecular and genetic basis of colon cancer. Med Clin North Am 86:1467–1495, 2002. Shepherd NA, Bussey HJR. Polyposis syndromes—an update. Curr Top Pathol 81:323–351, 1990. Soravia C, Berk T, Madlensky L, et al.: Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet 62:1290–1301, 1998. Spirio L, Olschwang S, Groden J, et al.: Alleles of the APC gene: an attenuated form of familial adenomatous polyposis. Cell 75:951–957, 1993. Trimbath JD, Giardiello FM: Review article: genetic testing and counselling for hereditary colorectal cancer. Aliment Pharmacol Ther 16:1843–1857, 2002. Van der Luijt RB, Meera KP, Vasen HF, et al.: Germline mutations in the 3’ part of APC exon 15 do not result in truncated proteins and are associated with attenuated adenomatous polyposis coli. Hum Genet 98:727–734, 1996. Winawer SJ, Fletcher RH, Miller L, et al.: Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 112:594–642, 1997.
FAMILIAL ADENOMATOUS POLYPOSIS
Fig. 1. Colon of an 8-year-old girl with familial adenomatous polyposis. Numerous small polyps were present on the mucosal surface of the entire colon. The polyps measured up to 3 mm in size. Occasional polyps had a slender stalk, up to 2 mm in length. Histologically, the polyps were of tubular (adenomatous) type.
Fig. 2. A segment of colon showing juvenile polyposis. The polyps are large and lobulated. Stalk are present in some of them. The number of polyps is not as numerous as seen in Fig. 1 (AFP).
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Familial Hyperlysinemia v. Dominant and recessive forms of inherited subluxation of the lens
Familial hyperlysinemia is an inborn error of metabolism caused by a defect in the bifunctional protein α-aminoadipic semialdehyde synthase.
DIAGNOSTIC INVESTIGATIONS
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. A heterogeneous group of at least three disorders a. Caused by mutations in the gene encoding α-aminoadipic semialdehyde synthase (AASS), the bifunctional protein that contains both lysine-ketoglutarate reductase (LKR) and saccharopine dehydrogenase (SDH) activity b. Deficiency in lysine-ketoglutarate reductase (LKR) and/or saccharopine dehydrogenase (SDH) activities leads to a clinical phenotype characterized by hyperlysinemia, lysinuria and variable saccharopinuria c. Deficiency in saccharopine oxidoreductase activity, along with deficient LKR and SDH activities, is also observed in children with familial hyperlysinemia.
1. 2. 3. 4.
Plasma amino acid quantitative analysis: hyperlysinemia Urinary amino acid quantitative analysis: hyperlysinuria Urinary organic acid analysis: variable saccharopinuria Cultured skin fibroblasts: absent lysine-ketoglutarate reductase and saccharopine dehydrogenase activities 5. Molecular genetic study: homozygous deletion in AASS gene 6. EEG for seizures
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased unless the spouse is a carrier in which case 50% of the offspring will be affected 2. Prenatal diagnosis has not been reported 3. Management a. Dietary control with reduction in lysine intake b. Other supportive therapies
CLINICAL FEATURES 1. Mental retardation of varying degree 2. Other neurolomuscular manifestations a. Poor muscle tone (hypotonia) b. Muscle weakness c. Clumsy hand movements d. Cross adductor reflexes e. Ankles clonus f. High arched feet g. Awkward gait h. Hyperactive deep tendon reflexes i. Seizures j. Progressive spastic paraparesis/diplegia 3. Developmental delay, especially speech delay 4. Hyperactive behavior 5. Ligamentous laxity 6. Ocular manifestations a. Bilateral subluxated lenses (ectopia lentis) b. Lateral rectus muscle paresis c. Bilateral spherophakia 7. Hyperlysinemia alone may not be associated with a clinical phenotype 8. Differential diagnosis a. Hyperlysinemia: periodic hyperlysinemia with ammonia intoxication b. Ectopia lentis i. Marfan syndrome ii. Homocystinuria iii. Marchesani syndrome iv. Ehlers-Danlos syndromes
REFERENCES Armstrong MD, Robinow M: A case of hyperlysinemia: biochemical and clinical observations. Pediatrics 39:546–554, 1967. Carson NAJ, Scally BG, Neill DW, et al.: Saccharopinuria: a new inborn error of lysine metabolism. Nature 218:679, 1968. Cederbaum SD, Shaw KN, Dancis J, et al.: Hyperlysinemia with saccharopinuria due to combined lysine-ketoglutarate reductase and saccharopine dehydrogenase deficiencies presenting as cystinuria. J Pediatr 95:234–238, 1979. Cox RP: Errors in lysine metabolism. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001, Chapter 86, Pp 1965–1970. Dancis J, Hutzler J, Cox RP, et al.: Familial hyperlysinemia with lysineketoglutarate reductase insufficiency. J Clin Invest 48:1447–1452, 1969. Dancis J, Hutzler J, Woody NC, et al.: Multiple enzyme defects in familial hyperlysinemia. Pediatr Res 10:686–691, 1976. Dancis J, Hutzler J, Cox RP: Familial hyperlysinemia: enzyme studies, diagnostic methods, comments on terminology. Am J Hum Genet 31: 290– 299, 1979. Dancis J, Hutzler J, Ampola MG, et al.: The prognosis of hyperlysinemia: an interim report. Am J Hum Genet 35:438–442, 1983. Ghadimi H, Binnington VI, Pecora P: Hyperlysinemia associated with retardation. N Engl J Med 273:723–729, 1965. Ghadimi H, Zischka R, Binnington VI: Further studies on hyperlysinemia associated with retardation. Am J Dis Child 113:146–151, 1967. Markovitz PJ, Chuang DT, Cox RP: Familial hyperlysinemias: purification and characterization of the bifunctional aminoadipic semialdehyde synthase with lysine-ketoglutarate reductase and saccharopine dehydrogenase activities. J Biol Chem 259:11643–11646, 1984. Özalp I, Hasanoˇglu A, Tunçbilek E, et al.: Hyperlysinemia without clinical findings. Acta Paediatr Scand 70:951–953, 1981.
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FAMILIAL HYPERLYSINEMIA Sacksteder KA, Biery BJ, Morrell JC, et al.: Identification of the alphaaminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia. Am J Hum Genet 66:1736–1743, 2000. Simell O, Visakarpi JK, Donner M: Saccharopinuria. Arch Dis Child 47:52, 1972. Smith TH, Holland MG, Woody NC: Ocular manifestations of familial hyperlysinemia. Trans Am Acad Ophthalmol Otolaryngol 75:355–360, 1971. Van Gelderen HH, Teijema HL: Hyperlysinemia: harmless inborn error of metabolism? Arch Dis Child 48:892, 1973. Woody NC: Hyperlysinemia. Am J Dis Child 108:543, 1964.
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Woody NC, Ong EB: Paths of lysine degradation in patients with hyperlysinemia. Pediatrics 40:986–992, 1967. Woody NC, Pupene MB: Excretion of pipecolic acid by infants and by patients with hyperlysinemia. Pediatr Res 4:89–95, 1970. Woody NC, Pupene MB: Excretion of hypusine by children and by patients with familial hyperlysinemia. Pediatr Res 7:994–995, 1973. Woody NC, Hutzler J, Dancis J: Further studies of hyperlysinemia. Am J Dis Child 112:577–580, 1966. Yiannikas C, Cordato D: Familial hyperlysinemia in a patient presenting with progressive spastic paraparesis. Neurology 47:846, 1996.
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Fig. 1. A 27-year-old female with hyperlysinemia showing global delay, spasticity, rigidity, and multiple joint contractures. She was diagnosed to have hyperlysinemia since about 1 1/2 years of age with markedly elevated serum lysine of 1,618 μM (45–144). As a neonate, she had frequent emesis and noted to be stiff and irritable with progressive developmental delay. She began to walk with a ramp and rails until approximately four years of age when she started to develop increased spasticity and significant scissoring, necessitating adductor release. On the recent plasma amino acid analysis, lysine was markedly elevated at 1252 μM (41–225).
Fanconi Anemia c. Phenotypic reversion to normal i. Correlated with intragenic homologous recombination in compound heterozygous patients giving rise to the segregation of a wild type allele at the disease locus ii. The resulting cells are thus essentially cured from the disease iii. Progeny from a reverted stem cell expected to have a proliferative advantage over affected cells and thus may gradually expand and take over hematopoiesis d. Patients with a high proportion of reverted cells may be falsely diagnosed as negatives 7. Defective FA functional pathway a. Defective DNA repair b. Prolonged G2/M transition in the cell cycle c. Increased oxygen sensitivity d. Abnormally regulated apoptosis and accelerated telomere shortening e. Defective hemopoiesis
In 1927 Fanconi described a familial form of aplastic anemia in three brothers with short stature, hypogonadism and skin pigmentation. The incidence of Fanconi anemia (FA) is estimated to be 1 in 360,000 births. The carrier frequency is estimated as 1 in 300 in Europe and the United States. Founder mutations have been described in Ashkenazi Jews, who have carrier frequency of 1 in 89.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal recessive b. Genetically and phenotypically heterogeneous 2. Presence of at least 11 complementation groups delineated by cell fusion studies a. FA-A (65–70%) b. FA-B (<2%) c. FA-C (10–15%) d. FA-D1 e. FA-D2 f. FA-E (2–5%) g. FA-F (<2%) h. FA-G (10%) i. FA-I j. FA-J k. FA-L 3. Eight FA genes have been identified by complementation cloning or by positional cloning techniques: a. FANCA, mapped to 16q24.3 b. FANCB, mapped to 13q12.3 c. FANCC, mapped to 9q22.3 d. FANCD1, mapped to 13q12.3 e. FANCD2, mapped to 3p25.3 f. FANCE, mapped to 6p21.22 g. FANCF, mapped to 11p15 h. FANCG, mapped to 9p13 4. A candidate-gene approach leads to the breast cancer susceptibility gene BRCA2 as the gene defective in FA-D1 patients. The Fanconi-BRCA pathway is activated in response to certain kinds of DNA damage, particularly DNA agents that cause double-strand breaks in DNA such as ultraviolet light, ionizing radiation, and cisplatin 5. FA cells are hypersensitive to cross-linking agents such as diepoxybutane (DEB), nitrogen mustard (NTM) and mitomycin C (MMC): induction of chromosomal aberrations (breaks and rearrangements) 6. Reverse mosaicism a. Not infrequent in Fanconi anemia b. Presence of two populations of lymphocytes in mosaic Fanconi anemia patients i. One being hypersensitive to the clastogen ii. The other normal
CLINICAL FEATURES
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1. Variable clinical expression and severity 2. Hematological abnormalities secondary to bone marrow failure (>90%) a. Clinical hallmark of Fanconi anemia b. Usually starting in childhood c. Increased incidence of aplastic anemia, myelodysplastic syndrome, and acute myeloid leukemia d. Initial presentation i. Pallor ii. Bleeding iii. Recurrent infections e. Thrombocytopenia or leukopenia typically preceding anemia f. Severe progressive pancytopenia due to loss of hematopoietic stem cells: the cardinal clinical feature g. Increased risk of infections due to neutropenia h. Sweet syndrome (neutrophilic skin infiltration) reported in a few patients with Fanconi anemia and myelodysplastic syndrome 3. Diverse congenital abnormalities (>63%) a. Growth retardation b. Short stature (60%) c. Upper limb anomalies (50%) i. Mainly radius and thumb abnormalities a) Absent, hypoplastic, or supernumerary thumbs with hypoplastic thenar eminence b) Absent, hypoplastic radii and ulnae associated with abnormal thumbs c) Absent first metacarpal
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d.
e.
f.
g.
h.
i.
j.
ii. Clinodactyly iii. Polydactyly iv. Short fingers v. Transverse palmar crease Other skeletal abnormalities i. Short webbed neck with low hairline ii. Spine anomalies a) Spina bifida b) Scoliosis c) Sacrococcygeal sinus d) Other vertebral anomalies iii. Lower limb anomalies a) Toe syndactyly b) Pes planus c) Abnormal toes d) Congenital hip dislocation Skin pigmentary changes (65%) i. Generalized hyperpigmentation ii. Café au lait spots iii. Hypopigmentation Eye anomalies (25%) i. Microphthalmia ii. Strabismus iii. Epicanthal folds iv. Hypertelorism/hypotelorism v. Ptosis vi. Cataracts vii. Epiphora viii. Nystagmus Ear anomalies (10%) i. Deafness, usually conductive secondary to middle ear abnormalities ii. Abnormal pinna iii. Stenosis or atresia of the external auditory meatus iv. Low-set ears Heart disease i. Congenital heart disease a) Patent ductus arteriosus b) Ventricular septal defect c) Pulmonary stenosis d) Aortic coarctation ii. Cardiomyopathy Renal anomalies (25%) i. Kidney a) Pelvic kidneys b) Horseshoe kidneys c) Hypoplastic/dysplastic kidneys ii. Collecting system (hydronephrosis, hydroureter, reflux) iii. Abnormal artery Gastrointestinal problems i. Atresia a) Esophagus b) Duodenum c) Jejunum ii. Tracheoesophageal fistula iii. Anteriorly placed anus iv. Imperforate anus v. Persistent cloaca
vi. Meckel diverticulum vii. Umbilical hernia viii. Abnormal biliary ducts ix. Megacolon x. Abdominal diastasis xi. Budd-Chiari syndrome xii. Annular pancreas k. CNS abnormalities i. Microcephaly ii. Hydrocephalus iii. Absent septum pellucidum iv. Neural tube defects l. Hypogonadism in males i. Underdeveloped gonads ii. Cryptorchidism iii. Hypospadias iv. Defective spermatogenesis (infertility) v. A few males with Fanconi anemia fathered children m. Hypogonadism in females i. Hypogenitalia ii. Bicornuate uterus iii. Absent uterus or vagina iv. Ovarian atresia v. Delayed menarche vi. Irregular menses vii. Early menopause viii. Successful pregnancies with liveborn children observed n. Absence of obvious congenital abnormalities in approximately 33% of patients with Fanconi anemia 4. Predisposition to malignancy a. Hematologic tumors (60%) i. Acute myelogenous leukemia (30%) ii. Myelodysplastic syndrome (26%) iii. Acute lymphocytic leukemia iv. CMMOL v. Burkitt lymphoma b. Nonhematologic tumors (40%) i. Liver tumors (9%) a) Adenoma b) Hepatocellular carcinoma c) Adenocarcinoma ii. Brain tumor (2%) a) Medulloblastoma b) Astrocytomas iii. Renal tumors (3%) a) Wilm tumor b) Renal cell carcinoma c) Nephroblastoma iv. Squamous cell carcinoma (20%) a) Head and neck b) Vulvar c) Cervix d) Cutaneous e) Anus f) Esophagus v. Miscellaneous tumors (6%) a) Breast carcinoma b) Basal cell carcinoma
FANCONI ANEMIA
c) Neuroblastoma d) Desmoid tumor e) Gonadoblastoma f) Melanoma g) Neurilemmoma h) Osteogenic sarcoma 5. Cumulative probability of developing leukemia, liver tumors, and solid tumors in FA patients a. Close to 40% by age 30 b. About 50% by age 45 c. An astounding 76% by age 45 6. Prognosis a. Mean survival: 16 years b. Main causes of death i. Pancytopenia which develops in the first decade of life ii. Associated progressive microcytosis iii. Extremely high probability of developing bone marrow failure iv. A predisposition to malignancy, particularly acute myeloid leukemia and aplastic anemia 7. Differential diagnosis a. VATER/VACTERL association overlap with FA i. Vertebral defects ii. Tracheo-esophageal atresia iii. Renal defects iv. Radial ray defects b. Diamond-Blackfan anemia i. Defective erythroid progenitor maturation ii. Normochromic or macrocytic anemia iii. Congenital malformations in over one third of patients a) Head (micrognathia, cleft lip) b) Upper limb defects c) Genitourinary anomalies iv. A heterogeneous disorder a) Sporadic in most cases b) Autosomal dominant in some cases c) Rarely autosomal recessive inheritance c. Nijmegen breakage syndrome i. A rare autosomal recessive disorder ii. Resulting from mutations in NBS1 which codes for the nibrin protein iii. Clinical characteristics a) Immune deficiency b) Microcephaly c) Hypersensitivity to ionizing radiation d. Other chromosomal breakage syndromes (Bloom syndrome, ataxia-telangiectasia) i. Also exhibit high rates of spontaneous chromosomal breakage ii. Only FA cells exhibit increased chromosomal breakage in response to DEB
DIAGNOSTIC INVESTIGATIONS 1. Difficult to diagnose FA because of phenotypic diversity 2. Hematologic investigation a. Progressive decrease in peripheral blood counts, often present by 7–8 years of age
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i. Thrombocytopenia ii. Leukopenia iii. Anemia b. Macrocytic red blood cells, often with increased fetal hemoglobin c. Generally increased serum erythropoietin concentration d. Hypocellular or dysplastic bone marrow e. Bone marrow failure with pancytopenia f. Bone marrow cytogenetic testing: Cytogenetic abnormalities may progress to leukemia or myelodysplastic syndrome 3. DEB testing a. 10- to 100-fold increased chromosomal breakage (breaks, rearrangements, radials, exchanges) of Fanconi anemia cells after incubation of the patient’s cells with chemical clastogen, DEB b. Highly sensitive and specific test for Fanconi anemia c. Allowing diagnosis of Fanconi anemia in persons with diverse clinical features including those without clinically detectable congenital abnormalities d. Used successfully in prenatal diagnosis of Fanconi anemia e. Remains underutilized mainly because there are some clinical conditions in which FA is not usually suspected f. Disadvantage i. Requires a high degree of cytogenetic expertise and meticulous attention to cell culture and safety conditions ii. Fails to distinguish among Fanconi anemia patients in different complementation groups iii. Fails to identify heterozygote carriers of mutant Fanconi anemia genes 4. Cell cycle test a. Alternative to cytogenetic testing b. Diagnostic potential of the cell cycle test for Fanconi anemia c. Based on the observation that Fanconi anemia cells experience difficulties in traversing the S and G2 compartment of the cell cycle d. Limitation of cell cycle test i. Applicable only to nonleukemic cells ii. Confirmatory DEB studies required in cases with evidence for G2-phase arrest 5. Molecular genetic testing a. Complicated by the presence of at least eleven complementation groups b. Direct sequence analysis not clinically available because of the following reasons: i. The number of possible affected genes ii. The large number of possible mutations in each gene iii. The large size of many of the Fanconi anemia genes c. Identification of “common” mutant alleles of the FANCA, FANCC, FANCF, and FANCG genes d. Linkage analysis once a family has been assigned to a complementation group by a functional assay or by the detection of a specific mutant allele using highly polymorphic microsatellite markers located in close proximity to both FAA and FAAC genes
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i. Used for carrier detection ii. Used for prenatal diagnosis 6. Cancer surveillance a. Annual bone marrow examination provides early evidence for myelodysplastic syndrome or leukemia i. Aspirate for cell types ii. Biopsies for cellularity iii. Cytogenetics b. Liver function tests and ultrasound examinations to identify adenomas or hepatomas before becoming symptomatic c. Screening for solid tumors: more complex because of multiplicity of cancer types i. Direct visualization of the oropharynx and fiberoptic endoscopy for screening for aerodigestive cancers and precancerous lesions ii. Gynecologic examinations for vulvar and cervical tumors beginning with menarche
c.
d.
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. 25% chance of inheriting both mutation alleles and being affected ii. 2/3 chance of being carriers in unaffected sibs who have a normal DEB test b. Patient’s offspring: recurrence risk not increased unless the spouse is a carrier, in which case 50% of offspring will be affected; otherwise all offspring of the affected parent will be carriers who will be asymptomatic 2. Prenatal diagnosis a. Prenatal ultrasonography to evaluate fetal anomalies consistent with FA b. Prenatal diagnosis available to at-risk families by CVS, amniocentesis or cordocentesis i. Demonstration of chromosome instability by DEB test ii. Molecular genetic testing of FA gene mutations if the disease-causing mutations are previously characterized in a given family iii. Preimplantation genetic diagnosis possible by using molecular methods, resulting in implantation of an embryo without FA mutations 3. Management a. Supportive care i. Developmental assessment ii. HLA typing of the patient, sibs, and parents in anticipation of possible bone marrow transplantation iii. Full blood typing iv. Packed red blood cells transfusions for symptomatic anemia v. Platelet transfusions for symptomatic thrombocytopenia vi. Antimicrobials for secondary infections b. Surgical care i. Splinting and hand surgery indicated for thumb and radial anomalies
e.
f. g.
ii. Surgery for congenital heart defects and gastrointestinal anomalies such as TE fistula Transient response i. Androgens (oxymetholone) shown to improve the blood counts in approximately 50% of patients ii. Corticosteroids iii. Cytokines iv. Granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor (shown to improve the neutrophil count in some patients) for symptomatic neutropenia Hematopoietic stem cell transplantation may cure aplastic anemia and prevent myelodysplastic syndrome or leukemia i. Peripheral blood stem cells ii. Allogenic bone marrow transplant with a histocompatible sibling donor: treatment of choice iii. Umbilical cord blood offers a potential source of hematopoiesis stem cells for Fanconi anemia patients without sibling matches Successful transplantation obtained by using in vitro fertilization and preimplantation genetic diagnosis of hematopoietic stem cells from a donor selected on the basis of specific, desirable disease and HLA characteristics i. Select embryos which are HLA-identical to the patient and unaffected by FA for intrauterine transfer and let the pregnancy continue to term ii. Obtain the umbilical cord blood from the healthy newborn infant and use it as the source of HLAidentical hematopoietic stem cells to reconstitute normal hematopoiesis in the affected sibling Follow up surveillance for solid malignancies Gene therapy not currently available
REFERENCES Ahmad SI, Hanaoka F, Kirk SH: Molecular biology of Fanconi anaemia—an old problem, a new insight. BioEssays 24:439–448, 2002. Alter BP: Fanconi’s anemia and its variability. Br J Haematol 85:9–14, 1993. Alter BP: Fanconi’s anemia and malignancies. Am J Hematol 53:99–110, 1996. Alter BP: Cancer in Fanconi anemia, 1927–2001. Cancer 97:425–440, 2003. Alter B, Lipton J: Anemia, Fanconi. Emedicine, 2002. http://www.emedicine.com Auerbach AD: Fanconi anemia diagnosis and the diepoxybutane (DEB) test. Exp Hematol 21:731–733, 1993. Auerbach AD, Wolman SR: Susceptibility of Fanconi’s anaemia fibroblasts to chromosome damage by carcinogens. Nature 261:494–496, 1976. Auerbach AD, Min Z, Ghosh R, et al.: Clastogen-induced chromosomal breakage as a marker for first trimester prenatal diagnosis of Fanconi anemia. Hum Genet 73:86–88, 1986. Auerbach AD, Rogatko A, Schroeder-Kurth TM: International Fanconi Anemia Registry: relation of clinical symptoms to diepoxybutane sensitivity. Blood 73:391–396, 1989. Blom E, van de Vrugt HJ, de Vries Y, et al.: Multiple TPR motifs characterize the Fanconi anemia FANCG protein. DNA Repair (Amst) 3:77–84, 2004. Deviren A, Yalman N, Hacihanefioglu S: Differential diagnosis of Fanconi anemia by nitrogen mustard and diepoxybutane. Ann Hematol 82:223–227, 2003. Erdmann J: Fanconi anemia research opens new doors in understanding of cancer. J Nat Cancer Inst 95:1190–1192, 2003. Esmer C, Sanchez S, Ramos S, et al.: DEB test for Fanconi anemia detection in patients with atypical phenotypes. Am J Med Genet 124A:35–39, 2004. Fanconi G: Familial constitutional panmyelocytopathy, Fanconi’s anemia (F.A.). I. Clinical aspects. Semin Hematol 4:233–240, 1967.
FANCONI ANEMIA Giampietro PF, Adler-Brecher B, Verlander PC, et al.: The need for more accurate and timely diagnosis in Fanconi anemia: a report from the International Fanconi Anemia Registry. Pediatrics 91:1116–1120, 1993. Giampietro PF, Verlander PC, Davis JG, et al.: Diagnosis of Fanconi anemia in patients without congenital malformations: an international Fanconi Anemia Registry Study. Am J Med Genet 68:58–61, 1997. Grewal SS, Kahn JP, MacMillan ML, et al.: Successful hematopoietic stem cell transplantation for Fanconi anemia from an unaffected HLA-genotypeidentical sibling selected using preimplantation genetic diagnosis. Blood 103:1147–1151, 2004. Joenje H, Oostra AB, Wijker M, et al.: Evidence for at least eight Fanconi anemia genes. Am J Hum Genet 61:940–944, 1997. Kutler DI, Singh B, Satagopan J, et al.: A 20 year perspective of the International Fanconi Anemia Registry (IFAR). Blood 101:1249–1256, 2002. Liu JM, Buchwald M, Walsh CE, et al.: Fanconi anemia and novel strategies for therapy. Blood 84:3995–4007, 1994. Lo Ten Foe JR, Kwee ML, Rooimans MA, et al.: Somatic mosaicism in Fanconi anemia: molecular basis and clinical significance. Eur J Hum Genet 5:137–148, 1997.
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Rosenberg PS, Greene MH, Alter BP: Cancer incidence in persons with Fanconi anemia. Blood 101:822–826, 2003. Schroeder TM, Tilgen D, Kruger J, et al.: Formal genetics of Fanconi’s anemia. Hum Genet 32:257–288, 1976. Seyschab H, Friedl R, Sun Y, et al.: Comparative evaluation of diepoxybutane sensitivity and cell cycle blockage in the diagnosis of Fanconi anemia. Blood 85:2233–2237, 1995. Shimamura A, Moreau L, D’Andrea A: Fanconi anemia. Gene Reviews, 2004. http://www.genetests.org Shimamura A, de Oca RM, Svenson JL, et al.: A novel diagnostic screen for defects in the Fanconi anemia pathway. Blood 100:4649–4654, 2002. Shipley J, Rodeck CH, Garrett C, et al.: Mitomycin C-induced chromosome damage in fetal blood cultures and prenatal diagnosis of Fanconi’s anemia. Prenat Diagn 4:217, 1984. Tischkowitz MD, Hodgson SV: Fanconi anaemia. J Med Genet 40:1–10, 2003. Wijker M, Morgan NV, Herterich S, et al.: Heterogeneous spectrum of mutations in the Fanconi anemia group A gene. Eur J Hum Genet 7:52–59, 1999.
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Fig. 1. A young boy with Fanconi anemia showing pallor and radial ray defects of the upper extremities.
Fig. 2. An adolescent girl with Fanconi anemia showing similar phenotype.
Femoral Hypoplasia-Unusual Facies Syndrome a) Hypoplastic penis b) Hypoplastic labia majora v. Inferiorly placed kidneys vi. Septated urinary bladder j. Rare cardiovascular anomalies i. Ventricular septal defect ii. Pulmonary stenosis iii. Truncus arteriosus
In 1973, Daentl et al. delineate a distinctive pattern of malformation which includes femoral hypoplasia and unusual facies in four unrelated individuals. The syndrome is also known as femoral facial syndrome.
GENETICS/BASIC DEFECTS 1. Inheritance a. Sporadic in most cases b. Familial cases with autosomal dominant inheritance reported c. Multifactorial trait in some families d. Maternal diabetes causative in more than 20% of the reported cases 2. Possible causes a. Fetal constraint (deformation) due to severe oligohydramnios b. Maternal diabetes (disruption) c. Undetermined etiology
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Mandibular hypoplasia b. Femoral hypoplasia including proximal femoral focal deficiency c. Less frequent thoracocostovertebral anomalies i. Thorax: congenital elevation of the scapula (Sprengel deformity) ii. Ribs a) Absent b) Hypoplastic c) Fused iii. Spine a) Dysplastic vertebrae b) Hemivertebrae c) Spina bifida occulta d) Lumbar scoliosis e) Sacral dysgenesis iv. Pelvis a) Small iliac wings b) Wide obturator foramen c) Hypoplasia/aplasia of the acetabula with dislocation of the hips d. Less frequent upper extremity anomalies i. Hypoplasia of the humerus ii. Radiohumeral/radioulnar synostosis iii. Ulnar deviation of the hands 2. Histopathology a. Femur from one infant showed hyaline cartilage with foci of fibrous dysplasia b. A disorganized growth plate and relative decrease in the resting cartilage matrix in another patient
CLINICAL FEATURES 1. Characteristic facial features a. Up-slanting eyes b. A short nose with broad tip c. Elongated philtrum d. Thin upper lip e. Micrognathia f. Cleft palate g. Low-set ears 2. Hypoplasia/aplasia of the femurs a. Presence of some degree of shortened lower extremities in most cases b. Variable shortening of the lower extremities depending on the absence or degree of hypoplasia of the femurs, with or without absent fibulas 3. Short stature due to reduced length of the lower extremities 4. Normal intelligence 5. Other anomalies a. Club foot in most cases b. Occasional polydactyly/syndactyly c. Sprengel deformity d. Upper extremity hypoplasia e. Restricted motion of the elbows f. Stiff shoulders g. Pelvic and spinal abnormalities h. Inguinal hernia i. Genitourinary anomalies i. Hypoplastic/dysplastic kidneys ii. Polycystic kidneys iii. Cryptorchidism iv. Genital hypoplasia
GENETIC COUNSELING
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1. Recurrence risk a. Patient’s sib i. Sporadic cases: not increased ii. Autosomal dominant inheritance: not increased unless one of the parents is affected iii. Maternal diabetes: risk is significantly increased b. Patient’s offspring: 50% if the patient has the autosomal dominant form of the syndrome
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2. Prenatal diagnosis possible by ultrasonography in at risk families a. Micrognathia b. Cleft palate c. Other facial features d. Short, bowed femora 3. Management a. Cleft palate repair b. Care for cardiovascular and genitourinary complications c. Orthopedic management of limb deformity and hip dysplasia
REFERENCES Baraitser M, Reardon W, Oley C, et al.: Femoral hypoplasia—unusual facies syndrome with preaxial polydactyly. Clin Dysmorphol 3:40–45, 1994. Burn J, Winter RM, Baraitser M, et al.: The femoral hypoplasia—unusual facies syndrome. J Med Genet 21:331–340, 1984. Daentl DL, Smith DW, Scott CI, et al.: Femoral hypoplasia—unusual facies syndrome. J Pediatr 86:107–111, 1973. DePalma L, Duray PH, Popeo VR: Femoral hypoplasia—unusual facies syndrome: autopsy findings in an unusual case. Pediatr Pathol 5:1–8, 1986. Eastman JR, Escobar V: Femoral hypoplasia—unusual facies syndrome: a genetic syndrome? Clin Genet 13:72–76, 1978. Giacoia GP, Tunnessen WW, Jr: Picture of the month. Femoral hypoplasia— unusual facies syndrome. Arch Pediatr Adolesc Med 150:761–762, 1996. Gleiser S, Weaver DD, Escobar V, et al.: Femoral hypoplasia—unusual facies syndrome, from another viewpoint. Eur J Pediatr 128:1–5, 1978. Hinson RM, Miller RC, Macri CJ: Femoral hypoplasia and maternal diabetes: consider femoral hypoplasia/unusual facies syndrome. Am J Perinatol 13:433–436, 1996. Holmes LB: Letter: Femoral hypoplasia—unusual facies syndrome. J Pediatr 87:668–669, 1975. Hurst D, Johnson DF: Brief clinical report: femoral hypoplasia—unusual facies syndrome. Am J Med Genet 5:255–258, 1980.
Iohom G, Lyons B, Casey W: Airway management in a baby with femoral hypoplasia—unusual facies syndrome. Paediatr Anaesth 12:461– 464, 2002. Johnson JP, Carey JC, Gooch WM, 3rd, et al.: Femoral hypoplasia—unusual facies syndrome in infants of diabetic mothers. J Pediatr 102:866– 872, 1983. Lampert RP: Dominant inheritance of femoral hypoplasia—unusual facies syndrome. Clin Genet 17:255–258, 1980. Lomo A, Headings V: Femoral hypoplasia—unusual facies syndrome and chromosome X trisomy. South Med J 73:1669–1670, 1980. Lord J, Beighton P: The femoral hypoplasia—unusual facies syndrome: a genetic entity? Clin Genet 20:267–275, 1981. Nguyen NH, Mayhew JF: Airway management in a baby with femoral hypoplasia—unusual facies syndrome. Paediatr Anaesth 13:87, 2003. Pitt D: Kyphomelic dysplasia versus femoral hypoplasia—unusual facies syndrome. Am J Med Genet 24:365–368, 1986. Pitt DB, Findlay II, Cole WG, et al.: Case report: femoral hypoplasia—unusual facies syndrome. Aust Paediatr J 18:63–66, 1982. Riedel F, Froster-Iskenius U: Caudal dysplasia and femoral hypoplasia— unusual facies syndrome: different manifestations of the same disorder? Eur J Pediatr 144:80–82, 1985. Robinow M, Sonek J, Buttino L, et al.: Femoral-facial syndrome-prenatal diagnosis-autosomal dominant inheritance. Am J Med Genet 57:397–399, 1995. Singh SK, Chandra D, Ravi RN, et al.: Femoral hypoplasia—unusual facies syndrome. Indian Pediatr 34:747–748, 1997. Sorge G, Ardito S, Genuardi M, et al.: Proximal femoral focal deficiency (PFFD) and fibular a/hypoplasia (FA/H): a model of a developmental field defect. Am J Med Genet 55:427–432, 1995. Tadmor OP, Hammerman C, Rabinowitz R, et al.: Femoral hypoplasia—unusual facies syndrome: prenatal ultrasonographic observations. Fetal Diagn Ther 8:279–284, 1993. Urban JE, Ramus RM, Stannard MW, et al.: Autopsy, radiographic, and prenatal ultrasonographic examination of a stillborn fetus with femoral facial syndrome. Am J Med Genet 71:76–79, 1997. Verma A, Jain N, Jain K: Additional malformations in femoral hypoplasia: unusual facies syndrome. Indian J Pediatr 69:531–532, 2002.
FEMORAL HYPOPLASIA-UNUSUAL FACIES SYNDROME
Fig. 1. A 3-month old infant with femoral hypoplasia-unusual facies syndrome showing short nose, long philtrum, thin upper lip, micrognathia, low-set ears, and marked bilateral rhizomelic shortening of the lower extremities. The radiograph showed hip dysplasia and bilateral proximal femoral hypoplasia.
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Fetal Akinesia Sequence Fetal akinesia sequence refers to the condition of decreased intrauterine fetal movement and its consequent manifestations of multiple joint contractures, pulmonary hypoplasia, and abnormal face present at birth. The incidence is estimated to be 1 in 12,000, reflecting causal heterogeneity
GENETICS/BASIC DEFECTS 1. Genetics a. Sporadic in majority of cases b. Familial cases i. Autosomal recessive inheritance ii. Possible X-linked recessive inheritance 2. Heterogeneous causes a. Inadequacy of the intrauterine fetal environment i. Etiologic factors a) Ovarian cyst b) Bicornuate uterus c) Umbilical cord wrapping d) Twins e) Extra-uterine pregnancy f) Insufficient placental circulation g) Maternal tetanus, drug treatment h) Amniotic bands ii. Oligohydramnios sequence a) Facial deformities (Potter’s facies) b) Arthrogryposis c) Lung hypoplasia iii. Types of defects determined by the timing of constraint a) Early in pregnancy leading to limb reduction defects, syndactyly and polydactyly b) Later in pregnancy (3rd trimester) leading to genu recurvatum, dislocated hips and deviated wrists c) Various developmental defects occurring earlier in the upper than in the lower limbs d) Embryonic onset of immobility interferes with limb development and results in joint fixation and pterygium formation, in contrast to fetal-onset immobility, which causes joint contractures alone b. Pena-Shokeir phenotype or sequence i. Pena-Shokeir syndrome a) Originally described by Pena and Shokeir in 1974 b) Syndrome consisting of camptodactyly, multiple ankyloses, facial anomalies, pulmonary hypoplasia, and lethal outcome ii. Curarization of fetal rats during pregnancy (study by Moessinger, 1983) resulted in better understanding of fetal akinesia deformation sequence with the following features almost identical with those described in the Pena-Shokeir syndrome: 398
a) Multiple contractures or arthrogryposis b) Pulmonary hypoplasia c) Craniofacial anomalies d) Polyhydramnios e) Intrauterine growth retardation f) Short umbilical cord iii. Currently the term “Pena-Shokeir phenotype or sequence” is recommended instead of “PenaShokeir syndrome” 3. Fetal akinesia not associated with primary malformations a. Mechanical causes i. Oligohydramnios ii. Polyhydramnios iii. Premature rupture of the membrane iv. Chorioamnionitis b. Congenital infections i. Rubella ii. CMV iii. Toxoplasmosis c. Physical or chemical agents i. Toxic agents ii. Drugs iii. X-rays iv. Hyperthermia d. Fetal hypoxia i. Fetal anemia a) Blood loss b) Hemolysis ii. Compression of umbilical cord iii. Placental insufficiency iv. Severe toxemia e. Maternal myasthenia gravis 4. Role of fetal akinesia in heterogeneous syndromes and conditions a. Cerebro-oculo-facio-skeletal (COFS) syndrome b. Potter sequence c. Neu-Laxova syndrome d. Syndrome described by Herva et al. (1985) e. Osteochondrodysplasias i. Thanatophoric dysplasia ii. Achondrogenesis iii. Diastrophic dysplasia f. Lethal multiple pterygium syndrome g. CNS anomalies i. Hydranencephaly ii. Dandy-Walker malformation with hydrocephalus iii. Schizencephaly iv. Olivo-ponto-cerebellar degeneration h. Skin/connective tissue disorders i. Restrictive dermopathy ii. Epidermolysis bullosa iii. Congenital ichthyosis
FETAL AKINESIA SEQUENCE
i. Metabolic disorders i. Lysosomal storage disorders ii. Generalized gangliosidosis syndrome type I iii. Glycogenosis type VII j. Neuromuscular disorders i. Congenital muscular dystrophy ii. Congenital myotonic dystrophy iii. Congenital spinal muscular atrophy iv. Central core disease v. Nemaline myopathy k. Other disorders causing restrictive fetal akinesia i. Loss of anterior horn cells ii. Radical disease iii. Peripheral neuropathy iv. Congenital myasthenia gravis v. Amyoplasia congenita vi. Prader-Willi syndrome vii. Cohen syndrome viii. Angelman syndrome ix. Neurofibromatosis I x. Moebius syndrome xi. Bilateral dislocation of the hips xii. Exstrophy of cloaca and bladder xiii. Chromosome abnormalities a) Fetal triploidy b) Trisomies 4p, 9, 9q, 9p, 10q, 11q, proximal 14, proximal 15, and 18 c) Monosomies 4p and 13q xiv. Miscellaneous a) Cornelia de Lange syndrome b) Catel-Manzke syndrome c) Opitz-Frias syndrome d) Bowen-Conradi syndrome e) Marden-Walker syndrome 5. Pathogenesis of fetal akinesia sequence (Hageman et al., 1987) a. Spinal cord lesions observed most often (28%) b. Brain lesions (19%) c. Miscellaneous or connective tissue disorders (11%) d. Combined brain and spinal cord lesions (9%) e. Mechanical restriction (7%) f. Muscle disorders (5%) g. Peripheral neuropathy and myasthenia gravis (1%) h. No underlying defect observed in 14% of cases
CLINICAL FEATURES 1. Pregnancy history a. Feeble fetal movement b. Polyhydramnios c. Oligohydramnios d. Craniofacial abnormalities i. Ocular hypertelorism ii. Micrognathia iii. Low-set ears iv. Depressed nasal tip v. Short neck e. Limb anomalies i. Lack of normal growth ii. Limitation of joint movement iii. Abnormal shape
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iv. Abnormal position v. Decreased bone calcification 2. Phenotype present at birth a. Multiple joint contractures b. Limb pterygia c. Craniofacial abnormalities d. Pulmonary hypoplasia e. Short umbilical cord f. Growth retardation 3. Lethal outcome with pulmonary hypoplasia
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Thin tubular bones b. Gracile ribs c. Multiple fractures possible at mid-diaphyses of humeri, distal diaphyses of femora, proximal diaphyses of tibiae and fibulae d. Camptodactyly 2. Histopathologic and other laboratory studies a. Trophoblastic inclusions in the chorionic villi of placenta: i. Triploidy ii. Lethal multiple pterygium syndrome b. Lung hypoplasia c. Bones i. Unremarkable resting cartilage ii. Normal cartilage cell columns at the chondroosseous junctions iii. Marrow bony spicules often unusually thin and underossified iv. Irregular and focal areas of extreme diaphyseal thinning: a consistent finding d. CNS, muscles, and other organ systems e. Biochemical studies for lysosomal storage disease f. Analysis for chromosome abnormality
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal recessive inheritance: 25% ii. A recurrence risk of 10–15% suggested in the nonfamilial sporadic cases b. Patient’s offspring: a lethal entity not surviving to reproductive age 2. Prenatal diagnosis by ultrasonography in high-risk pregnancies after the birth of a previous child with a heritable (mostly autosomal recessive) form of fetal akinesia sequence a. Marked decreased fetal activity i. Restricted limb movements ii. Decreased fetal chest movements b. Hydramnios/oligohydramnios c. Intrauterine growth retardation d. Other echographic abnormalities associated with fetal akinesia i. Brain a) Microcephaly b) Holoprosencephaly c) Hydranencephaly
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d) Meningomyelocele e) Lissencephaly f) Dilated ventricles g) Absence of septum pellucidum ii. Spinal cord: sacrococcygeal agenesis iii. Gastrointestinal tract a) Omphalocele b) Gastroschisis iv. Renal a) Bilateral renal agenesis b) Renal malformations v. Craniofacial a) Hypertelorism b) Hypotelorism c) Micrognathia d) Cleft palate vi. Limbs a) Contractures (arthrogryposis) b) Camptodactyly c) Webbing d) Syndactyly e) Polydactyly f) Overlapping fingers and toes g) Abnormal position h) Clubfoot i) Partial absence or shortness vii. Cardiopulmonary a) Pulmonary hypoplasia b) Cardiac defects 3. Management: no effective treatment for pulmonary hypoplasia
REFERENCES Bacino CA, Platt LD, Garber A, et al.: Fetal akinesia/hypokinesia sequence: prenatal diagnosis and intra-familial variability. Prenat Diagn 13: 1011–1019, 1993. Beemer FA: The fetal akinesia sequence: pitfalls and difficulties in genetic counseling. Genet Couns 1:41–45, 1990. Chen H, Blumberg B, Immken L, et al.: The Pena-Shokeir syndrome: report of five cases and further delineation of the syndrome. Am J Med Genet 16:213–224, 1983. Chen H, Immken L, Lachman R, et al.: Syndrome of multiple pterygia, camptodactyly, facial anomalies, hypoplastic lungs and heart, cystic hygroma, and skeletal anomalies: delineation of a new entity and review of lethal forms of multiple pterygium syndrome. Am J Med Genet 17:809–826, 1984. Chen H, Blackburn WR, Wertelecki W: Fetal akinesia and multiple perinatal fractures. Am J Med Genet 55:472–477, 1995.
Davis JE, Kalousek DK: Fetal akinesia deformation sequence in previable fetuses. Am J Med Genet 29:77–87, 1988. Grubben C, Gyselaers W, Moerman P, et al.: The echographic diagnosis of fetal akinesia. A challenge towards etiological diagnosis and management. Genet Couns 1:35–40, 1990. Hageman G, Willemse J: Arthrogryposis multiplex congenita. Review with comment. Neuropediatrics 14:6–11, 1983. Hageman G, Willemse J, van Ketel BA, et al.: The pathogenesis of fetal hypokinesia. A neurological study of 75 cases of congenital contractures with emphasis on cerebral lesions. Neuropediatrics 18:22–33, 1988. Hall JG: Editorial comment: the lethal multiple pterygium syndromes. Am J Med Genet 17:803–807, 1984. Hall JG: Invited editorial comment: Analysis of Pena Shokeir phenotype. Am J Med Genet 25:99–117, 1986. Hammond E, Donnenfeld AE: Fetal akinesia. Obstet Gynecol Surv 50:240–249, 1995. Herva R, Leisti J, Kirkinen P, et al.: A lethal autosomal recessive syndrome of multiple congenital contractures. Am J Med Genet 20:431–439, 1985. Ho NC: Monozygotic twins with fetal akinesia: the importance of clinicopathological work-up in predicting risks of recurrence. Neuropediatrics 31:252–256, 2000. Mease AD, Yeatman GW, Pettet G, et al.: A syndrome of ankylosis, facial anomalies and pulmonary hypoplasia secondary to fetal neuromuscular dysfunction. Birth Defects Original Article Series XII:193–200, 1976. Moerman P, Fryns JP: The fetal akinesia deformation sequence. A fetopathological approach. Genet Couns 1:25–33, 1990. Moerman P, Lammens M, Fryns JP, et al.: Fetal akinesia sequence caused by glycogenosis type VII. Genet Couns 6:15–20, 1995. Moessinger AC: Fetal akinesia deformation sequence: an animal model. Pediatrics 72:857–863, 1983. Ohlsson A, Fong KW, Rose TH, et al.: Prenatal sonographic diagnosis of PenaShokeir syndrome type I, or fetal akinesia deformation sequence. Am J Med Genet 29:59–65, 1988. Pena SDJ, Shokeir MHK: Syndrome of camptodactyly, multiple ankyloses, facial anomalies, and pulmonary hypoplasia: A lethal condition. J Pediatr 85:373–375, 1974. Pena S, Shokeir M: Autosomal recessive cerebro-oculo-facio-skeletal (COFS) syndrome. Clin Genet 5:285–293, 1974. Porter HJ: Lethal arthrogryposis multiplex congenital (fetal akinesia deformation sequence, FADS). Pediatr Pathol Lab Med 15:617–637, 1995. Reiser P, Briner J, Schinzel A: Skeletal muscular changes in Pena-Shokeir sequence. J Perinat Med 18:267–274, 1990. Rodriguez JI, Palacios J: Skeletal changes in fetal akinesia. Pediatr Radiol 19:347–348, 1989. Rodriguez JI, Palacios J: Pathogenetic mechanisms of fetal akinesia deformation sequence and oligohydramnios sequence. Am J Med Genet 40:284–289, 1991. Ruano R, Dumez Y, Dommergues M: Three-dimensional ultrasonographic appearance of the fetal akinesia deformation sequence. J Ultrasound Med 22:593–599, 2003. Witters I, Moerman P, Fryns JP: Fetal akinesia deformation sequence: a study of 30 consecutive in utero diagnoses. Am J Med Genet 113:23–28, 2002. Yfantis H, Nonaka D, Castellani R, et al.: Heterogeneity in fetal akinesia deformation sequence (FADS): autopsy confirmation in three 20–21-week fetuses. Prenat Diagn 22:42–47, 2002.
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Fig. 1. A neonate with fetal akinesia sequence showing micro/retrognathia, short neck, narrow thorax, flexion contractures of hips, fixed extension of the right knee, and inverted and rotated feet. The radiograph showed gracile ribs, thin long bones with multiple fractures at mid-diaphyses of humeri, distal diaphysis of femora, and proximal diaphyses of both tibiae and left fibula, and club hands.
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Fig. 2. A neonate with fetal akinesia sequence showing micrognathia and multiple contractures. The radiograph showed gracile ribs and fractures at mid-diaphyses of humeri.
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Fig. 3. A neonate with Pena-Shokeir sequence showing hypertelorism, a short nose with depressed nasal bridge, a small and recessed jaw, low-set malformed ears, a short neck, multiple contractures at the hip, elbows, knees, and ankles. The infant had scalp edema and pulmonary hypoplasia. Prenatal ultrasonography showed hydramnios, retrognathia, low-set ears, scalp edema, and flexion contractures at the elbows and knees.
Fetal Alcohol Syndrome f. Detrimental defects on the fetus when there is concomitant maternal use of other drugs (marijuana, nicotine, caffeine) 3. Key risk factors for alcohol-induced brain damage a. Peak blood alcohol concentration rather than the length of alcohol exposure: the critical variable in determining risk for adverse effects on brain development b. Cessation of drinking alcohol at any time during pregnancy likely to be beneficial on developing brain c. Cerebellum particularly vulnerable to alcoholinduced growth restriction as well as neuronal loss following alcohol exposure during the brain growth spurt (3rd trimester in humans) d. Heavy alcohol consumption during the first trimester associated strongly with craniofacial abnormalities in humans
In 1973, Jones et al. described, in the American medical literature, a constellation of features in children born to alcoholic mothers, now known as fetal alcohol syndrome (FAS). In 1996, the Institute of Medicine further defined criteria of FAS and proposed a new term: alcohol-related neurodevelopmental disorder (ARND) and alcohol-related birth defects (ARBD) to include structural CNS and cognitive abnormalities in children in whom fetal exposure to alcohol has been confirmed. The incidence of FAS in the United States is estimated to be about 1–3 per 1000 live births. The incidence is higher in certain population, such as Native Americans.
GENETICS/BASIC DEFECTS 1. Genetics a. Genetic susceptibility i. Observation of differences in the severity and spectrum of FAS based on genetic background ii. Higher concordance of FAS in monozygotic twins than in dizygotic twins supports the concept of genetic factors in the fetal effects of alcohol b. Possible mechanism of heritable susceptibility to FAS: genetically encoded differences in alcohol dehydrogenase, the enzyme responsible for metabolizing alcohol in the liver i. Mother of children with FAS: possibly with less functional enzyme resulting in higher peak blood alcohol concentration after the ingestion of alcohol ii. Fetuses with FAS: possibly with deficient alcohol dehydrogenase activity and thus less able to tolerate elevated maternal alcohol levels 2. Pathogenesis a. Clinical features of FAS: result from exposure of the developing fetus to toxic levels of alcohol and its metabolites at critical periods in development b. Specific pathophysiology unknown: may involve free radical formation that causes cellular damage in the developing tissues of the fetus c. Exposure in the 1st trimester i. Affects organogenesis and craniofacial development, leading to minor and major malformations such as the characteristic facial features and ARBD ii. Excessive cell death in the midline of the developing embryo may account for the development of these facial features d. Continuous use of alcohol by the mother later in pregnancy resulting in low birth weight and affecting postnatal growth e. Alcohol exposure at varying times in pregnancy may result in similar CNS neurodevelopmental effects
CLINICAL FEATURES
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1. Characteristic craniofacial features in the young child a. Discriminating features i. Short palpebral fissures ii. Flat midface iii. Indistinct (smooth, flat) philtrum iv. Thin upper lip b. Associated features i. Epicanthal folds ii. Low nasal bridge iii. Minor ear anomalies iv. Short nose v. Micrognathia 2. Growth retardation a. Low birth weight for gestational age b. Decelerating weight over time not due to nutrition c. Disproportionate low weight to height 3. Alcohol-related birth defects (ARBD): birth defects associated with in utero alcohol exposure a. Ocular abnormalities i. Strabismus ii. Retinal vascular anomalies iii. Optical nerve hypoplasia iv. Refractive problems secondary to small globes v. Coloboma b. Cardiovascular abnormalities i. Atrial septal defect ii. Ventricular septal defect iii. Aberrant great vessels iv. Tetralogy of Fallot c. Hepatic abnormality: extrahepatic biliary atresia d. Skeletal abnormalities i. Hypoplastic nails ii. Shortened 5th digits
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iii. Radioulnar synostosis iv. Flexion contractures v. Camptodactyly vi. Clinodactyly vii. Pectus excavatum/carinatum viii. Klippel-Feil syndrome ix. Hemivertebrae x. Scoliosis e. Muscular abnormalities i. Hernias a) Diaphragm b) Umbilicus c) Inguinal ii. Diastasis recti f. Renal abnormalities i. Aplastic/dysplastic/hypoplastic kidneys ii. Horseshoe kidneys iii. Ureteral duplications iv. Megaureter v. Hydronephrosis vi. Cystic diverticula vii. Vesicovaginal fistula g. Genital abnormalities i. Hypospadias ii. Labial hypoplasia h. Cutaneous abnormalities i. Hemangiomas ii. Hirsutism i. Auditory abnormalities i. Conductive hearing loss ii. Neurosensory hearing loss j. Neuroendocrine abnormalities i. Altered hypothalamic-pituitary-adrenocortical axis-heightened stress response ii. Abnormal thyroid function k. Other abnormalities: include virtually any malformation 4. Alcohol-related neurodevelopmental disorder (ARND) a. Structural CNS abnormalities associated with in utero alcohol exposure i. Microcephaly ii. Microencephaly iii. Decreased size of cerebrum, cerebellum, basal ganglia, diencephalons iv. Partial or complete agenesis of the corpus callosum v. Neuroglial heterotopia vi. Dendritic neuronal abnormalities vii. Holoprosencephaly sequence viii. Anencephaly ix. Porencephaly x. Ventricular enlargement xi. Dandy-Walker malformation b. Neurologic abnormalities associated with in utero alcohol exposure i. Impaired fine motor skills ii. Deficits in balance iii. Poor tandem gait iv. Neurosensory hearing loss v. Poor hand-eye coordination vi. Hypotonia
c. Neurobehavioral abnormalities associated with in utero alcohol exposure i. Learning disabilities ii. Decreased IQ scores iii. Mental retardation iv. Attention deficit/hyperactivity disorder v. Poor impulse control vi. Problems in memory, attention, or judgment vii. Problems in social perception viii. Deficits in higher level receptive or expressive language ix. Poor capacity for abstraction or metacognition x. Autism xi. Adult mental illness xii. Alcohol or drug dependence xiii. Psychotic disorders xiv. Avoidant, antisocial, or dependent personality disorder xv. Depression xvi. Suicide 5. Neonatal alcohol withdrawal signs a. Hypoglycemia b. Irritability c. Tremors d. Seizures e. Autonomic dysregulation, including temperature instability f. Blood pressure abnormalities i. Hypotension ii. Hypertension g. Excessive glucocorticoid release h. Altered behavioral state organization 6. Medical risks for women who drink alcohol a. Increased mortality and breast cancer in women who drink more than two drinks daily b. Increased menstrual symptoms, hypertension, and stroke in women with higher levels of alcohol consumption c. Increased infertility and spontaneous abortion in women who drink heavily d. Adverse fetal effects after variable amounts of alcohol consumption, making any alcohol use during pregnancy potentially harmful
DIAGNOSTIC INVESTIGATIONS 1. Diagnosis of FAS based on clinical features in the setting of maternal alcohol use 2. Radiography for skeletal abnormalities 3. CT and MRI imagings for CNS abnormalities 4. Echocardiography for cardiovascular anomalies 5. Ultrasound for renal abnormalities 6. Neurologic and neurobehavioral evaluations
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: high if the mother abuse alcohol during the pregnancy b. Patient’s offspring: high if the affected woman abuse alcohol during her pregnancy
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2. Prenatal diagnosis a. Low maternal serum alpha-fetoprotein and low pregnancy-specific beta L-glycoprotein observed in one report possibly reflecting primary or secondary effects of ethanol abuse in pregnancy and possibly useful in predicting fetal alcohol syndrome b. Prenatal ultrasound examination recommended for pregnant women who drinks to detect fetal growth retardation and various birth defects associated with in utero alcohol exposure 3. Management a. Beneficial effects of early diagnosis of FAS on medical intervention of affected infants and children b. Management of issues (medical and surgical interventions) regarding specific birth defects c. Implementation of resource programs for developmental delay, functional abilities, speech abilities, and social/behavioral interactions d. Appropriate interventions with educational evaluation and support and community resources such as The National Organization on Fetal Alcohol Syndrome (NOFAS) e. Evaluate and manage the siblings who also have FAS f. Prevention of alcohol-induced fetal brain damage i. Abstinence recommended for pregnant women and for those planning pregnancy since there is no known safe amount of alcohol consumption during pregnancy ii. High-quality educational programs regarding the deleterious effects of alcohol on the unborn child iii. High awareness of FAS and ARND and their prevention by health care professionals iv. Appropriate support services including prevention of recurrence for parents and children diagnosed as having FAS or ARND
REFERENCES Abel EL: Fetal alcohol syndrome: behavioral teratology. Psychol Bull 87: 29–50, 1980. Adams J, Bittner P, Buttar HS, et al.: Statement of the Public Affairs Committee of the Teratology Society on the fetal alcohol syndrome. Teratology 66: 344–347, 2002. American Academy of pediatrics Committee on Substance Abuse and Committee on Children with Disabilities. Fetal alcohol syndrome and alcohol-related neurodevelopmental disorders. Pediatrics 106:358–361, 2000. Belsky R: The role of the genetic counselor in fetal alcohol syndrome prevention. Birth Defects Orig Artic Ser 23:111–114, 1987. Bradley KA, Badrinath S, Bush K, et al.: Medical risks for women who drink alcohol. J Gen Intern Med 13:627–639, 1998. Church MW, Abel EL: Fetal alcohol syndrome. Hearing, speech, language, and vestibular disorders. Obstet Gynecol Clin North Am 25:85–97, 1998. Clarren SK: Recognition of fetal alcohol syndrome. JAMA 245:2436–2439, 1981. Clarren SK, Smith DW: The fetal alcohol syndrome. N Engl J Med 298:1063–1067, 1978.
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Colangelo W, Jones DG: The fetal alcohol syndrome: a review and assessment of the syndrome and its neurological sequelae. Prog Neurobiol 19:271–314, 1982. Erb L, Andresen BD: The fetal alcohol syndrome (FAS): a review of the impact of chronic maternal alcoholism on the developing fetus. Clin Pediatr (Phila) 17:644–649, 1978. Gleason CA: Fetal alcohol exposure: effects on the developing brain. NeoReviews 2:e231–e237, 2001. Gonzalez ER: Skeletal defects and fetal alcohol syndrome. Arch Intern Med 139:959, 1979. Halmesmäki E, Autti I, Granstrom ML, et al.: Alpha-fetoprotein, human placental lactogen, and pregnancy-specific beta 1-glycoprotein in pregnant women who drink: relation to fetal alcohol syndrome. Am J Obstet Gynecol 155:598–602, 1986. Hanson JW, Jones KL, Smith DW: Fetal alcohol syndrome. Experience with 41 patients. JAMA 235:1458–1460, 1976. IOM-Institute of Medicine (U.S.). Division of Biobehavioral Sciences and Mental Disorders. Committee to Study Fetal Alcohol Syndrome: In Stratton K, Howe C, Battaglia F (eds): Fetal Alcohol Syndrome: Diagnosis, Epidemiology, Prevention, and Treatment. National Academy Press, Washington, DC. 1996. Iosub S, Fuchs M, Bingol N, et al.: Fetal alcohol syndrome revisited. Pediatrics 68:475–479, 1981. Johnson VP, Swayze VW, II, Sato Y, et al.: Fetal alcohol syndrome: craniofacial and central nervous system manifestations. Am J Med Genet 61:329–339, 1996. Jones KL: Fetal alcohol syndrome. Pediatr Rev 8:122–126, 1986. Jones KL: From recognition to responsibility: Josef Warkany, David Smith, and the fetal alcohol syndrome in the 21st century. Birth Defects Res Part A Clin Mol Teratol 67:13–20, 2003. Jones KL, Smith DW: Recognition of the fetal alcohol syndrome in early infancy. Lancet 2:999–1001, 1973. Jones KL, Smith DW: The fetal alcohol syndrome. Teratology 12:1–10, 1975. Jones KL, Smith DW, Hanson JW: The fetal alcohol syndrome: clinical delineation. Ann N Y Acad Sci 273:130–139, 1976. Miller M, Israel J, Cuttone J: Fetal alcohol syndrome. J Pediatr Ophthalmol Strabismus 18:6–15, 1981. Moore ES, Ward RE, Jamison PL, et al.: New perspectives on the face in fetal alcohol syndrome: what anthropometry tells us. Am J Med Genet 109:249–260, 2002. Olson HC, Streissguth AP, Sampson P, et al.: Association of prenatal alcohol exposure with behavioral and learning problems in early adolescence. J Am Acad Child Adolesc Psychiatry 36:1187–1194, 1997. Sampson PD, Streissguth AP, Bookstein FL, et al.: Incidence of fetal alcohol syndrome and prevalence of alcohol-related neurodevelopmental disorder. Teratology 56:317–326, 1997. Spiegel PG, Pekman WM, Rich BH, et al.: The orthopedic aspects of the fetal alcohol syndrome. Clin Orthop 58–63, 1979. Spohr HL, Steinhausen HC: Clinical, psychopathological and developmental aspects in children with the fetal alcohol syndrome: a four-year follow-up study. Ciba Found Symp 105:197–217, 1984. Streissguth AP, Herman CS, Smith DW: Intelligence, behavior, and dysmorphogenesis in the fetal alcohol syndrome: a report on 20 patients. J Pediatr 92:363–367, 1978. Streissguth AP, Aase JM, Clarren SK, et al.: Fetal alcohol syndrome in adolescents and adults. JAMA 265:1961–1967, 1991. Stromland K: Ocular involvement in the fetal alcohol syndrome. Surv Ophthalmol 31:277–284, 1987. Stro˝mland K, Hellstrom A: Fetal alcohol syndrome—an ophthalmological and socioeducational prospective study. Pediatrics 97:845–850, 1996. Thackray Hum Mutat, Tifft C: Fetal alcohol syndrome. Pediatr Rev 22:47–55, 2001.
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Fig. 2. Another boy with fetal alcohol syndrome showing short stature and similar characteristic facial appearance.
Fig. 1. Two brothers with fetal alcohol syndrome showing prenatal and postnatal growth deficiency and characteristic facial features (short palpebral fissures, flat nasal bridge, flat midface, smooth philtrum, and thin upper lip).
Fetal Hydantoin Syndrome c. Limb defects i. Hypoplasia of distal phalanges and nails (most characteristic feature) ii. A finger-like thumb iii. Hyperphalangism iv. Adactyly/absent nails v. Acheiria (congenital absence of one or two hands) vi. Positional limb defects a) Calcaneovalgus deformity b) Pes cavus vii. Abnormal palmar creases 4. Less frequently observed abnormalities a. Neck webbing b. Cardiovascular anomalies i. Aortic coarctation ii. Patent ductus arteriosus iii. Septal defects c. Gastrointestinal abnormalities i. Pyloric stenosis ii. Duodenal atresia d. Renal defects e. Genital abnormalities in males i. Hypospadias ii. Bifid or shawl scrotum f. Hernias i. Diaphragmatic hernia ii. Umbilical hernia iii. Inguinal hernias g. Other skeletal anomalies i. Spinal anomalies a) Scoliosis b) Segmentation defects of vertebral bodies ii. Rib and sternal anomalies h. Occasional tumor association i. Neuroblastoma ii. Melanotic neuroectodermal tumor of infancy i. Single umbilical artery
Fetal hydantoin syndrome is by far the best-characterized malformation complexes induced by anticonvulsant drugs used to treat maternal epilepsy.
GENETICS/BASIC DEFECTS 1. Cause: maternal exposure to hydantoin anticonvulsant 2. Effect of prenatal exposure to hydantoin a. Fetal hydantoin syndrome in 11% of cases b. Fetal hydantoin effect in an additional 31% of cases 3. Teratogenicity of hydantoin a. Mediated not by the parent compound but by toxic intermediary metabolites that are produced during the biotransformation of the parent compound b. Epoxide (oxidative intermediates): the primary teratogenic agent of phenytoin i. Thought to occur before the formation of the dihydrodiol metabolite in a reaction catalyzed by the enzyme epoxide hydrolase ii. Highly reactive and capable of covalently binding to embryonic or fetal nucleic acids, which at critical periods of embryogenesis, are theoretically capable of disrupting normal development
CLINICAL FEATURES 1. 11% of infants exposed prenatally to hydantoin classified as having the fetal hydantoin syndrome 2. Presence of variable patterns of malformations 3. Classic features a. Growth and development i. Developmental delay ii. Mild to moderate mental retardation iii. Prenatal and postnatal growth deficiencies iv. Microcephaly b. Craniofacial anomalies i. Ridging of the metopic suture ii. Broad and low nasal bridge iii. Ocular defects a) Hypertelorism b) Ptosis c) Strabismus d) Wide epicanthal folds e) Congenital glaucoma f) Retinoschisis g) Nasolacrimal duct deformity and agenesis h) Coloboma of the iris and choroid iv. Short upturned nose v. Low-set ears vi. Wide mouth with prominent lips vii. Cleft lip and/or palate
DIAGNOSTIC INVESTIGATIONS 1. 2. 3. 4.
Radiography for skeletal defects Echocardiography for associated congenital heart defect Renal ultrasound for renal defects Developmental evaluation
GENETIC COUNSELING
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1. Recurrence risk a. Patient’s sib: minimal in the absence of maternal exposure to hydantoin during pregnancy b. Patient’s offspring: minimal in the absence of maternal exposure to hydantoin during pregnancy
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2. Prenatal diagnosis: prenatal ultrasound examination recommended for pregnant women who takes hydantoin anticonvulsant to detect fetal growth retardation and various birth defects associated with in utero hydantoin exposure 3. Management a. Management of issues (medical and surgical interventions) regarding specific birth defects b. Implementation of resource programs for developmental delay, functional abilities, speech abilities, and social/behavioral interactions c. Appropriate interventions with educational evaluation and support d. Avoid hydantoin anticonvulsant during pregnancy
REFERENCES Buehler BA, Bick D, Delimont D: Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med 329:1660–1661, 1993. Buehler BA, Delimont D, van Waes M, et al.: Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med 322:1567–1572, 1990. Buehler BA, Rao V, Finnell RH: Biochemical and molecular teratology of fetal hydantoin syndrome. Neurol Clin 12:741–748, 1994. Bustamante SA, Stumpff LC: Fetal hydantoin syndrome in triplets. A unique experiment of nature. Am J Dis Child 132:978–979, 1978.
Finnell RH, Chernoff GF: Genetic background: the elusive component in the fetal hydantoin syndrome. Am J Med Genet 19:459–462, 1984. Hampton GR, Krepostman JI: Ocular manifestations of the fetal hydantoin syndrome. Clin Pediatr (Phila) 20:475–478, 1981. Hanson JW, Buehler BA: Fetal hydantoin syndrome: current status. J Pediatr 101:816–818, 1982. Hanson JW, Myrianthopoulos NC, Harvey MA, et al.: Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome. J Pediatr 89:662–668, 1976. Hanson JW, Smith DW: The fetal hydantoin syndrome. J Pediatr 87:285– 290, 1975. Karpathios T, Zervoudakis A, Venieris F, et al.: Genetics and fetal hydantoin syndrome. Acta Paediatr Scand 78:125–126, 1989. Kogutt MS, Young LW: Radiological case of the month. Fetal hydantoin syndrome. Am J Dis Child 138:405–406, 1984. Kousseff BG, Root ER: Expanding phenotype of fetal hydantoin syndrome. Pediatrics 70:328–329, 1982. Kousseff BG, Stein M, Gellis SS, et al.: Picture of the month: fetal hydantoin syndrome. Am J Dis Child 135:371–372, 1981. Nagy R: Fetal hydantoin syndrome. Arch Dermatol 117:593–595, 1981. Robinow M: Fetal hydantoin syndrome characteristics. Am J Dis Child 138: 1154–1155, 1984. Sabry MA, Farag TI: Hand anomalies in fetal-hydantoin syndrome: from nail/ phalangeal hypoplasia to unilateral acheiria. Am J Med Genet 62: 410–412, 1996. Smith DW: Distal limb hypoplasia in the fetal hydantoin syndrome. Birth Defects Orig Artic Ser 13:355–359, 1977. Verdeguer JM, Ramon D, Moragon M, et al.: Onychopathy in a patient with fetal hydantoin syndrome. Pediatr Dermatol 5:56–57, 1988.
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Fig. 1. Three patients with fetal hydantoin syndrome showing typical craniofacial features (ocular hypertelorism, flat nasal bridge, epicanthal folds, small upturned nose, wide mouth with prominent lips) and nail hypoplasia.
Fibrodysplasia Ossificans Progressiva b. Inability of the altered noggin polypeptide of the FOP patient to bind efficiently to BMP-4: possible pathogenesis of the disease c. NF-κB may play an important functional role in the pathogenesis of the disease because of its multiple roles in inflammation, skeletogenesis, and bone morphogenetic protein-4 regulation 5. Precipitating factors for ectopic ossification a. Biopsies b. Intramuscular injections c. Dental therapy d. Prolonged pressure on the body, such as tight clothing e. Aggressive physical therapy f. Falls g. Injuries h. Exacerbation of bone formation common in response to surgery and other tissue trauma
Fibrodysplasia ossificans progressive (FOP) is a very rare inherited disorder of connective tissue, characterized by progressive ectopic ossification and congenital malformation of the great toes. It is also known as myositis ossificans progressiva. The prevalence is approximately one affected patient in 1.64 million people in the United Kingdom.
GENETICS/BASIC DEFECTS 1. Inheritance a. Usually sporadic in occurrence. Very few affected individuals have children because of the devastating nature of the disease b. Autosomal dominant inheritance i. Complete penetrance ii. Variable expression 2. Cause a. Mutations within the bone morphogenic protein (BMP) gene family, contributing both to limb patterning and to ossification. An abnormal regulation of BMP-4 expression was described in FOP. The secreted polypeptide noggin binds and inactivates BMP-4 b. Mutations of the Noggin (NOG) gene (However, linkage between NOG and FOP has been excluded and no disease-causing mutations was noted by one group) c. Mapping of the FOP gene i. Chromosome 4q27-31 ii. Chromosome 17q21-22 3. Presence of two skeletons in patients with FOP a. A normotopic bone formation during embryogenesis i. Grossly normal normotopic skeleton ii. Exceptions a) Segmentation defects in the cervical spine b) Malformation of the great toes at birth due to shortening of the first metatarsal and proximal phalanx c) Monophalangic great toes due to synostosis: the earliest phenotypic feature of fibrodysplasia ossificans progressiva b. A heterotopic bone formation i. Usually beginning in the first decade of life ii. Progressing in characteristic anatomic patterns iii. Typically involving upper back and neck iv. Heralded by large painful swellings of highly vascular fibroproliferative tissue involving ligaments, tendons, and skeletal muscle, often following minor trauma v. Early swelling regresses spontaneously but often matures to true heterotopic bone 4. Pathogenesis: a. Overexpression of bone morphogenetic protein 4 (BMP-4), which maps to 14q22-q23
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1. Extra-skeletal abnormalities a. Progressive widespread heterotopic ossification of muscles, tendons, ligaments, aponeurosis, and fascia. The heterotopic bony masses lead to progressive disability b. Onset: about 4 years of age in majority of patients c. Typical course of lesional progression at any site i. Early lesions during the first few weeks: characterized by pain, erythema, swelling, warmth, and tenderness ii. Intermediate lesions after several weeks a) Swelling beginning to subside b) Decrease in pain, tenderness, and erythema iii. Late lesions after approximately 12 weeks a) Disappearance of swelling b) A hard, non-tender lesion remains. It is roentgenographically a new area of heterotopic ossification d. Characteristic anatomical progression of heterotopic bone formation i. Typical earliest involvement: dorsal, axial, cranial and proximal regions of the body ii. Later involvement: ventral, appendicular, caudal, and distal regions of the body e. Variation in size of soft tissue nodules involving the neck and back: often the first indication of heterotopic ossification in a child f. Progressive ankylosis i. Shoulder joints ii. Elbow joints iii. Hip joints iv. Knee joints
FIBRODYSPLASIA OSSIFICANS PROGRESSIVA
v. Neck: painful swelling or stiffness of the neck in most patients vi. Spine a) Leading to complete fusion b) Mimicking ankylosing spondylitis c) Pain and stiffness of the spine present in most patients vii. Muscles of mastication a) Leading to limited mouth opening b) Inability to feed orally c) Poor oral hygiene d) Subsequent cachexia g. Severe restrictive pulmonary disease i. Causes a) Scoliosis of the thoracolumbar spine b) Ankylosis of costovertebral joints c) Ossification of the chest wall with resultant dependence on diaphragm for respiration ii. Severely reduced lung volume iii. Constrictive airway dysfunction developing over time iv. Recurrent pulmonary infections secondary to ineffective cough: a common cause of death in the third or fourth decade h. Eventual confinement to wheelchair 2. Congenital malformation of the great toes and thumbs (75–90%) a. Association with congenital great toe malformation i. Mainly short big toes with single phalanx (a cartilaginous anlage of the first metatarsal and proximal phalanx) present at birth ii. An important early diagnostic clue b. Shortened thumbs c. Clinodactyly of the 5th fingers 3. Other features a. Patients with FOP are prone to fractures with poor outcome b. Occasional baldness c. Occasional conductive hearing loss secondary to calcification and fusion of the ligaments, tendons, and bones of the middle ear d. Markedly reduced reproductive fitness e. Reduced life span but most patients survive to adulthood 4. Natural history a. Mobility becomes more restricted as the disease advances b. Typically confined to bed or wheelchair by early 30s
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Extra skeletal ossification i. Progressive widespread heterotopic ossification of muscles, tendons, ligaments, and fascia ii. Ankylosis a) Shoulder joints b) Elbow joints c) Hip joints: prevent ability to ambulate d) Knee joints e) Muscles of mastication
2.
3.
4. 5. 6. 7.
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b. Phalangeal abnormalities i. Characteristically affecting the great toes a) Shortened first digits b) Delta-shaped proximal phalanges c) Often monophalangism with absence of the interphalangeal joint of the great toes ii. Shortened thumbs iii. Clinodactyly of the 5th fingers c. Less common congenital malformations i. Small vertebral bodies and enlarged pedicles in early childhood ii. Variable degrees of vertebral fusion, especially apophysial joint fusion in late childhood iii. Short, broad femoral necks iv. Ossification of ligamentous insertions producing exostoses of the proximal tibia v. Delay in skeletal maturation vi. Enchondroma formation vii. Association with synovial chondromatosis Bone scintigraphy (radionuclide imaging) a. A very sensitive technique for new bone formation in FOP b. Reveals multiple foci of increased uptake in affected areas CT scan a. Useful for diagnosis because CT scan is very sensitive for calcification b. Soft tissue swelling in the fascial planes and muscle in the early course of FOP c. Evidence of soft tissue calcification, typically in the form of shell seen within days to a few weeks d. Calcification appearing as spicules in the soft tissue or in thin planes along the fascia often encircling muscle e. Able to delineate the presence or absence of bone destruction, differentiating FOP from invasive processes such as infection and tumor MRI: a sensitive imaging technique for soft tissue abnormalities but not particularly useful for diagnosis Ultrasonography to demonstrate echogenic and shadowing mass Audiography: mixed-type hearing loss with prominent conductive component Histopathology a. Earliest finding: an intense perivascular lymphocytic infiltration b. Followed by death of skeletal muscle and replacement by a highly vascular fibroproliferative soft tissue, which rapidly progresses through an endochondral process to form heterotopic bone
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected or has gonadal mosaicism b. Patient’s offspring: 50% 2. Prenatal diagnosis: no prenatal diagnosis available currently
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3. Management a. No effective treatment available i. Avoid multiple biopsies, trauma, intramuscular injections, and dysfunctional IV catheters to prevent precipitating the heterotopic ossification and exacerbating the disease ii. Physical therapy in general not recommended as stretching of the soft tissues around a joint can lead to a painful flare-up iii. Steroids, non-steroid anti-inflammatory agents, disodium etidronate, warfarin, and radiotherapy a) Used to halt the progression of disease b) Without proven benefit iv. Isotretinoin a) Principle based on its ability to inhibit differentiation of mesenchymal tissue into cartilage and bone b) Questionable benefit to decrease the incidence of heterotopic ossification at uninvolved anatomical sites v. Etidronate a) Blocks ectopic calcification and is approved by Food and Drug Administration for treatment of postoperative heterotopic ossification b) Short-term effect of bone metabolism shows diminished bone turnover rate c) Long-term effect on ectopic calcification is unchanged in most cases with few exceptions b. Primary therapy for the debilitating disease: supportive care i. Active range-of-motion exercises encouraged if the movements are comfortable ii. Available adaptations or modifications prescribed to a disabled patient with FOP to achieve functional independence in the home and community a) Shoes b) Canes c) Wheelchairs c. Surgery i. Nearly always contraindicated since new heterotopic ossification occurs at the operative site ii. Surgical removal of heterotopic bone a) Ineffective b) Leading to catastrophic exacerbation of the disease iii. Existence of intercurrent problems occasionally requiring surgery d. Anaesthesia i. Presenting numerous difficulties to the anesthesiologist including cervical spine ankylosis and restrictive pulmonary disease ii. Avoid tissue trauma in the form of local anesthetic injections iii. Presence of anatomical airway abnormalities iv. Alternative methods preferred a) Nebulized lidocaine b) IV sedation c) Nasotracheal intubation
v. Proper positioning and padding perioperatively vi. Vigorous chest physiotherapy and pulmonary toilet postoperatively
REFERENCES Ahn J, Feldman G, Terry L, et al.: Exoneration of NF-kappaB dysregulation in fibrodysplasia ossificans progressiva. Clin Orthop 205–213, 2003. Blaszczyk M, Majewski S, Brzezinska-Wcislo L, et al.: Fibrodysplasia ossificans progressiva. Eur J Dermatol 13:234–237, 2003. Brantus JF, Meunier PJ: Effects of intravenous etidronate and oral corticosteroids in fibrodysplasia ossificans progressiva. Clin Orthop 117–120, 1998. Bridges AJ, Hsu KC, Singh A, et al.: Fibrodysplasia (myositis) ossificans progressiva. Semin Arthritis Rheum 24:155–164, 1994. Carter SR, Davies AM, Evans N, et al.: Value of bone scanning and computed tomography in fibrodysplasia ossificans progressiva. Br J Radiol 62:269–272, 1989. Cohen RB, Hahn GV, Tabas JA, et al.: The natural history of heterotopic ossification in patients who have Fibrodysplasia ossificans progressive. J Bone Joint Surg [AM] 75:215–219, 1993. Cohen MM, Jr.: Bone morphogenetic proteins with some comments on fibrodysplasia ossificans progressiva and NOGGIN. Am J Med Genet 109:87–92, 2002. Cohen RB, Hahn GV, Tabas JA, et al.: The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients. J Bone Joint Surg Am 75:215–219, 1993. Connor JM, Evans DA: Extra-articular ankylosis in fibrodysplasia ossificans progressiva. Br J Oral Surg 20:117–121, 1982. Connor JM, Evans DA: Genetic aspects of fibrodysplasia ossificans progressiva. J Med Genet 19:35–39, 1982. Connor JM, Evans DA: Fibrodysplasia ossificans progressiva. The clinical features and natural history of 34 patients. J Bone Joint Surg Br 64:76– 83, 1982. Connor JM, Skirton H, Lunt PW: A three generation family with fibrodysplasia ossificans progressiva. J Med Genet 30:687–689, 1993. Connor JM, Smith R: The cervical spine in fibrodysplasia ossificans progressiva. Br J Radiol 55:492–496, 1982. Cramer SF, Ruehl A, Mandel MA: Fibrodysplasia ossificans progressiva: a distinctive bone-forming lesion of the soft tissue. Cancer 48:1016–1021, 1981. Cremin B, Connor JM, Beighton P: The radiological spectrum of fibrodysplasia ossificans progressiva. Clin Radiol 33:499–508, 1982. Delatycki M, Rogers JG: The genetics of Fibrodysplasia ossificans progressiva. Clin Orthop Rel Res 346:15–18, 1998. Hall JG, Schaller JG, Worsham NG, et al.: Fibrodysplasia ossificans progressiva (myositis ossificans progressiva) treatment with disodium etidronate. J Pediatr 94:679–680, 1979. Janoff HB, Muenke M, Johnson LO, et al.: Fibrodysplasia ossificans progressiva in two half-sisters: evidence for maternal mosaicism. Am J Med Genet 61:320–324, 1996. Kaplan FS, McCluskey W, Hahn G, et al.: Genetic transmission of fibrodysplasia ossificans progressiva. Report of a family. J Bone Joint Surg Am 75:1214–1220, 1993. Kocyigit H, Hizli N, Memis A, et al.: A severely disabling disorder: fibrodysplasia ossificans progressiva. Clin Rheumatol 20:273–275, 2001. Levy C, Berner TF, Sandhu PS, et al.: Mobility challenges and solutions for fibrodysplasia ossificans progressiva. Arch Phys Med Rehabil 80:1349–1353, 1999. Lucotte G, Bathelier C, Mercier G, et al.: Localization of the gene for fibrodysplasia ossificans progressiva (FOP) to chromosome 17q21–22. Genet Couns 11:329–334, 2000. Lucotte G, Semonin O, Lutz P: A de novo heterozygous deletion of 42 basepairs in the noggin gene of a fibrodysplasia ossificans progressiva patient. Clin Genet 56:469–470, 1999. Mahboubi S, Glaser DL, Shore EM, et al.: Fibrodysplasia ossificans progressiva. Pediatr Radiol 31:307–314, 2001. Rocke DM, Zasloff MA, Peeper J, et al.: Age and joint-specific risk of initial heterotopic ossification in patients who have Fibrodysplasia ossificans progressive. Clin Orthop Rel Res 301:243–248, 1994. Rogers JG, Geho WB: Fibrodysplasia ossificans progressiva. A survey of fortytwo cases. J Bone Joint Surg Am 61:909–914, 1979.
FIBRODYSPLASIA OSSIFICANS PROGRESSIVA Schroeder HW Jr, Zasloff M: The hand and foot malformations in fibrodysplasia ossificans progressiva. Johns Hopkins Med J 147:73–78, 1980. Sémonin O, Fontaine K, Daviaud C, et al.: Identification of three novel mutations of the noggin gene in patients with fibrodysplasia ossificans progressiva. Am J Med Genet 102:314–317, 2001. Shafritz AB, Shore EM, Gannon FH, et al.: Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva. N Engl J Med 335: 555–561, 1996. Smith R: Fibrodysplasia (myositis) ossificans progressiva. Clinical lessons from a rare disease. Clin Orthop Rel Res 346:7–14, 1998.
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Thornton YS, Birnbaun SJ, Liebowitz N: A viable pregnancy in a patient with myositis ossificans progressive. Am J Obstet Gynecol 156:577–578, 1987. Xu M, Shore EM: Mutational screening of the bone morphogenetic protein 4 gene in a family with fibrodysplasia ossificans progressiva. Clin Orthop 53–58, 1998. Xu MQ, Feldman G, Le Merrer M, et al.: Linkage exclusion and mutational analysis of the noggin gene in patients with fibrodysplasia ossificans progressiva (FOP). Clin Genet 58:291–298, 2000.
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Fig. 1. A boy with fibrodysplasia ossificans progressiva showing a stiff neck, a narrow chest, and inability to raise arms upward due to ossification of the soft tissues on the lateral chest wall and axillary region, illustrated by the chest radiograph. The radiographs of both feet showed shortened 1st toes and hallux valgus with delta-shaped proximal phalanges, monophalangism with absence of the interphalangeal joint of the great toes. The radiographs of both hands showed shortening of the first metacarpal and the middle phalanx of the 5th fingers with clinodactyly.
Finlay-Marks Syndrome e. f. g. h.
In 1978, Finlay and Marks described the association of scalp defect, malformed ears, and absence of nipples in a family. The association is also known as scalp-ear-nipple syndrome.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal dominant 2. Lymphoid enhancer factor-1 (Lef-1), identified as a candidate gene for scalp-ear-nipple syndrome a. Lef-1: an HMG-domain DNA-binding protein expressed in the neural crest, mesencephalon, tooth germs and other sites during embryogenesis b. Homozygous deficiency of this gene causing postnatal lethality in mice c. Mutant mice lacking teeth, mammary glands, whiskers, and hair d. Lack of hair, missing teeth and aplasia of breast tissue suggest that Lef-1 may be a candidate gene for scalp-ear-nipple syndrome
DIAGNOSTIC INVESTIGATIONS 1. No specific laboratory tests available 2. Histology of scalp defect resembling aplasia cutis congenita a. An excess of normal-appearing connective tissue b. Lack pilosebaceous elements 3. Renal sonography for renal hypoplasia 4. Diagnosis primarily by clinical features
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: low unless a parent is affected b. Patient’s offspring: 50% 2. Prenatal diagnosis: not been reported 3. Management: primarily supportive
CLINICAL FEATURES 1. Scalp abnormalities a. Raised firm nodules over the scalp in the occipital region, not covered by hairs b. The areas: raw at birth and heal during childhood c. Crumpled scalp over occipital region 2. External ear abnormalities a. Hypoplastic tragus, antitragus, and lobule b. Over-folding of the superior helix c. Flattening of the antihelix 3. Athelia (absent breasts and nipples) a. Rudimentary or absent nipples b. Breast hypoplasia or aplasia 4. Other reported features a. Ectodermal dysplasia features i. Dental anomalies a) Widely spaced teeth b) Missing secondary teeth c) Neonatal teeth ii. Reduction of axillary apocrine secretion and axillary hair growth iii. Hypohidrosis iv. Nail dysplasia b. Aplasia cutis vertices c. Renal hypoplasia d. Pyeloureteral duplication
Cataract Hypertension Diabetes mellitus Partial syndactyly
REFERENCES Aase JM, Wilroy SR: The Finlay-Marks (S.E.N.) syndrome: report of a new case and review of the literature. Proc Greenwood Genet Center 7:247–250, 1988. Berman DS, Silverstone LM: Natal and neonatal teeth. A clinical and histological study. Br Dent J 139:361–364, 1975. Edwards MJ, McDonald D, Moore P, et al.: Scalp-ear-nipple syndrome: additional manifestations. Am J Med Genet 50:247–250, 1994. Finlay AY, Marks R: A hereditary syndrome of lumpy scalp, odd ears and rudimentary nipples. Br J Dermatol 99:423–430, 1978. Le Merrer M, Renier D, Briard ML: Scalp defect, nipples absence and ears abnormalities: another case of Finlay syndrome. Genetic Counseling 2:233–236, 1991. Milatovich A, Travis A, Grosschedl R, et al.: Gene for lymphoid enhancerbinding factor 1 (LEF1) mapped to human chromosome 4 (q23–q25) and mouse chromosome 3 near EGF. Genomics 11:1040–1048, 1991. Picard C, Couderc S, Skojaei T, et al.: Scalp-ear-nipple (Finlay-Marks) syndrome: a familial case with renal involvement. Clin Genet 56:170–172, 1999. Plessis G, Le Treust M, Le Merrer M: Scalp defect, absence of nipples, ear anomalies, renal hypoplasia: another case of Finlay-Marks syndrome. Clin Genet 52:231–234, 1997. Taniai H, Chen H, Ursin S: Finlay-Marks syndrome: another sporadic case and additional manifestations. Int Pediatr 46:353–355, 2004. Tawil HM, Najjar SS: Congenital absence of the breasts. J Pediatr 73:751–753, 1968. van Steensel MA, Celli J, van Bokhoven JH, et al.: Probing the gene expression database for candidate genes. Eur J Hum Genet 7:910–919, 1999.
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Fig. 1. A 7-month-old boy with Finlay-Marks syndrome showing absence of nipples and abnormal ears. He also had scanty eyebrows and eyelashes, neonatal teeth, which were extracted, nasolacrimal duct stenosis, and lumpy scalp on the occiput region.
Fragile X Syndrome Fragile X syndrome is the most common form of heritable mental retardation affecting approximately 1 in 4000 males and 1 in 8000 females. Martin and Bell first documented X-linked mental retardation in 1943. Subsequent identification of a fragile site on the long arm of the X chromosome (Lubs, 1969), discovery of cell culture medium-dependent fragile site, and recognition of a unique constellation of physical features served to distinguish fragile X syndrome from other X-linked mental retardation syndromes. In 1991, Verkerk et al. identified a single gene that was associated with symptoms of the disorder. The gene, known as fragile X mental retardation gene 1 (FMR1), exhibited a novel form of mutation, a sequence of three nucleotides (CGG) that was repeated many times in patients with fragile X syndrome.
GENETICS/BASIC DEFECTS 1. Inheritance not conforming to usual rules governing Xlinked traits a. Presence of asymptomatic transmitting males b. Presence of affected female carriers who inherited the gene 2. Caused by mutations in a trinucleotide repeat expansion (CGG) found in the coding sequence of the FMR1 gene, mapped to Xq27.3 a. Expanded CGG repeats >200 (full mutation): associated with fragile X syndrome b. High repeat number (full mutation) leads to hypermethylation of an upstream promoter region and subsequent silencing (inactivating) of the FMR1 gene c. A small expansion (premutation) with approximately 50–200 CGG repeats: usually not associated with cognitive deficits d. Expansion to a full mutation from the premutation in normal carriers occurs only when it is transmitted by a female e. Presence of anticipation phenomenon 3. The Sherman paradox a. A perplexing and confusing fragile X pedigree pattern was discovered during mid-1980s by Sherman et al. who discovered the large discrepancy in risks for mental retardation within fragile X families containing transmitting males. This phenomenon was termed the “Sherman paradox” by Opitz (1986) i. 20% of males within fragile X families who carried the mutation are unaffected clinically and intellectually and became known as transmitting males ii. An increasing risk of mental retardation in grandsons of normal transmitting males: a special form of genetic anticipation (the increase in disease severity through successive generations) 417
iii. About a third of obligate carrier females are mentally impaired iv. More than half of known carrier females are either mildly impaired or expressed the fragile site on one of their X chromosomes b. Possible explanations of the Sherman paradox i. An unaffected transmitting male who inherits a premutation from his unaffected carrier mother, who has 50 to 200 repeats but probably a number closer to the lower end of the premutation range ii. Offspring of a carrier mother with the number of repeats still within the premutation range, even if amplification occurs during oogenesis iii. Transmission of the premutation to the daughters by the transmitting male. No amplification has occurred during spermatogenesis; hence the daughters also have a premutation and are unaffected iv. Amplification to more than 200 repeats occurs during oogenesis of the transmitting male’s daughters whose sons will receive a full mutation and be affected and their daughters may or may not be affected 4. Genotypic–phenotypic correlations a. Fragile X full mutation and mental retardation with a wide spectrum of phenotypic effects in both sexes i. Mental retardation in 100% of males ii. Usually a milder form of retardation in 60% of females b. Large CGG amplification i. Associated with hypermethylation ii. Almost invariably correlated with the most severe fragile X phenotype iii. Seen in males with the full mutation pattern c. Premutation expansions that are not usually accompanied by methylation: minimal or no neurologic repercussion d. Correlation of methylation in FMR1 expression and cognitive function i. Individuals with full mutation without methylation scored better than those with full mutation and complete methylation ii. Individuals with full mutation and partial methylation showed intermediate values e. Presence of the FMR1 protein (FMRP) responsible for: i. Lack of neurologic abnormalities in individuals with premutation ii. Milder phenotype of males having full mutation without full methylation 5. Pathogenesis a. A consequence of the absence or deficit of the FMRP b. Absence of FMRP in the brain: the likely cause of mental retardation in patients with fragile X syndrome
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CLINICAL FEATURES 1. Affected males a. CNS involvement i. Delayed developmental milestones ii. Mild to severe mental retardation iii. Difficulty with abstract thinking, sequential processing, mathematics, short-term memory, and visual motor coordination iv. Seizures b. Connective tissue dysplasia i. Hyperextensible finger joints ii. Double-jointed thumbs iii. Flat feet iv. High-arched palate v. Mitral valve prolapse (55%, diagnosed by echocardiography) vi. Dilatation of the ascending aorta vii. Inguinal hernia viii. Soft and velvet-like skin c. Typical facial features i. Long face ii. Prominent forehead iii. Prominent/long ears iv. Prominent jaw d. Other features i. Macroorchidism present in over 80% of adult fra(X) males ii. Pectus excavatum iii. Scoliosis iv. Strabismus v. Recurrent otitis media in early childhood vi. Reproduction documented but rare because of significant mental retardation e. Behavior abnormalities i. Stereotyped with odd mannerisms (hand flapping/biting) ii. Tactile defensiveness iii. Poor eye contact (excessive shyness) iv. Attention-deficit/hyperactivity disorder a) Hyperactivity b) Temper tantrums c) Distractibility d) Mood lability v. Speech disorder a) Perseveration b) Litany speech c) Echolalia vi. Autism vii. Autistic-like features viii. Schizotypal personality disorder ix. Anxiety disorder 2. Females heterozygous for full mutation alleles a. 50% with cognitive deficits with learning disabilities, borderline IQ, or mental retardation b. 50% with normal intellectual function 3. Females heterozygous for premutation alleles (carriers) at risk for premature ovarian failure (early onset of menopause before age 40 years)
DIAGNOSTIC INVESTIGATIONS 1. Pedigree analysis 2. Karyotyping of cells grown in folate- or thymidinedepleted cell culture media a. A “fragile” site on one of the X chromosomes (Xq27.3) that appeared as a constriction on the distal long arm in many patients b. Cells exhibiting fragile X chromosome: 5–50% c. Cytogenetic studies now rendered obsolete by direct DNA testing 3. Indications for molecular genetic testing a. Individuals of either sex with mental retardation, developmental delay, or autism i. Any physical or behavioral characteristics of fragile X syndrome ii. A family history of fragile X syndrome iii. Male or female relatives with undiagnosed mental retardation b. Individuals seeking reproductive counseling who have a family history of fragile X syndrome or undiagnosed mental retardation c. Fetus of a known carrier mother d. Patients with cytogenetic fragile X test result discordant with phenotype i. Patients with a strong clinical impression of being affected with or carrier of fragile X syndrome but had a negative or ambiguous cytogenetic test result ii. Patients with an atypical phenotype of fragile X syndrome but had a positive cytogenetic test result 4. Direct DNA analysis for point mutation or deletion in FMR1 gene. Mutation analysis to determine the CGG repeat size by Southern blot hybridization and polymerase chain reaction (PCR): mutation detection rate >99% (commercially available) 5. Methylation analysis by Southern blot analysis to determine the FMR1 methylation status 6. Types of FMR1 repeat expansion mutations a. Normal: 5–50 CGG repeats b. Premutation i. 51–200 CGG repeats ii. Methylation status of FMR1: premutation alleles are usually unmethylated and FMRP production is normal. Therefore, individuals with permutation are clinically unaffected iii. Males: clinically unaffected iv. Females: clinically unaffected c. Full mutation i. >200 CGG repeats. Expansion of the repeat more than 200 generally results in hypermethylation of both the CpG island and the CGG repeat within the FMR1 gene ii. Methylation status of FMR1: completely methylated iii. Males: affected iv. Females: affected in about 50% of cases; unaffected in about 50% of cases
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d. Mosaicism i. Number of CGG repeats varies between premutation and full mutation in different cell lines ii. Methylation status of FMR1: partially methylated (unmethylated in the premutation cell line and methylated in the full mutation cell line) iii. Males: affected but may function higher than individuals with full mutation iv. Females: highly variable clinical expression ranging from normal intellect to affected e. Methylation mosaicism i. Number of CGG repeats >200 ii. Methylation status of FMR1 gene: partially methylated (mixture of methylated and unmethylated cell lines) iii. Males: affected but may function higher than individuals with full mutation iv. Females: highly variable clinical expression ranging from normal intellect to affected f. Unmethylated full mutation i. Number of CGG repeats >200 ii. Methylation status of FMR1 gene: unmethylated iii. Males: nearly all are affected but may have high functioning mental retardation to low normal intellect iv. Females: highly variable clinical expression ranging from normal intellect to affected 7. Immunocytochemical tests based on the direct detection of FMRP using monospecific antibodies. This FMRP detection assay is based on the presence of FMRP in cells from unaffected individuals and its absence in cells from patients with fragile X syndrome. This assay is proven to be a reliable alternative method to identify male patients with fragile X syndrome. The new test on hair roots is suitable for use in large screening programs among males. The immunocytochemical tests can also be used in patients with mosaic pattern, affected premutation males, and intragenic mutations.
GENETIC COUNSELING 1. Recurrence risk: adequate genetic counseling depends on accurate diagnosis at the molecular level a. Individuals identified as non-carriers: the zero risk of transmitting fragile X syndrome to the next generation b. Individuals identified as carriers: the risk of having children with fragile X syndrome depending on the sex of the carrier parent, the sex of the child, and the size of the CGG repeats i. Premutation carrier males: considered “transmitting males”. All daughters of transmitting males are unaffected premutation carriers. However, the grandsons and granddaughters of a transmitting male are at risk for developing fragile X syndrome ii. All mothers of a child with FMR1 full mutation (expansion >200 CGG trinucleotide repeats), considered carriers of an FMR1 gene expansion (either full mutation or premutation and may be affected)
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iii. Females with premutation: an increased risk of passing on the full mutation and having offspring with the fragile X phenotype (the fragile X premutation can expand to the full mutation during maternal meiosis) iv. Carrier males who may reproduce: essentially zero risk of having male offspring with Fragile X syndrome, since all their sons receive their Y chromosome [except in the rare instance of the fragile X chromosome coming into the family from the other source (mother)]. All the daughters of male carriers will have premutations regardless of the size of paternal amplifications and will not have fragile X syndrome. Only a few reports with premutation males having full mutation daughters c. Females with full mutation: Her offspring, if they inherit the fragile X locus, all will have full mutation i. All her sons will have fragile X syndrome ii. About 50–60% of her daughters will have fragile X syndrome, exceeding the 35% applicable to all female carriers of the fragile X chromosome. Affected females generally have less severe intellectual disability than found in affected males d. Males with full mutations i. Mentally retarded ii. Generally do not reproduce 2. Risks to pregnant women with an expanded FMR1 gene a. A repeat size of 40–59: safe (0% risk) with no fetal full mutations b. A repeat size of 60–80: low risk (14%) of full mutation in the fetus c. A repeat size of over 80–100: a significant increase in risk (89%) of developing full mutation in the fetus d. A repeat size of 100–200: 100% risk of developing full mutation in the fetus 3. Prenatal diagnosis by amniocentesis or CVS a. Prenatal diagnosis using direct DNA analysis to women discovered to be premutation carriers b. The limitation: inability to accurately predict phenotype in female fetuses with full mutation c. CVS: follow-up amniocentesis or testing using PCR, necessary to determine the size of the FMR1 alleles in a methylation-independent manner 4. Management a. Early intervention programs for developmental delay including speech and language therapies, physical therapy, and occupational therapy b. Behavioral interventions including psychopharmacological therapy c. Special educations d. Vocational planning e. Anticonvulsants for seizure control f. Prophylactic antibiotics for surgical or dental procedures in patients with mitral valve prolapse g. Orthopedic care for joint dislocations, flat feet, and scoliosis
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REFERENCES American Academy of Pediatrics: Health supervision for children with fragile X syndrome. Pediatrics 98:297–300, 1996. Bardoni B, Mandel JL, Fisch GS: FMR1 gene and fragile X syndrome. Am J Med Genet (Semin Med Genet) 97:153–163, 2000. Brown WT: The fragile X: progress toward solving the puzzle. Am J Hum Genet 47:175–180, 1990. Brown WT: Perspectives and molecular diagnosis of the fragile X syndrome. Clin Lab Med 15:859–75, 1995. Caskey CT: Fragile X syndrome: improving understanding and diagnosis. JAMA 271:552–553, 1994. Caskey CT, Pizzuti A, Fu Y-H, et al.: Triplet repeat mutations in human disease. Science 256:784–789, 1992. Crawford DC, Acuna JM, Sherman SL: FMR1 and the fragile X syndrome: human genome epidemiology review. Genet Med 3:359–371, 2001. Das S, Kubota T, Song M, et al.: Methylation analysis of the fragile X syndrome by PCR. Genet Test 1:151–155, 1997. Davids JR, Hagerman RJ, Eilert RE: Orthopaedic aspects of fragile-X syndrome. J Bone Joint Surg [Am] 72:889–896, 1990. De Boulle K, Verkerk AJMH, Reyniers E, et al.: A point mutation in the FMR1 gene associated with fragile X mental retardation. Nature Genet 3:31–35, 1993. De Vries BB, Halley DJ, Oostra BA, et al.: The fragile X syndrome. J Med Genet 35:579–589, 1998. Dyer-Friedman J, Glaser B, Hessl D: Genetic and environmental influences on the cognitive outcomes of children with fragile X syndrome. J Am Acad Child Adolesc Psychiatry 41:237–244, 2002. Dykens EM, Hodapp RM, Leckman JF: Behavior and Development in Fragile X Syndrome. Thousand Oaks, CA: Sage. Feng Y, Lakkis D, Warren ST: Quantitative comparison of FMR1 gene expression in normal and permutation alleles. Am J Hum Genet 56:106–113, 1995. Fu Y-H, Kuhl DPA, Pizzuti A, et al.: Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox. Cell 67:1047–1058, 1991. Goldson E, Hagerman RJ: The fragile X syndrome. Dev Med Child Neurol 34:822–832, 1992. Hagerman RJ: Fragile X syndrome. In: Cassidy SB, Allanson JE (eds): Management of Genetic Syndromes. New York: Wiley-Liss, 2001. Hagerman RJ, Silverman AC: Fragile X syndrome. Diagnosis, Treatment, and Research. Baltimore, Johns Hopkins University Press, 1991. Hagerman RJ, Cronister A (eds): Fragile X syndrome: Diagnosis, Treatment, and Research. Baltimore: Johns Hopkins Univ Press, 1996. Hagerman RJ, Amiri K, Cronister A: Fragile X checklist. Am J Med Genet 38:283–287, 1991. Hagerman RJ, Kimbro LT, Taylor AK: Fragile X syndrome: a common cause of mental retardation and premature menopause. Contemporary OB/GYN 43:47–70, 1998. Hagerman RJ, Jackson C, Amiri K, et al.: Girls with fragile X syndrome: physical and neurocognitive status and outcome. Pediatrics 89:395–400, 1992. Hagerman RJ, Hull CE, Safanda JF, et al.: High functioning fragile X males: Demonstration of an unmethylated fully expanded FMR-1 mutation associated with protein expression. Am J Med Genet 51:298–308, 1994. Hansen RS, Gartler SM, Scott CR, et al.: Methylation analysis of CGG sites in the CpG island of the human FMR1 gene. Hum Mol Genet 1:571–578, 1992. Holden JJA, Percy M, Allingham-Hawkins D, et al.: Eighth international workshop on the fragile X syndrome and X-linked mental retardation, August 16-22, 1997. Am J Med Genet 83:221–236, 1999. Kallinen J, Heinonen S, Mannermaa A, et al.: Prenatal diagnosis of fragile X syndrome and the risk of expansion of a permutation. Clin Genet 58:111–115, 2000.
Kau ASM, Meyer WA, Kaufmann WE: Early development in males with fragile X syndrome: a review of the literature. Microsc Res Techniq 57:174–178, 2002. Kaufmann WE, Reiss AL: Molecular and cellular genetics of fragile X syndrome. Am J Med Genet 88:11–24, 1999. Kenneson A, Warren ST: The female and the fragile X reviewed. Semin Reprod Med 19:159–165, 2001. Laxova R: Fragile X syndrome. Adv Pediatr 41:305–342, 1994. Lubs HA: A marker X chromosome. Am J Hum Genet 21:231–244, 1969. Mulley JC, Sutherland GR: Diagnosis of fragile X syndrome. Fetal Matern Med Rev 6:1–15, 1994. Naber SP: Molecular diagnosis of fragile X syndrome. Diagn Mol Pathol 4:158–161, 1995. Nelson DL: Fragile X syndrome: review and current status. Growth Genet Horm 9:1–4, 1993. Noline SL, Lewis FA II, Ye LL, et al.: Familial transmission of the FMR1 CGG repeat. Am J Hum Genet 59:1252–1261, 1996. Nolin SL, Brown WT, Glicksman A, et al.: Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. Am J Hum Genet 72:454–464, 2003. Oostra BA, Willemsen R: Diagnostic tests for fragile X syndrome. Expert Rev Mol Diagn 1:226–232, 2001. Oostra BA, Jacky PB, Brown WT, et al.: Guidelines for the diagnosis of fragile X syndrome. J Med Genet 30:410–413, 1993. Opitz JM: On the gates of hell and a most unusual gene [editorial]. Am J Med Genet 23:1–10, 1986. Park V, Howard-Peebles P, Sherman S, et al.: Fragile X syndrome: Diagnostic and carrier testing. Am J Med Genet 53:380–381, 1994. Rousseau F, Heitz D, Biancalana V, et al.: Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. N Engl J Med 325: 1673–1681, 1991. Saul RA: Fragile X syndrome. Gene Reviews, 2002. http://www.genetests.org Sherman SL, Morton NE, Jacobs PA, et al.: The marker (X) syndrome: a cytogenetic and genetic analysis. Ann Hum Genet 48:21–37, 1984. Sherman SL, Jacobs PA, Morton NE, et al.: Further segregation analysis of the fragile X syndrome with special reference to transmitting males. Hum Genet 69:289–299, 1985. Simensen RJ, Rogers RC: Fragile-X syndrome. Am Fam Physician 39:185–193, 1989. Sutherland GR: Heritable fragile sites on human chromosomes. I. Factors affecting expression in lymphocyte culture. Am J Hum Genet 31:125–135, 1979. Sutherland GR, Gecz J, Mulley JC: Fragile X syndrome and other causes of Xlinked mental handicap. In Rimoin DL, Connor JM, Pyeritz RE, Korf BR (eds): Principles and Practice of Medical Genetics, 4th ed, Long Churchill Livingstone, 2002, pp 2801–2826. Sutherland GR, Brown WT, Hagerman R, et al.: Sixth International Workshop on the fragile X and X-linked mental retardation. Am J Med Genet 51:281–293, 1994. Tarleton JC, Saul RA: Molecular genetic advances in fragile X syndrome. J Pediatr 122:169–185, 1993. Warren ST, Nelson DL: Advances in molecular analysis of fragile X syndrome. JAMA 271:536–542, 1994. Warren ST, Sherman SL: The fragile X syndrome. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001, Chapter 179, pp 1257–1289. Webb T: The epidemiology of the fragile X syndrome. In Davis KE (ed): The Fragile X syndrome. Oxford, Oxford University, pp. 40–55, 1989. Willemsen R, Oostra BA: FMRP detection assay for the diagnosis of the fragile X syndrome. Am J Med Genet (Semin Med Genet) 97:183–188, 2000. Willemsen R, Oosterwijk JC, Los FJ, et al.: Prenatal diagnosis of fragile X syndrome. Lancet 348:967–968, 1997.
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Fig. 1. Two brothers with fragile X syndrome showing large ears, accompanied by their mother.
Fig. 2. A pair of brothers with fragile X syndrome showing a long face with large ears.
Fig. 3. Another pair of male siblings with fragile X syndrome.
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Fig. 4. A chromosome spread showing a fragile X chromosome (arrow).
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Fig. 6. A 66-year-old male with fragile X syndrome. The patient has mental retardation, a long face with large ears, and macroorchidism. Molecular analysis revealed CGG repeats of about 400.
Fig. 5. A large family affected by fragile X syndrome. The first boy (A, age 15) is the most affected one with CGG repeats of >1500. He was not toilet trained until age 5 or 6 years. He never spoke until after auditory training. He may watch TV for 6–8 hours straight and get agitated if someone approaches him. The brother (B, age 10) and sister (C, age 16) have CGG repeats of 1200 and 600 respectively. Another sister (D) is a carrier with CGG repeats of 110 who has 4 children. The daughter (age 3, the first one from the left) has CGG repeats of 700. She has a long face with prominent ears, a high-arched palate and flat feet. She suffers from hyperactivity, tactile/oral/olfactory defensiveness, gaze aversion, poor postural alignment, food cramming, hand biting, excessive drooling, poor self-regulation, and speech difficulties including echolalia. The other 3 children are normal with normal CGG repeats. The maternal grandmother has CGG repeats of 126.
Fig. 7. A 46-year-old male with methylation mosaic fragile X syndrome (mixture of methylated full mutation allele of approximately 450 repeats in some cells and unmethylated premutation size allele of approximately 200 repeats in some cells). He is tall and has mental retardation, a long narrow face, slightly large ears, and macroorchidism.
Fraser Syndrome Fraser syndrome is a malformation syndrome characterized by cryptophthalmos (“hidden eye,” a term coined by Zehender et al. in 1872), cutaneous syndactyly, and anomalies of the genitourinary system. It is also known as cryptophthalmossyndactyly syndrome or cryptophthalmos syndrome.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Familial cases (56%) 3. Three forms of cryptophthalmos, classified based on ophthalmic findings a. Complete (typical) cryptophthalmos i. The eyelids replaced by a sheet of skin running from forehead to cheek with absence or poor development of the eyebrow ii. Absence of the eyelashes or the gland structures iii. The elevated skin covering the globe moves when eye movements occur iv. The skin adherent to the underlying cornea v. Absence of the conjunctival sac vi. Microphthalmia usually present vii. Often associated with numerous congenital abnormalities, including anomalies of the head, ears, nose and genitalia and syndactyly. This pattern of anomalies is termed Fraser syndrome b. Incomplete (atypical) cryptophthalmos i. Presence of rudimentary eyelids ii. Lateral placement of a small conjunctival sac iii. The palpebral aperture about one-third of normal length iv. Usually small globe, covered almost completely by the skin c. Abortive form or congenital symblepharon i. The upper eyelids, without a defined margin, covers and adherent to up to 75% of the upper cornea ii. Absence of punctum in the eyelid iii. Absence of the upper conjunctival fornix iv. Free part of the cornea often keratinized or opaque v. Globes: usually normal or small size 4. Pathogenesis a. Primary failure of differentiation during embryogenesis b. Compression of the amniochorionic band c. Intrauterine inflammation d. Failure of lid fold development e. Inactivation of glutamate receptor interacting protein 1 (GRIP1), a cytoplasmic multi-PDZ scaffolding protein, leads to the formation of subepidermal hemorrhagic blisters, renal agenesis, syndactyly or polydactyly and permanent fusion of eyelids (cryptophthalmos), Fraser syndrome-like defects in mice
CLINICAL FEATURES 1. Intrafamilial clinical heterogeneity 2. Eyes a. Cryptophthalmos (a developmental anomaly in which the skin is continuous over the eyeballs without any indication of the formation of eyelids): the most common feature of Fraser syndrome (84–93%) i. Bilateral (more common) or unilateral ii. Total or partial b. Microphthalmia c. Absent or malformed lacrimal ducts d. Ocular hypertelorism e. Coloboma of the upper eyelid f. Supernumerary eyebrows g. Blindness 3. Head: unusually low lateral hairline on temples extending to lateral eyebrow 4. Nose a. Hypoplastic and notched nares b. Broad nasal bridge c. Midline nasal cleavage d. Choanal atresia 5. Mouth a. Cleft lip b. Cleft palate c. High-arched palate d. Crowding of the teeth 6. Ears a. Malformation of middle and external ears (cup-shaped and low-set) b. Microtia c. Low-set ears d. Absent pinna e. Skin of the upper helix contiguous with scalp f. Conductive hearing loss 7. Laryngeal stenosis/atresia 8. Chest: widely spaced nipples 9. Lungs a. Lung hyperplasia b. Lung hypoplasia 10. Umbilical hernia 11. Urogenital anomalies a. Renal agenesis/hypoplasia i. Unilateral ii. Bilateral iii. Hypoplastic bladder b. Male genital anomalies i. Small penis ii. Hypospadias iii. Cryptorchidism c. Female genital anomalies i. Bicornuate uterus
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14.
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ii. Hypoplastic uterus iii. Vaginal atresia iv. Hypoplastic labia majora v. Clitoral enlargement Limbs: syndactyly of the fingers (cutaneous in 54% of cases) and toes CNS involvement a. Mental retardation b. Microcephaly c. Meningomyelocele d. Encephalocele Natural history: death usually associated with renal agenesis and laryngeal stenosis or atresia a. Stillborn: 25% of affected infants b. Additional 20% of affected infants die before one year of age Diagnostic criteria a. Major criteria i. Cryptophthalmos ii. Syndactyly iii. Abnormal genitalia iv. Sib with Fraser syndrome b. Minor criteria i. Congenital malformation of nose ii. Congenital malformation of ears iii. Congenital malformation of larynx iv. Cleft lip/palate v. Skeletal defects vi. Umbilical hernia vii. Renal agenesis viii. Mental retardation
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Poor ossification of the calvarium b. Orbital structures c. Pulmonary hypoplasia d. Diastasis of the symphysis pubis e. Syndactyly 2. Renal ultrasound for renal anomalies 3. Hearing test
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sibs: 25% b. Patient’s offspring: recurrence risk not increased unless the spouse is a carrier or affected 2. Prenatal diagnosis a. Prenatal ultrasonography i. Major findings a) Microphthalmia b) Syndactyly c) Ambiguous genitalia ii. Other findings a) Oligohydramnios b) Ear defects c) Renal abnormalities d) Uropathy e) Hyperechogenic lungs
f) Laryngeal stenosis/atresia g) Ascites h) Intrauterine growth retardation i) Polyhydramnios b. Fetoscopy 3. Management a. Immediate ocular management: frequent use of artificial tears to maintain corneal luster and clarity b. Intubation or tracheotomy to provide an adequate airway when laryngeal atresia/stenosis is present. Final repair of the laryngeal stenosis is deferred until about 1–2 years of age when adequate thyroid cartilage development has occurred c. Surgical correction of associated anomalies d. Goals of reconstruction, considering the poor probability of restoring visual function i. To protect the cornea (if present) from infection and ulceration ii. To enhance cosmetic appearance iii. To preserve the globe e. Surgical treatment at a later age i. Reconstruction in partial cryptophthalmos a) Dissection of the eyelids from the cornea b) Reconstruction of the conjunctival fornices with buccal mucosa c) Repair the upper lid coloboma in a flap reconstruction using the inferior eyelid margin ii. Reconstruction without grafting in complete cryptophthalmos
REFERENCES Andiran F, Tanyel FC, Hicsonmez A: Fraser syndrome associated with anterior urethral atresia. Am J Med Genet 82:359–361, 1999. Azevedo ES, Biondi J, Ramalho M: Cryptophthalmos in two families from Bahia, Brazil. J Med Genet 10:389–392, 1973. Balci S: Laryngeal atresia presenting as fetal Ascites, oligohydramnios and lung appearance mimicking cystic adenomatoid malformation in a 25week-old fetus with Fraser syndrome. Prenat Diagn 19:856–858, 1999. Berg C, Geipel A, Germer U, et al.: Prenatal detection of Fraser syndrome without cryptophthalmos: case report and review of the literature. Ultrasound Obstet Gynecol 18:76–80, 2001. Bialer MG, Wilson WG: Syndromic Cryptophthalmos. Am J Med Genet 30:835– 837, 1988. Bieber FR, Page DV, Holmes LB: Variation in the expression of the cryptophthalmia syndrome. Am J Hum Genet 34:812, 1982. Boyd PA, Keeling JW, Lindenbaum RH: Fraser syndrome (cryptophthalmossyndactyly syndrome): a review of eleven cases with postmortem findings. Am J Med Genet 31:159–168, 1988. Brazier DJ, Hardman-Lea SJ, Collin JRO: Cryptophthalmos: surgical treatment of the congenital Symblepharon variant. Br J Ophthalmol 70:391–395, 1986. Burn J, Marwood RP: Fraser syndrome presenting as bilateral renal agenesis in three sibs. J Med Genet 19:360–361, 1982. Chattopadhyay A, Kher AS, Udwadia AD, et al.: Fraser syndrome. J Postgrad Med 39:228–230, 1993. Codere F, Brownstein S, Chen MF: Cryptophthalmos syndrome with bilateral renal agenesis. Am J Ophthal 91:737–742, 1981. Dibben K, Rabinowitz YS, Shorr N, et al.: Surgical correction of incomplete cryptophthalmos in Fraser syndrome. Am J Ophthalmol 124:107–109, 1997. Dinno ND, Edwards WC, Weiskopf B: The cryptophthalmos-syndactyly syndrome. Description, manner of inheritance, and notes on the eye lesions. Clin Pediatr 13:219–224, 1974. Feldman E, Shalev E, Weiner E, et al.: Microphthalmia prenatal ultrasonic diagnosis. Prenat Diagn 5:205, 1985.
FRASER SYNDROME Ferri M, Harvey JT: Surgical correction for complete cryptophthalmos: case report and review of the literature. Can J Ophthalmol 34:233–236, 1999. Francannet C, Lefrancois P, Dechelotte P, et al.: Fraser syndrome with renal agenesis in two consanguineous Turkish families Am J Med Genet 36:477–479, 1990. Francois J: Syndrome malformatif avec cryptophtalmie. Acta Genet Med Gemellol (Roma) 18:18–50, 1969. Gattuso J, Patton MA, Baraitser M: The clinical spectrum of the Fraser syndrome: report of three new cases and review. J Med Genet 24:549–555, 1987. Greenberg F, Keenan B, De Yanis V, et al.: Gonadal dysgenesis and gonadoblastoma in situ in a female with Fraser (Cryptophthalmos) syndrome. J Pediatr 108:952–954, 1986. Gupta SP, Saxena RC: Cryptophthalmos. Br J Ophthalmol 46:629–632, 1962. Howard RO, Fineman RM, Anderson B Jr, et al.: Unilateral cryptophthalmia. Am J Ophthal 87:556–1979. Ide CH, Wollschlaeger PB: Multiple congenital abnormalities associated with cryptophthalmos. Arch Ophthal 81:638–644, 1969. Kantaputra P: Cryptophthalmos, dental and oral abnormalities, and brachymesophalangy of second toes: new syndrome or Fraser syndrome? Am J Med Genet 98:263–268, 2001. Karas DE, Respler DS: Fraser syndrome: a case report and review of the otolaryngologic manifestations. Int J Pediatr Otorhinolaryngol 31:85–90, 1995. Koenig R, Spranger J: Cryptophthalmos-syndactyly syndrome without cryptophthalmos. Clin Genet 29:413–416, 1986. Lurie IW, Cherstvoy ED: Renal agenesis as a diagnostic feature of the cryptophthalmos-syndactyly syndrome. Clin Genet 25:528, 1984.
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Meinecke P: Cryptophthalmos-syndactyly syndrome without cryptophthalmos. Clin Genet 30:527, 1986. Pankau R, Partsch CJ, Janig U, et al.: Fraser (Cryptophthalmos-syndactyly) syndrome: a case with bilateral anophthalmia but presence of normal eyelids. Genet Counsel 5:191–194, 1994. Ramsing M, Rehder H, Holzgreve W, et al.: Fraser syndrome (Cryptophthalmos with syndactyly) in the fetus and newborn. Clin Genet 37:84–96, 1990. Rousseau T, Laurent N, Thauvin-Robinet C, et al.: Prenatal diagnosis and intrafamilial clinical heterogeneity of Fraser syndrome. Prenat Diagn 22:692–696, 2002. Schauer GM, Dunn LK, Godmilow L, et al.: prenatal diagnosis of Fraser syndrome at 18.5 weeks gestation, with autopsy findings at 19 weeks. Am J Med Genet 37:583–591, 1990. Serville F, Carles D, Broussin B: Fraser syndrome: prenatal ultrasonic detection. Am J Med Genet 32:561–563, 1989. Slavotinek AM, Tifft CJ: Fraser syndrome and cryptophthalmos: review of the diagnostic criteria and evidence for phenotypic modules in complex malformation syndromes. J Med Genet 39:623–633, 2002. Stevens CA, McClanahan C, Steck A, et al.: Pulmonary hyperplasia in the Fraser cryptophthalmos syndrome. Am J Med Genet 52:427–431, 1994. Takamiya K, Kostourou V, Adams S, et al.: A direct functional link between the multi-PDZ domain protein GRIP1 and the Fraser syndrome proteinRfas1. Nat Genet 36:172–177, 2004. Thomas IT, Frias JL, Felix V, et al.: Isolated and syndromic cryptophthalmos. Am J Med Genet 25:85–98, 1986. Weng C-J: Surgical reconstruction in cryptophthalmos. Br J Plast Surg 51:17–21, 1998. Zehender W, Ackermann E, Manz E: Eine Miβbildung mit hautüberwachsenen Augen oder Kryptophthalmos. Klin Mbl Augenheilk 10:225–249, 1872.
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Fig. 1. An infant with Fraser cryptophthalmos showing fused eyelids, lateral hair extending to lateral eyebrows, ocular hypertelorism, notched nares and a tracheostomy site for management of laryngeal stenosis. Postmortem photos show lung hypoplasia, a small uterus, and clitoral hypertrophy. The skull radiographs show poorly ossified calvarium.
Fig. 2. The sibling of the previous infant with Fraser syndrome showing microphthalmia, partial fusions of eyelids, ocular hypertelorism, genitourinary anomalies, and partial syndactyly of the toes. Variability of expression is illustrated in these two sibs.
Freeman-Sheldon Syndrome In 1938, Freeman and Sheldon described a syndrome characterized by a whistling face with a long philtrum, a puckered mouth, microstomia, H-shaped cutaneous dimpling on the chin, multiple joint contractures with camptodactyly, ulnar deviation of the fingers, bilateral talipes equinovarus, and kyphoscoliosis. The syndrome is also known as craniocarpotarsal dysplasia or “whistling face” syndrome.
5. 6.
GENETICS/BASIC DEFECTS 1. Genetic heterogeneity a. Autosomal dominant inheritance: i. Usually with normal psychomotor development, although mild motor delay attributable to joint anomalies might be present ii. A variant of autosomal dominant inheritance, mapped to chromosome 11p15.5-pter b. Autosomal recessive inheritance: severe developmental retardation reported in a few patients 2. Pathogenesis a. Considered a form of distal arthrogryposis i. Closely related to distal arthrogryposis type 1 a) Similar limb phenotypes but distinguished only by differences in facial morphology b) Reports of families in which different individuals were diagnosed with distal arthrogryposis type 1 or Freeman-Sheldon syndrome ii. Proposed to classify Freeman-Sheldon syndrome as distal arthrogryposis type 2 (a distinct disorder from distal arthrogryposis type 1 with overlapping phenotypes) in a revised classification of distal arthrogryposis b. Primary brain anomalies suggested to explain many manifestations of the syndrome c. Also considered possibly a nonprogressive or slowly progressive myopathy
7.
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DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Skull i. Shallow anterior cranial fossa ii. Hypoplastic mandible iii. Small malar bones b. Ulnar deviation and flexion contractures of the fingers c. Talipes equinovarus d. Kyphoscoliosis 2. Polysomnography for sleep-disordered breathing 3. Muscle biopsy findings: structural changes predominantly involving type I fibers suggesting that the muscle lesion is a form of congenital fiber type disproportion
CLINICAL FEATURES 1. Variable clinical severity and phenotypic abnormalities 2. Normal intelligence 3. “Whistling face” appearance a. Long philtrum b. Microstomia c. Puckered mouth d. Pursed lips e. H-shaped cutaneous dimpling on the chin 4. Musculoskeletal anomalies a. Multiple joint contractures b. Camptodactyly c. Ulnar deviation of fingers d. Windmill vane hand (bilateral ulnar deviation and contracture of fingers 2–5 at the metacarpophalangeal joints with adduction of thumbs)
e. Normal hands in a few reports f. Bilateral talipes equinovarus g. Kyphoscoliosis Growth retardation Other craniofacial features a. Masklike rigid face b. Flat midface c. Deep-sunken eyes with hypertelorism d. Antimongoloid slant of the palpebral fissures e. Blepharophimosis f. Convergent strabismus g. Full cheeks h. Small nose i. Coloboma alae of the nose j. Micrognathia k. Cleft palate or high-arched palate l. Choanal atresia m. Low-set and malformed ears n. Hearing loss Other features a. Nasal speech b. Short neck c. Inguinal hernia d. Cryptorchidism e. Spina bifida occulta Complications a. Difficulty in swallowing attributed to the mouth deformity b. Pulmonary problems due to decreased thoracic expansion
GENETIC COUNSELING
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1. Recurrence risk a. Patient’s sib i. Autosomal dominant inheritance: low unless a parent is affected ii. Autosomal recessive inheritance: 25% iii. Empirical risks for sibs of sporadic cases: 7%
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b. Patient’s offspring i. Autosomal dominant inheritance: 50% ii. Autosomal recessive inheritance: low unless the spouse is affected iii. Empirical risk for children of sporadic case: 37% 2. Prenatal diagnosis made by ultrasonography at 20 week of gestation in a fetus with a positive family history i. Bilateral equinovarus and abnormally positioned toes ii. Clenched hands with overlapping thumbs iii. An abnormally appearing mouth with pursing of the lips 3. Management a. Tracheostomy required for severe upper airway narrowing b. Management of anesthetic risks i. Risks primarily related to severe microstomia ii. Combinations of myopathic and skeletal abnormalities predisposing affected patients to significant postoperative respiratory difficulty iii. Awake endotracheal intubation or fiberoptic nasotracheal intubation in infants before induction of general anesthesia c. Functional hand reconstruction for hand deformities d. Orthopedic correction of clubfeet and scoliosis
REFERENCES Alves AF, Azevedo ES: Recessive form of Freeman-Sheldon’s syndrome or ‘whistling face’. J Med Genet 14:139–141, 1977. Burzynski NJ, Podruch PE, Howell J, et al.: Craniocarpotarsal dysplasia syndrome (whistling face syndrome). Case reports and survey of clinical findings. Oral Surg Oral Med Oral Pathol 39:893–900, 1975. Dallapiccola B, Giannotti A, Lembo A, et al.: Autosomal recessive form of whistling face syndrome in sibs. Am J Med Genet 33:542–544, 1989. Duggar RG Jr, DeMars PD, Bolton VE: Whistling face syndrome: general anesthesia and early postoperative caudal analgesia. Anesthesiology 70:545–547, 1989.
Fitzsimmons JS, Zaldua V, Chrispin AR: Genetic heterogeneity in the FreemanSheldon syndrome: two adults with probable autosomal recessive inheritance. J Med Genet 21:364–368, 1984. Freeman E, Sheldon J: Cranio-carpotarsal dystrophy: Undescribed congenital malformation. Arch Dis Child 13:277–283, 1938. Gross-Kieselstein E, Abrahamov A, Ben-Hur N: Familial occurrence of the Freeman-Sheldon syndrome: cranio-carpotarsal dysplasia. Pediatrics 47:1064–1067, 1971. Hall JG, Reed SD, Greene G: The distal arthrogryposes: delineation of new entities—review and nosologic discussion. Am J Med Genet 11:185–239, 1982. Kousseff BG, McConnachie P, Hadro TA: Autosomal recessive type of whistling face syndrome in twins. Pediatrics 69:328–331, 1982. Lev D, Yanoov M, Weintraub S, et al.: Progressive neurological deterioration in a child with distal arthrogryposis and whistling face. J Med Genet 37: 231–233, 2000. Malkawi H, Tarawneh M: The whistling face syndrome, or craniocarpotarsal dysplasia. Report of two cases in a father and son and review of the literature. J Pediatr Orthop 3:364–369, 1983. Marasovich WA, Mazaheri M, Stool SE: Otolaryngologic findings in whistling face syndrome. Arch Otolaryngol Head Neck Surg 115:1373–1380, 1989. Mustacchi Z, Richieri-Costa A, Frota-Pessoa O: The Freeman-Sheldon syndrome. Rev Brasil Genet II 4:259–266, 1979. O’Connell DJ, Hall CM: Cranio-carpo-tarsal dysplasia: a report of seven cases. Radiology 123:719–722, 1977. Robbins-Furman P, Hecht JT, Rocklin M, et al.: Prenatal diagnosis of Freeman-Sheldon syndrome (whistling face). Prenat Diagn 15:179–182, 1995. Robinson PJ: Freeman Sheldon syndrome: severe upper airway obstruction requiring neonatal tracheostomy. Pediatr Pulmonol 23:457–459, 1997. Sánchez JM, Kaminker CP: New evidence for genetic heterogeneity of the Freeman-Sheldon syndrome. Am J Med Genet 25:507–511, 1986. Vanˇek J, Janda J, Amblerov· V, et al.: Freeman-Sheldon syndrome: a disorder of congenital myopathic origin? J Med Genet 23:231–236, 1986. Weinstein S, Gorlin RJ: Cranio-carop-tarsal dysplasia or the whistling face syndrome. I. Clinical considerations. Am J Dis Child 117:427–433, 1969. Wettstein A, Buchinger G, Braun A, et al.: A family with whistling-facesyndrome. Hum Genet 55:177–189, 1980. Zampino G, Conti G, Balducci F, et al.: Severe form of Freeman-Sheldonsyndrome associated with brain anomalies and hearing loss. Am J Med Genet 62:293–296, 1996.
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Fig. 1. Freeman-Sheldon syndrome in a father and son showing whistling face appearance of the face and ulnar deviation and fixed position of the thumbs.
Fig. 2. Freeman-Sheldon syndrome in a neonate showing characteristic “whistling face”, ulnar deviation of the fingers with contractures, and talipes equinovarus.
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Fig. 4. A newborn with Freeman-Sheldon syndrome showing whistling appearance of the face, tight mouth opening, hypoplastic alae nose, arthrogryposis of the hands and fingers with contractures and ulnar deviation of the wrists, and metatarsus adductus. Intrauterine growth retardation and Dandy-Walker malformation were detected prenatally by ultrasound.
Fig. 3. Another neonate showing characteristic “whistling face” with H-shaped cutaneous dimpling on the chin and ulnar deviation and contractures of the fingers
Frontonasal Dysplasia Frontonasal dysplasia is a developmental field defect of craniofacial region characterized by hypertelorism and varying degrees of median nasal clefting. In 1967, DeMeyer first described the malformation complex ‘median cleft face syndrome’ to emphasize the key midface defects. Since then several terms have been introduced: frontonasal dysplasia, frontonasal syndrome, frontonasal dysostosis, and craniofrontonasal dysplasia.
GENETICS/BASIC DEFECTS 1. Inheritance a. Sporadic in most cases b. Rare autosomal dominant inheritance with variable expression c. Rare autosomal recessive inheritance d. Rare X-linked dominant inheritance 2. Rare association with chromosome anomalies a. Partial trisomy 2q and partial monosomy 7q from a balanced maternal t(2;7)(q31;q36) b. 22q11 microdeletion c. Reciprocal translocation t(15;22)(q22;q13) d. Complex translocation involving chromosomes 3, 7, and 11 3. Rare variants of frontonasal dysplasia/malformation with variable inheritance patterns 4. Embryologically classified as a developmental field defect 5. Extreme variable phenotypic expression
CLINICAL FEATURES 1. Pure frontonasal dysplasia a. Variable mental retardation b. Inheritance pattern i. Sporadic in majority of cases ii. Familial transmission in few cases c. Cranium bifidum occultum d. CNS anomalies i. Frontal cephalocele ii. Meningocele/meningoencephalocele iii. Agenesis of the corpus callosum iv. Mild holoprosencephaly v. Hydrocephalus e. Nasal anomalies i. Mild colobomas of the nostril ii. Flattening of the nose with widely separated nares iii. A broad nasal root iv. Broad nasal tip v. Notching or clefting of alae nasi (cleft nose) vi. Nasal tag
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f. Ocular anomalies i. Hypertelorism ii. Epicanthal folds iii. Narrowing of the palpebral fissures iv. Accessory nasal eyelid tissue with secondary displacement of inferior puncti colobomas v. Epibulbar dermoids vi. Upper eyelid colobomas vii. Microphthalmia viii. Vitreoretinal degeneration with retinal detachment ix. Congenital cataracts g. Facial anomalies i. Widow’s peak configuration of the anterior hairline in the forehead ii. Median cleft of upper lip iii. Median cleft palate iv. Preauricular tag v. Absent tragus vi. Low-set ears h. Other anomalies i. Conductive deafness ii. Hypoplastic frontal sinuses iii. Cardiac anomalies, especially teratology of Fallot iv. Limb anomalies a) Clinodactyly b) Polydactyly c) Syndactyly d) Tibial hypoplasia v. Umbilical hernia vi. Cryptorchidism 2. Other syndromes associated with frontonasal dysplasia or frontonasal malformation a. Autosomal dominant form of frontonasal dysplasia with vertebral anomalies b. Acromelic frontonasal dysplasia i. Autosomal recessive disorder ii. Similar frontonasal “dysplasia” iii. Rare agenesis of the corpus callosum iv. Tibial hypoplasia v. Polydactyly (duplicated hallux) c. Craniofrontonasal dysplasia i. Possible X-linked disorder ii. Rare mental retardation iii. Hypertelorism iv. Craniosynostosis v. Facial asymmetry vi. Broad nasal root vii. Bifid nasal tip viii. Syndactyly of toes and fingers ix. Split nails x. Broad first toe
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d. Acrocallosal syndrome i. Autosomal dominant or autosomal recessive disorder ii. Severe mental retardation iii. Hypertelorism iv. Hypoplastic or absent corpus callosum v. Prominent forehead vi. Small nose vii. Broad nasal bridge viii. Normal nasal tip ix. Cardiac defects x. Post-axial polydactyly of hands and feet xi. Pre-axial polydactyly of feet xii. Syndactyly of toes xiii. Clinodactyly e. Oral-facial-digital syndrome i. X-linked disorder ii. Variable mental retardation iii. Agenesis of the corpus callosum iv. Median cleft lip and palate v. Lobated/bifid tongue vi. Clinodactyly vii. Syndactyly viii. Polydactyly f. Oculo-auriculo-frontonasal dysplasia i. Frontonasal dysplasia ii. Ocular dermoids iii. Eyelid colobomata iv. Preauricular tags g. Fronto-facio-nasal dysplasia i. Autosomal recessive disorder ii. Frontonasal dysplasia iii. Ocular dermoids iv. Preauricular tags v. Cerebral lipoma h. Acro-fronto-facio-nasal dysplasia I i. Macrostomia ii. Broad and notched nasal tip iii. Fibular hypoplasia iv. Short stature i. Acro-fronto-facio-nasal dysplasia II i. Autosomal recessive disorder ii. Frontonasal dysplasia iii. Microcephaly iv. Nasal midline groove with blind dimples v. Broad thumbs vi. Syndactyly j. Greig acrocephalopolysyndactyly i. Autosomal dominant disorder ii. Mild mental retardation iii. Mild features of frontonasal dysplasia iv. Macrocephaly v. Broad nasal root vi. Normal nasal tip vii. Post-axial polydactyly of hands viii. Pre-axial polysyndactyly of feet ix. Broad thumbs and halluces x. Syndactyly k. Frontonasal dysplasia-cardiac defects i. Frontonasal dysplasia ii. Microcephaly iii. Cardiac defects, especially tetralogy of Fallot
3. Prognosis depending on severity of defects a. Normal intelligence in most patients b. Mental retardation affecting 12% of cases without CNS abnormalities c. Up to 50% of cases with mental retardation complicated by agenesis of the corpus callosum
DIAGNOSTIC INVESTIGATIONS 1. Radiography, CT, MRI of the brain a. Anterior cranium bifidum b. Agenesis of the corpus callosum c. Lipoma of the corpus callosum d. Arhinencephaly e. Hydrocephalus 2. Chromosome analysis for chromosome etiology
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal dominant disorder: not increased in de novo case unless a parent is affected ii. Autosomal recessive disorder: 25% iii. X-linked dominant disorder: 50% when the mother is a carrier iv. Chromosome disorder: not increased in a de novo case; risk of unbalanced segregation from a carrier parent b. Patient’s offspring i. Autosomal dominant disorder: 50% ii. Autosomal recessive disorder: not increased unless the spouse is a carrier iii. X-linked dominant disorder: 50% iv. Chromosome disorder: not surviving to reproductive age 2. Prenatal diagnosis a. Ultrasonography i. Hypertelorism ii. Frontonasal cephalocele iii. Agenesis of the corpus callosum iv. Median cleft lip b. Amniocentesis for associated chromosome anomaly 3. Management a. Speech therapy b. Maxillofacial surgeries for functional and cosmetic improvement i. Cleft lip/palate ii. Hypertelorism iii. Nose c. Psychosocial and/or psychiatric support
REFERENCES Chen H, Rightmire D, Fowler M, et al.: Frontonasal malformation and dup(2q) syndrome. Am J Med Genet (Suppl 4):191–192, 1988. Chen H, Rightmire D, Zapata C, et al.: Frontonasal dysplasia and arrhinencephaly resulting from unbalanced segregation of a maternal t(2;7) (q31;q36). Dysmorphol Clin Genet 6:99–106, 1992. Chervenak FA, Tortora M, Mayden K, et al.: Antenatal diagnosis of median cleft syndrome: sonographic demonstration of cleft lip and hypertelorism. Am J Obstet Gynecol 149:94–97, 1984. Cohen MM Jr: Craniofrontonasal dysplasia. Birth Defects Original Article Series XV(5B):85–89, 1979.
FRONTONASAL DYSPLASIA Cohen MM Jr, Sedano HO, Gorlin RJ, et al.: Frontonasal dysplasia (median cleft face syndrome): comments on etiology and pathogenesis. Birth Defects Original Article Series 7:117–119, 1971. DeMeyer W: The median cleft face syndrome: differential diagnosis of cranium bifidum occultum, hypertelorism and median cleft nose, face and palate.. Neurology 17:961–971, 1967. Dubey SP, Garap JP: The syndrome of frontonasal dysplasia, spastic paraplegia, mental retardation and blindness: a case report with CT scan findings and review of literature. Int J Pediatr Otorhinolaryngol 54:51–57, 2000. Edwards WC, et al.: Median cleft face syndrome. Am J Ophthalmol 72:202– 205, 1971. Fox FW, et al.: Frontonasal dysplasia with alar clefts in two sisters. Plast Reconstr Surg 57: 553–561, 1976. Frattarelli JL, Boley TH, Miller RA: Prenatal diagnosis of frontonasal dysplasia (median cleft syndrome). J Ultrasound Med 1:81–83, 1996. Fryburg JS, Persing JA, Lin KY: Frontonasal dysplasia in two successive generations. Am J Med Genet 46:712–714, 1993. Fuenmayor HM: The spectrum of frontonasal dysplasia in an inbred pedigree. Clin Genet 17:137, 1980. Gollop TR: Fronto-facio-nasal dysostosis. A new autosomal recessive syndrome. Am J Med Genet 10:409–412, 1981. Guinon-Almeida ML, Richieri-Costa A, Saavedra D, et al.: Frontonasal dysplasia: analysis of 21 cases and literature review. Int J Oral Surg 25:91–97, 1996. Kinsey JA, Streeten BW: Ocular abnormalities in the median cleft face syndrome. Am J Ophthalmol 83:261–266, 1977. Kurlander GJ, et al.: Roentgenology of the median cleft face syndrome. Radiology 88:473, 1967. Martinelli P, Russo R, Agangi A, et al.: Prenatal ultrasound diagnosis of frontonasal dysplasia. Prenat Diagn 22:375–379, 2002. Moreno Fuenmayor H: The spectrum of frontonasal dysplasia in an inbred pedigree. Clin Genet 17:137–142, 1980. Nelson MM, Thomson AJ: The acrocallosal syndrome. Am J Med Genet 12:195–199, 1982. Nevin NC, Leonard AG, Jones B: Frontonasal dysostosis in two successive generations. Am J Med Genet 87:251–253, 1999. Orr DJ, Slaney S, Ashworth GJ, et al.: Craniofrontonasal dysplasia. Br J Plast Surg 50:153–161, 1997.
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Qureshi IL, Naeem-uz-Zfar K: Experience with frontonasal dysplasia of varying severity. J Pediatr Surg 7:885–889, 1996. Reich EW, et al.: A clinical investigation into the etiology of frontonasal dysplasia. Am J Hum Genet 33:88A, 1981. Rohasco SA, Massa JL: Frontonasal syndrome. Br J Plast Surg 21:244– 249, 1968. Roubicek M, et al.: Frontonasal dysplasia as an expression of holoprosencephaly. Eur J Pediatr 137:229–231, 1981. Sedano HO, Gorlin RJ: Frontonasal malformation as a field defect and in syndromic associations. Oral Surg Oral Med Oral Path 65:704–710, 1986. Sedano HO, Cohen MM, Jirasek J, et al.: Frontonasal dysplasia. J Pediatr 6:906–913, 1970. Slaney SF, Goodman FR, Eilers-Walsman BLC, et al.: Acromelic frontonasal dysostosis. Am J Med Genet 83:109–116, 1999. Smith DW, Cohen MM Jr: Widow’s peak, scalp-hair anomaly and its relation to ocular hypertelorism. Lancet 2:1127–1128, 1973. Stevens CA, Qumsiyeh MB: Syndromal frontonasal dysostosis in a child with a complex translocations involving chromosomes 3, 7, 11. Am J Med Genet 55:494–497, 1995. Stratton RF, Payne RM: Frontonasal malformation with tetralogy of Fallot associated with a submicroscopic deletion of 22q11. Am J Med Genet 69:287–289, 1997. Temple IK, Brunner H, Jones B, et al.: Midline facial defects with ocular colobomata. Am J Med Genet 37:23–27, 1990. Tommerup N, Nielsen F: A familial reciprocal translocation t(3;7)(p21.1;p13) associated with the Greig polysyndactyly-craniofacial anomalies syndrome. Am J Med Genet 16:313–321, 1983. Toriello HV: Oral-facial-digital syndromes. Clin Dysmorphol 2:95–105, 1993. Toriello HV et al.. Familial occurrence of a developmental defect of the medial nasal process. Am J Med Genet 21: 131–135, 1985. Toriello HV, Higgins JV, Mann R: Oculoauriculofrontonasal syndrome: report of another case and review of differential diagnosis. Clin Dysmorphol 4:338–346, 1995. Warkany J, Bofinger MK, Benton D: Median facial cleft syndrome in half sisters: dilemmas in genetic counselling. Teratology 8:273–285, 1973.
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Fig. 1. A newborn with frontonasal dysplasia showing ocular hypertelorism, cephalocele, hydrocephalus, and cranium bifidum.
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Fig. 3. A mother and a child with frontonasal dysplasia showing hypertelorism and broad and notched nasal tip.
Fig. 2. A newborn with frontonasal dysplasia and arrhinencephaly resulting from unbalanced segregation of a maternal t(2;7)(q31;q36). The patient had partial trisomy 2q and partial monosomy 7q, iris coloboma, tetralogy of Fallot, and limb anomalies.
Galactosemia ii. Compound heterozygotes (D/G or N314D/Q188R) a) Relatively benign in most infants b) May or may not require dietary intervention c. Los Angels (LA) variant with identical N314D missense mutation but has normal erythrocyte GALT activity d. S135L allele i. Prevalent in Africa ii. A good prognosis if therapy is initiated in the neonatal period without neonatal hepatotoxicity and chronic problems e. K285N allele i. Prevalent in Southern Germany, Austria, and Croatia ii. A poor prognosis for neurological and cognitive dysfunction in either the homozygous state or compound heterozygous state with Q188R
Classic galactosemia (G/G) is an autosomal recessive disorder of galactose metabolism, caused by a deficiency of galactose-L-phosphate uridyl transferase. The incidence is estimated to be 1 in 30,000 births, based on the results of newborn screening programs.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Cause: deficiency of galactose- L -phosphate uridyl transferase (GALT) 3. Galactose-L-phosphate uridyl transferase a. The gene for GALT is mapped on chromosome 9p13 b. GALT is second enzyme in the Leloir pathway, catalyzing conversion of galactose-L-phosphate and UDP glucose to UDP galactose and glucose-L-phosphate c. Essential in human infants who consume lactose as their primary carbohydrate source d. Near total absence of GALT activity in infants with classical galactosemia e. A deficiency causes elevated levels of galactoseL-phosphate and galactitol in body tissues 4. Endogenous production of galactose may be responsible for the long-term effects, such as cognitive dysfunction and gonadal dysfunction in female patients 5. Duarte (D) allele a. Very common b. Defined biochemically by: i. Reduced enzyme activity ii. An isoform distinguishable by gel electrophoresis and isoelectric focusing c. Heterozygous Duarte variants (D/N) i. Observed in about 11% of Caucasian subjects ii. Have about 75% of normal GALT activity d. Homozygotes for the Duarte variant (D/D) i. Have approximately one half (50%) of normal transferase activity ii. Mimic carriers for galactosemia e. Infants with a galactosemia allele and a Duarte allele (D/G) i. Have one-quarter (25%) of normal enzyme activity ii. Have reduced capacity to metabolize galactose with abnormal accumulation of galactose-Lphosphate in the red cells iii. Phenotypically normal with no ill effect 6. Genotype-phenotype correlations a. Q188R mutations (prevalent in 70% of Caucasians): a poorer outcome in homozygous state associated with essentially no enzyme activity b. Duarte variant (N314D) i. Homozygous state (D/D or N314D/N314D) with erythrocyte GALT enzyme activity reduced by only 50%
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1. Onset of symptoms a. May present by the end of the first week of life b. May die or develop cataracts, hepatomegaly, cirrhosis, and mental retardation in late-detected cases 2. Neonatal toxicity syndrome a. Exposure to dietary galactose in infants with classical galactosemia results in acute deterioration of multiple organ systems, including the following: i. Liver dysfunction a) Jaundice b) Hepatomegaly ii. Coagulopathy iii. Poor feeding and weight loss iv. Vomiting and diarrhea v. Lethargy and hypotonia vi. Renal tubular dysfunction vii. Cerebral edema (encephalopathy) viii. Vitreous hemorrhage ix. Escherichia coli sepsis b. Withdrawal of dietary galactose results in reversal of neonatal toxicity syndrome and reducing mortality and morbidity in the early weeks of life 3. Cataracts a. Resulting from accumulation of galactitol within the lens b. Seen in infants with classical GALT-deficient galactosemia (and also in galactokinase deficiency) i. The ocular hallmark of untreated or late-detected patients ii. Severity of lens involvement dependent on the severity of galactosemia and the age at commencement of therapy
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4.
5.
6.
7.
GALACTOSEMIA
c. Reoccur in older patients who have poor dietary compliance d. May be prevented by dietary restriction of galactose Ovarian failure a. Hypergonadotropic hypogonadism occurring almost universally (>90%) in females with classical GALT deficiency b. The rapidity and severity of the ovarian failure vary widely among individuals c. Clinical manifestations i. Delayed puberty ii. Primary amenorrhea iii. Secondary amenorrhea iv. Oligomenorrhea Chronic brain effects a. Specific deficits i. Developmental speech dyspraxia and tremor ii. Globally decreased IQ and/or learning disability b. Uncertainty as to: i. Whether these deficits are initiated in early development, perhaps even prenatally, and unmasked, as more complex brain function is required ii. Whether these deficits represent true neurodegenerative processes compounded by dietary exposure and endogenous production of “intoxicants” Prognosis a. A life-threatening disorder if untreated b. Currently, affected infants are treated before becoming ill because of newborn screening in most states Differential diagnosis a. Galactokinase (GALK) deficiency i. An autosomal recessive disorder ii. Considered in patients with cataracts and galactosemia but otherwise healthy iii. Cataracts a) The main clinical feature b) Due to accumulation of galactitol iv. Pseudotumor cerebri a) Described in several cases b) Considered to be a true consequence of the disorder v. These features resolve when a galactose-restricted diet is introduced vi. Diagnosis made by detection of reduced galactokinase activity vii. Caused by mutations in the GALK1 gene b. UDP-galactose 4-epimerase (GALE) deficiency i. An autosomal recessive disorder ii. Considered in patients with liver disease, sensorineural deafness, failure to thrive, and elevated galactose-L-phosphate but normal GALT activity iii. Response to the removal of galactose from their diets iv. Diagnosis made by detection of reduced UDPgalactose 4-epimerase activity v. Caused by mutations in the GALE gene c. Neonatal hepatotoxicity i. Infectious diseases (sepsis) ii. Obstructive biliary disease
a) Progressive familial intrahepatic cholestasis (Byler disease) b) Metabolic diseases such as Niemann-Pick disease, type C and Wilson disease
DIAGNOSTIC INVESTIGATIONS 1. Newborn screening programs in most states a. An almost 100% detection of affected infants in states that include testing for galactosemia in their newborn screening programs b. Prevention of needless deaths associated with galactosemia, resulting from limiting diagnostic measures to infants who develop symptoms c. A positive (i.e., abnormal) screening, followed by a quantitative erythrocyte GALT analysis 2. Liver dysfunction a. Bilirubin determination i. Initial unconjugated hyperbilirubinemia ii. Later conjugated hyperbilirubinemia b. Abnormal liver function tests c. Abnormal clotting d. Raised plasma amino acids, particularly phenylalanine, tyrosine, and methionine. Raised phenylalanine may result in a false positive neonatal screening test for phenylketonuria 3. Renal tubular dysfunction a. Metabolic acidosis b. Urinalysis i. Galactosuria a) The presence of reducing substances or galactose in the urine is neither sensitive nor specific b) Small quantities of galactose commonly found in the urine of any patient with liver disease ii. Albuminuria a) Present in the initial stage b) Quick disappearance of albuminuria after eliminating lactose-containing formula from the diet iii. Aminoaciduria in the later stage 4. Abnormal carbohydrate metabolism a. Increased plasma galactose b. Increased red cell galactose-L-phosphate c. Increased urine and blood galactitol 5. Testing for hemolytic anemia 6. Study for septicemia, especially Escherichia coli 7. Slit lamp examination for cataract assessment 8. Computerized tomography and magnetic resonance imaging a. Abnormalities on brain imaging: common in classical galactosemia b. Patients with late neurologic disease i. Abnormal white matter ii. Ventricular enlargement iii. Diffuse cortical atrophy with basal ganglia and brainstem involvement iv. Cerebellar atrophy v. Failure of normal myelination 9. Endocrine investigations for hypergonadotropic hypogonadism
GALACTOSEMIA
10. 11.
12.
13.
14.
15.
a. Raised follicle stimulating hormone b. Raised luteinizing hormone c. Initially normal estradiol concentration with high gonadotropin levels, indicating continued follicular development, but fall as ovarian failure progresses Increased urinary galactitol excretion Beutler test a. A fluorescent spot test for galactose-L-phosphate uridyl transferase activity b. Now widely used for the diagnosis of galactosemia c. False negative resulting from recent blood transfusions (within 3 months) d. False positive resulting from glucose-6-phosphate dehydrogenase deficiency Red blood cell galactose-L-phosphate a. Concentration always raised in classical galactosemia b. Not significantly affected by blood transfusions Biochemical confirmation of the diagnosis a. Red blood cell galactose-L-phosphate uridyl transferase assay i. A quantitative assay to confirm the diagnosis (virtual absence of the enzyme activity in classical (G/G) galactosemia) ii. Also identifies variants with residual enzyme activity iii. False negative results due to blood transfusion within 3 months b. A GALT isoelectric-focusing electrophoresis test to distinguish variant forms such as the Duarte defect DNA analysis: GALT genotyping for providing specific molecular diagnosis a. Classic (G/G) galactosemia i. Mutation analysis for the six common GALT galactosemia (G) mutations a) Q188R mutation: the most common GALT allele in whites b) S135L: the most common allele in blacks c) K285N d) L195P e) Y209C f) F171S ii. GALT sequence analysis to detect private mutations under the following two conditions: a) Both disease-causing mutations not detected by mutation analysis b) Diagnosis of galactosemia confirmed by biochemical testing b. Mutation analysis for Duarte variant (D/G) galactosemia identified by biochemical testing of the patient and both parents i. Identification of Duarte allele (N314D) by mutation analysis ii. Identification of G allele by mutation analysis or sequence analysis Carrier testing a. Measuring GALT activity: about 50% of control values in carriers b. Molecular genetic testing for carriers available to family members, provided GALT mutation(s) has/have been identified in the proband
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GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. A proband with G/G galactosemia a) Given the parents are G/N and G/N: a 25% chance of being affected with G/G galactosemia for each sib b) Given the parents are D/G and G/N: a 25% chance of being affected with G/G galactosemia and a 25% chance of being affected with D/G galactosemia for each sib ii. A proband with D/G galactosemia, given the parents are D/N and G/N: a 25% chance of being affected with D/G galactosemia for each sib b. Patient’s offspring: i. Patient with G/G galactosemia and the normal spouse with N/N: All offspring are carriers ii. Patient with G/G galactosemia and the carrier spouse for a G allele (N/G): a 50% chance of having G/G galactosemia iii. Patient with G/G galactosemia and the carrier spouse for a G allele (D/G): a 50% chance of having G/G galactosemia and a 50% chance of having D/G galactosemia 2. Prenatal diagnosis possible for fetuses at a 25% risk for classical galactosemia a. Galactose-L-phosphate uridyl transferase assay in cultured amniotic fluid cells or in chorionic villus biopsies b. Galactitol estimation in amniotic fluid supernatant c. Mutation analysis of DNA extracted from chorionic villus biopsy if the genotype of the index case has been characterized d. Prenatal diagnosis of a treatable condition, such as classic galactosemia, may be controversial if the prenatal testing is being considered for the purpose of pregnancy termination rather than early diagnosis 3. Management a. Dietary intervention i. Lactose-galactose-restricted diet a) Restrict milk, the principal source of lactose, and products made from milk b) Breast milk and cows’ milk contraindicated ii. Milk substitutes a) Use a formula free of bioavailable lactose (e.g., Isomil or Prosobee) b) Casein hydrolysate (Alimentum, Nutramigen, Pregestimil): not recommended because they contain small amounts of bioavailable lactose iii. Difficult to totally eliminate galactose since it is present in a wide variety of food, such as infant foods, fruits, and vegetables iv. Older patients tolerating lactose much better than children, but recommend restrict milk intake throughout life v. Calcium supplementation vi. May prevent cataracts, hepatomegaly, liver cirrhosis, mental retardation, and other symptoms
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b. c. d.
e.
f.
vii. Effect of dietary restrictions during pregnancy on the long-term complications of an affected fetus: unknown viii. Management of D/G or N344D/Q188R compound heterozygotes a) Decision to treat should be based on the demonstration of abnormal biochemical indices b) No dietary therapy is instituted if the blood galactose and/or galactose-L-phosphate do not rise above 12 mg/dL within 4 hours following such ingestion and there are no clinical signs associated with galactosemia c) Dietary therapy should probably be given if there is a greater accumulation of galactose or of galactose-L-phosphate d) There is possible benefit of dietary intervention to individuals with variant forms of galactosemia with residual GALT activity in the range of 5%–20%: for prevention of cataracts, ataxia, dyspraxic speech, and cognitive deficits Vitamin K and fresh-frozen plasma to correct clotting abnormalities An appropriate intravenous antibiotic for Gramnegative sepsis Treat unconjugated hyperbilirubinemia with phototherapy or exchange transfusion to infants who may be at an increased risk of kernicterus if albumin levels are particularly low secondary to liver disease Parental feeding if the infant is too sick to tolerate enteral feeding for more than 1 or 2 days, unless there is significant liver disease or thrombocytopenia Treat the following long-term problems in older children and adults with classical galactosemia, despite early and adequate therapy i. Cataracts ii. Speech defects iii. Poor growth iv. Poor intellectual function
v. Neurological deficits, predominantly extrapyramidal findings with ataxia vi. Ovarian failure
REFERENCES Anadiotis GA, Berry GT: Galactose-1-phosphate uridyltransferase deficiency (galactosemia). http://www.emedicine.com Beutler E: Galactosemia: screening and diagnosis. Clin Biochem 24:293–300, 1991. Burke JP, O’Keefe M, Bowell R, et al.: Ophthalmic findings in classical galactosemia—a screened population. J Pediatr Ophthalmol Strabismus 26: 165–168, 1989. Elsas LJ: Prenatal diagnosis of galactose-1-phosphate uridyltransferase (GALT)-deficient galactosemia. Prenat Diagn 21:302–303, 2001. Elsas LJ II: Galactosemia. Gene Reviews. 2003. http://www.genetests.org Elsas LJ, Dembure PP, Langley S, et al.: A common mutation associated with the Duarte galactosemia allele. Am J Hum Genet 54:1030–1036, 1994. Elsas LJ II, Lai K: The molecular biology of galactosemia. Genet Med 1:40–48, 1998. Elsas LJ, Lai K, Saunders CJ, et al.: Functional analysis of the human galactose1-phosphate uridyltransferase promoter in Duarte and LA variant galactosemia. Mol Genet Metab 72:297–305, 2001. Holton JB: Effects of galactosemia in utero. Eur J Pediatr 154:S77–S81, 1995. Holton JB, Walter JH, Tyfield LA: Galactosemia. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001. Jakobs C, Kleijer WJ, Allen J, et al.: Prenatal diagnosis of galactosemia. Eur J Pediatr 154:S33–S36, 1995. Lai K, Elsas LJ: Structure-function analyses of a common mutation in blacks with transferase-deficiency galactosemia. Mol Genet Metab 74:264–272, 2001. Lai K, Langley SD, Singh RH, et al.: A prevalent mutation for galactosemia among black Americans. J Pediatr 128:89–95, 1996. Langley SD, Lai K, Dembure PP, et al.: Molecular basis for Duarte and Los Angeles variant galactosemia. Am J Hum Genet 60:366–372, 1997. Leslie ND: Insights into the pathogenesis of galactosemia. Annu Rev Nutr 23:59–80, 2003. Levy HL, Sepe SJ, Shih VE, et al.: Sepsis due to Escherichia coli in neonates with galactosemia. N Engl J Med 297:823–825, 1977. Nelson MD Jr, Wolff JA, Cross CA, et al.: Galactosemia: evaluation with MR imaging. Radiology 184:255–261, 1992. Ng WG, Xu YK, Kaufman FR, et al.: Biochemical and molecular studies of 132 patients with galactosemia. Hum Genet 94:359–363, 1994. Waggoner DD, Buist NR, Donnell GN: Long-term prognosis in galactosaemia: results of a survey of 350 cases. J Inher Metab Dis 13:802–818, 1990. Waisbren SE, Norman TR, Schnell RR, et al.: Speech and language deficits in early-treated children with galactosemia. J Pediatr 102:75–77, 1983. Walter JH, Collins JE, Leonard JV: Recommendations for the management of galactosaemia. UK Galactosaemia Steering Group. Arch Dis Child 80:93–96, 1999.
GALACTOSEMIA
Fig. 1. A 5-year-old boy with classical galactosemia. The initial clinical presentation was at 12 days of age with unconjugated hyperbilirubinemia, presence of reducing substance in the urine, and E. coli sepsis. The patient was found to have posterior stellate lens opacities OU. He was found to have deficient galactose-L-phosphate uridyltransferase activity of 0.3 (normal range: 17–37 μM/h/g Hgb). Galactokinase was within normal limits. The patient was put on galactose-free diet and has been growing well.
Fig. 2. A 2-month-old girl with D/G compound heterozygote. The newborn screening revealed total blood galactose (Gal + Gal-L-phosphate) level of 33.4 mg/dL (Normal, <15.0) and blood galactose (without Gal-L-phosphate) level of 3.7 mg/dL. Enzyme assay for uridyltransferase was 41.3 μM (Normal, >40.0). DNA analysis showed one copy of the N314D (Duarte galactosemia) variant and one copy of the Q188R (classical galactosemia) mutation. The patient is currently on Isomil and growing well.
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Gastroschisis Gastroschisis (Greek for belly cleft) is a congenital paraumbilical wall defect characterized by the protrusion of the intestines uncovered by peritoneum. The incidence of gastroschisis is approximately 1 in 10,000 live births.
e. Dilatation of bowel loops due to partial lymphatic and venous obstruction when they are mechanically compressed against the sidewall of the defect f. Massive dilatation of the bowel secondary to volvulus, atresia and ischemia 2. The incidence of associated anomalies relatively infrequent except associated gastrointestinal anomalies (10–20%) a. Intestinal stenosis/atresia, often related to: i. Intrauterine volvulus ii. Strangulation of the blood supply to the extruded segment of intestine at the extremely tight abdominal wall defect b. Adhesions c. Malabsorption d. Meckel diverticulum e. Protein-loosing enteropathy f. Midgut volvulus g. Necrosis h. Severe short gut syndrome i. Hypoperistalsis 3. Prognosis and complications a. Oligohydramnios i. Associated with a high incidence of intrauterine growth retardation, which occurs in up to 60% of affected fetuses ii. Possible secondary effects of severe oligohydramnios a) Pulmonary hypoplasia b) Limb compression c) Cord compression b. Polyhydramnios probably associated with reduced bowel motility or bowel obstruction c. Fetal distress during labor d. IUGR e. Small for gestational age f. Prematurity g. Sepsis h. Bowel damage i. Cardiac anomalies j. Non-gastointestinal associated anomalies including occasional occurrence of amyoplasia and arthrogryposis k. Problems with absorptive and motility functions l. Intraoperative complications m. Greater than 90% survival rate n. Higher mortality rate (50%) associated with herniation of the liver o. Rare reports of spontaneous resolution of gastroschisis and closure of the anterior abdominal wall defect
GENETICS/BASIC DEFECTS 1. Precise etiology unknown 2. Inheritance a. Isolated occurrence in most cases b. Rare autosomal dominant inheritance 3. Possible etiologies and risk factors a. Vascular insult i. Association of maternal smoking and maternal cocaine use with an increased incidence of gastroschisis ii. The association of intestinal atresia and gastroschisis b. Vascular disruption of the right omphalomesenteric artery c. Premature atrophy or abnormal persistence of the right umbilical vein d. In utero rupture of a hernia of the umbilical cord e. Risk factors for gastroschisis i. Young maternal age (<20 years of age): the most striking epidemiological association with gastroschisis (20–25%) ii. Primiparous mothers iii. Socially disadvantaged mothers iv. Maternal cigarette use v. Use of vasoactive drugs (e.g., decongestant pseudoephedrine) early in pregnancy vi. Recreational drug use (particularly the use of more than one drug) 4. Rare syndrome association a. Omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) b. Amniotic band syndrome c. Limb body wall complex 5. Rare association with chromosome abnormalities a. Trisomy 21 b. Trisomy 13
CLINICAL FEATURES 1. Herniation of abdominal contents a. Through a small abdominal wall defect i. Lateral to the insertion of the umbilical cord ii. Most often to the right side of the umbilical cord b. Without covering sac c. The herniated viscera floating freely in the amniotic cavity d. Rare extrusion of the liver
DIAGNOSTIC INVESTIGATIONS
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1. Routine blood work 2. Chromosome analysis rarely indicated (incidence of chromosomal anomalies <5%)
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3. Abdominal radiography 4. Abdominal ultrasound 5. Gastrointestinal investigations to rule out gastroesophageal reflux, abnormal intestinal absorption and motility, and Hirschsprung disease 6. Echocardiography
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected with an autosomal dominant disorder b. Patient’s offspring: not increased unless the patient is affected with an autosomal dominant disorder 2. Prenatal diagnosis a. Elevated maternal serum alpha-fetoprotein (MSAFP): MSAFP levels are greater in gastroschisis than in omphalocele b. Prenatal ultrasonography i. Demonstration of a mass adjacent to the anterior ventral wall representing the herniated viscera ii. Herniation almost always exit through the right rather than the left lower quadrant iii. Cord vessels observed to the left of the exiting bowel iv. Dilated bowel loops within or outside the abdomen observed when the abdominal wall defect is small v. Possible evisceration of stomach vi. Possible evisceration of the urinary bladder with secondary hydronephrosis vii. Polyhydramnios associated with bowel obstruction c. Amniocentesis i. Elevated amniotic fluid alpha-fetoprotein ii. Positive acetylcholinesterase iii. Chromosome analysis 3. Management a. Counseling of parents i. Inform 5–10% incidence of fetal or neonatal death ii. Inform long-term digestion problems associated with short gut syndrome b. No clear evidence indicating early cesarean section improve the outcome c. Endotracheal intubation for respiratory distress in neonates d. Avoid hypothermia, hypovolemia, and sepsis e. Fluid and electrolyte balance to prevent metabolic acidosis commonly observed as a result of poor perfusion related to hypovolemia f. Insertion of an orogastric tube i. To prevent air swallowing ii. To aspirate intestinal contents g. Parenteral antibiotics h. Surgical repair: primary repair versus staged repair with silastic silo i. Total parenteral nutritional support for prolonged adynamic ileus
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REFERENCES Baird PA, MacDonald EC: An epidemiologic study of congenital malformations of the anterior abdominal wall in more than half a million consecutive live births. Am J Hum Genet 33:470–478, 1981. Bair JH, Russ PD, Pretorius DH, et al.: Fetal omphalocele and gastroschisis: a review of 24 cases. Am J Roentgenol 147:1047–1051, 1986. Barisic I, Clement M, Häusler M, et al.: Evaluation of prenatal ultrasound diagnosis of fetal abdominal wall defects by 19 European registries. Ultrasound Obstet Gynecol 18:309–316, 2001. Bonilla-Musoles F, Machado LE, Bailao LA, et al.: Abdominal wall defects: two- versus three-dimensional ultrasonographic diagnosis. J Ultrasound Med 20:379–389, 2001. Brantberg A, Blaas HG, Salvesen KA, et al.: Surveillance and outcome of fetuses with gastroschisis. Ultrasound Obstet Gynecol 23:4–13, 2004. Calzolari E, Volpato S, Bianchi F, et al.: Omphalocele and gastroschisis: a collaborative study of the Italian congenital malformation registries. Teratology 47:47–55, 1993. Calzolari CF, Dolk BH, Milan M, EUOCAT Working Group: Omphalocoele and gastroschisis in Europe: a survey of 3 million births 1980–1990. Am J Med Genet 58:187–194, 1995. Chescheir NC, Azizkhan RG, Seeds JW, et al.: Counseling and care for the pregnancy complicated by gastroschisis. Am J Perinatol 8:323–329, 1991. Colombani PM, Cunningham MD: Perinatal aspects of omphalocele and gastroschisis. Am J Dis Child 131:1386–1388, 1977. De Vries P: The pathogenesis of gastroschisis and omphalocele. J Pediatr Surg 15:245–249, 1980. Fries MH, Filly RA, Callen PW, et al.: Growth retardation in prenatally diagnosed cases of gastroschisis. J Ultrasound Med 12:583–588, 1993. Glasser JG: Omphalocele and gastroschisis. Emedicine, 2001. http://emedicine.com Guzman Endocr Rev: Early prenatal diagnosis of gastroschisis with transvaginal ultrasonography. Am J Obstet Gynecol 162:1253–1254, 1990. Hoyme HE, Jones MC, Jones KL: Gastroschisis: abdominal wall disruption secondary to early gestational interruption of the omphalomesenteric artery. Semin Perinatol 7:294–298, 1983. Hunter A, Soothill P: Gastroschisis—an overview. Prenat Diagn 22:869–873, 2002. Kirk EP, Wah RM: Obstetric management of the fetus with omphalocele or Gastroschisis: a review and report of one hundred twelve cases. Am J Obstet Gynecol 146:512, 1983. Kitchanan S, Patole SK, Muller R, et al.: Neonatal outcome of gastroschisis and exomphalos: a 10-year review. J Paediatr Child Health 36: October 2000. Langer JC, Harrison MR, Adzick NS, et al.: Perinatal management of the fetus with an abdominal wall defect. Fetal Therapy 2:216–221, 1987. Langer JC, Khanna J, Caco C, et al.: Prenatal diagnosis of gastroschisis: development of objective sonographic criteria for predicting outcome. Obstet Gynecol 81:53–56, 1993. Lowry RB, Baird PA: Familial gastroschisis and omphalocele. Am J Hum Genet 34:517–519, 1982. Luck SR, Sherman JO, Raffensperger JG, et al.: Gastroschisis in 106 consecutive newborn infants. Surgery 98:677–683, 1985. Mayer T: Gastroschisis and omphalocele: an eight year review. Ann Surg 192:783–785, 1980. Nicolaides KH, Snijders RJM, Chen HH, et al.: Fetal gastrointestinal and abdominal wall defects: associated malformations and chromosomal abnormalities. Fetal Diagn Ther 7:102–115, 1992. Paidas M, Crombleholme TM, Robertson FM: Prenatal diagnosis and management of the fetus with an abdominal wall defect. Sem Perinatol 18:196–214, 1994. Palomski GE, Hill LE, Knight GJ: Second-trimester maternal serum alphafetoprotein levels in pregnancies associated with gastroschisis and omphalocele. Obstet Gynecol 71:906, 1988. Pinette MG, Pan Y, Pinette SG, et al.: Gastroschisis followed by absorption of the small bowel and closure of the abdominal wall defect. J Ultrasound Med 13:719–721, 1994. Saleh AA, Isada NB, Johnson MP, et al.: Amniotic fluid acetylcholinesterase is found in gastroschisis but not omphalocele. Fetal Diagnosis and Therapy 8(3):168–170, 1993.
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Segel SY, Marder SJ, parry S, et al.: Fetal abdominal wall defects and mode of delivery: a systematic review. Obstet Gynecol 98:867–873, 2001. Sharp M, Bulsara M, Gollow I, et al.: Gastroschisis: early enteral feeds may improve outcome. J Paediatr Child Health 36:472–476, 2000. Stringer MD, Adzick NS, Harrison MR: Mode of delivery and outcome of neonates with gastroschisis. Am J Obstet Gynecol 171:869, 1994. Tawil A, Comstock CH, Chang CC: Prenatal closure of abdominal defect in gastroschisis: case report and review of the literature. Pediatr Dev Pathol 4:580–584, 2001.
Torfs CP, Velie EM, Oechsli FW, et al.: A population-based study of gastroschisis demographic, pregnancy, and lifestyle risk factors. Teratology 50:44–53, 1994. Weber TR, Au-Fliegner M, Downard CD, et al.: Abdominal wall defects. Curr Opin Pediatr 14:491–497, 2002. Yang P, Beaty TH, Khoury MJ, et al.: Genetic-epidemiologic study of omphalocele and gastroschisis: evidence for heterogeneity. Am J Med Genet 44:668–675, 1992.
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Fig. 1. A premature neonate had herniation of gastric antrum, small intestine and colon through the gastroschisis, right of intact umbilicus. There was malrotation of the intestine.
Fig. 2. A stillborn with gastroschisis showing herniation of abdominal contents.
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Gaucher Disease Gaucher disease is the most common lysosomal storage disease and the most common genetic disorder among Ashkenazi Jews. The disease incidence in the Ashkenazi population in Israel is 1 in 7750 to 1 in 10,000. The disease frequency in the Caucasian population is approximately 1 in 50,000 live births.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal recessive b. The gene encoding β-glucocerebrosidase (acid βglucosidase) mapped to 1q2.1 2. Caused by mutation in the glucocerebrosidase (GBA) gene that results in deficiency of β-glucocerebrosidase activity a. Over 100 different mutations reported b. Four common mutations (N370S, L444P, 84GG, IVS2+1) i. Account for about 90% of the disease-causing alleles in the Ashkenazi Jewish population ii. Account for 50–60% of the disease-causing alleles in the nonJewish population iii. Presence of the common N370S precludes neuronopathic involvement, also in combination with severe L444P c. Other rare mutations and unique mutations 3. Consequences of deficient β-glucocerebrosidase activity a. Accumulation of glucocerebroside in the lysosomes of monocyte-derived macrophages in the reticuloendothelial system b. Resulting hypersplenism produces progressive anemia and thrombocytopenia c. Accumulation of glucocerebroside in bone marrow resulting in: i. Osteopenia ii. Lytic bone lesions iii. Pathologic fractures iv. Chronic bone pain v. Acute episodes of excruciating “bone crisis” vi. Bone infarct vii. Osteonecrosis
CLINICAL FEATURES 1. Notable for marked phenotypic variability 2. Type 1 (nonneuronopathic type) a. Adult or chronic form: the most common form b. Representing about 85% of cases with Gaucher disease c. Wide range of age of onset and rate of progression i. Ranging from disability in toddlers to asymptomatic disease in octogenarians ii. The mean age at diagnosis: 21 years 446
d. Skeletal involvement i. Clinical or radiographic evidence of bone disease in 70–100% of patients with type I Gaucher disease ii. May be the most debilitating and disabling aspect of type I Gaucher disease, leading to: a) Bone marrow infiltration by Gaucher cells b) Failure of remodeling c) Osteopenia d) Focal lytic or sclerotic lesions e) Osteonecrosis f) Bone crisis g) Chronic bone pain h) Pathologic fractures e. Hepatosplenomegaly i. Enlarged spleen with resultant hypersplenism associated with pancytopenia ii. Infarction of the spleen resulting in acute abdominal pain iii. Rare acute surgical emergencies because of splenic rupture iv. Hepatomegaly common but cirrhosis and hepatic failure rare f. Pancytopenia i. Anemia secondary to the following cause: a) Hemolysis secondary to hypersplenism b) Hemodilution such as pregnancy c) Splenic sequestration d) Depressed erythropoiesis due to bone marrow failure from Gaucher cell infiltration or medullary infarction (in advanced cases, particularly postsplenectomy) ii. Leukopenia a) Commonly noted b) Rarely severe enough to contribute to recurrent infections c) Risk of infection compounded by chemotactic defects in leukopenic patients iii. Thrombocytopenia a) Resulting from hypersplenism, splenic pooling of platelets, or marrow infiltration of Gaucher cells or infarction b) Associated with easy bruising or overt bleeding, particularly with trauma, surgery, or pregnancy c) The risk of bleeding increases when there are concomitant clotting abnormalities g. Pulmonary disease i. Interstitial lung disease ii. Alveolar/lobar consolidation iii. Pulmonary hypertension iv. Hepatopulmonary syndrome a) Dyspnea
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b) Cyanosis with digital clubbing c) Liver dysfunction h. Cholelithiasis in adult patients (32%) i. Cardiac and renal complications rarely encountered j. Neurological complications secondary to bone disease i. Severe osteopenia with vertebral compression ii. Emboli following long bone fracture iii. Coagulopathy secondary to hematomyelia iv. Parkinsonian features in a few patients: uncertain cause-and-effect relationship or just a coincidence k. Absence of primary central nervous system disease 3. Type 2 (acute neuronopathic type) a. Infantile form: the rarest and most severe form of the disease b. Representing about 10% of cases with Gaucher disease c. Onset before age 2, mostly symptomatic by age 6 months d. Normal at birth e. Development of hepatosplenomegaly f. Regression of developmental milestones g. Arrest of growth h. Bulbar signs i. Stridor ii. Squint iii. Swallowing difficulty i. Pyramidal signs i. Opisthotonus ii. Head retroflexion iii. Spasticity iv. Trismus j. Oculomotor abnormalities i. Oculomotor apraxia ii. Saccadic initiation failure iii. Opticokinetic nystagmus iv. Strabismus k. Collodion baby phenotype (congenital ichthyosis) in some neonates l. Perinatal lethal Gaucher disease: a subset of type 2 or a specific clinical entity i. Lethality of a homozygous null mutation reported ii. Nonneurological involvement a) Nonimmune hydrops fetalis b) Prematurity c) Fetal demise or death usually occurring within 2 days to 3 months d) Hepatosplenomegaly (92%) e) Thrombocytopenia (38%) associated with purpura (22%) f) Anemia (10%) g) Neonatal ichthyosis/collodion baby phenotype (41%) h) Bone marrow invasion by Gaucher cells, a constant finding at autopsy iii. Neurological involvement a) Neurologic signs overlapping with classical type 2 Gaucher disease b) Hypokinesia (43%) with facial dysmorphology c) Contractures of distal joints (club foot, camptodactyly) (30%)
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m. Universally progressive and fatal, succumb to apnea or aspiration by age 2–4 years 4. Type 3 (chronic neuronopathic type) a. Juvenile form: presenting in childhood or early adulthood b. Observed primarily in a cluster of cases from Sweden (Norrbottenian type) but may occur in other ethnic groups c. Hepatosplenomegaly d. Anemia e. Thrombocytopenia f. Bony involvement g. Pulmonary infiltrates and esophageal varices associated with liver cirrhosis h. Neurologic disease i. Supranuclear gaze palsy ii. Seizures in some patients a) Generalized tonic–clonic seizures b) Progressive myoclonic epilepsy iii. Advanced stage a) Dementia b) Ataxia i. Lifespan extending into the 3rd–4th decade 5. Type 4 (cardiovascular type) a. Calcification of the aortic and mitral valves b. Mild Splenomegaly c. Corneal opacities d. Supranuclear ophthalmoplegia e. Mild splenomegaly
DIAGNOSTIC INVESTIGATIONS 1. Blood tests a. Hemoglobin concentration for anemia b. Platelet count for thrombocytopenia c. Liver enzymes for liver disease d. Iron, ferritin, and total iron binding capacity for coexistent iron deficiency or iron overload e. Prothrombin time, activated partial thromboplastin time for: i. Clotting defects associated with liver disease ii. Factors IX and Factor X deficiency with Gaucher disease iii. Factor XI deficiency that may cosegregate with Gaucher disease among Ashkenazi Jewish population f. Alkaline phosphatase, serum calcium, phosphorous, 24-hours urinary calcium for markers of bone involvement and defects in calcium absorption and metabolism g. Total and direct bilirubin, total protein and albumin for monitoring liver function h. Serum protein electrophoresis and serum immunoelectrophoresis for detecting monoclonal gammopathies that may be more common in adult patients with Gaucher disease than in the general population i. Plasma chitotriosidase (markedly elevated in plasma) 2. Abdominal ultrasound a. Assessing organ volume and parenchymal abnormalities b. Gallstone detection
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3. Brainstem auditory evoked response (BAER) for abnormal wave form in type 2 and type 3 4. Bone densitometry for quantitative assessment of osteopenia 5. Radiography a. Erhlenmeyer flask deformity i. Common but not pathognomonic finding ii. Deformity resulting from the impairment of remodeling of the metaphyseal region of tubular bones iii. Manifesting as a flaring of the distal lateral aspects of the femur and proximal tibia b. Lytic lesions c. Osteosclerosis due to aberrant remodeling after bone infarction with deposition of calcium d. Generalized osteopenia i. Nearly universal in children and adults with Gaucher disease ii. Associated with increased risk of bone fractures e. Osteonecrosis (avascular necrosis) i. Believed to be secondary to chronic infarction ii. Affecting primarily the femoral head, proximal humerus and vertebral bodies iii. Resulting in fracture and joint collapse f. Fractures g. Bone marrow infiltration 6. MRI a. Extent of marrow involvement b. Fibrosis and/or infarction c. Cerebral atrophy 7. Bone marrow aspiration a. Presence of lipid-engorged macrophages (“Gaucher cells”) i. Fibrillary, ‘crumpled silk’ appearance to the cytoplasm ii. Eccentrically placed nucleus iii. Stained positively with Periodic Acid Schiff reagent b. Not a mandatory test since the bone marrow findings are nonspecific changes and not reliable 8. Assay of acid β-glucocerebrosidase enzyme activity in peripheral blood leukocytes, lymphoblasts, cultured fibroblasts, amniocytes, and chorionic villi samples a. The most efficient and confirmatory diagnostic test b. Affected individuals: 0–15% of normal activity c. Individuals with type 1 Gaucher disease: 10–15% of normal activity d. Individuals with type 2 Gaucher disease: ≤10% of normal value e. Unreliable for carrier detection since the values overlap in carriers and noncarriers 9. Molecular genetic testing to identify two disease-causing alleles providing additional confirmation of the diagnosis a. Mutation analysis b. Sequence analysis
GENETIC COUNSELING 1. Recurrence risk a. Patient’s parents i. Heterozygotes (carrying a single copy of a disease-causing mutation in the GBA gene) in most instances
ii. Asymptomatic iii. A homozygous parent possible a) High carrier frequency in certain population (approximately 1 in 14 in Ashkenazi Jews population) b) Variable phenotype with the N370S/N370S genotype b. Patient’s sib i. 25% affected, given the parents are carriers ii. 50% affected when one of the parents is a homozygote and the other a heterozygote c. Patient’s offspring i. When the spouse is not a carrier: all offspring obligate heterozygotes ii. When the spouse is a carrier: 50% of offspring affected and 50% of offspring carriers 2. Prenatal diagnosis a. Prenatal ultrasound findings in perinatal lethal Gaucher disease i. Nonimmune hydrops fetalis ii. Hepatosplenomegaly iii. Abnormal fetal movements, posture, and tone b. Available to pregnancies at increased risk i. Highly useful to predict nonneuronopathic disease with assurance ii. Overall difficulty in predicting disease progression adding complexity c. Analysis of β-glucocerebrosidase enzymatic activity (0–15% of normal), performed on fetal cells obtained by: i. CVS cells ii. Amniocytes d. Mutation analysis of the GBA gene when the diseasecausing GBA mutations have been identified in both parents or a prior affected sibling, performed on fetal cells obtained by: i. CVS cells ii. Amniocytes 3. Management a. Symptomatic care i. Partial or total splenectomy a) For patients who have massive splenomegaly with significant infarction and persistent severe thrombocytopenia with high risk of bleeding b) Enzyme replacement therapy alleviates hypersplenism and eliminates the need for splenectomy ii. Transfusion of blood products for severe anemia and bleeding iii. Analgesics for bone pain iv. Joint replacement surgery to relief bone pain and restore joint function v. Oral bisphosphonates suggested in patients with Gaucher disease and low bone density b. Therapy to reduce glycosylceramide accumulation i. Bone marrow transplantation ii. Enzyme replacement therapy iii. Substrate reduction therapy iv. Gene therapy c. Bone marrow transplantation
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i. ii. iii. iv.
Corrects metabolic defect Improves blood counts Reduces increased liver volume Stabilizes bone disease and neurologic disease in a few patients v. Limited use in patients with type I and type III Gaucher disease because of the morbidity and mortality associated with the bone marrow transplantation vi. Useful concomitant therapy for patients with chronic neurological Gaucher disease and progressive disease on enzyme replacement therapy d. Enzyme replacement therapy (ERT) i. Efficacy using alglucerase and imiglucerase a) For treating the visceral and hematological aspects of Gaucher disease b) Treatment responses seen within months c) Effective for halting or reversing the skeletal pathology of Gaucher disease d) The optimal dosage and the response time of ERT for treating the skeletal system, particularly for pediatric patients, are not well defined ii. Intravenous infusions of purified macrophagetargeted human β-glucocerebrosidase a) Alglucerase (Ceredase, Genzyme corporation), derived from human placenta b) Imiglucerase (Cerezyme, Genzyme corporation), derived from recombinant DNA production methods iii. Treatment results (visceral aspects of type 1 and type 3 Gaucher disease) a) Breakdown of stored glucocerebroside b) Reduction in liver and spleen size c) Ameliation or resolution of anemia and thrombocytopenia d) Decreased bone pain e) Increased bone mineralization f) Remodeling over a period of several years g) Improved health-related quality of life h) IgG antibodies to alglucerase reported to develop in approximately 13% of patients. These antibodies have little clinical effect and diminish with continued therapy in most circumstances. However, the presence of antibodies could be associated with an increased risk of hypersensitivity reactions iv. Treatment in patients with type 2 Gaucher disease a) Limited and disappointing b) Therapy at birth given to an infant, identified prenatally, failed to alter the inevitable neurologic outcome c) Currently not recommended to treat patients with type 2 Gaucher disease v. Currently, no hard data available to show the efficacy of enzyme therapy for reversing existing or rapidly progressing CNS disease in type 3 patients with Gaucher disease vi. Effect of enzyme therapy on the cardiac, valvular and hydrocephalic manifestations of type 4 patients remains unknown
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e. Substrate reduction therapy i. Miglustat, a formulation aimed at restoring metabolic homeostasis by limiting the amount of substrate precursor synthesized to a level that can be effectively cleared by the mutant enzyme with residual hydrolytic activity ii. Long-term safety needed to be carefully evaluated f. Gene therapy i. Currently under investigation ii. Involving the introduction of the GBA gene into hematopoietic stem cells
REFERENCES Balicki D, Beutler E: Gaucher disease. Medicine (Baltimore) 74:305–323, 1995. Barranger JA, O’Rourke E: Lessons learned from the development of enzyme therapy for Gaucher disease. J Inherit Metab Dis 24 (Suppl 2):89–96; discussion 87-88, 2001. Barranger JA, Rice E, Sakallah SA, et al.: Enzymatic and molecular diagnosis of Gaucher disease. Clin Lab Med 15:899–913, 1995. Bembi B, Ciana G, Mengel E, et al.: Bone complications in children with Gaucher disease. Brit J Radiol 75 (Suppl 1):A37–A43, 2002. Bove KE, Daugherty C, Grabowski GA: Pathological findings in Gaucher disease type 2 patients following enzyme therapy. Hum Pathol 26: 1040–1045, 1995. Cabrera-Salazar MA, Novelli E, Barranger JA: Gene therapy for the lysosomal storage disorders. Curr Opin Mol Ther 4:349–358, 2002. Charrow J, Andersson HC, Kaplan P, et al.: The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. Arch Intern Med 160:2835–2843, 2000. Charrow J, Esplin JA, Gribble TJ, et al.: Gaucher disease: recommendations on diagnosis, evaluation, and monitoring. Arch Intern Med 158:1754–1760, 1998. Desnick RJ: Gaucher disease: a century of delineation and understanding. Prog Clin Biol Res 95:1–30, 1982. Desnick RJ: Gaucher disease (1882–1982): Centennial perspectives on the most prevalent Jewish genetic disease. Mt Sinai J Med 49:443–455, 1982. Grabowski GA: Gaucher disease: gene frequencies and genotype/phenotype correlations. Genet Test 1:5–12, 1997. Grabowski GA: Gaucher disease: considerations in prenatal diagnosis. Prenat Diagn 20:60–62, 2000. Grabowski GA, Leslie N, Wenstrup R: Enzyme therapy in Gaucher disease: a five-year perspective. Blood Rev 12:115–133, 1998. Grabowski GA, Saal HM, Wenstrup RJ, et al.: Gaucher disease: a prototype for molecular medicine. Crit Rev Oncol Hematol 23:25–55, 1996. Maas M, Poll LW, Terk MR: Imaging and quantifying skeletal involvement in Gaucher disease. Br J Radiol 75 (Suppl 1):A13–A24, 2002. McCabe ERB, Fine BA, Golbus MS, et al.: Gaucher disease- Current issue in diagnosis and treatment. NIH Technology Assessment Conference. J Am Med Assoc 275:548–553, 1996. Meikle PJ, Hopwood JJ, Clague AE, et al.: Prevalence of lysosomal storage disorders. J Am Med Assoc 281:249–254, 1999. Mignot C, Gelot A, Bessieres B, et al.: Perinatal-lethal Gaucher disease. Am J Med Genet 120A:338–344, 2003. Orvisky E, Park JK, LaMarca ME, et al.: Glucosylsphingosine accumulation in tissues from patients with Gaucher disease: correlation with phenotype and genotype. Mol Genet Metab 76:262–270, 2002. Pastores GM: Gaucher disease. Gene Reviews. http://www.genetests.org Pastores GM, Barnett NL: Substrate reduction therapy: miglustat as a remedy for symptomatic patients with Gaucher disease type 1. Expert Opin Investig Drugs 12:273–281, 2003. Pastores GM, Sibille AR, Grabowski GA: Enzyme therapy in Gaucher disease type 1: dosage efficacy and adverse effects in 33 patients treated for 6 to 24 months. Blood. Pastores GM, Einhorn TA: Skeletal complications of Gaucher disease: pathophysiology, evaluation and treatment. Sem Hematol 32 S1:20–27, 1995. Pastores GM, Patel MJ, Firooznia H: Bone and joint complications related to Gaucher disease. Curr Rheumatol Rep 2:175–180, 2000. Poll LW, Maas M, Terk MR, et al.: Response of Gaucher bone disease to enzyme replacement therapy. Br J Radiol 75 (Suppl 1):A25–A36, 2002.
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Ringden O, Groth CG, Erikson A, et al.: Ten years’ experience of bone marrow transplantation for Gaucher disease. Transplantation 59:864–870, 1995. Rosenberg M, Kingma W, Fitzpatrick MA, et al.: Immunosurveillance of alglucerase enzyme therapy for Gaucher patients: induction of humoral tolerance in seroconverted patients after repeat administration. Blood 93:2081–2088, 1999. Rowlands S, Murray H: Prenatal ultrasound findings in a fetus diagnosed with Gaucher’s disease (type 2) at birth. Prenat Diagn 17:765–769, 1997. Rosenthal DI, Doppelt SH, Mankin HJ, et al.: Enzyme replacement therapy for Gaucher disease: skeletal responses to macrophage-targeted glucocerebrosidase. Pediatrics 96:629–637, 1995. Sibille A, Eng CM, Kim SJ, et al.: Phenotype/genotype correlations in Gaucher disease type I: clinical and therapeutic implications. Am J Hum Genet 52:1094–1101, 1993. Sidransky E: New perspectives in type 2 Gaucher disease. Adv Pediatr 44: 73–107, 1997. Sidransky E, Tayebi N, Ginns EI: Diagnosing Gaucher disease. Early recognition, implications for treatment, and genetic counseling. Clin Pediatr (Phila) 34:365–371, 1995.
Sidransky E, Tayebi N, Stubblefield BK, et al.: The clinical, molecular, and pathological characterisation of a family with two cases of lethal perinatal type 2 Gaucher disease. J Med Genet 33:132–136, 1996. Stone DL, Carey WF, Christodoulou J, et al.: Type 2 Gaucher disease: the collodion baby phenotype revisited. Arch Dis Child Fetal Neonatal Ed 82:F163–F166, 2000. Tayebi N, Cushner SR, Kleijer W, et al.: Prenatal lethality of a homozygous null mutation in the human glucocerebrosidase gene. Am J Med Genet 73:41–47, 1997. Tayebi N, Stone DL, Sidransky E: Type 2 Gaucher disease: an expanding phenotype. Mol Genet Metab 68:209–219, 1999. Vellodi A, Bembi B, de Villemeur TB, et al.: Management of neuronopathic Gaucher disease: a European consensus. J Inherit Metab Dis 24:319–327, 2001. Weinreb NJ, Charrow J, Andersson HC, et al.: Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. Am J Med 113:112–119, 2002. Wenstrup RJ, Roca-Espiau M, Weinreb NJ, et al.: Skeletal aspects of Gaucher disease: a review. Br J Radiol 75 (Suppl 1):A2–A12, 2002.
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Fig. 3. Higher magnification of bone marrow smear showing a Gaucher cell (Wright Giemsa stains).
Fig. 1. A 3-year-old African American female with Gaucher disease showing hepatosplenomegaly. She had history of “large belly” since she was 6-12 months of age, anemia (hemoglobin of 8.7 gm%), and thrombocytopenia (73,000). She had an elevated total acid phosphatase of 29 U/L (2.3–5.0), a very low leukocyte β-glucocerebrosidase of 0.01 U (0.08–0.35) and “Gaucher cells” in the bone marrow.
Fig. 2. Bone marrow smear from another patient with Gaucher disease showing extensive infiltration by Gaucher cells (H & E stain).
Generalized Arterial Calcification of Infancy General arterial calcification of infancy is a rare and usually fatal disease. The condition is also called idiopathic arterial calcification of infancy.
i. Tachypnea ii. Tachycardia iii. Cyanosis d. Hypertension e. Myocardial infarctions f. Progressive congestive cardiac failure 4. Prognosis a. Death (sudden death or unexpected infant death) i. Usually occurring during early infancy secondary to coronary insufficiency ii. 85% of cases dying before 6 months of age iii. Causes a) Ischemic cardiomyopathy b) Other complications of obstructive arteriopathy including renal artery stenosis b. Rare regression of calcification and prolonged survival
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Cause a. Loss-of-function mutations in ENPP1 gene that inactivate ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). This cell surface enzyme generates inorganic pyrophosphate, a solute that regulates cell differentiation and serves as an essential physiologic inhibitor of calcification b. Plasma cell membrane glycoprotein-1 (PC-1) deficiency i. Associated with human infantile arterial calcification, especially with peri-articular calcification ii. May explain the sharing of certain phenotypic features between some infantile arterial calcification patients and PC-1-deficient mice 3. Basic defects a. Possibly a defect of elastic fiber i. Occurrence of calcification particularly in the internal elastic lamina ii. Material with the staining properties of mucopolysaccharide accumulates around the elastic fibers b. Fundamental lesions i. A remarkable predilection for mineralization around the internal elastica laminae of medium to large-sized arteries ii. Narrowing of the arterial lumen due to a marked intimal proliferation c. Pathogenesis i. Incompletely understood ii. Involves calcification (calcium hydroxyapatite deposition) in the internal elastic lamina of large and medium-sized arteries, associated with a stenosing, fibroproliferative medial smooth muscle cell-mediated process, maximal in the area of the internal elastic lamina iii. Relates to decreased levels of plasma and urinary inorganic pyrophosphate whose role is to inhibit hydroxyapatite crystal deposition in bone and cartilage
DIAGNOSTIC INVESTIGATIONS
CLINICAL FEATURES 1. Stormy clinical course 2. Infant usually thrive normally right after birth 3. Thereafter, following symptoms develop rapidly a. Poor feeding b. Vomiting c. Respiratory distress 452
1. Blood work-up a. Normal calcium levels b. Normal phosphate levels 2. Radiography a. Demonstration of the calcified arteries, leading to possible diagnosis of the condition during life b. Extensive vascular calcification i. Upper and lower limbs ii. Neck iii. Subclavicular fossae iv. Axillae c. Periarticular calcification and stippled calcification of the epiphyseal cartilage d. Cardiac enlargement 3. ECG changes suggesting: a. Coronary occlusion b. Myocardial infarct 4. Echocardiography to demonstrate coronary calcification 5. Aortogram showing striking obliterations of the peripheral vessels 6. Biopsies of peripheral arteries showing extensive intimal mineralization 7. Postmortem gross pathological findings usually limited to the cardiovascular system a. An enlarged heart b. Focal calcifications of coronary arteries and other peripheral arteries c. Pale or mottled areas of the myocardium or other viscera indicative of infarction 8. Histopathology a. Extensive mineralization (calcium hydroxyapatite deposition) of arteries i. Usually noted around the internal elastic lamina of the medium-sized arteries
GENERALIZED ARTERIAL CALCIFICATION OF INFANCY
ii. Often accompanied by a marked intimal hyperplasia causing luminal narrowing iii. Tends to be most severe in the coronary arteries a) Resulting in myocardial ischemia and infarction b) Death usually attributable to myocardial infarction or heart failure b. Involvement of a variety of arteries i. Aorta ii. Pulmonary arteries iii. Carotid arteries iv. Iliac arteries v. Femoral arteries vi. Visceral arteries vii. Limb arteries viii. Vessels of the brain usually not affected c. Cardiac abnormalities i. Left or biventricular hypertrophy ii. Fibrointimal thickening iii. Calcification of the coronary arteries iv. Endocardial fibroelastosis v. Widespread ischemic myocardial damage d. Generalized arterial calcification of infancy generally indistinguishable from the following conditions i. Metastatic calcification of arteries secondary to advanced renal disease ii. Arterial lesions in hypervitaminosis D or secondary to other toxic agents iii. Hyperparathyroidism of pregnancy 9. Molecular genetic diagnosis not yet available clinically
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring i. Not surviving to reproductive age in majority of patients ii. Low recurrence risk for those who survive 2. Prenatal diagnosis a. Fetal ultrasonography and radiography to detect calcium hydroxyapatite deposits (echogenic walls of arterial vessels) b. Fetal echocardiography i. Fetal nonimmune hydrops ii. Increased echo (calcific-type) density of walls of the fetal aorta, pulmonary arteries, coronary arteries, within the lumen of the heart, and other arterial walls iii. Poor focal contraction of the heart, as a result of the expected accompanying cardiac ischemia due to coronary artery narrowing iv. Dilated cardiac chambers v. Pericardial effusion vi. Hypertrophic cardiomyopathy c. Prenatal diagnosis by amniocentesis or CVS not available since reference ranges for the disease-related enzymes in amniocytes or fibroblast cultures from CVS have not been established
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3. Management a. Therapy with diphosphonates (nonhydrolyzable analogs of inorganic pyrophosphate) i. Function of diphosphonates a) Simple chemical compounds containing phosphate-carbon-phosphate bonds b) Inhibit the precipitation of several calcium salts in vitro c) Block the conversion of amorphous calcium phosphate into crystalline hydroxyapatite d) Partially converting apatite crystals into a colloidal state with treatment of large amounts of certain diphosphonates ii. Effective in some patients a) Some apparent reduction of calcification b) Usually with persistence of ischemic effects of intimal fibroproliferation b. Management of arterial hypertension i. May be refractory to conventional medical therapy ii. Prostaglandin E1 infusion c. Management of myocardial infarctions d. In utero diphosphonate etidronate therapy i. Apparent radiographic and ultrasonographic improvement in the degree of vascular calcification ii. Unable to prevent the lethal progression of intimal vascular occlusive disease
REFERENCES Anderson KA, Burbach JA, Fenton LJ, et al.: Idiopathic arterial calcification of infancy in newborn siblings with unusual light and electron microscopic manifestations. Arch Pathol Lab Med 109:838–842, 1985. Bellah RD, Zawodniak L, Librizzi RJ, et al.: Idiopathic arterial calcification of infancy: prenatal and postnatal effects of therapy in an infant. J Pediatr 121:930–933, 1992. Bird T: Idiopathic arterial calcification in infancy. Arch Dis Child 49:82–89, 1974. Byard RW: Idiopathic arterial calcification and unexpected infant death. Pediatr Pathol Lab Med 16:985–994, 1996. Chen H, Fowler M, Yu CW: Generalized arterial calcification of infancy in twins. Birth Defects Orig Artic Ser 18:67–80, 1982. Lussier-Lazaroff J, Fletcher BD: Idiopathic infantile arterial calcification: roentgen diagnosis of a rare cause of coronary artery occlusion. Pediatr Radiol 1:224–228, 1973. Maayan C, Peleg O, Eyal F, et al.: Idiopathic infantile arterial calcification: a case report and review of the literature. Eur J Pediatr 142:211–215, 1984. Marrott PK, Newcombe KD, Becroft DM, et al.: Idiopathic infantile arterial calcification with survival to adult life. Pediatr Cardiol 5:119–122, 1984. Meradji M, de Villeneuve VH, Huber J, et al.: Idiopathic infantile arterial calcification in siblings: radiologic diagnosis and successful treatment. J Pediatr 92:401–405, 1978. Moran JJ: Idiopathic arterial calcification of infancy: a clinicopathologic study. Pathol Annu 10:393–417, 1975. Moran JJ, Becker SM: Idiopathic arterial calcification of infancy; report of 2 cases occurring in siblings, and review of the literature. Am J Clin Pathol 31:517–529, 1959. Moran JJ, Steiner GC: Idiopathic arterial calcification in a 5-year-old child. A case report. Am J Clin Pathol 37:521–526, 1962. Nagar AM, Hanchate V, Tandon A, et al.: Antenatal detection of idiopathic arterial calcification with hydrops fetalis. J Ultrasound Med 22:653–659, 2003. Rutsch F, Schauerte P, Kalhoff H, et al.: Low levels of urinary inorganic pyrophosphate indicating systemic pyrophosphate deficiency in a boy with idiopathic infantile arterial calcification. Acta Paediatr 89: 1265–1269, 2000. Rutsch F, Vaingankar S, Johnson K, et al.: PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification. Am J Pathol 158:543–554, 2001.
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Rutsch F, Ruf N, Vaingankar S, et al.: Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet 34:379–381, 2003. Sholler GF, Yu JS, Bale PM, et al.: Generalized arterial calcification of infancy: three case reports, including spontaneous regression with long-term survival. J Pediatr 105:257–260, 1984. Spear R, Mack LA, Benedetti TJ, et al.: Idiopathic infantile arterial calcification. In utero diagnosis. J Ultrasound Med 9:473–476, 1990. Stanley RJ, Edwards WD, Rommel DA, et al.: Idiopathic arterial calcification of infancy with unusual clinical presentations in sisters. Am J Cardiovasc Pathol 2:241–245, 1988. Stuart AG: Idiopathic arterial calcification of infancy and pyrophosphate deficiency. J Pediatr 123:170–171, 1993.
Stuart G, Wren C, Bain H: Idiopathic infantile arterial calcification in two siblings: failure of treatment with diphosphonate. Br Heart J 64:156–159, 1990. Thomas P, Chandra M, Kahn E, et al.: Idiopathic arterial calcification of infancy: a case with prolonged survival. Pediatr Nephrol 4:233–235, 1990. Thiaville A, Smets A, Clercx A, et al.: Idiopathic infantile arterial calcification: a surviving patient with renal artery stenosis. Pediatr Radiol 24:506–508, 1994. Van Dyck M, Proesmans W, Van Hollebeke E, et al.: Idiopathic infantile arterial calcification with cardiac, renal and central nervous system involvement. Eur J Pediatr 148:374–377, 1989. Vera J, Lucaya J, Garcia Conesa JA, et al.: Idiopathic infantile arterial calcification: unusual features. Pediatr Radiol 20:585–587, 1990. Whitehall J, Smith M, Altamirano L: Idiopathic infantile arterial calcification: sonographic findings. J Clin Ultrasound 31:497–501, 2003.
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Fig. 3. Gross view of vessels, especially the renal arteries, intercostalis, and iliacs, which were hard with mineralization of vessel walls.
Fig. 1. Postmortem picture of a neonate (twin B) with generalized arterial calcification showing ischemic changes of the right arm. The pregnancy was complicated by polyhydramnios. At 2 weeks of age, he was noted to have intercostal retraction and tachypnea with distended abdomen and hepatomegaly. Fig. 4. Artery on the right shows the earliest type of lesion with mild intimal hyperplasia, mild fragmentation, and early mineralization of internal elastic lamina. Artery on the left shows a more advanced lesion with moderate intimal proliferation, moderate fragmentation of internal elastica lamina, and heavy mineralization in and around elastic fibers.
Fig. 2. Radiograph examinations showed extensive vascular calcification extending down the upper and lower limbs, neck, supraclavicular fossae, and axillae. Radiograph here shows an enlarged heart and linear calcification (arrows) of the carotid and brachial arteries.
Fig. 5. Advanced mineralization in and around internal elastica lamina (coronary artery).
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Fig. 6. Radiographs of twin B show linear calcification (arrow) of the radial artery (upper) and popliteal artery (lower). At 35 days of age, the twin suffered a cardiac arrest and expired shortly thereafter. No autopsy was performed.
Glucose-6-Phosphate Dehydrogenase Deficiency iii. Neutralize agents that threaten to oxidize either hemoglobin or components of the red cell membrane d. In the absence of G6PD i. Red cell membrane and hemoglobin damaged by oxidant exposure ii. Leading to rapid hemolysis 5. Hemolysis secondary to inability of G6PD-deficient red cells to withstand the oxidative damage produced, directly or indirectly, by the triggering agents: a. Drugs b. Infections c. Ingestion of fava beans with life-threatening manifestations especially favism in children 6. G6PD deficiency conferring resistance against Plasmodium falciparum malaria based on: a. Prevalence of G6PD deficiency and the past and present endemicity of Plasmodium. falciparum malaria b. The high prevalence in malaria-endemic areas of G6PD mutants c. Heterozygote advantage
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most commonly known enzymopathy, affecting approximately 400 million people worldwide, especially in tropical Africa, the Middle East, tropical and subtropical Asia, some areas of the Mediterranean, and Papua New Guinea. The gene frequencies are estimated to be as high as 5–25% percent in these areas.
GENETICS/BASIC DEFECTS 1. Inheritance a. X-linked recessive in terms of clinical expression i. Not truly recessive since heterozygous females can even develop severe hemolytic attacks ii. Coexistence in female heterozygotes of two cell populations, G6PD(+) and G6PD(–), secondary to X-chromosome inactivation iii. Homozygous females not rare in many populations with high frequency of G6PD deficiency b. Co-dominant in terms of biochemical characteristics of electrophoretic variants segregating in a pedigree 2. The gene mapped to Xq28 region 3. Genetic heterogeneity a. Diverse biochemical characteristics i. Presence of about 400 different variants ii. Many allelic mutations in the G6PD gene causing these variants iii. Presence of several structural mutants without enzyme deficiency b. Heterogeneous molecular characteristics i. Some variants with different names proved to be identical ii. Some variants thought to be homogeneous proved to be heterogeneous c. Different mutations responsible for: i. Chronic hemolytic anemia: less common ii. Episodic hemolysis: more frequently seen d. Diverse clinical manifestations, to a large extent, explainable by the genetic heterogeneity 4. Pathogenesis a. G6PD i. A central enzyme in the pentose phosphate shunt of glucose metabolism ii. Catalyzes glucose-6-phosphate (G6P) to 6phosphogluconic acid (6PG) iii. Reduce nicotinamide adenine dinucleotide phosphate (NADP) to the reduced form of NADP (NADPH) b. NADPH: converts glutathione disulfide (GSSG) to reduced glutathione (GSH) c. Reduced glutathione GSH i. Inactivates hydrogen peroxides (H2O2) ii. Protects protein sulfhydryl groups from oxidation
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1. History a. Asymptomatic in the vast majority of G6PD-deficient individuals without being aware of their genetic abnormality b. No positive history of acute intravascular hemolytic crises without exposure to oxidant stress c. Neonatal jaundice d. Chronic hemolytic anemia i. An insidious decrease in hemoglobin ii. Observed in certain variant enzymes e. Required a careful investigation to establish the history of exposure to inciting agents 2. Common clinical manifestations a. Neonatal jaundice: may cause permanent neurologic damage or death in some severe cases b. Episodes of acute hemolytic anemia i. Drug-induced hemolysis ii. Infection-induced hemolysis iii. Favism: occurrence of acute hemolysis after ingestion of broad beans (Vicia faba) iv. Chronic nonspherocytic hemolytic anemia v. Associated with hemoglobinuria since red cell destruction in these acute hemolytic events is largely intravascular vi. Concomitance with a variety of clinical situations, including diabetic ketoacidosis, hypoglycemia, myocardial infarction with pericardial tamponade, and strenuous exercise
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c. Symptoms and signs of acute hemolytic crisis i. Headache ii. Lethargy iii. Pallor iv. Jaundice v. Red, clear urine 3. Symptoms and signs of chronic hemolytic crisis a. Pallor b. Jaundice c. Severe chronic hemolysis observed in a rare subset of G6PD-deficient patients 4. Drugs responsible for hemolysis a. Antimalarials i. Definite association (Primaquine, Pamaquine) ii. Possible association (Chloroquine) iii. Doubtful association (Quinacrine, Quinine) b. Sulfonamides i. Definite association (Sulfanilamide, Sulfacetamide, Sulfapyridine, Sulfamethoxazole) ii. Possible association (Sulfadimidine, Sulfasalazine, Glyburide) iii. Doubtful association (Sulfoxone, Sulfadiazine, Sulfisoxazole) c. Sulfones: definite association (Dapsone) d. Nitrofurantoin: definite association (Nitrofurantoin) e. Antipyretic/analgesic i. Definite association (Acetanilid) ii. Possible association (Aspirin) iii. Doubtful association (Acetaminophen, phenacetin) f. Other drugs i. Definite association (Nalidixic acid, Niridazole, Methyene blue, Phenazopyridine, Sepirin) ii. Possible association (Ciprofloxacin, Chloramphenicol, Vitamin K analogues, Ascobic acid, pAminosalicylic acid) iii. Doubtful association (PAS, Doxorbicin, Probenecid, Dimercaprol) g. Other chemicals i. Definite association (Naphthalene, Trinitrotoluene) ii. Possible association (Acalypha indica) 5. Types of G6PD deficiency a. X-minus variety i. Most common type seen in the U.S. ii. An X-linked condition primarily affecting African-American males iii. Females affected if homozygous for G6PD deficiency or if unfavorable random X chromosome inactivation resulting in a large proportion of deficient red cells b. Mediterranean variety i. Develops severe hemolysis when exposed to oxidant drugs ii. Characterized by enzyme deficiency in red cells of all ages, including reticulocytes, and shows no evidence of spontaneous recovery c. Other varieties i. Develops chronic hemolytic anemia without external oxidant exposure
ii. Susceptible to develop cholelithiasis because of heightened bilirubin turnover iii. Complaints of abdominal pain or fatty food intolerance
DIAGNOSTIC INVESTIGATIONS 1. Acute hemolysis a. Precipitous anemia i. A fall in hemoglobin ii. A fall in hematocrit iii. Subsequent rise in reticulocyte percentage b. Elevated bilirubin, particularly the indirect fraction c. Reduced haptoglobin as it binds free hemoglobin and is removed from the circulation d. Hemoglobinemia ± hemoglobinuria 2. Definitive diagnostic test involving assay of actual enzyme activity of G6PD a. A-minus variety i. G6PD activity may be higher during the acute stage of hemolysis ii. G6PD deficiency evident after hemolysis b. Other varieties: diminished G6PD activity even during acute hemolysis 3. Direct DNA analysis (targeted mutation analysis)
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib (if the mother is a carrier) i. 50% of male siblings affected ii. 50% of female siblings carriers (some female heterozygotes may be affected) b. Patient’s offspring: i. 100% of female offspring carriers (some female heterozygotes may be affected) ii. 50% of female offspring affected (homozygotes) if the spouse is a carrier iii. Male offspring not affected unless the spouse is a carrier 2. Diagnostic confirmation, neonatal screening, and carrier screening available by DNA analysis and enzyme assay 3. Management a. Remove precipitating agent b. Supportive transfusion
REFERENCES Beutler E. The genetics of glucose-6-phosphate dehydrogenase deficiency. Semin Hematol 27:137–164, 1990. Beutler E. Glucose-6-phosphate dehydrogenase deficiency. N Engl J Med 324:169–174, 1991. Beutler E: Study of glucose-6-phosphate dehydrogenase: History and molecular biology. Am J Hematol 42:53, 1993. Beutler E. G6PD deficiency. Blood 84:3613–3636, 1994. Beutler E: G6PD: Population genetics and clinical manifestations. Blood Rev 10:45, 1996. Beutler E, Kuhl W, Gelbart T, et al.: DNA-sequence abnormalities of human glucose-6-phosphate-dehydrogenase variants. J Biol Chem 266: 4145–4150, 1991. Beutler E, Westwood B, Prchal JT, et al.: New glucose-6-phosphate dehydrogenase mutations from various ethnic groups. Blood 80:255–256, 1992.
GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY Calabro V, Mason PJ, Civitelli D, et al.: Genetic heterogeneity of glucose-6phosphate dehydrogenase deficiency revealed by single strand conformation analysis. Am J Hum Genet 52:527–536, 1993. Carpentieri U, Moore RL, Nichols MM. Kernicterus in a newborn female with G-6-PD deficiency. J Pediatr 89:854–855, 1974. Chang JG, Liu TC: Glucose-6-phosphate dehydrogenase deficiency. Crit Rev Oncol Hematol 20:1, 1995. Cosgrove MS, Naylor C, Paludan S, et al.: On the mechanism of the reaction catalyzed by glucose 6-phosphate dehydrogenase. Biochemistry 37:27–59, 1998. Davidson RG, Nitowsky HM, Childs B: Demonstration of two populations of cells in the human female heterozygous for glucose-6-phosphate dehydrogenase variants. Proc Natl Acad Sci USA 50:481, 1963. Gaetani GF, Ferraris AM: Recent developments on Mediterranean G6PD. Br J Haematol 68:1, 1988. Hodge DL, Charron T, Stabile LP, et al.: Structural characterization and tissuespecific expression of the mouse glucose-6-phosphate dehydrogenase gene. DNA Cell Biol 17:283, 1998. Kaplan M, Hammerman C. Severe neonatal hyperbilirubinemia. A potential complication of glucose-6-phosphate dehydrogenase deficiency. Clin Perinatol 25:575–590, 1998. Kaplan M, Beutler E, Vreman HJ, et al.: Neonatal hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient heterozygotes. Pediatrics 104:68–74, 1999. Kattamis CA, Kyriazakou M, Chaidas S: Favism. Clinical and biochemical data. J Med Genet 6:34–41, 1969. Keats B: Genetic mapping: X chromosome. Hum Genet 64:28, 1983. Lopez R, Cooperman JM: Glucose-6-phosphate dehydrogenase deficiency and hyperbilirubinemia in the newborn. Am J Dis Child 122:66–70, 1971. Luisada L: Favism: a singular disease affecting chiefly red blood cells. Medicine 20:229, 1941. Luzzatto L, Testa U: Human erythrocyte glucose 6-phosphate dehydrogenase: structure and function in normal and mutant subjects. Curr Top Hematol 1:1, 1978.
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Luzzatto L, Mehta A, Vulliamy T: Glucose 6-phosphate dehydrogenase deficiency. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGrawHill, 2001, Chapter 179, pp 4517–4553. Mason PJ: New insights into G6PD deficiency. Br J Haematol 94:585–591, 1996. Martini G, Toniolo D, Vulliamy TJ, et al.: Structural analysis of the X-linked gene encoding human glucose 6-phosphate dehydrogenase. EMBO J 5:1849, 1986. Pai GS, Sprenkle JA, Do TT, et al.: Localization of the loci for hypoxanthine phosphoribosyltransferase and glucose-6-phosphate dehydrogenase and biochemical evidence of non-random X-chromosome expression from studies of human X-autosome translocation. Proc Natl Acad Sci USA 77:2810, 1980. Segel GB, Hirsh MG, Feig SA: Managing anemia in a pediatric office practice: Part 2. Pediatr Rev 23:111–122, 2002. Szabo P, Purrello M, Rocchi M, et al.: Cytological mapping of the human glucose-6-phosphate dehydrogenase gene distal to the fragile-X site suggests a high rate of meiotic recombination across this site. Proc Natl Acad Sci USA 81:7855, 1984. Valaes T: Severe neonatal jaundice associated with glucose-6-phosphate dehydrogenase deficiency: pathogenesis and global epidemiology. Acta Paediatr (Suppl 394):58–76, 1994. Venkataram MN, Al-Suwaid AR: Glucose-6-phosphate dehydrogenase deficiency. Int J Dermatol 38:730, 1999. Vulliamy TJ, Kaeda JS, Ait-Chafa D, et al.: Clinical and haematological consequences of recurrent G6PD mutations and a single new mutation causing chronic nonspherocytic haemolytic anaemia. Br J Haematol 101:670, 1998. Washington EC, Ector W, Abboud M, et al.: Hemolytic jaundice due to G6PD deficiency causing kernicterus in a female newborn. South Med J 88:776–779, 1995. WHO Working Group. Glucose-6-phosphate dehydrogenase deficiency. WHO Bull 67:601–611, 1989.
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Fig. 3. A 1-month-old boy with G6PD deficiency who is asymptomatic. The newborn screening revealed G6PD of 3.8 (10.8–16.2 U/g Hb). Molecular analysis showed one copy of A376G mutation.
Fig. 1. A 1-month-old and a 2-month-old boys with G6PD deficiency who are asymptomatic. The newborn screenings of both boys identified one (hemizygous) copy of the double mutations (G202A; A376G).
Fig. 4. Fava beans.
Fig. 2. An 8-week-old girl with G6PD deficiency who is asymptomatic. The newborn screening identified compound heterozygote consisting of one copy of the double mutation (G202A; A376G) and one copy of the A378G mutation. This phenotype is seen only in females since this is an X-linked disorder.
Glycogen Storage Disease, Type II Type II glycogen storage disease (GSD) is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme acid α-glucosidase (acid maltase). Incidence is estimated at 1 in 50,000 in most populations implying a carrier frequency of 1 in 100.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Caused by deficiency of acid maltase (acid α-glucosidase), leading to the pathological accumulation of glycogen in lysosomes, predominantly in the skeletal muscle, heart, and liver a. Virtual absence of α-glucosidase activity in infantile form (Pompe disease) b. Considerable residual enzyme activity in the great majority of patients with the adolescent or adult form 3. Identification of various mutations in the α-glucosidase (GAA) gene (mapped on 17q23-25), leading to the disease a. Types of mutations i. Point mutations ii. Deletions iii. Insertions b. Compound heterozygotes in most patients c. Relatively common mutations among European patients i. The single base pair deletion ΔT525 causing premature termination at nucleotide 658–660 ii. Deletion of exon 18 4. Genotype-phenotype correlation a. The nature of the mutation is generally considered a good predictor of a clinical phenotype b. Homozygosity for either Δexon 18 or ΔT525 mutation or compound heterozygosity for these two mutations results in a severe infantile form of GSDII c. Combination of either of these mutations with leaky IVS1t-13g mutation results in the majority of cases in the adult phenotype d. A splicing defect (IVS6 t-22g) results in a removal of exon 6 and insertion of 21 nucelotides of the intronic sequence defined the juvenile phenotype in a compound heterozygote patient who carries a silent second allele. Homozygosity for the same splicing defect resulted in a milder adult phenotype e. Growing number of cases in recent years where the genotype does not match the phenotype
CLINICAL FEATURES 1. Infantile form a. Classical infantile form i. Onset within first weeks or months of life or even at birth 461
ii. Characterized by complete or near complete deficiency of α-glucosidase iii. Poor feeding and failure to thrive, early complaints iv. Cyanosis and attacks of dyspnea beginning early v. Cardiomyopathy: the important finding suggesting diagnosis a) Marked cardiomegaly b) Congestive heart failure vi. Striking hypotonia a) Increasing generalized weakness b) Affecting bulbar musculature c) Without muscle atrophy vii. Macroglossia viii. Mild hepatomegaly ix. Calf hypertrophy x. Depressed or absent reflexes due to glycogen accumulation in spinal motor neurons xi. Impaired alertness xii. Accumulation of glycogen in the lysosomes rapidly disrupts cellular function in the most severe form a) Rapidly disrupts cellular function b) Leading to intractable cardiorespiratory failure c) Most patients die by 1 year of age b. Nonclassical infantile form i. Onset in infancy ii. Slower progression iii. Involving primarily skeletal muscle with minimal or no cardiac involvement (without cardiomegaly) iv. May present with delayed motor milestones if onset is in early preschool age v. May present with a decrease in motor skills if onset is later in childhood vi. Usually demonstrate progressive proximal weakness with different degrees of respiratory muscle involvement vii. Presence of respiratory complications often contributing to early death 2. Juvenile form a. Juvenile onset (first decade) b. Characterized by presence of reduced but residual αglucosidase activity c. Clinical boundaries between juvenile and adult forms not precisely defined d. Clinical manifestations i. Predominantly skeletal muscle weakness with respiratory muscle involvement and mild hepatomegaly ii. Cardiac involvement: absent or mild a) Arrhythmia b) Mild ventricular dysfunction iii. Death results from respiratory failure after a course lasting several years
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3. Adult form a. Onset: second to sixth decades b. Characterized by higher levels of residual α-glucosidase activity c. Slower progression of the skeletal muscle weakness i. Upper arms ii. Pectoral muscles iii. Asymmetry of affected muscle groups iv. Limb girdle weakness, a prominent finding v. Respiratory muscle involvement (weakness of the diaphragm) (about 33%): a hallmark of the disease vi. Little or no cardiac abnormality d. Acute respiratory failure
DIAGNOSTIC INVESTIGATIONS 1. Elevated serum creatine kinase in most patients 2. Elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactic dehydrogenase (LDH) 3. Radiography: tremendous cardiomegaly 4. EKG: can readily observe the signs of cardiac glycogenosis (indicators of relative myocardial ischemia) a. Very large QRS complex in all leads b. Short P-R interval: pathognomonic of infantile Pompe disease c. Left axis deviation or absence of the normal right axis deviation (presence of biventricular hypertrophy) d. Inverted T wave e. S-T segment depression 5. Echocardiography: Biventricular hypertrophy without outflow obstruction 6. EMG a. Infantile form: nonspecific myopathic changes or normal finding b. Adult form i. Pseudomyotonia ii. High-frequency discharges iii. Fibrillations 7. Muscle biopsy a. Presence of vacuoles that stain positive for glycogen (PAS) as well as for the lysosomal enzyme acid phosphatase b. A typical lacework appearance of histologic sections from the myocardium resulting from deposition of stored material in the cardiac fibrils c. Electron microscopy i. Membrane-bound glycogen ii. Glycogen accumulation within the lysosome 8. Glycogen accumulation a. Infantile form i. Muscle ii. Liver iii. Motor nuclei in the brain stem iv. Anterior horn cells of the spinal cord v. Placenta a) Amniotic storage cells identified and shown histochemically to contain glycogen b) Pathognomonic accumulation of lysosomal glycogen in the placenta by electron microscopy in the second trimester
9. 10. 11. 12.
c) Confirmation of the prenatal diagnosis made by enzyme assay vi. Other tissues a) Endothelial cells b) Kidneys c. Skin b. Adult form: not seen in the heart, liver, or brain Diagnostic enzymatic test: deficient acid maltase in leukocytes, muscle, and skin fibroblasts DNA analysis by targeted mutation analysis Newborn screening by determining the total α-glucosidase in plasma or dried blood spots Heterozygote detection a. Reduced α-glucosidase activity: not reliable b. DNA based detection more appropriate and definitive within families
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased unless the spouse is a carrier in which cases 50% of offspring will be affected and 50% will be carriers 2. Prenatal diagnosis a. Rapid prenatal diagnosis by electron microscopy of uncultured amniocytes b. Deficient activity of lysosomal acid α-glucosidase in cultured amniocytes or CVS c. Electron microscopic study of chorionic villus biopsies for the pregnancy at risk: fibrocytes with typical vacuoles filled with glycogen d. Mutation analysis on amniocytes or CVS: 100% reliable prediction of the genetic status of the fetus, including heterozygosity 3. Management a. Supportive therapy to manage symptoms and minimize complications whenever possible i. Respiratory therapy ii. Physical therapy iii. Dietary therapy iv. Infection prevention v. A high protein diet to improve muscle function vi. Ventilator support b. Administration of purified α-glucosidase not effective c. Bone marrow transplantation presumably to provide enzyme secreted by the normal cells continuously i. Results not promising ii. Transitory engraftment of the haploidentical transplant iii. No enzyme detected in muscle cells iv. Patient died of complications of the transplant d. Enzyme replacement therapy with recombinant human α-glucosidase from rabbit milk in Pompe patients in an open-label study i. Intended to directly address the underlying metabolic defect via intravenous infusions of recombinant human GAA (rhGAA) enzyme ii. The enzyme generally well tolerated iii. Normalization of muscle α-glucosidase activity
GLYCOGEN STORAGE DISEASE, TYPE II
iv. Improved tissue morphology and motor and cardiac function v. Significantly decreased left ventricular mass index vi. Recommend early treatment (before irreversible damage) and follow-up of long-term effects vii. Anti-rhGAA antibody may limit the efficacy of the treatment. viii. Extensive muscle damage may be unrefractive to therapy e. Gene therapy aiming at providing a permanent endogenous source of enzyme for the affected tissues: not available currently
REFERENCES Amalfitano A, Bengur AR, Morse RP, et al.: Recombinant human acid alphaglucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial. Genet Med 3:132–138, 2001. Amalfitano A, McVie-Wylie AJ, Hu H, et al.: Systemic correction of the muscle disorder glycogen storage disease type II after hepatic targeting of a modified adenovirus vector encoding human acid-alpha-glucosidase. Proc Natl Acad Sci USA 96:8861–8866, 1999. Amato AA: Acid maltase deficiency and related myopathies. Neurol Clin 18:151–165, 2000. Ausems MG, Kroos MA, Van der Kraan M, et al.: Homozygous deletion of exon 18 leads to degradation of the lysosomal alpha-glucosidase precursor and to the infantile form of glycogen storage disease type II. Clin Genet 49:325–328, 1996. Ausems MG, Lochman P, van Diggelen OP, et al.: A diagnostic protocol for adult-onset glycogen storage disease type II. Neurology 52:851–853, 1999. Ausems MG, ten Berg K, Beemer FA, et al.: Phenotypic expression of lateonset glycogen storage disease type II: identification of asymptomatic adults through family studies and review of reported families. Neuromuscul Disord 10:467–471, 2000. Ausems MG, Verbiest J, Hermans MP, et al.: Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet 7:713–716, 1999. Becker JA, Vlach J, Raben N, et al.: The African origin of the common mutation in African American patients with glycogen-storage disease type II. Am J Hum Genet 62:991–994, 1998. Bendon RW, Hug G: Morphologic characteristics of the placenta in glycogen storage disease type II (alpha-1,4-glucosidase deficiency). Am J Obstet Gynecol 152:1021–1026, 1985. Bodamer OA, Halliday D, Leonard JV: The effects of l-alanine supplementation in late-onset glycogen storage disease type II. Neurology 55: 710–712, 2000. Bodamer OA, Haas D, Hermans MM, et al.: L-alanine supplementation in late infantile glycogen storage disease type II. Pediatr Neurol 27:145–146, 2002. Boxer RA, Fishman M, LaCorte MA, et al.: Cardiac MR imaging in Pompe disease. J Comput Assist Tomogr 10:857–859, 1986. Chen YT, Amalfitano A: Towards a molecular therapy for glycogen storage disease type II (Pompe disease). Mol Med Today 6:245–251, 2000. Cottrill CM, Johnson GL, Noonan JA: Parental genetic contribution to mode of presentation in Pompe disease. Pediatrics 79:379–381, 1987. De Dominicis E, Finocchi G, Vincenzi M, et al.: Echocardiographic and pulsed Doppler features in glycogen storage disease type II of the heart (Pompe’s disease). Acta Cardiol 46:107–114, 1991. Engel AG, Gomez MR, Seybold ME, et al.: The spectrum and diagnosis of aced maltase deficiency. Neurology 23:95–106, 1973. Haley SM, Fragala MA, Skrinar AM: Pompe disease and physical disability. Dev Med Child Neurol 45:618–623, 2003. Hug G: More on bone marrow transplantation for glycogen storage disease type II (Pompe’s disease). N Engl J Med 315:1229, 1986. Hug G, Soukup S, Ryan M, et al.: Rapid prenatal diagnosis of glycogenstorage disease type II by electron microscopy of uncultured amnioticfluid cells. N Engl J Med 310:1018–1022, 1984.
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Kikuchi T, Yang HW, Pennybacker M, et al.: Clinical and metabolic correction of pompe disease by enzyme therapy in acid maltase-deficient quail. J Clin Invest 101:827–833, 1998. Kleijer WJ, van der Kraan M, Kroos MA, et al.: Prenatal diagnosis of glycogen storage disease type II: enzyme assay or mutation analysis? Pediatr Res 38:103–106, 1995. Laforêt P, Nicolino M, Eymard B, et al.: Juvenile and adult-onset acid maltase deficiency in France. Genotype-phenotype correlation. Neurology 55:1122–1128, 2000. Lee CC, Chen CY, Chou TY, et al.: Cerebral MR manifestations of Pompe disease in an infant. AJNR Am J Neuroradiol 17:321–322, 1996. Mehler M, DiMauro S: Residual acid maltase activity in late-onset acid maltase deficiency. Neurology 27:178–184, 1977. Meikle PJ, Yan M, Ravenscroft EM, et al.: Altered trafficking and turnover of LAMP-1 in Pompe disease-affected cells. Mol Genet Metab 66:179–188, 1999. Melvin JJ: Pompe’s disease. Arch Neurol 57:134–135, 2000. Nicolino MP, Puech JP, Kremer EJ, et al.: Adenovirus-mediated transfer of the acid alpha-glucosidase gene into fibroblasts, myoblasts and myotubes from patients with glycogen storage disease type II leads to high level expression of enzyme and corrects glycogen accumulation. Hum Mol Genet 7:1695–1702, 1998. Noori S, Acherman R, Siassi B, et al.: A rare presentation of Pompe disease with massive hypertrophic cardiomyopathy at birth. J Perinat Med 30:517–521, 2002. Nyhan WL, Sakati NA: Diagnostic Recognition of Genetic Disease. Philadelphia: Lea & Febiger, 1987. pp 198–205. Phupong V, Shuangshoti S, Sutthiruangwong P, et al.: Prenatal diagnosis of Pompe disease by electron microscopy. Arch Gynecol Obstet May, 2004. Poenaru L: Approach to gene therapy of glycogenosis type II (Pompe disease). Mol Genet Metab 70:163–169, 2000. Raben N, Plotz P, Byrne BJ: Acid alpha-glucosidase deficiency (glycogenosis type II, Pompe disease). Curr Mol Med 2:145–166, 2002. Reuser AJ, Van Den Hout H, Bijvoet AG, et al.: Enzyme therapy for Pompe disease: from science to industrial enterprise. Eur J Pediatr 161 Suppl 1:S106–S111, 2002. Slonim AE, Bulone L, Ritz S, et al.: Identification of two subtypes of infantile acid maltase deficiency. J Pediatr 137:283–285, 2000. Smit GP, Fernandes J, Leonard JV: The long-term outcome of patients with glycogen storage diseases. J Inherit Metab Dis 13:411–418, 1990. Schlenska GK, Heene R, Spalke G, et al.: The symptomatology, morphology and biochemistry of glycogenosis type II (Pompe) in the adult. J Neurol 212:237–252, 1976. Sun B, Chen YT, Bird A, et al.: Long-term correction of glycogen storage disease type II with a hybrid Ad-AAV vector. Mol Ther 7:193–201, 2003. Temple JK, Dunn DW, Blitzer MG, et al.: The “muscular variant” of Pompe disease: clinical, biochemical and histologic characteristics. Am J Med Genet 21:597–604, 1985. Umapathysivam K, Hopwood JJ, Meikle PJ: Determination of acid α-glucosidase activity in blood spots as a diagnostic test for Pompe disease. Clin Chem 47:1378–1383, 2001. Van den Hout H, Reuser AJ, Vulto AG, et al.: Recombinant human α-glucosidase from rabbit milk in Pompe patients. Lancet 356:397–398, 2000. Van den Hout JM, Reuser AJ, de Klerk JB, et al.: Enzyme therapy for pompe disease with recombinant human alpha-glucosidase from rabbit milk. J Inherit Metab Dis 24:266–274, 2001. Vorgerd M, Burwinkel B, Reichmann H, et al.: Adult-onset glycogen storage disease type II: phenotypic and allelic heterogeneity in German patients. Neurogenetics 1:205–211, 1998. Watson JG, Gardner-Medwin D, Goldfinch ME, et al.: Bone marrow transplantation for glycogen storage disease type II (Pompe’s disease). N Engl J Med 314:385, 1986. Winkel LPF, Kkamphoven JHJ, Hannerieke JMP, et al.: Morphological changes in muscle tissue of patients with infantile Pompe’s disease receiving enzyme replacement therapy. Muscle & Nerve 27:743–751, 2003. Wolfsdorf JI, Holm IA, Weinstein DA: Glycogen storage diseases. Phenotypic, genetic, and biochemical characteristics, and therapy. Endocrinol Metab Clin North Am 28:801–823, 1999.
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Fig. 2. Different patient with Pompe disease. (A) Myocardium. Note numerous vacuolated fibers (arrows) due to glycogen accumulation. HE, X40. (B) Smooth muscle from GI tract. Note clear areas represent glycogen deposition (arrows).
Fig. 1. An infant with massive cardiomegaly and hypotonia. Diagnosis of Pompe disease was confirmed by deficient acid maltase in the leukocytes.
Goldenhar Syndrome xii. Trisomy 22 (mosaic) xiii. 47,XXY xiv. 49,XXXXY 4. Pathogenesis: unknown but likely heterogeneous a. Interference with vascular supply and focal hemorrhage in the developing first and second branchial arch region b. Impaired interaction of cranial neural crest cells with branchial arch mesenchyme c. A disorder of blastogenesis 5. Hypothesis: candidate genes for OAVS, particularly in familial cases a. Homeobox genes, especially of the MSX class i. Msx critical for the differentiation of first branchial arch ectoderm-mesenchyme leading to various craniofacial structures ii. Strongly expressed in cephalic neural crest cells prior to migration of the cells that contribute extensively to craniofacial development b. Encompasses previous partial pathogenetic explanations for OAVS, including neurocristopahty and developmental field defects, and represents a unifying concept regarding the wide spectrum of involvement in OAVS c. Mutations result in partial loss of function of these gene could explain incomplete penetrance and clinical variability occurring in individuals with different genetic backgrounds
In 1952, Goldenhar described a pair of monozygotic twins discordant for hemifacial microsomia, mandibular hypoplasia, auricular malformations, and epibulbar dermoids. Gorlin et al. later in 1963 coined the term “oculoauriculovertebral dysplasia” to describe patients with mandibular hypoplasia, microtia, epibulbar dermoids, and vertebral anomalies. Goldenhar syndrome occurs in about 1 in 3500 live births.
GENETICS/BASIC DEFECTS 1. The term, “Oculoauriculovertebral dysplasia spectrum”, suggested to represent an etiologically diverse spectrum of congenital anomalies a. Oculoauriculovertebral dysplasia (OAVS) b. Facioauriculovertebral syndrome (Goldenhar-Gorlin syndrome) c. Hemifacial microsomia (2nd most common facial anomaly, second only to cleft lip and palate) d. Hemifacial microtia e. Otomandibular dysostosis f. Original Goldenhar syndrome g. Goldenhar-Gorlin syndrome h. Anomalies of the first and second branchial arches 2. Congenital anomalies a. Usually unilateral b. Primarily right sided c. More common in monozygous twins usually with one affected 3. Causes: unknown but likely heterogeneous a. Usually sporadic occurrence b. Maternal teratogenic exposures i. Retinoic acid ii. Thalidomide iii. Primidone iv. Cocaine c. Presumed vascular disruption d. Maternal diabetes e. Discordant occurrence in monozygotic twins: arising from a disturbance of blastogenesis leading to malformations f. Autosomal dominant inheritance g. Autosomal recessive inheritance h. Associated chromosome abnormalities i. Del(5p) ii. Monosomy 6q iii. Trisomy 7 iv. Dup(7q) v. Dup(8q) vi. Trisomy 9 (mosaic) vii. Del(18q) viii. Der(18) ix. R(21) x. Del(22)(q13.31) xi. Dup(22)(q11.2q13.1)
CLINICAL FEATURES
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1. Major clinical features a. Ocular manifestations i. Epibulbar dermoids or lipodermoid ii. Unilateral microphthalmia iii. Upper eyelid coloboma iv. Strabismus v. Diminished visual acuity vi. Tilted optic disc vii. Optic nerve hypoplasia viii. Tortuous retinal vessels ix. Macular hypoplasia and heterotropia x. Microphthalmia xi. Anophthalmia b. Ear anomalies i. Microtia ii. Preauricular tags and/or pits iii. Middle ear anomaly iv. Inner ear defects v. Variable deafness c. Vertebral defects i. Hemivertebrae ii. Hypoplasia of vertebrae, usually cervical iii. Abnormal ribs
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d. Hemifacial microsomia i. Unilateral microtia ii. Ipsilateral hypoplasia of malar, maxillary, and mandibular region, especially temporomandibular joint iii. Ipsilateral macrostomia iv. Ipsilateral hypoplasia of the facial musculature 2. Other associated features a. Craniofacial features i. Cranial nerve palsy ii. Cleft lip/palate iii. Malfunction of soft palate iv. Decreased parotid secretion v. Anomalies in function or structure of the tongue vi. Low scalp hair line vii. Brachial cleft remnants in anterior-lateral neck b. CNS anomalies i. Hydrocephaly ii. Microcephaly iii. Plagiocephaly iv. Frontal/occipital encephalocele v. Cranial bifidum vi. Lipoma vii. Dermoid cyst viii. Arnold-Chiari malformation ix. Lissencephaly x. Holoprosencephaly/arhinencephaly xi. Arachnoid cyst c. Congenital heart diseases (5–58% depending on ascertainment of cases) i. Tetralogy of Fallot (with or without right aortic arch) and VSD (account for over half of the cases with congenital heart diseases) ii. Pulmonary stenosis iii. Patent ductus arteriosus iv. Coarctation of aorta v. Total atrioventricular canal defect vi. ASD vii. Transposition of great vessel viii. Rare isolation of the left innominate artery infradiaphragmatic total anomalous pulmonary venous connection ix. Wolf-Parkinson-White syndrome d. Respiratory tract anomalies i. Laryngeal anomaly ii. Incomplete lobulation of the lung iii. Pulmonary hypoplasia to aplasia iv. Sequestration v. Focal tracheomalacia due to extrinsic vascular compression vi. Obstructive sleep apnea e. Gastrointestinal anomalies i. Esophageal atresia ii. Tracheo-esophageal fistula iii. Diaphragmatic hernia iv. Imperforate anus f. Renal anomalies i. Renal agenesis ii. Hydronephrosis iii. Ectopic kidney
iv. Double ureter v. Hydroureter g. Prenatal growth deficiency h. Normal intelligence in most cases
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Platybasia/occipitalization of atlas b. Hypoplasia of the mandibular-maxillary bones c. Fused vertebrae, especially cervical d. Segmentation anomaly of the vertebra e. Hemivertebrae f. Klippel-Feil anomaly g. Rib anomalies h. Aplasia of radius/thumb i. Spina bifida 2. Echocardiography: variable and nonspecific findings because cardiovascular abnormalities are complex in most cases
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: empiric recurrence risk of 2% b. Patient’s offspring: unknown 2. Prenatal diagnosis by ultrasonography a. Hemifacial microsomia b. Microphthalmia or anophthalmia c. Cleft lip/palate d. Unilateral facial cleft with macrostomia e. Unilateral ear hypoplasia f. Unilateral preauricular tag g. Hemiatrophy of the nose h. Hyposegmentation of the unilateral lung i. Single umbilical artery j. Imperforate anus k. Polyhydramnios 3. Management a. Surgical removal of epibulbar dermoids, if needed b. Cleft lip/palate repair c. Combined surgical-orthodontic approach for dental occlusion d. Traditional osteotomies, followed by acute orthopedic movement and osseous fixation for adult patients with maxillomandibular hypoplasia, facial asymmetry, congenital micrognathia and hemifacial microsomia e. Alternative procedure: distraction osteogenesis f. Assess cervical spine for instability before undergoing any general surgery. C1–C2 fusion or occipitocervical fusion may be needed g. Anesthesia: anticipate airway obstruction and difficulty in tracheal incubation, resulting from a combination of micrognathia, unilateral mandibular hypoplasia and vertebral anomalies including vertebral fusion and odontoid elongation
REFERENCES Andrews TM, Shott SR: Laryngeal manifestations of Goldenhar syndrome. Am J Otol 13:312–315, 1992.
GOLDENHAR SYNDROME Baum JL, Feingold M: Ocular aspects of Goldenhar’s syndrome. Am J Ophthalmol 75:250–257, 1973. Benacerraf BR, Frigoletto FD Jr: Prenatal Ultrasonographic recognition of Goldenhar’s syndrome. Am J Obstet Gynecol 159:950–952, 1988. Bennum RD, Mulliken JB, Kaban LB, et al.: Microtia: a microform of hemifacial microsomia. Plast Reconstr Surg 76:859–863, 1985. Boles DJ, Bodurtha J, Nance WE: Goldenhar complex in discordant monozygotic twins: a case report and review of the literature. Am J Med Genet 28:103–109, 1987. Burck U: Genetic aspects of hemifacial microsomia. Hum Genet 64:291–296, 1983. Cohen MM, Rollnick BR, Kaye CI: Oculoauriculovertebral spectrum: an updated critique. Cleft Palate J 26:276, 1989. Converse JM, Coccaro PJ, Becker M, et al.: On hemifacial microsomia. The first and second branchial arch syndrome. Plast Reconstr Surg 51:268, 1973. De Catte L, Laubach M, Legein J, et al.: Early prenatal diagnosis of oculoauriculovertebral dysplasia or the Goldenhar syndrome. Ultrasound Obstet Gynecol 8:422–424, 1996. De Ravel TJ, Legius E, Brems H, et al.: Hemifacial microsomia in two patients further supporting chromosomal mosaicism as a causative factor. Clin Dysmorphol 10:263–267, 2001. Ewart-Toland A, Yankowitz J, Winder A, et al.: Oculoauriculovertebral abnormalities in children of diabetic mothers. Am J Med Genet 90:303–309, 2000. Forest-Potts L, Sadler TW: Disruption of Msx-1 and Msx-2 reveals roles for these genes in craniofacial, eye and axial development. Dev Dyn 209:70–84, 1997. Friedman S, Caracal M: The high frequency of congenital heart disease in Oculoauriculovertebral dysplasia (Goldenhar syndrome) [letter]. J Pediatr 85:873–874, 1974. Gastavson EE, Chen H: Goldenhar syndrome, anterior encephalocele, and aqueduct stenosis following fetal primidone exposure. Teratology 32:13–17, 1985. Godel V et al.: Autosomal dominant Goldenhar syndrome. Birth Defects 18(6):621–628, 1982. Goldenhar M: Associations malformatives de l’oeil et de l’oreille, en particulier le syndrome epibulbaire-appendices auriculaires dermoide fistula auris congenita et ses relations avec la dysostose mandibulo faciale. J Genet Hum 1:243–282, 1952. Gorlin RJ, Jue KL, Jacobson L, et al.: Oculoauriculovertebral dysplasia. J Pediatr 63:991–999, 1963. Gosain AK, McCarthy JG, Pinto RS: Cervicovertebral anomalies and basilar impression in Goldenhar syndrome. Plast Reconstr Surg 93:498–506, 1994. Greenberg F, Herman GE, Stal S, et al.: Chromosomal abnormalities associated with Facioauriculovertebral spectrum. Am J Med Genet (Suppl 4):170, 1988. Hathout EH, Elmendorf E, Bartley J: Hemifacial microsomia and abnormal chromosome 22. Am J Med Genet 76:71–73, 1998. Healey D, Letts M, Jarvis JG: Cervical spine instability in children with Goldenhar’s syndrome. Can J Surg 45:341–344, 2002. Kaymak C, Gulban Y, Ozcan AO, et al.: Anaesthetic approach in a case of Goldenhar’s syndrome. Eur J Anaesthesiol 19:832–838, 2002. Kelberman D, et al. Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome. Hum Genet 109:638–645, 2001. Kumar A, Friedman JM, Taylor GP, et al.: Pattern of cardiac malformation in oculoauriculovertebral spectrum. Am J Med Genet 46:423–426, 1993. Kumar R, Blani B, Patwari AK, et al.: Goldenhar syndrome with rare associations. Indian J Pediatr 67:231–233, 2000. Lessick M, Vasa R, Israel J: Severe manifestations of oculoauriculovertebral spectrum in a cocaine exposed infant. J Med Genet 28:803–804, 1991. Lin HJ, Owens TR, Sinow RM, et al.: Anomalous inferior venae cavae with oculoauriculovertebral defect: Review of Goldenhar complex and malformations of left–right asymmetry. Am J Med Genet 75:88–94, 1998. Madan R, Trikha A, Venkataraman RK, et al.: Goldenhar’s syndrome: an analysis of anaesthetic management. A retrospective study of seventeen cases. Anaesthesia 45:49–52, 1990. Mandelberg A, Ariel I, Mogle P, et al.: Tracheo-oesophageal anomalies in the Goldenhar anomalad. J Med Genet 22:149–150, 1985.
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Mansour AM, Wang F, Henkind P, et al.: Ocular findings in the facioauriculovertebral sequence (Goldenhar-Gorlin syndrome). Am J Ophthalmol 100:555–559, 1985. Margolis S, Aleksic S, Charles N, et al.: Retinal and optic nerve findings in Goldenhar-Gorlin syndrome. Ophthalmology 91:1327–1333, 1984. McCarthy VP, Zimo DA, Lucas MA: Airway in the oculo-auriculo-vertebral spectrum: two cases and a review of the literature. Pediatr Pulmonol 32:250–256, 2001. Monahan R, Seder K, Patel P, et al.: Etiology, diagnosis and treatment. J Am Dent Assoc 132:1402–1408, 2001. Morrison PJ, Mulholland HC, Craig BG, et al.: Cardiovascular abnormalities in the oculo-auriculo-vertebral spectrum (Goldenhar syndrome). Am J Med Genet 44:425–428, 1992. Nakajima H, Goto G, Tanaka N, et al.: Goldenhar syndrome associated with various cardiovascular malformations. Jpn Circ J 62:617–620, 1998. Opitz JM: Blastogenesis and the “primary field” in human development. Birth Defects Original Article Series 29:3–37, 1993. Phelps Prenat Diagn, Lloyd GAS, Poswillo DE: The ear deformities in craniofacial microsomia and oculo-auriculo-vertebral dysplasia. J Laryngol Otol 97:995–1005, 1983. Pierpont MEM, Moller JH, Gorlin RJ: Congenital cardiac, pulmonary, and vascular malformations in oculoauriculovertebral dysplasia. Pediatr Cardiol 2:297–302, 1982. Poswillo D: The pathogenesis of the first and second branchial arch syndrome. Oral Surg 35:302–328, 1973. Poswillo D: Otomandibular deformity: pathogenesis as a guide to reconstruction. J Maxillofac Surg 2:64–72, 1974. Rees DO, Collum LM, Bowen DI: Radiological aspects of oculo-auriculo-vertebral dysplasia. Br J Radiol 45:15–18, 1972. Regenbogen L et al.: Further evidence for an autosomal dominant form of oculoauriculovertebral dysplasia. Clin Genet 21:161–167, 1982. Robinow M, Reynolds JF, Fitzgerald J, et al.: hemifacial microsomia, ipsilateral facial palsy, and malformed auricle in two families: an autosomal dominant malformation. Am J Med Genet (Suppl 2):129–133, 1986. Roesch C, Steinbicker V, Korb C, et al.: Goldenhar anomaly in one triplet derived from Intracytoplasmic sperm injection (ICSI). Am J Med Genet 101:82–83, 2001. Rollnick BR, Kaye CI: Hemifacial microsomia and variants: pedigree data. Am J Med Genet 15:233–235, 1983. Rollnick BR, Kaye CI, Nagatoshi K, et al.: Oculoauriculovertebral dysplasia and variants: phenotypic characteristics of 294 patients. Am J Med Genet 26:361–375, 1987. Schrander-Stumpel CT, Die-Smulders CE, Hennekam RC, et al.: Oculoauriculovertebral spectrum and cerebral anomalies. J Med Genet 29:326–331, 1992. Scholtz AW, Fish JH III, Kammen-Jolly K, et al.: Goldenhar’s syndrome: congenital hearing deficit of conductive or sensorineural origin? Temporal bone histopathologic study. Otology Neurotology 22:501–505, 2001. Setzer ES, Ruiz-Castaneda N, Severn C, et al.: Etiologic heterogeneity in the oculoauriculovertebral syndrome. J Pediatr 98:88–90, 1981. Stehling L: Goldenhar syndrome and airway management. Am J Dis Child 132:818, 1978. Stoll C, Viville B, Treisser A, et al.: A family with dominant oculoauriculovertebral spectrum. Am J Med Genet 78:345–349, 1998. Summitt RL: Familial Goldenhar syndrome. Birth Defects 5(2):106–109, 1969. Sze RW, Paladin AM, Lee S, et al.: Hemifacial microsomia in pediatric patients: asymmetric abnormal development of the first and second branchial arches. Am J Roentgenol 178:1523–1530, 2002. Sutphen R, Galan-Gomez E, Cortada X, et al.: Tracheoesophageal anomalies in oculoauriculovertebral (Goldenhar) spectrum. Clin Genet 48:66–71, 1995. Tamas DE, Mahony BS, Bowie JD, et al.: Prenatal sonographic diagnosis of hemifacial microsomia (Goldenhar-Gorlin syndrome). J Ultrasound Med 5:461–463, 1986. Taysi K, Marsh JL, Wise DM: Familial hemifacial microsomia: observations on three patients. Eur J Pediatr 20:47–53, 1983. Thomas P: Goldenhar syndrome and hemifacial microsomia: observations on three patients. Europ J Pediatr 133:287–292, 1980. Wilson GN: Cranial defects in the Goldenhar syndrome. Am J Med Genet 14:435–443, 1983. Witters I, Schreurs J, Van Wing J, et al.: Prenatal diagnosis of facial clefting as part of the oculo-auriculo-vertebral spectrum. Prenat Diagn 21:62–64, 2001.
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Fig. 2. An 8-month-old child with hemifacial microsomia showing facial asymmetry, unilateral microtia, and preauricular tags.
Fig. 1. Two infants (A,B,C,D,E) with Goldenhar syndrome showing hemifacial microsomia, epibulbar dermoids, upper eyelid coloboma, clefting nose, macrostomia, and unilateral microtia with preauricular tag.
Fig. 3. An infant with primidone embryopathy presenting as Goldenhar syndrome showing hemifacial microsomia, facial palsy, upper eyelid coloboma, epibulbar dermoid, and hydrocephaly by MRI.
Hallermann-Streiff Syndrome Hallermann-Streiff syndrome was independently described by Hallermann in 1948 and Streiff in 1950. The syndrome is characterized by proportionate short stature, craniofacial dysostoses consisting of skeletal, ophthalmologic, and cutaneous defects.
GENETICS/BASIC DEFECTS 1. Sporadic in virtually all cases 2. Inheritance pattern unknown
CLINICAL FEATURES 1.
Characteristic craniofacial features a. Dyscephaly (malformation of the cranium and bones of the face) (89–90%) i. Calvarium a) Brachycephaly b) Thin calvarium c) Delayed closure of fontanelles d) Wide cranial sutures ii. Cranial base a) Platybasia b) Depressed sella c) Elevated anterior cranial fossa iii. Parrot-like face a) A beaked nose b) Hypoplastic mandible b. Hypotrichosis (80–82%) i. Alopecia a) Characteristic sutural alopecia (hair loss following the lines of the cranial sutures) b) Frontal alopecia c) Alopecia at the scalp margins ii. Hypotrichosis involving the eye-brows and eyelashes iii. Brittle and sparse scalp hair c. Cutaneous atrophy (68–70%) i. Face ii. Scalp d. Ocular abnormalities i. Congenital cataracts (81–90%) ii. Microphthalmos (78–83%) iii. Nystagmus iv. Strabismus v. Glaucoma vi. Blue sclerae vii. Fundal anomalies viii. Conjunctival defects ix. Corneal abnormalities x. Down slanting palpebral fissures xi. Intraocular hypertension
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xii. Lower lid coloboma xiii. Iris atrophy xiv. Persistent pupillary membrane xv. Enophthalmos xvi. Epicanthal folds e. Mouth i. Microstomia ii. Narrow high-arched palate iii. Dental abnormalities (80–85%) a) Natal teeth b) Partial anodontia/hypoplasia c) Persistent deciduous teeth d) Irregular implantation of the teeth e) Anterior open bite 2. Musculoskeletal abnormalities a. Proportionate short stature (45–69%) b. Syndactyly c. Lordosis d. Scoliosis e. Spina bifida f. Winged scapulae g. Hyperextensible joints including temporomandibular joints h. Hip dislocation i. Periodic osteoporosis 3. Other abnormalities a. Mild to severe mental retardation (15%) b. Calcified falx cerebri c. Neurologic abnormalities i. Neurofibromatosis ii. Epilepsy d. Genital anomalies (10–12%) i. Hypogenitalism ii. Cryptorchidism iii. Hypospadias iv. Subseptate uterus v. Clitoral hypertrophy e. Cardiac defects (2–9%) i. Pulmonic stenosis ii. Atrial septal defect iii. Ventricular septal defect iv. Patent ductus arteriosus v. Tetralogy of Fallot f. Endocrinological abnormalities i. Immune deficiency ii. Hypoparathyroidism iii. Hypothyroidism iv. Hypopituitarism g. Ear anomalies (9%) h. Hematopoietic abnormalities (7%) i. Pulmonary anomalies (3%)
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i. Obstructive sleep apnea ii. Tracheomalacia iii. Recurrent pulmonary infections iv. Cor pulmonale j. Gastrointestinal abnormalities (3%) k. Muscular hypotrophy (3%) l. Hepatic anomalies (2%) m. Renal anomalies (1–2%): bilateral duplication of renal collecting system 4. Prognosis a. Some patients succumb in infancy to respiratory infections and pulmonary insufficiency, possibly related to airway obstruction and abnormal compliance b. Majority of patients with a normal life span 5. Diagnostic criteria a. Major features i. Dyscephaly with beak nose and mandibular hypoplasia ii. Dental abnormalities iii. Proportional short stature iv. Hypotrichosis v. Cutaneous atrophy vi. Microphthalmia vii. Congenital cataracts b. Minor features i. Narrow/high-arched palate ii. Ocular features a) Blue sclera b) Antimongoloid palpebral fissures c) Synechiae irides d) Choroid atrophy iii. Hypoplastic genitalia iv. Musculoskeletal features a) Elevated scapulae b) Scoliosis c) Lordosis d) Hyperextensible joints v. Mental retardation
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Skull i. A large, poorly ossified skull ii. Delayed closure of fontanelles with persistent wide sutures iii. Presence of Wormian bones iv. Brachycephaly v. Platybasia vi. Depressed sella turcica vii. Frontal or parietal bossing viii. Small orbits ix. Disproportion between the large cranial vault and the small facial skeleton x. Midfacial hypoplasia a) Hypoplastic mandibular ramus b) Possible absent condyles c) Anteriorly displaced temporomandibular joint d) Hypoplastic malar bones xi. A bird-like nose
xii. Micrognathia xiii. Dental anomalies a) Presence of natal teeth b) Retained decidual teeth c) Partial anodontia d) Supernumerary and hypoplastic teeth e) Anterior open bite malocclusion b. Long bones i. Thin/gracile ii. Retarded bone age c. Other skeletal anomalies i. Scaphocephaly ii. Cervical vertebral anomalies iii. Mild platyspondyly iv. Scoliosis v. Lordosis vi. Elevated scapulae vii. Hip dislocation viii. Spina bifida ix. Syndactyly 2. Overnight polysomnography to confirm obstructive sleep apnea 3. Endocrine evaluation for hypothyroidism, hypoparathyroidism, or hypopituitarism 4. Chromosome study: no diagnostic cytogenetic characteristics
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: not increased 2. Prenatal diagnosis: not been reported 3. Management a. Surgery i. Repair of cardiovascular defect ii. Ophthalmological procedure (cataracts removal) iii. Rhinoplasty iv. Facial augmentation v. Dental surgery a) General restorative dentistry b) Orthodontic palatal expansion c) Realignment of the dental arches vi. Mandibular advancement b. General anesthesia and airway management i. Difficult laryngoscopy and endotracheal intubation secondary to micrognathia, microstomia, and serious upper airway compromise ii. Brittle and easily broken natal teeth during laryngoscopy iii. Orotracheal intubation precluded by anterior placement or absence of the temporomandibular joints iv. Difficult nasotracheal intubation secondary to hypoplastic nose and deviated nasal septum v. Consider preoperative tracheotomy or prepare for emergency tracheotomy c. Long-term nasal continuous positive airway pressure therapy for obstructive sleep apnea d. Management for endocrine problem if present
HALLERMANN-STREIFF SYNDROME
REFERENCES Aracena T, Sangueza P: Hallermann-Streiff-Francois syndrome. J Pediatr Ophthalmol 14:373–378, 1977. Christian CL, Lachman RS, Aylsworth AS, et al.: Radiological findings in Hallermann-Streiff syndrome: report of five cases and a review of the literature. Am J Med Genet 41:508–514, 1991. Cohen MM Jr: Hallermann-Streiff syndrome: a review. Am J Med Genet 41:488–499, 1991. David LR, Finlon M, Genecov D, et al.: Hallermann-Streiff syndrome: experience with 15 patients and review of the literature. J Craniofac Surg 10:160–168, 1999. Dinwiddie R, Gewitz M, Taylor JFN: Cardiac defects in the Hallermann-Streiff syndrome. J Pediatr 92:77–78, 1978. François J: Francois dysencephalic syndrome. Birth Defects 18(6):595–619, 1982. François J, Pierard J: The Francois dysencephalic syndrome and skin manifestations. Am J Ophthalmol 71:1241–1250, 1971. Friede H, Lopata M, Fisher E, et al.: Cardiorespiratory disease associated with Hallermann-Streiff syndrome: analysis of craniofacial morphology by cephalometric roentgenograms. J Craniofac Genet Dev Biol Suppl 1: 189–198, 1985. Golomb RS, Porter PS: A distinct hair shaft abnormality in the HallermannStreiff syndrome. Cutis 16:122–128, 1975. Haberman H, Clement PA: The value of anthropometrical measurements in a case of Hallermann-Streiff syndrome. Rhinology 17:179–184, 1979. Hendrix SL, Sauer HJ: Successful pregnancy in a patient with HallermannStreiff syndrome. Am J Obstet Gynecol 164:1102–1104, 1991. Hutchinson D: Oral manifestations of oculomandibulodyscephaly with hypotrichosis (Hallermann-Streiff syndrome). Oral Surg Oral Med Oral Pathol 31:234–244, 1971. Malde AD, Jagtap SR, Pantvaidya SH: Hallermann-Streiff syndrome: airway problems during anaesthesia. J Postgrad Med 40:216–218, 1994.
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Nevin NC, Scally BG, Thomas P, et al.: The Hallermann-Streiff syndrome. J Ment Defic Res 18:145–151, 1974. Ohishi M, Murakami E, Haita T, et al.: Hallermann-Streiff syndrome and its oral implications. ASDC J Dent Child 53:32–37, 1986. Patterson GT, Braun TW, Sotereanos GC: Surgical correction of the dentofacial abnormality in Hallermann-Streiff syndrome. J Oral Maxillofac Surg 40:380–384, 1982. Ryan CF, Lowe AA, Fleetham JA: Nasal continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea in Hallermann-Streiff syndrome. Clin Pediatr (Phila) 29:122–124, 1990. Salbert BA, Stevens CA, Spence JE: Tracheomalacia in Hallermann-Streiff syndrome. Am J Med Genet 41:521–523, 1991. Sataloff RT, Roberts BR: Airway management in Hallermann-Streiff syndrome. Am J Otolaryngol 5:64–67, 1984. Scheuerle A: Commentary on Hallermann-Streiff Syndrome: experience with 15 patients and review of the literature. J Craniofac Surg 10:225, 1999. Sclaroff A, Eppley BL: Evaluation and surgical correction of the facial skeletal deformity in Hallermann-Streiff syndrome. Int J Oral Maxillofac Surg 16:738–744, 1987. Slootweg PJ, Huber J: Dento-alveolar abnormalities in oculomandibulodyscephaly (Hallermann-Streiff syndrome). J Oral Pathol 13:147–154, 1984. Spaepen A, Schrander-Stumpel C, Fryns JP, et al.: Hallermann-Streiff syndrome: clinical and psychological findings in children. Nosologic overlap with oculodentodigital dysplasia? Am J Med Genet 41: 517–520, 1991. Steele RW, Bass JW: Hallermann-Streiff syndrome. Clinical and prognostic considerations. Am J Dis Child 120:462–465, 1970. Sugar A, Bigger JF, Podos SM: Hallermann-Streiff-Francois syndrome. J Pediatr Ophthal 8:234–238, 1971. Suzuki Y, Fujii T, Fukuyama Y: Hallermann-Streiff syndrome. Dev Med Child Neurol 12:496–506, 1970.
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Fig. 2. A male infant with Hallermann-Streiff syndrome showing frontal bossing, microphthalmia, thin nose, mandibular hypoplasia, hypotrichosis involving eyelashes and eyebrows, and genital hypoplasia.
Fig. 1. An infant with Hallermann-Streiff syndrome showing brachycephaly, frontal and parietal bossing, microphthalmia, thin, pointed nose, mandibular hypoplasia, and hypotrichosis.
Fig. 3. An adult with Hallermann-Streiff syndrome with mental retardation, short stature, alopecia, scanty eyelashes, a beaked nose, and scoliosis.
Harlequin Ichthyosis (Harlequin Fetus) 4. Natural history a. Restricted fetal movement caused by dense masses of hyperkeratotic scale b. Prematurity in most cases c. Perinatal death (usually in the first few weeks) secondary to: i. Respiratory compromise due to mechanical limitation of ribcage excursion ii. Sepsis iii. Hypothermia iv. Dehydration v. Malnutrition vi. Severe anemia vii. Renal failure d. Rare survivals i. Variable neurologic impairment ii. Short stature iii. Failure to thrive iv At risk for severe keratitis due to ectropion of all eyelids
Harlequin ichthyosis is a rare severe scaling disorder, which manifests in utero and is often fatal early in life.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Pathogenesis a. Lack of desquamation and massive accumulation of scale due to abnormal lamellar granules and absence of extracellular lamellar structures between the granular cells and the cornified cells b. Defect in lipid synthesis or metabolism c. A defect of conversion from profilaggrin to filaggrin i. Suggests possible defects of protein phosphatase activity in the epidermis ii. Leads to the clinical features of harlequin ichthyosis because protein phosphatase is thought to work both in the conversion from profilaggrin to filaggrin and in the synthesis of the lipid content of lamellar granules 3. Report of a male with harlequin ichthyosis with a de novo deletion of the long arm of chromosome 18 [46, XY, del(18)(q21.3)] suggesting the possible gene localization within the deleted region
DIAGNOSTIC INVESTIGATIONS 1. Light microscopy findings a. Extraordinary compact orthohyperkeratosis (thickened orthokeratotic stratum corneum) b. Keratin plugs in hair follicles and sweat ducts c. Absent lamellar bodies and abundant vesicles in both the stratum granulosum and stratum corneum d. Abnormal lipid droplets and vacuoles in the cytoplasm of keratinized cells in the thick stratum corneum 2. Ultrastructural findings a. Abnormal lipid droplets and vacuoles in the cytoplasm of keratinized cells in the thick stratum corneum b. Absent normal lamellar granules in the cytoplasm of granular layer keratinocytes c. Lack of lamellar structure in the extracellular space between the first cornified cell and the granular cell 3. Biochemical analysis of skin samples: a defect of conversion from profilaggrin to filaggrin 4. Family history for evidence of consanguinity
CLINICAL FEATURES 1. Major clinical features a. Large, thick and yellowish armor-like plaques (platelike scales) with redish, moist, oozing fissures and cracks, covering the whole body b. Severe ectropion (complete eversion of the nonkeratinizing mucosa of the eyelids with occlusion of the eyes) c. Eclabium (eversion of the nonkeratinizing mucosa of the lips) d. “Frog-like” grostesque appearance of the face e. Crumpled and flattened ears f. Flattened nasal tip with anteversion of the nares (nasal hypoplasia) g. Permanently opened mouth unable to suck properly h. Swollen extremities secondary to tight sausage-like encasement by the thickened stratum corneum i. Semiflexed rigid extremities (allowing little limb movement) with hypoplastic fingers 2. Minor clinical features a. Absent eyebrows and eyelashes b. Scalp hair may or may not be present 3. Associate anomalies a. Renal tubular defects b. Altered thymic structures c. Pulmonary hypoplasia
GENETIC COUNSELING
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1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: patient not surviving to reproductive age 2. Prenatal diagnosis possible in families at risk a. Ultrasonography (2D and especially 3D) after 24 weeks i. Minimal fetal movement with stiff limbs in a semiflexed position
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ii. Swollen limbs with hypoplastic fingers and toes and short phalanges iii. Shriveled hands that do not open iv. Abnormal facies v. Absence of typical ear morphology vi. Large open mouth vii. Absence of typical nasal morphology viii. Partitioned cystic formations in front of the eyes ix. Thick skin x. Hyperechogenic amniotic fluid xi. Absence of associated visceral anomalies b. Amniocentesis: demonstration of clumping of keratinocyte cells in the amniotic fluid containing lipid droplets and amorphous electron dense material c. Electron microscopy of the fetal skin biopsy specimen from fetoscopy at 20-22 weeks i. Abnormal vacuoles in keratinized cells ii. Abnormal lamellar granules in the hair canal 3. Management a. Temperature control b. Electrolyte and fluid balance c. Adequate caloric intake d. Prevention of infection with antibiotics e. Topical steroids to reduce secondary inflammation f. Tretinoin creams or ointments or oral retinoid treatment to reduce the amount of scale g. Pain management with anti-inflammatory drugs and morphine sulfate if necessary h. Ocular management i. Intensive topical eye ointment ii. Treat keratitis promptly iii. Surgical management of the ectropion by skinrelease surgery with autologous skin grafting in patients with severe exposure keratitis or cosmetically unacceptable ectropion i. Careful handling to avoid hard friction and physical contract for prevention of blistering
REFERENCES Akiyama M: Severe congenital ichthyosis of the neonate. Int J Dermatol 37:722–728, 1998. Akiyama M, Suzumori K, Shimizu H: Prenatal diagnosis of harlequin ichthyosis by the examination of keratinized hair canals and amniotic
fluid cells at 19 weeks’ estimated gestational age. Prenat Diagn 19:167–171, 1999. Akiyama M, Dale BA, Smith LT, et al.: Regional difference in expression of characteristic abnormality of harlequin ichthyosis in affected fetuses. Prenat Diagn 18:425–436, 1998. Anton-Lamprecht I: Genetically induced abnormalities of epidermal differentiation and ultrastructure in ichthyoses and epidermolyses: pathogenesis, heterogeneity, fetal manifestation, and prenatal diagnosis. J Inv Dermatol 81 (suppl):149S–156S, 1983. Badden HP, Kubilus J, Rosenbaum K, et al.: Keratinization in the harlequin fetus. Arch Dermatol 118:14–18, 1982. Blanchet-Bardon S, Dumez Y, Labbe F, et al.: Prenatal diagnosis of a harlequin fetus using EM. Ann Pathol 3:321–325, 1983. Bongain A, Benoit B, Ejnes L, et al.: Harlequin fetus: three-dimensional sonographic findings and new diagnostic approach. Ultrasound Obstet Gynecol 20:82–85, 2002. Buxman MM, Goodkin PE, Fahrenback WH, et al.: Harlequin ichthyosis with an epidermal lipid abnormality. Arch Dermatol 115:189–193, 1979. Craig JM, Goldsmith LA, Baden HP: An abnormality of keratin in the harlequin fetus. Pediatrics 46:437–440, 1970. Dale BA, Holbrook KA, Fleckman P, et al.: Heterogeneity in Harlequin ichthyosis, an inborn error of epidermal keratinization: vVariable morphology and structural protein expression and a defect in lamellar granules. J Inv Dermatol 94:6–18, 1990. Dale BA ,Kam E: Harlequin ichthyosis. Variability in expression and hypothesis for disease mechanism. Arch Dermatol 129:1471–1477, 1993. Hashimoto K, Khan S: Harlequin fetus with abnormal lamellar granules and giant mitochondria. J Cutan Pathol 19:247–252, 1992. Haftek M, Cambazard F, Dhouailly D, et al.: A longitudinal study of a harlequin infant presenting clinically as non-bullous congenital ichthyosiform erythroderma. Br J Dermatol 135:448–453, 1996. Moreau S, Salame E, Goullet de Rugy M, et al.: Harlequin fetus: a case report. Surg Radiol Anat 21:215–216, 1999. Multani AS, Sheth FJ, Shah VC, et al.: Three siblings with harlequin ichthyosis in an Indian family. Early Hum Dev 45:229–233, 1996. Prasad RS, Pejaver RK, Hassan A, et al.: Management and follow-up of harlequin siblings. Br J Dermatol 130:650–653, 1994. Roberts LJ: Long-term survival of a harlequin fetus. J Am Acad Dermatol 21:335–339, 1989. Sarkar R, Sharma RC, Sethi S, et al.: Three unusual siblings with harlequin ichthyosis in an Indian family. J Dermatol 27:609–611, 2000. Singh S, Bhura M, Maheshwari A, et al.: Successful treatment of harlequin ichthyosis with acitretin. Int J Dermatol 40:472–473, 2001. Stewart H, Smith PT, Gaunt L, et al.: De novo deletion of chromosome 18q in a baby with harlequin ichthyosis. Am J Med Genet 102:342–345, 2001. Sybert VP: Genetic Skin Disorders. New York: Oxford University Press, 1997, pp 13–16. Unamuno P, Pierola JM, Fernandez E, et al.: Harlequin foetus in four siblings. Br J Dermatol 116:569–572, 1987. Watson WJ, Mabee LM, Jr: Prenatal diagnosis of severe congenital ichthyosis (harlequin fetus) by ultrasonography. J Ultrasound Med 14:241–243, 1995.
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Fig. 1. A newborn with harlequin ichthyosis, covered with yellowish plaques with moist fissures and cracks and grostesque appearance of face with ectropion, eclabium, a flat nose, crumpled/flat ears, and swollen/semiflexed rigid limbs.
Hemophilia A Hemophilia A is a congenital X-chromosome linked coagulation disorder affecting 1 in 5000 to 1 in 10,000 male births.
GENETICS/BASIC DEFECTS 1. Inheritance a. An X-linked recessive disorder b. New mutations in approximately 1/3rd of patients c. Hemophilia A in females i. Rarely reported ii. Possible explanation a) Extreme skewing of X chromosome inactivation resulting in unusually low factor VIII levels in female hemophilia A carriers b) Rare individuals carrying a hemophilia A mutation associated with an X chromosome:autosome translocation or other cytogenetic abnormality, which may result in exclusive inactivation of the normal Xchromosome c) Rare individuals carrying a hemophilia A mutation in the rearranged X-chromosome 2. Molecular genetics a. Caused by absent or decreased factor VIII (FVIII) procoagulant function, resulting from mutations in FVIII gene, mapped on chromosome Xq28 b. A unique rearrangement within the FVIII gene (intron 22 gene inversion), recently identified as a common, recurrent mechanism for hemophilia A i. Accounting for approximately 45% of all severe hemophilia A patients ii. The mutation almost always arises during a male meiosis iii. The mother of an apparently new mutation patient with an identified gene inversion can generally be assumed to be a carrier, with the recombination event often identified in the maternal grandfather’s allele c. The remaining 55% of severe hemophilia patients shown to have a more conventional molecular defect in the FVIII gene i. Approximately 50% of patients with specific point mutations in exons or at splice junctions within the FVIII gene ii. Approximately 5% of patients with deletions which remove varying sized segments of the FVIII gene iii. Rare small insertions and deletions d. Nearly all patients with mild or moderately severe hemophilia A have some residual level of FVIII activity, shown to have a point mutation within the FVIII coding sequence, resulting in a single amino acid substitution
e. Clinical severity of the hemophilia A phenotype correlates very closely with the amount of residual factor VIII activity
CLINICAL FEATURES
476
1. Clinical features suspecting a coagulation disorder a. Hemarthrosis, especially with mild or no antecedent trauma b. Deep muscle hematomas c. Intracranial bleeding in the absence of major trauma d. Cephalohematoma or intracranial bleeding at birth e. Prolonged oozing or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision f. Prolonged bleeding or renewed bleeding following surgery or trauma g. Unexplained gastrointestinal bleeding or hematuria h. Menorrhagia, especially at menarche i. Prolonged nosebleeds, especially recurrent and bilateral j. Excessive bruising, especially with firm, subcutaneous hematomas 2. Severe hemophilia A (43% of hemophiliacs) a. Spontaneous bleeding i. Joints: the most frequent symptom ii. Other sites a) Kidneys b) Gastrointestinal tract c) Brain b. Without treatment i. Bleeding from minor mouth injuries and large “goose eggs” from minor head bumps during the toddler period ii. Rare intracranial bleeding resulting from head injuries iii. Almost always with subcutaneous hematomas iv. Frequency of bleeding a) Relating to the FVIII clotting activity b) Varying from two to five spontaneous bleeding episodes each month c) Bleeding episodes more frequent in childhood and adolescence than in adulthood c. Age of diagnosis i. Usually diagnosed during the first year of life ii. Relating to the FVIII clotting activity 3. Moderately severe hemophilia A (26% of hemophiliacs) a. Seldom with spontaneous bleeding b. Without treatment i. Prolonged or delayed oozing after relatively minor trauma ii. Frequency of bleeding
HEMOPHILIA A
4.
5.
6.
7. 8.
a) Varying from once a month to once a year b) Bleeding episodes more frequent in childhood and adolescence than in adulthood c. Usually diagnosed before the age of five to six years Mild hemophilia A (31% of hemophiliacs) a. Absent spontaneous bleeding b. Without treatment i. Occurrence of abnormal bleeding with surgery, tooth extraction, and major injuries ii. Frequency of bleeding a) Varying from once a year to once every ten years b) Bleeding episodes more frequent in childhood and adolescence than in adulthood c. Often not diagnosed until later in life Carrier females a. Risk of bleeding in approximately 10% of carrier females b. Mild symptoms Complications of untreated bleeding a. Intracranial hemorrhage: the leading cause of death b. Chronic joint disease: the major cause of disability Life expectancy: 60–70 years Differential diagnosis a. Inherited bleeding disorders associated with a low factor VIII clotting activity i. Type 1 vWD (mild von Willebrand disease) a) An autosomal dominant disorder b) Predominant feature: mucous membrane bleeding c) Quantitative deficiency of von Willebrand factor (low vWF antigen, factor VIII clotting activity, and ristocetin cofactor activity) in 80% of patients ii. Type 2 vWD a) Quantitative deficiency of vWF with a decrease of the high molecular weight multimers b) Low normal to mildly decreased vWF antigen and factor VIII clotting activity c) Low functional vWF level in a ristocetin cofactor assay iii. Type 2N vWD a) An uncommon variant due to several missense mutations in the amino terminus of the vWF protein, resulting in defective binding of factor VIII to vWF b) Low factor VIII clotting activity usually showing autosomal recessive inheritance c) Indistinguishable clinically from mild hemophilia A, which can be differentiated with molecular genetic testing of the FVIII gene, molecular genetic testing of the vWF gene, or measuring binding of factor VIII to vWF using ELISA or column chromatography iv. Type 3 vWD (severe von Willebrand disease) a) An autosomal recessive disorder b) Frequent episodes of mucous membrane bleeding and joint and muscle bleeding similar to hemophilia A
477
c) <1% vWF level d) 2–8% FVIII clotting activity v. Mild combined factor V and factor VIII deficiencies a) A rare autosomal recessive disorder b) Deficiency of a chaperone protein (ERGIC53) b. Other bleeding disorders with normal factor VIII clotting activity i. Hemophilia B a) An X-linked recessive disorder caused by mutations in the factor IX (FIX) gene b) Clinically indistinguishable from hemophilia A c) Diagnosis based on factor IX clotting activity of <30% ii. Factor XI deficiency a) An autosomal recessive disorder b) Homozygotes with factor XI coagulant activity of <1–15% c) Heterozygotes with factor XI coagulant activity of 25–75% iii. Factor XII, prekallekrein or high molecular weight kininogen deficiencies a) Do not cause clinical bleeding b) A prolonged PTT iv. Prothrombin (factor II) or factors V, X, or VII deficiencies a) Autosomal recessive disorders b) Clinical features: easy bruising and hematoma formation, epistaxis, menorrhagia, bleeding after trauma and surgery c) Diagnosis established by specific coagulation factor assays v. Fibrinogen disorders a) Afibrinogenemia: an autosomal recessive disorder characterized by prolonged bleeding from minor cuts due to the lack of fibrinogen to support platelet aggregation b) Hypofibrinogenemia: inherited either in an autosomal dominant or recessive fashion with mild to moderate bleeding symptoms or may be asymptomatic c) Dysfibrinogenemia: an autosomal dominant disorder with symptoms similar to hypofibrinogenemia vi. Factor XIII deficiency a) An autosomal recessive disorder b) Occurrence of umbilical stump bleeding in >80% of cases c) Intracranial bleeding occurring spontaneously or following minor trauma in 30% of cases d) Subcutaneous hematomas e) Muscle hematomas f) Defective wound healing g) Recurrent spontaneous abortion h) Rare joint bleeding vii. Platelet function disorders a) General features: bleeding problems similar to thrombocytopenia (skin and mucous
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HEMOPHILIA A
membrane bleeding, recurring epistaxis, gastrointestinal bleeding, menorrhagia, excessive bleeding during or immediately after trauma and surgery) b) Bernard-Soulier syndrome: an autosomal recessive disorder involving the vWF receptor and platelet GPIb c) Glanzmann thrombasthenia: an autosomal recessive disorder involving the GPIIb-IIIa receptor necessary for platelet aggregation
DIAGNOSTIC INVESTIGATIONS 1. Coagulation screening test a. Prolonged partial thromboplastin time (PTT) in severe and moderately severe hemophilia A b. PTT often normal in mild hemophilia A 2. Coagulation factor assay for factor VIII clotting activity a. Normal range: 50–150% b. Low to low normal: above 35% i. Usually do not have bleeding ii. Bleeding can occur in association with mild von Willebrand disease c. Factor VIII clotting activity unreliable in the detection of carriers d. Diagnosis of hemophilia A established in patients with low FVIII clotting activity (<35%) in the presence of a normal von Willebrand factor (vWF) level i. Activity <1%: severe hemophilia A ii. Activity 1–5%: moderately severe hemophilia A iii. Activity 5–35%: mild hemophilia A 3. Molecular genetic diagnosis a. Direct genetic analysis i. Direct identification of the pathogenic mutation in the FVIII gene (up to 98% of patients with hemophilia A), using mutation analysis, mutation scanning, and sequence analysis a) Severe hemophilia A: FVIII intron 22-A gene inversion (45% of cases); an intron 1 gene inversion (3% of cases); gross gene alterations including large deletions or insertions, frameshift and splice junction changes, and nonsense and missense mutations (50% of cases) b) Mild to moderately severe hemophilia A: most patients with missense mutations within the exons coding for the three A domains or the two C domains ii. Possibility of misclassification due to presence of neutral mutations in the FVIII gene and the risk of mosaicism in sporadic families a) Essential to confirm that a characterized mutation causes the hemophilia since neutral amino acid substitutions (polymorphisms) may not cause detrimental change in the FVIII gene b) Look for other mutations in the FVIII gene if a missense mutation has not been described as causing hemophilia A previously c) Possibility of mosaicism in germinal or somatic cells of the mother in the sporadic
families who does not carry the mutation that her hemophilic son has b. Indirect genetic linkage analysis i. Using linked polymorphic markers (restriction fragment length polymorphisms, RFLP) to trace the inheritance of the hemophilia gene within a pedigree if mutation is not found ii. Limitation of linkage analysis a) Uninformative patterns of polymorphic markers b) Ethnic variation c) Linkage disequilibrium d) Need for participation of family members e) Not useful in sporadic families which constitute more than half of the hemophilia families
GENETIC COUNSELING 1. Recurrence risk a. Obligatory carrier i. A woman whose father has hemophilia ii. A woman who has given birth to two boys with hemophilia, excluding identical twins iii. A woman who has given birth to one son with hemophilia and a daughter who has a son with hemophilia b. Establish the genetic probability for carriership for women in a pedigree who are not genetic obligatory carriers based on: i. Pedigree data ii. Clotting factor (FVIII:C) analysis c. Patient’s sib: risk to the sibs depending on the carrier status of the mother i. A 50% risk of having a male sib with hemophilia A and a 50% risk of having a carrier female sib if the mother is a carrier ii. A low recurrence risk of having a male sib with hemophilia A if the mother has a normal factor VIII clotting activity and no evidence of her carrying her son’s FVIII disease-causing mutation in her leukocytes, unless she has germline mosaicism d. Patient’s offspring i. No sons will inherit the mutant allele and therefore will not be affected with hemophilia A ii. All daughters will be carriers for hemophilia A 2. Prenatal diagnosis available to pregnancies of carrier women with hemophilia A a. Fetal karyotyping to determine male fetus (46,XY) b. DNA extracted from fetal cells by amniocentesis or CVS analyzed for: i. The known FVIII disease-causing mutation ii. The informative linked polymorphic markers c. Fetal blood sample obtained by percutaneous umbilical blood sampling (PUBS) for assay of factor VIII clotting activity if the disease-causing FVIII mutation is not known and if linkage testing is not informative 3. Management a. Prophylactic treatment using plasma-derived concentrate of coagulation factor in the past
HEMOPHILIA A
b.
c. d.
e.
f.
i. Preventing majority of bleeding episodes ii. Minimizing the impact of arthropathy iii. Complications a) Concentrates manufactured from plasma, pooled from thousands of donors, invariably contaminated with blood-born viruses that caused posttransfusion hepatitis B and non-A non-B (hepatitis C) in practically all treated hemophiliacs b) Optimistic perception of hemophilia: benefits of concentrates seemed to outweigh hepatitis risks c) Tragedy: 60–80% of person with severe hemophilia became infected with the human immunodeficiency virus (HIV) with contaminated concentrates in the early 1980s Infusion of plasma-derived or recombinant FVIII i. Markedly improves both the life expectancy and the quality of life of patients suffering from hemophilia A ii. Still at risk for life-threatening bleeding episodes and chronic joint damage iii. Side effect of clotting factor substitution therapy: develop neutralizing antibodies against FVIII, rendering further substitution ineffective (10–40% of cases) Treatment of early chronic synovitis by nonsurgical means (radionuclide synoviorthesis) Obstetrical issues i. Asymptomatic carrier a) Uncommon intracranial hemorrhage in affected male fetuses (1–2%) b) Cesarean section reserved for complicated deliveries ii. Symptomatic carrier (baseline factor VIII clotting activity <35%) a) Somewhat protected by the natural rise of factor VIII clotting activity during pregnancy b) Delayed postpartum bleeding when factor VIII clotting activity returns to baseline within 48 hours Neonatal issues i. Early determination of the genetic status of male infants at risk a) Assay factor VIII clotting activity from a cord blood sample obtained by venipuncture of the umbilical vein b) Molecular genetic testing for the FVIII mutation identified in the family ii. Avoid circumcision in infants with a family history of hemophilia A, unless; a) Hemophilia A is excluded, or b) Factor VIII concentrate is administered just prior and subsequent to the procedure to prevent delayed oozing and poor wound healing Analysis of patient’s DNA i. Permits identification of the gene lesions that cause hemophilia ii. Allows the disease to be controlled through carrier detection and prenatal diagnosis
479
g. Future gene therapy i. Providing a cure for the disease ii. Providing constant, sustained FVIII synthesis in the patient a) Obviate the risk of spontaneous bleeding b) Obviate the need for repeated FVIII infusions c) Obviate the risk of viral infections associated with plasma-derived FVIII iii. Requires the use of a gene delivery system that is efficient, safe, non-immunogenic and allows for long-term gene expression iv. Must compare favorably with existing protein replacement therapies v. Initiation of several gene therapy phase I clinical trials in patient’s suffering from severe hemophilia A a) Fewer bleeding episodes reported in some patients b) Occasional detection of low levels of clotting factor activity
REFERENCES Aledort LM: Current concepts in diagnosis and management of hemophilia. Hosp Pract (Off Ed) 17:77–84, 89–92, 1982. Bagnall RD, Waseem N, Green PM, et al.: Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood 99:168–174, 2002. Becker J, Schwaab R, Moller Taube A, et al.: Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: family studies indicate a mutation type-dependent sex ratio of mutation frequencies. Am J Hum Genet 58:657–670, 1996. Chambost H, Gaboulaud V, Coatmelec B, et al.: What factors influence the age at diagnosis of hemophilia? Results of the French hemophilia cohort. J Pediatr 141:548–552, 2002. Chowdhury MR, Tiwari M, Kabra M, et al.: Prenatal diagnosis in hemophilia A using factor VIII gene polymorphism—Indian experience. Ann Hematol 82:427–430, 2003. Francis RB Jr, Kasper CK: Reproduction in hemophilia. J Am Med Assoc 250:3192–3195, 1983. Graham JB: Genetic counseling in classic hemophilia A. N Engl J Med 296:996–998, 1977. Graham JB, Rizza CR, Chediak J, et al.: Carrier detection in hemophilia A: a cooperative international study. I. The carrier phenotype. Blood 67:1554–1559, 1986. Green PP, Mannucci PM, Briet E, et al.: Carrier detection in hemophilia A: a cooperative international study. II. The efficacy of a universal discriminant. Blood 67:1560–1567, 1986. Hedner U, Ginsburg D, Lusher JM, et al.: Congenital Hemorrhagic Disorders: New Insights into the Pathophysiology and Treatment of Hemophilia. Hematology (Am Soc Hematol Educ Program) 241–265, 2000. High K: Gene-based approaches to the treatment of hemophilia. Ann N Y Acad Sci 961:63–64, 2002. Johnson MJ, Thompson AR: Hemophilia A. Gene Reviews, 2003. http://www. genetests.org Kaufman RJ: Advances toward gene therapy for hemophilia at the millennium. Hum Gene Ther 10:2091–2107, 1999. Kazazian HH Jr: The molecular basis of hemophilia A and the present status of carrier and antenatal diagnosis of the disease. Thromb Haemost 70:60–62, 1993. Kraus EM, Brettler DB: Assessment of reproductive risks and intentions by mothers of children with hemophilia. Am J Med Genet 31:259–267, 1988. Leuer M, Oldenburg J, Lavergne JM, et al.: Somatic mosaicism in hemophilia A: a fairly common event. Am J Hum Genet 69:75–87, 2001. Ljung R, Sj˝orin E: Origin of sporadic cases of haemophiliia A. Br J Haematol 106:870–874, 1999. Ljung R and Tedgård U: Genetic counseling of hemophilia carriers. Semin Thromb Hemost 29:31–36, 2003.
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Mannucci PM: Treatment of hemophilia: recombinant factors only? No. J Thromb Haemost 1:216–217, 2003. Mannucci PM: Hemophilia: treatment options in the twenty-first century. J Thromb Haemost 1:1349–1355, 2003. Tedgård U, Ljung R, McNeil TF: How do carriers of hemophilia and their spouses experience prenatal diagnosis by chorionic villus sampling? Clin Genet 55:26–33, 1999. Tedgård U, Ljung R, McNeil TF: Long-term psychological effects of carrier testing and prenatal diagnosis of haemophilia: comparison with a control group. Prenat Diagn 19:411–417, 1999.
Thompson AR: Structure and function of the factor VIII gene and protein. Semin Thromb Hemost 29:11–22, 2003. Vandendriessche T, Collen D, Chuah MKL: Gene therapy for the hemophiliac. J Thrombosis Haemostasis 1:1550–1558, 2003. Varekamp I, Suurmeijer T, Broker Vriends A, et al.: Hemophilia and the use of genetic counseling and carrier testing within family networks. Birth Defects Orig Artic Ser 28(1):139–148, 1992. Varekamp I, Suurmeijer T, Broker Vriends A, et al.: Carrier testing and prenatal diagnosis for hemophilia: experiences and attitude of 549 potential and obligate carriers. Am J Med Genet 37:147–154, 1990.
HEMOPHILIA A
Fig. 1. A boy with hemophilia A who is asymptomatic with prophylactic infusions of recombinant FVIII.
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Hereditary Hemochromatosis Hereditary hemochromatosis (HHC; HFE 1) is a common hereditary disorder of iron metabolism and the most common inherited autosomal recessive disorder in Caucasians with a prevalence of 1 in 300 to 1 in 500 individuals. It is characterized by inappropriately high iron absorption resulting in progressive iron overload.
6. Hereditary hemochromatosis not attributable to mutations in HFE a. A subgroup of hereditary hemochromatosis indistinguishable from HFE-associated HHC b. Does not have mutations in HFE c. The disease does not appear to be linked to the HLA complex d. The genetic basis has not been defined
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Cause: result of a single faulty HFE gene on chromosome 6p21.3 near the HLA complex that codes for a glycoprotein called HFE, which binds to the transferrin receptor and reduces its affinity for iron-bound transferrin, allowing cellular uptake of iron-based transferrin 3. Two common mutations (missense) a. C282Y i. Accounts for most cases of HHC ii. Homozygotes for C282Y mutation are at high risk for HHC iii. Heterozygote for C282Y mutation a) Have increased levels of transferrin saturation b) Rarely have organ damage b. H63D: Homozygotes for H63D are unlikely to develop HHC c. C282Y/H63D: compound heterozygotes for C282Y/ H63D have a milder form of HHC than C282Y homozygotes 4. Other HFE mutations a. Missense mutations i. S65C: the third most common mutation ii. G93R iii. I105T iv. Q127H v. R330M b. Frameshift mutations i. P160ΔC ii. V68ΔT c. Nonsense mutations d. Spice site mutation 5. Clinical expression of the disease a. Homozygotes: affected clinically b. Heterozygotes i. Can have minor abnormalities of the parameters that reflect body iron status ii. Can develop significant iron overload only when other diseases that affect iron metabolism coexist, such as: a) Heterozygous β-thalassemia b) Hereditary spherocytosis c) Sporadic Porphyria cutanea tarda
CLINICAL FEATURES
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1. Variable clinical presentation 2. Median age at presentation of symptoms a. 51 years in males b. Females homozygotes i. Less likely to develop symptomatic disease ii. Median age: age 50 3. Asymptomatic: abnormal serum iron studies on routine screening 4. Early manifestations a. Often subtle b. Vague arthralgias c. Fatigue d. Lethargy e. Apathy f. Weight loss 5. Later manifestations as tissue iron progressively accumulates a. Discoloration of the skin b. Arthropathy i. Due to iron accumulation in joint tissues ii. Arthritis with joint swelling, most commonly involves: a) Metacarpophalangeal (MCP) joints b) Proximal interphalangeal joints c) Knees d) Feet e) Wrists f) Back g) Neck iii. Chondrocalcinosis a) Involves the knees and wrists b) May be asymptomatic iv. Symptoms usually do not respond to iron removal c. Liver involvement i. Abdominal pain associated with hepatomegaly ii. Hepatomegaly iii. Splenomegaly iv. Cirrhosis v. Portal hypertension a) Ascites b) Encephalopathy
HEREDITARY HEMOCHROMATOSIS
6.
7.
8.
9.
vi. Hepatocellular carcinoma in about 30% of cases d. Cardiac involvement i. Dilated cardiomyopathy ii. Arrhythmias iii. Cardiac failure e. Endocrine abnormalities i. Diabetes mellitus ii. Pituitary hypogonadism a) Decreased libido and impotence (testicular atrophy) in men b) Amenorrhea in women iii. Hypothyroidism Suspect diagnosis from characteristic clinical manifestations a. Classical clinical triad of “bronzed cirrhosis with diabetes” in a middle-age man: i. Diffuse hyperpigmentation (melanodermia), often with a metallic grey or “bronze” rather than a brown discoloration ii. Hepatomegaly, with the liver markedly enlarged, firm and sharp to palpation but without signs of hepatocellular insufficiency (no palmar erythema, no spider nevi, no bruises, normal prothrombin time) or of portal hypertension iii. Diabetes mellitus, often requiring insulin b. Presence of cardiomyopathy c. Diagnosis at this late stage: considered a diagnostic failure Suspect diagnosis from earlier signs and symptoms a. Sex and age: both young adults and older women are at risk b. “Rule of three A’s” i. Asthenia: unexplained chronic fatigue ii. Arthralgia a) A “painful hand-shake: resulting from chronic arthritis of the second and third MCP joints” b) Other joints affected especially the knees and writs c) Can also suffer from pseudo-gout (pyrophosphate arthropathy) d) Arthritis greatly diminishes the quality of life iii. Aminotransferase (transaminases) elevation Cause of death a. Liver failure b. Cancer c. Congestive heart failure d. Arrhythmia Other conditions associated with significant iron overload a. NonHFE associated hereditary hemochromatosis i. Juvenile hemochromatosis (HFE 2) (increased iron absorption) ii. Congenital atransferrinemia (HFE 3, transferrin receptor 2 mutation) (defective internal iron exchange, increased iron absorption) iii. Ferroportin 1 mutations (HFE 4) b. Secondary iron overload i. Iron loading anemias (ineffective erythropoiesis, increased iron absorption, blood transfusions)
ii.
iii.
iv.
v. vi. vii. viii. ix.
483
a) β-thalassemia b) Congenital dyserythropoietic anemias c) Sideroblastic anemia d) Pyridoxine-responsive anemia Hypoplastic anemias (blood transfusions) a) Aplastic anemia b) Myelodysplastic syndromes c) Pure red cell aplasia Chronic hemolytic anemias (increased iron absorption) a) Spherocytosis b) Sickle cell anemia c) Pyruvate kinase deficiency Parental iron overload a) Red blood cell transfusion b) Iron-dextran injections c) Long term hemolysis Neonatal hemochromatosis Ceruloplasmin deficiency (aceruloplasminemia) (decreased ferroxydase activity) Sub-Saharian iron overload (increased dietary iron, increased iron absorption) Porphyria cutanea tarda (increased iron absorption) Hepatic disorders a) Chronic viral hepatitis b) Alcoholic cirrhosis c) Porta-caval shunts (increased iron absorption)
DIAGNOSTIC INVESTIGATIONS 1. Biochemical testing a. High serum ferritin levels b. High transferrin-iron saturation value: an early and reliable indicator for risk of iron overload/HFE-HHC i. A fasting transferrin-iron saturation of ≥60% for men and ≥50% for women on at least two occasions, in the absence of other known causes of elevated transferrin-iron saturation, is observed in about 80% of individuals with HFE–HHC and is considered suggestive of HFE–HHC ii. A threshold transferring-iron saturation of 45% is more sensitive for detecting HFE–HHC suggested by recent studies iii. Some overlap occurs in serum transferrin-iron saturation among homozygotes and heterozygotes 2. Radiography a. Arthropathy i. Squared-off bone ends and hook-like osteophytes in the MCP joints, particularly in the second and third MCP joints ii. Subchondral arthropathy iii. Chondrocalcinosis 3. MRI of the liver a. The most promising noninvasive technique for identification of HHC. High hepatic iron content causes: i. A decrease in signal intensity of the liver ii. A marked decrease in transverse (T2) relaxation time 4. Liver biopsy to assess histologic hepatic iron stores
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a. Usually not indicated for diagnostic purposes in HFE–HHC b. Recommended to C282Y homozygotes with a serum ferritin concentration of >1000 ng/mL to determine if cirrhosis is present; those with a serum ferritin concentration <1000 ng/mL need not undergo biopsy c. Useful to determine hepatic iron overload, particularly in patients with presumed hemochromatosis who lack the common HFE mutations associated with HFE–HHC 5. Molecular genetic testing: a. Mutation analysis for the disease-causing alleles in the HFE gene (C282Y and H63D) i. C282Y/C282Y homozygotes (60–90%) ii. C282Y/H63D compound heterozygotes (3–8%) iii. H63D/H63D homozygote (1%) iv. H63D/? (4%) v. C282Y/? (1%) vi. ?/? (6%) b. Testing strategy for a proband i. Mutation analysis warranted in adults with serum transferrin-ion saturation of >45% ii. Individuals with homozygous C282Y/C282Y or compound heterozygous C282Y/H63D: have genetic make-up to develop HFC–HHC iii. Individuals who are not C282Y homozygotes a) Generally represent a heterogeneous group b) Many have liver disease unrelated to HFE–HHC or other metabolic syndromes c) Some may have primary iron overload in a pattern identical to HFE–HHC d) The next diagnostic step: perform liver biopsy with assessment of histology and measurement of hepatic iron concentration c. Carrier detection: identification of carriers and noncarriers in at-risk family members possible provided both HFE alleles have been identified in the proband 6. Screening for HHC a. HHC: a prime target for screening because of its high prevalence, morbidity and mortality, as well as the benefits of early diagnosis and treatment b. Initial screening probe for HHC diagnosis i. Transferrin saturation ii. Unsatured iron-binding capacity
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. 25% if both parents are HFE–HHC heterozygotes ii. 50% if one parent is HFE–HHC heterozygotes and other parent HFE–HHC homozygote b. Patient’s offspring: 5% risk to be affected due to the high carrier rate for HFE mutant alleles in the general population i. The risk that the partner of an individual with HFE–HHC is heterozygous for the C282Y allele is 1/9 ii. Therefore, the risk to the offspring to be a homozygote for C282Y allele is 1/2 × 1/9 = 1/18
2. Prenatal diagnosis a. Technically feasible when both parents carry identified HFE mutations b. Highly unusual to request prenatal diagnosis because HHC is an adult-onset, treatable disease 3. Management a. Early diagnosis and treatment i. Can completely prevent the development of clinical complications ii. Offer patients a normal life expectancy b. Treatment of iron overload i. Periodic phlebotomy a) Goal of therapy: to achieve and maintain a serum ferritin concentration of ≤50 ng/mL b) Usual therapy: removal of the excess iron by weekly phlebotomy until the serum ferritin concentration is ≤50 ng/mL ii. Dietary management a) Avoid medicinal iron b) Avoid mineral supplements c) Avoid excess vitamin C which increases intestinal absorption of inorganic iron d) Avoid uncooked shellfish or other seafood which can be contaminated with V vulnificus causing sepsis in patients with HHC e) Avoid alcohol consumption for patients with liver involvement iii. Iron chelation therapy: not recommended unless the patient has an elevated serum ferritin concentration and concomitant anemia that makes therapeutic phlebotomy impossible c. Conventional therapies for diabetes, hepatic failure, and cardiac failure d. Cirrhosis: screen for hepatocellular cancer i. Bi-annual abdominal ultrasound ii. Annual serum alpha-fetoprotein testing e. Orthotopic liver transplantation for end-stage liver disease from decompensated cirrhosis f. Surveillance of at-risk asymptomatic adults with C282Y homozygotes i. Monitor serum ferritin concentrations yearly starting in early adulthood ii. Initiate therapeutic phlebotomy when serum ferritin concentrations are elevated
REFERENCES Andrews NC: Disorders of iron metabolism. N Engl J Med 341:1986–1995, 1999. Bothwell TH, MacPhail AP: Hereditary hemochromatosis: etiologic, pathologic, and clinical aspects. Semin Hematol 35:55–71, 1998. Brittenham GM, Weiss G, Brissot P, et al.: Clinical consequences of new insights in the pathophysiology of disorders of iron and heme metabolism. Hematology :39–50, 2000. Camaschella C, Piperno A: Hereditary hemochromatosis: recent advances in molecular genetics and clinical management. Haematologica 82:77–84, 1997. Edwards CQ, Griffen LM, Dadone MM, et al.: Mapping the locus for hereditary hemochromatosis: localization between HLA-B and HLA-A. Am J Hum Genet 38:805–811, 1986. Feder JN, Gnirke A, Thomas W, et al.: A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13:399–408, 1996.
HEREDITARY HEMOCHROMATOSIS Fleming RE, Sly WS: Mechanisms of iron accumulation in hereditary hemochromatosis. Ann Rev Physiol 64:663–680, 2002. Hanson EH, Imperatore G, Burke W: HFE gene and hereditary hemochromatosis: a HuGE review. Human Genome Epidemiology. Am J Epidemiol 154:193–206, 2001. Harrison SA, Bacon BR: Hereditary hemochromatosis: update for 2003. J Hepatol 38 (Suppl 1):S14–S23, 2003. Kowdley KV, Tait JF, Bennett RL, et al.: HFE-associated hereditary hemochromatosis. Gene Reviews, 2004. http://www.genetests.org McLaren CE, McLachlan GJ, Halliday JW, et al.: Distribution of transferrin saturation in an Australian population: relevance to the early diagnosis of hemochromatosis. Gastroenterology 114:543–549, 1998. Merryweatherclarke AT, Pointon JJ, Shearman JD, et al.: Global prevalence of putative haemochromatosis mutations. J Med Genet 34:275–278, 1997. Morrison ED, Brandhagen DJ, Phatak PD, et al.: Serum ferritin level predicts advanced hepatic fibrosis among U.S. patients with phenotypic hemochromatosis. Ann Intern Med 138:627–633, 2003.
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Nichols GM, Bacon BR: Hereditary hemochromatosis: pathogenesis and clinical features of a common disease. Am J Gastroenterol 84:851–862, 1989. Niederau C, Fischer R, Sonnenberg A, et al.: Survival and cause of death in crirrhotic and noncirrhotic patients with primary hemochromatosis. N Engl J Med 313:1256–1262, 1985. Niederau C, Fischer R, Purschel A, et al.: Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 110:1107–1119, 1996. Phatak PD, Cappuccio JD: Management of hereditary hemochromatosis. Blood Rev 8:193–198, 1994. Phatak PD, Guzman G, Woll JE, et al.: Cost-effectiveness of screening for hereditary hemochromatosis. Arch Intern Med 154:769–776, 1994. Piertrangelo A: haemochromatosis. Gut 52 (Suppl II):ii23–ii30, 2003. Ramrakhiani S, Bacon BR: Hemochromatosis: advances in molecular genetics and clinical diagnosis. J Clin Gastroenterol 27:41–46, 1998. Tavill AS: Diagnosis and management of hemochromatosis. Hepatology 33:1321–1328, 2001.
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Fig. 1. Father (40-year-old) and son (12-year-old) both carry heterozygous C282Y mutation. H63D and S65C were not detected. The father currently receives periodic phlebotomy with fasting transferrin-iron saturation level of 56% (15–50) and ferritin level of 1238 ng/ML (20–345). The son is currently asymptomatic. Approximately 3–5% of patients with hereditary hemochromatosis have this genotype. The molecular results do not rule out the possibility of disease causing mutations in other regions of the HFE gene or in other as yet undefined genes.
Fig. 2. Real-time PCR of HFE gene in another patient. The patient is homozygous for C282Y mutation, demonstrated by the green line (Melting point (Tm) = 62.89).
Hereditary Multiple Exostoses Hereditary multiple exostoses is a type of skeletal dysplasia characterized by the formation of abnormal bony growths at the growing ends of the bones. The estimated prevalence is about 1 in 50,000 Caucasians.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant with nearly complete penetrance b. About 90% of patients have an affected parent. c. About 10% of patients result from a de novo gene mutation. 2. Genetic heterogeneity: Linkage analysis identified the following 3 three genes associated with hereditary multiple exostoses: a. EXT1 gene i. A ubiquitously expressed gene located on chromosome 8q23-24 ii. Normal gene product: exostosin 1 iii. Mutations in EXT1 are responsible for about half of cases. b. EXT2 gene i. A ubiquitously expressed gene located on chromosome 11p11-p12 ii. Normal gene product: exostosin 2 iii. Mutations in EXT2 are responsible for about one third of cases. c. EXT3 gene i. A gene located on chromosome 19p ii. Mutations in EXT3 are implicated in a minority of cases. 3. Loss of heterozygosity in the EXT1 or EXT2 implicated in causing osteochondromas, which are the most common bone tumors in children, characterized by cartilagecapped, bony excrescences (exostoses) arising from the metaphyseal ends of rapidly growing long bones 4. Deletion of EXT1 gene and adjacent TRPS1 gene (a gene located on chromosome 8 proximal to the EXT1 gene) resulting in Langer-Giedion syndrome (trichorhinophalangeal syndrome, type II) in which multiple exostoses are distinguishing features
CLINICAL FEATURES 1. Exostoses (cartilage-capped bony growths) a. Painless bony swellings (bumps) near the growing ends of the long bones b. Onset: childhood (asymptomatic) c. Sites i. Humerus ii. Distal ends of the femur
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iii. Proximal ends of the tibia and fibula iv. Distal ends of the radius v. Ribs vi. Scapula vii. Ilium d. Types i. Peduculated with a narrow pedicle ii. Sessile with a broad pedicle e. Size and number i. Grow in size and gradually ossify during skeletal development ii. Ceases with skeletal maturity after which no new exostoses develop Bowing a. Often occurs without exostoses b. Bowing of forearms: ulnar deviation of the wrist secondary to a bowing of the radius and shortening of the ulna c. Bowing of lower legs Genu valgum Deformities observed in children a. Most common deformities i. Disproportionate short stature (40%) ii. Limb length discrepancies iii. Valgus deformities of the knee and ankle iv. Asymmetry of the pectoral and pelvic girdles v. Bowing of the radius with ulnar subluxation of the carpus vi. Subluxation of the radial head vii. Relative shortening of the metatarsals, metacarpals, and phalanges b. Less common deformities i. Scoliosis ii. Coxa valga iii. Acetabular dysplasia Prognosis and complications a. Normal life span b. Normal intelligence c. Cosmetic concern (one of the most common clinical complaints) d. Mechanical restriction of adjacent joint movements e. Adventitious bursa with bursitis f. Compression or displacement of the adjacent nerves (22%) i. Pain (one of the most common clinical complaints) ii. Sensory or motor deficits g. Compression or displacement of the adjacent vessels (11%) h. Spontaneous hemothorax as a result of rib exostoses (rare)
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i. Urinary or intestinal obstruction resulting from large pelvic exostoses (rare) j. Compression of spinal cord i. Very rare occurrence ii. Extremely serious complication k. Slipping of the adjacent tendons l. Fractures at the pedicle m. Malignant transformation of osteochondroma to osteochondrosarcoma (1%) i. Rapid growth ii. Increasing pain iii. A bulky cartilage cap
DIAGNOSTIC INVESTIGATIONS 1. Radiographic features a. Pedunculated or sessile exostoses pointing away from the joint b. Cortex of exostoses continuous with that of the underlying bone c. Exostoses originated in the metaphysis in the long bones and migrate to the diaphysis as growth continues in the epiphysis d. Cartilagenous cap i. Usually radiolucent ii. Appearance of irregular zones of calcification after puberty iii. Extensive calcification with irregularities of the cap suggesting possibility of malignant change e. Exostoses prevent normal bone tabulation resulting in metaphyseal widening and growth retardation. f. Broad and barrel shaped metaphyses without normal remodeling g. Wrist i. Shortening of the ulna ii. Bowing of the radius with subluxations of the inferior radioulnar joint 2. CT and MRI imagings: evaluate spinal cord compression from an osteochondroma 3. Serial technetium bone scans: iIncreased radionucleotide uptake suggests malignancy 4. Histology of exostosis a. Core: cancellous bone b. Surrounding: cortical bone c. Apex: covered with a cap of hyaline cartilage 5. DNA analysis of mutations in the EXT1, EXT2, and EXT3 genes
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Usually with 50% risk of inheriting the gene alteration, since most probands (about 90%) have a parent with the altered gene and 95% risk of manifesting symptoms (penetrance) ii. Low risk if both parents are normal b. Patient’s offspring: 50% risk of inheriting the mutant allele 2. Prenatal diagnosis: available clinically 3. Management
a. Exostoses without clinical problems required no therapy b. Surgical intervention of exostoses i. Simple excision of exostoses a) Painful lesion without bony deformity b) Slowing growth disturbance c) Improving cosmesis ii. Angular deformities iii. Pain due to irritation of skin, tendons, or nerves iv. Either epiphyseodesis of the longer leg or lengthening of the involved leg for leg-length discrepancy greater than one inch v. Excision of the exostoses and corrective osteotomies for forearm deformity (pain and stiffness of the elbow and wrist are a common cause of disability) c. Sarcomatous degeneration i. Surgical resection ii. Adjuvant radiotherapy and chemotherapy for secondary osteosarcoma
REFERENCES Ahn J, Ludecke HJ, Lindow S, et al.: Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nature Genet 11:137–143, 1995. Arms DM, Strecker WB, Manske PR, et al.: Management of forearm deformity in hereditary multiple Osteochondromatosis. J Pediatr Orthop 17:450–454, 1997. Bernard MA, Hogue DA, Cole WG, et al.: Cytoskeletal abnormalities in chondrocytes with EXT1 and EXT2 mutations. J Bone Miner Res 15:442–450, 2000. Bovee JV, Cleton-Jansen AM, Wuyts W, et al.: EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochodromas and secondary chondrosarcomas. Am J Hum Genet 65:689–698, 1999. Bouvier JF, Chassard JL, Brunat-Mentigny M, et al.: Radionuclide bone imaging in diaphyseal aclasis with malignant change. Cancer 57:2280–2284, 1986. Carroll KL, Yandow SM, Ward K, et al.: Clinical correlation to genetic variations of hereditary multiple exostosis. J Pediatr Orthop 19:785–791, 1999. Castells L, Comas P. Gonsalez A, et al.: Haemothorax in hereditary multiple exostosis. Br J Radiol 66:269–270, 1993. Chansky HA, Raskind WH: Hereditary multiple exostoses. Gene Reviews. http://genetests.org Cook A, Raskind W, Blanton SH, et al.: Genetic heterogeneity in families with hereditary multiple exostoses. Am J Hum Genet 53:71–79, 1993. Fogel Genome Res, McElfresh EC, Peterson HA, et al.: Management of deformities of the forearm in multiple hereditary osteochondromas. J Bone Joint Surg 66A:670–680, 1984. Gross RH: Leg length discrepancy: how much is too much? Orthopedics 1:307–310, 1978. Hecht JT, Hogue D, Wang Y, et al.: Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies. Am J Hum Genet 60:80–86, 1997. Hennekam RC: Hereditary multiple exostoses. J Med Genet 28:262–266, 1991. Lange RH, Lange TA, Rao BK: Correlative radiographic, scintigraphic, and histological evaluation of exostoses. J Bone Joint Surg AM 66: 1454–1459, 1984. Le Merrer M, Legeai-Mallet L, Jeannin PM, et al.: A gene for hereditary multiple exostoses maps to chromosome 19p. Hum Mol Genet 3:717–722, 1994. Legeai-Mallet L, Munnich A, Maroteaux P, et al.: Incomplete penetrance and expressivity skewing in hereditary multiple exostoses. Clin Genet 52:12–16, 1997. McBride WZ: Hereditary multiple exostoses. Am Fam Physician 38:191–192, 1988. Peterson HA: Multiple hereditary osteochondromata. Clin Orthop 239:222–230, 1989.
HEREDITARY MULTIPLE EXOSTOSES Philippe C, Porter DE, Emerton ME, et al.: Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses. Am J Hum Genet 61:520–528, 1997. Pierz KA, Stieber JR, Kusumi K, et al.: hereditary Hereditary multiple exostoses: one center’s experience and review of etiology. Clin Orthop Rel Res 401:49–59, 2002. Porter DE, Emerton ME, Villanueva-Lopez F, et al.: Clinical and radiographic analysis of osteochondromas and growth disturbance in hereditary multiple exostoses. J Pediatr Orthop 20:246–250, 2000. Schmale GA, Conrad EU III, Raskind WH: The natural history of hereditary multiple exostoses. J Bone Joint Surg AM 76:986–992, 1994. Shapiro F, Simon S, Glimcher MJ: Hereditary multiple exostoses. Anthropometric, roentgenographic, and clinical aspects. J Bone Joint Surg AM 61:815–824, 1979.
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Taniguchi K: A practical classification system for hereditary multiple exostosis in children. J Pediatr Orthop 15:585–591, 1995. Van Hul W, Wuyts W, Hendrick XJ, et al.: Identification of a third EXT-like gene (EXTL3) belonging to the EXT gene family. Genomics 47:230–237, 1998. Wicklund CL, Pauli RM, Johnston D, et al.: Natural history study of hereditary multiple exostoses. Am J Med Genet 55:43–46, 1995. Wood VE, Sauser D, Mudge D: The treatment of hereditary multiple exostoses of the upper extremity. J Hand Surg 10A:505–513, 1985. Wuyts W, Van Hul W: Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes. Hum Mutat 15:220–227, 2000. Wuyts W, Van Hul W, De Boulle K, et al.: Mutations in the EXT1 and EXT2 gene in hereditary multiple exostoses. Am J Hum Genet 62:346–354, 1998.
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Fig. 1. A boy with hereditary multiple exostoses showing bony growths on both sides of ribs and the lower legs, illustrated by the radiograph
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Fig. 2. Radiographs of a 5-year-old boy with hereditary multiple exostoses showing multiple exostoses of the humerus, radius, tibia, and fibula.
Fig. 3. A 7-year-old boy with hereditary multiple exostoses showing more severe degree of multiple exostoses of the humerus, radius, tibia, and fibula.
Fig. 4. A 20-year-old female with hereditary multiple exostoses showing pedunculated exostosis on the left proximal tibia and fibula, exostosis on the shaft of the left fibula, and exostoses on the distal radius and ulna. She was discovered to have multiple exostoses since one year of age and has had multiple surgeries to remove multiple tumors from right femur, left tibia, and left fibula. Currently, she has bumps on the right distal femur, right proximal fibula, right distal tibia, left distal fibula, left distal forearm, right distal phalange of the right fifth finger, and left second toe. Her father is also affected.
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Fig. 5. A 27-year-old male with hereditary multiple exostoses showing exostoses, ulnar shortening, and ulnar carpal drift.
Holoprosencephaly The holoprosencephaly (HPE) is a heterogeneous entity of CNS anomalies caused by the impaired midline cleavage of the embryonic forebrain. The incidence is estimated to be 1 in 16,000 live births and observed in 1 of 250 spontaneous abortions.
GENETICS/BASIC DEFECTS 1. Isolated and sporadic in most cases 2. Genetically heterogeneous involving at least 12 loci on eleven chromosomes. There are at least five putative loci for HPE: a. HPE1 i. Map locus: 21q22.3 ii. Familial alobar holoprosencephaly b. HPE2 (SIX3) i. Map locus: 2p21 ii. Chromosome 2 form of holoprosencephaly, including midline cleft syndrome and DeMyer sequence iii. Caused by mutations in the homeo box-containing SIX3 gene c. HPE3 on 7q36-qter, characterized as the locus containing the human sonic hedgehog gene (SHH) i. Either loss-of-function mutation or disruption of one of the sonic hedgehog alleles at 7q36 (haploinsufficiency) shown to cause variable phenotype of holoprosencephaly ii. A broad spectrum of holoprosencephaly present in patients with de novo 7q, or with autosomal dominant holoprosencephaly having a linkage on 7q36 iii. 7q deletion syndrome without typical holoprosencephaly in some patients iv. Interaction of partial trisomy 3p and partial monosomy 7q: invariably associated with severe forms of holoprosencephaly and facial dysmorphism. This delineates an autosomal imbalance syndrome or a dosage effect involving distal 3p duplication/terminal 7q deletion and dysmorphogenesis of the forebrain and mid-face d. HPE4 (TG-interacting factor, TGIF) on 18p11.3. Mutations of TGIF have been associated with holoprosencephaly and premaxillary agenesis e. HPE5 (ZIC2) on 13q32 3. Other known HPE-associated genes a. PTCH i. Patched mutations in humans result in haploinsufficiency ii. A few of such mutations cause holoprosencephaly b. DHCR7 i. Mutations resulting in reduced serum cholesterol and accumulation of 7-dehydrocholesterol in autosomal recessive Smith-Lemli-Opitz syndrome 493
ii. 4% of cases with Smith-Lemli-Opitz syndrome have holoprosencephaly 4. Subtypes of holoprosencephaly and the range of possible craniofacial features a. Alobar holoprosencephaly i. Cyclopia (a single eye or partially divided eye in a single orbit with or without proboscis above the eye) ii. Ethmocephaly (extreme ocular hypotelorism with proboscis located between the eyes) iii. Cebocephaly (ocular hypotelorism with a singlenostril nose) iv. Premaxillary agenesis (ocular hypotelorism with median cleft lip and palate) v. Bilateral cleft lip vi. Ocular hypotelorism only vii. Anophthalmia or microophthalmia viii. Relatively normal facial appearance b. Semilobar holoprosencephaly i. Bilateral cleft lip with median process representing the philtrum-premaxilla anlage ii. Flat nasal bridge iii. Absent nasal septum iv. Flat nasal tip v. Midline cleft lip and/or palate vi. Ocular hypotelorism vii. Flat nose viii. Anophthalmia/microophthalmia ix. Relatively normal facial appearance c. Lobar holoprosencephaly i. Bilateral cleft lip with median process ii. Ocular hypotelorism iii. Flat nose iv. Relatively normal facial appearance 5. Causes a. Detectable chromosome abnormalities (24–45%) i. Numerical chromosomal abnormalities a) Trisomy 13 (most common) b) Trisomy 18 c) Triploidy ii. Structural chromosomal abnormalities: reported in virtually all chromosomes. The most frequent ones are as follows: a) Involving 13q [del(13q), r(13)] b) Del(18p) c) Del(7)(q36) (20%) d) Dup(3)(p24-pter) (10%) e) Del(2)(p21) f) Del(21)(q22.3) g) Del(22q11) h) Partial monosomy 14q b. Monogenic holoprosencephaly (18–25%) i. Autosomal dominant
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a) b) c) d)
Pallister-Hall syndrome Rubinstein-Taybi syndrome Kallmann syndrome Martin syndrome (with club foot and spinal anomalies) e) Steinfeld syndrome (with congenital heart disease, absent gallbladder, renal dysplasia, and radial defects) f) Ectrodactyly and hypertelorism ii. Autosomal recessive a) Meckel-Gruber syndrome b) Smith-Lemli-Opitz syndrome c) Pseudotrisomy 13 syndrome d) XK aprosencephaly syndrome e) Heterotaxy and holoprosencephaly f) Genoa syndrome (with craniosynostosis) g) Lambotte syndrome (with microcephaly, prenatal growth retardation, and hypertelorism) h) Hydrolethalus syndrome (with hydrocephalus, polydactyly, and other anomalies) i) Facial clefts and brachial amelia iii. X-linked recessive (holoprosencephaly-fetal hypokinesia/akinesia) c. Agnathia-otocephaly (10%) d. Fronto-nasal dysplasia (6.7%) e. Sirenomelia association f. Holoprosencephaly, ectopia cordis, and embryonal neoplasms 6. Nongenetic risk factors a. Maternal diabetes: 1–2% of newborn infants of diabetic mothers develop holoprosencephaly b. Retinoic acid i. CNS anomalies, particularly hydrocephalus ii. Holoprosencephaly c. Ethyl alcohol i. Holoprosencephaly/arhinencephaly ii. Agnathic cyclopia iii. Midline cerebral dysgenesis with hypothalamicpituitary dysfunction iv. Hydrocephalus v. Agenesis of the corpus callosum and anterior commissure d. Salicylates e. Estrogen/progestin f. Anticonvulsants g. Low-calorie weight reduction diets h. Prenatal infections i. Cytomegalovirus ii. Rubella iii. Toxoplasma i. Poverty j. Previous pregnancy loss
CLINICAL FEATURES 1. Variable expression, ranging from a small brain with a single cerebral ventricle and cyclopia to clinically unaffected carriers in familial holoprosencephaly 2. Face: Holoprosencephaly is often associated with distinct facial appearance (holoprosencephaly facies syndrome).
The face predicts the brain approximately 80% of the time. In decreasing order of severity: a. Absence of eye(s) (the most severe form) b. Cyclopia i. The most severe dysmorphism ii. A median monophthalmia (a single midline eye) iii. Synophthalmia (fusion of two eyes in a single midline orbit) iv. Anophthalmia v. Presence of a single median orbit (sine qua non for the diagnosis) vi. Without or with proboscis (single or double protruding from the glabella, just above the median eye) vii. Complete arhinia with no nose, no nasal bones viii. Degree of facial dysmorphism strongly correlated with the severity of brain malformation (facial and the oculo-orbital phenotype reflect the underlying central nervous system pathology) c. Ethmocephaly i. Rarest type ii. Close-set eyes (ocular hypotelorism) located in two separate orbits iii. A median proboscis between the two eyes as a rudimentary tube-like nose iv. Hypoplastic or absent median facial bones d. Cebocephaly i. Close-set eyes (ocular hypotelorism) into separate orbits ii. A nose with a single nostril iii. No cleft lip e. Premaxillary agenesis i. Close-set eyes (ocular hypotelorism) ii. Median cleft lip and palate 3. Eyes a. Anophthalmia b. Microphthalmia c. Cyclopia d. Fused eyes e. Coloboma f. Hypotelorism g. Bulging eyes h. Other eye malformations i. Fused lids ii. Optic disk hypoplasia iii. Cataract 4. Nose a. Proboscis b. Arhinia with or without proboscis c. Flat nose i. With proboscis ii. Absent or nonpatent nares iii. Other malformations 5. Mouth a. Median cleft lip b. Bilateral cleft lip c. Unilateral cleft lip d. Cleft palate alone e. Cleft lip with cleft palate f. Cleft lip alone
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6.
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g. Cleft uvula h. Microstomia i. Macrostomia j. Agnathia k. Microganthia Ear a. Fused ears b. Other ear malformations Neurodevelopmental deficits a. Hoarse or “barking” voice, high-pitched crying b. Major feeding problems with choking spells c. Common growth delay d. Seizures e. Spasticity or floppy muscle tone f. Brain-stem dysfunction with irregular breathing and heart rate and erratic body temperature control g. Profound developmental delay with very limited expressive language and minimal attainment of motor skills h. Behavioral problems Endocrine disorders a. Occasional diabetes insipidus with episodes of dehydration b. Rare panhypopituitarism Presence of microforms of holoprosencephaly in relatives of patients with holoprosencephaly a. Microcephaly b. Single central maxillary incisor c. Ocular hypotelorism d. Anosmia/hyposmia secondary to absent olfactory tracts and bulbs e. Iris coloboma f. Absent superior labial frenulum g. Midface hypoplasia h. Congenital nasal pyriform aperture stenosis i. Developmental delay Prognosis a. Infants born with cyclopia, ethmocephaly, and cebocephaly: virtually all die within a week of birth b. Infants born with premaxillary agenesis, unilateral or bilateral cleft lip, or more normal facies i. Half of the patients die before 4–5 months ii. 20–30% of the patients live to one year of age. Longer survival is possible to at least 11 years c. Cases diagnosed in utero will have an extremely poor neurologic development after birth d. Causes of death most often due to brain-stem malfunction (unable to control the respiration and heart rate) aggravated by infections and other stresses
DIAGNOSTIC INVESTIGATIONS 1. Neuroimagings (MRI/CT of the brain) a. A single ventricle b. Absence of olfactory bulb and tracts c. Absence of corpus callosum d. Absence of inferior frontal and temporal regions e. Fused thalami f. Absence of optic nerve g. Incomplete anterior and posterior pituitary
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h. Normal brainstem and cerebellum i. Lack of ethmoid bone 2. Cytogenetic analysis 3. Adjunctive molecular analyses of distinct human gene for HPE 4. Necropsy: Holoprosencephaly is generally classified into three types. The distinction among the following three types is not always clear a. Alobar holoprosencephaly i. The most severe form ii. Complete failure of brain tissue to develop into the normal right and left cerebral hemispheres iii. The brain consisting of a single fused cerebral hemispheres located in the frontal region iv. Total absence of interhemispheric fissure and falx cerebri v. The brain surface is smooth with sparse convolutional markings vi. A single dilated ventricle communicating with a large dorsal cyst vii. Absence of the third ventricle, neurohypophysis, olfactory bulbs and tracts viii. Fused thalami and basal ganglia ix. Migrational anomalies often present b. Semilobar holoprosencephaly i. The less severe form ii. Rudimentary cerebral lobes. Only partial separation into two cerebral hemispheres; the hemispheres are not separated across the midline in the front part of the brain iii. A single ventricle iv. Olfactory bulbs and corpus callosum are usually absent v. Partial presence of the septum pellucidum and corpus callosum pending on the severity c. Lobar holoprosencephaly i. The least severe form ii. Well-formed lobes that may be of normal size iii. Virtual complete separation of the cerebral hemispheres iv. Various degree of rostral and basilar nonseparation v. Absent, hypoplastic or normal olfactory bulbs, tracts and corpus callosum vi. Gray matter heterotopias and other associated migrational anomalies
GENETIC COUNSELING 1. Recurrence risk: depending on the basis for the actual condition a. Patient’s sib i. Empirical estimate of 20% for holoprosencephaly, 15% for a microform, and 15% for normal phenotype ii. Increased recurrence risk depending on the type of Mendelian inheritance (autosomal recessive and dominant conditions with holoprosencephaly). Existence of incomplete penetrance or an incomplete form or microform of holoprosencephaly makes the interpretation of familial occurrence difficult
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iii. 50% recurrence risk of having affected siblings with variable clinical symptoms and severity if a parent is affected with holoprosencephaly iv. Germline mosaicism in which apparently unaffected parents with negative family history having more than one affected child v. Increased in a case where a parent carries a chromosome translocation or other chromosome rearrangement b. Patient’s offspring i. Severe cases of prosencephaly: not surviving to reproductive age ii. Individuals with mild form or microform holoprosencephaly (with a gene mutation for the autosomal dominant nonsyndromic holoprosencephaly): 50% recurrence risk of having an affected child 2. Prenatal diagnosis a. Prenatal ultrasonography i. General characteristics a) Polyhydramnios b) Ocular hypotelorism c) Cleft lip/palate d) Arhinia e) Cyclopia and proboscis: identifiable at the beginning of the 9th week of gestation by 2-D and 3-D ultrasonography f) Absence of central falx g) Demonstration of a single rudimentary cerebral ventricle ii. Alobar holoprosencephaly a) Single ventricle b) Presence or absence of dorsal sac c) Fused thalami d) Absence of septum cavum pellucidum iii. Semilobar holoprosencephaly a) Single ventricles with rudimentary occipital horns b) Presence or absence of dorsal sac c) Fused thalami d) Absence of septum cavum pellucidum iv. Lobar holoprosencephaly a) Almost divided ventricles except at frontal horns of lateral ventricles b) Some enlargement of lateral ventricle c) Flat roof of frontal horns in microtonal view d) Wide communication between the frontal horns and the inferior third ventricles e) Absence of dorsal sac f) Divided thalami g) Absence of septum cavum pellucidum b. Cytogenetic analysis from CVS or amniocytes i. Parent with a balanced chromosomal rearrangement ii. Fetus with multiple anomalies including holoprosencephaly from prenatal ultrasonography c. Molecular analysis on fetal DNA obtained from amniocentesis or CVS for the disease-causing mutation previously identified in the proband in a research laboratory
i. Sequencing of entire coding region for the HPE panel a) SIX3 gene b) SHH gene c) TGIF gene d) ZIC2 gene ii. Pallister-Hall syndrome: mutation analysis for mutation panel GLI3 (2023delG and 2012delG) iii. Rubinstein-Taybi syndrome: FISH analysis of the deletion of the CREBBP gene on chromosome 16 (16p13.3) iv. Smith-Lemli-Opitz syndrome a) Detection of two disease-causing mutations in the DHCR7 gene previously identified in the proband b) Abnormal concentration of 7-dehydrocholesterol levels d. Preimplantation diagnosis reported for Sonic Hedgehog mutation causing familial holoprosencephaly 3. Management a. Treatment strategies based on the types of brain malformations and associated anomalies i. Lethal entity: no specific treatment available ii. Nonlethal entity e) Ventriculo-peritoneal shunt for hydrocephalus f) Cleft lip and palate repair if indicated g) Monitoring of fluid and electrolyte intake in patients with diabetes insipidus h) Hormone replacement therapy for pituitary dysfunction b. Supportive i. Multidisciplinary team approach ii. Support and counseling of the parents iii. Seizure management iv. Gastrostomy tube placement and fundoplication for gastroesophageal reflux and vomiting
REFERENCES Barr M, Cohen MM Jr: Holoprosencephaly survival and performance. Am J Med Genet (Semin Med Genet) 89:116–120, 1999. Berry SA, Pierpont ME, Gorlin RJ: Single central incisor in familial holoprosencephaly. J Pediatr 104:877–880, 1984. Berry SM, Gosden C, Snijders RJ, et al.: Fetal holoprosencephaly: associated malformations and chromosomal defects. Fetal Diagn Ther 5:92–99, 1990. Blaas H-GK, Eik-Nes SH, Vainio T, et al.: Alobar holoprosencephaly at 9 weeks gestational age visualized by two- and three-dimensional ultrasound. Ultrasound Obstet Gynecol 15:62–65, 2000. Blaas H-GK, Eriksson AG, Salvesen KÅ, et al.: Brain and faces in holoprosencephaly: pre- and postnatal description of 30 cases. Ultrasound Obstet Gynecol 19:24–38, 2002. Brown SA, Warburton D, Brown LY, et al.: Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd–paired. Nature Genet 20:180–183, 1998. Chen C-P, Liu F-F, Jan S-W, et al.: Prenatal diagnosis of terminal deletion 7q and partial trisomy 3p in fetuses with holoprosencephaly. Clin Genet 50:321–326, 1996. Chen C-P, Devriendt K, Lee C-C, et al.: Prenatal diagnosis of partial trisomy 3p(3p23→pter) and monosomy 7q(7q36→qter) in a fetus with microcephaly, Alobar holoprosencephaly and cyclopia. Prenat Diagn 19:986–989, 1999.
HOLOPROSENCEPHALY Chen C-P, Chern S-R, Wang W, et al.: Prenatal diagnosis of partial monosomy 18p(18p11.2→pter) and trisomy 21q(q22.3→qter) with alobar holoprosencephaly and premaxillary agenesis. Prenat Diagn 21:346–350, 2001. Chen C-P, Chern S-R, Du S-H, et al.: Molecular diagnosis of a novel heterozygous 268C→T (R90C) mutation in TGIF gene in a fetus with holoprosencephaly and premaxillary agenesis. Prenat Diagn 22:5–7, 2002. Chen H, Rightmire D, Zapata C, et al.: Frontonasal dysplasia and arhinencephaly resulting from unbalanced segregation of a maternal t(2;7)(q31;q36). Dysmorphol Clin Genet 6:99–106, 1992. Cohen MM Jr: An update on the holoprosencephalic disorders. J Pediatr 101:865–869, 1982. Cohen MM Jr: Perspectives on holoprosencephaly: Part I. Epidemiology, genetics and syndromology. Teratology 40:211–235, 1989. Cohen MM Jr: Perspectives on holoprosencephaly. Part III. Spectra, distinctional, continuities, and discontinuities. Am J Med Genet 34:271–288, 1989. Cohen MM Jr: Problems in the definition of holoprosencephaly. Am J Med Genet 103:183–187, 2001. Cohen MM Jr: Malformations of the craniofacial region: Evolutionary, embryonic, genetic, and clinical perspectives. Am J Med Genet (Semin Med Genet) 115:245–268, 2002. Cohen MM Jr, Shiota K: Teratogenesis of holoprosencephaly. Am J Med Genet 109:1–15, 2002. Cohen MM, Sulik K: Perspectives on holoprosencephaly: part II. Central nervous system, craniofacial anatomy, syndrome commentary, diagnostic approach, and experimental studies. J Craniofac Genet Dev Biol 12:196–244, 1992. DeMyer W, Zeman W: Alobar holoprosencephaly (arhinencephaly) with median cleft lip and palate. Clinical nosologic and electroencephalographic considerations. Conf Neurol 23:1–36, 1963. DeMyer W, Zeman W, Palmer CG: The face predicts the brain. Diagnostic significance of median facial anomalies for holoprosencephaly arhinencephaly. Pediatrics 43:256–263, 1964. Ebina Y, Yamada H, Kato EH, et al.: Prenatal diagnosis of agnathia- holoprosencephaly: three-dimensional imaging by helical computed tomography. Prenat Diagn 21:68–71, 2001. Frints SGM, Schoenmakers EFPM, Smeets E, et al.: De novo 7q36 deletions: breakpoint analysis and types of holoprosencephaly. Am J Med Genet 75:153–158, 1998. Gripp KW, Edwards MC, Mowat D, et al.: Mutations in the transcription factor TGIF in holoprosencephaly. Am J Hum Genet 63:A32, 1998. Gurrieri F, Trask BJ, van den Engh G, et al.: Physical mapping of holoprosencephaly critical region of chromosome 7q36. Nat Genet 3:247–251, 1993.
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Lai T-H, Chang C-H, Yu C-H, et al.: Prenatal diagnosis of alobar holoprosencephaly by two-dimensional and three-dimensional ultrasound. Prenat Diagn 20:400–403, 2000. Matsunaga E, Shiota K: Holoprosencephaly in human embryos. Epidemiologic studies of 150 cases. Teratology 16:261–272, 1977. Muenke M: Clinical, cytogenetic and molecular approaches to the genetic heterogeneity of holoprosencephaly. Am J Med Genet 34:237–245, 1989. Muenke M: Holoprosencephaly as a genetic model to study normal craniofacial development. Semin Dev Biol 5:293–301, 1994. Muenke M, Beachy PA: Genetics of ventral forebrain development and holoprosencephaly. Curr Opin Genet Dev 10:262–269, 2000. Muenke M, Cohen MM Jr: Genetic approaches to understanding brain development: Holoprosencephaly as a model. Ment Retard Dev Disabil Res Rev 6:15–21, 2000. Muenke M, Gropman AL: Holoprosencephaly overview. Gene Reviews, 2003. http://www.genetests.org Muenke M, Beachy PA: Holoprosencephaly. In Scriver CR, Beaudet Al, Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001 Muenke M, Gropman AL: Holoprosencephaly overview. Gene Reviews, 2001. Nanni L, Roen LA, Lammer EJ, et al.: Holoprosencephaly: molecular study of a California population. Am J Med Genet 90:315–319, 2000. Nyberg DA, Mack LA, Bronstein A, et al.: Holoprosencephaly: Prenatal sonographic diagnosis. Am J Roentgenol 149:1051–1058, 1987. Pilu GL, Sandri F, Perolo A, et al.: Prenatal diagnosis of lobar holoprosencephaly. Ultrasound Obstet Gynecol 2:88–92, 1992. Roessler E, Muenke M: Midline and laterality defects: left and right meet in the middle. BioEssays 23:888–900, 2001. Roessler E, Belloni E, Gaudenz K, et al.: Mutations in the human sonic hedgehog gene cause holoprosencephaly. Nature Genet 14:357–360, 1996. Siebert JR, Cohen MM Jr, Sulik KK, et al.: Holoprosencephaly: An Overview and Atlas of Cases. Wiley-Liss: New York; 362, 1990. Vance GH, Nickerson C, Sarnat L, et al.: Molecular cytogenetic analysis of patients with holoprosencephaly and structural rearrangements of 7q. Am J Med Genet 76:51–57, 1998. Verlinsky Y, Rechitsky S, Verlinsky O, et al.: Preimplantation diagnosis for sonic hedgehog mutation causing familial holoprosencephaly. N Engl J Med 348:1449–1454, 2003. Wallis DE, Muenke M: Molecular mechanisms of holoprosencephaly. Mol Genet Metab 68:126–138, 1999. Wallis DE, Muenke M: Mutations in holoprosencephaly. Hum Mutat 16:99–108, 2000. Wallis DE, Roessler E, Hehr U, et al.: Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat Genet 22:196–198, 1999.
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Fig. 1. An aborted embryo with cyclopia.
Fig. 3. Another neonate with cyclopia.
Fig. 4. An infant with ethmocephaly.
Fig. 2. A neonate with cyclopia. The infant had holoprosencephaly (arrhinencephaly), agenesis of olfactory and optic nerves, agenesis of pituitary, cor binoculare, left diaphragmatic hernia, bilobar spleen, agenesis of adrenal glands, and absence of right umbilical artery.
Fig. 5. Postmortem brain with holoprosencephaly (dorsal view) showing a dilated single ventricle. The large dorsal cyst was ruptured during dissection, and the remnants of the membranous cyst wall are vaguely visible at the margins of the ventricle, especially on right side.
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Fig. 6. A neonate with cebocephaly.
Fig. 7. A neonate with cebocephaly and 48,XXY,+13.
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Fig. 8. A premature neonate with cebocephaly. The infant had anophthalmia, bilateral nasal atresia, alobar holoprosencephaly (ventral view) with a 4.5 × 5.5 × 6.0 cm dorsal cyst (not shown), atresia of left external auditory canal with hypoplastic malformed auricle, agenesis of left lung, left kidney and left ureter, hypoplasia of left posterior cranial fossa and left cerebellum, multiple skin tags, hemivertebrae, and absence of right umbilical artery.
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Fig. 10. A fetus with premaxillary agenesis showing facial dysmorphism, including hypotelorism, absence of nose, median cleft lip and palate, and low-set ears. In addition, the fetus had thirteen pairs of ribs, and absence of uterus and left kidney. The pregnancy was terminated at 17 weeks gestation because of alobar holoprosencephaly detected by ultrasonography. The postmortem brain showed alobar prosencephaly with a cerebral vesicle. Gyri were not developed.
Fig. 9. Front and lateral view of an infant with arrhinencephaly. The postmortem brain showed absence of olfactory tract and sulci and septum pellucidum and fused thalami.
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Fig. 13. A girl with mild hypotelorism, antimongoloid slant, and a central incisor. Fig. 11. Four infants with premaxillary agenesis.
Fig. 12. An infant with hypotelorism and duplicated nose.
Holt-Oram Syndrome In 1960, Holt and Oram described a family in which nine members in four generations were affected by skeletal abnormalities of the upper limbs, cardiac malformations, and arrhythmias. The prevalence is about 1 in 100,000 live births. About 40 to 85% of cases are due to fresh mutation.
GENETICS/BASIC DEFECTS 1. An autosomal dominant disorder a. Complete penetrance b. Widely variable expression 2. Holt-Oram syndrome frequently linked to the gene TBX5, which is mapped to 12q24.1 3. Caused by mutations in the TBX5 gene, a member of the T-box family that encodes a transcription factor a. Mutations predicted to create null alleles cause substantial abnormalities in both the limb and heart b. Nonsense mutations of TBX5 produce distinct phenotypes i. One class of missense mutations: causes significant cardiac malformations but only minor skeletal abnormalities ii. Other class of nonsense mutations: causes extensive upper limb malformations but less significant cardiac abnormalities 4. Intrafamilial variations of the malformations: suggest that genetic background or modifier genes plays an important role in the phenotypic expression of Holt-Oram syndrome 5. Hand-heart syndromes (syndromes with frequent association of congenital cardiac and upper-limb malformations): genetically heterogeneous a. Holt-Oram syndrome: the most common form b. Heart-hand syndrome type II (Tabatznik syndrome) i. Hypoplastic deltoids ii. Skeletal anomalies in the humeri, radii, ulnae, and thenar bones iii. Brachydactyly type D iv. Congenital cardiac arrhythmias (junctional rhythms and atrial fibrillation) c. Heart-hand syndrome type III i. Cardiac conduction defects (intraventricular delays and sick sinus syndrome) ii. Skeletal malformations limited to the hands and feet (Brachydactyly type C) d. Autosomal dominant “partial phenocopy” conditions i. Familial atrial septal defects with conduction disease occurring without limb deformities ii. Familial limb malformations occurring without cardiac defects
CLINICAL FEATURES 1. Preaxial radial ray abnormalities of the upper limb(s) a. Almost always present 502
b. Unilateral or bilateral c. Symmetric or asymmetric (left side more affected than the right side) d. Severe (phocomelia) to mild phenotype due to aplasia, hypoplasia, fusion, or anomalous development of involved bones e. Thumbs i. Aplasia ii. Hypoplasia iii. Triphalangeal iv. Syndactyly v. Long vi. Normal f. Fingers i. Clinodactyly ii. Brachydactyly iii. Hypoplasia iv. Absent v. Syndactyly vi. Normal g. Radial bones i. Hypoplasia ii. Aplasia h. Ulnar i. Hypoplasia ii. Aplasia i. Carpal bones i. Deformed ii. Extra j. Thenar bones: hypoplastic thenar eminence k. Humerus i. Hypoplasia ii. Abnormal head iii. Aplasia iv. Normal l. Clavicles i. Hypoplasia ii. Prominent acromioclavicular joint iii. Normal m. Thorax i. Pectus excavatum ii. Hypoplasia pectoralis major n. Limited supination o. Limited extension of the elbow 2. Cardiac anomaly (75% of cases) a. Structural defects i. Atrial septal defect (most common type, usually of secundum variety) ii. Ventricular septal defect iii. Pulmonary stenosis (including peripheral arterial) iv. Mitral valve prolapse v. Complex cardiac malformations (tetralogy of Fallot, hypoplastic left heart, endocardial cushion defects, truncus arteriosus)
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b. Cardiac conduction defects i. Paroxysmal tachycardia ii. Prolonged PR interval (ECG) iii. Wandering atrial pacemaker iv. Atrial ectopics v. Sinus bradycardia vi. Syncope vii. Sinus arrest viii. Atrioventricular block ix. Atrial fibrillation 3. Mild to no symptoms in children and young adult a. Recurrent respiratory infections b. Failure to thrive 4. Older adults a. Congestive heart failure b. Supraventricular arrhythmia, especially atrial fibrillation 5. Differential diagnosis a. Fanconi anemia syndrome i. Multiple congenital anomalies consisting of malformations of the thumbs, forearms, and heart ii. Progressive bone marrow failure with pancytopenia, typically in the first decade iii. An increased risk for myelodysplasia or acute myelogenous leukemia iv. Diagnosis based on detection of chromosomal breakage or rearrangement in the presence of diepoxybutane or Mitomycin C b. Thrombocytopenia-absent radius i. Both radii always absent ii. Thumbs always present iii. Occasional phocomelia iv. Possible involvement of lower limbs a) Club foot b) Knee instability v. Thrombocytopenia a) Present in infancy b) Generally improves with time vi. Heart defect can be present c. Heart-hand syndrome II (Tabatznik) i. Type D brachydactyly (shortening of the distal phalanx of the thumb with or without shortening of the 4th and 5th metacarpals) ii. Sloping shoulders iii. Short upper limbs iv. Bowing of the distal radii v. Absence of the styloid process of the ulna vi. Supraventricular tachycardia vii. Possible mild mental retardation and mild facial dysmorphism d. Heart-hand syndrome III i. Type C brachydactyly (shortening of the middle phalanges) ii. An accessory wedged-shaped ossicles on the proximal phalanx of the index fingers iii. Sick sinus syndrome e. Okihiro syndrome i. Duane syndrome
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a) A congenital eye-movement disorder resulting from abnormal development of cranial nerve VI b) Absence of abduction of the globe c) Narrowing of the palpebral fissure on adduction of the globe ii. Upper extremity reduction defects iii. Cardiac malformations f. Long thumb brachydactyly syndrome i. Elongation of the thumb distal to the proximal interphalangeal joint ii. Often associated with index finger brachydactyly, and clinodactyly iii. Narrow shoulders iv. Secondary short clavicles v. Pectus excavatum vi. Occasional rhizomelic limb shortening vii. Frequent with cardiac conductive defect g. VACTERL anomalies association i. Radial defect usually unilateral ii. Accompanied by other malformations such as imperforate anus and tracheoesophageal fistula, and congenital heart defect
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Phocomelia of the upper limbs b. Shortened humeri c. Shortened forearms i. Aplasia/hypoplasia of the radius ii. Hypoplastic ulna iii. Radio-ulnar synostosis iv. Humeral-ulnar synostosis d. Thumbs i. Absent thumbs ii. Triphalangeal thumbs iii. Clinodactyly iv. Syndactyly v. Absent first metacarpals vi. Hypoplastic thenar eminences e. First metacarpals i. Absent ii. Hypoplastic f. Fifth fingers i. Short middle phalanx ii. Clinodactyly g. Carpal bones i. Deformed ii. Extra carpals iii. Fused iv. Irregular v. Delayed formation h. Shoulders i. Deformed scapula and/or clavicle ii. Deformed head of the humerus iii. Accessory bones i. Deformed sternum
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2. Echocardiography for structural cardiac defects 3. Electrocardiography for cardiac conduction defects a. Sinus arrest b. Various degrees of atrioventricular block c. Right bundle branch block d. Sinus node dysfunction e. Wandering pacemaker f. Bradycardia g. Atrial fibrillation/flutter h. Supraventricular tachycardia and WPW syndrome i. Premature ventricular complexes 4. Molecualr genetic testing of TBX5 by sequencing of entire coding region or mutation scanning
GENETIC COUNSELING 1. Recurrence risk a. Probands i. 60–70% have an affected parent ii. 30–40% have a de novo mutation b. Patient’s sib: not increased unless a parent is affected in which case, there is 50% recurrence risk c. Patient’s offspring: 50% 2. Prenatal diagnosis a. Ultrasonography of Holt-Oram syndrome for fetuses at risk involving severe anomalies by demonstrating cardiac defect associated with upper limb defects, especially the radial ray defects b. Molecular genetic testing of TBX5 of fetal DNA obtained from amniocentesis or CVS, provided the disease-causing mutation has been identified in the family 3. Management a. A permanent pacemaker for advanced heart block b. Surgery for severe cardiac defect c. Prostheses for children with severe limb shortening d. Orthopedic management of severe limb defects
REFERENCES Akrami SM, Winter RM, Brook JD, et al.: Detection of a large TBX5 deletion in a family with Holt-Oram syndrome. J Med Genet 38:e44, 2001. Ashby DW, Chadha JS, Henderson CB: Associated skeletal and cardiac abnormalities: the Holt-Oram syndrome. Quart J Med New Series 38:267–276, 1969. Basson CT, Vaughan CJ: Holt-Oram syndrome. eMed J 2(5), 2001. Basson CT, Bachinsky DR, Lin RC, et al.: Mutations in human cause limb and cardiac malformations in Holt-Oram syndrome. Nat Genet 15:30–35, 1997. Basson CT, Cowley GS, Solomon DS, et al.: The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand) syndrome). N Engl J Med 330:885–891, 1994. Basson CT, Solomon SD, Weissman B, et al.: Genetic heterogeneity of hearthand syndromes. Circulation 91:1326–1329, 1995. Basson CT, Huang T, Lin RC, et al.: Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proc Natl Acad Sci USA 96:2919–2924, 1999.
Bossert T, Walther T, Gummert J, et al.: Cardiac malformations associated with the Holt-Oram syndrome—Report on a family and review of the literature. Thorac Cardiov Surg 50:312–314, 2002. Brons JTJ, Van Geijn HP, Wladimiroff JW, et al.: Prenatal ultrasound diagnosis of the Holt-Oram syndrome. Prenat Diagn 8:175–181, 1988. Bruneau BG, Logan M, Davis N, et al.: Chamber-specific cardiac expression of Tbx5 and heart defects in Holt-Oram syndrome. Dev Biol 211:100–108, 1999. Fan C, Duhagon MA, Oberti C, et al.: Novel TBX5 mutations and molecular mechanism for Holt-Oram syndrome. J Med Genet 40:e29, 2003. Gall JC Jr, Stern AM, Cohen MM, et al.: Holt-Oram syndrome: clinical and genetic study of a large family. Am J Hum Genet 18:187–200, 1966. Gladstone I, Sybert VP: Holt-Oram syndrome: penetrance of the gene and lack of maternal effect. Clin Genet 21:98–103, 1982. Ghosh TK, Packham EA, Bonser AJ, et al.: Characterization of the TBX5 binding site and analysis of mutations that cause Holt-Oram syndrome. Hum Mol Genet 10:1983–1994, 2001. Holmes LB: Congenital heart disease and upper-extremity deformities. A report of two families. N Engl J Med 272:437–444, 1965. Holt M, Oram S: Familial heart disease with skeletal malformations. Br Heart J 22:236–242, 1960. Horb ME, Thomsen GH: Tbx5 is essential for heart development. Development 126:1739–1751, 1999. Huang T: Current advances in Holt-Oram syndrome. Curr Opin Pediatr 14:691–695, 2002. Hurst JA, Hall CM, Baraitser M: The Holt-Oram syndrome. J Med Genet 28:406–410, 1991. Kaufman RL, Rimoin DL, McAlister WH, et al.: Variable expression of the Holt-Oram syndrome. Am J Dis Child 127:21–25, 1974. Letts RM, Chudley AE, Cumming G, et al.: The upper limb-cardiovascular syndrome (Holt-Oram syndrome). Clin Orthop Rel Res 116:149–154, 1976. Li QY, Newbury-Ecob RA, Terrett JA, et al.: Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene. Nat Genet 15:21–29, 1997. Massumi RA, Nutter DO: The syndrome of familial defects of heart and upper extremities (Holt-Oram syndrome). Circulation 34:65–76, 1966. Newbury-Ecob R, Leanage R, Raeburn JA, et al.: The Holt-Oram syndrome: a clinical genetic study. J Med Genet 33:300–307, 1996. Packham EA, Brook JD: T-box genes in human disorders. Hum Mol Genet 12:R37–R44, 2003. Poznanski AK, Gall JC, Stern AM: Skeletal manifestations of the Holt-Oram syndrome. Radiology 94:45–53, 1970. Silengo MC, Gulala BA, Lopez-Bell G, et al.: Heart-hand syndrome II. A report of Tabatznik syndrome with new findings. Clin Genet 38:105–113, 1990. Sletten LJ, Pierpont MEM: Variation in severity of cardiac disease in HoltOram syndrome. Am J Med Genet 65:128–132, 1996. Smith AT, Sack GH, Taylor GJ: Holt-Oram syndrome. J Pediatr 95:538–543, 1979. Terrett JA, Newbury-Ecob R, Cross GS, et al.: Holt-Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q. Nat Genet 6:401–404, 1994. Tongsong T, Chanprapaph P: Prenatal sonographic diagnosis of Holt-Oram syndrome. J Clin Ultrasound 28:98–100, 2000. Vaughan CJ, Basson CT: Molecular determinants of atrial and ventricular septal defects and patent ductus arteriosus. Am J Med Genet (Semin Med Genet) 97:304–309, 2001. Venugopalan P: Holt-Oram syndrome. eMed J 2(8), 2001.
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Fig. 2. A child with Holt-Oram syndrome showing bilateral club hands, absent radius and absent thumbs, demonstrated by radiographs.
Fig. 1. An infant with Holt-Oram syndrome showing club hands and fingerlike thumbs.
Fig. 3. A child with Holt-Oram syndrome showing left club hand and hypoplastic radius, illustrated by radiography.
Hydrops Fetalis Hydrops fetalis is a condition in which fluid accumulates in the serous cavities and/or in the soft tissues of the fetus. It is classified as immune if there is an indication of a fetomaternal blood group incompatibility, otherwise classified as nonimmune. The incidence of nonimmune hydrops fetalis is estimated to be approximately 1 in 2500 to 1 in 3500 neonates.
GENETICS/BASIC DEFECTS 1. Causes of immune hydrops a. Rh-D disease (approximately 90% of immune hydrops) i. Prior to 1960s, this is the most common cause (up to 80%) of all cases with hydrops fetalis. The incidence of Rhesus isoimmunization has declined steadily because of the widespread use of anti-D gamma globulin. The majority of hydrops is now of the nonimmune type. ii. Mother (Rh–), father (Rh+), fetus (Rh+) iii. After sensitization, maternal Rh antibody (IgG anti-D) crosses the placenta and destroys the Rhpositive fetal red blood cells. It results in fetal anemia iv. Previous pregnancy, including maternal-fetal blood mixing v. Previous abortion (spontaneous, missed, therapeutic) vi. First trimester bleeding vii. Trauma viii. Blood transfusion b. ABO incompatibility (rare, overall incidence about 1%) i. ABO incompatible pregnancies (about 20%) in which only 5% of these cases lead to hydrops ii. Mother (nearly always O+ with antibodies to A, B, or both) iii. Fetus (A, B, or AB) c. Other autoimmune causes (targeting other RBC antigens) i. Anti-Lewis antibodies: benign (“Lewis lives”) ii. Anti-Kell antibodies (the second most common type accounting for about 10% of antibody mediated severe fetal anemia): mild to severe hydrops (“Kell kills”) iii. Anti-Duffy antibodies: mild to severe hydrops (“Duffy dies”) 2. Pathophysiology of immune hydrops a. Sensitization of the mother to an antigen (usually Rh-D) i. Presence of antigen on fetal RBC but not on mother’s RBC ii. Primary response generally a maternal IgM antiRBC response b. Production of IgG antibodies by the mother on the secondary exposure. The IgG antibodies can cross the placenta 506
c. Destruction of fetal RBC by maternal anti-fetal RBC antibodies i. A Coombs’ positive process ii. Destruction most likely mediated by complement and macrophages iii. Jaundice frequently observed secondary to increased bilirubin production d. Compensatory increase in fetal cardiac output due to decreased fetal hematocrit e. Heart failure resulting from high cardiac output by the fetal heart i. Edema ii. Ascites iii. Circulatory failure with fetal death in utero 3. Conditions associated with nonimmune hydrops fetalis. Nonimmune type now represents majority of hydrops fetalis after the practice of anti-D gammaglobulin prophylaxis since 1960s a. Cardiovascular disorders (5.3–26%, the most frequent underlying cause of NIHF) i. Tachyarrhythmia (supraventricular tachycardia, atrial flutter) ii. Bradyarrhythmias (complete heart block) iii. Congenital heart block iv. Hypoplastic left heart syndrome (31%) v. Endocardial cushion defects (13%) vi. Agenesis of the ductus venosus vii. Other anatomic defects of the heart viii. Premature closure of the ductus arteriosus ix. Generalized arterial calcification x. Cardiomyopathy xi. Myocarditis (Coxsackie virus or CMV) xii. Cardiac rhabdomyoma xiii. Intracardiac teratoma b. Chromosome abnormalities (7.5–77.8%, the second most frequent underlying causes of NIH) i. Trisomies a) Trisomy 21 b) Trisomy 18 c) Trisomy 13 ii. Turner syndrome (most common chromosome anomaly) iii. Triploidies iv. Deletions v. Others c. Recognizable syndromes (2.2–27.6%) i. Skeletal dysplasias a) Thanatophoric dysplasia b) Arthrogryposis multiplex congenita c) Asphyxiating thoracic dystrophy d) Hypophosphatasia e) Osteogenesis imperfecta f) Achondrogenesis
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g) Saldino-Noonan syndrome h) McKusick-Kaufman syndrome i) Klippel-Trenaunay-Weber syndrome j) Conradi syndrome k) Other types of skeletal dysplasias ii. Metabolic diseases a) Mucopolysaccharidosis type IV Morquio disease (β-galactosidase deficiency) b) Mucopolysaccharidosis Type VII (β-glucuronidase deficiency) c) I-cell disease d) Niemann-Pick disease e) Gaucher disease f) Sialidosis g) Galactosialidosis h) Salla disease (Finnish type sialuria) i) Wolman disease j) Farber disease k) Carnitine deficiency iii. Other genetic syndromes a) Pena-Shokeir syndrome b) Neu-Laxova syndrome c) Recessive cystic hygroma d) Multiple pterygium syndrome e) Meckel syndrome f) Caudal regression syndrome g) Noonan syndrome h) Tuberous sclerosis i) Myotonic dystrophy j) X-linked dominant disorders with male lethality (e.g., hypomelanosis of Ito) k) Other single gene disorders d. Twin pregnancy (twin-twin transfusion syndrome) (3–8%) e. Hematologic disorders (10–27%) i. Intrinsic hemolysis a) α-thalassemia syndromes (Homozygous αthalassemia-1 is the most common cause of hydrops fetalis in South-East Asia) b) G6PD deficiency c) Pyruvate kinase deficiency d) Glucosephosphate isomerase deficiency e) Spectin abnormalities ii. Extrinsic hemolysis (Kasabach-Merritt syndrome) iii. Hemorrhage a) Fetomaternal hemorrhage b) Twin-twin transfusion syndrome c) Fetal hemorrhage iv. Fetal liver and bone marrow replacement syndromes a) Transient myeloproliferative disorder b) Congenital leukemia v. Red cell aplasia and dyserythropoiesis a) Parvovirus B19 infection b) Blackfan-Diamond syndrome c) Congenital dyserythropoiesis f. Thoracic abnormalities (2.5–13%) i. Diaphragmatic hernia ii. Congenital cystic adenomatous malformation of the lung
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iii. Extralobar pulmonary sequestration iv. Congenital hydrothorax or chylothorax v. Mediastinal teratoma vi. Laryngeal atresia vii. Pulmonary hypoplasia Genitourinary malformations (2.5–3.5%) i. Urethral obstruction ii. Posterior urethral valves iii. Neurogenic bladder with reflux iv. Ureterocele v. Prune-belly syndrome vi. Upper urinary tract obstruction vii. Renal dysplasia viii. Cloacal malformations Gastrointestinal anomalies . Jejunal atresia ii. Midgut volvulus iii. Malrotation of the intestine iv. Duplication of the intestinal tract v. Meconium peritonitis vi. Gastroschisis vii. Tracheoesophageal fistula Hepatic diseases i. Polycystic disease of the liver ii. Hepatic fibrosis iii. Cholestasis iv. Biliary atresia v. Hepatic vascular malformations vi. Familial cirrhosis Neurological abnormalities i. Encephalocele ii. Intracranial hemorrhage iii. Cerebral aneurysm iv. Intracranial arteriovenous malformation Maternal diseases/complications i. Medications (indomethacin taken to stop premature labor causing fetal ductus closure and secondary nonimmune hydrops fetalis) ii. Mirror syndrome a) Maternal edema b) Preeclampsia iii. Systemic diseases a) Severe diabetes mellitus b) Severe anemia c) Hypoproteinemia iv. Antepartum/postpartum hemorrhage v. Theca lutein cysts development Placenta-umbilical cord abnormalities i. Chorioangioma ii. Chorionic vein thrombosis iii. Fetomaternal transfusion iv. Placental and umbilical vein thrombosis v. Umbilical cord torsion vi. True cord knots vii. Angiomyxoma of the umbilical cord viii. Aneurysm of umbilical artery Intrauterine infections (2–17.5%) i. Viruses a) Parvovirus B19 b) CMV
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c) Rubella d) Adenovirus e) Enteroviruses f) Coxsackie virus g) Polio h) Influenza B i) Respiratory syncytial virus j) Congenital hepatitis k) Herpes simplex, type I ii. Bacteria/spirochetes a) Treponema pallidum b) Listeria monocytogenes c) Leptospira interogans iii. Parasites a) Toxoplasma gondii b) Trypanosoma cruzii iv. Other a) Chlamydia b) Ureaplasma urealyticum n. Miscellaneous conditions i. Congenital lymphedema ii. Congenital hydrothorax or chylothorax iii. Polysplenia syndrome iv. Amniotic band syndrome v. Congenital neuroblastoma vi. Tuberous sclerosis vii. Ovarian cyst torsion viii. Fetal trauma ix. Large fetal angioma x. Sacrococcygeal teratoma xi. Cloacal malformation o. Idiopathic (without an identifiable cause) 4. Pathophysiology of nonimmune fetal hydrops a. Cardiac failure directly involving the heart i. Arrhythmias ii. Malformations iii. Myocarditis iv. Infarction v. Cardiomyopathy b. Abnormal vascularization causing high output cardiac failure i. Twin-twin transfusion syndrome ii. Acardiac twinning iii. Tumors iv. A-V fistulas v. Placental vascular anomalies c. Profound anemia i. Hemolytic anemias ii. Parvovirus B19 (fifth disease) iii. Fetal-maternal hemorrhage iv. Alpha-thalassemia, hemoglobin Bart’s v. G6PD deficiency vi. Glucose phosphate isomerase deficiency vii. Pyruvate kinase deficiency viii. Defects of red cell membrane d. Decreased plasma oncotic pressure i. Congenital nephrosis ii. Hepatic necrosis e. Fetal infections i. Increased capillary permeability (anoxia due to congenital infection)
ii. Infection of erythroid progenitor cells (e.g., parvovirus B19) iii. Myocarditis (e.g., adenovirus, coxsackie virus) iv. Hepatic destruction (e.g., syphilis) f. Obstruction of venous return i. Congenital cystic adenomatoid malformation ii. Fetal closure or restriction in the size of the ductus arteriosus, foramen ovale or ductus venosus iii. Diaphragmatic hernia iv. Pulmonary sequestration v. Tumors of the heart, lungs, abdomen or pelvis vi. Umbilical cord lesions g. Obstruction of lymphatic flow (e.g., Turner syndrome)
CLINICAL FEATURES 1. Maternal history associated with hydropic infants a. Previous history of hydrops b. Severe maternal anemia c. Associated polyhydramnios in at least 50% of hydropic fetuses d. Size-date discrepancy e. Twin gestation f. Maternal diabetes mellitus g. Maternal pregnancy induced hypertension/ preeclampsia h. Fetal arrhythmia i. Placentomegaly j. Positive antibody screen k. Syphilis or other TORCH infections 2. Edema due to right sided heart failure a. Circulatory failure b. Ascites i. First sign of fetal hydrops caused by anemia ii. Hypertension iii. Hypoalbuminemia iv. Prune-belly secondary to marked fetal ascites c. Pleural effusions d. Pericardial effusions e. Jaundice (hyperbilirubinemia) 3. Hemolysis with extramedullary hematopoiesis 4. Hepatosplenomegaly a. A hallmark for immune hydrops b. Absent in nonimmune hydrops fetalis 5. Fetal prognosis: presence of fetal hydrops often indicating fetal compromise with a significant risk of mobility and death a. Cardiovascular disorders i. Best prognosis among abnormalities underlying nonimmune hydrops ii. Cumulative survival rate: 29% iii. Treatment of tachycardia improves prognosis b. Chromosome abnormalities: 2% survival rate c. Syndromes: 5% survival rate d. Fetal infections: 19% cumulative survival rate e. Thoracic lesions: one of the best cumulative prognosis, 26% f. Fetofetal transfusion syndrome: 20% survival rate g. Extremely poor prognosis i. Anemia secondary to parvovirus infection ii. Anemia resulting from fetomaternal hemorrhage
HYDROPS FETALIS
iii. α-thalassemia. All fetuses with the Hb Bart’s hydrops fetalis syndrome succumb to severe fetal hypoxia in utero during the third trimester of gestation or within hours after birth h. Good prognosis for psychomotor development in survivors with nonimmune hydrops fetalis 6. Morbidity a. Morbidity depending on the underlying disorder b. Short-term mobidity high (neonate requires difficult resuscitation, long and intensive hospitalization, multiple invasive procedures) c. Relatively low long-term mobidity 7. Mortality a. Mortality rate: 50–98% b. Contribute to 3% of perinatal mortality c. Mortality depending on the underlying disorder
DIAGNOSTIC INVESTIGATIONS 1. Diagnostic evaluation of immune hydrops a. ABO and Rh typing and a serum antibody screen (positive indirect Coombs’ test) for every pregnant woman as early as possible during each pregnancy b. Spectrophotometric estimation of bilirubin pigments in the amniotic fluid, obtained by amniocentesis in selected patients, to estimate the risk of severe hemolytic disease while the fetus is still in utero c. Direct Coombs’ test on cord blood i. Nearly always positive in Rh-induced hemolytic disease of newborns (HDN) ii. Frequently but not always positive in ABOinduced HDN d. Usually increased cord blood bilirubin and decreased cord blood hemoglobin in severe HDN 2. Diagnostic evaluation of newborn babies with nonimmune hydrops a. Cardiovascular disorders i. Echocardiogram ii. Electrocardiogram b. Thoracic abnormalities i. Chest radiographs ii. Pleural fluid examination c. Hematologic disorders i. Complete blood cell count ii. Differential iii. Platelet count iv. Blood type v. Coombs’ test vi. Blood smear for morphology vii. Hemoglobin electrophoresis d. Gastrointestinal abnormalities i. Abdominal radiographs ii. Abdominal ultrasound iii. Liver function tests iv. Peritoneal fluid examination v. Total protein vi. Albumin e. Renal malformations i. Urinalysis ii. BUN iii. Creatinine
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f. Genetics i. Chromosome analysis ii. Skeletal radiographs g. Congenital infections i. Parvovirus B19 a) Maternal infection: specific IgM and IgG b) Fetal/neonatal infection: specific IgM, virus detection by PCR ii. Syphilis a) Maternal infection: RPR or VDRL b) Fetal/neonatal infection: RPR or VDRL, darkfield examination of material from lesions iii. CMV a) Maternal infection: CMV-IgM or IgG seroconversion b) Fetal/neonatal infection: isolation of virus from amniotic fluid, fetal or neonatal body fluid iv. HSV a) Maternal infection: HSV culture of lesion b) Fetal/neonatal infection: HSV culture of amniotic fluid, fetal tissue, or neonate v. Toxoplasmosis a) Maternal infection: capture IgM, specific IgG b) Fetal/neonatal infection: capture IgM ELISA vi. Rubella a) Maternal infection: specific IgM and IgG or proven exposure plus compatible illness b) Fetal/neonatal infection: isolation of virus from fetal or neonatal body fluid, rubella IgM h. Autopsy indicated for stillbirth or perinatal death including examination of the placenta and babygram
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Immune hydrops fetalis: will be affected unless sensitization is prevented ii. Nonimmune hydrops fetalis a) Sporadic: no increased risk b) Autosomal recessive disorder: 25% c) Autosomal dominant disorder: not increased unless a parent is affected d) Chromosome disorder: increased especially when a parent is a translocation carrier b. Patient’s offspring i. Immune hydrops fetalis: recurrence risk not increased ii. Nonimmune hydrops fetalis a) Sporadic: no increased risk b) Autosomal recessive disorder: not increased unless the spouse is a carrier c) Autosomal dominant disorder: 50% d) Chromosome disorder: increased if the patient survives to reproductive age 2. Prenatal evaluation of immune hydrops fetalis a. Rh testing and ABO typing indicated for all pregnancies b. Positive maternal antibody screen (indirect Coombs’ test) c. Suspicious for immune hydrops
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i. Cord blood for testing of hemolysis and hematocrit ii. Amniocentesis for bilirubin d. Specific testing for antibodies in women with previous pregnancy losses e. Doppler ultrasonography i. Used to measure peak velocity of systolic blood flow in fetus ii. Increased peak systolic blood flow velocity in fetuses with anemia iii. Increased systolic velocity: 100% sensitive to fetal anemia f. Prenatal diagnosis of fetal RhD status by molecular analysis 3. Maternal evaluation of nonimmune hydrops fetalis a. Complete blood count and indices for hematological disorders b. Hemoglobin electrophoresis (α-thalassemia) c. Kleihauer-Betke stain for evidence of fetomaternal hemorrhage d. Maternal blood chemistry for fetal red cell enzyme deficiency i. Glucose-6-phosphate deficiency screen ii. Pyruvate kinase carrier status e. Infection screening i. Syphilis by VDRL ii. TORCH titers iii. Parvovirus titers iv. Group B streptococcus v. Listeria monocytogenes f. Autoantibody screen i. Systemic lupus erythematosus ii. Anti-Ro (anti-SS-A) and Anti-La (anti-SS-B) antibody titers for Sjorgren syndrome g. Fetal echocardiography for presence of congenital heart defects 4. Prenatal ultrasonography a. Immune hydrops secondary to α-thalassemia i. Hepatosplenomegaly (>95%) ii. Cardiomegaly (>95%) iii. Edematous placenta (>95%) iv. Ascites (>95%) v. Oligohydramnios (82%) vi. Subcutaneous edema (75%) vii. Decreased fetal movement (74%) viii. Cord edema (63%) ix. Enlarged umbilical vessel (62%) x. Pericardial/pleural effusion (15%) b. Nonimmune hydrops i. Fetal ascites ii. Fetal pleural effusion iii. Fetal pericardial effusion (the earliest finding) iv. Fetal skin thickening v. Maternal polyhydramnios vi. Placentomegaly, especially Rh disease or chorioangioma vii. Cystic hygroma as early as 13 weeks of gestation 5. Fetal evaluation of nonimmune hydrops fetalis a. Fetal echocardiography, M-mode, pulsed and color flow Doppler
i. Congenital heart defects ii. Fetal rhythmic abnormalities iii. Cardiac biometry b. Doppler flow velocity studies i. Umbilical artery ii. Middle cerebral artery iii. Tricuspid ejection velocity c. Amniocentesis i. Amniotic fluid index ii. Fetal karyotype (chromosome abnormality) iii. Amniotic fluid viral cultures iv. Alpha-fetoprotein (congenital nephrosis, sacrococcygeal teratomas) v. Isolation of CMV virus for identification of CMV DNA by PCR vi. Specific metabolic tests a) Tay-Sachs disease b) Gaucher disease c) GM1 gangliosidosis vii. Metabolic disease screening panel a) Acid sphingomyelinase deficiency b) Deficient cholesterol esterification c) Acid β-glucosidase deficiency d) Acid β-galactosidase deficiency e) Acid sialidase deficiency f) Sialidase deficiency g) β-galactosidase deficiency h) Ceramidase deficiency i) Glucose phosphate isomerase deficiency j) N-acetylglucosamine phosphotransferase deficiency viii. Restriction endonucleases tests (e.g., thalassemias) d. Fetal blood sampling i. Rapid karyotype (chromosome abnormality) ii. Fetal complete blood count (fetal anemia) iii. Blood group and Coombs test iv. Hemoglobin electrophoresis (α-thalassemia) v. Fetal plasma analysis for specific IgM (e.g., CMV-specific IgM antibody, PCR) vi. G6PD in male fetuses vii. Fetal plasma albumin (fetal hypoalbuminemia) viii. Metabolic testing a) Tay-Sachs disease b) Gaucher disease c) GM1 gangliosidosis e. Fluid aspirated for biochemistry and viral screen i. Pleural effusion ii. Ascites iii. Amniotic fluid f. Placenta i. Morphology ii. Thickness 6. Management a. Immune hydrops fetalis i. Prevent sensitization by Rhogam or Rh immune globulin ii. Prevent fetal heart failure when mother has sensitization reaction iii. Fetal transfusion for fetal anemia via cordocentesis
HYDROPS FETALIS
iv. Induction of labor v. Postpartum exchange blood transfusion to prevent kernicterus, the most feared complication of Rh-induced HDN b. Nonimmune hydrops fetalis i. Screen tests to detect couples at risk for having a fetus with the Hb Bart’s hydrops fetalis by simple blood counts and hemoglobin electrophoresis ii. Neonatal resuscitation iii. Intrauterine or immediate post-delivery transfusions to babies (e.g., homozygous α-thalassemia, Parvovirus B19 infection) iv. Fetal cardiac arrhythmias treated by transplacental antiarrhythmic therapy v. Flecainide acetate for fetal supraventricular tachycardia with hydrops fetalis vi. Continuous arteriovenous hemodilution for fluid overload in newborns with hydrops fetalis vii. Pleurocentesis in utero to drain pleural effusion to minimize pulmonary hypoplasia viii. Treatment of maternal infection a) Parvovirus B19: intrauterine transfusion b) Syphilis: IV penicillin c) CMV: No pharmaceutic regimens available for treatment of maternal and fetal CMV infections. Treatment with antiviral agents (ganciclovir, foscarnet) is limited to severe infections (CMV retinitis) in immunocomromised patients and not currently used in pregnancy. d) HSV: Acyclovir warranted in disseminated disease; fetal effect unknown e) Toxoplasmosis: Spiramycin and/or pyrimethamine, sulfadiazine, and folinic acid ix. Fetal surgery attempted for congenital cystic adenomatoid malformation, pulmonary sequestration, fetal pleural effusions, and sacrococcygeal teratoma
REFERENCES Arcasoy MO, Gallagher PG: Hematologic disorders and nonimmune hydrops fetalis. Semin Perinatol 19:502–515, 1995. Anandakumar C, Biswas A, Wong YC, et al.: Management of non-immune hydrops: 8 years’ experience. Ultrasound Obstet Gynecol 8:196–200, 1996. Barron SD, Pass RF: Infectious causes of hydrops fetalis. Semin Perinatol 19:493–501, 1995. Bukowski R, Saade GR: Hydrops fetalis. Clin Perinatol 27:1007–1031, 2000. Bullard KM, Harrison MR: Before the horse is out of the barn: fetal surgery for hydrops. Semin Perinatol 19:462–473, 1995. Carlton DP, McGillivray BC, Schreiber MD: Nonimmune hydrops fetalis: a multidisciplinary approach. Clin Perinatol 16:839–851, 1989. Chui DH, Waye JS: Hydrops fetalis caused by alpha-thalassemia: an emerging health care problem. Blood 91:2213–2222, 1998. Forouzan I: Hydrops fetalis: recent advances. Obstet Gynecol Surv 52:130–138, 1997. Haverkamp F, Noeker M, Gerresheim G, et al.: Good prognosis for psychomotor development in survivors with nonimmune hydrops fetalis. Br J Obstet Gynecol 107:282–284, 2000.
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Heinonen S, Ryynanen M, Kirkinen P: Etiology and outcome of second trimester non-immunologic fetal hydrops. Acta Obstet Gynecol Scand 79:15–18, 2000. Holzgreve W, Curry CJ, Golbus MS, et al.: Investigation of nonimmune hydrops fetalis. Am J Obstet Gynecol 150:805–812, 1984. Holzgreve W, Holzgreve B, Curry CJ: Nonimmune hydrops fetalis: Diagnosis and management. Semin Perinatol 9:52–67, 1985. Hutchinson AA, Drew JH, Yu VY, et al.: Nonimmune hydrops fetalis: A review of 61 cases. Obstet Gynecol 59:347–352, 1982. Iskaros J, Jauniaux E, Rodeck C: Outcome of nonimmune hydrops fetalis diagnosed during the first half of pregnancy. Obstet Gynecol 90:321–325, 1997. Iskarps K, Jauniaux E, Rodeck C: Outcome of nonimmune hydrops fetalis diagnosed during the first half of pregnancy. Obstet Gynecol 90:321–325, 1997. Ismail KM, Martin WL, Ghosh S, et al.: Etiology and outcome of hydrops fetalis. J Matern Fetal Med 10:175–181, 2001. Jauniaux E: Diagnosis and management of early nonimmune hydrops fetalis. Prenat Diagn 17:1261–1268, 1997. Jauniaux E, Van Maldergem L, De Munter C, et al.: Nonimmune hydrops fetalis associated with genetic abnormalities. Obstet Gynecol 75:568–572, 1990. Jones DC: Nonimmune fetal hydrops: diagnosis and obstetrical management. Semin Perinatol 19:447–461, 1995. Knilans TK: Cardiac abnormalities associated with hydrops fetalis. Semin Perinatol 19:483–492, 1995. Knisely AS: The pathologist and the hydropic placenta, fetus, or infant. Semin Perinatol 19:525–531, 1995. Lo YMD, Hjelm NM, Fidler C, et al.: Prenatal diagnosis of fetal RhD status by molecular analysis of maternal plasma. N Engl J Med 339:17341738, 1998. Machin GA: Hydrops revisited: Literature review of 1,414 cases published in the 1980s. Am J Med Genet 34:366–390, 1989. Mari G, et al.: N Engl J Med 342:9, 2000. McGillivray BC, Hall JG: Nonimmune hydrops fetalis. Pediatr Rev 9:197–202, 1987. McMahan MJ, Donovan EF: The delivery room resuscitation of the hydropic neonate. Semin Perinatol 19:474–482, 1995. Norton ME: Nonimmune hydrops fetalis. Sem Perinatol 18:321–332, 1994. Poeschmann RP, Verheijen RH, Van Dongen PW: Differential diagnosis and causes of nonimmunological hydrops fetalis: a review. Obstet Gynecol Surv 46:223–231, 1991. Rodriguez MM, Chaves F, Romaguera RL, et al.: Value of autopsy in nonimmune hydrops fetalis: series of 51 stillborn fetuses. Pediatr Dev Pathol 5:365–374, 2002. Salzman DH, Frigoletto FD Jr, Harlow BL, et al.: Sonographic evaluation of hydrops fetalis. Obstet Gynecol 74:106–111, 1989. Santolaya J, Alley D, Jaffe R, et al.: Antenatal classification of hydrops fetalis. Obstet Gynecol 79:256–259, 1992. Socol ML, MacGregor SN, Pielet BW, et al.: Percutaneous umbilical transfusion in severe rhesus isoimmunization: resolution of fetal Hydrops. Am J Obstet Gynecol 157:1369–1375, 1987. Sosa ME: Nonimmune hydrops fetalis. J Perinat Neonatal Nurs 13:33–44, 1999. Steiner RD: hydrops fetalis: role of the geneticist. Sem Perinatol 19:516–524, 1995. Stone DL, Sidransky E: Hydrops fetalis: lysosomal storage disorders in extremis. Adv Pediatr 46:409–440, 1999. Swain S, Cameron AD, McNay MB, et al.: Prenatal diagnosis and management of nonimmune hydrops fetalis. Aust N Z J Obstet Gynaecol 39:285–290, 1999. Tongsong T, Wanapirak C, Srisomboon J, et al.: Antenatal sonographic features of 100 alpha-thalassemia hydrops fetalis fetuses. J Clin Ultrasound 24:73–77, 1996. Van Maldergem L, Jauniaux E, Fourneau C, et al.: Genetic causes of hydrops fetalis. Pediatrics 89:81–86, 1992. Watson J, Camphell S: Antenatal evaluation and management of nonimmune hydrops fetalis. Obstet Gynecol 67:589–593, 1986.
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Fig. 1. An 18-week gestation fetus with hydropic change of the scalp and chest.
Fig. 2. A fetus showing hydropic change of the abdominal wall.
Fig. 3. A macerated fetus and an infant with nonimmune hydrops fetalis.
Hyper-IgE Syndrome Hyper-IgE syndrome is a rare, hereditary multisystem disorder characterized clinically by hyperimmuno-globulinemia E, recurrent infections, and eczematoid dermatitis. In 1966, Job reported two patients with eczematous dermatitis, recurrent staphylococcal boils, hyperextensible joints, and distinctive coarse facies. In 1972, Buckley et al. expanded the clinical picture by adding elevated immunoglobulin E (IgE).
GENETICS/BASIC DEFECTS 1. Inheritance: a. Autosomal dominant with variable penetrance and expressivity b. Linkage to a region on chromosome 4q demonstrated in several affected families c. An up-regulating mutation in the interleukin-4 receptor gene on chromosome 16, demonstrated in some patients with hyper IgE syndrome 2. Etiology a. The underlying cause of hyper IgE syndrome still unknown b. Reduced neutrophil chemotaxis c. Variable T cell defects demonstrated in some patients d. Cytokine and chemokine dysregulation
CLINICAL FEATURES 1. Classic triad (77%) a. Abscesses b. Pneumonia c. An elevated IgE 2. Skin manifestations a. Onset with distinctive neonatal rash i. Typically pruritic, secondary to intradermal mast cell histamine release triggered by the elevation of available IgE ii. Often lichenified iii. A distribution atypical for true atopic dermatitis b. Chronic eczema and dermatitis c. Skin infections i. Frequent presentation in infancy a) Furuncles b) Occasional “Cold” abscesses c) Cellulitis ii. Multiple staphylococcal abscesses on the skin (furunculosis) a) Most common around the face b) Tender and warm to touch iii. Cold abscesses a) A large fluctuant mass that feels like a tumor or cyst b) Neither hot or tender
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c) Not associated with systemic symptoms, fever or other signs of local or generalized inflammation d) Filled with pus that always grows Staphylococcus aureus e) Pathognomic to hyper IgE syndrome f) Not essential to the diagnosis d. Skin abscesses e. Candidiasis 3. Infections a. Pulmonary infections i. Recurrent and severe ii. Most common infecting organism: Staphylococcus aureus iii. Chronic infections a) Sinusitis b) Discharging otitis media c) Otitis externa d) Mastoiditis iv. Long-term complications a) Bronchiectasis b) Bronchopleural fistulae c) Pneumatocele secondary to staphylococcal pneumonia b. Mucocutaneous candidiasis and fungal infection i. Chronic candidiasis (83%) a) Mucosa sites (oral moniliasis) b) Nail fungal infection and dystrophy secondary to Candida albicans ii. Aspergillus infection iii. Cryptococcal infection c. Other serious infections i. Skin, sinopulmonary and bone infections: most common ii. Staphylococcus: the most frequently infecting organisms iii. Encapsulated organisms a) Haemophilus b) Streptococcus pneumoniae iv. Opportunistic infections: Pneumocystis carinii 4. Facial and dental abnormalities a. Characteristic coarse facies i. Frontal bossing ii. Wide alar base of the nose iii. Wide outer canthal distance iv. Rare craniosynostosis v. Midline facial defects vi. High arched palate b. Red hair: uncommon finding c. Retained primary teeth (72%): failure or delay of shedding of the primary teeth secondary to lack of root resorption
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5. Skeletal abnormalities a. Scoliosis (76%) b. Pathological fractures i. Secondary to minor trauma ii. Associated with osteopenia iii. Frequent recurrent fractures (57%) iv. Systemic infections at fracture sites a) Recurrent bacterial arthritis b) Staphylococcal osteomyelitis c. Generalized joint hyperextensibility (68%) i. Fingers ii. Wrists iii. Shoulders iv. Hips v. Knees vi. Genu valgum 6. Association with isolated reports of autoimmune disease a. Systemic lupus erythematosus b. Dermatomyositis c. Membranoproliferative glomerulonephritis 7. Malignant changes a. Hodgkin disease b. Lymphoma
DIAGNOSTIC INVESTIGATIONS 1. Routine laboratory workup a. Grossly elevated serum polyclonal IgE: at least 10 times normal (>2000 IU/mL) b. Accompanying eosinophilia 2. Radiographs and CT scan a. Pulmonary abnormalities i. Recurrent alveolar lung infections ii. Pneumatoceles iii. Occasional pneumothorax b. Skeletal abnormalities i. Full evaluations and monitor vigilantly for fractures after even minor trauma ii. Scoliosis 3. Skin biopsy a. An eosinophilic infiltrate similar to that seen in eosinophilic pustular folliculitis b. Spongiosis c. Perivascular dermatitis
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless one of the parents is affected, in which case there will be 50% risk of sibling affected b. Patient’s offspring: 50% 2. Prenatal diagnosis currently not available 3. Management a. Antibiotics prophylaxis b. Dermatitis i. Topical steroid ii. Topical antifungals iii. Emollient creams c. Prompt treatment of infection with prolonged intravenous antibiotics
d. Dental extraction of primary teeth e. Surgical intervention by incision and drainage of abscesses f. Chest tube drainage and lobectomy for complications of pneumonias g. Orthopedic cares for fractures and scoliosis h. Cimetidine, the histamine receptor-2 (H2) antagonist i. Shown to reverse the hyper-IgE syndrome neutrophil chemotactic defect in vitro ii. A single patient showed a clinical improvement on treatment with improved neutrophil chemotaxis in spite of a clinical relapse iii. Another seven patients treated with H2 antagonist with benefit i. Cromoglycate tried in a single patient with good clinical effect j. Isotretinoin used to improve dermatitis k. High dose intravenous γ-globulin for patients with aberrant humoral immunity l. Invasive approach with plasmapheresis with temporary improvement of skin condition and free of infections m. Bone marrow transplantation: only hope of cure at present n. A single report of a peripheral stem cell transplantation i. Serum IgE returned to normal ii. Disappearance of symptoms iii. Unfortunately, patient died of interstitial pneumonia
REFERENCES Buckley RH: The hyper-IgE syndrome. Clin Rev Allergy Immunol 20:139–154, 2001. Buckley RH, Wray BB, Belmaker EZ: Extreme hyperimmunoglobulin E and undue susceptibility to infection. Pediatrics 49:59–70, 1972. Chamlin SL, McCalmont TH, Cunningham BB, et al.: Cutaneous manifestations of hyper-IgE syndrome in infants and children. J Pediatr 141:572–575, 2002. Chehimi J, Elder M, Greene J, et al.: Cytokine and chemokine dysregulation in hyper-IgE syndrome. Clin Immunol 100:49–56, 2001. Dahl MV: Hyper-IgE syndrome revisited. Int J Dermatol 41:618–619, 2002. Dau PC: Remission of hyper-IgE treated with plasmapheresis and cytotoxic immunosuppression. J Clin Apheresis 4:8–12, 1988. Davis SD, Schaller J, Wedgwood RJ: Job’s syndrome: recurrent, “cold,” staphylococcal abscesses. Lancet 1:1013–1015, 1966. Donabedian H, Gallin JI: The hyperimmunoglobulin E recurrent – infection (Job’s) syndrome: a review of the NIH experience and the literature. Medicine 62:195–208, 1983. Erlewyn-Lajeunesse MDS: Hyperimmunoglobulin-E syndrome with recurrent infection: A review of current opinion and treatment. Pediatr Allergy Immunol 11:133–141, 2000. Gennery AR, Flood TJ, Abinun M, et al.: Bone marrow transplantation does not correct the hyper IgE syndrome. Bone Marrow Transplant 25:1303–1305, 2000. Grimbacher B, Holland SM, Gallin JI, et al.: Hyper-IgE syndrome with recurrent infections—an autosomal dominant multisystem disorder. N Engl J Med 340:692–702, 1999. Grimbacher B, Schaffer AA, Holland SM, et al.: Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet 65:735–744, 1999. Jhaveri KS, Sahani DV, Shetty PG, et al.: Hyperimmunoglobulinaemia E syndrome: Pulmonary imaging features. Austral Radiol 44:328–330, 2000. Khurana-Hershey GK, Friedrich MF, Esswein LA, et al.: The association of atopy with a gain of function mutation in the alpha subunit of the interleukin-4 receptor. N Engl J Med 337:1720–1725, 1997. Kikkawa Y, Kamimura K, Hamajima T, et al.: Thymic alymphoplasia with hyper-IgE-globulinemia. Pediatrics 51:690–696, 1973.
HYPER-IgE SYNDROME Kimata H: High-dose intravenous gamma-globulin treatment for hyperimmunoglobulin E syndrome. J Allergy Clin Immunol 95:771–774, 1995. Mawhinney H, Killen M, Fleming WA, et al.: The hyperimmunoglobulin E syndrome-a neutrophil chemotactic defect reversible by histamine H2 receptor blockade? Clin Immunol Immunopathol 17:483–491, 1980. Nester TA, Wagnon AH, Reilly WF, et al.: Effects of allogeneic peripheral stem cell transplantation in a patient with Job syndrome of hyperimmunoglobulinemia E and recurrent infections. Am J Med 105:162–164, 1998. Ochs HD, Kraemer MJ, Lindgren CG, et al.: Immune regulation in the hyperIgE/Job syndrome. Birth Defects Orig Artic Ser 19:57–61, 1983. Ohga S, Nomura A, Ihara K, et al.: Cytokine imbalance in hyper-IgE syndrome: reduced expression of transforming growth factor beta and interferon gamma genes in circulating activated T cells. Br J Haematol 121:324–331, 2003.
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Paganelli R, Quinti I, Carbonari M, et al.: IgG anti-IgE in circulating immune complexes in the hyper-IgE syndrome. Clin Allergy 16:513–521, 1986. Ring J, Landthaler M: Hyper-IgE syndromes. Curr Probl Dermatol 18:79–88, 1989. Shemer A, Weiss G, Confino Y, et al.: The hyper-IgE syndrome. Two cases and review of the literature. Int J Dermatol 40:622–628, 2001. Thompson RA, Kumararatne DS: Hyper-IgE syndrome and H2-recptor blockade. Lancet 2:630, 1989. Vercelli D, Jabara HH, Cunningham-Rundles C, et al.: Regulation of immunoglobulin (Ig)E synthesis in the hyper-IgE syndrome. J Clin Invest 85:1666–1671, 1990. Wakim M, Alazard M, Yajima A, et al.: High dose intravenous immunoglobulin in atopic dermatitis and hyper-IgE syndrome. Ann Allergy Asthma Immunol 81:153–158, 1998. Yokota S, Mitsuda T, Shimizu H, et al.: Cromoglycate treatment of a patient with Hyperimmunoglobulin E syndrome. Lancet 335:857–858, 1990.
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Fig. 1. A 3 year 9 month old patient with hyperimmunoglobulin E syndrome showing bowing of the legs. He had history of recurrent pneumonias, otitis media, asthma, and fractures of the leg bones. At 2 year 10 month of age, IgE was 15,610 (≤93 KU/L). He is currently on intravenous immunoglobulin therapy with antibiotic prophylaxis.
Hypochondroplasia Hypochondroplasia is a disproportionate short stature disorder resembling achondroplasia but with less severe phenotype.
a. General features: usually similar but miler to achondroplasia b. Limbs i. Disproportionately short compared with the length of the trunk ii. Shortening of the proximal (rhizomelia) or middle (mesomelia) segments of the extremities iii. Mild limitation of elbow extension iv. Broad and short hands and feet (brachydactyly) v. Absence of trident hand deformity vi. Bow legs (genu varum): usually mild vii. Adult onset osteoarthritis: less common c. Spine i. Scoliosis ii. Slight lumbar lordosis with a sacral tilt 5. Medical complication a. Following complications: less frequent compared to achondroplasia i. Spinal stenosis with neurologic complications ii. Tibial bowing iii. Obstructive apnea b. Deficits in mental capacity and/or function: may be more prevalent than achondroplasia
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant with full penetrance b. Sporadic in 90% of cases c. Observation of an increased paternal age effect at the time of conception, suggesting involvement of de novo mutations of paternal origin d. Presence of locus heterogeneity 2. Evidence supporting the view that hypochondroplasia and achondroplasia are allelic disorders a. A remarkable inter- and intra-familial variation in expression of hypochondroplasia with some cases resembling minor forms of achondroplasia b. Offspring of an achondroplastic parent and hypochondroplastic parent with severe neonatal achondroplasia resembling homozygous achondroplasia c. Similar histopathological aspects of the growth cartilage for the two disorders 3. Molecular defect a. About 70% of affected individuals who are heterozygous for a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, which is mapped on chromosome 4p16.3 b. FGFR3 mutations reported i. 1620C-A (Asn540Lys): 2/3rd of cases ii. 1620C-G (Asn540Lys): 1/3rd of cases iii. 1658A-C (Asn540Thr) and other FGFR3 mutations: rare 4. Hypochondroplasia–achondroplasia compound heterozygote a. Born to a hypochondroplastic parent and an achondroplastic parent b. The severity of the child: clinical and radiographic findings more severe than achondroplasia or hypochondroplasia alone c. Demonstration of both the hypochondroplasia (Asn540Lys) and achondroplasia (Gly380Arg) mutations at the FGFR3 locus in a patient with the genetic compound
DIAGNOSTIC INVESTIGATIONS
CLINICAL FEATURES 1. Short stature a. Evident by school age b. Adult height: 128–165 cm 2. Stocky build 3. Facial appearance a. Usually normal b. Mild macrocephaly may be present 4. Skeletal features 517
1. Radiography a. The most common features i. Short proximal (rhizomelic) and/or middle (mesomelic) segments of the long bones with mild metaphyseal flare, especially femora and tibiae ii. Caudal narrowing or unchanged lumbar interpedicular distance iii. Mild to moderate brachydactyly iv. Short and broad femoral neck v. Squared and shortened ilia b. The less common but significant features i. Elongation of the distal fibula ii. Anterior–posterior shortening of the lumbar vertebrae iii. Dorsal concavity of the lumbar vertebral bodies iv. Shortening of the distal ulna v. Long ulnar styloid in adults vi. Prominence of muscle insertions on the long bones vii. Shallow “chevron” deformity of distal femur metaphysis viii. Low articulation of sacrum on pelvis with a horizontal orientation ix. Flattened acetabular roof 2. Molecular genetic testing a. Mutation analysis i. 1620C-A (Asn540Lys) ii. 1620C-G (Asn540Lys) iii. Other FGFR3 mutations
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b. Sequence analysis of mutations in FGFR3 exons 10, 13, and 15
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: an extremely low risk (<0.01%) of having an affected sib if parents are not affected (germline mosaicism has not been reported for hypochondroplasia) b. Patient’s offspring i. 50% risk of having an affected offspring if the spouse is normal ii. If the spouse is an achondroplastic a) 25% chance of having an affected offspring with hypochondroplasia b) 25% chance of having an affected offspring with achondroplasia c) 25% chance of having an affected offspring with achondroplasia–hypochondroplasia genetic compound d) 25% chance of having a normal offspring iii. If the spouse also has hypochondroplasia or other dominant form of skeletal dysplasia: genetic counseling becoming more complicated due to the high incidence of genetic heterogeneity and the lack of medical literature addressing these circumstances 2. Prenatal diagnosis a. Prenatal diagnosis by amniocentesis or CVS for family with high-risk pregnancy with a parent who has hypochondroplasia i. When the spouse is normal: testing for diseasecausing FGFR3 mutation in the fetus ii. When the spouse is affected with another dominantly inherited skeletal dysplasia caused by a known gene mutation: testing for the known mutation for that skeletal dysplasia and the mutation for the hypochondroplasia in the fetus b. Prenatal diagnosis by ultrasonography, amniocentesis or CVS in low-risk pregnancy without family history of affected individual i. Ultrasonography: short limbs detected by routine ultrasound examination late in pregnancy ii. DNA-based diagnosis of FGFR3 mutations to confirm the diagnosis of hypochondroplasia 3. Management a. Follow closely developmental milestones and signs of learning disability or mental retardation b. Treatment of short stature i. Trials of growth hormone therapy with mixed results ii. Surgical limb lengthening for severe case of hypochondroplasia a) An invasive procedure b) Entails considerable disability and discomfort over a long period of time c) Prefer postponement of the procedure until adolescence when the patient can make an informed decision
REFERENCES Appan S, Laurent S, Chapman M, et al.: Growth and growth hormone therapy in hypochondroplasia. Acta Paediatr Scand 79:796–803, 1990. Beals RK: Hypochondroplasia. A report of five kindreds. J Bone Joint Surg Am 51:728–736, 1969. Bellus GA, McIntosh I, Smith EA, et al.: A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet 10:357–359, 1995. Bellus GA, McIntosh I, Szabo J, et al.: Hypochondroplasia: molecular analysis of the fibroblast growth factor receptor 3 gene. Ann N Y Acad Sci 785:182–187, 1996. Bellus GA, Kelly TE, Aylsworth AS: Hypochondroplasia. Gene Reviews, 2003. http://www.genetests.org Bonaventure J, Rousseau F, Legeai-Mallet L, et al.: Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism. Am J Med Genet 63:148–154, 1996. Chitayat D, Fernandez B, Gardner A, et al.: Compound heterozygosity for the Achondroplasia-hypochondroplasia FGFR3 mutations: prenatal diagnosis and postnatal outcome. Am J Med Genet 84:401–405, 1999. Cohen MM Jr: Achondroplasia, hypochondroplasia and thanatophoric dysplasia: clinically related skeletal dysplasias that are also related at the molecular level. Int J Oral Maxillofac Surg 27:451–455, 1998. Dorst JP: Hypochondroplasia. Birth Defects IV(5):260–276, 1969. Flynn MA, Pauli RM: Double heterozygosity in bone growth disorders: four new observations and review. Am J Med Genet 121A:193–208, 2003. Frydman M, Hertz M, Goodman RM: The genetic entity of hypochondroplasia. Clin Genet 5:223–229, 1974. Hall BD, Spranger J: Hypochondroplasia: clinical and radiological aspects in 39 cases. Radiology 133:95–100, 1979. Huggins MJ, Mernagh JR, Steele L, et al.: Prenatal sonographic diagnosis of hypochondroplasia in a high-risk fetus. Am J Med Genet 87:226–229, 1999. Huggins MJ, Smith JR, Chun K, et al.: Achondroplasia-hypochondroplasia complex in a newborn infant. Am J Med Genet 84:396–400, 1999. Kozlowski K: Hypochondroplasia. Progr Pediatr Radiol 4:238–249, 1973. Le Merrer M, Rousseau F, Legeai-Mallet L, et al.: A gene for achondroplasiahypochondroplasia maps to chromosome 4p. Nat Genet 6:318–321, 1994. Lemyre E, Azouz EM, Teebi AS, et al.: Bone dysplasia series. Achondroplasia, hypochondroplasia and thanatophoric dysplasia: review and update. Can Assoc Radiol J 50:185–197, 1999. McKusick VA, Kelly TE, Dorst JP: Observations suggesting allelism of the achondroplasia and hypochondroplasia genes. J Med Genet 10:11–16, 1973. Mortier G, Nuytinck L, Craen M, et al.: Clinical and radiographic features of a family with hypochondroplasia owing to a novel Asn540Ser mutation in the fibroblast growth factor receptor 3 gene. J Med Genet 37:220–224, 2000. Newman DE, Dunbar JC: Hypochondroplasia. J Can Assoc Radiol 26:95–103, 1975. Prinos P, Costa T, Sommer A, et al.: A common FGFR3 gene mutation in hypochondroplasia. Hum Mol Genet 4:2097–2101, 1995. Prinster C, Carrera P, Del Maschio M, et al.: Comparison of clinical-radiological and molecular findings in hypochondroplasia. Am J Med Genet 75: 109–112, 1998. Ramaswami U, Hindmarsh PC, Brook CG: Growth hormone therapy in hypochondroplasia. Acta Paediatr Suppl 88:116–117, 1999. Ramaswami U, Rumsby G, Hindmarsh PC, et al.: Genotype and phenotype in hypochondroplasia. J Pediatr 133:99–102, 1998. Rousseau F, Bonaventure J, Legeai-Mallet L, et al.: Clinical and genetic heterogeneity of hypochondroplasia. J Med Genet 33:749–752, 1996. Scott CI Jr: Achondroplastic and hypochondroplastic dwarfism. Clin Orthop Rel Res 114:18–30, 1976. Sommer A, Young-Wee T, Frye T: Achondroplasia-hypochondroplasia complex. Am J Med Genet 26:949–957, 1987. Tanaka N, Katsumata N, Horikawa R, et al.: The comparison of the effects of short-term growth hormone treatment in patients with achondroplasia and with hypochondroplasia. Endocr J 50:69–75, 2003. Wynne-Davies R, Patton MA: The frequency of mental retardation in hypochondroplasia [letter]. J Med Genet 28:644, 1991. Wynne-Davies R, Walsh WK, Gormley J: Achondroplasia and hypochondroplasia. Clinical variation and spinal stenosis. J Bone Joint Surg Br 63B:508–515, 1981.
HYPOCHONDROPLASIA
Fig. 1. A young child affected with hypochondroplasia showing mild short stature and mild rhizomelic shortening of the extremities.
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Fig. 2. Three families with familial hypochondroplasia showing stocky build, mild short stature, normal facial appearance, rhizomelic shortening of the extremities, and absence of trident hands.
Fig. 3. Radiographs of two patients with hypochondroplasia showing unchanged interpedicular distance and mild shortening of long bones.
Hypoglossia-Hypodactylia Syndrome Hypoglossia-hypodactylia syndrome is an extremely rare condition characterized by a small tongue associated with distal limb deficiency. The syndrome is also called aglossiaadactylia syndrome, which is a misnomer since the tongue is never completely absent and the term “adactylia” does not convey the variation in limb defects of affected individuals.
ii. Adactylia (congenital absence of the fingers and toes) iii. Peromelia (severe congenital malformation of the extremity, including absence of hand and foot) c. Syndactyly 3. Other associated anomalies a. Moebius syndrome b. Fused labia majora c. Unilateral renal agenesis d. Imperforate anus 4. Normal intelligence 5. Differential diagnosis with other oromandibular-limb hypogenesis syndromes a. Hanhart syndrome i. Micrognathia a) Microglossia b) Hypodontia ii. Limb anomalies a) Ranging from stunted digits, oligodactyly, to more severe Peromelia b) May affect any limb b. Glossopalatine and ankylosis syndrome i. Tongue a) Usually attached to the hard palate b) May adhere to the maxillary alveolar ridge c) Mildly cleft tongue tip ii. High-arched or cleft palate iii. Hypoplastic mandible iv. Hypodontia principally affects the incisor teeth v. Ankylosis of the temporomandibular joint vi. Facial paralysis vii. Extremely variable limb anomalies a) Oligodactyly b) Syndactyly c) Polydactyly d) Peromelia c. Limb deficiency-splenogonadal fusion syndrome i. Splenogonadal fusion a) A rare malformation in which the spleen is abnormally connected to the gonad, or, more rarely, to a derivative of the mesonephros b) May occur as a rare malformation ii. Association with other malformations, especially with terminal limb defects d. Mobius syndrome (please refer to the chapter of Mobius syndrome)
GENETICS/BASIC DEFECTS 1. Inheritance a. Sporadic in all reported cases b. Autosomal dominant inheritance cannot be ruled out. 2. Pathogenesis a. Impairments or insults to fetus during the early fetal life (4–7th week) may be responsible for the findings of tongue and limb abnormalities seen in hypoglossiahypodactylia syndrome because of the close chronological relationship between the development of the tongue and limbs. b. A hypoplastic mandible with concurrent hypoglossia could be explained by the fact that the mandible originates from the same visceral arch as the tongue. c. Vascular mechanism (either hemorrhage or vasocclusion) may be responsible for defects that are asymmetric and always distal.
CLINICAL FEATURES 1. Mouth a. Mandible i. Micro/retrognathia a) Minor feeding problems in infancy b) Minor speech impairment ii. Oligodontia iii. Absent mandibular incisors with concomitant hypoplasia of the associated alveolar ridge iv. Other features a) Mild lower lip defect b) Microstomia (markedly reduced mouth opening) c) Intraoral bands d) Oral frenula e) Oral syngnathia b. Tongue i. Varying degree of hypoglossia ii. Ankyloglossia iii. Marked enlargement of the sublingual muscular ridges iv. Hypertrophy of the sublingual and submandibular glands 2. Variable limb anomalies a. May involve any limb b. Distal reduction anomalies i. Oligodactyly (absence of some fingers and toes)
DIAGNOSTIC INVESTIGATIONS
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1. Radiography a. Fusion of the temporomandibular joints b. Micro/retrognathia c. Hypodontia d. Limb defects
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i. Variable distal limb deficiency ii. Asymmetric reduction deformities of the distal extremities iii. Severity ranging from hypoplastic digits to peromelia e. Other rare anomalies i. Dextrocardia ii. Transposition of abdominal organs iii. Jejunal atresia iv. Short bowel v. “Apple peel” bowel 2. Reconstructed 3D CT imaging of the craniofacial skeletal structures a. Retruded and reduced mandible b. Steep inclination of the anterior surface of the mandible in relation to the lower mandibular plane c. Defect of bony alveolar ridge at the midline area of the mandible 3. MRI of the tongue and the floor of the mouth a. Degree of the hypoglossia b. Space between the tongue and the inferior surface of the palate c. Hypertrophy of the floor of the mouth
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: not increased unless the condition represents an autosomal dominant inheritance, in which case there will be 50% risk of having an affected offspring 2. Prenatal diagnosis: not been reported 3. Management a. Early surgical intervention for presence of severe anomalies that are life threatening and interfere swallowing, breathing, and eating b. Extraction of the supernumerary tooth c. Orthodontic expansion appliance for widening the mandibular dental arch d. Distraction osteogenesis to improve the size and shape of the hypoplastic mandible e. Mandibular advancement
REFERENCES Alexander R, Friedman JS, Eichen MM, et al.: Oromandibular-limb hypogenesis syndrome: type II A, hypoglossia-hypodactylia—report of a case. Br J Oral Maxillofac Surg 30:404–406, 1992. Alvarez GE: The aglossia-adactylia syndrome. Br J Plast Surg 29:175–178, 1976.
Bersu ET, Pettersen JC, Charboneau WJ, et al.: Studies of malformation syndromes of man XXXXIA: anatomical studies in the Hanhart syndrome— a pathogenetic hypothesis. Eur J Pediatr 122:1–17, 1976. Bonneau D, Roume J, Gonzalez M, et al.: Splenogonadal fusion limb defect syndrome: report of five new cases and review. Am J Med Genet 86:347–358, 1999. Cohen MM Jr, Pantke H, Siris E: Nosologic and genetic considerations in the aglossy-adactyly syndrome. Birth Defects Orig Artic Ser VII(7):237–240, 1971. Coskunfirat OK, Velidedeoglu HV, Demir Z, et al.: An unusual case of hypoglossia-hypodactyly syndrome. Ann Plast Surg 42:333–336, 1999. David A, Roze JC, Remond S, et al.: Hypoglossia-hypodactylia syndrome with jejunal atresia in an infant of a diabetic mother. Am J Med Genet 43:882–884, 1992. Dellagrammaticas H, Tzaki M, Kapiki A, et al.: Hanhart syndrome: possibility of autosomal recessive inheritance. Prog Clin Biol Res 104:299–305, 1982. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck. 4th ed. Oxford University Press, 2001. Grippaudo FR, Kennedy DC: Oromandibular-limb hypogenesis syndromes: a case of aglossia with an intraoral band. Br J Plast Surg 51:480–483, 1998. Hall BD: Aglossia-adactylia. Birth Defects Orig Artic Ser VII(7):233–236, 1971. Harwin SM, Lorinsky LC: Picture of the month: Aglossia-adactylia syndrome. Am J Dis Child 119:255–256, 1970. Herrmann J, Pallister PD, Gilbert EF, et al.: Studies of malformation syndromes of man XXXXI B: nosologic studies in the Hanhart and the Mobius syndrome. Eur J Pediatr 122:19–55, 1976. Johnson GF, Robinow M: Aglossia-adactylia. Radiology 128:127–132, 1978. Kelln EE, Bennett CG, Klingberg WG: Aglossia-adactylia syndrome. Am J Dis Child 116:549–552, 1968. Lustmann J, Lurie R, Struthers P, et al.: The hypoglossia-hypodactylia syndrome. Report of 2 cases. Oral Surg Oral Med Oral Pathol 51:403–408, 1981. McPherson F, Frias JL, Spicer D, et al.: Splenogonadal fusion-limb defect “syndrome” and associated malformations. Am J Med Genet 120A: 518–522, 2003. Mishima K, Sugahara T, Mori Y, et al.: Case report: hypoglossia-hypodactylia syndrome. J Craniomaxillofac Surg 24:36–39, 1996. Nevin NC, Burrows D, Allen G, et al.: Aglossia-adactylia syndrome. J Med Genet 12:89–93, 1975. Nevin NC, Dodge JA, Kernohan DC: Aglossia-adactylia syndrome. Oral Surg Oral Med Oral Pathol 29:443–446, 1970. Pauli RM, Greenlaw A: Limb deficiency and splenogonadal fusion. Am J Med Genet 13:81–90, 1982. Robertson SP, Bankier A: Oromandibular limb hypogenesis complex (Hanhart syndrome): a severe adult phenotype. Am J Med Genet 83:427–429, 1999. Robinow M, Marsh JL, Edgerton MT, et al.: Discordance in monozygotic twins for aglossia-adactylia, and possible clues to the pathogenesis of the syndrome. Birth Defects Orig Artic Ser 14:223–230, 1978. Scott CI, Jr.: Aglossia-adactylia syndrome. Birth Defects Orig Artic Ser 7:281, 1971. Stallard MC, Saad MN: Aglossia-adactylia syndrome. Case reports. Plast Reconstr Surg 57:92–95, 1976. Steigner M, Stewart RE, Setoguchi Y: Combined limb deficiencies and cranial nerve dysfunction: Report of six cases. Tuncbilek E, Yalcin C, Atasu M: Aglossia-adactylia syndrome (special emphasis on the inheritance pattern). Clin Genet 11:421–423, 1977. Wada T, Inoue K, Fukuda T, et al.: Hypoglossia-hypodactylia syndrome: report of a case. J Osaka Univ Dent Sch 20:297–304, 1980. Yasuda Y, Kitai N, Fujii Y, et al.: Report of a patient with hypoglossia-hypodactylia syndrome and a review of the literature. Cleft Palate Craniofac J 40:196–202, 2003.
HYPOGLOSSIA-HYPODACTYLIA SYNDROME
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Fig. 1. A 2-month-old female infant with hypoglossia-hypodactylia syndrome showing antimongoloid slant of the palpebral fissures, facial palsy, micro/retrognathia, microstomia, hypoglossia, adactylia of the right hand and both feet, and oligodactyly of left hand.
Hypohidrotic Ectodermal Dysplasia Hypohidrotic ectodermal dysplasia (HED) is a common form of ectodermal dysplasia characterized by a defect in the hair, in the teeth, and in mucosal and sweat glands. It is also known as anhidrotic ectodermal dysplasia. The incidence is estimated to be 1 in 10,000 to 1 in 100,000 male live births.
GENETICS/BASIC DEFECTS 1. Inheritance: genetically heterogeneous a. X-linked recessive type: the most common form of over 170 different ectodermal dysplasias b. Autosomal dominant type: less common c. Autosomal recessive type: less common 2. X-linked HED a. Caused by mutations in the EDA1 gene which: i. Codes for the tumor necrosis factor family member ectodysplasin-A (EDA) ii. Maps to chromosome Xq12–q13.1 by X;autosome translocations of female EDA patients iii. Affects a transmembrane protein expressed by keratinocytes, hair follicles, and sweat glands iv. Possibly has a key role in epithelial-mesenchymal signaling b. Over 94% of patients with X-linked HED carry mutations in the EDA1 gene c. Tabby phenotype is caused by mutation in mouse homolog of the human EDA gene 3. Autosomal dominant form and some familial cases of autosomal recessive form of HED a. Caused by mutations on the human downless (DL) gene b. The DL gene is mapped to chromosome 2q11–q13
CLINICAL FEATURES 1. General features a. Variable clinical features b. Short stature c. Recurrent benign infectious disease seen in most patients with HED d. Unusually severe infections observed in: i. Anhidrotic ectodermal dysplasia with immunodeficiency: a distinct syndrome ii. Ectodermal dysplasia with cleft lip/palate iii. Ectrodactyly–ectodermal dysplasia-cleft lip/palate e. Otitis media f. Infantile fever of unknown etiology g. Hyperthermia h. Hoarse voice 2. Clinical features in X-linked recessive hypohidrotic ectodermal dysplasia a. Affected individuals 524
i. Hemizygous males: affected ii. Heterozygous female carriers: variable clinical symptoms (normal, or mild or partially affected) a) Dental abnormalities, such as hypodontia b) Mild hypohidrosis c) Mild hypotrichosis b. Clinical evidence of the distribution of normal and abnormal skin along Blaschko lines in heterozygous and postzygotic mutation carriers of X-linked hypohidrotic ectodermal dysplasia i. Presence of two different cell lines in a female heterozygous for the XHED due to random inactivation of one of the two X chromosomes during embryogenesis, reflected by the presence of different skin areas, some normal and some showing the result of the genetic abnormality ii. These abnormal areas, disposed along Blaschko lines, reflect the lines of embryonal development of the epidermis and epidermal derivatives iii. This clonal inactivation (“lyonization”) of the X chromosome results in variable degree of clinical expression of the disorder c. Clinically differentiating X-linked HED from autosomal forms of HED i. Finding heterozygous females with XHED ii. Finding parents with partial manifestations of the disorder due to a postzygotic mutation d. Clinical features i. Scalp hair a) Sparse b) Thin c) Light pigmented d) Slow growing e) Excessive fragility of the shafts, breaking easily with the usual wear and tear of childhood ii. Body hair a) Sparse b) Normal sexual hair (beard, pubic hair) iii. Sweating a) Greatly deficient sweating (hypohidrosis) b) Leading to hyperthermia iv. Teeth a) Congenital absence of teeth (hypodontia) b) Teeth that are present (smaller than average and have conical crowns) v. Facial features a) Frontal bossing b) A saddle-nose (depressed nasal bridge) c) Thick lips d) Periorbital hyperpigmentation vi. Other features
HYPOHIDROTIC ECTODERMAL DYSPLASIA
a) Normal growth and psychomotor development b) Atopic dermatitis c) Bronchial asthma d) Fever of unknown reason e) Sudden death during infancy and early childhood 3. Clinical features in autosomal recessive hypohidrotic ectodermal dysplasia a. Similar to (but indistinguishable from) the hemizygous form of X-linked hypohidrotic ectodermal dysplasia i. Decreased sweating ii. Hypodontia iii. Conical teeth iv. Hypotrichosis of the scalp v. Sparse or absent eyebrows and eyelashes vi. Sparse or absent body hair vii. Dry skin or eczema viii. Hypoplastic nails ix. Hypoplastic breasts x. Atrophic rhinitis xi. Depressed nasal bridge xii. Hyperpigmented and wrinkled periorbital skin b. Males and females equally affected 4. Clinical features in autosomal Dominant hypohidrotic ectodermal dysplasia: milder in expression a. Hypodontia, anodontia, microdontia, or other dental anomalies (100%) b. Sparse eyelashes (100%) c. Sparse eyebrows (96%) d. Sparse, fine, slow-growing hair (89%) e. Decreased sweating (85%) f. Thin skin (78%) g. Sparse body hair (62%) h. Decrease heat tolerance (50%) i. Onychodysplasia (39%)
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Hypodontia and adontia i. Essential to determine the extent of hypodontia and adontia ii. Useful in the diagnosis of mildly affected individuals b. Recurrent respiratory infections 2. Normal hair morphology under electron microscopy 3. Starch-iodine test to confirm a mosaic distribution of functional sweat glands in a heterozygous female carrier of X-linked HED 4. Molecular analysis a. Mutation in EDA1 gene for the X-linked form b. Mutation in human Downless (DL) gene for autosomal dominant and autosomal recessive forms
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ii. Autosomal dominant: not increased unless a parent is affected, in which case the risk to the sibs is 50% iii. Autosomal recessive: 25% of the sibs affected b. Patient’s offspring i. X-linked recessive a) Offspring of a male proband: none of the sons will be affected; 50% of the daughters will be carriers b) Offspring of a female proband: 50% of her son will be affected and 50% of her daughters will be carriers and may show minimal manifestations ii. Autosomal dominant: 50% risk to each child iii. Autosomal recessive: not increased unless the spouse is also a carrier, in which case the risk to offspring is 50% 2. Prenatal diagnosis a. Analysis of fetal skin obtained from fetoscopy-guided skin biopsy in the second trimester b. Three-dimensional ultrasonography to identify the distinct facial features during the third trimester c. Identification of the disease-causing mutation in the fetus 3. Management a. Environmental modification to control temperature i. Air condition for home, school, and work ii. Adequate supply of water during the hot weather b. Control body temperature i. Tepid sponging ii. Showers iii. Cold drink iv. Antipyretics v. Wet clothing c. Use moisturizers to prevent xerosis or eczema for dry skin d. Use artificial tears (eye drops) to prevent damage to the cornea in patients with defective tearing e. Remove nasal and aural concretions with suction devices or forceps and humidification of the ambient air to prevent their formation f. Treatment and prophylaxis for infections g. Dental evaluation and intervention i. Early dental treatment a) Simple restoration b) Dentures c) Orthodontics ii. Dental implants iii. Orthodontic treatment h. Wear wigs to improve appearance for patients with severe alopecia i. Avoid vigorous physical activities for patients with hypohidrosis j. Monitor growth
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. X-linked recessive: 50% of affected brothers if the mother is a carrier, otherwise the risk to sibs is low
REFERENCES Aswegan AL, Josephson KD, Mowbray R, et al.: Autosomal dominant hypohidrotic ectodermal dysplasia in a large family. Am J Med Genet 72:462–467, 1997.
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Baala L, Hadj Rabia S, Zlogotora J, et al.: Both recessive and autosomal dominant forms of anhidrotic/hypohidrotic ectodermal dysplasia map to chromosome 2q11–q13. Am J Hum Genet 64:651–653, 1999. Cambiaghi S, Restano L, Pääkkönen K, et al.: Clinical findings in mosaic carriers of hypohidrotic ectodermal dysplasia. Arch Dermatol 136:217–224, 2000. Clarke A: Hypohidrotic ectodermal dysplasia. J Med Genet 24:659–663, 1987. Clarke A, Burn J: Sweat testing to identify female carriers of X linked hypohidrotic ectodermal dysplasia. J Med Genet 28:330–333, 1991. Clarke A, Phillips DI, Brown R, et al.: Clinical aspects of X-linked hypohidrotic ectodermal dysplasia. Arch Dis Child 62:989–996, 1987. Crawford PJM, Alder JM, Clarke A: Clinical and radiographic dental findings in X linked hypohidrotic ectodermal dysplasia. J Med Genet 28:181–185, 1991. Dhanrajani PJ, Jiffry AO: Management of ectodermal dysplasia: a literature review. Dent Update 25:73–75, 1998. Doffinger R, Smahi A, Bessia C, et al.: X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-κB signaling. Nat Genet 27:277–285, 2001. Ho L, Williams MS, Spritz RA: A gene for autosomal dominant hypohidrotic ectodermal dysplasia (EDA3) maps to chromosome 2q11–q13. Am J Hum Genet 62:1102–1106, 1998. Jorgenson RJ: Hypohidrotic ectodermal dysplasia. 2003. http://www.genetests.org Monreal AW, Ferguson BM, Headon DJ, et al.: Mutations in the human homologue of the mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nature Genet 22:366–369, 1999. Monreal AW, Zonana J, Ferguson B: Identification of a new spice form of the EDA1 gene permits detection of nearly all X-linked hypohidrotic ectodermal dysplasia mutations. Am J Hum Genet 63:380–389, 1998.
Munoz F, Lestringant G, Sybert V, et al.: Definitive evidence for an autosomal recessive form of hypohidrotic ectodermal dysplasia clinically indistinguishable from the more common X-linked disorder. Am J Hum Genet 61:94–100, 1997. Passarge E et al.: Anhidrotic ectodermal dysplasia as autosomal recessive trait in an inbred kindred. Humangenetik 3:181–185, 1966. Pinheiro M, Freire-Maia N: Ectodermal dysplasia: a clinical classification and a causal review. Am J Med Genet 53:153–162, 1994. Priolo M, Silengo M, Lerone M, et al.: Ectodermal dysplasias: not only ‘skin’ deep. Clin Genet 58:415–430, 2000. Rossman RE, Johnson WP, Jr.: Anhidrotic ectodermal dysplasia; a surgical problem. JAMA 195:494–495, 1966. Sepulveda W, Sandoval R, Carstens E, et al.: Hypohidrotic ectodermal dysplasia: prenatal diagnosis by three-dimensional ultrasonography. J Ultrasound Med 22:731–735, 2003. Srivastava AK, Montonen O, Saarialho-Kere U, et al.: Fine mapping of the EDA gene: a translocation breakpoint is associated with a CpG island that is transcribed. Am J Hum Genet 58:126–132, 1996. Tanner BA: Psychological aspects of hypohidrotic ectodermal dysplasia. Birth Defects Orig Artic Ser 24:263–275, 1988. Zonana J et al.: Recognition and reanalysis of a cell line from a manifesting female with X linked hypohidrotic ectodermal dysplasia and an X;autosome balanced translocation. J Med Genet 25:383–386, 1988. Zonana J, Schinzel A, Upadhyaya M, et al.: Prenatal diagnosis of X-linked hypohidrotic ectodermal dysplasia by linkage analysis. Am J Med Genet 35:132–135, 1990.
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Fig. 1. Three boys (A,B,C,D) with X-linked hypohidrotic ectodermal dysplasia showing sparse scalp hair, frontal bossing, sparse eyebrows and eyelashes, saddle nose, hypodontia and irregularly shaped conical and pointed primary incisors.
Fig. 2. Two brothers with X-linked hypohydrotic ectodermal dysplasia showing sparse eyebrows, hypodontia, and conical permanent teeth.
Hypomelanosis of Ito In 1952, Ito reported a female patient with a widespread, symmetric pattern of depigmented whorls and streaks, naming it incontinentia pigmenti achromians, because the distribution of the depigmented lesions is the negative image of the hyperpigmented streaks of incontinentia pigment. Hypomelanosis of Ito (HI) is a relatively common disorder with a frequency of 1 in 8000–10,000 patients in a general pediatric hospital and 1 in 1000 patients in a pediatric neurology service.
GENETICS/BASIC DEFECTS 1. Inheritance a. Sporadic occurrence in nearly all cases with no affected sibs or parents i. Result of a de novo postzygotic mutation ii. Mutation can only survive in a mosaic state b. Only a few cases with possible genetic inheritance reported i. X-linked dominant inheritance ii. Autosomal dominant iii. Autosomal recessive 2. Pathogenesis a. Chromosome abnormalities (52%) i. Mosaicism leading to generation of two cell lineages producing patterns of hypopigmented and hyperpigmented skin ii. Balanced X/autosome translocations iii. Supernumerary X chromosome/ring fragment iv. Ring chromosomes (10, 14, 22) v. Mosaic triploidy vi. Mosaic trisomies (8, 13, 14, 18, 22) vii. Mosaic translocations viii. Mosaic deletions ix. Autosomal deletions and duplications involving chromosomes 7, 12, 13, 14, 15, and 18 b. X chromosome abnormalities i. Inactivation ii. Activation iii. Mosaicism 3. A descriptive term rather than a true syndrome a. Suggested by the pattern of chromosomal aberrations and the polymorphic nature of the disease b. A term used for a phenotype i. Presence of linear streaks lighter than the patient’s background skin color, extending around the trunk and down the long axes of the extremities, roughly following the lines of Blaschko ii. Association with systemic findings
CLINICAL FEATURES 1. Cutaneous symptoms a. Onset 528
i. Recognizable at birth (54%) ii. Visible during childhood (70%) b. No signs of inflammation or verrucous changes characteristically seen in incontinentia pigmenti c. Hypopigmented lesions i. Typical phenotype a) Cutaneous pattern: essentially the reverse of the third stage of incontinentia pigmenti b) Bilateral or unilateral whirls, patches, and streaks corresponding to the lines of Blaschko, often showing a midline cutoff c) Eruption not preceded by any inflammatory lesions (unlike incontinentia pigmenti) ii. Unilateral skin lesions contralateral to the side of brain malformation in patients with HI and hemimegalencephaly iii. Wood lamp useful in demonstrating hypopigmented lesions in persons with fair skin iv. Atypical phenotype: checkerboard pattern, zosteriform, dermatomal, or plaquelike arrangement d. Nonspecific skin lesions (20–40%) i. Café-au-lait spots ii. Persistent mongolian blue spots iii. Nevus of Ota iv. Nevus marmoratus and angiomatous nevi v. Soft fibroma vi. Pilomatrixoma vii. Aplasia cutis viii. Atopic dermatitis 2. Hair/nail/sweat gland anomalies a. Focal hypertrichosis b. Slow growth c. Diffuse alopecia d. Coarse, curly hair e. Trichorrhexis f. Widows peak g. Generalized hirsutism h. Facial hypertrichosis i. Low hairline j. Ungual hypoplasia k. Hypohidrosis corresponding to hypopigmented areas 3. Associated extracutaneous anomalies (75%) a. CNS anomalies i. Mental retardation (50–75%) ii. Seizures (50%) iii. Autistic behavior (11%) iv. Microcephaly v. Hypotonia vi. Hyperkinesia vii. Ataxia viii. Deafness ix. Hemimegalencephaly
HYPOMELANOSIS OF ITO
x. Brain tumors (medulloblastoma, choroid plexus papilloma) b. Ophthalmological abnormalities (20%) i. Microphthalmia ii. Ptosis iii. Nonclosure of the upper lid iv. Symblepharon v. Dacryostenosis vi. Strabismus vii. Nystagmus viii. Myopia ix. Hyperopia x. Astigmatism xi. Amblyopia xii. Megalocornea xiii. Corneal opacification xiv. Cataracts xv. Iridal heterochromia xvi. Scleral melanosis xvii. Heterochromia of the iris xviii. Optic atrophy xix. Striated patchy hypopigmented fundi xx. Retinal detachment c. Dental abnormalities i. Defective dental implantation ii. Conical teeth iii. Partial anodontia iv. Dental dysplasia/hypoplasia v. Defective enamel vi. Hamartomatous dental cusps d. Skeletal defects i. Short stature ii. Facial and limb asymmetry (hemihypertrophy) iii. Pectus carinatum or excavatum iv. Scoliosis v. Syndactyly vi. Polydactyly vii. Brachydactyly viii. Clinodactyly e. Congenital heart defect i. Tetralogy of Fallot ii. Pulmonary stenosis iii. Ventricular septal defect iv. Atrial septal defect v. Incomplete right bundle branch block vi. Cardiomegaly of unknown etiology f. Abdomen/gastrointestinal anomalies i. Diastasis recti ii. Hepatomegaly iii. Segmental dilation of the colon iv. Diaphragmatic, umbilical, and inguinal hernias g. Genitourinary anomalies i. Hypospadias ii. Micropenis iii. Single kidney iv. Urethral duplication v. Cryptorchidism vi. Precocious puberty vii. Gynecomastia viii. Asymmetrical breasts ix. Nephritis
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4. Diagnostic criteria (Ruiz-Maldonado et al., 1992) a. Sine qua non criterion: congenital or early acquired nonhereditary cutaneous hypopigmentation in linear streaks or patches involving more than two body segments b. Major criterion i. One or more nervous system anomalies ii. One or more musculoskeletal anomalies c. Minor criterion i. Two or more congenital malformations other than nervous system or musculoskeletal anomalies ii. Chromosomal anomalies d. Definitive diagnosis: sine qua non criterion plus one or more major criteria or two or more minor criteria e. Presumptive diagnosis: sine qua non criterion alone or in association with one minor criterion
DIAGNOSTIC INVESTIGATIONS 1. Cytogenetic investigation a. Peripheral blood karyotyping indicated especially when systemic manifestations are present b. Fibroblast karyotyping by sampling the dark and light skin for demonstrating mosaicism or chromosomal abnormalities c. Presence of a wide variety of karyotypic abnormalities 2. Histopathology a. Decreased numbers of melanocytes b. Decreased numbers and size of pigmented melanosomes c. Neuropathological features i. Polymicrogyria ii. Disarray of cortical lamination iii. Heterotopic neurons in the white matter iv. Giant cells 3. CT and MRI of the brain a. White matter abnormalities somewhat predictive of a poor neurological outcome b. Neuroblast migration i. Heterotopia ii. Pachygyria iii. Polymicrogyria c. Localized or generalized cerebral atrophy d. Cerebral hemiatrophy e. Hemimegalencephaly f. Other rare anomalies i. Noncommunicating hydrocephalus ii. Megacisterna magna iii. Arteriovenous malformation iv. Cerebellar hypoplasia (hemispheres and vermis) v. Brainstem hypoplasia vi. Brain tumors 4. Radiography for musculoskeletal anomalies 5. EEG for seizures
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent shows chromosomal abnormalities b. Patient’s offspring: i. Not increased unless the patient has chromosomal abnormalities
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HYPOMELANOSIS OF ITO
ii. Guarded counseling in women with a phenotype similar to HI who have nonmosaic balanced X; autosome translocations 2. Prenatal diagnosis: undetermined for affected mother who has a specific type of chromosome abnormality 3. Management a. Early intervention programs including physical, occupational, and speech therapies b. Special education c. Seizure control d. Surgical treatment of cataracts and retinal detachment
REFERENCES De Menezes MS: Hypomelanosis of Ito. EMedicine, 2002. http://www. emedicine.com Flannery DB: Pigmentary dysplasias, hypomelanosis of Ito, and genetic mosaicism. Am J Med Genet 35:18–21, 1990. Fryburg JS, Lin KY, Matsumoto J: Abnormal head MRI in a neurologically normal boy with hypomelanosis of Ito. Am J Med Genet 66:200–203, 1996. Glover MT, Brett EM, Atherton DJ: Hypomelanosis of Ito: spectrum of the disease. J Pediatr 115:75–80, 1989. Gordon N: Hypomelanosis of Ito (incontinentia pigmenti achromians). Dev Med Child Neurol 36:271–274, 1994. Happle R: Mosaicism in human skin: understanding the patterns and mechanisms. Arch Dermatol 129:1460–1470, 1993. Happle R: Pigmentary patterns associated with human mosaicism: a proposed classification. Eur J Dermatol 3:170–184, 1993. Harre J, Millikan LE: linear and whorled pigmentation. Int J Dermatol 33:529–537, 1994. Hatchwell E, Robinson D, Crolla JA, et al.: X inactivation analysis in a female with hypomelanosis of Ito associated with a balanced X;17 translocation: evidence for functional disomy of Xp. J Med Genet 33:216–220, 1996. Ishikawa T, Kanayama M, Sugiyama K, et al.: Hypomelanosis of Ito associated with benign tumors and chromosomal abnormalities: a neurocutaneous syndrome. Brain Dev 7:45–49, 1985. Ito M: A singular case of naevus depigmentosus systematicus bilateralis. Jpn J Dermatol 61:31–32, 1951. Koiffmann CP, de Souza DH, Diament A, et al.: Incontinentia pigmenti achromians (hypomelanosis of Ito, MIM 146150): Further evidence of Localization at Xp11. Am J Med Genet 46:529–533, 1993. Küster W, Konig A: Hypomelanosis of Ito: no entity, but a cutaneous sign of mosaicism. Am J Med Genet 85:346–350, 1999. Metzker A, Morag C, Weitz R: Segmental pigmentation disorder. Acta Derm Venereol (Stockh) 63:167–169, 1982. Moss C ,Burn J: Genetic counselling in hypomelanosis of Ito: case report and review. Clin Genet 34:109–115, 1988.
Nehal KS, PeBenito R, Orlow SJ: Analysis of 54 cases of hypopigmentation and hyperpigmentation along the lines of Blaschko. Arch Dermatol 132:1167–1170, 1996. Ohashi H, Tsukahara M, Murano I, et al.: Pigmentary dysplasias and chromosomal mosaicism: report of 9 cases. Am J Med Genet 43:716–721, 1992. Ono J, Harada K, Kodaka R, et al.: Regional cortical dysplasia associated with suspected hypomelanosis of Ito. Pediatr Neurol 17:252–254, 1997. Pascual-Castroviejo I, Lopez-Rodriguez L, de la Cruz Medina M, et al.: Hypomelanosis of Ito. Neurological complications in 34 cases. Can J Neurol Sci 15:124–129, 1988. Pascual-Castroviejo I, Roche C, Martinez-Bermejo A, et al.: Hypomelanosis of ITO. A study of 76 infantile cases. Brain Dev 20:36–43, 1998. Ritter CL, Steele MW, Wenger SL, et al.: Chromosome mosaicism in hypomelanosis of Ito. Am J Med Genet 35:14–17, 1990. Ross DL, Liwnicz BH, Chun RW, Gilbert E: Hypomelanosis of Ito (incontinentia pigmenti achromians)—a clinicopathologic study: macrocephaly and gray matter heterotopias. Neurology 32:1013–1016, 1982. Rott H-D, Lang GE, Huk LW, et al.: Hypomelanosis of Ito (incontinentia pigmenti achromians). Ophthalmological evidence for somatic mosaicism. Ophthalmic Paediatr Genet 11:273–279, 1990. Rubin MB: Incontinentia pigmenti achromians. Multiple cases within a family. Arch Dermatol 105:424–425, 1972. Ruggieri M, Tigano G, Mazzone D, et al.: Involvement of the white matter in hypomelanosis of Ito (incontinentia pigmenti achromians). Neurology 46:485–492, 1996. Ruggieri M: Familial hypomelanosis of Ito: implications for genetic counselling. Am J Med Genet 95:82–84, 2000. Ruggieri M, Pavone L: Hypomelanosis of Ito: clinical syndrome or just phenotype? J Child Neurol 15:635–644, 2000. Ruiz-Maldonado R, Toussaint S, Tamayo L, et al.: Hypomelanosis of Ito: diagnostic criteria and report of 41 cases. Pediatr Dermatol 9:1–10, 1992. Steiner J, Adamsbaum C, Desguerres I, et al.: Hypomelanosis of Ito and brain abnormalities: MRI findings and literature review. Pediatr Radiol 26:763–768, 1996. Sybert VP, Pagon RA, Donlan M, Bradley CM: Pigmentary abnormalities and mosaicism for chromosomal aberration: association with clinical features similar to hypomelanosis of Ito. J Pediatr 116:581–586, 1990. Sybert VP, Pagon RA: Hypomelanosis of Ito in a girl with plexus papilloma and translocation (X;17) [letter]. Hum Genet 93:227, 1994. Sybert VP: Hypomelanosis of Ito: a description, not a diagnosis. J Invest Dermatol 103(5 Suppl):141S–143S, 1994. Tagawa T, Futagi Y, Arai H: Hypomelanosis of Ito associated with hemimegalencephaly: a clinicopathological study. Pediatr Neurol 17:180–184, 1997. Urgelles E, Pascual-Castroviejo I, Roche C, et al.: Arteriovenous malformation in hypomelanosis of Ito. Brain Dev 18:78–80, 1996. Weaver RG Jr, Martin T, Zanolli MD: The ocular changes of incontinentia pigmenti achromians (hypomelanosis of Ito). J Pediatr Ophthalmol Strabismus 28:160–163, 1991. Zajac V, Kirchhoff T, Levy ER, et al.: Characterisation of X;17(q12;p13) translocation breakpoints in a female patient with hypomelanosis of Ito and choroid plexus papilloma. Eur J Hum Genet 5:61–8, 1997.
HYPOMELANOSIS OF ITO
Fig. 1. Two children with hypomelanosis of Ito showing hypopigmented skin lesions in a characteristic distribution of whirls and streaks on the trunk and limbs. The first patient has 49,XXXXY.
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Hypophosphatasia Hypophosphatasia is a heritable metabolic disease, characterized by impaired ossification of the bones, reduction in tissue and plasma levels of alkaline phosphatase, and the presence of phosphoethanolamine in the urine. The incidence is estimated to be about 1 in 100,000 live births. The incidence of severe disease is especially high in Canadian Mennonites (1 in 2500 newborns).
different amnio acid substitutions in the alkaline phosphatase protein ii. Individuals with dominant hypophosphatasia with only one defective TNSALP allele: usually manifest moderate symptoms, such as the premature exfoliation of fully rooted primary teeth iii. Division between dominant and recessive hypophosphatasia sometimes is not well defined because the heterozygous siblings with one defective TNSALP allele in kindreds with recessive hypophosphatasia may show mild or moderate symptoms of the disease b. Missense mutations in the TNSALP gene have been observed in some hypophosphatasia kindreds, particularly those families with the more severe perinatal and infantile forms of the disease c. Autosomal recessive inheritance has been observed in most cases of hypophosphatasia with affected individuals being compound heterozygotes for two different mutant hypophosphatasia alleles d. Autosomal dominant alleles causes a few relatively mild cases of hypophosphatasia
GENETICS/BASIC DEFECTS 1. Genetic heterogeneity a. Perinatal lethal hypophosphatasia form: autosomal recessive b. Infantile hypophosphatasia form: autosomal recessive c. Childhood hypophosphatasia form: autosomal recessive and dominant d. Adult hypophospatasia form: autosomal recessive and dominant with variable penetrance e. Odontohypophosphatasia form: autosomal recessive and dominant 2. Cause a. Caused by mutations in the gene (ALPL) which: i. Codes for tissue nonspecific (‘liver/bone/kidney’) alkaline phosphatase (TNSALP) ii. Is mapped on chromosome 1p36.1–p34 b. Typically, the other isoenzymes (placental and intestinal forms) are not affected 3. Pathophysiology a. Defects in mineralization i. Caused by deficiency in TNSALP ii. Resulting in increased urinary excretion of phosphoethanolamine and inorganic pyrophosphate and an increase in serum pyridoxal 5′-phosphate b. Osteoclasts, although morphologically normal, lack membrane-associated alkaline phosphatase activity on histochemical analysis i. Impede the proper incorporation of calcium into newly formed bone matrix ii. Result in bone demineralization and hypercalcemia when the impaired matrix calcification process occurs with a rapid rate of bone resorption 4. Genotype–phenotype correlations a. A number of different mutations account for the clinical heterogeneity i. Individuals with recessive hypophosphatasia with both defective TNSALP alleles a) In general, manifest more severe symptoms, with many of those affected being stillborn or expiring shortly after birth b) Exception when consanguineous marriage is a factor: the two defective alleles tend to have distinct point mutations resulting in
CLINICAL FEATURES
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1. Presence of a wide phenotypic variability ranging from intrauterine death and extreme hypomineralization of the skeleton to lifelong absence of clinical symptoms a. The following four different forms of the hypophosphatasia have been defined: i. Perinatal lethal form ii. Infantile form iii. Childhood form iv. Adult form b. In general, the earlier the age of presentation the more severe the presenting features 2. Perinatal lethal form a. Often stillborn b. Skeletal deformities: presenting features i. A profound lack of skeletal mineralization ii. Skin-covered spurs extending from the forearms or legs (skin dimples) iii. Markedly shortening and bowing of the long bones (short limbed dwarfism) iv. Fractures (perinatal) v. Rickety rosary vi. Metaphyseal swelling vii. Soft, pliable cranial bones (‘Vault like a balloon’) viii. Bulging anterior fontanelle c. Respiratory distress due to hypoplastic lungs and rachitic deformities of the chest
HYPOPHOSPHATASIA
d. Other features i. Hypotonia ii. High-pitched cry iii. Vomiting iv. Constipation v. Unexplained fever vi. Apnea vii. Cyanosis viii. Irritability ix. Seizures e. Prognosis: lethal in utero or within a few days of birth 3. Infantile form a. Appears normal at birth b. Onset of symptoms i. Before 6 months of age ii. Poor feeding iii. Failure to thrive (growth failure) iv. Hypotonia v. Convulsions c. Associated with progressive bony demineralization i. Abnormal skull with apparent wide separation of the cranial sutures and a wide, bulging anterior fontanelle ii. Tendency toward developing craniosynostosis a) Formation of a sagittal ridge b) A bony prominence at the position of the anterior fontanelle iii. Rachitic skeletal deformities manifesting by age 6 months iv. Flail chest v. Pulmonary insufficiency d. Late in walking e. Development of genu valgum f. Short stature g. Complications i. Recurrent pneumonia ii. Increased intracranial pressure iii. Renal compromise secondary to: a) Hypercalcemia b) Hypercalcinuria c) Nephrocalcinosis h. Prognosis: i. Fatal in approximately 50% of cases by the age of one year ii. Survivors a) Tend to improve symptomatically b) Deformities persist and often become worse 4. Childhood form a. Appears normal at birth b. Often present after 6 months of age c. History of delayed walking and waddling gait d. Early loss of deciduous teeth (before age 5 years): the most consistent clinical sign e. Frequent bone pain f. Defective bone mineralization presenting clinically as rickets in children g. Respiratory complications due to rachitic deformities of the chest
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h. Premature craniosynostosis despite open fontanelle resulting in increased intracranial pressure i. Dolichocephalic skull j. Enlarged joints k. Short stature l. Bone fractures m. Presence of hypercalcemia causes increased excretion of calcium resulting in renal damage n. Prognosis: improving both clinically and radiographically with age in some childhood hypophosphatasia patients 5. Adult form a. Variable age of onset and severity b. Onset usually during middle age c. Defective bone mineralization presents clinically as osteomalacia in adults d. Premature loss of deciduous teeth e. Usually presents clinically with loss of adult teeth f. Multiple fractures secondary to osteomalacia, often after minimal fractures g. Foot pain due to stress fractures of the metatarsals h. Thigh pain due to pseudofractures of the femur i. Delay in healing after a fracture j. Joint pain due to deposition of calcium pyrophosphate dihyrate
DIAGNOSTIC INVESTIGATIONS 1. Laboratory tests a. Low serum alkaline phosphatase levels in all types of hypophosphatasia b. Increased levels of urinary phosphoethanolamine levels c. Elevated plasma levels of pyridoxal 5′-phosphate d. Normal serum calcium, except in infantile cases where hypercalcemia can be seen due to renal failure e. Normal serum phosphate: hyperphosphatemia in various forms of hypophosphatasia reported 2. Skeletal survey a. Lethal perinatal form i. Near absence of skeletal mineralization ii. Skull: tiny ossification of occipital and/or frontal bones or complete absence of ossification iii. Teeth: very poorly formed iv. Spine a) Some vertebrae frequently unossified b) Occasionally unossified vertebrae c) Abnormally shaped vertebrae: rectangular, round, flattened, sagitally cleft, or butterfly shaped vertebrae v. Shortening and bowing of the long and tubular bones vi. Diaphyseal spurs vii. Skin-covered spurs extending from the medial and lateral aspects of the knee and elbow joints viii. Fractures ix. Rachitic changes a) Pathology most evident at metaphyses as in rickets where growth is most rapid, namely the wrists, knees, hips, and proximal humeri
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b) Defective, irregular ossification of the metaphysis: the most diagnostic feature of the disease c) Nearly absent provisional zone of calcification d) Irregular widening of the epiphyseal plate e) Grossly irregular ossification of metaphysis giving a ‘frayed’ or ‘tufted’ appearance: a distinguished feature in hypophosphatasia. In rickets, the decalcification is usually regular and may give a ‘ground glass’ effect to the affected metaphysis (metaphyseal cupping) b. Infantile form i. Deficient skeletal mineralization ii. Congenital bowing of the long bones iii. Bands of decreased density in metaphyses iv. Widened cranial sutures v. Later craniosynostosis: Premature craniosynostosis occurs despite an open fontanelle vi. Asymmetrical, moderate to severe rickets-like metaphyseal changes vii. Metaphyseal and epiphyseal ossification defects viii. Distorted bone trabeculation with areas of decreased and increased transradiancy ix. Thin cortical bone x. Diaphyseal spurs c. Childhood form i. Mild, asymmetrical, metaphyseal changes resembling rickets or metaphyseal dysplasia ii. Distorted bone trabeculation with areas of decreased and increased transradiancy iii. Thin cortical bone iv. Hypotubulation and bowing of long bones v. Stress fractures vi. Radiolucent projections from the epiphyseal plate into the metaphysis d. Adult form i. Pseudofractures often occur in the lateral aspect of the proximal femur: a hallmark of this form ii. Osteomalacia iii. An increased incidence of poorly healing stress fractures, especially of the metatarsals e. Odontohypophosphatasic form: normal radiographic findings 3. Radiography and ultrasound screening for nephrocalcinosis 4. Histology a. Growth plates i. Rachitic abnormalities ii. Poorly mineralized and ossified columns with broad osteoid seams in metaphysis iii. Osteoblasts lacking membrane associated alkaline phosphatase activity on histochemical testing, disrupting incorporation of calcium into the matrix b. Teeth i. A decrease in cementum ii. Enlarged pulp chamber iii. Incisors tend to be affected
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib
i. Autosomal recessive: 25% ii. Autosomal dominant: not increased unless a parent is affected in which case the recurrence risk is 50% b. Patient’s offspring i. Autosomal recessive: not increased unless a spouse is a carrier in which case the recurrence risk is 50% ii. Autosomal dominant: 50% 2. Prenatal diagnosis a. Fetal radiography b. Prenatal ultrasonography i. Failure to visualize a well-defined skull ii. Other fetal skeletal structures not readily discernable c. Assay of the alkaline phosphatase activity: a useful complementary and independent method, especially when a mutation is unidentified and DNA from the index case is unavailable i. Assay of the tissue nonspecific alkaline phosphatase activity in chorionic villus samples in the first trimester ii. Absent alkaline phosphatase activity in the amniotic fluid and cultured amniotic fluid cells in the second trimester d. Mutation analysis of fetal DNA from amniocentesis or CVS where the disease-causing mutation has been identified in the family 3. Management a. No specific treatment available: Efforts to effect improved mineralization in patients with hypophosphatasia has not been successful i. Nonsteroidal anti-inflammatory drugs for control of the bone pain ii. Large dose of Vitamin D: reversal of improvement in the bony architecture upon withdrawal of the drug iii. Oral cortisone: reversal of improvement in serum alkaline phosphatase level and radiographic appearance of the bones upon withdrawing of the drug iv. Avoid saline solution, fluosemide diuresis, steroid therapy, or a low calcium diet because these approaches may actually worsen bone mineralization and nephrocalcinosis v. Inhibition of osteoclastic activity with calcitonin: continued demineralization despite returning of normal serum calcium concentration vi. Plasma infusions designed to supplement alkaline phosphatase activity or induce alkaline phosphatase production: not consistently improve bone mineralization b. A clinical trial of marrow cell transplantation for infantile hypophosphatasia i. A significant, prolonged clinical and radiographic improvement followed soon after receiving a boost of donor marrow cells ii. Biochemical features of hypophosphatasia, however, remain unchanged to date iii. The most plausible hypothesis for the patient’s survival and progress: Transient and long-term
HYPOPHOSPHATASIA
engraftment of sufficient numbers of donor marrow mesenchymal cells form functional osteoblasts and perhaps chondrocytes, to ameliorate the skeletal disease c. Surgical care i. Rachitic deformities ii. Gait abnormalities iii. Adult form a) Rod placement for pseudofractures of the adult type results in the union and relief of the pain b) Primary bone grafting and plating for midshaft fractures c) Anticipate delayed union of fractures
REFERENCES Anadiotis GA: Hypophosphatasia. 2002. http://www.emedicine.com Anderton JM: Orthopaedic problems in adult hypophosphatasia: a report of two cases. J Bone Joint Surg Br 61:82–84, 1979. Barcia JP, Strife CF, Langman CB: Infantile hypophosphatasia: treatment options to control hypercalcemia, hypercalciuria, and chronic bone demineralization. J Pediatr 130:825–828, 1997. Brock DJ, Barron L: First-trimester prenatal diagnosis of hypophosphatasia: experience with 16 cases. Prenat Diagn 11:387–391, 1991. Fallon MD, Teitelbaum SL, Weinstein RS, et al.: Hypophosphatasia: clinicopathologic comparison of the infantile, childhood, and adult forms. Medicine (Baltimore) 63:12–24, 1984. Fraser D: Hypophosphatasia. Am J Med 22:730–746, 1957. Gehring B, Mornet E, Plath H, et al.: Perinatal hypophosphatasia: diagnosis and detection of heterozygote carriers within the family. Clin Genet 56:313–317, 1999.
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Henthorn PS, Whyte MP: Missense mutations of the tissue-nonspecific alkaline phosphatase gene in hypophosphatasia. Clin Chem 38:2501–2505, 1992. Hu JC, Plaetke R, Mornet E, et al.: Characterization of a family with dominant hypophosphatasia. Eur J Oral Sci 108:189–194, 2000. James W, Moule B: Hypophosphatasia. Clin Radiol 17:368–376, 1966. Kozlowski K, Sutcliffe J, Barylak A, et al.: Hypophosphatasia. Review of 24 cases. Pediatr Radiol 5:103–117, 1976. Leroy JG, Vanneuville FJ, De Schepper AM, et al.: Prenatal diagnosis of congenital hypophosphatasia: challenge met most adequately by fetal radiography. Prog Clin Biol Res 104:525–539, 1982. Maxwell DJ, Blau K, Johnson RD, et al.: Activities of alkaline phosphatase in first trimester chorion biopsy tissue. Prenat Diagn 5:283–286, 1985. Mornet E, Muller F, Ngo S, et al.: Correlation of alkaline phosphatase (ALP) determination and analysis of the tissue non-specific ALP gene in prenatal diagnosis of severe hypophosphatasia. Prenat Diagn 19:755–757, 1999. Mulivor RA, Mennuti M, Zackai EH, et al.: Prenatal diagnosis of hypophosphatasia; genetic, biochemical, and clinical studies. Am J Hum Genet 30: 271–282, 1978. Rathbun JC: “Hypophosphatasia”, a new developmental anomaly. Am J Dis Child 75:822–831, 1948. Shohat M, Rimoin DL, Gruber HE, et al.: Perinatal lethal hypophosphatasia; clinical, radiologic and morphologic findings. Pediatr Radiol 21: 421–427, 1991. Tongsong T, Pongsatha S: Early prenatal sonographic diagnosis of congenital hypophosphatasia. Ultrasound Obstet Gynecol 15:252–255, 2000. Wendling D, Jeannin-Louys L, Kremer P, et al.: Adult hypophosphatasia. Current aspects. Joint Bone Spine 68:120–124, 2001. Whyte MP: Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocr Rev 15:439–461, 1994. Whyte MP, McAlister WH, Patton LS, et al.: Enzyme replacement therapy for infantile hypophosphatasia attempted by intravenous infusions of alkaline phosphatase-rich Paget plasma: results in three additional patients. J Pediatr 105:926–933, 1984. Whyte MP, Kurtzberg J, McAlister WH, et al.: Marrow cell transplantation for infantile hypophosphatasia. J Bone Miner Res 18:624–636, 2003.
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Fig. 2. Radiograph of another neonate with hypophosphatasia shows rickets-like metaphyseal cupping and poor mineralization of cranial bones.
Fig. 1. A neonate with perinatal lethal form of hypophosphatasia showing severe shortening of limbs. Radiograph shows markedly deficient ossification and abnormal bone development similar to achondrogenesis type I.
Fig. 3. Photomicrograph of a rib. Broad columns of hypertrophic chondrocytes with osteoid seams are present in the metaphysis. These columns are poorly mineralized and ossified.
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Fig. 4. Radiographs of another neonate with perinatal lethal form of hypophosphatasia showing marked deficient skeletal mineralization, prenatal fracture of the left femur, and abnormal metaphyseal ossification of the proximal femurs.
Fig. 5. Childhood hypophosphatasia in two brothers showing short stature and bowed legs.
Incontinentia Pigmenti Bloch and Sulzberger, in 1926 and 1928 respectively, were credited for the first description of the clinical syndrome of incontinentia pigmenti (IP), known as Bloch-Sulzberger syndrome. It is a rare genodermatoses occurring in approximately 1 in 50,000 newborns. 5.
GENETICS/BASIC DEFECTS 1. Inheritance a. X-linked dominant transmission, usually prenatally lethal in males, suggested by pedigree analyses b. A high affected female/affected male ratio c. Instances of female-to-female transmission d. 1:1:1 affected female:normal female:normal male ratio in the offspring of an affected mother e. Increased incidence of miscarriages in patients with incontinentia pigmenti, presumably representing affected male conceptuses that typically fail to survive past the second trimester 2. Female patients with IP mutations a. Dizygosity for the X chromosome b. Skewed X-inactivation i. Cells expressing the mutant X chromosome are eliminated selectively around the time of birth, so that females with IP exhibit extremely skewed X-inactivation, based on the Lyon hypothesis (random inactivation of one X chromosome in each cell of the female at an early developmental stage, resulting in an X-chromosomal mosaic for each female with one X functioning in some of the cells and the other X functioning in the rest of the cells) ii. Female heterozygous for an X-linked incontinentia pigmenti gene: the pigmented areas on the skin represent cell populations in which the abnormal gene is active and the areas of normal skin tissue in which the normal gene is active iii. Highly variable phenotype explainable by the chance variability in the number and position of the cells carrying the active incontinentia pigmenti gene 3. The gene for IP: linked genetically to the factor VIII gene in Xq28 4. Expression of the disease IP: caused by mutations in the NEMO (NF-κB essential modulator)/IKKγ (IκB kinase-γ) gene located at Xq28 a. NEMO/IKKγ: an essential component of the newly discovered nuclear factor κB (NF-κB) signaling pathway. When activated, NF-κB controls the expression of multiple genes, including cytokines and chemokines, and protects cells against apoptosis
539
6.
7. 8.
b. NEMO/IKKγ deficiency causes the phenotypical expression of the disease via the NF-κB pathway c. A knockout mice heterozygous for NEMO/IKKγ gene deficiency develops a clinical phenotype very similar to that of incontinentia pigmenti Mechanisms for occasional survival of affected males a. Presence of an extra X chromosome (47,XXY Klinefelter syndrome) b. Skewed X inactivation c. Hypomorphic alleles d. Mosaics for common mutations (somatic mosaicism) e. A parent with gonadal mosaicism Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID): a. A disorder allelic to incontinentia pigmenti but with different phenotype due to various natures of genetic mutations underlying the 2 disorders b. A rare X-linked recessive disorder affecting only males c. Caused by mutations in the NEMO gene d. Possible family history of IP in boys with EDA-ID e. Presentation with severe recurrent infections caused by common encapsulated bacterial pathogens, suggesting functional defects in the immune response f. Rare opportunistic diseases i. Mycobacterial infections ii. Cytomegaloviral infections iii. Pneumocystis carinii pneumonitis g. Immunologic studies i. Normal or increased levels of B cells ii. Normal T-cell counts iii. Normal to low levels of IgG iv. Elevated levels of either IgM or IgA Eosinophil recruitment through eotaxin release by activated keratinocytes Incontinentia nomenclature: the localization of the gene for IP to Xq28, coupled with reports of children with “incontinentia pigmenti” and X-autosome translocations with breakpoints at Xp11, resulting in a nomenclature differentiation of IP1 and IP2. However, IP1 and IP2 designation should be abandoned a. IP1 i. Disorder applied to cases associated with Xp11 breakpoints ii. Skin changes different from patients to patients iii. Serves no useful purpose either causally or clinically iv. More appropriately using descriptive phrase “Xautosome translocation associated with pigmentary abnormalities” b. IP2: applied to cases of familial IP mapped to Xq28
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CLINICAL FEATURES 1. Highly variable clinical presentations among affected female family members a. Attributed to lyonization in females, resulting in functional mosaicism b. Clonal expansion of the progenitor cell along lines of embryonic development in that each cell determines which X chromosome to express during the first weeks of gestation i. Manifesting along the curvilinear lines of Blaschko in skin ii. Percentage of progenitor cells that express the mutated X chromosome reflecting the extent of expression iii. Mutation in a high percentage of ectodermal cells in severe cases 2. Clinical expression among small number of liveborn male patients a. Generally not severer than that in affected females b. Many male patients with disease expression limited to cutaneous involvement of one or two limbs 3. Cutaneous manifestations: most often the first observed sign of IP and are present in nearly all patients. They are classically subdivided into the following 4 classic cutaneous stages: a. Vesicular, vesiculobullous, or inflammatory stage i. Frequency: about 90% of cases ii. Age of onset: within first 2 weeks of life (92%), by 6 weeks of age (4%), starting after the 1st year of life (several cases) iii. Age at resolution: blisters generally clearing by 4 months, recurrence usually short-lived and less severe than the original eruption iv. Clinical features: erythema, superficial vesicles in linear distribution on torso and extremities (64%) and extremities alone (33%) b. Verrucous (wart-like) stage i. Frequency: about 70% of cases ii. Age of onset: peak of onset between 2–6 weeks of age iii. Age at resolution: clearance by 6 months (80%) iv. Clinical features: verrucous hyperkeratotic papules and plaques almost exclusively involving extremities c. Hyperpigmented stage i. Frequency: nearly all patients with IP (98%) ii. Age of onset: 12–26 weeks of age iii. Age at resolution: puberty iv. Clinical features: whorls and streaks of brown pigmentation following lines of Blaschko (multiple lines on the human body corresponding to the distribution of linear nevi and dermatoses) on torso and extremities (65%) and torso alone (27%) d. Atrophic (dermal scarring) stage i. Frequency: 42% ii. Age of onset: early teens to adulthood iii. Age at resolution: permanent lesion iv. Clinical features: pale, hairless, atrophic patches and/or hypopigmentation
4. Hair abnormalities (50%) a. Vertex alopecia i. The most common hair manifestation ii. Most commonly mild and unnoticed iii. Follows inflammation and vesiculation iv. May be associated with scarring b. Agenesis of eyebrows and eyelashes: infrequent 5. Nail abnormalities (7–40%) a. Ridging, pitting, or nail disruption i. Starting early childhood and involving all or most of the fingernails and toenails ii. Tend to regress and disappear with age b. Subungual and periungual keratotic tumors i. Appear at a later stage ii. Affect fingers more than toes iii. Continued growth results in pain, nail dystrophy, and destruction of the underlying bone of the terminal phalanx iv. Bone lytic lesions caused by pressure from the overlying tumor 6. Dental anomalies (>80%) a. Partial adontia or adontia (43%) b. Pegged and conical teeth (30%) c. Late eruption of teeth (18%) d. Enamel hypoplasia 7. Ophthalmologic anomalies (35%) a. Blindness (7.5%) b. Nonretinal manifestations i. Strabismus (18–33%) ii. Optic atrophy (4%) iii. Cataracts (4%) iv. Pseudoglioma (3.5%) v. Microphthalmia (3%) vi. Rare conjunctival pigmentation, iris hypoplasia, nystagmus, and uveitis c. Retinal manifestations i. Foveal hypoplasia ii. Mottled or hypopigmented retinal pigment epithelium iii. Avascular retina iv. Neovascularization v. Vitreous hemorrhages vi. Fibrovascular proliferation vii. Retinal detachment (3%) 8. Neurologic deficits (30%) a. Infantile spasms and seizure disorder (13%) b. Mental retardation (12%) c. Spastic paralysis (11%) d. Motor retardation (7.5%) e. Microcephalus (5%) f. Infrequent manifestations i. Cerebellar ataxia ii. Congenital hearing loss iii. Muscle paresis iv. Aseptic encephalomyelitis 9. Other associated anomalies a. Nipple anomalies i. Supernumerary nipple ii. Nipple hypoplasia iii. Breast hypoplasia/aplasia
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b. Oral anomalies i. High arched palate ii. Cleft lip/palate c. Skeletal anomalies i. Dwarfism ii. Chondrodysplasias iii. Short stature iv. Spina bifida v. Skull defects vi. Club foot d. Increased risk of serious and unusual infection in some patients e. Occasional hypohidrosis with increased rates of bacterial skin infections: may be evidence of the continuum between IP and the allelic anhidrotic ectodermal dysplasia-immune deficiency f. Cardiac abnormalities i. Tricuspid insufficiency ii. Pulmonary vein-to-superior vena cava shunt 10. Diagnostic criteria for incontinentia pigment (Landy and Donnai, 1993) a. Negative family history (no evidence of IP in a firstdegree female relative): at least one major criterion is necessary to make a firm diagnosis of sporadic incontinentia pigmenti. The minor criteria, if present, will support the diagnosis. Because of their high incidence, complete absence of minor criteria should induce a degree of uncertainty i. Major criteria a) Typical neonatal rash (erythema, vesicles, eosinophilia) b) Typical hyperpigmentation (mainly trunk, Blaschko’s lines, fading in adolescence) c) Linear, strophic, hairless lesions ii. Minor criteria a) Dental involvement b) Alopecia c) Woolly hair/abnormal nails d) Retinal disease b. Positive family history (evidence of IP in a firstdegree female relative of an affected female) plus demonstration of any of the following features, alone or in combination i. Suggestive history or evidence of typical rash ii. Skin manifestation of IP a) Hyperpigmentation b) Scarring c) Hairless streaks d) Alopecia at vertex iii. Anomalous dentition iv. Woolly hair v. Retinal disease vi. Multiple male miscarriages
DIAGNOSTIC INVESTIGATIONS 1. Major histopathologic features from skin biopsy samples a. Vesicular, vesiculobullous, or inflammatory stage i. Spongiotic dermatitis ii. Dermal and epidermal eosinophilia iii. Eosinophil-filled vesicles
2. 3. 4.
5. 6. 7. 8. 9.
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b. Verrucous stage i. Papillomas ii. Epidermal hyperplasia iii. Hyperkeratosis iv. Dyskeratotic cells c. Hyperpigmented stage i. Dermal melanophages ii. Vascuolar changes in basal layer of epidermis d. Atrophic stage i. Loss of rete ridges ii. Loss of dermal sweat coils CBC: marked peripheral blood leukocytosis an eosinophilia Abnormal immune system: not a consistent finding CT/MRI imagings of the brain a. Optic atrophy b. Retinal vasculopathy c. Hypoplasia of the corpus callosum d. Ventriculomegaly e. Periventricular white matter lesions f. Ischemic strokes g. Hemorrhagic necrosis h. Porencephalic cyst Magnetic resonance angiography/spectroscopy for cerebral ischemia and a vaso-occlusive phenomenon Fluorescein angiography for retinal vascular abnormalities EEG for seizures Chromosome analysis in male patients with IP Molecular genetic testing: mutation detection for the majority of families, facilitated by the high frequency of specific deletion, using Southern blotting, PCR amplification, or DNA sequencing a. X-inactivation assay and Xq28 marker studies: X-inactivation analysis is indicated wherever a recombination event between Xq28 markers and the disease locus is suspected. Absence of recombination between the disease locus and Xq28 loci suggests that mosaicism is responsible for the discrepancy where Xq28 marker studies are at odds with the clinical assessment b. Identification of the NEMO gene mutation as a biological marker for a molecular diagnosis of IP i. Carrier testing for the mother who has an affected daughter with a known mutation ii. Determine whether the miscarried or stillborn male fetus has IP iii. Prenatal testing of a fetus at risk
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Recurrence risk: <1%, provided the mother is not a carrier of the gene: a small increased risk due to either a new mutation in a second child or germline mosaicism in a parent ii. Recurrence risk of 50% for sisters to be affected when the mother is a carrier of the gene iii. Recurrence risk of 50% for brothers to be affected (prenatally aborted fetuses or stillborns) when the mother is a carrier of the gene
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b. Offspring of an affected female i. Daughters: 50% affected; 50% normal ii. Sons: 50% affected (prenatally aborted fetuses or stillborns); 50% normal (all the live-born sons will be normal) c. Offspring of an affected male i. All daughters affected ii. All sons normal 2. Prenatal diagnosis possible if the disease-causing mutation has been detected in the families at risk a. Determination of the fetal sex by amniocentesis or CVS b. An increased risk of miscarriage or stillborn for an affected male fetus c. Molecular genetic testing of a female fetus 3. Management a. Reduce the risk of secondary infection of blisters b. Keep lesions dry c. Avoid trauma to blisters d. Dental care e. Early photocoagulation or cryotherapy in cases of retinal involvement f. Intervention programs for learning disabilities and developmental delay g. Anti-seizure medications for seizures
REFERENCES Aradhya S, Courtois G, Rajkovic A, et al.: Atypical forms of incontinentia pigmenti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKKgamma). Am J Hum Genet 68:765–767, 2001. Aradhya S, Woffendin H, Jakins T, et al.: A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations. Hum Mol Genet 10: 2171–2179, 2001. Avrahami E, Harel S, Jurgenson U, et al.: Computed tomographic demonstration of brain changes in incontinentia pigmenti. Am J Dis Child 139: 372–374, 1985. Adeniran A, Townsend PL, Peachey RD: Incontinentia pigmenti (BlochSulzberger syndrome) manifesting as painful periungual and subungual tumours. J Hand Surg [Br] 18:667–669, 1993. Berlin AL, Paller AS, Chan LS: Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology. J Am Acad Dermatol 47:169–187; quiz 188–190, 2002. Bessems PJ, Jagtman BA, van de Staak WJ, et al.: Progressive, persistent, hyperkeratotic lesions in incontinentia pigmenti. Arch Dermatol 124:29–30, 1988. Bitoun P, Philippe C, Cherif M, et al.: Incontinentia pigmenti (type 1) and X;5 translocation. Ann Genet 35:51–54, 1992. Bloch B: Eigentumliche bischer nicht beschriebene pigmentaffektion (incontinentia pigmenti). Schweiz Med Wochenschr 7:404–405, 1926. Cannizzaro LA, Hecht F: Gene for incontinentia pigmenti maps to band Xp11 with an (X;10) (p11;q22) translocation. Clin Genet 32:66–69, 1987. Chatkupt S, Gozo AO, Wolansky LJ, et al.: Characteristic MR findings in a neonate with incontinentia pigmenti. AJR Am J Roentgenol 160:372–374, 1993. Cohen PR: Incontinentia pigmenti: clinicopathologic characteristics and differential diagnosis. Cutis 54:161–166, 1994. Curth HO, Warburton D: The genetics of incontinentia pigmenti. Arch Dermatol 92:229–235, 1965. de Grouchy J, Turleau C, Doussau de Bazignan M, et al.: Incontinentia pigmenti (IP) and r(X). Tentative mapping of the IP locus to the X juxtacentromeric region. Ann Genet 28:86–89, 1985. Devriendt K, Matthijs G, Fryns JP, et al.: Second trimester miscarriage of a male fetus with incontinentia pigmenti. Am J Med Genet 80:298–299, 1998. Di Landro A, Marchesi L, Reseghetti A, et al.: Warty linear streaks of the palm and sole: possible late manifestations of incontinentia pigmenti. Br J Dermatol 143:1102–1103, 2000.
Doffinger R, Smahi A, Bessia C, et al.: X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet 27:277–85, 2001. Francois J: Incontinentia pigmenti (Bloch-Sulzberger syndrome) and retinal changes. Br J Ophthalmol 68:19–25, 1984. Francis JS, Sybert VP: Incontinentia pigmenti. Semin Cutan Med Surg 16:54–60, 1997. Garcia-Dorado J, de Unamuno P, Fernandez-Lopez E, et al.: Incontinentia pigmenti: XXY male with a family history. Clin Genet 38:128–138, 1990. Gilgenkrantz S, Tridon P, Pinel-Briquel N, et al.: Translocation (X;9)(p11;q34) in a girl with incontinentia pigmenti (IP): implications for the regional assignment of the IP locus to Xp11? Ann Genet 28:90–92, 1985. Goldberg MF, Custis PH: Retinal and other manifestations of incontinentia pigmenti (Bloch-Sulzberger syndrome). Ophthalmology 100:1645–1654, 1993. Gordon H, Gordon W: Incontinentia pigmenti: clinical and genetical studies of two familial cases. Dermatologica 140:150–168, 1970. Gurevitch AW, Farrell W, Horlick S, et al.: Incontinentia pigmenti: a systemic genodermatosis with striking cutaneous findings. Clin Pediatr (Phila) 12:396–401, 1973. Happle R: Lyonization and the lines of Blaschko. Hum Genet 70:200–206, 1985. Happle R: Incontinentia pigmenti versus hypomelanosis of Ito: the whys and wherefores of a confusing issue. Am J Med Genet 79:64–65, 1998. Harre J, Millikan LE: Linear and whorled pigmentation. Int J Dermatol 8:529–537, 1994. Hodgson SV, Neville B, Jones RW, et al.: Two cases of X/autosome translocation in females with incontinentia pigmenti. Hum Genet 71:231–234, 1985. Jackson R: The lines of Blaschko: a review and reconsideration. Br J Dermatol 95:349–360, 1976. Jain A, Ma CA, Liu S, et al.: Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol 2:223–228, 2001. Jessen RT, Van Epps DE, Goodwin JS, et al.: Incontinentia pigmenti. Evidence for both neutrophil and lymphocyte dysfunction. Arch Dermatol 114:1182–1186, 1978. Kajii T, Tsukahara M, Fukushima Y, et al.: Translocation (X;13)(p11.21;q12.3) in a girl with incontinentia pigmenti and bilateral retinoblastoma. Ann Genet 28:219–223, 1985. Kasai T, Kato Z, Matsui E, et al.: Cerebral infarction in incontinentia pigmenti: the first report of a case evaluated by single photon emission computed tomography. Acta Paediatr 86:665–667, 1997. Kenwrick S, The International IP Consortium: Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome. Am J Hum Genet 69: 1210–1217, 2001. Kirchman TT, Levy ML, Lewis RA, et al.: Gonadal mosaicism for incontinentia pigmenti in a healthy male. J Med Genet 32:887–890, 1995. Landy SJ, Donnai D: Incontinentia pigmenti (Bloch-Sulzberger syndrome). J Med Genet 30:53–59, 1993. Lee AG, Goldberg MF, Gillard JH, et al.: Intracranial assessment of incontinentia pigmenti using magnetic resonance imaging, angiography, and spectroscopic imaging. Arch Pediatr Adolesc Med 149:573–580, 1995. Makris C, Godfrey VL, Krahn-Senftleben G, et al.: Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol Cell 5:969–79, 2000. Mascaro JM, Palou J, Vives P: Painful subungual keratotic tumors in incontinentia pigmenti. J Am Acad Dermatol 13:913–918, 1985. McCrary JA III, Smith JL: Conjunctival and retinal incontinentia pigmenti. Arch Ophthalmol 79:417–22, 1968. Menni S, Piccinno R, Biolchini A, et al.: Immunologic investigations in eight patients with incontinentia pigmenti. Pediatr Dermatol 7:275–277, 1990. Miteva L, Nikolova A: Incontinentia pigmenti: a case associated with cardiovascular anomalies. Pediatr Dermatol 18:54–56, 2001. Moss C, Ince P: Anhidrotic and achromians lesions in incontinentia pigmenti. Br J Dermatol 116:839–849, 1987. O’Brien JE, Feingold M: Incontinentia pigmenti. A longitudinal study. Am J Dis Child 139:711–712, 1985. Ormerod AD, White MI, McKay E, et al.: Incontinentia pigmenti in a boy with Klinefelter’s syndrome. J Med Genet 24:439–441, 1987. Pascual-Castroviejo I, Roche MC, Martinez Fernandez V, et al.: Incontinentia pigmenti: MR demonstration of brain changes. AJNR Am J Neuroradiol 15:1521–1527, 1994. Pfau A, Landthaler M: Recurrent inflammation in incontinentia pigmenti of a seven-year-old child. Dermatology 191:161–163, 1995.
INCONTINENTIA PIGMENTI Roberts WM, Jenkins JJ, Moorhead EL II, et al.: Incontinentia pigmenti, a chromosomal instability syndrome, is associated with childhood malignancy. Cancer 62:2370–2372, 1988. Rosenfeld SI, Smith ME: Ocular findings in incontinentia pigmenti. Ophthalmology 92:543–546, 1985. Russell DL, Finn SB: Incontinentia pigmenti (Bloch-Sulzberger syndrome): a case report with emphasis on dental manifestations. J Dent Child 34:494–500, 1967. Scheuerle AE: Male cases of incontinentia pigmenti: case report and review. Am J Med Genet 77:201–218, 1998. Schamburg-Lever G, Lever WF: Electron microscopy of incontinentia pigmenti. J Invest Dermatol 61:151–158, 1973. Sefiani A, Abel L, Heuertz S, et al.: The gene for incontinentia pigmenti is assigned to Xq28. Genomics 4:427–429, 1989. Smahi A, Hyden-Granskog C, Peterlin B, et al.: The gene for the familial form of incontinentia pigmenti (IP2) maps to the distal part of Xq28. Hum Mol Genet 3:273–278, 1994. Smahi A, Courtois G, Vabres P, et al.: Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature 405:466–472, 2000.
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Sulzberger MB: Uber eine bischer nicht beschriebene congenitale pigmentanomalie (incontinentia pigmenti). Arch Dermatol Syph (Berl) 154:19–32, 1928. Sybert VP: Incontinentia pigmenti nomenclature. Am J Hum Genet 55: 209–211, 1994. Sybert VP: A case revisited: recent presentation of incontinentia pigmenti in association with a previously reported X; autosome translocation. Am J Med Genet 75:334, 1998. Wettke-Schäfer R, Kanter G: X-linked dominant inherited diseases with lethality in hemizygous males. Hum Genet 64:1–23, 1983. Wiklund DA, Weston WL: Incontinentia pigmenti. A four-generation study. Arch Dermatol 116:701–703, 1980. Worret WI, Nordquist RE, Burgdorf WH: Abnormal cutaneous nerves in incontinentia pigmenti. Ultrastruct Pathol 12:449–454, 1988. Zillikens D, Mehringer A, Lechner W, et al.: Hypo- and hyperpigmented areas in incontinentia pigmenti. Light and electron microscopic studies. Am J Dermatopathol 13:57–62, 1991. Zonana J, Elder ME, Schneider LC, et al.: A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am J Hum Genet 67:1555–1562, 2000.
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Fig. 1. Two girls with incontinentia pigmenti showing classical hyperpigmentation on the trunk following Blaschko lines. Fig. 2. A girl with incontinentia pigmenti showing streaks and whorls of brown pigmentation on the leg and trunk.
Infantile Myofibromatosis Infantile myofibromatosis, previously known as congenital generalized fibromatosis, is the most prevalent fibrous tumor of infancy. It is characterized by the formation of tumors, either in a solitary or in a multicentric fashion, in the skin, muscle, viscera, bone, and subcutaneous tissue.
GENETICS/BASIC DEFECTS 1. Etiology: unknown but appears to originate in utero. Fetal estrogenic hormone stimulation or hamartomas of myofibroblasts have been considered a. Sporadic in most cases b. Several reports of familial cases i. Autosomal dominant ii. Autosomal recessive 2. Types a. Solitary myofibroma i. More common in males (69%) ii. Affects chiefly the soft tissues of the head-neck region and the trunk b. Multicentric myofibromatosis (more common in females, 63%) i. Without visceral involvement (bones) ii. With visceral involvement (bones and viscera) 3. Spontaneous regression of tumors: possibly due to apoptotic cell death
CLINICAL FEATURES 1. Affects almost exclusively infants and young children a. 60% noted at birth or shortly thereafter b. 80% occurred before the age of two years 2. Characteristics of tumors a. Superficial i. Palpable, rubbery, firm, and freely moveable nodules ii. Fibrotic, plaquelike, indurated, and crusted lesions b. Deeper lesions: generally immovable c. Nontender and painless 3. Overlying skin a. Erythema or a purple discoloration resembling a hemangioma b. Ulceration and atrophic scar 4. Affected bones a. Radiolucent lytic lesions (cystic defects) b. Most commonly involved locations i. Cranium ii. Femurs iii. Tibias iv. Spine v. Ribs c. Circumscribed lytic tumors not present at birth but develop quickly over the first few days or weeks of life 545
5. Solitary form (myofibroma) a. About 80% of the cases b. Boys more commonly affected c. Mostly involves the skin and bones, and rarely the CNS and viscera d. A good outcome provided there is no visceral involvement e. Natural history of myofibromas of the CNS without visceral involvement: frequently characterized by a period of initial rapid growth, subsequent stabilization, and spontaneous regression in many cases 6. Multicentric form (myofibromatosis) a. Without visceral involvement i. Girls more commonly affected ii. Typically undergoing spontaneous regression within the first 1 or 2 years of life when limited to the skin or bone iii. A good outcome b. With visceral involvement i. One fourth of cases of multicentric cases ii. Multiple nodules distributed throughout the body a) Soft tissues b) Bone c) Skeletal muscle d) Viscera (kidney, pancreas, retroperitoneum, lungs, gastrointestinal tract, peritoneum, diaphragm, heart, tongue, lymph nodes, peripheral nerves, liver) iii. Fatal outcome with visceral involvement usually within 4 months of life a) Localized mass effect on the lung, gastrointestinal tract, or within the conduction system of the heart b) Mortality rate approaches 75% iv. Possible survival: spontaneous resolution of visceral lesions within the first year of life v. Disseminated pathologic process including proliferation of multiple nodules of collagenforming fusiform cells vi. Likely origin of proliferating cells: myofibroblast (displaying both smooth muscle and fibroblast features) 7. Differential diagnosis a. Neurofibromatosis b. Leiomyomas c. Hyaline fibromatoses d. Hemangiomas e. Soft tissue sarcomas f. Metastatic neuroblastomas 8. Prognosis depending on the extent of involvement and location of the lesions a. Solitary forms usually cause little morbidity and virtually no mortality. However, a solitary nodule
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involving the central nervous system (CNS) may be fatal b. Lesions confined to soft tissue and bone: usually selflimited with good prognosis c. Good prognosis with frequent spontaneous regression when viscera are not involved d. Poor prognosis with infantile myofibromatosis with multiple visceral involvement i. Progression to death: usual outcome ii. Death resulting from complications due to cardiopulmonary or gastrointestinal involvement
DIAGNOSTIC INVESTIGATIONS 1. Radiography, U/S, CT, and MRI a. Soft tissue lesions: round and well defined on U/S and MRI b. Invaluable in assessing the extent and progression or regression of the disease i. Soft tissue lesions (multiple subcutaneous and intramuscular tumors) ii. Bone lesions iii. Visceral lesions c. Radiography: lesions appearing as multiple areas of osteolysis with a sclerotic margin d. Ultrasonography: hyperechoic nodules with peripheral hyperperfusion on color Doppler e. CT scan of the brain i. Partially calcific masses or isodense cystic lesions with intense peripheral contrast enhancement and smoothly marginated bone erosion ii. Typical absence of sclerosis of the margins f. MRI: intramuscular, subcutaneous and visceral (liver, lungs) lesions i. Iso- or hypointense on T1-W images ii. Iso- or hypointense on T2-W images 2. Histology (biopsy of tumors) a. Gross appearance of tumors: well demarcated b. Lesion consisting of bundles of elongated cells with features of both fibroblasts and smooth-muscle cells c. Staining characteristics: intermediate between fibroblasts and smooth muscle d. Central part of the tumors often necrotic 3. Electron microscopy a. Characteristic intracytoplasmic myofilaments b. Dense bodies c. Focal basal lamina and macula adherens
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Sporadic form: not increased ii. Autosomal recessive form: 25% risk iii. Autosomal dominant form: not increased unless a parent is affected b. Patient’s offspring i. Sporadic form: not increased ii. Autosomal recessive form: not increased unless the spouse is a carrier iii. Autosomal dominant form: 50% risk
2. Prenatal diagnosis by ultrasonography for detecting solitary or multicentric tumors in soft tissue, bones, or viscera 3. Management a. Observation i. Spontaneous regression ii. Possible sequelae (tissue loss or damage) resulting from spontaneous regression b. Surgical excision i. To prevent complications and improve prognosis ii. Reserved for symptomatic lesions or if vital organs are compromised, in view of the tendency to spontaneous regression iii. Radical resection reserved for those lesions posing an immediate threat due to their locations or massive size and those showing obvious progression iv. 7–10% of lesions recurred after excision c. Chemotherapy with or without radiotherapy i. Necessary for recurrent or unresectable lesions ii. A combination of vincristine, adriamycin-D and cyclophosphamide iii. Interferon
REFERENCES Allen PW: The fibromatoses: a clinicopathologic classification based on 140 cases. Part 2. Am J Surg Pathol 1:305–321, 1977. Baer JW, Radkowski MA: Congenital multiple fibromatosis: a case report with review of the world literature. Am J Roentgenol Tad Ther Nucl Med 118:200–205, 1973. Baird PA, Worth AJ: Congenital generalized fibromatosis: an autosomal recessive condition? Clin Genet 9:488–494, 1976. Baerg J, Murphy JJ, Magee JF: Fibromatoses: Clinical and pathological features suggestive of recurrence. J Pediatr Surg 34:1112–1114, 1999. Beaty EC Jr: Congenital generalized fibromatosis in infancy. Am J Dis Child 103:128–132, 1962. Bellman B, Wooming G, Landsman L, et al.: Infantile myofibromatosis: a case report. Pediatr Dermatol 8:306–309, 1991. Bracˇko M, Cindro L, Golouh R: Familial occurrence of infantile myofibromatosis. Cancer 69:1294–1299, 1992. Brill PW, Yandow DR, Langer LO, et al.: Congenital generalized fibromatosiscase report and literature review. Pediatr Radiol 12:269–278, 1982. Chung EB, Enzinger FM: Infantile myofibromatosis. Cancer 48:1807–1818, 1981. Coffin CM, Dehner LP: Soft tissue tumors in the first year of life. A report of 190 cases. Pediatr Pathol 10:509–526, 1990. Coffin CM, Neilson KA, Ingels S, et al.: Congenital generalized myofibromatosis: a disseminated angiocentric myofibromatosis. Pediatr Pathol Lab Med 15:571–587, 1995. Counsell SJ, Devile C, Mercuri E, et al.: Magnetic resonance imaging assessment of infantile myofibromatosis. Clin Radiol 57:67–70, 2002. Day M, Edwards Arch Otolaryngol, Weinberg A, et al.: Successful therapy of a patient with infantile generalized fibromatosis. Med Pediatr Oncol 38:371–373, 2002. Duffy MT, Harris M, Hornblass A: Infantile myofibromatosis of orbital bone. A case report with computed tomography, magnetic resonance imaging, and histologic findings. Ophthalmol 104:1471–1474, 1997. Eich GF, Hoeffel JC, Tschappeler H, et al.: Fibrous tumours in children: imaging features of a heterogeneous group of disorders. Pediatr Radiol 28:500–509, 1998. Fleischhack G, Zernikow B, Bolefahr H, et al.: Successful treatment of progressive multifocal infantile myofibromatosis by chemotherapy—a case report. Med Pediatr Oncol 23:281 (#369), 1994. Fletcher CDM, Achu P, Noorden SV, et al.: Infantile myofibromatosis: a light microscopic, histochemical and immunohitochemical study suggesting true smooth muscle differentiation. Histopathology 11:245–258, 1987. Francis IR, Dorovini-Zis K, Glazer GM, et al.: The fibromatoses: CT-pathologic correlation. Am J Roentgenol 147:1063, 1986.
INFANTILE MYOFIBROMATOSIS Fukasawa Y, Ishikura H, Takada A, et al.: Massive apoptosis in infantile myofibromatosis. A putative mechanism of tumor regression. Am J Pathol 144:480–485, 1994. Goldberg NS, Bauer BS, Kraus H, et al.: Infantile myofibromatosis: A review of clinicopathology with perspectives on new treatment choices. Pediatr Dermatol 5:37–46, 1988. Hasegawa M, Kida S, Yamashima T, et al.: Multicentric infantile myofibromatosis in the cranium: case report. Neurosurg 36:1200–1203, 1995. Hasegawa T, Hirose T, Seki K, et al.: Solitary infantile myofibromatosis of bone. An immunohistochemical and ultrastructural study. Am J Surg Pathol 17:308–313, 1993. Hudson TM, Vandergriend RA, Springfield DS, et al.: Aggressive fibromatosis: evaluation by computed tomography and angiography. Radiology 150:495, 1984. Inwards CY, Unni KK, Beabout JW, et al.: Solitary congenital fibromatosis (infantile myofibromatosis) of bone. Am J Surg Pathol 15:935–941, 1991. Jennings TA, Sabetta J, Duray PH, et al.: Infantile myofibromatosis. Evidence for an autosomal-dominant disorder. Am J Surg Pathol 8:529–538, 1984. Johnson GL, Baisden BL, Fishman EK: Infantile myofibromatosis. Skelet Radiol 26:611–614, 1997. Kaplan SS: Intracranial infantile myofibromatosis with intraparenchymal involvement. Pediatr Neurosurg 36:214–217, 2002. Kubota A, Imano M, Yonekura T, et al.: Infantile myofibromatosis of the triceps detected by prenatal sonography. J Clin Ultrasound 27:147–150, 1999. Liew SH, Haynes M: Localized form of congenital generalized fibromatoses. A report of three cases with myofibroblasts. Pathology 13:257–266, 1981. Meizner I: Prenatal ultrasound diagnosis of infantile myofibromatosis—a case report. Ultrasound Obstet Gynecol 16:84–86, 2000. Michel M, Ninane J, Claus D, et al.: Major malformations in a case of infantile myofibromatosis. Eur J Pediatr Surg 149:251, 1990. Morettin LB, Mueller E, Schreiber M: Generalized hamartomatosis (congenital generalized fibromatosis). Am J Roentgenol Tad Ther Nucl Med 114:722–734, 1972. Narchi H: Infantile myofibromatosis. Int Pediatr 16:238–239, 2001. Ng WT: Infantile myofibromatosis of the ovary presenting with ascites. Eur J Pediatr Surg 11:415–418, 2001. Orozco-Covarrubias L, Soriano-Hernandez Y, Duran-McKinster C, et al.: Infantile myofibromatosis: a cause of leg length discrepancy. Pediatr Dermatol 19:520–522, 2002. Parker RK, Mallory SB, Baker GF: Infantile myofibromatosis. Pediatr Dermatol 8:129–132, 1991. Plaschkes J: Congenital fibromatosis: localized and generalized forms. J Pediatr Surg 9:95–101, 1974. Quinn SF, Erickson SJ, Dee PM, et al.: MR imaging in fibromatosis: results in 26 patients with pathologic correlation. Am J Roentgenol 156:539–542, 1991. Raney B, Evans A, Granowetter L, et al.: Nonsurgical management of children with recurrent or unresectable fibromatosis. Pediatrics 79:394–398, 1987. Roggli VL, Kim HS, Hawkins E: Congenital generalized fibromatosis with visceral involvement. A case report. Cancer 45:954–960, 1980.
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Salamah MM, Hammoudi SM, Sadi AR: Infantile myofibromatosis. J Pediatr Surg 23:975–977, 1988. Schaffzin EA, Chung SMK, Kaye R: Congenital generalized fibromatosis with complete spontaneous regression. J Bone Joint Surg 54-A:657–662, 1972. Schrodt BJ, Callen J Pediatr: A case of congenital multiple myofibromatosis developing in an infant. Pediatrics 104:113–115, 1999. Shnitka TK, Asp DM, Horner RH: Congenital generalized fibromatosis. Cancer 11:627–639, 1958. Skapek SX, Hawk BJ, Hoffer FA, et al.: Combination chemotherapy using vinblastine and methotrexate for the treatment of progressive desmoid tumor in children. J Clin Oncol 16:3021–3027, 1998. Soper JR, Silva MD: Infantile myofibromatosis: a radiological review. Pediatr Rev 23:189–194, 1993. Söylemezoglu F, Tezel GG, Köybasoglu F, et al.: Cranial infantile myofibromatosis: report of three cases. Child’s Nerv Syst 17:524–527, 2001. Spadola L, Anooshiravani M, Sayegh Y, et al.: Generalised infantile myofibromatosis with intracranial involvement: imaging findings in a newborn. Pediatr Radiol 32:872–874, 2002. Spraker MK, Stack C, Esterly NB: Congenital generalized fibromatosis: A review of the literature and report of a case with porencephaly, hemiatrophy, and cutis marmorata telangiectatica congenita. J Am Acad Dermatol 10:365–371, 1984. Stanford D, Rogers M: Dermatological presentations of infantile myofibromatosis: a review of 27 cases. Australas J Dermatol 41:156–161, 2000. Stout AP: Juvenile fibromatoses. Cancer 7:953–978, 1954. Tamburrini G, Gessi M, Colosimo C Jr., et al.: Infantile myofibromatosis of the central nervous system. Childs Nerv Syst 2003. Teng P, Warden MJ, Cohn WL: Congenital generalized fibromatosis (renal and skeletal) with complete spontaneous regression. J Pediatr 62:748–753, 1963. Thunnissen BTMJ, Bax NMA, Rovekamp MH, et al.: Infantile myofibromatosis: an unusual presentation and a review of the literature. Eur J Pediatr Surg 3:179, 1993. Variend S, Bax NMA, Van Gorp J: Are infantile myofibromatosis, congenital fibrosarcoma, and congenital hemangiopericytoma histogenetically related? Histopathology 26:57–62, 1995. Venencie PY, Bigel P, Desgruelles C, et al.: Infantile myofibromatosis. Report of two cases in one family. Brit J Dermatol 117:255–259, 1987. Wada H, Akiyama H, Seki H, et al.: Spinal canal involvement in infantile myofibromatosis: case report and review of the literature. J Pediatr Hematol Oncol 20:353–356, 1998. Wiswell TE, Davis J, Cunningham BE, et al.: Infantile myofibromatosis: the most common fibrous tumor of infancy. J Pediatr Surg 23:315–318, 1988. Wiswell TE, Sakas EL, Stephenson Skelet Radiol, et al.: Infantile myofibromatosis. Pediatrics 76:981–984, 1985. Wyatt AJ, Hansen RC: Pediatric skin tumors. Pediatr Clin North Amer 47(4): August, 2000. Zeller B, Storm-Mathisen I, Smevik B, et al.: Cure of infantile myofibromatosis with severe respiratory complications without antitumor therapy. Eur J Pediatr 156:841–844, 1997.
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Fig. 1. An infant with multicentric myofibromatosis showing subcutaneous nodules in the back, arm (pointed by a finger), cystic lytic lesions in the humeri and femori (radiographs), and multicentric nodules (identified by dark lines) in the chest wall by MRI.
Ivemark Syndrome Ivemark syndrome consists of viscero-atrial heterotaxia associated with asplenia. It is also known as asplenia syndrome, heterotaxy syndrome, cardiosplenic syndrome, right atrial isomerism (two morphologically right atrial appendage), or bilateral right-sidedness. The incidence of the syndrome is estimated to be 1/10,000–1/40,000 live births.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive suggested by: a. Reports of multiple affected siblings, both males and females, born to normal parents b. Reports of several instances of parental consanguinity c. Report of mutations in the gene encoding connexin 43 (CX43) 2. Other possible cause: maternal diabetes 3. Heterotaxy syndrome a. A rare congenital disorder occurring in approximately 0.8% of patients with congenital heart disease b. Often associated with complex cyanotic heart disease and an abnormal cardiac conduction system c. Consisting of the following two groups of disease: i. Right isomerism (asplenia syndrome) a) Commonly has a combination of complete atrioventricular canal defect, total anomalous pulmonary venous return, double outlet right ventricle, and pulmonary stenosis b) Often has paired atrioventricular nodes that may serve as the substrate for a special reentrant tachycardia (“nodal-to-atrioventricular nodal tachycardia”) ii. Left isomerism (polysplenia syndrome) a) Tends to have less complex cardiac anomalies and therefore a better prognosis b) Likely to have defective sinus and atrioventricular nodes that may result in sinus node dysfunction, junctional escape rhythm, and atrioventricular block
3.
4.
5.
CLINICAL FEATURES 1. Congenital absence of the spleen (asplenia) 2. Congenital heart malformations a. Cardiac malpositions (44%) i. Dextrocardia ii. Right sided aortic arch b. Venous system i. Systemic veins: bilateral superior vena cava (53%) ii. Pulmonary veins a) Total anomalous pulmonary venous drainage (72%) b) Partial anomalous pulmonary venous drainage (6%) 549
6.
c. Great vessels i. Transposition of the great arteries (72%) ii. Pulmonary stenosis or atresia (78%) d. Coronary arteries: single coronary artery (19%) e. Intracardiac defects i. Single ventricle (44%) ii. Single AV valve (87%) iii. Absent coronary sinus (85%) iv. Endocardial cushion defect v. Double inlet ventricle vi. Discordant ventriculoarterial connection Maldevelopment of the abdominal organs a. Abnormalities of the mesenteric attachment (intestinal malrotation), a major predisposing cause of mid-gut volvulus b. Situs inversus (heterotaxia) c. A midline (central) liver d. Tubular stomach e. Imperforate anus f. Annular pancreas and obstructing duodenal bands g. Esophageal varices h. Duplication of stomach i. Agenesis of gallbladder j. Rudimentary pancreas k. Meckel diverticulum l. Esophageal atresia and TE fistula m. Hiatus hernia n. Gastric hypoplasia o. Acute gastric volvulus: a rare complication p. Cleft palate q. Duplication of the hindgut r. Aganglionosis Bronchopulmonary isomerism a. Abnormal lobation of the lungs i. Bilaterally tri-lobed ii. Bilateral bi-lobed b. Bilateral eparterial bronchi c. Pulmonary hypoplasia CNS malformations: uncommon a. Agenesis of the corpus callosum b. Porencephalic cyst c. Cerebellar cysts d. Focal cerebellar dysplasia e. Hydrocephalus f. Septum pellucidum abnormality Genitourinary anomalies a. Horseshoe kidney b. Cystic kidney c. Bilobed urinary bladder d. Hydroureter e. Posterior urethral valves f. Ureteral valve with hydronephrosis g. Double collecting system
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IVEMARK SYNDROME
h. Recto-urethral fistula i. Bicornuate uterus j. Ovarian cysts Endocrine abnormalities a. Fused or horseshoe adrenal b. Absent adrenal Musculoskeletal abnormalities a. Equinovarus deformity b. Overlapping toes c. Clubbing of hands d. Absent radii Miscellaneous a. Microphthalmia b. Single umbilical artery Prognosis a. Prognosis related to cardiac malformations i. Severe and incompatible with life (as a rule) ii. Anoxia iii. Cyanotic neonates die from cardiac insufficiency iv. Most die from cardiac disease during the first year of life (usually the 1st month) v. Complications of surgery vi. Hemorrhage b. Prognosis related to asplenia i. Greater risk from infection for those who survive the first 12 months ii. Sudden death in infancy from sepsis and impaired resistance to infection
DIAGNOSTIC INVESTIGATIONS 1. Echocardiography for delineating congenital heart defects 2. Diagnosis of asplenia a. No splenic uptake on technetium sulfur colloid scan b. Presence of Howell-Jolly bodies in a peripheral blood smear after the first week of life 3. Immunologic assessment in congenital asplenia a. Quantitation of serum immunoglobulins b. Most common pathogens i. In children less than 6 months of age a) Escherichia coli b) Klebsiella ii. In children surviving past 6 months of age a) Haemophillus influenzae b) Pneumococci
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased unless the spouse is a carrier or affected 2. Prenatal diagnosis by fetal echocardiography a. No identifiable spleen (The fetal spleen can usually be detected at 20 weeks of gestation in the left gastrorenal angle.) b. Levocardia c. Complete atrioventricular septal defect d. Double outlet right ventricle e. Dextro malposition of the great arteries
f. Pulmonary atresia/stenosis g. Other cardiac anomalies 3. Management a. Prophylactic antibiotics to prevent life-threatening sepsis b. Palliative cardiac surgery for congenital heart defects c. Surgical intervention for gastrointestinal malformations and other anomalies
REFERENCES Ando F, Shirotani H, Kawai J, et al.: Successful total repair of complicated cardiac anomalies with asplenia syndrome. J Thorac Cardiovasc Surg 72:33–38, 1976. Aoyama K, Tateishi K: Gastric volvulus in three children with asplenic syndrome. J Pediatr Surg 21:307–310, 1986. Bendon RW: Ivemark’s renal-hepatic-pancreatic dysplasia: analytic approach to a perinatal autopsy. Pediatr Dev Pathol 2:94–100, 1999. Berman W, Jr., Yabek SM, Burstein J, et al.: Asplenia syndrome with atypical cardiac anomalies. Pediatr Cardiol 3:35–38, 1982. Biggar WD, Ramirez RA, Rose V: Congenital asplenia: immunologic assessment and a clinical review of eight surviving patients. Pediatrics 67:548–551, 1981. Bisno AL, Freeman JC: The syndrome of asplenia, pneumococcal sepsis, and disseminated intravascular coagulation. Ann Intern Med 72:389–393, 1970. Britz-Cunnigham SH, Shah MM, Zuppan CW, et al.: Mutations of the connexin 43 gap-junction gene in patients with heart malformations and defects of laterality. N Engl J Med 332:1323–1329, 1995. Burn J: Disturbance of morphological laterality in humans. Ciba Foundation Symposium 162:282–296, Discussion 296–299, 1991. Cesko I, Hajdú J, Tóth T, et al.: Ivemark syndrome with asplenia in siblings. J Pediatr 130:822–824, 1997. Chen SC, Monteleone PL: Familial splenic anomaly syndrome. J Pediatr 91:160–161, 1977. Chitayat D, Lao A, Wilson RD, et al.: Prenatal diagnosis of asplenia/polysplenia syndrome. Am J Obstet Gynecol 158:1085–1087, 1988. Colloridi V, Pizzuto F, Ventriglia F, et al.: Prenatal echocardiographic diagnosis of right atrial isomerism. Prenat Diagn 14:299–302, 1994. Ditchfield MR, Hutson JM: Intestinal rotational abnormalities in polysplenia and asplenia syndromes. Pediatr Radiol 28:303–306, 1998. Durairaj M, Bakthaviziam A, Vijayaraghavan G, et al.: Asplenia syndrome—a study of cardiac anomalies in 10 cases. Indian Pediatr 13:237–241, 1976. Esterly JR, Oppenheimer EH: Lymphangiectasis and other pulmonary lesions in the asplenia syndrome. Arch Pathol 90:553–560, 1970. Feder HM, Jr., Pearson HA: Assessment of splenic function in familial asplenia. N Engl J Med 341:210–212, 1999. Freedom RM: The asplenia syndrome: a review of significant extracardiac structural abnormalities in 29 necropsied patients. J Pediatr 81:1130– 1133, 1972. Freedom RM: Aortic valve and arch anomalies in the congenital asplenia syndrome. Case report, literature review and re-examination of the embryology of the congenital asplenia syndrome. Johns Hopkins Med J 135:124–135, 1974. Freedom RM, Fellows KE, Jr.: Radiographic visceral patterns in the asplenia syndrome. Radiology 107:387–391, 1973. Gilbert B, Menetrey C, Belin V, et al.: Familial isolated congenital asplenia: a rare, frequently hereditary dominant condition, often detected too late as a cause of overwhelming pneumococcal sepsis. Report of a new case and review of 31 others. Eur J Pediatr 161:368–372, 2002. Gillis J, Harvey J, Isaacs D, et al.: Familial asplenia. Arch Dis Child 67:665–666, 1992. Gonzales A, Krassikoff N, Gilbert-Barness EF: Polyasplenia complex with mesocardia and renal agenesis in an infant of a diabetic mother. Am J Med Genet 32:457–460, 1989. Gorg C, Eichkorn M, Zugmaier G: The small spleen: Sonographic patterns of functional hyposplenia or asplenia. J Clin Ultrasound 31:152–155, 2003. Hurwitz RC, Caskey CT: Ivemark syndrome in siblings. Clin Genet 22:7–11, 1982. Ivemark BI: Implications of agenesis of the spleen on the pathogenesis of conotruncus anomalies in childhood. An analysis of the heart malformations
IVEMARK SYNDROME in the splenic agenesis syndrome, with fourteen new cases. Acta Paediatr 44:1–110, 1955. Kiuchi M, Kawachi Y, Kimura Y: Sudden infant death due to asplenia syndrome. Am J Forensic Med Pathol 9:102–104, 1988. Lin J-H, Chang C-I, Wang J-K, et al.: Intrauterine diagnosis of heterotaxy syndrome. Am Heart J 143:1002–1008, 2002. Lindor NM, Smithson WA, Ahumada CA, et al.: Asplenia in two father-son pairs. Am J Med Genet 56:10–11, 1995. Majeski JA, Upshur JK: Asplenia syndrome. A study of congenital anomalies in 16 cases. JAMA 240:1508–1510, 1978. Marino B, Capolino R, Digilio MC, et al.: Transposition of the great arteries in asplenia and polysplenia phenotypes. Am J Med Genet 110:292–294, 2002. Markowitz RI, Shashikumar VL, Capitanio MA: Volvulus of the colon in a child with congenital asplenia (Ivemark’s syndrome). Radiology 122:442, 1977. McChane RH, Hersh JH, Russell LJ, et al.: Ivemark’s “asplenia” syndrome: a single gene disorder. South Med J 82:1312–1313, 1989. Mishalany H, Mahnovski V, Woolley M: Congenital asplenia and anomalies of the gastrointestinal tract. Surgery 91:38–41, 1982. Moller JH, Amplatz K, Wolfson J: Malrotation of the bowel in patients with congenital heart disease associated with splenic anomalies. Radiology 99:393–398, 1971. Monie IW: The asplenia syndrome: an explanation for absence of the spleen. Teratology 25:215–219, 1982. Nakada K, Kawaguchi F, Wakisaka M, et al.: Digestive tract disorders associated with asplenia/polysplenia syndrome. J Pediatr Surg 32:91–94, 1997.
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Niikawa N, Kohsaka S, Mizumoto M, et al.: Familial clustering of situs inversus totalis, and asplenia and polysplenia syndromes. Am J Med Genet 16:43–47, 1983. Noack F, Sayk F, Ressel A, et al.: Ivemark syndrome with agenesis of the corpus callosum: a case report with a review of the literature. Prenat Diagn 22:1011–1015, 2002. Phoon CK, Neill CA: Asplenia syndrome: insight into embryology through an analysis of cardiac and extracardiac anomalies. Am J Cardiol 73:581–587, 1994. Putschar WGJ, Manion WC: Congenital absence of the spleen and associated anomalies. Am J Clin Pathol 26:429–470, 1956. Rose V, Izukawa T, Moes CA: Syndromes of asplenia and polysplenia. A review of cardiac and non-cardiac malformations in 60 cases with special reference to diagnosis and prognosis. Br Heart J 37:840–852, 1975. Rubino M, Van Praagh S, Kadoba K, et al.: Systemic and pulmonary venous connections in visceral heterotaxy with asplenia. Diagnostic and surgical considerations based on seventy-two autopsied cases. J Thorac Cardiovasc Surg 110:641–650, 1995. Simpson J, Zellweger H: Familial occurrence of Ivemark syndrome with splenic hypoplasia and asplenia in sibs. J Med Genet 10:303–304, 1973. Tkebuchava T, von Segesser LK, Lachat M, et al.: Ivemark syndrome. A case with successful surgical intervention. Scand Cardiovasc J 31:173–175, 1997. Waldman JD, Rosenthal A, Smith AL, et al.: Sepsis and congenital asplenia. J Pediatr 90:555–559, 1977.
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Fig. 1. A 3-month-old with Ivemark syndrome who has asplenia with complex cardiovascular malformations (AV canal, single ventricle, transposition of the great vessels, pulmonary atresia, and total anomalous pulmonary venous return). She also has malrotation of intestine.
Fig. 2. A 19-month-old boy with Ivemark syndrome. He had heterotaxy syndrome with asplenia, situs ambiguous, and complex congenital heart defects consisting of a single ventricle, atrioventricular septal defect with small ostium primum ASD, pulmonary stenosis, interrupted IVC with azygous continuation to a left SVC, right aortic arch, and congenital complete heart block.
Jarcho-Levin Syndrome c. Absence of intrinsic rib anomalies d. Other clinical features i. Short-trunk dwarfism ii. Craniofacial features a) Brachycephaly b) Low posterior hairline c) Prominent nasal bridge d) High-arched palate iii. Short and rigid neck iv. Short thorax v. Protuberant abdomen vi. Inguinal and umbilical hernias vii. Urinary tract abnormalities viii. Talipes equinovarus e. Prognosis: poor but not an invariably lethal condition with 56% of survival among the prospectively evaluated patients i. Normal intelligence ii. Respiratory complications such as pneumonia iii. Congestive heart failure iv. Pulmonary hypertension 2. Spondylocostal dysostosis a. Constitutes a heterogeneous group of radiologic phenotypes with axial skeletal malformations b. Generally milder phenotype c. Multiple vertebral segmentation and formation defects d. Typical findings i. Intrinsic asymmetric rib anomalies a) Broadening b) Bifurcation c) Fusion ii. No symmetric fusion of the ribs iii. Do not display a fan-like configuration of the thorax iv. No cervical spine anomalies in some patients v. Short-trunk dwarfism e. Associate anomalies i. Congenital heart disease ii. Urogenital and anal anomalies iii. Limb abnormalities iv. Torticolis v. Diaphragmatic, umbilical, and inguinal hernias f. Prognosis i. A good prognosis, due in part to the asymmetry of the thoracic anomalies resulting in a less restrictive thorax ii. Normal intelligence
In 1938, Jarcho and Levin first described a syndrome of malformations with abnormal fusion of thoracic vertebrae and ribs associated with a short trunk and respiratory insufficiency. At present, Jarcho-Levin syndrome is an eponym used to describe a variety of clinical phenotypes, consisting of short-trunk dwarfism associated with rib and vertebral anomalies. Two phenotypic subtypes of spondylothoracic dysplasia and spondylocostal dysostosis have recently been proposed.
GENETICS/BASIC DEFECTS 1. Inheritance and molecular defects a. Presence of considerable genetic heterogeneity with varied clinical presentations and associated abnormalities b. Spondylothoracic dysplasia i. Autosomal recessive inheritance ii. Linked to chromosome 2q32.1 iii. No mutations found in the DLL3 gene c. Spondylocostal dysostosis i. Inheritance: either autosomal recessive or autosomal dominant ii. Mutations in the Delta-like 3 (DLL3) gene on chromosome 19q13.1-q13 a) As the major cause of autosomal recessive spondylocostal dysostosis b) DLL3 encodes a ligand in the Notch gene signal pathway. When mutated, defective somitogenesis occurs resulting in a consistent and distinctive pattern of abnormal vertebral segmentation affecting the entire spine iii. Mutated MESP2 gene that codes for a basic helix-loop-helix transcription factor was found to cause spondylocostal dysostosis in one consanguineous family with two affected children (linkage to 15q21.3-15q26.1) 2. Pathogenesis a. Vertebral anomalies: probably attributed to defective segmentation of the somite at about the 4th or 5th week of intrauterine life b. Costal anomalies: probably secondary to the vertebral anomalies c. Pax1 and Pax9 might be required for the phenotypic expression of Jarcho-Levin syndrome
CLINICAL FEATURES 1. Spondylothoracic dysplasia a. Vertebral segmentation and formation defects throughout cervical, thoracic, and lumbar spine i. Hemivertebrae ii. Block vertebrae iii. Unsegmented bars b. Fusion of all the ribs at the costovertebral joints bilaterally
DIAGNOSTIC INVESTIGATIONS
553
1. Radiography a. Spondylothoracic dysplasia i. Bilateral fanning of the ribs with posterior fusion, giving the appearance of a common origin of ribs at the posterior thoracic spine
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ii. A decreased number of cervical, thoracic, and lumbar vertebrae iii. Multiple vertebral segmentation and formation defects a) Block and wedge vertebrae b) Unsegmented bars c) Hemivertebrae d) Anterior–posterior–lateral failure of closure b. Spondylocostal dysostosis i. Multiple vertebral formations and segmentation defects along the entire spine a) A decreased number of cervical, thoracic, and lumbar vertebrae b) Block and wedge vertebrae c) Agenesis of the coccygeal region d) Progressive scoliosis of the thoracic spine due to tethering effect secondary to the rib anomalies ii. Asymmetric rib malformations 2. Reconstructed tridimensional CT scan of the chest a. Spondylothoracic dysplasia i. Bilateral rib fusion at the costovertebral junction ii. Segmentation and formation defects in all cervical, thoracic, and lumbar vertebrae. Sacrococcygeal regions are spared from any abnormality iii. Increase in the coronal diameter of the thoracic and lumbar vertebrae, which acquire a sicklelike appearance b. Spondylocostal dysostosis i. Varying extent of the thoracic fusion ii. Thoracic fusion always asymmetric with respect to each side of the thorax iii. Increase in the coronal diameter of the thoracic and lumbar vertebrae, which acquire a sicklelike appearance 3. Pulmonary function tests for restrictive lung disease 4. Molecular genetic analysis: DLL3 mutations in spondylocostal dysplasia (homozygous or compound heterozygous mutations)
GENETIC COUNSELING 1. Recurrence risk a. Autosomal recessive inheritance (spondylothoracic dysplasia and spondylocostal dysostosis) i. Patient’s sib: 25% ii. Patient’s offspring: not increased unless the spouse is also a carrier, in which case there is a 50% risk of having an affected offspring b. Autosomal dominant inheritance (spondylocostal dysostosis) i. Patient’s sib: not increased unless a parent is affected in which case, there is a 50% risk of having an affected sibling ii. Patient’s offspring: 50% 2. Prenatal diagnosis a. Ultrasonography i. Grossly distorted thoracic and lumbar spine ii. Marked kyphoscoliosis iii. Multiple vertebral segmentation anomalies
iv. Fanned ribs v. A small chest with foreshortened spine vi. Increased fetal nuchal translucency thickness b. Molecular genetic diagnosis of DLL3 gene mutation is available clinically by sequencing the entire coding region of fetal DNA obtained from amniocytes or CVS, provided the disease-causing allele has been previously identified. 3. Management a. Minimize positive end-expiratory pressure to avoid bronchopulmonary dysplasia b. Continuous feeding instead of in boluses to avoid stomach distension that will lead to increase diaphragmatic pressure c. Aggressive treatment of infections d. Treat the spinal deformities
REFERENCES Apuzzio JJ, Diamond N, Ganesh V, et al.: Difficulties in the prenatal diagnosis of Jarcho-Levin syndrome. Am J Obstet Gynecol 156:916–918, 1987. Aymé S, Preus M: Spondylocostal/spondylothoracic dysostosis: the clinical basis for prognosticating and genetic counseling. Am J Med Genet 24:599–606, 1986. Bannykh SI, Emery SC, Gerber JK, et al.: Aberrant Pax1 and Pax9 expression in Jarcho-Levin syndrome: report of two Caucasian siblings and literature review. Am J Med Genet 120A:241–246, 2003. Bautista DB, Kahlstrom EJ, Gozal D: Recurrence of spondylothoracic dysplasia (Jarcho-Levin syndrome) in a family. South Med J 90:1234–1237, 1997. Bonafe L, Giunta C, Gassner M, et al.: A cluster of autosomal recessive spondylocostal dysostosis caused by three identified DLL3 mutations segregating in a small village. Clin Genet 64:28–35, 2003. Bulman MP, Kusumi K, Frayling TM, et al.: Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat Genet 24:438–441, 2000. Cornier AS, Ramirez N, Carlo S, et al.: Controversies surrounding JarchoLevin syndrome. Curr Opin Pediatr 15:614–620, 2003. Cornier AS, Ramirez N, Arroyo S, et al.: Phenotype characterization and natural history of spondylothoracic dysplasia syndrome: a series of 27 new cases. Am J Med Genet Part A Early View. Online, 2000. Dunwoodie SL, Clements M, Duncan S, et al.: Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene DLL3 are associated with disruption of the segmentation clock within the presomitic mesoderm. Development 129:1795–1806, 2002. Eliyahu S, Weiner E, Lahav D, et al.: Early sonographic diagnosis of JarchoLevin syndrome: a prospective screening program in one family. Ultrasound Obstet Gynecol 9:314–318, 1997. Hayek S, Burke SW, Boachie-Adjei O, et al.: Jarcho-Levin syndrome: report on a long-term follow-up of an untreated patient. J Pediatr Orthop B 8:150–153, 1999. Herold HZ, Edlitz M, Baruchin A: Spondylothoracic dysplasia. A report of ten cases with follow-up. Spine 13:478–481, 1988. Hull AD, James G, Pretorius DH: Detection of Jarcho-Levin syndrome at 12 weeks’ gestation by nuchal translucency screening and three-dimensional ultrasound. Prenat Diagn 21:390–394, 2001. Jarcho S, Levin PM: Hereditary malformation of the vertebral bodies. Bull Johns Hopkins Hosp 62:216–226, 1938. Karnes P, Day D, Berry S, et al.: Jarcho-Levin syndrome: four new cases and classification of subtypes. Am J Med Genet 40:264–270, 1991. Kauffmann E, Roman H, Barau G, et al.: Case report: a prenatal case of JarchoLevin syndrome diagnosed during the first trimester of pregnancy. Prenat Diagn 23:163–165, 2003. Lawson ME, Share J, Benacerraf B, et al.: Jarcho-Levin syndrome: prenatal diagnosis, perinatal care, and follow-up of siblings. J Perinatol 17:407–409, 1997. Marks F, Hernanz-Schulman M, Horii S, et al.: Spondylothoracic dysplasia. Clinical and sonographic diagnosis. J Ultrasound Med 8:1–5, 1989. Mart`inez-Fr`ias ML, Urioste M: Segmentation anomalies of the vertebras and ribs: a developmental field defect: epidemiologic evidence. Am J Med Genet 49:36–44, 1994.
JARCHO-LEVIN SYNDROME Mooney JF III, Emans JB: Progressive kyphosis and neurologic compromise complicating spondylothoracic dysplasia in infancy (Jarcho-Levin syndrome). Spine 20:1938–1942, 1995. Mortier GR, Lachman RS, Maureen B, et al.: Multiple vertebral segmentation defects: analysis of 26 new patients and review of the literature. Am J Med Genet 61:310–319, 1996. Moseley JE, Bonforte RJ: Spondylothoracic dysplasia—a syndrome of congenital anomalies. Am J Roentgenol Radium Ther Nucl Med 106:166–169, 1969. Rimoin DL, Fletcher BD, McKusick VA: Spondylocostal dysplasia. A dominantly inherited form of short-trunked dwarfism. Am J Med 45:948–953, 1968. Romeo MG, Distefano G, Di Bella D, et al.: Familial Jarcho-Levin syndrome. Clin Genet 39:253–259, 1991. Roberts AP, Conner Adv Neurol, Tolmie JL, et al.: Spondylothoracic and Spondylocostal dysostosis. J Bone Joint Surg 70-B:123–126, 1988. Rodriguez MM, Mejias A Jr, Haun RL, et al.: Spondylocostal dysostosis with perinatal death and meningomylocele. Pediatr Pathol 14:53–59, 1994.
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Solomon L, Jimenes R, Riener L: Spondylothoracic dysostosis: report of two cases and review of literature. Arch Pathol Lab Med 102:201–205, 1978. Tolmie JL, Whittle MJ, McNay MB, et al.: Second trimester prenatal diagnosis of the Jarcho-Levin syndrome. Prenat Diagn 7:129–134, 1987. Turnpenny PD, Thwaites RJ, Boulos FN, et al.: Evidence for variable gene expression in a large inbred kindred with Autosomal recessive spondylocostal dysostosis. J Med Genet 28:27–33, 1991. Turnpenny PD, Bulman MP, Frayling TM, et al.: A gene for autosomal recessive spondylocostal dysostosis maps to 19q13.1-q13.3. Am J Hum Genet 65:175–182, 1999. Turnpenny PD, Whittock N, Duncan J, et al.: Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signaling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis. J Med Genet 40:333–339, 2003. Whittock NV, Sparrow DB, Wouters MA, et al.: Mutated MESP2 causes spondylocostal dysostosis in humans. Am J Hum Genet 74:1249–1254, 2004. Wong G, Levine D: Jarcho-Levin syndrome: two consecutive pregnancies in a Puerto Rican couple. Ultrasound Obstet Gynecol 12:70–73, 1998.
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Fig. 1. Two infants with spondylocostal dysostosis with typical crablike deformities of the chest with fused ribs (radiographs).
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Fig. 3. Radiograph of an infant with spondylothoracic dysplasia showing severe chest deformity.
Fig. 2. Radiographs of another infant with spondylocostal dysostosis showing fused ribs and fused vertebrae.
Kabuki Syndrome In 1981, Niikawa and Kuroki independently described a previously unrecognized mental retardation-malformation syndrome, characterized by a unique combination of craniofacial anomalies, congenital heart defects, skeletal anomalies, persistent fetal fingertip pads, dermatoglyphic abnormalities, mental retardation, and short stature. Because the peculiar facial appearance resembles the makeup of Kabuki actors in a traditional Japanese theater, the Niikawa-Kuroki syndrome is also known as Kabuki or Kabuki makeup syndrome. The prevalence of the syndrome is estimated to be 1 in 32,000 live births in Japan. The syndrome is increasingly recognized in other parts of the world.
GENETICS/BASIC DEFECTS 1. Sporadic in most cases 2. Autosomal dominant inheritance suggested in a few families 3. Other hypotheses a. Postzygotic mutation, suggested by discordance between the twins, although multifactorial causes cannot be ruled out b. Several instances of chromosomal abnormalities have been reported in the literature but without identical breakpoints in those autosomal abnormalities c. Microdeletion involving several contiguous genes, suggested by sporadic cases in the majority of patients and a wide spectrum of clinical manifestations. So far, no chromosomal deletion was detected at the sites of the DiGeorge/velocardiofacial chromosomal region within 22q11.2 or flanking the van der Woude syndrome region at 1q32-q41
2.
3.
CLINICAL FEATURES 1. Craniofacial abnormalities a. Peculiar facial appearance (100%): the most striking feature of the syndrome i. Peculiar face that consists of eversion of the low lateral eyelid that is reminiscent of a Kabuki actor’s makeup and arched eyebrows with sparseness of their lateral one-third ii. Long palpebral fissures iii. Depressed nasal tip iv. Prominent, large ears b. Microcephaly (26%) c. Eye abnormalities i. Long palpebral fissure (99%) ii. Lower palpebral eversion (92%) iii. Arched eyebrow (85%) iv. Ptosis (50%) v. Epicanthus (46%) vi. Strabismus (36%) vii. Blue sclerae (31%) 559
4.
5. 6.
d. Nasal abnormalities i. Short nasal septum (92%) ii. Depressed nasal tip (83%) e. Ear abnormalities i. Prominent ears (84%) ii. Malformed ears (87%) iii. Preauricular dimple/fistula (22%) f. Oral abnormalities i. High-arched palate (72%) ii. Abnormal dentition (68%) iii. Microganthia (40%) iv. Cleft palate/lip (35%) v. Lower lip pit (27%) g. Low posterior hair line (57%) Skeletal abnormalities (88%) a. Pilonidal sinus (83%) b. Short fifth middle phalanges (80%) c. Short fifth fingers (79%) d. Joint laxity (74%) e. Clinodactyly of fifth fingers (50%) f. Sagittal cleft of vertebral body (36%) g. Scoliosis (35%) h. Short metacarpals (35%) i. Deformed vertebra/rib (32%) j. Foot deformity (24%) k. Spina bifida occulta (19%) l. Hip dislocation (18%) m. Rib anomaly (18%) n. Coarse carpal bone (17%) o. Cone-shaped epiphyses (13%) p. Patellar dislocation Dermatoglyphic abnormalities a. Abnormal dermatoglyphics (96%) i. Frequent fingertip ulnar loop patterns ii. Absence of digital triradius “c” or “d” iii. An interdigital triradius “bc” or “cd” iv. Fourth interdigital area patterns a) Hypothenar loop patterns b) Ulnar loop patterns b. Presence of fingertip pads (89%): possible remnants of fetal pads Neurologic abnormalities a. Mild to moderate mental retardation (IQ<80) (84%) b. Hypotonia (68%) c. Neonatal hypotonicity (28%) d. Seizures (17%) e. Brain atrophy (4%) f. Retinal pigmentation (3%) Short stature (55%) Visceral abnormalities a. Cutaneous abnormalities i. Hyperpigmented nevus (22%) ii. Generalized hirsutism (11%)
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b. Cardiovascular anomalies (42%) i. Ventricular septal defect ii. Atrial septal defect iii. Coarctation of the aorta iv. Transposition of great vessels c. Gastrointestinal abnormalities i. Umbilical hernia (9%) ii. Inguinal hernia (7%) iii. Malrotation of the colon (6%) iv. Anal atesia/rectovaginal fistula (5%) d. Genitourinary abnormalities i. Kidney/urinary tract malformations (28%) ii. Undescended testes (24%) iii. Small penis (10%) 7. Other features a. Susceptibility to infections i. Recurrent otitis media (63%) ii. Repeat upper respiratory tract infections and pneumonias iii. Single case reports a) Severe immunodeficiency b) Autoimmune hemolytic anemia and Polycythemia c) Chronic idiopathic thrombocytopenia d) Acquired hypogammaglobulinemia with antiIgA antibody b. Early breast development (28%) c. Hearing loss (27%) d. Neonatal hyperbilirubinemia (20%) e. Obesity (19%) f. Anemia (9%) g. Polycythemia (4%) h. Cystic fibrosis (2%) i. Primary ovarian dysfunction (2%)
DIAGNOSTIC INVESTIGATIONS 1. Blood sugar during infancy for neonatal hypoglycemia (7%) 2. Thyroid profile for rare TBG deficiency (2%) 3. Growth hormone determination for rare growth hormone deficiency 4. Work up for autoimmune hemolytic anemia if present 5. Audiologic screening for hearing loss 6. Radiography for skeletal abnormalities a. Frequent features i. Abnormalities of the spinal column a) Thoracic or lumbar scoliosis b) Sagittal cleft vertebra c) Narrow disc space d) Cervical ribs e) Schmorl node ii. Dislocation of the hip joints iii. Abnormalities of the hands a) Brachymesophalangy of the fifth fingers b) Short fifth metacarpals c) Cone-shaped epiphysis of proximal phalanges II–V b. Less frequent features i. Defective dentition ii. Underpneumatized mastoids iii. Sacral spina bifida occulta
7. 8. 9. 10.
iv. Osteoporotic changes of the carpal bone and metacarpals v. Underdeveloped ulnar styloids vi. Dysplastic acetabulum vii. Horseshoe kidney viii. Bifid renal pelvis Renal ultrasonography for renal abnormalities Echocardiography for congenital heart defects MRI/CT scan for rare CNS anomalies Dermatoglyphic analysis
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: low recurrence risk unless a parent has an autosomal dominant form of the syndrome b. Patient’s offspring: low recurrence risk unless the patient has an autosomal dominant form of the syndrome 2. Prenatal diagnosis: none described to date 3. Management a. Multidisciplinary approach to developmental delay and mental retardation b. Hearing aids for hearing loss c. Treat infections d. Growth hormone replacement therapy for growth hormone deficiency e. Orthopedic intervention for scoliosis, dislocations, and foot deformities f. Cardiac surgery for severe congenital heart defects g. Surgical repair of cleft lip/palate, gastrointestinal, and anorectal anomalies
REFERENCES Courtens W, Rassart A, Stene JJ, et al.: Further evidence for autosomal dominant inheritance and ectodermal abnormalities in Kabuki syndrome. Am J Med Genet 93:244–249, 2000. Digilio MC, Marino B, Toscano A, et al.: Congenital heart defects in Kabuki syndrome. Am J Med Genet 100:269–274, 2001. Halal F, Gledhill R, Dudkiewicz A: Autosomal dominant inheritance of the Kabuki make-up (Niikawa-Kuroki) syndrome. Am J Med Genet 33:376–381, 1989. Handa Y, Maeda K, Toida M, et al.: Kabuki make-up syndrome (NiikawaKuroki syndrome) with cleft lip and palate. J Craniomaxillofac Surg 19:99–101, 1991. Kobayashi O, Sakuragawa N: Inheritance in Kabuki make-up (NiikawaKuroki) syndrome. Am J Med Genet 61:92–93, 1996. Kuroki Y, Suzuki Y, Chyo H, et al.: A new malformation syndrome of long palpebral fissure, large ears, depressed nasal tip and skeletal anomalies associated with postnatal dwarfism and mental retardation. J Pediatr 99:570–573, 1981. Kuroki Y, Katsumata N, Eguchi T, et al.: Precocious puberty in Kabuki makeup syndrome. J Pediatr 110:750–752, 1987. Matsumoto N, Niikawa N: Kabuki make-up syndrome: a review. Am J Med Genet 117C:57–65, 2003. Niikawa N, Matsuura N, Fukushima Y, et al.: Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J Pediatr 99:565–569, 1981. Niikawa N, Kuroki Y, Kajii T: The dermatoglyphic pattern of the Kabuki makeup syndrome. Clin Genet 21:315–320, 1982. Niikawa N, Kuroki Y, Kajii T, et al.: Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 62 patients. Am J Med Genet 31:565–589, 1988. Schrander-Stumpel C, Meinecke P, Wilson G, et al.: The Kabuki (NiikawaKuroki) syndrome: further delineation of the phenotype in 29 nonJapanese patients. Eur J Pediatr 153:438–445, 1994. Tsukahara M, Kuroki Y, Imaizumi K, et al.: Dominant inheritance of Kabuki make-up syndrome. Am J Med Genet 73:19–23, 1997. Wessels MW, Brooks AS, Hoogeboom J, et al.: Kabuki syndrome: a review study of three hundred patients. Clin Dysmorphol 11:95–102, 2002.
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Fig. 2. A one-year-old girl with Kabuki syndrome showing arched eyebrows, long palpebral fissures, short nasal septum, and hypertrophic breasts. The infant also has cleft palate, large ears, and congenital hip dislocations.
Fig. 3. A one-year-old boy with Kabuki syndrome showing arched eyebrows, long palpebral fissures, everted lateral half of the lower eyelids, blue sclera, strabismus, short nasal septum, small chin, and large and prominent ears. Fig. 1. A 12-year-old girl with Kabuki syndrome showing arched eyebrows, long palpebral fissures, everted lateral half of the lower eyelid, short nasal septum, post-cleft lip repair, prominent ears, and prominent finger pads.
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Fig. 4. A 12-year-old boy with Kabuki syndrome showing characteristic facial features consisting of long palpebral fissures, arched eyebrows, bilateral lower lateral palpebral eversion, short nasal septum, high-arched palate, low hair line, and prominent finger pads. Other anomalies include mild mental retardation, neonatal hypotonia, recurrent otitis media and upper respiratory infections, joint laxity, ventricular septal defect, hip dysplasia, and short and clinodactyly of the 5th fingers.
Kasabach-Merritt Syndrome Kasabach-Merritt syndrome (or phenomenon) is the association of a vascular tumor and thrombocytopenic coagulopathy.
GENETICS/BASIC DEFECTS 1. Genetics a. Sporadic in majority of cases b. Autosomal dominant inheritance in rare reports c. Can be a part of recognized syndromes 2. Pathophysiology a. Platelet trapping by abnormally proliferating endothelium within the hemangioma, resulting in the activation of platelets with a secondary consumption of clotting factors b. Continued consumption of both platelets and clotting factors along with the initiation of fibrinolysis eventually resulting in intralesional bleeding which manifests as rapid enlargement of the hemangioma
CLINICAL FEATURES 1. Diverse clinical presentation a. Type of hemangiomas i. Kaposiform hemangioendothelioma: often found in noncutaneous sites such as the retroperitoneum, mediastinum and pelvis, as well as the skin ii. Tufted angioma iii. Mixture of Kaposiform hemangioendothelioma and tufted angioma iv. Not “true” common hemangioma of infancy b. Reddish brown skin lesion progressing to a violaceous bulging mass i. Often painful ii. Aggressive infiltration with ulceration iii. Bruising in other areas iv. Possible infection c. Bleeding from thrombocytopenia and intravascular coagulopathy d. Increase in size and becoming tense, woody, and purplish of preexisting hemangiomas during pregnancy 2. Cutaneous involvement of Kaposiform hemangioendothelioma a. Smooth, shiny, dark purple, indurated, tender and poorly delineated b. Nearly always single 3. Visceral involvement of hemangiomata a. Single b. Multiple c. Isolated within one organ as single or diffuse lesions d. Retroperitoneal hemangiomata i. Often giant in size ii. Easily missed clinically: diagnosis suspected in patients presenting with an unexplained thrombocytopenia and coagulopathy iii. Generally associated with high mortality 563
4. Diffuse and multiple nature a. Diffuse infantile (neonatal) hemangiomatosis i. Presence of multiple cutaneous and visceral hemangiomata ii. High morbidity and mortality b. Intraosseous and soft tissue hemangiomata 5. Life-long hemangioma in adults a. Hormone alterations and increase in blood volume in pregnancy may affect pre-existing lesions, triggering episodes of acute disseminated intravascular coagulation b. Development of acute consumptive coagulopathy after surgery of other unrelated tumor 6. Thrombocytopenic coagulopathy in patients with hemangiomata as a part of a recognized syndrome a. Klippel-Trenaunay syndrome i. A rare congenital generalized mesodermal abnormality ii. Macular vascular nevus, skeletal/soft tissue hypertrophy iii. Venous and lymphatic anomalies including viscera and facial hemangiomata b. Blue rubber bleb nevus syndrome i. Multiple cutaneous cavernous hemangiomata ii. Cutaneous and occasional visceral hemangiomata c. Gorham-Stout disease (‘vanishing bone disease’) i. Massive osteolysis (Gorham sign) ii. Followed by replacement of the bony matrix by proliferating thin-walled vascular and lymphatic channels iii. Extension of these angiomatous masses into soft tissues 7. Prognosis a. Incomplete regression of the lesion after months or years b. Visceral involvement i. Mediastinum ii. Neck iii. Retroperitoneum iv. Pelvis c. Hemorrhage by aggressive invasion d. Petechiae, ecchymoses, or purpura e. Profound thrombocytopenia f. Anemia g. Congestive heart failure h. Severe infections i. Residual lesions after “cure” of Kasabach-Merritt phenomenon i. Common after the resolution of thrombocytopenia and coagulopathy ii. Clinical patterns a) Cutaneous red stain with or without associated red papules
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b) Telangiectatic streaks and swelling c) A minor, firm, irregular subcutaneous mass assessed by palpation or deep infiltration evidenced by CT scan or MRI d) Sequelae in muscles and/or joints j. Overall mortality estimated to be 20–30%
c.
DIAGNOSTIC INVESTIGATIONS 1. Laboratory studies a. Generally severe thrombocytopenia: occurs in 1–2 per 300–700 cases of hemangioma b. Consumptive coagulopathy i. Prominent fibrinogenopenia ii. Usually elevated fibrin split (degration) products iii. Usually elevated D-dimers iv. Depressed clotting factors V and VII 2. Ultrasound, MRI or CT a. To assess extent of the lesions b. To identify the occult lesions 3. Histology to determine subtypes of hemangioma a. Kaposiform hemangioendothelioma of infancy and childhood i. The most frequently reported histological type ii. A locally aggressive, low-grade malignant tumor iii. Lobules or sheets of tightly packed spindle cells or more rounded endothelial cells and pericytes iv. Infiltrative pattern of the cellular areas in the dermis and subcutaneous fat and muscles, generally containing few obvious vascular lumina v. Aggregates of rounded dilated capillaries, lined by attenuated endothelial cells with small dark nuclei and filled with red blood cells vi. Containing lymphatic-like vessels b. Tufted angioma i. A benign lesion ii. Small tufts or lobules of rounded capillaries with small lumina iii. Tufts: discrete and evenly distributed in a cannon ball pattern, characterized by peripheral crescentic slit-like vessels and fibrosis iv. Aggregates of rounded dilated capillaries, lined by attenuated endothelial cells with small dark nuclei and filled with red blood cells
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected b. Patient’s offspring: 50% in case of autosomal dominant inheritance 2. Prenatal diagnosis: Prenatal diagnosis of fetal face hemangioma in a case of Kasabach-Merritt syndrome 3. Management a. General premise regarding treatment: resolution of the lesion will lead to a correction of the consumptive coagulopathy, which is heralded by a recovery in the platelet count b. Prompt and vigorous management i. Help to optimize the outcome
d.
e.
f.
g.
ii. No one treatment modality established as consistently efficacious Blood product support in the presence of sudden decompensation or enlargement of the lesion i. Fresh frozen plasma ii. Cryoprecipitate if fibrinogen still less than 1.0 g/L iii. Platelets for thrombocytopenic patient who is bleeding iv. Tranexamic acid for profound fibrinolysis Simple or single lesion i. Vascular ligation ii. Embolization iii. Surgical excision a) Surgical removal of a giant hemangioma: usually hazardous in the presence of an uncontrolled consumptive coagulopathy b) Supporting and stabilizing hemostasis while trying to remove or ablate the lesion Diffuse or extensive lesions i. Prednisone ii. Alpha interferon Adjuvant therapies i. Vincristine ii. Localized radiotherapy iii. Combination chemotherapy (vincristine, cyclophosphamide) iv. Antifibrinolytic or antiplatelet agents (tranexamic acid, ε-amino caproic acid, pentoxifylline, ticlopidine) Potential future therapies i. Laser therapy ii. Antiangiogenic agents iii. Pegylated recombinant human megakaryocyte growth and development factor (peg-rHuMGDF)
REFERENCES Alvarez-Mendoza A, Lourdes TS, Ridaura-Sanz C, et al.: Histopathology of vascular lesions found in Kasabach-Merritt syndrome: review based on 13 cases. Pediatr Dev Pathol 3:556–560, 2000. Biban P: Kasabach-Merritt syndrome and interferon alpha: still a controversial issue. Arch Dis Child 88:645–646, 2003. Billio A, Pescosta N, Rosanelli C, et al.: Treatment of Kasabach-Merritt syndrome by embolisation of a giant liver hemangioma. Am J Hematol 66:140–141, 2001. Blei F: Successful multimodal therapy for kaposiform hemangioendothelioma complicated by Kasabach-Merritt phenomenon: case report and review of the literature. Pediatr Hematol Oncol 15:293–305, 1998. Brizel HE, Raccuglia G: Giant hemangioma with thrombocytopaenia-radioisotope demonstration of platelet sequestration. Blood 26:751–756, 1965. Cheerva AC, Bartolone C: Kasabach-Merritt syndrome. Emedicine, 2002. http://www.emedicine.com de Terlizzi M, Bonifazi E, Toma MG, et al.: Kasabach-Merritt syndrome: successful management of coagulopathy with heparin and cryoprecipitate. Pediatr Hematol Oncol 5:325–328, 1988. Dresse MF, David M, Hume H, et al.: Successful treatment of KasabachMerritt syndrome with prednisone and epsilon-aminocaproic acid. Pediatr Hematol Oncol 8:329–334, 1991. Enjolras O, Wassef M, Mazoyer E: Infants with Kasabach-Merritt syndrome do not have “true” hemangiomas. J Pediatr 130:631–640, 1997. Enjolras O, Mulliken JB, Wassef M: Residual lesions after Kasabach-Merritt phenomenon in 41 patients. J Am Acad Dermatol 42:225–235, 2000. Esterly NB: Kasabach-Merritt syndrome in infants. J Am Acad Dermatol 8:504–513, 1983. Esterly NB: Cutaneous hemangiomas, vascular stains and malformations, and associated syndromes. Curr Probl Dermatol 7(3):65–108, 1995.
KASABACH-MERRITT SYNDROME Frevel T, Rabe H, Uckert F, et al.: Giant cavernous haemangioma with KasabachMerritt syndrome: a case report and review. Eur J Pediatr 161:243–246, 2002. Gianotti R, Gelmetti C, Alessi E: Congenital cutaneous multifocal kaposiform hemangioendothelioma. Am J Dermatopathol 21:557–561, 1999. Haisley-Royster C, Enjolras O, Frieden IJ, et al.: Kasabach-merritt phenomenon: a retrospective study of treatment with vincristine. J Pediatr Hematol Oncol 24:459–462, 2002. Hatley RM, Sabio H, Howell CG, et al.: Successful management of an infant with a giant hemangioma of the retroperitoneum and Kasabach-Merritt syndrome with alpha-interferon. J Pediatr Surg 28:1356–1357; discussion 1358–1359, 1993. Hall GW: Kasabach-Merritt syndrome: pathogenesis and management. Br J Haematol 112:851–862, 2001. Hesselmann S, Micke O, Marquardt T, et al.: Case report: Kasabach-Merritt syndrome: a review of the therapeutic options and a case report of successful treatment with radiotherapy and interferon alpha. Br J Radiol 75:180–184, 2002. Kasabach HH, Merritt KK: Capillary hemangioma with extensive purpura. Report of a case. Am J Dis Child 59:1063–1070, 1940.
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Krafchik BR, Hendricks LK: Kasabach-Merritt syndrome. Emedicine, 2003. http://www.emedicine.com Larsen EC, Zinkham WH, Eggleston JC, et al.: Kasabach-Merritt syndrome: therapeutic considerations. Pediatrics 79:971–980, 1987. Lee JH Jr, Kirk RF: Pregnancy associated with giant hemangiomata, thrombocytopenia, and fibrinogenopenia (Kasabach-Merritt syndrome). Report of a case. Obstet Gynecol 29:24–29, 1967. Ogino I, Torikai K, Kobayasi S, et al.: Radiation therapy for life- or functionthreatening infant hemangioma. Radiology 218:834–839, 2001. Ozsoylu S: Treatment of Kasabach-Merritt syndrome by megadose methylprednisolone. Pediatr Hematol Oncol 19:373–374, 2002. Phillippe M, Acker D, Frigoletto FD Jr: Pregnancy complicated by the Kasabach-Merritt syndrome. Obstet Gynecol 56:256–258, 1980. Powell J: Update on hemangiomas and vascular malformations. Curr Opin Pediatr 11:457–463, 1999. Respondek-Liberska M, Janiak K, Jakubek A, et al.: Prenatal diagnosis of fetal face hemangioma in a case of Kasabach-Merritt syndrome. Ultrasound Obstet Gynecol 19:627–629, 2002. Singh G, Rajendran C: Kasabach-Merritt syndrome in two successive pregnancies. Int J Dermatol 37:690–693, 1998.
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Fig. 2. A patient with blue rubber bleb nevus syndrome.
Fig. 1. An infant with Kasabach-Merritt syndrome showing a giant cavernous hemangioma over most of the chest.
KID Syndrome KID syndrome is an acronym for the syndrome characterized by keratitis, ichthyosis, and deafness, a term proposed by Skinner et al. in 1981.
GENETICS/BASIC DEFECTS 1. Genetic heterogeneity a. Sporadic in most cases b. Existence of familial cases suggesting a genetic etiology i. A vertical transmission suggesting an autosomal dominant disease ii. The occurrence in two sisters born to consanguineous, unaffected parents suggesting an autosomal recessive inheritance 2. Caused by heterozygous missense mutations in the connexin26 gene, GJB2, which is implied in the normal corneal function, hair growth, and carcinogenesis. Mutations in several other genes [GJB3 (connexin-31), GJB6 (connexin30)], which encodes members of the connexin family of gap-junction proteins, are shown to be responsible for hearing impairment and skin disorders. 3. Pathogenesis: failure in development and differentiation of multiple stratifying epithelia
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CLINICAL FEATURES 1. Cutaneous features a. Abnormal skin at birth: red, dry, thickened, and leathery b. Subsequent development of keratodermatous, nonscaly plaques i. Generally develop during the first year of life ii. Described as verrucous, ichthyotic, doughy, rugal, or elephant-skin-like iii. Develop primarily on the face and extremities iv. Plaques sharply demarcated and map-like in contour v. Plaques symmetrically located on the face a) Especially the cheeks b) With variable involvement of the forehead, ears, chin, and nose c) Furrows in the thickened skin of the chin and around the mouth vi. Transverse ripples marking the surface of plaques over the knees vii. Follicular keratoses, occasionally with spine-like projections, on the extremities, eyebrows, scalp, earlobes, neck, and nose c. Distinct keratoderma of the palms and soles i. Pebbly excrescences and an intervening coarsely stippled pattern analogous to heavily grained leather ii. Patulous stippling rendering a moth-eaten appearance 567
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d. Abnormal hair i. Sparse, fine, and sometimes absent scalp, eyebrow, and eyelash hair ii. Pattern of patch scalp alopecia resembling pseudopelade iii. Body hair may be absent iv. Nails a) Thickened b) Hypoplastic c) Absent d) White e) Infrequently normal Ophthalmologic features a. Invariably involving epibulbar structures with inflammation of the cornea i. Vascularized keratitis in majority of cases ii. Secondary pannus formation b. Photophobia c. Varying degree of visual impairment d. Onset: usually before adolescence Auditory features a. Sensorineural deafness b. Repeat otitis media and externa Other ectodermal abnormalities a. Dental abnormalities i. Carious ii. Brittle iii. Malformed iv. Delayed adult dentition b. Hypohidrosis Neuroectodermal abnormalities a. Short heel cord b. Cerebellar hypoplasia Other associated features a. Normal intelligence b. Growth delay c. Increased risk of developing squamous cell carcinoma d. Increased susceptibility to viral, bacterial and mycotic infections i. Most commonly reported pathogens a) Staphylococcus aureus b) Eschericia coli c) Pseudomonas aeruginosa d) Trychophyton rubrum e) Candida albicans ii. Invasive and overwhelming infection may be present in infancy and early childhood. Death secondary to overwhelming sepsis has been reported in infancy iii. Infections typically persistent and recurrent, but usually limited to the skin in older children and adults iv. No consistent pattern of immunologic dysfunction demonstrated in patients with KID syndrome
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DIAGNOSTIC INVESTIGATIONS 1. Dental examinations for teeth abnormalities 2. Ophthalmological examination for corneal pathology and visual acuity 3. Audiologic examination to demonstrate sensorineural hearing loss 4. Histopathology of the skin a. Findings not specific b. Stratum corneum i. Always hyperkeratotic, usually with a basketweave pattern ii. Orthokeratotic and occasionally parakeratotic c. Stratum granulosum: generally intact d. Eccrine sweat glands appearing normal, although a diminished number and aberrant morphology have been noted e. Absent or atrophic hair follicles indicating the customary state of alopecia f. Follicular plugging is the rule 5. Molecular genetic study to detect connexin 26 gene (GJB2) mutation
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal dominant inheritance: not increased unless a parent is affected ii. Autosomal recessive inheritance: 25% b. Patient’s offspring i. Autosomal dominant inheritance: 50% ii. Autosomal recessive inheritance: not increased unless the spouse is a carrier or affected 2. Prenatal diagnosis: none reported to date 3. Management a. No specific treatment for the skin lesions b. Isotretinoin with inconsistent results i. May cause exacerbation of eye lesion a) Marked increase in pannus formation b) Marked increase in vascularization
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ii. Side effects of higher doses of isotretinoin a) Corneal opacities b) Punctate erosions c) Blepharo-conjunctivities Ophthalmologic evaluations and follow up. Corneal grafts revascularize rapidly with subsequent loss of vision Treat infections vigorously Surveillance for skin and mucosal malignancy Hearing aids Appropriate school placement
REFERENCES Alvarez A, del Castillo I, Pera A, et al.: De novo mutation in the gene encoding connexin-26 (GJB2) in a sporadic case of keratitis-ichthyosisdeafness (KID) syndrome. Am J Med Genet 117A:89–91, 2003. Caceres-Rios H, Tamayo-Sanchez L, Duran-Mckinster C, et al.: Keratitis, ichthyosis, and deafness (KID syndrome): review of the literature and proposal of a new terminology. Pediatr Dermatol 13:105–113, 1996. Ghadially R, Chong LP: Ichthyoses and hyperkeratotic disorders. Dermatol Clin 10:597–607, 1992. Gilliam A, Williams ML: Fatal septicemia in an infant with keratitis, ichthyosis, and deafness (KID) syndrome. Pediatr Dermatol 19:232–236, 2002. Grob JJ, Breton A, Bonafe JL, et al.: Keratitis, ichthyosis, and deafness (KID) syndrome. Vertical transmission and death from multiple squamous cell carcinomas. Arch Dermatol 123:777–782, 1987. Kelsell DP, Di WL, Houseman MJ: Connexin mutations in skin disease and hearing loss. Am J Hum Genet 68:559–568, 2001. Langer K, Konrad K, Wolff K: Keratitis, ichthyosis and deafness (KID)syndrome: report of three cases and a review of the literature. Br J Dermatol 122:689–697, 1990. McGrae J: Keratitis, ichthyosis, and deafness (KID) syndrome. Int J Dermatol 29:89–93, 1990. Richard G: Connexins: a connection with the skin. Exp Dermatol 9:77–96, 2000. Richard G, Rouan F, Willoughby CE, et al.: Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitisichthyosis-deafness syndrome. Am J Hum Genet 70:1341–1348, 2002. van Geel M, van Steensel MA, Kuster W, et al.: HID and KID syndromes are associated with the same connexin 26 mutation. Br J Dermatol 146:938–942, 2002. van Steensel MA, van Geel M, Nahuys M, et al.: A novel connexin 26 mutation in a patient diagnosed with keratitis-ichthyosis-deafness syndrome. J Invest Dermatol 118:724–727, 2002. Wilson GN, Squires RH Jr, Weinberg AG: Keratitis, hepatitis, ichthyosis, and deafness: report and review of KID syndrome. Am J Med Genet 40:255–259, 1991.
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Fig. 2. Marked hyperkeratosis is visible around the eye and the outer rim of the ear.
Fig. 3. Chronic Candida albicans onychia and paronychia with hypertrophy of distal digits and hyperkeratosis of the skin are apparent on both hands.
Fig. 1. A 26-year-old woman with keratitis, ichthyosis, and deafness. Cutaneous manifestations show sharply demarcated red-brown hyperkeratotic plaques on the central face, around both eyes, and upper and lower extremities.
Klinefelter Syndrome Klinefelter syndrome is the most common sex chromosomal disorder associated with male hypogonadism and infertility. Approximately 1 in 500–1000 males is born with an extra X chromosome. Over 3000 affected males are born yearly in the US.
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GENETICS/BASIC DEFECTS 1. Caused by at least an additional X chromosome in a male 2. The XXY form of Klinefelter syndrome a. Due to meiotic nondisjunction of the sex chromosomes during gametogenesis in either parent b. Responsible meiotic nondisjunction i. About 40% occur in the father ii. About 60% occur in the mother a) Meiosis I errors (75%) when origin is maternal b) Presence of maternal age effect in the maternally derived cases 3. The mosaic forms of Klinefelter syndrome a. Due to mitotic nondisjunction after fertilization of the zygote b. Can arise from a 46,XY zygote or a 47,XXY zygote 4. The variant forms a. 48,XXXY b. 49,XXXXY: please refer to 49, XXXXY chapter c. 48,XXYY and 49,XXXYY: occurrence of nondisjunction in paternal meiosis to have two Y chromosomes i. An X ovum fertilized by an XYY sperm arising from successive nondisjunction in the first and second meiotic divisions, or ii. An XX ovum from 47,XXX mother fertilized by a YY sperm
CLINICAL FEATURES 1. Growth a. Infants and children: normal heights, weights, and head circumferences b. Adolescents and adults i. Eunuchoid body habitus ii. Usually taller than average iii. Disproportionately long arms and legs 2. Mild developmental, learning, and behavioral difficulties (70% of patients) a. Delayed speech and language acquisition b. Academic and reading difficulties c. Attention deficit disorder d. Poor self-esteem e. Insecurity f. Shyness g. Poor judgment h. Inappropriate assertive activity 570
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i. Decreased ability to deal with stress j. Fatigue k. Weakness CNS a. Normal intelligence in most cases b. Subnormal intelligence or mental retardation associated with a higher number of X chromosomes c. Diminished short term memory d. Prone to epilepsy and essential tremor e. Psychiatric disorders involving anxiety, depression, neurosis, and psychosis: more common than general population Taurodontism (enlargement of the molar teeth by an extension of the pulp): present in about 40% of patients (vs 1% in normal XY individuals) Cardiac and circulatory problems a. Mitral valve prolapse (55% of patients) b. Varicose veins (20–40% of patients) i. Venous ulcers ii. Deep vein thrombosis iii. Pulmonary embolism A slightly increased risk of autoimmune disorder a. Systemic lupus erythematosis b. Thyroid disease c. Rheumatoid arthritis d. Sjogren syndrome e. Diabetes mellitus Sexual characteristics a. Gynecomastia secondary to elevated estradiol levels and increased estradiol/testosterone ratio i. Develop by late puberty in 30–50% of boys with Klinefelter syndrome ii. Risk of developing breast cancer: at least 20 times higher than normal b. Lack of secondary sexual characteristics secondary to decrease in androgen production i. Sparse facial, body, and sexual hair ii. High-pitched voice iii. Female type of fat distribution c. Male psychosexual orientation in most patients d. Subnormal libido e. Erectile dysfunction f. Oligospermia or azoospermia g. Testicular dysgenesis in postpubertal patients i. Small, firm testes ii. Testis size <10 mL h. Infertility and azoospermia resulting from atrophy of the seminiferous tubules i. Seen practically in all patients with a 47,XXY karyotype ii. Klinefelter syndrome mosaics (46,XY/47,XXY): can be fertile
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8. Other characteristics a. An increased prevalence of extragonadal germ cell tumors in the mediastinum and brain b. More common varicose veins, venous stasis ulcers, and thromboembolic disease c. The syndrome may go undiagnosed in the majority of affected men 9. Klinefelter mosaics and variants a. Klinefelter mosaic (46,XY/47,XXY) i. Less severe manifestations ii. May have normal sized testes iii. Less severe endocrine abnormalities iv. Less common gynecomastia and azoospermia v. Occasional fertile men b. Klinefelter variants i. 48,XXYY variant a) Tall stature b) Disproportionately long lower extremities c) Gynecomastia d) Delinquent behavior e) Unusual dermatoglyphic patterns f) Peripheral vascular disease, especially varicose veins and stasis dermatitis g) Poorly developed secondary sexual characteristics h) Testicular histology similar to that of 47,XXY patients i) The sex chromatin pattern indistinguishable from that of the 47,XXY patients except two fluorescent Y bodies are present in a high proportion of somatic nuclei ii. 48,XXXY variant a) Moderate to severe mental retardation b) Normal to tall stature c) Dysmorphic facies d) Small testes e) Signs of androgen deficiency iii. 49,XXXYY variant a) Mental retardation b) Somatic anomalies c) Small testes iv. 49,XXXXY variant (Severity and frequency of somatic anomalies increase as the number of X chromosomes increases) a) Mental retardation b) Short neck c) Epicanthal folds d) Radioulnar synostosis e) Clinodactyly
DIAGNOSTIC INVESTIGATIONS 1. Cytogenetic studies a. 47,XXY (80–90%) b. Mosaicism (10%) i. 46,XY/47,XXY ii. 46,XY/48,XXXY iii. 47,XXY/48,XXXY c. Variants i. 48,XXYY ii. 48,XXXY
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iii. 49,XXXYY iv. 49,XXXXY d. Structural abnormal X in addition to a normal X and Y i. 47,X,i(Xq)Y ii. 47,X,del(X)Y 2. Endocrinologic studies a. A variable degree of feminization and insufficient androgenization i. Elevated plasma FSH, luteinizing hormone, and estradiol levels ii. Low plasma testosterone levels in patients age 12–14 years c. Subnormal increased testosterone in response to human chorionic gonadotropin administration 3. Imaging studies a. Echocardiography to demonstrate mitral valve prolapse b. Radiography i. Lower bone mineral density ii. Radioulnar synostosis iii. Taurodontism 4. Histology a. Small, firm testes b. Seminiferous tubular hyalinization, sclerosis, and atrophy with focal hyperplasia of mostly degenerated Leydig cells c. Deficient or absent germ cells d. Rare spermatogenesis (azoospermia) e. Progressive degeneration and hyalinization of seminiferous tubules after puberty in mosaic patients
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sibs: recurrence risk not increased for nonmosaic patients b. Patient’s offspring i. Recurrence risk not increased since all 47,XXY individuals are infertile ii. Report of paternity in nonmosaic 47,XXY males (no other tissues were examined for possible mosaicism with a 46,XY cell line) c. A risk of having a 47,XXY offspring in a few 46,XY/47,XXY mosaic patients who fathered a child 2. Prenatal diagnosis a. Cytogenetic analysis of fetal cells obtained from amniocentesis and CVS b. Dilemma for parents since prognosis is good but the possibility of phenotypic abnormalities does exist 3. Management a. Reassurance of patients that most of the clinical features can be explained by the diminished ability of the testes to produce testosterone b. Testosterone replacement: optimal time to initiate therapy is at age 11–12 years of age to allow for the maximum effect and permit boys to experience pubertal changes with their peers i. Corrects hormone imbalance ii. Improves self-image iii. Positive effect on mood and behavior iv. Increase in masculinity
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v. Increase in strength vi. Increases libido vii. Increase in facial and pubic hair viii. Diminish fatigue and irritability c. Management of gynecomastia i. Androgen replacement therapy effective in achieving regression of less severe gynecomastia in some patients ii. Reduction mammoplasty or liposuction for severe or psychologically disturbing gynecomastia
REFERENCES Abramsky L, Chapple J: 47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of indication for postnatal diagnosis with implications for prenatal counselling. Prenat Diagn 17:363–368, 1997. Anawalt BD, Bebb RA, Matsumoto AM: Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction. J Clin Endocrinol Metab 81:3341–3345, 1996. Bagatell CJ, Bremner WJ: Androgens in men—uses and abuses. N Engl J Med 334:707–714, 1996. Bender BG, Harmon RJ, Linden MG: Psychosocial adaptation of 39 adolescents with sex chromosome abnormalities. Pediatrics 96:302–308, 1995. Bhasin S, Ma K, Sinha I: The genetic basis of male infertility. Endocrinol Metab Clin North Am 27:783–805, 1998. Boltshauser E, Meyer M, Deonna T: Klinefelter syndrome and neurologic disease. J Neurol 219:253–259, 1978. Campbell WA, Price WH: Congenital hypothyroidism in Klinefelter’s syndrome. J Med Genet 16:439–442, 1979. Carothers AD, Filippi G: Klinefelter’s syndrome in Sardinia and Scotland. Comparative studies of parental age and other aetiological factors in 47,XXY. Hum Genet 81:71–75, 1988. Chen H: Klinefelter syndrome. EMed J 1(12): December 10, 2000. De la Chapelle A: Sex Chromosome Abnormalities. In Emery AEH, Rimoin DL (eds): Principles and Practice of Medical Genetics. Edinburgh: Churchill Livingstone 1990; Vol 1:273–299. Ferrier PE, Ferrier SA, Pescia G: The XXXY Klinefelter syndrome in childhood. Am J Dis Child 127:104–105, 1974. Geschwind DH, Boone KB, Miller BL, et al.: Neurobehavioral phenotype of Klinefelter syndrome. Ment Retard Dev Disabil Res Rev 6:107–116, 2000. Harvey J, Jacobs PA, Hassold T, et al.: The parental origin of 47,XXY males. Birth Defects Original Article Series 26:289–296, 1990. Khalifa MM, Struthers JL: Klinefelter syndrome is a common cause for mental retardation of unknown etiology among prepubertal males. Clin Genet 61:49–53, 2002. Kleczkowska A, Fryns JP, Van den Berghe H: X-chromosome polysomy in the male. The Leuven experience 1966–1987. Hum Genet 80:16–22, 1988. Klinefelter HF Jr, Reifenstein EC Jr, Albright F: Syndrome characterized by gynecomastia aspermatogenesis without a-Leydigism and increased excretion of follicle-stimulating hormone. J Clin Endocr Metabl 2:615–624, 1942.
Kruse R, Guttenbach M, Schartmann B, et al.: Genetic counseling in a patient with SSY/XXXY/XY mosaic Klinefelter’s syndrome: estimate of sex chromosome aberrations in sperm before intracytoplasmic sperm injection. Fertility and Sterility 69:482–485, 1998. Laron Z, Dickerman Z, Zamir R, et al.: Paternity in Klinefelter’s syndrome-A case report. Arch Androl 8:149–151, 1982. Linden MG, Bender BG, Robinson A: Sex chromosome tetrasomy and pentasomy. Pediatrics 96:672–682, 1995. Mandoki MW, Sumner GS: Klinefelter syndrome: the need for early identification and treatment. Clin Pediatr (Philadelphia) 30:161–164, 1991. Mandoki MW, Sumner GS, Hoffman RP: A review of Klinefelter’s syndrome in children and adolescents [published erratum appears in J Am Acad Child Adolesc Psychiatry 30:516, 1991], J Am Acad Child Adolesc Psychiatry 30:167–72, 1991. Meschede D, Louwen F, Nippert I: Low rates of pregnancy termination for prenatally diagnosed Klinefelter syndrome and other sex chromosome polysomies. Am J Med Genet 80:330–334, 1998. Myhre SA, Ruvalcaba RH, Johnson HR, et al.: The effects of testosterone treatment in Klinefelter’s syndrome. J Pediatr 76:267–276, 1970. Nielsen J, Pelsen B, Sorensen K: Follow-up of 30 Klinefelter males treated with testosterone. Clin Genet 33:262–269, 1988. Peet J, Weaver DD, Vance GH: 49,XXXXY: a distinct phenotype. Three new cases and review. J Med Genet 35:420–424, 1998. Ratcliffe SG, Bancroft J, Axworthy D, et al.: Klinefelter’s syndrome in adolescence. Arch Dis Child 57:6–12, 1982. Robinson A, Bender BG, Linden MG: Prognosis of prenatally diagnosed children with sex chromosome aneuploidy. Am J Med Genet 44:365–368, 1992. Robinson A, Lubs HA, Nielsen J: Summary of clinical findings: profiles of children with 47,XXY, 47,XXX and 47,XYY karyotypes. Birth Defects Orig Artic Ser 15:261–266, 1979. Schulte-Beerbuhl M, Nieschlag E: Comparison of testosterone, dihydrotestosterone, luteinizing hormone, and follicle-stimulating hormone in serum after injection of testosterone enanthate and testosterone cypionate. Fertil Steril 33:201–203, 1980. Schwartz ID, Root AW: The Klinefelter syndrome of testicular dysgenesis. Endocrinol Metab Clin North Am 20:153–163, 1991. Smith S: Index of suspicion. Case 1. Diagnosis: Klinefelter syndrome. Pediatr Rev 13:435–436, 1992. Smyth CM, Bremner WJ: Klinefelter syndrome. Arch Intern Med 158:1309–1314, 1998. Veraart JC, Hamulyak K, Neumann HA: Leg ulcers and Klinefelter’s syndrome. Arch Dermatol 131:958–959, 1995. Verp MS, Simpson JL, Martin AO: Hypostatic ulcers in 47,XXY Klinefelter’s syndrome. J Med Genet 20:100–101, 1983. Winter JS: Androgen therapy in Klinefelter syndrome during adolescence. Birth Defects Original Article Series 26:235–245, 1990. Yoshida A, Mirura K, Nago K, et al.: Sexual function and clinical features of patients with Klinefelter’s syndrome with the chief complaint of male infertility. Int J Androl 20:80–85, 1997. Zaleski WA, Houston CS, Pozsonyi J: The XXXXY chromosome anomaly: report of three new cases and review of 30 cases from the literature. Can Med Assoc J 94:1143–1154, 1966.
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Fig. 1. A child with Klinefelter syndrome showing normal phenotype.
Fig. 3. A child with Klinefelter syndrome associated with paralyzed diaphragm requiring intubation.
Fig. 2. A child with Klinefelter syndrome showing pectus excurvatum and multiple fractures of ribs in the neonatal period during hospital stay.
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Fig. 4. 2 Adolescent boys and an adult with Klinefelter syndrome showing gynecomastia.
Fig. 7. A G-banded Karyotype showing 47,XXY chromosome constitution.
Fig. 5. An adolescent boy and an adult with Klinefelter syndrome showing female distribution of pubic hair and small scrotum containing atrophic testicles.
Fig. 6. Interphase FISH showing 2 copies of CEPX (green), 1 copy of CEPY (orange), and 2 copies of CEP18 (aqua), which was confirmed by chromosome karyotype of 47,XXY.
Klippel-Feil Syndrome In 1912, Klippel and Feil described a patient with a short neck, a low posterior hairline, and severe restriction of motion of the neck due to complete fusion of the cervical vertebrae. These features now constitute a clinical triad of the KlippelFeil syndrome (KFS).
GENETICS/BASIC DEFECTS 1. Genetic etiology unknown a. Sporadic in majority of cases b. Rare autosomal dominant transmission: identification of a familial KFS gene locus on 8q [inv(8) (q22.2-q23.3)] segregated with congenital vertebral fusion 2. Mechanism: failure in the process of segmentation of the vertebra 3. Possible causes of phenotypic variation a. Variable expression of single genes b. Associated phenotypes due to deletions or large-scale rearrangements that disrupt several genes c. Secondary phenotypes resulting from disruption of normal cervical vertebral patterning 4. Familial Klippel-Feil syndrome a. Characterized by congenital fusion of spinal vertebrae in addition to other congenital anomalies i. Otolaryngological abnormalities ii. Craniofacial abnormalities b. The first KFS gene (SGM1) locus identified on chromosome 8q [inv(8)(q22.2-q23.3)] segregating with vertebral fusions and associated vocal impairment within the family 5. Suggestion of a possible role of PAX1 haplo insufficiency in Klippel-Feil syndrome a. Observation that the mouse Pax1 mutant phenotype undulated is characterized by vertebral segmentation defects reminiscent of the human disorder KlippelFeil syndrome b. Observation of differences in the PAX1 sequence (missense, silent or intronic changes not represented in the control panel tested) in 6 out of 63 patients
CLINICAL FEATURES 1. Triad seen in <50% of patients indicating almost complete cervical involvement and may be clinically evident at birth a. Short, webbed neck b. Low posterior hair line c. Limitations of cervical motion (lateral bend and rotation) with associated congenital cervical fusions 2. Facial asymmetry 3. Torticollis 4. Associated anomalies a. Congenital scoliosis (60%) 575
b. Sprengel deformity (30%) i. Congenital elevation of the scapula resulting from interruption of the normal caudal migration of the scapula ii. Hypoplastic scapula iii. Scapula fixation iv. Associated anomalies including absent or fused ribs, chest-wall asymmetry, Klippel-Feil syndrome, cervical ribs, congenital scoliosis, cervical spina bifida, and presence of omovertebral bone c. Hearing impairment (audiologic testing) (30%) d. Synkinesia (mirror movements) (20%) e. Renal anomalies (35%) (renal ultrasound) i. Unilateral renal agenesis (most common renal anomaly) ii. Renal malrotation iii. Horseshoe kidney iv. Ectopic kidney v. Renal pelvic and ureteral duplication vi. Renal dysgenesis f. Congenital heart disease (14%): most common being ventricular septal defect g. Hemifacial microsomia h. Neural tube defects i. Ptosis j. Cervico-oculo-acoustic (Wildervanck) syndrome i. Mixed hearing loss ii. Fused cervical vertebra iii. Bilateral abducens palsy with retracted bulb (Duane syndrome) k. Lateral rectus palsy l. Facial nerve palsy m. Upper extremity anomalies 5. Complaints a. Issues of appearance b. Torticollis (head tilt) c. Neck pain d. Changes in exercise tolerance e. Excessive instability of the upper cervical spine f. Problems related to associated anomalies g. Neurological problems from direct irritation of or impingement on a nerve root or from compression of the spinal cord i. Cranial nerve abnormalities ii. Cervical radiculopathy from involvement of the nerve root iii. Symptoms from spinal cord compression a) Spasticity b) Hyperreflexia c) Muscle weakness d) Complete paralysis iv. At risk for sustaining a neurologic deficit including quadriplegia after minor trauma
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6. Three clinical subtypes a. Type I characterized by massive cervical and thoracic vertebral fusions b. Type II with fusion at one or two vertebral junctures, occipitoatlantal fusion, lower thoracic abnormalities, and more severe cerivothoracic fusions c. Type III with both cervical and lower thoracic fusions 7. Risk factors a. Type I and III fusions i. Various neurologic, cutaneous, cardiac, skeletal, and oral anomalies ii. Difficulty in the birth process iii. Marked abnormal facial appearance with Sprengel deformity, accessory ear lobes, and pterygium colli iv. Serious neurologic anomalies with early death or long-term neurologic deficits b. Type II fusion i. Normal appearance ii. Normal lives iii. Incidental symptoms from osteoarthritis, basilar impression or occiptio-atlas fusion c. Hypermobility of the upper cervical spine at increased risk of neurologic injury with presentation of neurologic sequelae in the teens or 20s d. Lower cervical involvement at risk of developing cervical spondylosis at more advanced ages
DIAGNOSTIC INVESTIGATIONS 1. Audiologic evaluation for hearing loss 2. Renal ultrasonography 3. Radiography a. Cervical spine fusion on flexion and extension views: roentgenographic hallmark of the Klippel-Feil syndrome i. Type I cervical fusion (C2–C3 fusion with occipitalization of the atlas) ii. Type II cervical fusion (long cervical fusion with an abnormal occipitocervical junction) iii. Type III cervical fusion (two blocked vertebral segments with a single open interspace) b. Other associated skeletal anomalies i. Flattening and widening of involved vertebral bodies ii. Absent disc spaces 4. CT scan helpful in diagnosing nerve root and spinal cord impingement by osteophyte 5. MRI to evaluate instability and the risk of neurological compromise a. Spinal stenosis b. Cord compression c. Syringomyelia
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent has an autosomal dominant disorder
b. Patient’s offspring: not increased unless the patient has an autosomal dominant type of the disorder 2. Prenatal diagnosis: difficult to diagnose cervical vertebral anomalies and torticollis by ultrasonography 3. Management a. Treat renal, cardiovascular, and auditory anomalies accordingly b. Mechanical symptoms caused by degenerative joint disease i. Traction ii. Wearing a cervical collar iii. Analgesics c. Neurological symptoms i. Surgical stabilization with or without decompression ii. Surgical correction of Sprengel deformity to improve appearance
REFERENCES Bernard TN Jr, Burke SW, Johnston CE III, et al.: Congenital spine deformities. A review of 47 cases. Orthopedics 8:777–783, 1985. Carson WG, Lovell WW, Whitesides TE: Congenital elevation of the scapula. J Bone Joint Surg Am 63:1199–1207, 1981. Clarke RA, Davis PJ, Tonkin J: Klippel-Feil syndrome associated with malformed larynx. Case report. Ann Otol Rhinol Laryngol 103:201–207, 1994. Clarke RA, Singh S, McKenzie H, et al.: Familial Klippel-Feil syndrome and paracentric inversion inv(8)(q22.2q23.3). Am J Hum Genet 57:1364–1370, 1995. Clarke RA, Kearsley JH, Walsh DA: Patterned expression in familial KlippelFeil syndrome. Teratology 53:152–157, 1996. Cremers WRJ, Hoogland GA, Kuypers W: Hearing loss in the cervico-oculoacoustic (Wildervanck) syndrome. Arch Otolaryngol 110:54–57, 1984. Danilidis J, Demetriadis A, Triaridis C, et al.: Otological findings in cervicooculo-auditory dysplasia. J Layngol Otol 94:533–544, 1980. Elster A: Quadriplegia after minor trauma in the Klippel-Feil syndrome. A case report and review of the literature. J Bone Joint Surg Am 64:1473–1774, 1984. Gunderso CH, Greenspan RH, Glaser GH, et al.: The Klippel-Feil syndrome: genetic and clinical reevaluation of cervical fusion. Medicine 46:491–512, 1967. Hensinger RN, Lang JE, MacEwen GD: Klippel-Feil syndrome: a constellation of related anomalies. J Bone Joint Surg Am 56:1246–1253, 1974, Herman MJ, Pizzutillo PD: Cervical spine disorders in children. Orthop Clin N Am 30:457–466, 1999. Klippel M, Feil A: Un cas d’absence des vertebras cervicales. Nov Iconogr Salpet 25:223–250, 1912 Manaligod JM, Bauman NM, Menezes AH, et al.: Cervical vertebral anomalies in patients with anomalies of the head and neck. Ann Otol Rhinol Laryngol 108:925–933, 1999. McBride WZ: Klippel-Feil syndrome. Am Fam Physician 45:633–635, 1992. McGaughran JM, A Oates A, D Donnai D, et al.: Mutations in PAX1 may be associated with Klippel-Feil syndrome. Eur J Hum Genet 11:468–474, 2003. Moore WB, Matthews TJ, Rabinowitz R: Cenitourinary anomalies associated with Klippel-Feil syndrome. J Bone Joint Surg Am 57:355–357, 1975. Pizzutillo PD, Woods M, Nicholson L, et al.: Risk factors in Klippel-Feil syndrome. Spine 19:2110–2116, 1994. Pourquie O, Kusumi K: When body segmentation goes wring. Clin Genet 60:409–416, 2001. Van Rijn PM, Cremers CWRJ: Surgery for congenital conductive deafness in Klippel-Feil syndrome. Ann Otol Rhinol Laryngol 97:347–352, 1988. Visootsak J, et al.: Klinefelter syndrome reviewed. Clin Pediatr 40:639, 2001. Winter RB, Moe JH, Lonstein JE: The incidence of Klippel-Feil syndrome in patients with congenital scoliosis and kyphosis. Spine 9:363–366, 1984.
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Fig. 1. A child with Klippel-Feil syndrome and Sprengel deformity showing Torticolis, short/webbed neck, and inability to raise left arm due to congenital elevation of left scapula.
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Fig. 2. A girl with Klippel-Feil syndrome showing torticollis, short, webbed, and stiff neck, and cervical fusion (failure of segmentation) demonstrated by radiographs.
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Fig. 3. A child with Klippel-Feil syndrome showing torticolis, short, webbed, and stiff neck, hemifacial microsomia, microtia, and cervical fusion, demonstrated by radiograph.
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Fig. 4. A 10-year-old with Klippel-Feil syndrome showing torticolis, short, webbed, and stiff neck, low posterior hair line, elevated left scapula, failure of segmentation (fusion) of the cervical vertebrae and cervicothoracic scoliosis demonstrated by radiograph. He has no neurologic defects or cervical discomfort.
Fig. 5. A 15-year-old with Klippel-Feil syndrome, Sprengel deformity, and deafness.
Klippel-Trenaunay Syndrome Klippel-Trenaunay syndrome is primarily a rare congenital capillary-venous vascular malformation associated with altered limb bulk and/or length. In 1900, Klippel and Trenaunay first reviewed systematically a condition consisting of capillary nevus, early onset of varicosities, and hypertrophy of tissues and bones of the affected limb. These three features constitutes the primary diagnostic criteria of the syndrome today. The additional name Weber is sometimes added to describe those individuals who also have clinically significant arteriovenous malformations as a component of the syndrome, an association noted by Weber in 1918. More than 1000 cases of Klippel-Trenaunay syndrome have now been reported in the literature.
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GENETICS/BASIC DEFECTS 1. Etiology unknown a. Sporadic occurrence b. Somatic mutation of an as-yet-unknown gene c. Multifactorial inheritance d. Autosomal dominant inheritance with variable expression 2. One potential site of localization of gene: either chromosome arm 5q or 11p based on the report of an affected child with KT syndrome and a balanced reciprocal chromosome translocation, t(5;11)(q13.3;p15.1) 3. Possible mechanisms/pathogenesis leading to overgrowth of the affected limb: poorly defined a. Two phases of manifestations i. Increased bulk or girth ii. Increased length accompanied by bone enlargement b. Increased girth and size of bone due to venous hypertension, based on observations following hindleg deep vein ligation in dogs c. Atresia of the venous system leading to stasis, edema, varicosities and ultimately to limb elongation and hypertrophy d. Limb enlargement seen in children following thrombosis or ligation of a deep vein postnatally e. Overgrowth in fetal life promoted by increased blood flow through the abnormal capillary network and cutaneous venous channels f. A mesodermal defect acting on angiogenesis leading to the formation of the hemangiomata and varicose veins g. A defect in the process of vessel remodeling during embryogenesis
CLINICAL FEATURES 1. Triad a. Combined vascular malformations of the capillary, venous, and lymphatic types 580
4.
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b. Varicosities of unusual distribution, in particular the lateral venous anomaly observed during infancy or childhood c. Limb enlargement Cutaneous manifestations a. Primarily a diffuse capillary malformation b. Typically present on an affected limb c. May be present on any body part d. Often presenting as an irregular but relatively linear border e. Rarely crossing the midline when present on the trunk, sometimes exhibiting a sharp demarcation Vascular malformations a. Typically combined with cutaneous capillary malformation b. Persistence of abnormal superficial veins associated with deep venous hypoplasia/duplications and abnormal venous valve formation c. Presence of mixed vascular malformations including capillary, venous, arterial, and lymphatic systems d. Classification of vascular malformations by Mulliken and Glowacki (1982) i. Capillary-venous malformation (CVM): typical finding ii. CVLM (CVM + lymphatic malformation): common finding iii. CLAVM (including arterial malformation): uncommon e. Congenital in nature f. Not responding to agents used in the treatment of hemangiomas such as prednisone or interferon-α Limb hypertrophy a. Due to an increase in bulk of the subcutaneous tissues b. Bony hypertrophy Sites of involvement a. Lower limb most common (about 95%) b. Upper limb (about 5%) c. Trunk only: uncommon d. Orofacial involvement i. Jaw enlargement ii. Facial asymmetry iii. Malocclusions iv. Premature tooth eruption v. Hemangioma of the lips, tongue and oral mucosa Sex ratio: males and females affected equally Complications a. Abnormal vasculature i. Thrombosis ii. Coagulopathy iii. Pulmonary embolism iv. Heart failure (in the presence of significant AVM) v. Bleeding from abnormal vessels in gut, kidney, or genitalia
KLIPPEL-TRENAUNAY SYNDROME
b. Gastrointestinal varicoses i. Bleeding ii. Pain iii. Diarrhea c. Protein-losing enteropathy secondary to intestinal lymphangiectasia d. Infection a particular risk for patients with abnormal lymphatic drainage. Antibiotics indicated in: i. Cellulitis ii. Surgery iii. Injury in an affected limb e. Pain due to venous insufficiency or lymphedema in some older children and adults f. Venous thromboembolism i. Chronic thromboembolic pulmonary hypertension ii. Subsequent right ventricular failure g. Occurrence of ulceration on affected leg h. Rare occurrence of skin tumors on the affected limb i. Squamous cell carcinoma possibly secondary to a long-standing venous ulcer ii. Basal cell carcinoma i. Complications of pregnancy depending on location of vascular anomalies i. Depending on the location (e.g., vulva, lower abdomen) ii. Potential for a refractory coagulopathy presenting as Kasabach-Merritt phenomenon 8. Four commonly held conceptions about Klippel-Trenaunay syndrome challenged a. Renaming Klippel-Trenaunay-Weber syndrome by addition of arteriovenous fistulas i. Significant arteriovenous communications not observed in Klippel-Trenaunay syndrome in large surgical series ii. Parkes Weber syndrome characterized by enlarged arteries and veins, capillary or venous malformations and enlargement of a limb iii. Lymphatic malformations found in KlippelTrenaunay syndrome not observed in Parkes Weber syndrome b. Overlap with Sturge-Weber syndrome i. Characteristics of Sturge-Weber syndrome: craniofacial angiomatosis, port-wine nevus and cerebral calcification ii. Overgrowth in Sturge-Weber tends to be minor and is always secondary to the vascular anomaly. In contrast, overgrowth in Klippel-Trenaunay syndrome is striking. c. Presence of a bleeding diathesis of the KasabachMerritt type i. Kasabach-Merritt syndrome erroneously applied to patients with extensive venous or lymphaticovenous malformations who develop a localized intravascular coagulopathy in which the platelet count is minimally depressed (varying from 50,000 to 150,000/mm3) ii. Profound thrombocytopenia in true KasabachMerritt phenomenon (varying from 3000 to 60,000/mm3)
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d. Familial aggregation with various genetic interpretations i. Inadequate documentation of cases ii. Over interpretation of minor manifestations in relatives, including “nevus flammeus”, hemangiomas, and varicosities (common manifestations in general populations) iii. Klippel-Trenaunay syndrome defined as a capillary malformation with or without “hemihypertrophy” without mentioning of lymphatic malformations, lateral venous anomaly, lymphatic vesicles, or venous flares within the capillary malformation, or macrodactyly e. Klippel-Trenaunay syndrome, Parkes Weber syndrome, and Sturge-Weber syndrome i. Each occurring sporadically ii. Each considered separate entity because clinical manifestations and types of complications are different
DIAGNOSTIC INVESTIGATIONS 1. Color duplex ultrasonography a. AV malformation b. Deep venous hypoplasia (a decrease in caliber of at least 50% of a vein along its length) c. Venous duplication d. Variable varicosities 2. Radiography a. Enlargement of the limb bones b. Yearly to monitor evidence of leg length discrepancy 3. Noninvasive imaging and endoscopy for severe gastrointestinal bleeding 4. Lymphoscintigraphy using radionuclide tracers a. Indication: edema or a girth discrepancy more than 4 cm b. No uptake of tracer along major lymphatics of the affected limb during repeated scans over at least a 1-hour period 5. MRI a. Pelvis: to look for vascular malformations involving the kidneys, bladder, or intestines b. MRI with gadolinium to distinguish lymphatic from venous malformations c. Magnetic resonance venogram or phlebography/venography to document the lateral venous anomaly and any abnormalities that may be present in the deep veins of the leg d. Able to demonstrate arteriovenous fistulas in Parkes Weber syndrome
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: not increased (doubtful that autosomal dominant inheritance exists) 2. Prenatal diagnosis a. Ultrasonography i. Asymmetric limb hypertrophy associated with cutaneous or subcutaneous cystic or multicystic lesions
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ii. Limb edema iii. Cardiac failure ranging from isolated cardiomegaly to severe hydrops b. MRI i. Limb hypertrophy ii. Multiple subcutaneous and internal hemangiomata iii. Good definition of soft tissue lesions iv. Identify vascular malformations and their extent v. Presence of low signal indicating flow voids, hemosiderin deposits or calcification indicative of vascular malformations 3. Management a. Compression garments b. Pulsed dye laser treatment c. Reduction of significant arteriovenous malformations d. Orthopedic procedures for overgrowth i. Significant leg length discrepancy ii. Prominent digital anomalies
REFERENCES Berry SA, Peterson C, Mize W, et al.: Klippel-Trenaunay syndrome. Am J Med Genet 79:319–326, 1998.
Cohen MM, Jr.: Klippel-Trenaunay syndrome. Am J Med Genet 93:171–175, 2000. De Simone C, Giampetruzzi AR, Guerriero C, et al.: Squamous cell carcinoma arising in a venous ulcer as a complication of the Klippel-Trenaunay syndrome. Clin Exp Dermatol 27:209–211, 2002. Hale EK: Klippel-Trenaunay syndrome. Dermatol Online J 8:13, 2002. James CA, Allison JW, Waner M: Pediatric case of the day. Klippel-Trenaunay syndrome. Radiographics 19:1093–1096, 1999. Jih MH: Klippel-Trenaunay syndrome. Dermatol Online J 9:31, 2003. Martin WL, Ismail KM, Brace V, et al.: Klippel-Trenaunay-Weber (KTW) syndrome: the use of in utero magnetic resonance imaging (MRI) in a prospective diagnosis. Prenat Diagn 21:311–313, 2001. Mueller-Lessmann V, Behrendt A, Wetzel WE, et al.: Orofacial findings in the Klippel-Trenaunay syndrome. Int J Paediatr Dent 11:225–229, 2001. Paladini D, Lamberti A, Teodoro A, et al.: Prenatal diagnosis and hemodynamic evaluation of Klippel-Trenaunay-Weber syndrome. Ultrasound Obstet Gynecol 12:215–217, 1998. Roberts RV, Dickinson JE, Hugo PJ, et al.: Prenatal sonographic appearances of Klippel-Trenaunay-Weber syndrome. Prenat Diagn 19:369–371, 1999. Vazquez-Sequeiros E, Sorbi D, Kamath PS, et al.: Klippel-Trenaunay-Weber syndrome: role of EUS. Gastrointest Endosc 54:660–661, 2001. Vajo Z, Stratakis CA: Picture of the month. Klippel-Trenaunay syndrome. Arch Pediatr Adolesc Med 152:1149; discussion 1150, 1998. Walder B, Kapelanski DP, Auger WR, et al.: Successful pulmonary thromboendarterectomy in a patient with Klippel-Trenaunay syndrome. Chest 117:1520–1522, 2000. Zoppi MA, Ibba RM, Floris M, et al.: Prenatal sonographic diagnosis of Klippel-Trenaunay-Weber syndrome with cardiac failure. J Clin Ultrasound 29:422–426, 2001.
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Fig. 1. A newborn with Klippel-Trenaunay syndrome showing overgrowth of left leg with vascular malformation
Fig. 2. A boy with Klippel-Trenaunay syndrome showing of right arm and right leg with vascular malformation
Fig. 3. A 6-year-old boy with Klippel-Trenaunay syndrome showing overgrowth of left arm (illustrated by radiographs) associated with vascular malformation
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Fig. 4. A one-year-old infant with Klippel-Trenaunay syndrome showing asymmetric lower extremities with hypertrophic left lower extremity associated with vascular malformation (A). T1-enhanced MRI (B,C) and T2-enhanced MRI (D,E) images at thigh level show cystic and vascular lesions, indicated by high signals suggesting lymphangiomas and hemangiomas.
Kniest Dysplasia d. Prominent eyes e. Flat nasal bridge f. Short nose g. Micrognathia h. Cleft palate 3. Ocular manifestations a. Abnormal long axial length causing high early onset myopia b. Vitreoretinal degeneration c. Retinal detachment d. Cortical and posterior subcapsular opacity of the lens e. Veil-like vitreous opacity in the periphery f. Congenital glaucoma g. Blindness 4. Hearing loss 5. Prognosis: phenotype varying significantly a. Frequently potentially life threatening complications i. Early postnatal tracheomalacia resulting in respiratory insufficiency and feeding difficulties ii. Secondary failure to thrive b. Can lead a relatively normal life with mild disproportionate short stature, kyphoscoliosis, and/or craniofacial manifestations
Kniest dysplasia is a type II collagenopathy with characteristic clinical, radiographic, and histological findings.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant b. New dominant mutations in most cases 2. Molecular basis a. Caused by mutations in the gene (COL2A1) that encodes type II collagen, the predominant protein of cartilage b. A specific type of mutation and/or position of mutation within the collagen chain may explain the unique features of Kniest dysplasia among the type II collagenopathies 3. Kniest dysplasia in the middle of the following phenotypic spectrum of disease a. Achondrogenesis type II/hypochondrogenesis at the severe end b. Spondyloepiphyseal dysplasias/spondyloepimetaphyseal dysplasias in the middle c. Genetically heterogeneous Stickler syndrome and familial osteoarthritis at the milder end
DIAGNOSTIC INVESTIGATIONS
CLINICAL FEATURES 1. Skeletal anomalies a. Disproportionate dwarfism b. A short trunk c. Short, slightly bowed limbs d. More severe rhizomelic shortness in the lower limbs e. Prominent joints f. Delayed motor milestones secondary to joint deformities g. Progressive and painful joint enlargement accompanied by joint contractures h. Muscle atrophy resulting from disuse i. Short and broad thorax with sternal protrusion j. Kyphoscoliosis i. Dorsal kyphosis ii. Accentuated lumbar lordosis iii. Thoracic scoliosis k. Odontoid hypoplasia resulting in atlanto-axial instability l. Clubfoot m. Small pelvis n. Premature osteoarthritis that restrict movement o. Waddling gait 2. Craniofacial characteristics a. Relatively large head b. Flat face c. Shallow supraorbital ridges
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1. Radiography a. Distinguishing radiographic features from other type II collagenopathies identifiable at birth i. Coronal clefts of the vertebrae ii. Dumbbell-shaped femora b. Other radiographic features i. Narrowed joint spaces ii. Platyspondyly iii. Kyphoscoliosis iv. Short tubular bones v. Dysplastic epiphyses and metaphyses a) Broad metaphyses b) Enlarged and deformed epiphyses 2. Histopathology: a. Pathologic changes of cartilage i. “Swiss-cheese” appearance of the cartilage matrix ii. Soft crumbly cartilage b. Microscopic changes i. Disorganization of the growth plate ii. Deficiency of collagen matrix iii. Poorly staining cartilage with myxoid degeneration iv. PAS positive cytoplasmic inclusions in many chondrocytes. Ultrastructurally the inclusions correspond to pools of proteinaceous material within dilated rough endoplasmic reticulum 3. Hearing test
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4. Visual evaluation 5. Molecular genetic analysis of COL2A1 mutation a. Targeted mutation b. Mutation scanning and sequencing of entire coding region
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: low recurrence risk unless a parent is affected or has gonadal mosaicism b. Patient’s offspring: 50% 2. Prenatal diagnosis a. Difficult to diagnose Kniest dysplasia by early sonography since the biometry does not become notably abnormal until the third trimester b. Molecular genetic analysis of COL2A1 mutation on fetal DNA obtained from amniocentesis or CVS for previously characterized disease-causing gene mutation in the proband 3. Management a. Cleft palate repair b. Hearing aid for hearing loss c. Vitrectomy and silicon oil injection for reattaching the retina from retinal detachment d. Orthopedic care for clubfoot and kyphoscoliosis
REFERENCES Bromley B, Miller W, Foster SC, et al.: The prenatal sonographic features of Kniest syndrome. J Ultrasound Med 10:705–707, 1991. Chen H, Yang SS, Gonzalez E: Kniest dysplasia: neonatal death with necropsy. Am J Med Genet 6:171–178, 1980. Cole WG: Abnormal skeletal growth in Kniest dysplasia caused by type II collagen mutations. Clin Orthop 162–169, 1997. Douglas GR: The ocular findings in Kniest dysplasia. Am J Ophthalmol 100:860–861, 1985.
Gilbert-Barnes E, Langer LO, Jr., Opitz JM, et al.: Kniest dysplasia: radiologic, histopathological, and scanning electronmicroscopic findings. Am J Med Genet 63:34–45, 1996. Hicks J, De Jong A, Barrish J, et al.: Tracheomalacia in a neonate with Kniest dysplasia: histopathologic and ultrastructural features. Ultrastruct Pathol 25:79–83, 2001. Horton WA, Rimoin DL: Kniest dysplasia. A histochemical study of the growth plate. Pediatr Res 13:1266–1270, 1979. Kniest W: Zur Abgrenzung der Dysostosis enchondralis von der Chondrodystophie. Ztschr Kinderh 70:633–640, 1952. Kozlowski K, Barylak A, Kobielowa Z: Kniest syndrome (report of two cases). Australas Radiol 21:60–67, 1977. Lachman RS, Rimoin DL, Hollister DW, et al.: The Kniest syndrome. Am J Roentgenol Radium Ther Nucl Med 123:805–814, 1975. Maumenee IH, Traboulsi EI: The ocular findings in Kniest dysplasia. Am J Ophthalmol 100:155–160, 1985. Rimoin DL, Siggers DC, Lachman RS, et al.: Metatropic dwarfism, the Kniest syndrome and the pseudoachondroplastic dysplasias. Clin Orthop 70–82, 1976. Siggers CD, Rimoin DL, Dorst JP, et al.: The Kniest syndrome. Birth Defects Orig Artic Ser 10:193–208, 1974. Springer JW, Maroteaux P: Kniest disease. Birth Defects Original Article Series X(12):50–56, 1974. Spranger J, Menger H, Mundlos S, et al.: Kniest dysplasia is caused by dominant collagen II (COL2A1) mutations: parental somatic mosaicism manifesting as Stickler phenotype and mild spondyloepiphyseal dysplasia. Pediatr Radiol 24:431–435, 1994. Spranger J, Winterpacht A, Zabel B: The type II collagenopathies: A spectrum of chondrodysplasias. Eur J Pediatr 153:56–65, 1994. Spranger J, Winterpacht A, Zabel B: Kniest dysplasia: Dr. W. Kniest, his patient, the molecular defect. Am J Med Genet 69:79–84, 1997. Wilkin DJ, Artz AS, South S, et al.: Small deletions in the type II collagen triple helix produce Kniest dysplasia. Am J Med Genet 85:105–112, 1999. Wilkin DJ, Bogaert R, Lachman RS, et al.: A single amino acid substitution (G103D) in the type II collagen triple helix produces Kniest dysplasia. Hum Mol Genet 3:1999–2003, 1994. Winterpacht A, Hilbert M, Schwarze U, et al.: Kniest and Stickler dysplasia phenotypes caused by collagen type II gene (COL2A1) defect. Nat Genet 3:323–326, 1993. Yokoyama T, Nakatani S, Murakami A: A case of Kniest dysplasia with retinal detachment and the mutation analysis. Am J Ophthalmol 136:1186–1188, 2003.
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Fig. 1. A neonate with Kniest dysplasia showing short trunk and large head, similar to SED congenita. However, the moderately shortened limbs show prominent joints. Radiographs show enlarged metaphyses of limb bones (dumbbell-shaped femora) and coronal clefts of the vertebrae. The remaining findings are similar to those of SED congenita. The physeal growth zone of femur is hypercellular and disorganized. The transverse cleft beneath the physis is an artifact. Many chondrocytes contain cytoplasmic inclusions (arrows); they are seen in the resting cartilage and the zone of proliferation, similar to those of SED congenita.
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Fig. 2. Three children with Kniest dysplasia showing varying features of the dysplasia: short trunk dwarfism, flat facies, myopia, deafness requiring hearing aids, dorsal kyphosis, accentuated lumbar lordosis, short and broad thorax with sternal protrusion, and prominent joints with restricted joint mobility.
Larsen Syndrome In 1950, Larsen et al. described a condition characterized by multiple large joint dislocations and flat face. The condition occurs in approximately 1 in 100,000 births.
GENETICS/BASIC DEFECTS 1. Subtypes a. Sporadic form b. Autosomal dominant form c. Autosomal recessive form: clinical phenotype more debilitating with higher mortality than the autosomal dominant form d. Possible lethal form 2. The first known gene mutated in Larsen syndrome, LAR1, for autosomal dominant form: mapped to 3p21.114.1 in the proximity of, but distinct from, the COL7A1 locus 3. Unilateral manifestation of typical skeletal defects in some patients indicates that this condition might represent unilateral somatic cell-line mosaicism
CLINICAL FEATURES 1. Broad inter- and intrafamilial clinical variability 2. Characteristic flat facial appearance (“dish face”) a. Prominent forehead (frontal bossing) b. Hypertelorism c. Hypoplastic midface d. Depressed nasal bridge e. Micrognathia f. Occasional cleft palate, lip or uvula 3. Bilateral multiple joint dislocations a. Shoulders b. Elbows c. Wrists d. Hips e. Patella f. Ankles g. Knees 4. Variable handicap due to joint luxations 5. Hand abnormalities a. Long, cylindrical, and tapering fingers (pseudoclubbing) b. Spatulate/bifid thumbs c. Dislocation of distal radioulnar joint d. Delayed carpal ossification e. Supernumerary ossification centers f. Brachymetacarpia g. Brachytelephalangia h. Hyperextension of distal interphalangeal joints 6. Feet abnormalities a. Spatulate hallux b. Equinovarus or valgus deformities of the feet
7. Respiratory distress due to tracheolaryngomalacia a. Stridor i. Inspiratory reflecting laryngomalacia or extrathoracic cervical tracheomalacia ii. Expiratory reflecting intrathoracic tracheomalacia b. Cyanosis c. Obstructive apnea d. Possibly life-threatening 8. Bronchomalacia a. Lobar atelectasis b. Hyperinflation c. Pneumonias 9. Respiratory embarrassment in infancy due to soft tracheolaryngeal cartilage 10. Soft/collapsing thorax 11. Cardiovascular abnormalities a. Congenital defects i. Bicuspid aortic valve ii. Subaortic stenosis iii. Atrial septal defect iv. Ventricular septal defect v. Patent ductus arteriosus vi. Pulmonary stenosis vii. Endocardial fibroelastosis b. Acquired lesions i. Dilated aortic root ii. Elongated aorta iii. Mitral valve prolapse iv. Aneurysm of ductus arteriosus v. Arterial tortuosity and dilatation 12. Associated spinal anomalies a. Cervical spine involvement i. More often affected than thoracic or lumbar spine ii. Results in: a) Midcervical kyphosis, usually at the C4–C5 region b) Cervicothoracic lordosis c) Spinal instability iii. Flattened, hypoplastic, and often bifid cervical vertebrae b. Atlantoaxial instability i. A rare finding ii. May be associated with other abnormalities of the upper cervical spine a) Occipitalization of the atlas b) Basilar impression c. Lumbosacral dysraphism: may lead to neurological impairment d. Thoracic scoliosis e. Hypoplasia of the vertebral bodies or posterior elements f. Quadriplegia secondary to segmentation abnormalities of the vertebrae
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13. Mixed hearing loss due to ossicular abnormality 14. CNS anomalies a. Hydrocephalus (rare) b. Glial proliferation in the brain 15. Short stature 16. Normal intelligence 17. Possible lethal form a. Tracheomalacia b. Pulmonary hypoplasia c. Collagen fiber dysmaturity 18. Prognosis a. Generally good after aggressive orthopedic management, except some lethal cases due to tracheolaryngomalacia and/or lung hypoplasia b. Compatible with successful pregnancy if the maternal and fetal safety issues are properly considered
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Bilateral dislocations of shoulders, elbows, wrists, hips, patella, ankles, and knees (anterior dislocation of the tibia on the femur, most characteristic) b. Genu recurvata c. Talipes deformities (club feet) d. Spatulate thumbs e. Shortened metacarpals f. Multiple supernumerary carpal ossification centers (short, small, and increased in number) g. Poor ossification of phalanges h. Delayed coalescence (duplication) of calcaneal ossification centers i. Occasional abnormal segmentation of vertebrae (± fusion defects of cervical spine) j. Cervical kyphosis k. Spina bifida occulta l. Scoliosis m. Craniofacial disproportion 2. Polysomnography for assessing the severity of airway obstruction 3. Echocardiography for cardiovascular lesions 4. MRI of the brain for cerebral malformations
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Sporadic form (consider germ-line mosaicism when neither parent appears to be affected) ii. Autosomal dominant inheritance: risk not increased unless a parent is affected iii. Autosomal recessive inheritance: 25% risk of having sibs affected b. Patient’s offspring i. Sporadic form: risk not increased unless the patient has germ-line mosaicism ii. Autosomal dominant inheritance: 50% risk of having offspring affected iii. Autosomal recessive inheritance: risk not increased unless the spouse is also a carrier
2. Prenatal diagnosis accomplished in rare cases by ultrasonography in pregnancies at risk a. Multiple joint dislocations i. Elbow ii. Knees iii. Hips b. Flat facial profile i. Prominent forehead ii. Hypertelorism iii. A depressed nasal bridge iv. Micrognathia v. Cleft palate c. Genu recurvatum d. Club feet 3. Management a. Supporting therapy for airway difficulty i. Antibiotics as needed ii. Supplemental oxygen iii. Chest physiotherapy to augment mucus clearance iv. Require intubation for severe respiratory distress with positive end-expiratory pressure (PEEP) to maintain a patent airway b. Cleft palate repair c. Closed or open reduction and stabilization of dislocated joints i. Securing stability of the knee joints for weightbearing: primary importance ii. Correction of foot deformities through operative and nonoperative measures d. Stabilization of the cervical spine i. Early bracing and stabilization ii. Stabilization of the neck may be required before surgical correction of joint abnormalities to prevent possible complications associated with the induction of anesthesia e. Care for possible poor wound healing f. Obstetrical care of an affected mother and fetus i. Regional anesthesia for possible difficulty in intubation and the cervical spine may be subluxated during extension of the neck for intubation ii. Cesarean section if the patient is unable to abduct the hips, making vaginal delivery potentially traumatic for both mother and infant iii. Risk of fetal injury includes cervical spine instability
REFERENCES Al-Kaissi A, Ammar C, Ben Ghachem MB, et al.: Facial features and skeletal abnormalities in Larsen syndrome—a study of three generations of a Tunisian family. Swiss Med Wkly 133:625–628, 2003. Banks JT, Wellons JC, Tubbs RS, et al.: Cervical spine involvement in Larsen’s syndrome: a case illustration. Pediatrics 111:199–201, 2003. Becker R, Wegner R-D, Kunze J, et al.: Clinical variability of Larsen syndrome: diagnosis in a father after sonographic detection of a severely affected fetus. Clin Genet 57:148–150, 2000. Bowen R, Ortega K, Ray S, et al.: Spinal deformities in Larsen’s syndrome. Clin Orthop 197:159–163, 1985. Chen H, Chang C, Perrin E, et al.: A lethal, Larsen-like multiple joint dislocation syndrome. Am J Med Genet 13:149–161, 1982. Clayton-Smith J, Donnai D: A further patient with the lethal type of Larsen syndrome. 25:499–450, 1988.
LARSEN SYNDROME De Nazar NM: Larsen syndrome: Clinical and genetic aspects. J Genet Hum 28:83–88, 1980. Debeer P, De Borre L, De Smet L, et al.: Asymmetrical Larsen syndrome in a young girl: a second example of somatic mosaicism in this syndrome. Genet Couns 14:95–100, 2003. De Smet L, Legius E, Fabry G, et al.: The Larsen syndrome. The diagnostic contribution of the analysis of the metacarpophalangeal pattern profile. Genet Couns 4:157–164, 1993. Fryns JP, Lenaerts J, Van den Berghe H: Larsen syndrome presenting as a familial syndrome of dwarfism, distinct oldish facial appearance and bilateral clubfeet in mother and daughter. Genet Couns 4:43–46, 1993. Habermann ET, Sterling A, Dennis RI: Larsen’s syndrome: a heritable disorder. J Bone Joint Surg Am 58:558–561, 1976. Harris R, Cullen CH: Autosomal dominant inheritance in Larsen’s syndrome. Clin Genet 2:87–90, 1971. Kiel EA, Frias JL, Victorica BE: Cardiovascular manifestations in the Larsen syndrome. Pediatrics 71:942–946, 1983. Knoblauch H, Urban M, Tinschert S: Autosomal recessive versus autosomal dominant inheritance in Larsen syndrome: report of two affected sisters. Genet Couns 10:315–320, 1999. Kozlowski K, Robertson F, Middleton R: Radiographic findings in Larsen’s syndrome. Australas Radiol 18:336–344, 1974. Larsen LJ, Schottstaedt EF, Bost FC: Multiple congenital dislocations associated with characteristic facial abnormality. J Pediatr 37:574–581, 1950. Latta RJ, Graham CB, Aase J, et al.: Larsen’s syndrome: a skeletal dysplasia with multiple joint dislocations and unusual facies. J Pediatr 78:291–298, 1971. Le Marec B, Chapuis M, Treguier C, et al.: A case of Larsen syndrome with severe cervical malformations. Genet Couns 5:179–181, 1994. Lewit N, Batino S, Groisman GM, et al.: Early prenatal diagnosis of Larsen’s syndrome by transvaginal sonography. J Ultrasound Med 14:627–629, 1995. Liang C-D, Hang CL: Elongation of the aorta and multiple cardiovascular abnormalities associated with Larsen syndrome. Pediatr Cardiol 22:245–246, 2001. Lutter LD: Larsen syndrome: clinical features and treatment—A report of two cases. J Pediatr Orthop 10:270–274, 1990.
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Malik P, Choudhry DK: Larsen syndrome and its anaesthetic considerations. Paediatr Anaesth 12:632–636, 2002. Marques MDNT: Larsen’s syndrome: Clinical and genetic aspects. J Genet Hum 28:83–88, 1980. Mostello D, Hoechstetter L, Bendon RW, et al.: Prenatal diagnosis of recurrent Larsen syndrome: further definition of a lethal variant. Prenat Diagn 11:215–225, 1991. Petrella R, Rabinowitz JG, Steinmann B, et al.: Long-term follow-up of two sibs with Larsen syndrome possibly due to parental germ-line mosaicism. Am J Med Genet 47:187–197, 1993. Robertson FW, Kozlowski K, Middleton RW: Larsen’s syndrome: three cases with multiple congenital joint dislocations and distinctive facies. Clin Genet 14:53–60, 1975. Rochelson B, Petrikovsky B, Shmoys S: Prenatal diagnosis and obstetric management of Larsen syndrome. Obstet Gynecol 81:845–847, 1993. Rock MJ, Green Clin Genet, Pauli RM, et al.: Tracheomalacia and bronchomalacia associated with Larsen syndrome. Pediatr Pulmonol 5:55–59, 1988. Silverman FN: Larsen’s syndrome: Congenital dislocation of the knees and other joints, distinctive facies, and frequently, cleft palate. Ann Radiol 15:297–328, 1972. Stanley D, Seymour N: The Larsen syndrome occurring in four generations of one family. Int Orthop 8:267–272, 1985. Steel HH, Kohl J: Multiple congenital dislocations associated with other skeletal anomalies (Larsen’s syndrome) in three siblings. J Bone Joint Surg 54A:75–82, 1972. Strisciuglio P, Sebastio G, Andria G, et al.: Severe cardiac anomalies in sibs with Larsen syndrome. J Med Genet 20:422–424, 1983. Tongson T, Wanapirak C, Pongsatha S, et al.: Prenatal sonographic diagnosis of Larsen syndrome. J Ultrasound Med 19:419–421, 2000. Topley JM, Varady E, Lestringant GG: Larsen syndrome in siblings with consanguineous parents. Clin Dysmorphol 3:263–265, 1994. Vujic M, Hallstensson K, Wahiström, et al.: Localization of a gene for autosomal dominant Larsen syndrome to chromosome region 3p21.1-14.1 in the proximity of, but distinct from, the COL7A1 locus. Am J Hum Genet 57:1104–1113, 1995. Wieisenbach J, Melegh B, et al.: Vertebral anomalies in Larsen’s syndrome. Pediatr Radiol 26:682–683, 1996.
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Fig. 1. An infant with Larsen syndrome showing characteristic flat facies with hypertelorism, depressed nasal bridge, cleft palate, dislocations of hips, knees, and talipes equinovarus, demonstrated by radiographs.
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Fig. 2. Another infant with Larsen syndrome showing flat facies with prominent forehead, hypertelorism, depressed nasal bridge, and micrognathia, tracheostomy for tracheomalacia, scoliosis, and dislocation of knees, and club feet.
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Fig. 3. A girl with Larsen syndrome showing characteristic flat facies with prominent forehead, and depressed nasal bridge, bilateral knee dislocations, long, cylindrical fingers with Spatulate thumbs and great toes. Radiograph shows lateral and anterior dislocation of both knees.
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Fig. 4. A girl with Larsen syndrome wearing orthosis showing flat facies. Radiographs show increased number of carpal bones, anterior and lateral dislocation of tibiae, hyperextended cervical vertebrae, and coronal clefting of the lumber vertebrae.
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Fig. 5. An infant with lethal, Larsen-like syndrome showing characteristic flat facies (prominent forehead, hypertelorism, depressed nasal bridge, micrognathia, cleft palate), multiple dislocations involving shoulders, elbows, wrists, knees, ankles, and hips, and talipes equinovarus. The radiographs showed anterior dislocation of the tibia, lateral dislocation of the hips, hypoplasia of fibulae and of distal ends of the fibulae, cervical kyphosis with the apex at C-4, and coronal clefts of the lower lumbar vertebrae. Necropsy showed tracheomalasia. The dermal histology showed relatively broad and smudgy collagen bundles. The electronmicroscopic study showed a relative increase in small short fibers with a reduction of mature collagen fibers in the hyaline cartilage of the trachea.
LEOPARD Syndrome LEOPARD syndrome consists of lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, growth retardation, and sensorineural deafness. It is also known as multiple lentigines syndrome.
GENETICS/BASIC DEFECTS 1. Inheritance a. An autosomal dominant disorder with high penetrance and variable expressivity b. Allelic to Noonan syndrome 2. Caused by mutations in the Noonan syndrome gene, PTPN11, mapped on chromosome 12q22-qter a. Missense mutation (836A→G; Tyr279Cys) in exon 7 b. Missense mutation (1403C → T; Thr468Met) in exon 12 c. Both mutations affect the PTPN11 phosphotyrosine phosphatase domain, which is involved in <30% of the Noonan syndrome PTPN11 mutations
CLINICAL FEATURES 1. Cutaneous features a. Lentigines i. Dark brown irregularly shaped macules ranging from pinpoint size to 5 cm in diameter ii. Noted in infancy or childhood iii. Continue to increase in number until puberty iv. Primarily on the face, neck, and upper trunk with some involvement of the extremities v. Less commonly on the palms, soles, genitalia, iris, and sclera, but sparing oral mucosa vi. Generalized symmetric distribution of lentigines b. Other cutaneous abnormalities i. Café-au-lait spots (38% of patients) ii. Melanoma iii. Localized hypopigmentation iv. Interdigital webs v. Dermatoglyphic abnormalities vi. Onychodystrophy vii. Multiple granular cell myoblastomas viii. Steatocystoma multiplex ix. Hyperelastic skin 2. Noncutaneous features a. Cardiac anomalies i. Valvular pulmonary stenosis: the most common cardiac anomaly (40% of cases) ii. Subaortic stenosis iii. Subpulmonic stenosis iv. Mitral valve involvement v. Hypertrophic obstructive cardiomyopathy 597
vi. Left and right ventricular outflow tract obstructions vii. Atrial septal defect viii. Atrial myxomas ix. Variable conduction abnormalities a) Benign asymptomatic arrhythmia b) Malignant arrhythmias resulting in sudden cardiac death x. Cardiac symptoms a) Dyspnea on exertion b) Congestive heart failure c) Paroxysmal atrial tachycardia d) Sudden death e) Death at cardiac surgery b. Noncardiac anomalies i. Craniofacial features a) Ocular hypertelorism (25%) b) Epicanthic folds c) Ptosis d) Mandibular prognathism e) High-arched palate f) Dental abnormalities g) Low-set posteriorly rotated ears ii. Skeletal abnormalities a) Joint hypermobility b) Short webbed neck c) Winging of the scapula d) Pectus excavatum and carinatum e) Rib anomalies f) Cervical spine fusion g) Syndactyly h) Scoliosis iii. Genitourinary abnormalities (26% of cases) a) A small penis b) Cryptorchidism c) Hypospadias d) Ovarian disorders iv. Neurologic abnormalities a) Learning disability b) Mild mental retardation c) Sensorineural deafness d) Nystagmus e) Seizures f) Hyposmia g) Mild atrophy of the brain v. Retardation of growth (short stature) vi. Delayed puberty 3. Diagnostic criteria (Voron et al., 1976) a. Multiple lentigines plus two other features, or b. Immediate family member with LEOPARD syndrome plus at least three other features in the absence of lentigines
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DIAGNOSTIC INVESTIGATIONS 1. ECG abnormalities a. Left axis deviation b. Bundle branch block c. Abnormal P wave d. Prolongation of the P–R interval e. ST and T wave changes f. Right or left ventricular hypertrophy 2. Careful cardiac assessment including echocardiography 3. Hearing tests 4. Histology of lentigines a. Large membrane-bound accumulations of melanin granules within the Langerhans cells b. Giant melanosomes rarely seen within keratinocytes and melanocytes 5. Mutation screening of PTP11 a. SSCP analysis b. Direct sequencing of selected exons or entire coding region
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: low unless a parent has the syndrome b. Patient’s offspring: 50% 2. Prenatal diagnosis: available clinically by mutation analysis of PTPN11 on fetal DNA obtained by amniocentesis or CVS, provided the disease-causing allele has been identified in an affected family member 3. Management a. Avoid strenuous physical exercise when outflow tract obstruction or significant cardiac dysrhythmias is present b. β-adrenergic receptor or calcium channel blocking agents to reduce cardiac outflow tract obstruction and adrenergic responsiveness c. Amiodarone treatment in cases of life-threatening ventricular ectopy
d. Surgery may be needed to relieve severe cardiac outflow tract obstruction e. Surgery for cryptorchidism or severe skeletal deformity f. Hearing aids for sensorineural deafness g. Dermabrasion for cosmetic correction on the face
REFERENCES Abdelmalek NF, Gerber TL, Menter A: Cardiocutaneous syndromes and associations. J Am Acad Dermatol 46:161–183, 2002. Char F: Leopard syndrome in mother and daughter. Birth Defects Orig Artic Ser 7:234–235, 1971. Coppin BD, Temple IK: Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis). J Med Genet 34:582– 586, 1997. Digilio MC, Conti E, Sarkozy A, et al.: Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 71:389–394, 2002. Dociu I, Galaction-Nitelea O, Sirjita N, et al.: Centrofacial lentiginosis: a survey of 40 cases. Br J Dermatol 94:39–43, 1976. Fryer PR, Pope FM: Accumulation of membrane-bound melanosomes occurs in Langerhans cells of patients with the Leopard syndrome. Clin Exp Dermatol 17:13–15, 1992. Gorlin RJ, Anderson RC, Blaw M: Multiple lentigines syndrome. Am J Dis Child 117:652–662, 1969. Gorlin RJ, Anderson RC, Moller JH: The Leopard (multiple lentigines) syndrome revisited. Birth Defects 7:110–115, 1971. Jó´zwiak S, Schwartz RA, Janniger CL: LEOPARD syndrome (cardiocutaneous Lentiginosis Syndrome). Cutis 57:208–214, 1996. Jó´zwiak S, Schwartz RA, Janniger CK, et al.: Familial occurrence of the LEOPARD syndrome. Int J Dermatol 37:48–51, 1998. Legius E, Schrander-Stumpel C, Schollen E, et al.: PTPN11 mutations in LEOPARD syndrome. J Med Genet 39:571–574, 2002. Nordlund JJ, Lerner AB, Braverman IM, et al.: The multiple lentigines syndrome. Arch Dermatol 107:259–261, 1973. Rotter JI, Rimoin DL: Additional comments on the ulcer-multiple lentigines syndrome. Am J Med Genet 11:251–252, 1982. Sarkozy A, Conti E, Seripa D, et al.: Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet 40:704–708, 2003. Seuanez H, Mane-Garzon F, Kolski R: Cardio-cutaneous syndrome (the “LEOPARD” syndrome). Review of the literature and a new family. Clin Genet 9:266–276, 1976. Voron DA, Hartfield HH, Kalkhoff MD: Multiple lentigines syndrome. Case report and review of the literature. Am J Med 60:447–456, 1976.
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Fig. 1. A lady (A,B) with LEOPARD syndrome showing ocular hypertelorism and generalized symmetric distribution of lentigines. Close views of lentigines (C,D,E) show variation in size and color. There is striking mottling of pigment within any one lentigo.
Lesch-Nyhan Syndrome In 1964, Lesch and Nyhan provided the first detailed clinical description of Lesch-Nyhan syndrome with a report of two brothers with hyperuricemia and a characteristic neurobehavioral syndrome that included motor dysfunction and self-injurious behavior. The prevalence of the syndrome is estimated to be approximately 1:380,000.
GENETICS/BASIC DEFECTS 1. Inheritance: X-linked recessive 2. Enzymatic defect: caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), which catalyzes the conversion of hypoxanthine to inosine monophosphate and guanine to guanine monophosphate in the presence of phosphoribosylpyrophosphate 3. Hypoxanthine-guanine phosphoribosyltransferase gene (HPRT1) a. Mapped to chromosome Xq26-q27.2 b. The only gene known to be associated with LeschNyhan syndrome c. Heterogeneous mutations i. Single base substitutions ii. Deletions iii. Insertion iv. Substitutions 4. Pathogenesis a. Metabolic basis of overproduction of uric acid: results from changes in the regulation of purine synthesis and degradation b. Pathogenesis of neurologic and behavioral features remains incompletely understood. Growing evidence suggests that these features result from dysfunction of the dopamine transmitter systems of the basal ganglia
CLINICAL FEATURES 1. Normal prenatal and perinatal course 2. Early developmental milestones a. Hypotonia and developmental delay: most common presenting features evident by 3–6 months of age b. Failure to reach normal motor milestones, such as delayed in crawling, sitting, and walking 3. Within the first few years a. Extrapyramidal involvement i. Dystonia ii. Choreoathetosis iii. Opisthotonus iv. Ballismus b. Pyramidal involvement i. Spasticity ii. Hyperreflexia iii. Extensor plantar reflexes iv. Ankle clonus v. Scissoring of the legs 600
4. Between 2 to 3 years a. Impaired cognition i. Moderate to severe mental retardation in most patients ii. Varying degree of impairment iii. Difficult to obtain adequate assessments of cognitive abilities b. Compulsive behavioral disturbances i. Aggressiveness ii. Vomiting iii. Spitting iv. Coprolalia v. Copropraxis vi. Manipulative behavior c. Persistent self-injurious behavior: a hallmark of the disease i. Biting the fingers, hands, lips, and buccal mucosa ii. Banging the head or limbs 5. Overproduction of uric acid a. Uric acid crystalluria noted as orange crystals in the diaper during the first weeks of life b. Deposition of uric acid crystals or calculi in the kidneys, ureters, or bladder c. Leading to nephrolithiasis, obstructive uropathy, and azotemia, if untreated d. Gouty arthritis develops later in the course of the disease 6. Other features a. Delayed growth and puberty b. Testicular atrophy in most affected males c. Associated orthopedic problems i. Hip subluxation or dislocation ii. Fractures iii. Autoamputation iv. Infections v. Minor scoliosis vi. Contractures 7. Life expectancy a. Most surviving into the second or third decade of life if properly managed b. No evidence suggesting disease progression over time c. Complications i. Aspiration pneumonia ii. Chronic nephrolithiasis iii. Renal failure iv. Sudden unexpected death 8. Lesch-Nyhan syndrome in females a. Extremely rare b. Female carriers i. Generally considered to be asymptomatic ii. Have increased uric acid excretion iii. Develop symptoms of hyperuricemia in later years
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c. Affected females i. Affected carrier females: considered to have nonrandom X-chromosome inactivation or skewed inactivation of the normal HPRT1 allele ii. The first female case reported was caused by a microdeletion of the maternally derived HPRT gene and nonrandom inactivation of the paternally derived X chromosome iii. Two additional cases were caused by a point mutation in one allele and markedly reduced mRNA expression from the other allele
DIAGNOSTIC INVESTIGATIONS 1. EEG: nonspecific changes of slowing or disorganization 2. CT and MRI of the brain: nonspecific changes of atrophy of the basal ganglia or cerebrum 3. Positron emission tomography to demonstrate a selective decrease of 50–70% in dopamine transporters in the caudate and putamen 4. Hyperuricuria or hyperuricemia (serum uric aid concentration >8mg/dL): often present but not sensitive or specific enough for diagnosis 5. 24 Hour uric acid excretion (>20 mg/kg): characteristic but not diagnostic 6. Uric acid to creatinine ratio >2.0: characteristic for patients under 10 years of age 7. Hypoxanthine-guanine phosphoribosyltransferase enzyme activity <1.5% of normal enzyme activity in cells from any tissue (blood, cultured fibroblasts, or lymphoblasts): establishes the diagnosis 8. Molecular genetic testing of the HPRT1 gene a. Purposes i. To define the mutation in the affected males ii. To determine carrier status in at-risk females b. Sequence analysis to detect HPRT1 mutations in males affected with Lesch-Nyhan syndrome: available on clinical basis c. Direct DNA analysis using RT-PCR, multiplex genomic PCR, and sequence analysis performed on research basis
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. When the mother is not a carrier: not increased unless the mother has germline mosaicism in which case there is an undetermined, but real, risk of having future affected sons or carrier daughters ii. When the mother is a carrier a) A 25% risk of having an affected male b) A 25% risk of having a carrier female c) A 50% risk of having an unaffected male or female b. Patient’s offspring i. Severely affected males: not surviving to reproductive age ii. Less severely affected males: all of his daughters are obligatory carriers and none of his sons affected
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2. Prenatal diagnosis available to at-risk pregnancies a. Fetal sex determination by amniocentesis or CVS b. Confirmation of a previously known HPRT1 diseasecausing mutation in a male fetus i. Perform HPRT enzyme activity ii. Perform molecular genetic testing c. Assay of HPRT enzyme activity in cultured amniocytes or chorionic villus cells: the method of choice if the HPRT1 mutation has not been identified in the family d. Preimplantation genetic diagnosis possible for a previously characterized disease-causing mutation 3. Management a. Hyperuricemia i. Control hyperuricemia to reduce the risk of nephropathy, nephrolithiasis, and gouty arthritis ii. Allopurinol a) To block the conversion of oxypurines into uric acid b) To prevent uric acid accumulation and subsequent arthritic tophi, renal stones, and nephropathy b. Neurologic dysfunction i. No medication known to be consistently effective in controlling the extrapyramidal motor features ii. Baclofen or benzodiazepine for spasticity c. Neurobehavioral symptoms i. No effective intervention available ii. Use behavioral modification techniques iii. Control self-injurious behavior a) Require physical restraints b) Removal of teeth c) A noninvasive approach with a special appliance fabricated for the prevention of damage to oral and perioral soft tissues d) Carbamezapine to attenuate the behavioral manifestations d. Surgery for orthopedic problems e. Bone marrow transplantation or red blood cell transfusions not significantly ameliorate the neurologic disorder
REFERENCES Alford RL, Redman JB, O’Brien WE, et al.: Lesch-Nyhan syndrome: carrier and prenatal diagnosis. Prenat Diagn 15:329–338, 1995. Baumeister AA, Frye GD: The biochemical basis of the behavioral disorder in the Lesch-Nyhan syndrome. Neurosci Biobehav Rev 9:169–178, 1985. Crawhall JC, Henderson JF, Kelley WN: Diagnosis and treatment of the LeschNyhan syndrome. Pediatr Res 6:504–513, 1972. Fardi K, Topouzelis N, Kotsanos N: Lesch-Nyhan syndrome: a preventive approach to self-mutilation. Int J Paediatr Dent 13:51–56, 2003. Graham GW, Aitken DA, Connor JM: Prenatal diagnosis by enzyme analysis in 15 pregnancies at risk for the Lesch-Nyhan syndrome. Prenat Diagn 16:647–651, 1996. Jinnah HA: Lesch-Nyhan syndrome. 2002. http://www.emedicine.com Jinnah HA, Friedman T: Lesch-Nyhan disease and its variants. In Scriver CR, Beaudet al., Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001. Jinnah HA, De Gregorio L, Harris JC, et al.: The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res 463:309–326, 2000. Lesch M and Nyhan WL: A familial disorder of uric acid metabolism and central nervous system function. Am J Med Genet 36:561–570, 1964.
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Nicklas JA, O’Neill JP, Jinnah HA, et al.: Lesch-Nyhan syndrome. Gene Reviews. 2003. http://genetests.org Nyhan WL: The Lesch-Nyhan syndrome. Annu Rev Med 24:41–60, 1973. Nyhan WL: Behavior in the Lesch-Nyhan syndrome. J Autism Child Schizophr 6:235–252, 1976. Nyhan WL: The Lesch-Nyhan syndrome. Dev Med Child Neurol 20:376– 380, 1978. Nyhan WL: The recognition of Lesch-Nyhan syndrome as an inborn error of purine metabolism. J Inherit Metab Dis 20:171–178, 1997. Ray PF, Harper JC, Ao A, et al.: Successful preimplantation genetic diagnosis for sex Link Lesch-Nyhan Syndrome using specific diagnosis. Prenat Diagn 19:1237–1241, 1999.
Seegmiller JE, Rosenbloom FM, Kelley WN: Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Science 155:1682–1684, 1967. Seegmiller JE: Lesch-Nyhan syndrome. Management and treatment. Fed Proc 27:1097–1104, 1968. Sponseller PD, Ahn NU, Choi JC, et al.: Orthopedic problems in Lesch-Nyhan syndrome. J Pediatr Orthop 19:596–602, 1999. Watts RW, Spellacy E, Gibbs DA, et al.: Clinical, post-mortem, biochemical and therapeutic observations on the Lesch-Nyhan syndrome with particular reference to the Neurological manifestations. Q J Med 51: 43–78, 1982.
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Fig. 1. Two boys with Lesch-Nyhan syndrome showing severe mental retardation and self-mutilation of the lips and tongue.
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Lethal Multiple Pterygium Syndrome b. Late LMPS i. Survival into the third trimester ii. Absence of fetal hydrops c. Finnish type LMPS i. Feta hydrops from the 15th gestational week ii. Lethality at average gestation of 29 weeks iii. Occasional pterygia of the neck and elbows iv. Distinct neuropathologic findings 4. Pathogenesis a. Combination of the following two sequences i. Fetal akinesia deformation sequence a) Resulting from myoneural dysfunction (generalized amyoplasia) and/or intrauterine growth constraint leading to fetal akinesia b) Fetal akinesia, in turn, leading to growth retardation, pulmonary hypoplasia, short umbilical cord, limb positional defects, and facial anomalies ii. Jugular lymphatic obstruction sequence: delay in development of the connection between jugular lymph sacs and the internal jugular vein resulting in dilatation of tributary lymphatics and peripheral lymphedema b. Fragile collagen proposed as a possible pathogenesis
Lethal multiple pterygium syndrome (LMPS) is a lethal hereditary disorder characterized by a distinct constellation of multiple anomalies, consisting of multiple pterygia, flexion contractures of multiple joints, characteristic facial appearance, cystic hygroma, hydrops, and pulmonary and cardiac hypoplasia.
GENETICS/BASIC DEFECTS 1. Inheritance: possible heterogeneity a. Autosomal recessive inheritance b. Possible X-linked recessive inheritance 2. Classification by Hall (1982, 1984) and Entezami et al. (1998) a. Based on the following concominant abnormalities i. Age of onset of intrauterine growth retardation ii. Timing and extent of neck swelling iii. Presence or absence of bony fusions and bone modeling errors b. Type I (Gillin-Pryse-Davis syndrome) i. Multiple pterygia ii. Pulmonary hypoplasia iii. Genital anomalies iv. Facial anomalies v. Strongly flexed extremities with a reduced muscle mass c. Type II (Chen syndrome) i. Multiple pterygia ii. Hygroma colli iii. Facial anomalies iv. Undermodeled long bones, with shortened extremities v. Cartilaginous fusion of joints and bony fusion of the spinous processes of the vertebrae vi. Polyhydramnios vii. Hypoplastic lungs and heart viii. Diaphragmatic hernia d. Type III (van Regemorter syndrome) i. Multiple pterygia ii. Pulmonary hypoplasia iii. Facial anomalies iv. Thin extremities with reduced muscle mass v. Fusions of the long tubular bones e. Type IV (Herva syndrome) i. Multiple pterygia ii. Degeneration of the anterior horn cells of the spinal cord iii. Found particularly in Finland 3. Classification by De Die-Smulders et al. (1990) a. Early LMPS i. A group with presumed genetic heterogeneity ii. Lethality in the second trimester iii. Hydrops fetalis iv. Cystic hygroma
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1. Prenatal history a. Nonimmune fetal hydrops b. Diminished fetal activity c. Maternal hydramnios d. Often presented with fetal demise 2. Characteristic facial features a. Ocular hypertelorism b. Antimongoloid slant of the palpebral fissures c. Epicanthal folds d. Markedly flattened nasal bridge with hypoplastic nasal alae e. Micrognathia f. Cleft palate g. Apparently low-set malformed ears 3. Neck a. Short b. Cystic hygroma 4. Chest a. Small chest b. Hypoplastic lungs c. Hypoplastic heart 5. Multiple pterygia a. Symmetrical b. Sites i. Chin-to-sternum ii. Cervical
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iii. Axillary iv. Antecubital v. Crural vi. Popliteal Other limb anomalies a. Multiple contractures: always present b. Camptodactyly c. Calcaneovalgus foot deformities Gastrointestinal anomalies a. Intestinal malrotation b. Short bowel c. Thin colon d. Colonic atresia e. Absent vermiform appendix Genitourinary anomalies a. Hydronephrosis b. Unilateral renal dysplasia c. Cryptorchidism Other associated anomalies a. Kyphoscoliosis b. Near complete absence of diaphragmatic muscle c. Aortic coarctation d. Absent abdominal wall muscle e. Adrenal hypoplasia f. Short umbilical cord g. Rare cerebral anomalies i. Hydranencephaly ii. Holoprosencephaly iii. Dilated ventricles with intracerebral cyst
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Craniofacial abnormalities i. Scalp edema ii. Microbrachycephaly iii. Flattened mandibular angle b. Hypoplasia and undermodeling of the bones i. Thin crowded ribs ii. Markedly hypoplastic scapulae iii. Hypoplastic iliac wings, ischia and pubic bones iv. Lack of normal curvature at the cervico-thoracic junction c. Bony fusion i. Marked bony fusion of posterior spinous processes ii. Radio-ulnar synostosis 2. Histologic studies of the skeletal system a. Cartilaginous and bony fusion of the spinous processes b. Fusion of epiphyseal cartilages of distal humerus and proximal ulna c. Poorly developed joint space d. An abnormal growth plate e. Weak safranin staining of the resting cartilages f. Placenta i. Scalloped chorionic villi ii. Intravillous trophoblast invaginations g. Muscular and neural abnormalities 3. Chromosome analysis: normal
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GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosome recessive inheritance: 25% ii. X-linked recessive inheritance: 50% risk of having an affected brother if the mother is a carrier b. Patient’s offspring: a lethal entity not surviving to reproductive age 2. Prenatal diagnosis a. Ultrasonography: possible i. Nonimmune fetal hydrops ii. Cystic hygroma iii. Diminished fetal activity iv. Short and fixed limbs v. Maternal hydramnios vi. Other ultrasonographically detectable anomalies a) Diaphragmatic hernia b) Scoliosis c) Pterygia 3. Management: a lethal entity
REFERENCES Anthony J, Mascarenhas L, O’Brien J, et al.: Lethal multiple pterygium syndrome. The importance of fetal posture in mid-trimester diagnosis by ultrasound: discussion and case report. Ultrasound Obstet Gynecol 3:212–216, 1993. Brink DS, Luisiri A, Grange DK: Case report: lethal multiple pterygium syndrome. Pediatr Pathol Mol Med 22:461–470, 2003. Chen H, Chang CH, Misra RP, et al.: Multiple pterygium syndrome. Am J Med Genet 7:91–102, 1980. Chen H, Immken L, Lachman R, et al.: Syndrome of multiple pterygia, camptodactyly, facial anomalies, hypoplastic lungs and heart, cystic hygroma, and skeletal anomalies: delineation of a new entity and review of lethal forms of multiple pterygium syndrome. Am J Med Genet 17:809–826, 1984. Clementi M, Notari L, Tenconi R: Lethal multiple pterygium syndrome: importance of fetal physical examination. Am J Med Genet 57:119–120, 1995. Cox PM, Brueton LA, Bjelogrlic P, et al.: Diversity of neuromuscular pathology in lethal multiple pterygium syndrome. Pediatr Dev Pathol 6:59–68, 2003. de Die-Smulders CE, Schrander-Stumpel CT, Fryns JP: The lethal multiple pterygium syndrome: a nosological approach. Genet Couns 1:13–23, 1990. de Die-Smulders CE, Vonsee HJ, Zandvoort JA, et al.: The lethal multiple pterygium syndrome: prenatal ultrasonographic and postmortem findings; a case report. Eur J Obstet Gynecol Reprod Biol 35:283–289, 1990. Elias S, Boelen L, Simpson JL: Syndromes of camptodactyly, multiple ankylosis, facial anomalies, and pulmonary hypoplasia. Birth Defects Original Article Series 14(6B):243–251, 1978. Entezami M, Runkel S, Kunze J, et al.: Prenatal diagnosis of a lethal multiple pterygium syndrome type II. Case report. Fetal Diagn Ther 13:35–38, 1998. Escobar V, Weaver D: Popliteal pterygium syndrome: a phenotypic and genetic analysis. J Med Genet 15:35–42, 1978. Francesco P, Nicola L: Nosological difference between the Bartsocas-Papas syndrome and lethal multiple pterygium syndrome. Am J Med Genet 29:699–700, 1988. Froster UG, Stallmach T, Wisser J, et al.: Lethal multiple pterygium syndrome: suggestion for a consistent pathological workup and review of reported cases. Am J Med Genet 68:82–85, 1997. Froster-Iskenius UG, Curry C, Philp M, et al.: Brief clinical report: an unusual bandlike web in an infant with lethal multiple pterygium syndrome. Am J Med Genet 30:763–769, 1988. Gericke GS: Fragile collagen and the lethal multiple pterygium syndrome: does heat stress play a role? Am J Med Genet 38:630–633, 1991. Gillin ME, Pryse-Davis J: Pterygium syndrome. J Med Genet 13:249–251, 1976. Hall JG: The lethal multiple pterygium syndromes. Am J Med Genet 17:803–807, 1984.
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Hall JG, Reed SD, Rosenbaum KN, et al.: Limb pterygium syndromes: A review and report of eleven patients. Am J Med Genet 12:377–409, 1982. Hartwig NG, Vermeij-Keers C, Bruijn JA, et al.: Case of lethal multiple pterygium syndrome with special reference to the origin of pterygia. Am J Med Genet 33:537–541, 1989. Hertzberg BS, Kliewer MA, Paulyson-Nunez K: Lethal multiple pterygium syndrome: antenatal ultrasonographic diagnosis. J Ultrasound Med 19:657–660, 2000. Herva R, Leisti J, Kirkinen P, et al.: A lethal autosomal recessive syndrome of multiple congenital contractures. Am J Med Genet 20:431–439, 1985. Hogge WA, Golabi M, Filly RA, et al.: The lethal multiple pterygium syndromes: is prenatal detection possible? Am J Med Genet 20:441–442, 1985. Isaacson G, Gargus JJ, Mahoney MJ: Brief clinical report: lethal multiple pterygium syndrome in an 18-week fetus with hydrops. Am J Med Genet 17:835–839, 1984. Lakshminarayana P, Jegatheesan T, Venkataraman P: Lethal multiple pterygium syndrome. Indian Pediatr 29:1305–1309, 1992. Lockwood C, Irons M, Troiani J, et al.: The prenatal sonographic diagnosis of lethal multiple pterygium syndrome: a heritable cause of recurrent abortion. Am J Obstet Gynecol 159:474–476, 1988. Martin NJ, Hill JB, Cooper DH, et al.: Lethal multiple pterygium syndrome: three consecutive cases in one family. Am J Med Genet 24:295–304, 1986.
Mbakop A, Cox JN, Stormann C, et al.: Lethal multiple pterygium syndrome: report of a new case with hydranencephaly. Am J Med Genet 25:575–579, 1986. Meizner I, Hershkovitz R, Carmi R, et al.: Prenatal ultrasound diagnosis of a rare occurrence of lethal multiple pterygium syndrome in two siblings. Ultrasound Obstet Gynecol 3:432–436, 1993. Meyer-Cohen J, Dillon A, Pai GS, et al.: Lethal multiple pterygium syndrome in four male fetuses in a family: evidence for an X-linked recessive subtype? Am J Med Genet 82:97–99, 1999. Moerman P, Fryns JP, Cornelis A, et al.: Pathogenesis of the lethal multiple pterygium syndrome. Am J Med Genet 35:415–421, 1990. Sciarrone A, Verdiglione P, Botta G, et al.: Prenatal diagnosis of lethal multiple pterygium syndrome in mid-pregnancy. Ultrasound Obstet Gynecol 12:218–219, 1998. Spearritt DJ, Tannenberg AE, Payton DJ: Lethal multiple pterygium syndrome: report of a case with neurological anomalies. Am J Med Genet 47:45–49, 1993. Tolmie JL, Patrick A ,Yates JR: A lethal multiple pterygium syndrome with apparent X-linked recessive inheritance. Am J Med Genet 27:913–919, 1987. Turnpenny PD, Hole R: The first description of lethal pterygium syndrome with facial clefting(Bartsocas-Papas syndrome) in 1600. J Med Genet 37:314–315, 2000. Van Regemorter N, Wilkin P, Englert Y, et al.: Lethal multiple pterygium syndrome. Am J Med Genet 17:827–834, 1984.
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Fig. 1. The macerated 32-week stillborn (A,B) with Chen syndrome showing multiple pterygia involving the neck, axillae, antecubital, crural, popliteal, and interphalangeal areas, hygroma coli, and facial anomalies (hypertelorism, antimongoloid slant of the palpebral fissures, a shortened nose, depressed nasal bridge and tip of the nose, a long philtrum, a receding chin, apparently low-set and malformed ears). Contractures of the fingers were present with ulnar deviation of the hands. Polyhydramnios and fetal hydrops were noted by ultrasonography at 30 weeks of gestation. Autopsy showed hypoplastic lungs and heart and a large left diaphragmatic hernia (containing intestine, pancreas, and part of the stomach and ascites). Radiographs (C,D) and postmortem section (E) revealed a large cystic hygroma, hypoplastic vertebral bodies, fusion of the posterior elements extended from the cervical into the midthoracic spine, angulated cervicothoracic junction, and undermodeled long bones. Representative section of the elbow (F) showed fusion of epiphyseal cartilages of the distal humerus and proximal ulna resulting in bending of the proximal portion of the ulna and a deficient joint space. The resting cartilage (G) was distinctly demarcated from the physeal growth plate, which showed slightly retarded but normally arranged chondrocytic column.
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Fig. 2. A malformed macerated 28-week fetus (A,B) with Chen syndrome showing impressive skin webbing at the neck, axillae, antecubital, crural, and popliteal areas, and abnormal facies (markedly flattened nasal bridge with anteverted and hypoplastic nasal alae, low-set ears, and a small mouth with cleft soft palate). In addition, there were contractures of the hands and fingers and rocker bottom feet. The prenatal ultrasound at 25 weeks of gestation (C) showed a large cystic hygroma at the back of the head. Radiographs (D,E) revealed massive edema of the scalp contiguous with the neck pterygia, hypoplastic vertebral bodies, multiple fusions of the posterior elements of the cervical and lumbosacral spine bodies, and incipient fusion of the radius and ulna bilaterally. Post mortem study revealed markedly hypoplastic lungs and heart.
Fig. 3. A 19-week fetus with Chen syndrome (A,B) showing a large cystic hygroma, detected by prenatal ultrasonography, multiple pterygia involving neck, axillae, elbows, fingers, and knees with contractures, illustrated by radiographs (C,D). Distinctive facial features include hypertelorism, flat nasal bridge, cleft palate, and micrognathia. Postmortem study revealed hypoplastic lungs and heart, fusion of cartilage of the elbow joints, and hypoplastic cervical vertebral bodies with posterior elements beginning to come together but were not yet fused.
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Fig. 4. A fetus with lethal multiple pterygium (A,B) syndrome showing multiple pterygia involving neck, axilla, elbows, and knees associated with multiple contractures, illustrated by radiographs (C,D). There were hypertelorism, small nose, micrognathia and micrognathia.
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Fig. 5. A stillbirth with lethal multiple pterygium syndrome showing flexion of all 4 limbs with multiple pterygia involving neck, axillae, elbows, and knees, short neck, and cystic hygroma colli. There were antimongoloid slant of the palpebral fissures, hypertelorism, flat nasal bridge, micrognathia, and high arched palate. The upper extremities were held in extreme flexion with ulnar deviation of both hands and camptodactyly. The lower limbs were rotated externally and flexed in a crossed position with bilateral calcaneus deformities of the feet. Postmortem findings include multiloculated cystic hygroma, hypoplastic lungs and kyphoscoliosis.
Lowe Syndrome Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare X-linked recessive disorder. It was initially recognized in 1952 by Lowe who described the triad of congenital cataracts, mental retardation, and generalized aminoaciduria. Its prevalence is estimated to be several cases per 100,000 males.
GENETICS/BASIC DEFECTS 1. Inheritance a. X-linked recessive disorder predominantly affecting males b. New mutations in 31.6% of affected males c. Germline mosaicism in 4.5% 2. The gene involved (OCRL1) a. Map locus: Xq26.1, based on: i. Balanced X;autosome translocations with a break-point in band Xq25-q26 in two unrelated female patients ii. Linkage analysis with RLFP in families with multiple affected individuals b. Mapped in 1977 c. Cloned in 1992 d. Encoding OCR11, a 105-kD enzyme with phosphatidylinositol 4,5-bisphosphate 5-phosphatase (PtdIns-4,5-P2) activity localized to the Golgi complex i. Loss or reduction of the enzyme demonstrated in affected males ii. Carrier status of OCRL in females not readily determined by assays of the enzyme due to the X-linked nature of OCRL1 and random X inactivation 3. Mutations of OCRL1 gene responsible for Lowe syndrome a. Nonsense mutations and deletions causing frameshifts and premature termination b. Deletions c. Missense mutations in domains conserved among all the known PtdIns(4,5)P2 5-phosphatases 4. Carrier females with typical lens opacities 5. Affected females as a result of a. Unfavorable Lyonization b. Turner syndrome c. X-autosome translocation through the relevant gene
CLINICAL FEATURES 1. Variable age of onset and severity of clinical manifestations 2. Eye abnormalities a. Congenital cataracts (the hallmark of the disease) i. Developed prenatally ii. Always present prior to birth 613
b. Congenital glaucoma with or without buphthalmos (50–60%) c. Microphthalmos d. Nystagmus e. Decreased visual acuity (blindness) f. Corneal scarring and keloid formation i. Develops spontaneously without trauma ii. Onset usually after age 5 iii. Causes significant visual impairment 3. Renal abnormalities a. Fanconi syndrome of renal tubules (the cardinal features) i. Bicarbonaturia ii. Proximal tubular acidosis iii. Generalized aminoaciduria iv. Hyperphosphaturia leading to osteomalacia, renal rickets, and pathologic fractures v. Hypercalciuria vi. Proteinuria vii. Glycosuria (not a feature of the renal tubular dysfunction) viii. Impairment in urine-concentration (polyuria) ix. Carnitine wasting b. Variable age of onset and severity of the tubular dysfunction i. Failure to thrive ii. Recurrent infections iii. Metabolic collapse iv. Severe hypokalemia or hypocalcemia requiring replacement therapy in a minority of patients. This is probably a part of preterminal exacerbation of tubular dysfunction v. Slowly progressive renal failure may occur in the second to fourth decade of life 4. CNS (prominently involved organ) and behavioral abnormalities a. Cardinal features i. Neonatal/infantile hypotonia ii. Delay in motor milestones iii. Cognitive impairment iv. Areflexia by one year of age b. Mental retardation (common but not cardinal feature) c. Seizures d. Neuropathologic and neuroimaging abnormalities e. Stereotypic behaviors i. Temper tantrum (Lowe tantrum) ii. Aggression iii. Irritability iv. Stubbornness v. Rigidity of thought vi. Self injury vii. Repetitive non-purposeful movements
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5. Musculoskeletal abnormalities a. Secondary consequences of hypotonia, renal tubular acidosis, and/or hypophosphatemia i. Short stature ii. Joint hypermobility iii. Dislocated hips iv. Genu valgum v. Scoliosis vi. Kyphosis vii. Platyspondylia viii. Fractures b. Primary abnormality of excessive connective tissue growth i. Nontender joint swelling ii. Subcutaneous nodules 6. Typical facies a. Frontal bossing b. Characteristic deep-set eyes c. Inattentiveness 7. Cryptorchidism 8. Natural history a. Succumb to either severe renal insufficiency and dehydration or infection b. Survival to adulthood if metabolic abnormalities are adequately treated 9. Manifestation in the carriers a. Lens involvement i. Micropunctate cataracts clustered in a radial wedge pattern ii. Occasional dense posterior cortical cataract b. Sensitivity of carrier detection by slit-lamp examination (>90%), due to random inactivation of Lowe syndrome allele in the proportion of cells in the lens of female carriers c. Germ line or somatic mosaicism documented d. Positive family history of early cataracts in mother, maternal female relatives, and institutionalized maternal uncles
DIAGNOSTIC INVESTIGATIONS 1. Blood chemistry a. Blood gas for metabolic acidosis b. Electrolyte disturbances (likely absent in neonates and young infants) 2. Urine a. Aminoaciduria b. Hyperphosphaturia c. Proteinuria d. Glycosuria e. Low urine osmolality f. Elevated 24-hour volume 3. Serum enzyme values a. Elevated CK b. Elevated SGOT c. Elevated LDH d. Elevated α2-globulin 4. Radiography a. Rickets/osteoporosis b. Pathological fractures
c. Frontal bossing d. Kyphoscoliosis e. Cervical spine anomalies f. Platyspondyly g. Hip subluxations/dislocation 5. Neuroimaging a. Cranial MRI i. Mild ventriculomegaly (33%) ii. Multiple tiny periventricular cysts (no clinical significance) b. Neuropathologic examination of the brain i. Normal in some cases ii. Diffuse or focal myelin pallor without myelin breakdown iii. Ventriculomegaly iv. Mild cerebral abnormalities v. Isolated cases of subependymal cysts vi. Mesencephalic porencephaly vii. Postencephalitic changes viii. Blunted and foreshortened frontal lobes ix. Acute pontine necrosis x. Cerebellar hypoplasia xi. Aberrant neuronal migration xii. Multiple tiny cysts without inflammatory changes 6. Affected male patients a. Biochemical assay of reduced activity (<10%) of PtdIns(4,5)P2 5-phosphatase in cultured fibroblasts to confirm diagnosis of patients with OCRL. Peripheral blood cannot be tested since the enzyme is not present in lymphocytes b. Molecular analysis to detect mutations in the OCRL gene in about 95% of affected males i. Sequence analysis ii. Fluorescence in situ hybridization analysis (FISH), with cosmid probes that span the entire OCRL1 gene 7. Carrier females a. Karyotyping to rule out X/autosome translocation with a breakpoint through the OCRL locus b. Carrier detection i. Biochemical assay of reduced activity of PtdIns(4,5)P2 5-phosphatase in cultured fibroblasts is not suitable for determining OCRL carrier status, since random X inactivation could result in a wide range of enzyme activity that may overlap with the normal range ii. An obligatory carrier based on evaluation of the family pedigree iii. Slip-lamp examination for numerous punctate opacities, especially in prepubertal females, is a better method and it has a low false-negative rate iv. By direct detection of mutations when the mutation is previously identified (in about 95% of carrier females) v. By mutation scanning of high-risk females by denaturing high performance liquid chromatography (DHPLC) when:
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a) The affected male is not available b) The diagnosis has been confirmed by enzyme analysis vi. By linked markers when the mutation is unknown
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. A 50% risk of having an affected brother if the mother is a carrier ii. A low but finite recurrence risk (estimated to be about 1.5%) in case of a new mutation due to possibility of nonpenetrance or gonadal mosaicism in the mother b. Patient’s offspring: Affected males not known to reproduce 2. Prenatal diagnosis available for pregnancies at risk a. Determine fetal gender by amniocentesis or CVS b. Biochemical assay for deficiency of PtdIns(4,5)P2 5phosphatase from cultured amniotic fluid cells or cultured CVS if the fetal karyotype shows 46,XY (not suitable for determining OCRL carrier status for females) c. Molecular analysis i. By direct detection of mutations when the OCRL disease-causing mutation in the family is known ii. By linked markers in informative families when the mutation is unknown d. Offer prenatal diagnosis by enzymatic analysis to every mother of a son with Lowe syndrome because of the relatively high rate (4.5%) of germline mosaicism, even with the following situations: i. Negative family history ii. Negative dilated slit-lamp examination iii. DNA testing showing that the mother is not a carrier 3. Management a. Ocular management i. Cataract extraction ii. Refraction for aphakia iii. Control of glaucoma iv. Removal of corneal keloids: often with recurrence and enlargement of the lesions b. Speech and physical therapy for developmental delay c. Medications i. Anticonvulsants ii. Behavior-modifying medications if needed d. Replacement/supplementation i. Urinary bicarbonate, water, and phosphate losses in case of acidosis or bone disease ii. L-carnitine iii. Vitamin D as indicated e. Anesthetic risks i. Chronic metabolic acidosis ii. Existing hypokalemia, a risk for serious cardiac arrhythmia iii. A risk of glaucoma iv. Hypophosphatemic rickets causing fragility of bone structures
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a) Requires attention while positioning b) Difficulty in maintaining the airway due to craniofacial abnormalities and abnormal teeth structure
REFERENCES Abbassi V, Lowe CU, Calcagno PL: Oculo-cerebro-renal syndrome: A review. Am J Dis Child 115:143–168, 1968. Attree O, Olivos IM, Okabe I, et al.: The Lowe’s oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5phosphatase. Nature 358:239–242, 1992. Charnas LR, Gahl WA: The oculocerebrorenal syndrome of Lowe. Adv Pediatr 38:75–107, 1991. Charnas LR, Bernardini I, Rader D, et al.: Clinical and laboratory findings in the oculocerebrorenal syndrome of Lowe, with special reference to growth and renal function. N Engl J Med 324:1318–1325, 1991. Demmer LA, Wippold FJ, 2nd, Dowton SB: Periventricular white matter cystic lesions in Lowe (oculocerebrorenal) syndrome. A new MR finding. Pediatr Radiol 22:76–77, 1992. Elliman D, Woodley A: Tenosynovitis in Lowe syndrome. J Pediatr 103:1011, 1983. Gardner RJ, Brown N: Lowe’s syndrome: identification of carriers by lens examination. J Med Genet 13:449–454, 1976. Gazit E, Brand N, Harel Y, et al.: Prenatal diagnosis of Lowe’s syndrome: a case report with evidence of de novo mutation. Prenat Diagn 10:257–260, 1990. Ginsberg J, Bove KE, Fogelson MH: Pathological features of the eye in the oculocerebrorenal (Lowe) syndrome. J Pediatr Ophthalmol Strabismus 18:16–24, 1981. Hayashi Y, Hanioka K, Kanomata N, et al.: Clinicopathologic and molecularpathologic approaches to Lowe’s syndrome. Pediatr Pathol Lab Med 15:389–402, 1995. Hodgson SV, Heckmatt JZ, Hughes E, et al.: A balanced de novo X/autosome translocation in a girl with manifestations of Lowe syndrome. Am J Med Genet 23:837–847, 1986. Holtgrewe JL, Kalen V: Orthopedic manifestations of the Lowe (oculocerebrorenal) syndrome. J Pediatr Orthop 6:165–171, 1986. Kawano T, Indo Y, Nakazato H, Shimadzu M, Matsuda I. Oculocerebrorenal syndrome of Lowe: three mutations in the OCRL1 gene derived from three patients with different phenotypes. Am J Med Genet 77:348 355, 1998. Kenworthy L, Charnas L: Evidence for a discrete behavioral phenotype in the oculocerebrorenal syndrome of Lowe. Am J Med Genet 59:283–290, 1995. Lavin CW, McKeown CA: The oculocerebrorenal syndrome of Lowe. Int Ophthalmol Clin 33:179–191, 1993. Lin T, Lewis RA, Nussbaum RL: Molecular confirmation of carriers for Lowe syndrome. Ophthalmology 106:119–122, 1999. Lin T, Orrison BM, Leahey AM, et al.: Spectrum of mutations in the OCRL1 gene in the Lowe oculocerebrorenal syndrome. Am J Hum Genet 60: 1384–1388, 1997. Lowe CU, Terrey M, MacLachan EA: Organic aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation: A clinical entity. Am J Dis Child 83:164–184, 1952. Mueller OT, Hartsfield JK Jr, Gallardo LA, et al.: Lowe oculocerebrorenal syndrome in a female with a balanced X;20 translocation: mapping of the X chromosome breakpoint. Am J Hum Genet 49:804–810, 1991. Nussbaum RL, Suchy SF: The Oculocerebrorenal Syndrome of Lowe (Lowe Syndrome). In Scriver CR, Beaudet al., Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, Ch 252, pp 6257–6266, 2001 Nussbaum RL, Orrison BM, Janne PA, et al.: Physical mapping and genomic structure of the Lowe syndrome gene OCRL1. Hum Genet 99: 145–150, 1997. Ono J, Harada K, Mano T, et al.: MR findings and neurologic manifestations in Lowe oculocerebrorenal syndrome. Pediatr Neurol 14:162–164, 1996. Peverall J, Edkins E, Goldblatt J, et al.: Identification of a novel deletion of the entire OCRL1 gene detected by FISH analysis in a family with Lowe syndrome. Clin Genet 58:479–482, 2000.
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Reilly DS, Lewis RA, Ledbetter DH, et al.: Tightly linked flanking markers for the Lowe oculocerebrorenal syndrome, with application to carrier assessment. Am J Hum Genet 42:748–755, 1988. Reilly DS, Lewis RA, Nussbaum RL: Genetic and physical mapping of Xq24q26 markers flanking the Lowe oculocerebrorenal syndrome. Genomics 8:62–70, 1990. Roschinger W, Muntau AC, Rudolph G, et al.: Carrier assessment in families with Lowe oculocerebrorenal syndrome: novel mutations in the OCRL1 gene and correlation of direct DNA diagnosis with ocular examination. Mol Genet Metab 69:213–222, 2000. Satre V, Monnier N, Berthoin F, et al.: Characterization of a germline mosaicism in families with Lowe syndrome, and identification of seven novel mutations in the OCRL1 gene. Am J Hum Genet 65:68–76, 1999. Saricaoˇglu F, Demirtas F, Aypar Ü: Preoperative and perioperative management of a patient with Lowe syndrome diagnosed to have Fanconi’s syndrome. Pediatr Anesth 14:530–532, 2004.
Silver DN, Lewis RA, Nussbaum RL: Mapping the Lowe oculocerebrorenal syndrome to Xq24-q26 by use of restriction fragment length polymorphisms. J Clin Invest 79:282–285, 1987. Suchy SF, Lin T, Horwitz JA, et al.: First report of prenatal biochemical diagnosis of Lowe syndrome. Prenat Diagn 18:1117–1121, 1998. Suchy SF, Olivos-Glander IM, Nussbaum RL: Lowe syndrome, a deficiency of phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi apparatus. Hum Mol Genet 4:2245–2250, 1995. Wadellius C, Fagerholm P, Pettersson U, et al.: Lowe oculocerebrorenal syndrome: DNA-based linkage of the gene to Xq24-q26,using tightly linked flanking markers and the correlation to lens examination in carrier diagnosis. Am J Hum Genet 44:241–247, 1989. Wappner RS: Lowe syndrome. Gene Reviews, 2003. http://www.genetests.org Zhang X, Jefferson AB, Auethavekiat V, et al.: The protein deficient in Lowe syndrome is a phosphatidylinositol-4,5-bisphosphate 5-phosphatase. Proc Natl Acad Sci USA 92:4853–4856, 1995.
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Fig. 2. A 10-year-old boy with Lowe syndrome showing short stature and visual impairment. The diagnosis was confirmed by assay of markedly deficient phosphatidylinositol bisphosphate phosphatase activity (0.05 with normal control of 2–5 nmol/min/mg protein) in the cultured fibroblasts.
Fig. 1. 11⁄2 year-old boy with Lowe syndrome showing frontal bossing and deep-set eyes. He had a history of profound hypotonia, failure to thrive, cataracts, glaucoma, seizures, and generalized aminoaciduria. The diagnosis was confirmed by assay of markedly deficient phosphatidylinositol bisphosphate phosphatase activity in the cultured fibroblasts (0.05, control: 2–5 mmol/min/mg protein). The recent photo was taken at 6 years of age.
Marfan Syndrome Marfan syndrome (MFS) is an inherited connective tissue disorder, noteworthy for its worldwide distribution, relatively high prevalence, clinical variability, and pleiotropic manifestations involving primarily the ocular, skeletal, and cardiovascular systems, some of which are life threatening. Its estimated frequency is 2–3 per 10,000 individuals.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant b. New mutation in about 25–30% of the cases c. About 70–75% of individuals diagnosed with Marfan syndrome have an affected parent 2. Caused by a wide variety of mutations in the fibrillin-1 (FBN1) gene located on chromosome 15q21.1 3. Molecular defects in the fibrillin gene are responsible for the impaired structural integrity of the skeletal, ocular, and cardiovascular systems 4. Almost all mutations are specific (unique) to a particular individual or family 5. FBN1 mutation is helpful diagnostically only if it has been previously found in the person who independently meets the criteria for Marfan syndrome 6. No obvious correlation between location of mutation and phenotypic severity (except an apparent clustering of mutations associated with the most severe form of Marfan syndrome, i.e., neonatal Marfan syndrome) 7. Pathophysiological consequence of the elastic fiber degeneration: reduced distensibility in response to the pulse pressure wave or increased stiffness 8. Intrafamilial and interfamilial variability of clinical expression 9. Fibrillin-1 mutations also observed in related disorders of connective tissue (type I fibrillinopathies) a. Autosomal dominant ectopia lentis (bilateral ectopia lentis without the typical skeletal and cardiovascular manifestations of the Marfan syndrome) b. Shprintzen-Goldberg syndrome i. Marfanoid habitus ii. Craniosynostosis iii. Marfanoid habitus iv. Mental retardation v. Rarely aortic root dilatation vi. Mitral valve prolapse c. Autosomal dominant Weill-Marchesani syndrome i. Ectopia lentis ii. Short stature d. Ectopic lentis i. Bilateral ectopia lentis ii. Scoliosis in some cases iii. No cardiovascular manifestations
e. Familial aortic aneurysm i. Ascending aortic aneurysm and dissection ii. No ectopia lentis iii. No specific skeletal findings f. MASS phenotype i. Mitral valve prolapse ii. Aortic root dilation without dissection iii. Skeletal and skin abnormalities g. New variant of Marfan syndrome i. Skeletal features of Marfan syndrome ii. Joint contractures iii. Knee joint effusions iv. Ectopia lentis v. No cardiovascular manifestations h. Marfan-like (Marfanoid) skeletal abnormalities i. Tall stature ii. Scoliosis iii. Pectus excavatum iv. Arachnodactyly 10. The gene for fibrillin-2 (FBN2) a. Mapped to chromosome 5q23-31 b. Highly homologous to FBN1 c. FBN2 mutations shown to cause a phenotypically related disorder called congenital contractural arachnodactyly (Beals syndrome), which is characterized by: i. Marfanoid habitus ii. Arachnodactyly iii. Camptodactyly iv. Crumpled ears v. Mild contractures of the elbows, knees, and hips vi. Mild muscle hypoplasia especially of the calf muscles
CLINICAL FEATURES Ghent criteria: For the diagnosis of Marfan syndrome in the first (index) case in a family, major criteria must be found in at least two different organ systems and minor criteria in a third body system. If a fibrillin-1 mutation is identified, a major criterion in one system and involvement of another system are required. In a relative of an individual with confirmed Marfan syndrome, a major criterion in one body system and involvement of another system is all that is needed for the diagnosis. 1. Skeletal system (requires at least 2 majors or 1 major plus 2 minors): affected patients are usually tall and thin with respect to the family profile. Limbs are disproportionately long compared with the trunk (dolichostenomelia). Arachnodactyly is a very common feature a. Major criteria (requires at least four manifestations) i. Pectus carinatum ii. Pectus excavatum requiring surgery
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iii. Reduced upper-to-lower body segment ratio (<0.85 in Caucasians and <0.78 in African descents) or arm span-to-height ratio greater than 1.05. Arms and legs may be unusually long in proportion to the torso iv. Positive wrist (Walker-Murdoch) and thumb (Steinberg) signs for arachnodactyly. Two simple maneuvers may help demonstrate arachnodactyly. First, the thumb sign is positive if the thumb, when completely opposed within the clenched hand, projects beyond the ulnar border. Secondly, the wrist sign is positive if the distal phalanges of the first and fifth digits of one hand overlap when wrapped around the opposite wrist v. Scoliosis ≥20° or spondylolisthesis. More than 60% of patients have scoliosis. Progression is more likely with curvature greater than 20° in growing patients vi. Reduced extension of the elbows (<170°) vii. Medial displacement of the medial malleolus, resulting in pes planus viii. Protrusio acetabula (intrapelvic protrusion of the acetabulum; abnormally deep acetabulum with accelerated erosion) of any degree (ascertained by pelvic radiograph). Prevalence is about 50% b. Minor criteria i. Pectus excavatum of moderate severity ii. Joint hypermobility iii. High arched palate with dental crowding iv. Typical face a) Dolichocephaly b) Malar hypoplasia c) Enophthamos d) Retrognathia e) Down-slanting palpebral fissures 2. Ocular system (requires 1 major or at least 2 minors) a. Major criterion: ectopia lentis (usually superior temporal dislocation, almost always bilateral, occurs in up to 80% of affected individuals). This may present at birth or develop during childhood or adolescence b. Minor criteria i. Abnormally flat cornea (measured by keratometry) ii. Increased axial length of the globe (measured by ultrasound) iii. Hypoplastic iris or hypoplastic ciliary muscle causing decreased miosis 3. Cardiovascular system (requires one major or one minor): the most serious problems associated with Marfan syndrome a. Major criteria i. Dilatation of the ascending aorta with or without aortic regurgitation and involving at least the sinuses of Valsalva. The prevalence of aortic dilatation in Marfan syndrome is 70–80%. It presents at an early age, and tends to be more common in men than women ii. Dissection involving the ascending aorta
4.
5.
6.
7.
8.
9.
b. Minor criteria i. Mitral valve prolapse with or without mitral valve regurgitation. The prevalence of mitral valve prolapse is 55–69% ii. Dilatation of main proximal pulmonary artery in the absence of valvular or peripheral pulmonic stenosis or any other obvious cause, below the age of 40 years iii. Calcification of mitral annulus in patients less than 40 years of age iv. Dilatation or dissection of abdominal or descending thoracic aorta in patients less than 50 years of age Pulmonary system (requires 1 minor) a. Major criterion: none b. Minor criteria i. Spontaneous pneumothorax: occurs in about 5% of patients ii. Apical blebs (on chest radiography) Skin and integument (requires 1 minor) a. Major criterion: none b. Minor criteria i. Striae atrophicae (stretch marks) not associated with marked weight changes, pregnancy, or repetitive stress. Stretch marks are usually found on the shoulder, midback and thighs ii. Recurrent or incisional hernia Dura (requires the major) a. Major criterion: lumbosacral ectasia (ballooning or widening of the dural sac) by CT or MRI. Fewer than 20% of patients experience serious dural ectasia. Dural ectasia is thought to be caused by CSF pulsations against weakened dura b. Minor criteria: none Family history (requires one major) a. Major criteria i. Having a parent, child, or sibling who meets the diagnostic criteria independently ii. Presence of a mutation in FBN1 known to cause the MFS iii. Presence of a haplotype around FBN1, inherited by descent, known to be associated with unequivocally diagnosed MFS in the family b. Minor criterion: none Other features not in the Ghent criteria a. Ocular features i. Myopia (most common ocular feature) ii. At increased risk for retinal detachment, glaucoma, and early cataract formation b. Skeletal system i. Bone overgrowth ii. Disproportionately long extremities for the size of the trunk (dolichostenomelia) iii. Overgrowth of the ribs pushing the sternum in (pectus excavatum) or out (pectus carinatum) iv. Mild, severe, or progressive scoliosis Natural history: age-related nature of some clinical manifestations and variable phenotypic expression
MARFAN SYNDROME
a. At birth, early in life, and childhood i. Dolichostenomelia ii. Arachnodactyly iii. Manifestations of other organ systems usually not present at birth, making the diagnosis during neonatal period difficult in the absence of family history iv. Asthenic habitus v. Lens dislocation or lens subluxations (a hallmark feature) commonly diagnosed during the first year of life (not present at birth) b. Childhood and puberty i. Skeletal manifestations apparent during childhood ii. Pectus deformities and scoliosis worsen during puberty iii. Upper normal or larger than normal aortic root size in early childhood iv. Rapidly increasing magnitude of dilatation during puberty c. Adulthood i. Lumbosacral dural ectasia manifesting as progressive dilatation of the dura with consequent erosion of vertebral bone during adulthood ii. Aortic disease as the major cause of cardiovascular morbidity and reduced life expectancy (initial life expectancy: 32 ± 16 years) iii. Increased life expectancy attributes to successive elective and emergent aortic surgery and to the use of beta-adrenergic receptor antagonists for the prevention of the progression of aortic root dilatation (current life expectancy; 41 ± 18 years) 10. Neonatal Marfan syndrome a. Diagnosed early in life because of striking and severe clinical manifestations i. Mitral or tricuspid insufficiency (multivalvular involvement) ii. Congestive heart failure iii. Pulmonary emphysema iv. Joint contractures v. Death usually within the first year of life b. Characteristic aged facial appearance i. Deep-set eyes ii. Down-slanted palpebral fissures iii. Crumpled ears iv. High arched palate c. Striking arachnodactyly of the fingers and toes d. Pectus deformities e. Scoliosis f. Flexion contractures g. Pes planus h. Aortic root dilatation i. Ectopia lentis j. A cluster of mutations in exons 24–27 as well as in exons 31–32
DIAGNOSTIC INVESTIGATIONS 1. Annual physical examination including blood pressure measurement 2. Slit lamp examination for lens dislocation
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3. Electrocardiogram for symptomatic palpitations, syncope or near-syncope, and conduction disturbance 4. Echocardiography and targeted imaging studies to carefully monitor the cardiovascular status a. Cross-sectional echocardiography for detecting aortic root dilatation b. Standard echocardiography for assessing mitral valve prolapse, left ventricular size and function, left atrial size and tricuspid valve function c. Transesophageal echocardiography for visualizing the distal ascending and descending aorta and assessing prosthetic valves d. Doppler echocardiography for detecting and assessing the severity of aortic and mitral regurgitation 5. Radiography a. Chest X-ray for apical blebs, enlargement of cardiac silhouette, and detecting dissecting aneurysm of aorta b. Pelvic X-ray for additional diagnostic criteria of protrusio acetabulae c. Feet X-ray for medial displacement of the medial malleolus, responsible for pes planus 6. Computed tomography (CT) and magnetic resonance imaging (MRI) a. MRI best choice for assessing chronic dissection of any region of the aorta b. CT or MRI of the lumbosacral spine for detecting dural ectasia 7. Aortograph: still considered by many to be the gold standard for diagnosing acute aortic dissection, although sensitivity is not 100% and there are associated risks 8. Molecular analysis of FBN1 mutations a. Routine mutation detection not available clinically due to the large size and complexity of FBN1 gene b. Mutations detected nearly always specific to each family c. FBN1 mutations observed in 20–80% of patients depending upon the clinical selection of patients and the mutation detection method used d. Genotype–phenotype correlations i. Little correlation observed in several hundred mutations reported to date ii. Severe MFS detected in infancy (inappropriately termed neonatal MFS) usually caused by point mutations or small deletions in-frame in the epidermal growth factor (ECF)-like motifs in the middle third of the fibrillin-1 protein iii. Less severe phenotype, verging on the MASS phenotype, usually caused by chain-terminating mutations resulting in essence in null mutants iv. Marked variability among individuals with the same mutation e. FBN1 mutations of various types reported i. Classic Marfan syndrome ii. Nonclassical Marfan related phenotypes f. Molecular diagnosis practical in the following two situations i. Information about a known FBN1 mutation in a person with MFS applied to relatives
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ii. Linkage analysis using sufficient intragenic and tightly linked polymorphisms to MFS families with several available and willing relatives 9. Histology of the aorta a. Elastic fiber fragmentation and disarray b. Paucity of smooth muscle cells c. Deposition of collagen and the mucopolysaccharide between the cells of the media
c.
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Recurrence risk: small if neither parent is affected ii. Gonadal mosaicism reported as the cause of multiple affected offspring being born to unaffected parents iii. 50% if one parent is affected b. Patient’s offspring i. 50% if the spouse is normal ii. “Homozygous” MFS reported in case of an affected spouse iii. “Compound heterozygosity” at the FBN1 locus confirmed at the molecular level; the affected child had a severe phenotype leading to early death 2. Prenatal diagnosis a. Ultrasonography insensitive in the first two trimesters for detecting a fetus with MFS b. Fetal echocardiography with careful limb length measurements by level II ultrasonography for at-risk pregnancy during 20th–24th weeks of gestation c. Molecular diagnosis i. Only if the family’s mutation is known in an affected parent ii. Presence of sufficient affected family members available for genetic linkage analysis if linkage with markers in and around the FBN1 locus can be established d. Preimplantation diagnosis accomplished but complicated by the potential for selective PCR amplification of the normal allele as with all autosomal dominant conditions 3. Management a. Address patients’ perceptions of Marfan syndrome and its associated pain, fatigue, and depressive symptoms to enhance patient adaptation b. Stress benefits about medication use (β- or calciumchannel blockers to retard aortic root dilatation and dissection) and restriction of physical activities (to delay the onset of a severe cardiovascular event and prevent other syndrome-related problems such as lens dislocation) i. β-blockers a) Should be considered in all Marfan patients, particularly in the younger age group b) Not suitable for patients with asthma, cardiac failure, or bradyarrhythmias ii. Other treatments aimed at reducing the ejection impulse a) Calcium antagonists
d.
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b) Angiotensin converting enzyme (ACE) inhibitors Life style changes i. Avoid competitive and collision/contact sports which are potentially dangerous due to underlying aortic weakness and dilatation, valvular insufficiency, ocular abnormalities, and skeletal problems ii. Avoid blows to the head such as boxing and high diving iii. Protect against blows to the globe (racquet sports) with cushioned spectacles iv. Avoid activities involving isometric work to prevent excessive elevations of systolic blood pressure and sudden death a) Weight lifting b) Climbing steep inclines c) Gymnastics d) Water skiing e) Pull-ups v. Avoid rapid decompression associated with quick ascents in elevators, scuba diving, and flying in unpressurized aircraft to protect against pneumothorax vi. Favor noncompetitive, isokinetic activity performed at a nonstrenous aerobic pace a) Golfing b) Walking c) Fishing Surgical intervention recommended for affected individuals with significantly dilated or dissected aortic roots Management of scoliosis i. Bracing ii. Physical therapy iii. Surgery for severe scoliosis Pectus repair i. Repair of pectus excavatum to improve respiratory mechanics: should be delayed until midadolescence to lessen the chance of recurrence ii. Repair of pectus carinatum performed mainly for cosmetic purpose Pneumothorax i. Chest tube: an appropriate initial therapy ii. Bleb resection and pleurodesis recommended after one recurrence Ocular management i. Removal of dislocated lens (pars plana Lensectomy and Vitrectomy), only in the following few instances, due to an increased risk of retinal detachment related to lens extraction a) Dislocation of a lens in the anterior chamber, especially when it touches the corneal endothelium b) Significant lens opacity c) Evidence of lens-induced uveitis and glaucoma d) Inadequate visual acuity that is not correctable by refraction and iris manipulation e) Imminent complete luxation of the lens ii. Lasers to restore a detached retina
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i. Pregnancy in women with MFS i. Preconceptional counseling of maternal risks during pregnancy and risk of transmitting the condition to offspring ii. A significantly increased risk of cardiovascular complications during pregnancy, particularly risk of dissecting aortic aneurysm iii. A high risk of spontaneous abortion but no other adverse maternal or fetal effects iv. Need for close surveillance during pregnancy v. Avoid pregnancy if echocardiography suggests a high risk of life-threatening cardiovascular compromise. Pregnancy bears a 1% risk of fatal complication; the risk rises with increasing aortic root diameter. vi. β-blockers recommended in pregnant women to prevent aortic dilatation vii. Caesarean section should be offered at 38 weeks gestation if aortic root diameter is greater than 4.5 cm
REFERENCES Aoyama T, Francke U, Gasner C, et al.: Fibrillin abnormalities and prognosis in Marfan syndrome and related disorders. Am J Med Genet 58:169– 176, 1995. Baumgartner WA, Cameron DE, Redmond JM, et al.: Operative management of Marfan syndrome: The Johns Hopkins experience. Ann Thorac Surg 67:1859–1860, 1868–1870, 1999. Braverman AC: Exercise and the Marfan syndrome. Med Sci Sports Exerc 30 (Suppl):S387–S395, 1998. Blaszczyk A, Tang YX, Dietz HC, et al.: Preimplantation genetic diagnosis of human embryos for Marfan’s syndrome. J Asst Reprod Genet 15:281– 284, 1998. Blum K, Kambich MP: Maternal genetic disease and pregnancy. Clin Perinatol 24:451–465, 1997. Chen H: Marfan syndrome. Emedicine, 2002. http://emedicine.com Child AH: Marfan syndrome-Current medical and genetic knowledge: how to treat and when. J Card Surg 12:131–136, 1997. De Paepe A, Devereux RB, Dietz HC, et al.: Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 62:417–426, 1996. Dean J Craniofac Surg: Management of Marfan syndrome. Heart 88:97– 103, 2002. Dietz HC, Cutting Genome Res, Pyeritz RE, et al.: Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352:337–339, 1991. Dietz HC, Pyeritz RE: Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders. Hum Mol Genet 4:1799–1809, 1995. Dietz HC, Pyeritz RE, Hall BD, et al.: The Marfan syndrome locus: confirmation of assignment to chromosome 15 and identification of tightly linked markers at 15q15-q21.2. Genomics 9:355–361, 1991. Eldadah ZA, Grifo JA, Dietz HC: Marfan syndrome as paradigm for transcripttargeted preimplantation diagnosis of heterozygous mutations. Nat Med 1:798–803, 1995. Geva T, Hegesh J, Frand M: The clinical course and echocardiographic features of Marfan’s syndrome in childhood. Am J Dis Child 141:1179– 1182, 1987. Giampietro PF, Raggio C, Davis JG: Marfan syndrome: orthopedic and genetic review. Curr Opin Pediatr 14:35–41, 2002.
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Godfrey M, Vandemark N, Wang M, et al.: Prenatal diagnosis and a donor splice site mutation in fibrillin in a family with Marfan syndrome. Am J Hum Genet 53:472–480, 1993. Groenink M, Lohuis TA, Tijssen JG, et al.: Survival and complication free survival in Marfan’s syndrome: implications of current guidelines. Heart 82:499–504, 1999. Halliday DJ, Hutchinson S, Lonie L, et al.: Twelve novel FBN1 mutations in Marfan syndrome and Marfan related phenotypes test the feasibility of FBN1 mutation testing in clinical practice. J Med Genet 39:589–593, 2002. Kartunnen L, Raghunath M, Lönnqvist L, et al.: A compound heterozygous Marfan patient: two defective fibrillin alleles result in a lethal phenotype. Am J Hum Genet 55:1083–1091, 1994. Kilpatrick MW, Harton GL, Phylactou LA, et al.: Preimplantation genetic diagnosis in Marfan syndrome. Fetal Diagn Ther 11:402–406, 1996. Koenig SB, Mieler WF: Management of ectopia lentis in a family with Marfan syndrome. Arch Ophthalmol 114:1058–1061, 1996. Loeys B, Nuytinck L, Delvaux I, et al.: Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med 161: 2447–2454, 2001. Nienaber CA, Von Kodolitsch Y: Therapeutic management of patients with Marfan syndrome: focus on cardiovascular involvement. Cardiol Rev 7:332–341, 1999. Peters KF, Kong F, Horme R, et al.: Living with Marfan syndrome I. Perceptions of the condition. Clin Genet 60:273–282, 2001. Peters KF, Kong F, Horme R, et al.: Living with Marfan syndrome II. Medication adherence and physical activity modification. Clin Genet 60:283–292, 2001. Pyeritz R: Disorders of fibrillins and microfibrilogenesis: Marfan syndrome, MASS phenotype, contractural arachnodactyly and related conditions. In: Rimoin D, Connor J, Pyeritz R (eds). Principles and Practice of Medical Genetics. 3rd ed. New York: Churchill Livingstone, 1996. Pyeritz RE: The Marfan syndrome. Annu Rev Med 51:481–510, 2000. Pyeritz RE, McKusick VA: The Marfan syndrome: diagnosis and management. N Engl J Med 300:772–779, 1979. Robinson PN, Godfrey M: The molecular genetics of Marfan syndrome and related microfibrillopathies. J Med Genet 37:9–25, 2000. Roman MJ, Devereux RB, Kramer-Fox R, et al.: Two-dimensional echocardiographic aortic root dimensions in normal children and adults. Am J Cardiol 64:506–512, 1989. Rozendaal L, Groenink M, Naeff MS, et al.: Marfan syndrome in children and adolescents: an adjusted nomogram for screening aortic root dilatation. Heart 79:69–72, 1998. Schneider MB, Davis JG, Boxer RA, et al.: Marfan syndrome in adolescents and young adults: psychosocial functioning and knowledge. J Dev Behav Pediatr 11:122–127, 1990. Sermon K, Lissens W, Messiaen L, et al.: Preimplantation genetic diagnosis of Marfan syndrome with the use of fluorescent polymerase chain reaction and the automated laser fluorescence DNA sequence. Fertil Steril 71:163–166, 1999. Silverman DI, Burton KJ, Gray J, et al.: Life expectancy in the Marfan syndrome. Ann Med J Cardiol 75:157–160, 1995. Sponseller PD, Sethi N, Cameron DE, et al.: Infantile scoliosis in Marfan syndrome. Spine 22:509–516, 1997. Tsipouras P, Devereux RB: Marfan syndrome: genetic basis and clinical manifestations. Semin Dermatol 12:219–228, 1993. Tsipouras P, Silverman DI: The genetic basis of aortic disease. Marfan syndrome and beyond. Cardiology Clin 17:683–696, 1999. Van Karnebeek CDM, Naeff MSJ, Mulder JM, et al.: Natural history of cardiovascular manifestations in Marfan syndrome. Arch Dis Child 84:129–137, 2001. Van Tongerbo A, DePaepe A: psychosocial adaptation in adolescents and young adults with Marfan syndrome: an exploratory study. J Med Genet 35:405–409, 1998.
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Fig. 2. Two Children with Marfan syndrome showing pectus and arachnodactyly. The first patient had dural ectasia detected by MRI. The second patient had aortic root dilatation and mitral valve prolapse.
Fig. 1. A boy with severe Marfan syndrome showing arachnodactyly, joint contractures, and aortic root dilatation, illustrated by the chest radiography.
Fig. 3. A 4-year-old girl with Marfan syndrome showing pectus excurvatum and the operation scar from surgical correction of marked aortic dilatation. She also has hyperextensible joints and scoliosis.
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Fig. 5. A child and an adult with Marfan syndrome showing higharched palate.
Fig. 4. A 5-year-old boy with Marfan syndrome showing tall and slender body habitus. He was noted to have mitral valve prolapse and aortic root dilatation at age 2. In addition, he has bilateral lens dislocations and scoliosis.
Fig. 6. A child with Marfan syndrome showing cubitus valgus, arachnodactyly, post-surgical spinal fusion for severe scoliosis (illustrated by radiograph).
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Fig. 7. A boy with Marfan syndrome showing a slender/tall habitus and arachnodactyly.
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Fig. 8. A girl with Marfan syndrome showing a slender/tall habitus, typical facies, arachnodactyly, and toe anomalies.
Fig. 10. Thumb and wrist signs.
Fig. 9. Arachnodactyly in two adult patients with Marfan syndrome.
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Fig. 11. Hypermobile joints in two patients with Marfan syndrome.
Fig. 13. Familial Marfan syndrome in a mother and a son showing extreme myopia (lens dislocation) and thumb and wrist signs.
Fig. 12. Stretch marks in the shoulders in one patient and in the buttock region in other patient with Marfan syndrome.
Fig. 14. MRI of the lumbosacral spine in two patients showing dural ectasia.
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Fig. 15. A 20-year-old male with Marfan syndrome with repeat spontaneous pneumothorax from ruptures of apical blebs. The chest X-ray shows collapsed left lung with pleural line (arrows). The CT of the chest shows pneumothorax on the right lung (arrows). Thoracoscope image from the right lung shows two bands representing the old adhesions due to previously ruptured apical blebs (black arrows) and two intact blebs (white arrows). The wedge biopsy specimen of the right apex shows two emphysematous blebs (white arrows) which were demonstrated in the previous figure.
McCune-Albright Syndrome McCune-Albright syndrome (MAS) consists of polyostotic fibrous dysplasia, precocious puberty, café-au-lait spots, and other endocrinopathies secondary to hyperactivity of various endocrine glands.
GENETICS/BASIC DEFECTS 1. Inheritance a. A sporadic condition b. Lack of genetic transmission in this syndrome 2. Molecular basis a. Caused by a noninherited postzygotic somatic mutations in the guanine nucleotide-binding protein alpha subunit (GNAS1) gene on chromosome 20q13.2 coding for the alpha subunit of the stimulatory G protein (Gsα) b. Mutations in GNAS1 result in the constitutive activation of adenyl cyclase, which stimulates the synthesis of cAMP from ATP within cells c. G proteins i. Involved in transmitting hormone signals intracellularly by coupling cell surface receptors to intracellular signaling cascades ii. Constitutively activated Gs protein stimulates autonomous cell proliferation in skin and bones and hormonal hypersecretion of gonads, hypophisis, thyroid, and adrenal glands iii. Constitutive activation of these intracellular signaling cascades is caused by the specific mutations in the absence of hormone stimulation d. Vast majority of Gsα mutations i. Point mutations at the Arg201 position ii. Most being Arg201His or Cys e. The term gsp oncogene assigned to these mutations due to their association with certain neoplasms f. Presence of somatic mosaicism is reflected by the identification of normal and mutated cells throughout the body g. Timing of mutations i. Early in embryogenesis: widespread involvement of the tissue and is likely lethal (accounts for the lack of autosomal dominant transmission of this disorder) ii. Late in embryogenesis: milder phenotype iii. Very late in tissue development after differentiation into a specific cell line a) Development of a single adenoma b) Gsα activating mutations reported in isolated hyperfunctioning thyroid nodules and in somatotroph adenomas
CLINICAL FEATURES 1. Clinical features a. Extremely variable among affected individuals 630
b. Consistent with a postzygotic somatic mutational event resulting in a mosaic distribution of the mutation c. Clinical triad i. Fibrous dysplasia of bones ii. Patchy cutaneous pigmentation iii. Various hyperfunctional endocrinopathies 2. Endocrine abnormalities a. Precocious puberty i. The most common endocrine feature and a central hallmark of MAS ii. Resulting from gonadotropin independent autonomous ovarian or testicular function iii. Far more commonly observed in girls than boys (>50% of affected girls; only 15% of affected boys) iv. The signs of puberty (development of breasts, testes, pubic and axillary hair, body odor, menstrual bleeding and increased growth rate) may appear before the age of 8 years girls and 91⁄2 years in boys v. Affected girls a) Breast development or vaginal bleeding as early as 4 months of age b) Premature development of secondary sex characteristics c) Excessive estrogen production, independent of gonadotrophins activities, with development of ovarian cysts, sexual precocity, increased growth velocity, and markedly advanced skeletal maturity vi. Affected boys a) Premature testicular enlargement b) Premature spermatogenesis c) Premature development of secondary sex characteristics b. Hyperthyroidism (30%) i. The second most commonly associated endocrinopathy ii. Typically occurring in later childhood but occasionally within the first year of life iii. Primarily due to multinodular toxic goiter iv. Clinical effects a) Severe failure to thrive in infants and young children b) Decreased attention span c) Osteoporosis d) Tachycardia c. Acromegaly/gigantism i. Resulting from excess growth hormone secreted by somatotroph adenomas in the pituitary ii. Characteristic stigmata a) Coarsening of facial features, such as frontal bossing and prognathism
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b) Enlargement of hands and feet c) Arthritis iii. Complications a) Glucose intolerance b) Hypertriglyceridemia c) Hypertension d) Mild myopathy d. Cushing syndrome i. Adrenocorticotropic hormone (ACTH) independent ii. Caused by adrenal enlargement and excessive secretion of the adrenal hormone cortisol iii. Described mostly in infants and children iv. Clinical signs a) Cessation of growth b) Poor muscle tone c) Obesity of the face and trunk d) Weight gain e) Skin fragility f) Hypertension in infancy g) Death possible in long-term untreated hypercortisolism e. Gonadotrophinomas f. Hyperprolactinemia g. Hyperparathyroidism h. Gynecomastia 3. Nonendocrine abnormalities a. Skin pigmentation (café-au-lait spots) i. Flat brown patches of pigmentation with irregular contour (coast of Maine) of varying size ii. Frequently evident at birth iii. Involved area may be extensive b. Fibrous dysplasia i. The invariable component of the syndrome ii. Bone lesions usually evident by age 10 years, often presenting with a limp, leg pain, or fractures iii. Polyostotic in nature a) Affecting any bones b) Most commonly involving the femur, tibia, pelvis, phalanges, ribs, and the base of the skull iv. Size and extent of involvement: ranging from small asymptomatic areas to markedly disfiguring lesions resulting in limping, deformities a) Leg length discrepancy b) Coxa vara c) Shepherd’s crook deformity of the femur (a characteristic sign of the disease) d) Bowing of the tibia e) Harrison’s groove f) Protrusio acetabuli g) Frequent pathologic fractures h) Impingement on vital nerves v. Craniofacial form (50% of the polyostotic form) a) Involvement of orbital and periorbital bones resulting in hypertelorism, cranial asymmetry, facial deformity such as leontiasis ossea, visual impairment, exophthalmos, and blindness b) Involvement of the sphenoid wing and temporal bones resulting in vestibular dysfunction, tinnitus, and hearing loss
c.
d.
e. f.
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c) Involvement of cribriform plate resulting in hyposmia or anosmia vi. Low risk of malignant degeneration (0.4%) vii. Fibrous dysplasia associated with single or multiple intramuscular or juxtamuscular myxomas (Mazabraud syndrome) Hypophosphatemia i. Resulting from decreased reabsorption of phosphate in the renal tubule ii. Causing rickets and short stature iii. Normal parathyroid hormone levels Chronic liver disease i. Mild cases: mild elevation of hepatic transaminases ii. Severe cases: neonatal jaundice and chronic cholestasis Persistent tachycardia: rare sudden death presumably due to cardiac arrhythmias Associated malignancies (rare) i. Osteosarcomas (most common) ii. Chondrosarcomas iii. Fibrosarcomas iv. Liposarcomas v. Breast cancer vi. Thyroid cancer
DIAGNOSTIC INVESTIGATIONS 1. Elevated estradiol levels and suppressed or undetectable gonadotropins: diagnostic of gonadotropin independent precocious puberty 2. Suppressed or undetectable levels of LH and FSH after administration of luteinizing hormone-releasing hormone: consistent with the diagnosis 3. Elevated liver enzymes or hyperbilirubinemia even after normalization of cortisol or thyroxine levels suggests presence of Gsα activating mutations in the liver 4. Hypophosphatemia (rickets and osteomalacia) results from increased urinary phosphate excretion 5. Elevated thyroxine levels and suppressed TSH levels: consistent with hyperthyroidism 6. Generally suppressed ACTH levels despite elevated cortisol levels since the glucocorticoid secretion is ACTH independent 7. Elevated cortisol levels after dexamethasone suppression test: suggestive of Cushing syndrome 8. Elevated 24-hour urine free cortisol levels: suggestive of Cushing syndrome 9. Elevated serum growth hormone and insulin-like growth factor 1 levels in individuals with somatotroph adenomas due to Gsα activating mutations 10. Histology a. Ovarian cyst: generally large, unilateral, and follicular in nature b. Fibrous dysplasia: i. Caused by hyperproliferation of preosteoblastic cells ii. Replacement of normal bones by irregular masses of fibroblasts c. Thyroid nodules: ranging from multinodular to colloid goiter
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d. Adrenal hyperplasia e. Somatotroph adenoma f. Liver: ranging from normal hepatocytes with some fatty infiltration to focal nodular hyperplasia with fibrosis and chronic cholestasis 11. Pelvic ultrasound to detect ovarian cysts 12. Bone scan to detect asymptomatic fibrous dysplasia sites 13. Skeletal survey a. Advanced skeletal maturation b. Premature closure of growth plates resulting in short stature c. Polyostotic fibrous dysplasia i. Often unilateral ii. More frequently involved sites a) Lower extremities: femur (91%), tibia (81%) b) Pelvis (78%) c) Skull and facial bones (50%) d) Ribs e) Upper extremities f) Spine g) Shoulder girdle d. Pathological fractures (up to 85%) e. Long and short tubular bones i. Lucent lesions in the diaphysis or metaphysis a) With endosteal scalloping b) With or without bone expansion c) Absence of periosteal reaction d) Usually smooth and relatively homogeneous matrix of the lucency, described as a groundglass appearance e) Presence of irregular areas of sclerosis with or without calcification f) The ring sign (a lucent lesion with a thick sclerotic border) ii. Extension of lesions into the epiphysis observed only after fusion a) Premature fusion of the ossification centers resulting in adult dwarfism b) Dysplastic bone undergoing calcification and enchondral bone formation f. Skull and facial bones i. Sclerotic skull base. Diffuse sclerosis of the base of the skull often involves the sphenoid, sella turcica, roof of the orbit, thickening of the occiput, and obliteration of the paranasal sinuses ii. Mixed radiolucent and radiopaque pattern of maxillary and mandibular bones a) Displacement of the teeth b) Distortion of the nasal cavities g. Pelvis and ribs i. Common cystic lesions characterized by a diffuse ground-glass appearance and ring lesions ii. Protrusio acetabuli h. Spine i. Well-defined, expansile, radiolucent lesions with multiple internal septa or striations involving the vertebral body, and occasionally, the pedicles and arches ii. Kyphotic deformity
iii. Spinal cord compression iv. Rare paraspinal soft tissue extension and vertebral collapse i. Radiographic features suggestive of malignant degeneration i. A rapid increase in the size of the lesion ii. A change from a previously mineralized bony lesion to a lytic lesion 14. Bone scintigraphy: valuable in early detection of the bone lesions 15. CT scan of the abdomen to demonstrate bilateral enlargement of the adrenal glands in infantile Cushing syndrome 16. Mutation detection a. Standard PCR-based amplification b. Followed by sequencing of the appropriate region of the GNAS1 gene
GENETIC COUNSELING 1. Recurrent risk a. Patient’s sib: not increased since MAS is due to a somatic mutation b. Patient’s offspring: not increased since a germline activating mutation in the Gsα gene might be lethal 2. Prenatal diagnosis: not been reported 3. Management a. Precocious puberty i. Medical care a) Difficulty to treat precocious puberty b) The biosynthetic forms of gonadotropin releasing hormone such as Deslorelin, Histerelin, and Lupron, which suppress LH and FSH are not effective in most girls with MAS c) Provera, a progesterone-like hormone, for cessation of vaginal bleeding but not effective in slowing the rapid rates of growth and bone development and may have unwanted effects on adrenal functioning d) Ketoconazole, aimed at interrupting adrenal steroid biosynthesis, for cessation of vaginal bleeding e) Testolactone and Fadrozole (aromatase inhibitors, to block the conversion of testosterone to estradiol, thus lowering circulating estrogen levels) for halting pubertal progression f) A multicenter trial of tamoxifen (an estrogen agonist/antagonist) treatment of precocious puberty in girls resulting in a reduction of vaginal bleeding and significant improvements in growth velocity and rate of skeletal maturation ii. Surgical care: ovarian cystectomy or oophorectomy not typically warranted because of the likelihood of cyst recurrence in residual ovarian tissue b. Hyperthyroidism i. Medical care: Propylthiouracil or Methimazole, drugs which block thyroid hormone synthesis,
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d.
e.
f. g.
for patients with excessively high thyroid hormone levels ii. Surgical care: thyroidectomy or hemithyroidectomy for hyperthyroidism associated with a goiter Infantile Cushing syndrome i. Medical care a) Treat with drugs that block cortisol synthesis b) Adequate adrenal steroid replacement after bilateral adrenalectomy ii. Surgical care: surgical removal of the affected adrenal glands Acromegaly/gigantism i. Medical care: treat with synthetic analogs of the hormone somatostatin to suppress growth hormone secretion ii. Surgical care: surgical removal of the area of the pituitary which is secreting the pituitary growth hormone Early detection and treatment of patients with excess growth hormone to prevent morbidity related to the craniofacial form of the fibrous dysplasia (50% of polyostotic form) i. Morbidity a) Hearing loss b) Blindness ii. Therapy a) Cabergoline b) Long acting octreotide therapy Hypophosphatemic rickets: treat with oral phosphates, supplement with vitamin D Fibrous dysplasia i. Medical care a) Monitor vision and hearing closely if lesions are located near the orbits or around b) Avoid contact sports to minimize the risk of pathologic fractures c) Bisphosphonates used to inhibit bone absorption by osteoclast activity through apoptosis induction and protein prenylation inhibition d) Pamidronate, a second generation aminobisphosphonate for reduction in bone pain and markers of bone turnover ii. Surgical care: grafting, pinning and casting to surgically correct fractures and deformities
REFERENCES Albright F, Butler AM, Hampton AO: Syndrome characterized by osteitis fibrosa disseminate, areas of pigmentation and endocrine dysfunction, with precocious puberty in females. N Engl J Med 216:727–747, 1937. Anand MKN: Fibrous dysplasia. Emedicine, 2002. http://www.emedicine.com Bareille P, Azcona C, Stanhope R: Multiple neonatal endocrinopathies in McCune-Albright syndrome. J Paediatr Child Health 35:315–318, 1999. Benedict PH: Endocrine features in Albright’s syndrome (fibrous dysplasia of bone). Metabolism 1:30–45, 1962. Bhansali A, Sharma BS, Sreenivasulu P, et al.: Acromegaly with fibrous dysplasia: McCune-Albright syndrome-Clinical studies in 3 cases and brief review of literature. Endocr J 50:793–799, 2003.
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Boston BA: McCune-Albright syndrome. Emedicine, 2003. http://www. emedicine.com Cabral CE, Guedes P, Fonseca T, et al.: Polyostotic fibrous dysplasia associated with intramuscular myxomas: Mazabraud’s syndrome. Skelet Radiol 27:278–282, 1998 Cavanah SF, Dons RF: McCune-Albright syndrome: how many endocrinopathies can one patient have? South Med J 86:364–367, 1993. Coutant R, Lumbroso S, Rey R, et al.: Macroorchidism due to autonomous hyperfunction of Sertoli cells and Gs alpha gene mutation: an unusual expression of McCune-Albright syndrome in a prepubertal boy. J Clin Endocrinol Metab 86:1778–1781, 2001. Danon M, Robboy SJ, Kim S, et al.: Cushing syndrome, sexual precocity, and polyostotic fibrous dysplasia (Albright syndrome) in infancy. J Pediatr 87:917–921, 1975. De Sanctis C, Lala R, Matarazzo P: McCune-Albright syndrome: a longitudinal clinical study of 32 patients. J Pediatr Endocrinol Metab 12:817–826, 1999. Eugster EA, Rubin SD, Reiter EO, et al.: Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial. J Pediatr 143:60–66, 2003. Feuillan PP: The MAGIC Foundation. McCune-Albright syndrome Division. http://www.magicfoundation.org Firat D, Stutzman L: Fibrous dysplasia of the bone. Review of twenty-four cases. Am J Med 44:421–429, 1968. Foster CM, Feuillan P, Padmanabhan V, et al.: Ovarian function in girls with McCune-Albright syndrome. Pediatr Res 20:859–863, 1986. Gross CW, Montgomery WW: Fibrous dysplasia and malignant degeneration. Arch Otolaryngol 85:97–101, 1967. Gurler T, Alper M, Gencosmanoglu R: McCune-Albright syndrome progressing with severe fibrous dysplasia. J Craniofac Surg 9:79–82, 1998. Harris WH, Dudley HR, Barry RJ: The natural history of fibrous dysplasia, an orthopaedic, pathologic and roentgenographic study. J Bone Joint Surg [Br] 44:207–233, 1962. Isaia GC, Lala R, Defilippi C, et al.: Bone turnover in children and adolescents with McCune-Albright syndrome treated with Pamidronate for bone fibrous dysplasia. Calcif Tissue Int 71:121–128, 2002. Lee PA, Van Dop C, Migeon CJ: McCune-Albright syndrome. Long-term follow-up. JAMA 256:2980–2984, 1986. Lightner ES, Penny R, Frasier SD: Growth hormone excess and sexual precocity in polyostotic fibrous dysplasia (McCune-Albright syndrome): evidence for abnormal hypothalamic function. J Pediatr 87(6 pt 1):922– 927, 1975. McCune DJ, Bruch H: Osteodystrophia fibrosa: report of a case in which the condition was combined with precocious puberty, pathologic pigmentation of the skin and hyperthyroidism, with a review of the literature. Am J Dis Child 806–848, 1936. Riminucci M, Fisher LW, Shenker A, et al.: Fibrous dysplasia of bone in the McCune-Albright syndrome: abnormalities in bone formation. Am J Pathol 151:1587–1600, 1997. Schwartz DT, Alpert M: The malignant transformation of fibrous dysplasia. Am J Med Sci 247:1–20, 1964. Shenker A, Weinstein LS, Moran A, et al.: Severe endocrine and nonendocrine manifestations of the McCune-Albright syndrome associated with activating mutations of stimulatory G protein GS. J Pediatr 123:509–518, 1993. Shenker A, Weinstein LS, Sweet DE: An activating Gs alpha mutation is present in fibrous dysplasia of bone in the McCune-Albright syndrome. J Clin Endocrinol Metab 79:750–755, 1994. Singer FR: Fibrous dysplasia of bone: the bone lesion unmasked. Am J Pathol 151:1511–1515, 1997. Spiegel AM: The molecular basis of disorders caused by defects in G proteins. Horm Res 47:89–96, 1997. Tinschert S, Geri H, Gewies A: McCune-Albright syndrome: clinical and molecular evidence of mosaicism in an unusual giant patient. Am J Med Genet 83:100–108, 1999. Weinstein LS, Shenker A, Gejman PV, et al.: Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 325:1688–1695, 1991.
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MCCUNE-ALBRIGHT SYNDROME
Fig. 1. A girl with McCune-Albright syndrome showing precocious puberty, hyperpigmentation, and fibrous dysplasia affecting many bones shown by radiographs.
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Meckel-Gruber Syndrome c. d. e. f.
Short neck Hypoplastic thyroid Congenital heart defect Gastrointestinal abnormalities i. Omphalocele ii. Malrotated bowel iii. Fibrotic or cystic liver g. Absent or small adrenals h. Accessory spleen i. Urinary tract anomalies j. Short limbs k. Abnormal palmar creases l. Club feet m. Syndactyly 3. Lethal outcome a. Abortions b. Stillborns c. Neonatal deaths d. Rare survivals till 2 years of age
Meckel-Gruber syndrome (MKS) is a rare, lethal, autosomal recessive disorder, characterized by occipital encephalocele, cystic dysplastic kidneys, and postaxial polydactyly. The incidence is estimated to be 1/13,250 (in USA)–1/140,000 (in Great Britain) live births. The incidence in North Africa and Finnish population is much higher at 1/3500 and 1/9000 respectively. Meckel-Gruber syndrome is considered the most frequent syndromic cause of neural tube defects.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Locus heterogeneity a. MKS1 locus to 17q21-24 in Finnish kindreds b. MKS2 locus to 11q13 in North African-Middle Eastern cohorts c. MKS3 to 8q24 in Indian sub-continent cohorts
CLINICAL FEATURES 1. Major clinical features a. Clinical triad i. Occipital encephalocele (85%) a) Extrusion of rhombic roof elements (cerebellar vermis, caudal 3rd ventricle, distended 4th ventricle) through a widened posterior fontanelle b) Protruding CNS structures covered by a dural sac c) Medial occipital cortex occasionally included in the sac formed by the dilated caudal 3rd ventricle ii. Dysplastic kidneys (100%) a) Result in oligohydramnios b) Lead to fetal pulmonary hypoplasia iii. Postaxial polydactyly (55%) b. Microcephaly c. Oral clefts i. Cleft lip ii. Cleft palate d. Ambiguous genitalia 2. Other clinical features a. CNS abnormalities i. Absent olfactory lobe ii. Absent pituitary gland (hypopituitarism) iii. Hydrocephalus iv. Dandy-Walker malformation b. Craniofacial features i. Sloping forehead ii. Microphthalmia/anophthalmia iii. Micrognathia iv. Malformed tongue v. Abnormal ears
DIAGNOSTIC INVESTIGATIONS
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1. Ultrasonography a. CNS anomalies b. Cystic dysplastic kidneys 2. MRI of the brain for CNS anomalies 3. Echocardiography for congenital heart defect 4. Radiography a. Microcephaly with an occipital bone defect and encephalocele or hydrocephaly b. Short upper extremities c. Bell-shaped thorax with abdominal distension d. Postaxial polydactyly in the hands and feet 5. Necropsy a. Renal anomalies i. Cystic dysplastic kidneys ii. Hypoplastic kidneys/ureters/bladder iii. Rectovesicular fistula b. Triad of CNS malformations i. Prosencephalic dysgenesis a) Agenesis of olfactory bulbs and tracts (arhinencephaly) b) Complete holoprosencephaly c) Hypoplasia of optic nerves and chiasm d) Microphthalmia e) Agenesis of the corpus callosum f) Fused thalami g) Hypoplasia of the 3rd ventricle h) Small or absent pituitary gland i) Microcephaly j) Cleft/high arched palate k) Micrognathia
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MECKEL-GRUBER SYNDROME
c.
d.
e. f.
g.
ii. Occipital exencephalocele a) Displacement of rhombic roof elements including caudal third ventricle, cerebellar vermis and fourth ventricle b) Extruded through an enlarged posterior fontanelle rather than through an occipital cranium bifidum c) Often associated with a variant of DandyWalker cyst with Chiari malformation iii. Rhombic roof dysgenesis a) Absent brain stem tectum b) Agenesis/dysgenesis cerebellar vermis c) Elongated brain stem d) Aqueduct stenosis Histologic features of the CNS i. Polymicrogyria ii. Heterotopias iii. Characteristic neuroepithelial rosettes Hepatic dysgenesis i. A consistent features ii. Arrested development of the intrahepatic biliary system a) Reactive biliary bile duct proliferation b) Bile duct dilatation c) Portal fibrovascular proliferation Lung hypoplasia Gastrointestinal anomalies i. Pancreatic cyst ii. Malrotated bowel iii. Anal atresia Genital anomalies i. Hypoplastic genitalia ii. Bicornuate uterus iii. Persistent urogenital sinus
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not surviving to reproductive age 2. Prenatal diagnosis a. Ultrasonography: diagnosis more difficult in the 2nd trimester because of oligohydramnios secondary to poor renal output impairing visualization i. Occipital encephalocele ii. Renal anomalies (large cystic kidneys, renal agenesis, renal hypoplasia, and ureteral duplication) iii. Polydactyly iv. Oligohydramnios v. Dandy-Walker malformation vi. Cerebellar hypoplasia b. MRI, a valuable complement to ultrasonography in assessing fetal anomalies in the presence of severe oligohydramnios c. Elevated serum α-fetoprotein d. Amniocentesis i. Elevated amniotic fluid α-fetoprotein ii. Normal karyotype
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3. Management a. No specific treatment b. Supportive care for lethal cases c. Operative excision of a small encephalocele d. Ventriculoperitoneal shunt for hydrocephalus
REFERENCES Ahdab-Barmada M, Claassen D: A distinctive triad of malformations of the central nervous system in the Meckel-Gruber syndrome. J Neuropathol Exp Neurol 49:610–620, 1990. Anderson VM: Meckel syndrome: morphologic considerations. Birth Defects Orig Artic Ser 18:145–160, 1982. Aula P, Karjalainen O, Rapola J, et al.: Prenatal diagnosis of the Meckel syndrome. Am J Obstet Gynecol 129:700–702, 1977. Blankenberg TA, Ruebner BH, Ellis WG, et al.: Pathology of renal and hepatic anomalies in Meckel syndrome. Am J Med Genet (Suppl 3):395–410, 1987. Braithwaite JM, Economides DL: First-trimester diagnosis of Meckel-Gruber syndrome by transabdominal sonography in a low-risk case. Prenat Diagn 15:1168–1170, 1995. Carter SM, Gross SJ: Meckel-Gruber syndrome. Emedicine, 2003. http://www.emdicine.com Farag TI, Usha R, Uma R, et al.: Phenotypic variability in Meckel-Gruber syndrome. Clin Genet 38:176–179, 1990. Friedrich U, Hansen KB, Hauge M, et al.: Prenatal diagnosis of polycystic kidneys and encephalocele (Meckel syndrome). Clin Genet 15:278–286, 1979. Herman TE, Siegel MJ: Special imaging casebook. Meckel-Gruber syndrome. J Perinatol 16:144–146, 1996. Hsia YE, Bratu M, Herbordt A: Genetics of the Meckel syndrome (dysencephalia splanchnocystica). Pediatrics 48:237–247, 1971. Johnson VP, Holzwarth DR: Prenatal diagnosis of Meckel syndrome: case reports and literature review. Am J Med Genet 18:699–711, 1984. Kjaer KW, Fischer Hansen B, Keeling JW, et al.: Skeletal malformations in fetuses with Meckel syndrome. Am J Med Genet 84:469–475, 1999. Morgan NV, Gissen P, Sharif SM, et al.: A novel locus for Meckel-Gruber syndrome, MKS3, maps to chromosome 8q24. Hum Genet 111:456–461, 2002. Nevin NC, Thompson W, Davison G, et al.: Prenatal diagnosis of the Meckel syndrome. Clin Genet 15:1–4, 1979. Nyberg DA, Hallesy D, Mahony BS, et al.: Meckel-Gruber syndrome. Importance of prenatal diagnosis. J Ultrasound Med 9:691–696, 1990. Opitz JM (ed): The Meckel Symposium. Am J Med Genet 18(4): 1984. Opitz JM, Howe JJ: The Meckel syndrome (dysencephalia splanchnocystica, the Gruber syndrome). Birth Defects Orig Artic Ser V(2):167–179, 1968. Paavola P, Salonen R, Baumer A, et al.: Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet 101:88–92, 1997. Paavola P, Salonen R, Weissenbach J, et al.: The locus for Meckel syndrome with multiple congenital anomalies maps to chromosome 17q21-q24. nature Genet 11:213–215, 1995. Paetau A, Salonen R, Haltia M: Brain pathology in the Meckel syndrome: a study of 59 cases. Clin Neuropathol 4:56–62, 1985. Roume J, Genin E, Cormier-Daire V, et al.: A gene for Meckel syndrome maps to chromosome 11q13. Am J Hum Genet 63:1095–1101, 1998. Roume J, Ma HW, Le Merrer M, et al.: Genetic heterogeneity of Meckel syndrome. J Med Genet 34:1003–1006, 1997. Salonen R: The Meckel syndrome: clinicopathological findings in 67 patients. Am J Med Genet 18:671–689, 1984. Salonen R, Norio R: The Meckel syndrome in Finland: epidemiologic and genetic aspects. Am J Med Genet 18:691–698, 1984. Salonen R, Paavola P: Meckel syndrome. J Med Genet 35:497–501, 1998. Seller MJ: Phenotypic variation in Meckel syndrome. Clin Genet 20:74–77, 1981. Seppänen U, Herva R: Roentgenologic features of the Meckel syndrome. Pediatr Radiol 13:329–331, 1983. Shanks J, Kerr B, Russell SA, et al.: Skeletal abnormalities in Meckel syndrome. Pediatr Pathol Lab Med 17:625–630, 1997. Wright C, Healicon R, English C, et al.: Meckel syndrome: what are the minimum diagnostic criteria? J Med Genet 31:482–485, 1994.
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Fig. 2. Another neonate with Meckel-Gruber syndrome showing a large occipital encephalocele, microcephaly, sloping forehead, micro/retrognathia, low-set malformed ears, short neck and post-axial polydactylies.
Fig. 1. A neonate with Meckel-Gruber syndrome showing a large occipital encephalocele, microcephaly, sloping forehead, micro/retrognathia, low-set malformed ears, and short neck. The infant also had post-axial polydactylies. Necropsy showed unilateral renal dysgenesis. Contralateral renal cystic dysplasia was present.
Menkes Disease (Kinky-Hair Syndrome) Menkes and colleagues described Menkes disease in 1962 that reported five male infants in a family affected with a distinctive syndrome of neurologic degeneration, peculiar hair, and failure to thrive. The Menkes disease is also called “kinky or steely hair disease”. The incidence of the Menkes disease is estimated to be 1/100,000–1/250,000 live births.
GENETICS/BASIC DEFECTS 1. Inheritance a. An X-linked recessive disorder of copper metabolism i. Recognized to segregate as an X-linked recessive trait when it was described by Menkes et al. in 1962 ii. Observation of two different cell populations (normal fibroblasts and mutant cells with increased copper accumulation) in cultured fibroblasts of female Menkes carriers, suggesting that the Menkes disease gene was subject to random Xinactivation and also confirming the X-linked recessive inheritance of the disease b. New mutations in one third of cases 2. Menkes gene mapped to chromosome Xq13.3 a. Physical evidence of the location of the Menkes disease gene (ATP7A; MNK) suggested by observation of a female patient with a de novo balanced X:2 translocation (X break point at Xq13) and a male patient with X chromosome rearrangements with a breakpoint at Xq13.3 b. The Xq13.3 breakpoint subsequently shown to be at the MNK locus by fluorescence in situ hybridization (FISH) analyses c. MNK belongs to a large family of cation-transporting P-type ATPases 3. Cause: mutations in ATP7A gene, which encodes a transmembrane copper-transporting P-type adenosine triphosphatase (ATPase) protein, leading to deficiencies of copper absorption in intestinal absorption and in intracellular processing of copper in the central nervous system and connective tissues, whereby enzymes requiring copper as a cofactor no longer function properly 4. Mutation spectrum a. Cytogenetic abnormalities i. Visible cytogenetic abnormalities comprising about 1% of the underlying genetic defect in Menkes disease ii. Four female patients reported to have balanced X;autosomal translocations iii. A male patient reported to have a unique rearrangement of the X chromosome where the long arm segment Xq13.3-q21.2 was inserted into the short arm b. Gross deletion mutations (20%) 639
c. Point mutations (remaining genetic defects) i. Splice-site (23%) ii. Nonsense (20.7%) iii. Missense (17.2%) iv. Small insertions/deletions (39.1%) 5. Genetic defect/pathogenesis a. Failure of copper transport to the affected fetus resulting in copper deficiency in utero; compounded by impairment of copper absorption and ineffective copper transport into the central nervous system after birth b. Decreased copper transport across cellular compartments, particularly the gut c. Decreased availability of copper for cuproenzymes d. Dysfunction of numerous copper-dependent enzyme systems (decreased enzyme activities) i. Dopamine β-hydroxylase a) Severe neurodegeneration b) Hypothermia c) Abnormalities in serum catecholamines ii. Ascorbate oxidase: skeletal deformities iii. Cytochrome c oxidase a) Hypothermia b) Severe neurodegeneration c) Impaired myelination d) Muscle weakness e) Mitochondrial abnormalities iv. Lysyl oxidase: decreased strength of collagen and elastin a) Frayed/split internal elastic layer of arteries b) Bladder diverticula c) Loose skin and joints v. Monamide oxidase: a) Kinky hair b) Reduced pigmentation of hair and skin c) Severe neurodegeneration vi. Tyrosinase: a) Depigmentation of hair b) Skin pallor vii. Sulfhydryl oxidase: pili torti viii. Ceruloplasmin: decreased levels of circulating copper ix. Copper-zinc superoxide dismutase a) Failure of free radical detoxification, contributing to profound Purkinje cell loss b) Cytotoxic effects 6. Loss of function of specific cuproenzymes resulting in the clinical features of Menkes disease a. Abnormal hair and pigmentation b. Laxity of the skin c. Metaphyseal dysplasia d. Cerebellar degeneration e. Failure to thrive
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7. Allelic heterogeneity resulting in milder forms of the disease, occipital horn syndrome, also known as X-linked cutis laxa or Ehlers-Danlos syndrome type IX a. Clinical resemblances to Menkes disease with milder manifestations b. Biochemical resemblances to Menkes disease i. Low serum copper and ceruloplasmin ii. Increased copper accumulation and markedly low lysyl oxidase activity iii. Impairment of MNK in patients with occipital horn syndrome (base-pair substitution mutations affecting the normal mRNA splicing) giving a direct molecular evidence for the allelic relationship between the two diseases
12.
CLINICAL FEATURES 1. Phenotype: considerable variability in the severity of clinical expression encompassing the severe classical form (90–95% of patients) to the mild occipital horn syndrome 2. Distinctive clinical features present by 3 months of age, often manifested by: a. Loss of early developmental milestones b. Poor weight gain (failure to thrive) 3. Neonatal hypothermia 4. Neonatal hypoglycemia 5. Hyperbilirubinemia 6. Poor feeding 7. Impaired weight gain (failure to thrive) 8. CNS abnormalities a. Profound (truncal) hypotonia b. Abnormal head control c. Hyperactive reflexes d. Generalized seizures i. Myoclonic ii. Occasional tonic-clonic e. Developmental delay f. Severe mental retardation 9. Abnormal and characteristic hair, responsible for the synonyms of “kinky hair disease” or “steely hair disease” in the past a. Depigmented, short, sparse, coarse, and twisted scalp hair: a striking and pathognomonic feature b. Fragile, frequently broken hair c. Twisted strands reminiscent of steel wool cleaning pads d. Eyebrows i. Unusual appearance ii. Scant e. White or grey hair lacking pigment secondary to absence of tyrosinase activity 10. Characteristic face a. “Jowly”, “pudgy”, or “cherubic” face b. Sagging cheeks c. Large appearing ears d. High arched palate e. Delayed tooth eruption 11. Ocular abnormalities a. Retinal hypopigmentation b. Retinal vessel tortuosity c. Macular dystrophy d. Congenital cataracts
13.
14.
15.
e. Partial optic nerve atrophy f. Decreased retinal ganglion cells g. Microcysts in the pigment epithelium of the iris Connective tissue abnormalities secondary to loss of lysyl oxidase activity a. Loose skin (cutis laxa) b. Pectus excurvatum c. Umbilical and/or inguinal hernias d. Diverticula of the bladder, uterus, and other organs e. Vascular complications including aortic aneurysms commonly present f. Tortuosity of the intracranial blood vessels by neuroimaging techniques g. Radiographic evidence i. Wormian skull bones ii. Osteoporosis iii. Metaphyseal dysplasia including anterior flaring and fracture of the ribs Progressive neurologic deterioration a. Usually death by 3 years of age b. Rare survival beyond childhood in some children with profound neurologic deficits c. Long survival, especially with cupper therapy, to teen and twenties Patients with milder or atypical manifestations than “classical” Menkes disease a. Milder phenotype i. Mild intellectual delay ii. Ataxia b. Later onset of symptoms c. Less severe clinical course d. A longer life span Occipital horn disease: a very mild allelic form of Menkes disease a. A connective tissue disorder caused by a secondary deficiency of the cuproenzymes, lysyl oxidase b. Milder phenotypic manifestations c. Connective tissue abnormalities i. Hyperelastic and easily bruisable skin ii. Bladder diverticulae iii. Varicosities iv. Hypermobile joints d. Skeletal abnormalities i. Short broad clavicles ii. Fused carpal bones iii. Thoracic malformations iv. Bony exostosis of the occiput (occipital horn) secondary to calcifications of the muscle at the insertion sites e. Occasional mild neurologic impairment f. Any male infant with connective tissue abnormalities and mental retardation should be evaluated for the possibility of Menkes disease because of somewhat atypical presentation of these milder phenotypes
DIAGNOSTIC INVESTIGATIONS 1. Biochemical phenotype a. Low levels of copper in serum, liver, and brain resulting from impaired intestinal absorption b. Low serum ceruloplasmin levels
MENKES DISEASE
8.
9.
10. 11.
12.
c. Diagnosis of Menkes disease confirmed by decreased serum copper and ceruloplasmin. Interpretation of these values is difficult in the first months of life. In such cases, the following analysis may be helpful in confirming the diagnosis i. Copper accumulation in the placenta or chorionic villi ii. Copper accumulation in the cultured skin fibroblasts d. Low activities of numerous copper-dependent enzymes i. Dopamine β-hydroxylase a) Temperature instability b) Hypoglycemia c) Eyelid Ptosis d) Pupillary constriction ii. Peptidylglycine α-amidating monooxygenase (reduced bioactivity of many neuroendocrine peptides) iii. Cytochrome c oxidase (impaired myelination, muscle weakness) iv. Copper-zinc superoxide dismutase (diminished protection against O2 free radicals, possible motor neuron damage) v. Tyrosinase (reduced pigmentation of hair and skin) vi. Diamine oxidase (reduced histamine degradation) vii. Lysine oxidase (decreased strength of collagen and elastin) viii. Ceruloplasmin (decreased circulating copper levels) e. Paradoxical accumulation of copper in certain tissues, such as duodenum, kidney, spleen, pancreas, skeletal muscle, and placenta Light microscopy of hair a. Pathognomonic pili torti (180-degree twisting of the hair shaft) b. Trichoclasis (transverse fracture of the hair shaft) c. Trichoptilosis (longitudinal splitting of the shaft) d. Trichorrhexis nodosa (small, beaded swelling with fractures at regular intervals) e. Monilethrix elliptica (swelling with intervening tapered constrictions) MRI/MRA of the brain a. White matter abnormalities reflecting impaired myelination b. Progressive degeneration of grey matter c. Cortical encephalomalacia d. Diffuse cerebral atrophy e. Cerebellar atrophy f. Ventriculomegaly g. Tortuosity (corkscrew appearance) of cerebral blood vessels h. Subdural hematoma (common in infants) i. Cerebrovascular accidents in older patients Cerebral angiogram for tortuous winding vessels Variable electroencephalogram (normal, moderately to severely abnormal) a. Hypsarrhythmia after 5 months of age b. Low amplitude or absent evoked potentials Echocardiography a. Dysplastic coronary vessels b. Vascular complications including aortic aneurysms
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13. Pelvic ultrasound to detect diverticula of the urinary bladder 14. Renal ultrasound a. Hydronephrosis b. Hydroureter c. Bladder diverticulate 15. Radiography a. Skull radiograph i. Wormian bones in the lambdoidal and posterior sagittal sutures ii. “Occipital horn” b. Metaphyseal spurring of long bones c. Diaphyseal periosteal reaction d. Anterior flaring or multiple fractures of ribs e. Scalloping of the posterior aspects of the vertebral bodies f. Osteoporosis seen after 6 months of age 16. Histologic examination of torturous cerebral blood vessels a. Thinning of the connective tissue b. Disruption of the elastic lamina 17. Cytogenetic studies using traditional chromosome banding techniques verified by FISH using yeast artificial chromosomes spanning the gene a. Mainly carried out in affected females for identification of possible X:autosome translocation at Xq13.3 b. Rare chromosome abnormality in male patients 18. Molecular diagnosis a. Molecular diagnosis of Menkes disease: complicated by the heterogeneity at this locus b. Almost all mutations detected in the Menkes disease gene are unique to an affected family c. About 20 percent of these mutations involve rearrangements or partial gene deletions that can be identified by Southern blot analysis d. Molecular diagnosis (superior to biochemical information) when the mutation in a given family is known, especially in cases of prenatal diagnosis e. Carrier diagnosis is best done with mutation analysis and is readily accomplished when the specific mutation is known. In families where the mutation has not been identified, polymorphic markers and intragenic repeats have been used to facilitate carrier diagnosis 19. Female carrier determination a. Measurement of copper (64Cu) accumulation in fibroblasts: difficult to interpret negative results because of random X inactivation of one of the X chromosomes. Normal results do not completely exclude carrier status b. Presence of pili torti in the hair: a positive clinical indicator but its absence does not eliminate the possibility c. Heterozygote detection by mutation detection in a given family with a known mutation i. Allele-specific PCR ii. Restriction enzyme analysis iii. Heteroduplex analysis iv. SSCP followed by DNA sequencing v. Southern blot analysis d. Linkage studies using intragenic polymorphic markers helpful in carrier detection, prenatal diagnosis and genetic counseling where the mutation has not been identified
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GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Carrier mother: 50% of brothers affected, 50% of brothers normal; 50% of sisters carriers, 50% of sisters normal ii. Noncarrier mother: instances of recurrence reported due to gonadal mosaicism b. Patient’s offspring: not surviving to reproduction 2. Prenatal diagnosis of a male fetus at risk a. 1st trimester: measurement of total copper content in chorionic villus samples b. 2nd trimester: copper (64Cu) accumulation and kinetic studies in cultured amniotic fluid cells c. Mutation detection in a given family with a known mutation 3. Management a. No definitive therapeutic options currently available b. Oral copper treatment not effective c. Early parenteral administrations of cupric acetate i. Normalizes serum copper and ceruloplasmin levels but not CNS copper levels ii. Improves seizure control iii. Will not interrupt the progression of neurologic manifestations d. Early subcutaneous injections of copper-histidine with encouraging results i. Normalizes serum copper, ceruloplasmin, dopamine, and norepinephrine levels after 3 months of treatment ii. May be able to cross the blood-brain barrier and thus disrupt the progression of neurological symptoms including decreased seizures iii. Prolong survival, especially if treatment started within 1 month of life iv. Does not prevent the connective tissue complications because lysyl oxidase may not incorporate copper-histidine well
REFERENCES Abusaad I, Mohammed SN, Ogilvie CM, et al.: Clinical expression of Menkes disease in a girl with X;13 translocation. Am J Med Genet 87:354–359, 1999. Bankier A: Menkes disease. J Med Genet 32:213–215, 1995. Chang CH: Menkes disease. Emedicine J, 2002. Chelly J, Tumer Z, Tonnesen T, et al.: Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nature Genet 3:14–19, 1993. Christodoulou J, Danks DM, Sarkar B, et al.: Early treatment of Menkes disease with parenteral copper-histidine: long-term follow-up of four treated patients. Am J Med Genet 76:154–164, 1998. Culotta VC, Gitlin JD: Disorders of copper transport. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001, Chapter 126, pp 3105–3126. Danks DM, Campbell PE, Stevens BJ, et al.: Menkes’ kinky hair syndrome. An inherited defect in copper absorption with widespread effects. Pediatrics 50:188–201, 1972. Das S, Whitney S, Taylor J, et al.: prenatal diagnosis of Menkes disease by mutation analysis. J Inher Metab Dis 18:364–365, 1995. Gu YH, Kodama H, Murata Y, et al.: ATP7A gene mutations in 16 patients with Menkes disease and a patient with occipital horn syndrome. Am J Med Genet 99:217–222, 2001.
Gu YH, Kodama H, Sato E, et al.: Prenatal diagnosis of Menkes disease by genetic analysis and copper measurement. Brain Dev 24:715–718, 2002. Horn N: Menkes X linked disease: Heterozygous phenotype in uncloned fibroblast cultures. J Med Genet 17:257–261, 1980. Horn N: Menkes X-linked disease: Prenatal diagnosis of hemizygous males and heterozygous females. Prenat Diagn 1:107–120, 1981. His G, Cox DW: A comparison of the mutation spectra of Menkes disease and Wilson disease. Hum Genet 114:165–172, 2004. Imaeda S: Menkes kinky hair disease. Emedicine J 2002. Kaler SG: Mendes disease. Adv Pediatr 41:263–304, 1994. Kaler S: Metabolic and molecular bases of Menkes disease and occipital horn syndrome. Pediatr Dev Pathol 1:85–98, 1998. Kaler SG, Tümer Z: Prenatal diagnosis of Menkes disease. Prenat Diagn 18:287–289, 1998. Kapur S, Higgins JV, Delp K, et al.: Menkes syndrome in a girl with X-autosome translocation. Am J Med Genet 26:503–510, 1987. Kim B-E, Smith K, Petris MJ: A copper treatable Menkes disease mutation associated with defective trafficking of a functional Menkes copper ATPase. J Med Genet 40:290–295, 2003. Kodama H, Murata Y: Molecular genetics and pathophysiology of Menkes disease. Pediatr Int 41:430–435, 1999. Kodama H, Murata Y, Kobayashi M: Clinical manifestations and treatment of Menkes disease and its variants. Pediatr Int 41:423–429, 1999. Kreuder J, Otten A, Fuder H, et al.: Clinical and biochemical consequences of copper-histidine therapy in Menkes disease. Eur J Pediatr 152:828–832, 1993. Lazoff SG, Ryback JJ, Parker BR, et al.: Skeletal dysplasia, occipital horns, diarrhea and obstructive uropathy: a new hereditary syndrome. Birth Defects 41:71–74, 1975. Martins C, Goncalves C, Moreno A, et al.: Menkes’ kinky hair syndrome: ultrastructural cutaneous alterations of the elastic fibers. Pediatr Dermatol 14:347–350, 1997. Menkes JH: Kinky hair disease. Pediatrics 50:181–183, 1972. Menkes JH: Disorders of copper metabolism. In Rosenberg R, Prusiner S, DiMauro S, Barchi R (eds): The Molecular and Genetic Basis of Neurological Disease. Butterworth-Heinemann, Boston, 1997, pp 1273–1290. Menkes JH: Kinky hair disease: twenty five years later. Brain Dev 10:77–79, 1988. Menkes JH: Menkes disease and Wilson disease: two sides of the same copper coin. Part I: Menkes disease. Eur J Paediatr Neurol 3:147–158, 1999. Menkes JH, Alter M, Steigleder GK, et al.: A sex-linked recessive disorder with retardation of growth, peculiar hair and focal cerebral and cerebellar degeneration. Pediatrics 29:764–779, 1962. Mercer J, Livingston J, Hall B: Isolation of a partial candidate gene for Menkes disease by positional cloning. Nature Genet 3:20–25, 1993. Packman S: Copper metabolism. In Rimoin DL, Connor JM, Pyeritz RE, Korf BR (eds): Emery and Rimoin’s Principles and Practice of Medical Genetics, 4th ed, Vol 2, London, Churchill Livingstone, 2002, pp 2624–2637. Poulsen L, Horn N, Møller LB: X-linked recessive Menkes disease: carrier detection in the case of a partial gene deletion. Clin Genet 62:440–448, 2002. Poulsen L, Horn N, Heilstrup H, et al.: X-linked recessive Menkes disease: identification of partial gene deletions in affected males. Clin Genet 62:449–457, 2002. Peltonen L, Kuivaniemi H, Palotie A, et al.: Alterations in copper and collagen metabolism in the Menkes syndrome and a new subtype of the EhlersDanlos syndrome. Biochemistry 22:6156–6163, 1983. Poulsen L, Horn N, Heilstrup H, et al.: X-linked recessive Menkes disease: identification of partial gene deletions in affected males. Clin Genet 62:449–457, 2002. Poulsen L, Horn N, Møller LB: X-linked recessive Menkes disease: carrier detection in the case of a partial gene deletion. Clin Genet 62:440–448, 2002. Proud V, Mussel H, Kaler S, et al.: Distinctive Menkes disease variant with occipital horns: Delineation of natural history and clinical phenotype. Am J Med Genet 65:44–51, 1996. Sarkar B: Early copper histidine therapy in classic Menkes disease. Ann Neurol 41:134–136, 1997. Sarkar B, Lingertat-Walsh K, Clarke JT: Copper-histidine therapy for Menkes disease. J Pediatr 123:828–830, 1993. Sander C, Niederhoff H, Horn N: Life span and Menkes kinky hair syndrome: report of a 13-year course of this disease. Clin Genet 33:228–233, 1998.
MENKES DISEASE Sugio Y, Kuwano A, Miyoshi O, et al.: Translocation t(X;21)(q13.3; p11.1) in a girl with Menkes disease. Am J Med Genet 79:191–194, 1998. Tommerup N, Tümer Z, Tønnesen T, et al.: A cytogenetic survey in Menkes disease: Implication for the detection of chromosomal rearrangements in X linked disorders. J Med Genet 30:314–315, 1993. Tønnesen T, Horn N: Prenatal and postnatal diagnosis of Menkes disease, an inherited disorder of copper metabolism. J Inher Metab Dis 12 (Suppl 1):201–214, 1989. Tønnesen T, Gerdes A, Damsgaard E, et al.: First-trimester diagnosis of Menkes disease: intermediate copper values in chronic villi from three affected male fetuses. Prenatal Diagn 9:159–165, 1989. Tønnesen T, Kleijer WJ, Horn N: Incidence of Menkes disease. Hum Genet 86:408–410, 1991. Tümor Z: Genetics of Menkes disease. J Trace Elem Exp Med 11:147–161, 1998. Tümer Z, Horn N: Menkes disease: recent advances and new aspects. J Med Genet 34:265–274, 1997. Tümor Z, Horn N: Menkes disease: Underlying genetic defect and new diagnostic possibilities. J Inher Metab Dis 21:604–612, 1998.
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Tümor Z, Chelly J, Tommerup N, et al.: Characterization of a 1.0 Mb YAC contig spanning two chromosome breakpoints related to Menkes disease. Hum Mol Genet 1:483–489, 1992 Tümer Z, Tømmerup N, Tønnesen T, et al.: Mapping of the Menkes locus to Xq13.3 distal to the X-inactivation center by an intrachromosomal insertion of the segment Xq13.3-q21.2. Hum Genet 88:668–672, 1992. Tümer Z, Tonnesen T, Bohmann J, et al.: First trimester prenatal diagnosis of Menkes disease by DNA analysis. J Med Genet 31:615–617, 1994. Verga V, Hall BK, Wang S, et al.: Localization of the translocation breakpoint in a female with Menkes syndrome to Xq13.2-q13.3 proximal to PGK-1. Am J Hum Genet 48:1133–1138, 1991. Vulpe C, Levinson B, Whitney S, et al.: Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nature Genet 3:7–13, 1993. Westman J, Richardson D, Rennert O, et al.; Atypical Menkes steely hair disease. Am J Med Genet 30:853–858, 1988. Williams DM, Atkin CL: Tissue copper concentrations of patients with Menke’s kinky hair disease. Am J Dis Child 135:375–376, 1981.
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MENKES DISEASE
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Fig. 2. A cousin of the previous child with Menkes disease at 3 years of age showing coarse/twisting hair, sagging cheeks, and large appearing ears.
Fig. 1. A boy with Menkes disease at 1 month, 9 months, 1 year, 27 months, and 9 years showing sparse, coarse, twisted hair, sagging cheeks, large appearing ears, and pectus excurvatum The boy was treated with cuprous sulfate and survived to his twenties. Fig. 3. Hairs showing pili torti (moderate variation in diameters; two hair shafts are twisted) in an 8-month-old male infant affected with Menkes disease.
Metachromatic Leukodystrophy Metachromatic leukodystrophy (MLD) is a lysosomal storage disease resulting from the deficient arylsulfatase A activity and the accumulation of sulfatides. The incidence among Caucasian is estimated to be about 1 in 40,000 births. The name of MLD originated from the metachromatic staining of the stored substance in histological sections.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Caused by deficiency of arylsulfatase A (ASA) activity a. Resulting in accumulation of the enzyme substrate sulfatide (cerebroside sulfuric ester) in: i. Oligodendrocytes and Schwann cells ii. Visceral organs such as kidneys (sulfatide excreted in high amounts in the urine) b. Leading to severe myelin breakdown i. Resulting in demyelination of the white matter of the brain, spinal cord, and peripheral nerves ii. Providing the pathophysiologic basis for the deterioration and eventual premature demise 3. Arylsulfatase (ARSA) gene a. Mapped to 22q13.31 b. MLD caused by ARSA mutations: two most common mutations observed in Europe are: i. 459+1G>A ii. P426L c. ASA pseudodeficiency (ASA-PD) caused by ARSA mutation i. Originally described in healthy individuals ii. Low ASA activity iii. Normal urinary sulfatide levels iv. The pseudodeficiency, in most cases, is caused by homozygosity for the arylsulfatase A pseudodeficiency (Pd) allele v. MLD mutations also known to occur within this allele: 1–2% of Pd alleles are estimated to have a disease-causing mutation
CLINICAL FEATURES 1. Three main clinical forms based on the age of onset of the disease a. Late infantile form b. Juvenile form c. Adult form 2. Late infantile form a. The most common form b. Onset of the disease: between the ages of 15 months and 2 years c. Clinical symptoms i. Loss of acquired motor skills ii. Flaccid weakness and hypotonia iii. Ataxic gait with absent tendon reflexes 646
d. Progression of the disease i. Quadriplegia ii. Speech disturbances a) Dysarthria b) Aphasia c) Speech deterioration leading to loss of speech iii. Difficulty in feeding (dysphagia) with bulbar and pseudobulbar palsies iv. Irritability v. Muscle wasting vi. Peripheral neuropathy vii. Ataxia viii. Ophthalmic features a) Nystagmus b) A cherry-red spot in the macula in some patients c) Optic atrophy leading to blindness ix. Epileptic seizures usually occur at advanced stages of the disease x. Mental deterioration progresses with the disease until the patients are no longer able to establish any contact with their surroundings xi. Death generally occur one to seven years after onset 3. Juvenile form a. Clinical symptoms usually develop between the ages of 4 and 12 years b. Progression of the illness similar to that of the infantile form c. Clinical characteristics i. Loss of developmental milestones by the end of the first decade ii. Gross motor a) Incoordination b) Clumsiness c) Ataxia with progressive gait disturbance leading to loss of ambulation d) Progressive hypertonia with tremor, postural abnormalities, and/or leg scissoring e) Diminished deep tendon reflexes iii. Speech and language a) Slurred speech b) Speech deterioration iv. Cognitive and behavioral changes a) Abnormal and bizarre behavior b) Day dreaming c) Difficulty in following directions d) Emotional difficulties e) Intellectual decline f) Mental deterioration v. Ophthalmologic features optic atrophy leading to blindness
METACHROMATIC LEUKODYSTROPHY
vi. Other CNS manifestations a) Pseudobulbar palsy b) Epileptic seizures usually occur at advanced stages of the disease c) Mental illness with features of psychosis, dementia, and emotional disorders in older children d) Progressive neurological problems but less severe than in the late infantile form d. Prognosis i. Fatal in majority of cases ii. Course of disease may last more than 20 years in a few cases 4. Adult form a. Wide range of onset: from 19–46 years b. Very rare occurrence c. Slow progression of the disease d. Survival of 5–10 years common e. Cognitive and behavioral changes: the first symptoms in many cases i. Personality changes a) Anxiety b) Apathy c) Bewilderment d) Emotional instability e) Psychosis ii. Poor school or job performance a) Decreased mental alertness b) Defective visual-spatial discrimination c) Disorganized thinking d) Poor memory f. Mental deterioration i. Often the first symptom ii. Loss of professional abilities leading to total incapacity iii. Progressive deterioration eventually leading to dementia g. Rare epileptic seizures h. Ophthalmologic features i. Horizontal nystagmus ii. Optic atrophy leading to blindness i. Final stages i. Lose of speech ii. Immobility iii. Incontinence 5. Arylsulfatase pseudodeficiency a. Low arylsulfatase activity in healthy individuals b. Allelic variant metachromatic leukodystrophy 6. Nonallelic variants of MLD a. Multiple sulphatase deficiency b. Sphingolipid activator protein B deficient MLD
DIAGNOSTIC INVESTIGATIONS 1. Demonstration of decreased or absence ASA enzyme in the urine, leukocytes, or cultured skin fibroblasts a. Low ASA activity also observed in: i. Individuals with multiple sulfatase deficiency ii. Individuals with copies of pseudodeficiency (Pd) allele
2. 3. 4.
5. 6. 7. 8.
9. 10. 11.
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b. Low ASA activity is seen in individuals without MLD due to the high frequency of the common Pd allele in the general population c. Differentiation of ASA pseudodeficiency from MLD i. Inability to reliably distinguish MLD and ASA pseudodeficiency, based solely on enzyme activity determinations ii. Cerebroside sulfate loading test a) Exposure of the cells to radioactively labeled cerebroside sulfate, the natural substrate of arylsulfatase A b) Cultured cells from a pseudodeficient individuals will degrade this substrate at normal rates, whereas those from MLD patients do not c) Disadvantages: require experienced investigator, noncommercially available substrate, and tissue culture facilities iii. Pd allele mutations studies using allele specific amplification Urinalysis showing metachromatic granules in the urine sediment Urine chemistry showing markedly increased sulfatide levels Sulfatide loading of fibroblast cultures and subsequent measurement of hydrolysis of added substrate: the differences in hydrolysis of added sulfatide provides a functional test that separates late-infantile, juvenile and adult forms Absence of gallbladder function on a cholecystography Abnormal brain stem auditory, visual, and somatosensory evoked potentials Elevated CSF protein levels Brain imagings show progressive loss of white matter due to demyelination a. Symmetric diffuse high intensity signal on proton density and T2-weighted images throughout the white matter consistent with demyelination b. Hypointense signal abnormalities in the white matter of the centrum semiovale with following two distinct appearances: i. A radiating pattern (“tigroid” appearance) of linear tubular structures or horizontal linear hypodensity indicative of spared perivascular white matter ii. Areas of relatively normal-appearing white matter: a punctate appearance to the linear structures (“leopard-skin” appearance) within the demyelinated centrum semiovale c. Cerebral atrophy with ventricular enlargement Nerve conduction studies show decreased nerve conduction velocities Nerve biopsies show metachromasia of Schwann cells Molecular studies of ASA mutations by mutation scanning of the entire coding sequence of the arylsulfatase-A gene
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Recurrence risk: 25% ii. Younger siblings in the same family with an older sibling who is clinically affected by MLD
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a) Require appropriate and rapid evaluation b) May be affected but clinically presymptomatic c) Therapy with bone marrow transplantation in affected but asymptomatic sibling may be curative d) Sibling with very low levels of white blood cell arylsulfatase A may not indicate the presence of disease because of the combination of the pseudodeficient gene with a metachromatic leukodystrophy gene b. Patient’s offspring i. Do not survive into reproductive age in late infantile and juvenile forms ii. Not increased in adult form unless the spouse is a carrier 2. Carrier detection a. Individuals with about 50% of arylsulfatase A i. Suspected to be carriers of a MLD allele and have genetic risk for MLD ii. Likely to be carriers of a pseudodeficiency allele and have no genetic risk for MLD b. Enzyme activity determination: impossible to distinguish heterozygotes of a pseudodeficiency allele from heterozygous of a MLD allele c. Mutation detection of the pseudodeficiency allele in the DNA to facilitate the differential diagnosis of MLD and pseudodeficiency 3. Prenatal diagnosis for couples at risk a. Demonstration of the absence of arylsulfatase A in cultured chorionic villi or amniocytes b. A combination of biochemical and molecular tests performed on chorionic villus samples or cultured amniotic fluid cells c. Demonstration of the disease-causing mutation previously identified in the proband on fetal DNA obtained from amniocentesis or CVS 4. Management a. Primarily supportive i. Nasogastric or G-tube feeding for dysphagia of bulbar and pseudobulbar palsies ii. Multidisciplinary approach b. Bone marrow transplantation i. For individuals who are presymptomatic or have only mild neurologic manifestations ii. Significant risks associated with this procedure iii. Highly dependent on the availability of adequately matched donors iv. Appears to slow the progression of the disease and improve the quality of life
REFERENCES Barth ML, Fensom A, Harris A: The arylsulphatase A gene and molecular genetics of metachromatic leukodystrophy. J Med Genet 31:663–666, 1994.
Baumann N, Masson M, Carreau V, et al.: Adult forms of metachromatic leukodystrophy: clinical and biochemical approach. Dev Neurosci 13:211–215, 1991. Berger J, Loschl B, Bernheimer H, et al.: Occurrence, distribution, and phenotype of arylsulfatase A mutations in patients with metachromatic leukodystrophy. Am J Med Genet 69:335–340, 1997. Clark JR, Miller RG, Vidgoff JM: Juvenile-onset metachromatic leukodystrophy: biochemical and electrophysiologic studies. Neurology 29:346–343, 1979. Eto Y, Tahara T, Koda N, et al.: Prenatal diagnosis of metachromatic leukodystrophy: a diagnosis by amniotic fluid and its confirmation. Arch Neurol 39:29–32, 1982. Faerber EN, Melvin J, Smergel EM: MRI appearances of metachromatic leukodystrophy. Pediatr Radiol 29:669–672, 1999. Farrell DF, MacMartin MP, Clark AF: Multiple molecular forms of arylsulfatase A in different forms of metachromatic leukodystrophy (MLD). Neurology 29:16–20, 1979. Farooqui AA, Horrocks LA: Biochemical aspects of globoid and metachromatic leukodystrophies. Neurochem Pathol 2:189–218, 1984. Gieselmann V: An assay for the rapid detection of the arylsulfatase A pseudodeficiency allele facilitates diagnosis and genetic counseling for metachromatic leukodystrophy. Hum Genet 86:251–255, 1991. Gieselmann V, Fluharty AL, Tonnesen T, et al.: Mutations in the arylsulfatase A pseudodeficiency allele causing metachromatic leukodystrophy. Am J Hum Genet 49:407–413, 1991. Gieselmann V, Kreysing J, von Figura K: Genetics of metachromatic leukodystrophy. Gene Ther 1 (Suppl 1):S87, 1994. Gieselmann V, Polten A, Kreysing J, et al.: Molecular genetics of metachromatic leukodystrophy. Dev Neurosci 13:222–227, 1991. Gieselmann V, Polten A, Kreysing J, et al.: Molecular genetics of metachromatic leukodystrophy. J Inherit Metab Dis 17:500–509, 1994. Gieselmann V, Zlotogora J, Harris A, et al.: Molecular genetics of metachromatic leukodystrophy. Hum Mutat 4:233–242, 1994. Greene HL, Hug G, Schubert WK: Metachromatic leukodystrophy. Treatment with arylsulfatase-A. Arch Neurol 20:147–153, 1969. Gustavson KH, Hagberg B: The incidence and genetics of metachromatic leukodystrophy in northern Sweden. Acta Paediatr 60:585–590, 1971. Haltia T, Palo J, Haltia M, et al.: Juvenile metachromatic leukodystrophy. Clinical, biochemical, and neuropathologic studies in nine new cases. Arch Neurol 37:42–46, 1980. Kidd D, Nelson J, Jones F, et al.: Long-term stabilization after bone marrow transplantation in juvenile metachromatic leukodystrophy. Arch Neurol 55:98–99, 1998. Kihara H: Genetic heterogeneity in metachromatic leukodystrophy. Am J Hum Genet 34:171–181, 1982. Krivit W, Lockman LA, Watkins PA, et al.: The future for treatment by bone marrow transplantation for adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy and Hurler syndrome. J Inherit Metab Dis 18:398–412, 1995. Krivit W, Peters C, Shapiro EG: Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, aspartylglucosaminuria, Hurler, Maroteaux-Lamy, and Sly syndromes, and Gaucher disease type III. Curr Opin Neurol 12:167–176, 1999. Langenbeck U, Dunker P, Heipertz R, et al.: Inheritance of metachromatic leukodystrophy. Am J Hum Genet 29:639–640, 1977. Moore T, Steiner RD: Metachromatic leukodystrophy. www.emedicine.com Ohashi T, Watabe K, Sato Y, et al.: Gene therapy for metachromatic leukodystrophy. Acta Paediatr Jpn 38:193–201, 1996. Rafi MA, Coppola S, Liu SL, et al.: Disease-causing mutations in cis with the common arylsulfatase A pseudodeficiency allele compound the difficulties in accurately identifying patients and carriers of metachromatic leukodystrophy. Mol Genet Metab 79:83–90, 2003. van der Hagen CB, Borresen AL, Molne K, et al.: Metachromatic leukodystrophy. I. Prenatal detection of arylsulphatase A deficiency. Clin Genet 4:256–259, 1973.
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Fig. 2. A 3-year-old girl presented with progressive muscle weakness in the lower limbs for 2–4 months. The low leukocyte arylsulfatase A at 0.4 (control: ≥2.5) was consistent with diagnosis of metachromatic leukodystrophy.
Fig. 1. A 28-month-old boy with late infantile form metachromatic leukodystrophy showing extreme hypotonia. At about 15 months of age he stopped talking and showed muscle weakness. MRI of the brain demonstrated demyelination. Aryl sulfatase A activity was absent in the cultured fibroblasts. Urinary excretion of excess sulfatides confirmed the diagnosis of metachromatic leukodystrophy. DNA analysis shows no copies of the pseudodeficiency allele or the common late infantile mutation. Mutation screening of the entire coding sequence of the arylsulfatase-A gene revealed the mutation E253K which was inherited from the mother and the second mutation P192R which was inherited from the father. The E253K mutation has been described as a disease-causing mutation in the literature. The second mutation P192R most likely is a disease causing mutation.
Miller-Dieker Syndrome 3. Classification of lissencephaly (Dobyns et al., 1984) a. Type I i. Isolated lissencephaly sequence ii. Miller-Dieker syndrome iii. Nonclassified forms b. Type II i. Walker-Warburg syndrome ii. Fukuyama congenital muscular dystrophy iii. Nonunclassified forms c. Rare forms i. Neu-Laxova syndrome ii. Cerebro-cerebellar syndrome 4. Cytogenetic mechanisms in Miller-Dieker syndrome (Dobyns et al., 1991) a. De novo abnormalities (44%) i. Deletion (terminal or interstitial) (36%) ii. Dicentric translocation (4%) iii. Ring chromosome (4%) b. Familial rearrangement (12%) i. Reciprocal translocation (8%) ii. Pericentric inversions (4%) c. Normal karyotype (44%) i. Submicroscopic deletion (36%) ii. No deletion detected (8%) 5. Molecular explanation for Miller-Dieker syndrome a. Heterozygous deletions of 17p13.3 result in the human neuronal migration disorders i. Isolated lissencephaly sequence ii. More severe Miller-Dieker syndrome b. Mutations in PAFAH1B1 (the gene encoding LIS1): responsible for isolated lissencephaly sequence and contributing to Miller-Dieker syndrome c. The gene encoding 14-3-3 Ó (YWHAE), one of a family of ubiquitous phosphoserine/threonine-binding proteins: always deleted in individuals with Miller-Dieker syndrome, providing a molecular explanation for the differences in severity of human neuronal migration defects with 17p13.3 deletions
In 1963, Miller reported two siblings with a specific pattern of malformations in which lissencephaly was a key feature. Later in 1969, Dieker et al. described a similar condition. Jones et al. in 1980 further characterized the phenotype and suggested the designation Miller-Dieker syndrome to distinguish it from other lissencephaly syndromes. At present, Miller-Dieker syndrome is known to be a contiguous gene disorder caused by haplo-insufficiency of a gene or genes having a major role in the development of the brain and the face.
GENETICS/BASIC DEFECTS 1. Genetics: a contiguous gene deletion syndrome involving chromosome 17p13.3 a. Association of Miller-Dieker syndrome and del(17) (p13) i. First reported by Dobyns et al. in 1983 ii. Familial cases reported by Miller (1963) with affected members being carriers of an unbalanced rearrangement from t(15;17)(q26.1;p13.3) iii. Family reported by Dieker et al. (1969) with affected members being carriers of an unbalanced rearrangement from t(12;17) (q24.31; p13.3) b. A microdeletion in a critical 350 kb region of chromosome 17p13.3 observed in familial and sporadic cases, detected by high resolution banding c. Southern blot analysis of restriction fragment length polymorphism with several different DNA markers in 17p13.3, and later FISH analysis using different DNA probes of this segment i. Observed in >90% of patients with MillerDieker syndrome ii. Observed in 38% of patients with isolated lissencephaly 2. Mutations and large deletions of the lissencephaly gene (LIS1) a. Deletions involving LIS1: more common than mutations b. LIS1 deleted in Miller-Dieker syndrome c. LIS1 mutations observed in patients with isolated lissencephaly sequence i. Missense mutations ii. Nonsense mutations iii. Small deletions or insertions iv. Splice site mutations v. Partial deletions d. Phenotype–genotype correlations i. Most severe LIS phenotypes observed in patients with large deletions of 17p13.3 ii. Milder phenotypes observed in patients with intragenic mutations iii. Mildest phenotypes observed in patients with missense mutations
CLINICAL FEATURES
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1. Prenatal and neonatal history a. Polyhydramnios b. Prenatal growth deficiency c. Neonatal resuscitation d. Neonatal jaundice e. Postnatal growth deficiency 2. CNS anomalies a. Type I (classical) lissencephaly: can occur either in association with the Miller-Dieker syndrome or as an isolated finding, termed “isolated lissencephaly sequence” i. Agyria (absent gyration of the cerebral cortex) ii. Pachygyria (unusually thick convolutions of the cerebral cortex)
MILLER-DIEKER SYNDROME
b. c. d. e. f.
3.
4. 5. 6.
7. 8. 9. 10.
Absent or hypoplastic corpus callosum Cavum septi pellucidi Midline calcification Ventricular dilatation Abnormal positioning of the olivary nuclei in the midbrain g. Occasional mild cerebellar vermis hypoplasia h. Microcephaly i. Seizures usually by age 9 weeks j. Cerebral palsy k. Profound mental retardation Craniofacial features a. High, prominent and wrinkled forehead b. Bitemporal narrowing c. Furrowed brow d. Epicanthal folds e. Broad nasal bridge f. Short and pointed nose with anteverted nostrils g. Long prominent upper lip with thin upper vermilion border h. Micrognathia i. High arched palate j. Low-set and malformed ears Congenital heart defects Omphalocele Hands and fingers a. Clinodactyly b. Camptodactyly c. Transverse palm crease Sacral dimple Cryptorchidism Prognosis: often die within the first few months of life Differential diagnosis a. Isolated lissencephaly sequence i. Brain abnormalities a) Lissencephaly (type I) b) Numerous heterotopias c) Failure of opercularization d) Enlarged ventricles (usually colpocephaly) e) Probable hypoplasia of the corpus callosum ii. Neurologic abnormalities a) Profound mental retardation b) Decreased spontaneous activity c) Early hypotonia d) Subsequent hypertonia e) Poor feeding f) Seizures iii. Craniofacial features a) Microcephaly b) Bitemporal hollowing c) Prominent occiput d) Micrognathia iv. Occasional abnormalities a) Prenatal: polyhydramnios, decreased fetal movement b) Postnatal: may require resuscitation at birth c) Neurological: infantile spasms v. Chromosome studies a) Normal chromosomes by conventional studies
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b) Submicroscopic deletions by FISH observed in increasing numbers b. Norman-Roberts syndrome i. Probably an autosomal recessive disorder ii. Brain abnormalities a) Lissencephaly (type I) b) Numerous heterotopias c) Failure of opercularization d) Slightly enlarged ventricles (probable colpocephaly) e) Probable hypoplasia of the corpus callosum iii. Neurologic abnormalities a) Profound mental retardation b) Decreased spontaneous activity c) Poor feeding d) Seizures iv. Cranial abnormalities a) Microcephaly b) Bitemporal hollowing c) Slightly prominent occiput d) Low, sloping forehead v. Facial features a) Widely set eyes b) Broad, prominent nasal bridge c) Micrognathia d) Absence of upturned nares e) Normal eyes vi. Other features a) Clinodactyly b) Chordee c) Low birth weight vii. Normal chromosomes c. Walker-Warburg syndrome i. Most commonly seen in the United Kingdom ii. An autosomal recessive disorder iii. Type II lissencephaly iv. Hydrocephalus v. Cerebellar malformation (vermian hypoplasia) vi. Eye abnormalities a) Retinal dysplasia b) Microphthalmia c) Colobomata d) Cataracts e) Glaucoma f) Corneal clouding commonly due to a Peter anomaly g) Congenital muscular dystrophy in all patients h) Elevated CK i) Abnormal EMG j) Pathological changes on muscular histology vii. Other abnormalities a) Cleft lip/palate b) Genital anomalies in males: cryptorchidism, small penis c) Occasional contractures d. Muscle-eye-brain disease i. Mainly reported in Finnish population ii. An autosomal recessive disorder iii. Type II lissencephaly
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iv. Hydrocephalus v. Eye abnormalities a) Primarily myopia b) Occasional glaucoma, retinal dystrophy, and cataracts vi. Congenital muscular dystrophy: a constant feature vii. Elevated CK levels viii. Hypotonia ix. Feeding difficulties x. Severe mental retardation xi. Seizures common e. Fukuyama congenital muscular dystrophy i. Mainly reported in the Japanese population ii. An autosomal recessive disorder iii. Cobblestone lissencephaly (type II) iv. Eye abnormalities a) Myopia b) Optic atrophy in some patients v. Muscular dystrophy in all patients vi. CK levels ranging from 10–50 times of normal vii. Hypotonia viii. Marked mental retardation
DIAGNOSTIC INVESTIGATIONS 1. Chromosome analysis to detect microdeletion at 17p13.3 a. High resolution analysis indicated for all patients with type I or atypical lissencephaly b. Molecular cytogenetic technology using FISH to detect a submicroscopic deletion when chromosome analysis is normal and Miller-Dieker syndrome is suspected based on clinical evaluation c. Parental studies in case of positive findings 2. MRI of the newborn brain a. Smooth brain b. Bilateral primitive Sylvian fissure giving rise to a “figure 8” appearance of the brain c. Persistent fetal configuration of the posterior horns of the ventricular system (colpocephaly) 3. DNA mutation analysis a. Direct sequencing b. Southern blot analyses
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: based on the specific cytogenetic mechanism involved i. Very low recurrence risk in most patients whose abnormalities occur de novo ii. Very high recurrence risk in families where one parent is the carrier of a balanced chromosome rearrangement involving 17p13 b. Patient’s offspring: patients not surviving to reproductive age c. A high risk for abnormal phenotypes for an individuals carrying a balanced translocation with a breakpoint in 17p13 ascertained because of a relative with Miller-Dieker syndrome or dup(17p)
i. Approximately 26% risk in all recognized pregnancies ii. 33% risk in pregnancies which remain viable in the second trimester or after iii. Frequency of spontaneous miscarriages and stillbirths not appear to be unduly elevated in these families 2. Prenatal diagnosis a. Ultrasonography for pregnancy at risk i. Polyhydramnios ii. IUGR iii. Lissencephaly iv. Microcephaly v. Mild ventriculomegaly vi. Absence of corpus callosum vii. Cardiac and other malformations b. Prenatal diagnosis by amniocentesis or CVS i. Indications a) Carrier parents with balanced chromosome rearrangements involving 17p13 b) Probably parents of all Miller-Dieker syndrome patients because of the small possibility of gonadal mosaicism in apparently de novo cases c) Normal relatives of unknown karyotype ii. Cytogenetic analysis a) High resolution analysis of chromosome 17 b) Molecular cytogenetic studies (FISH) 3. Management a. Supportive care b. Early infant intervention c. Anticonvulsants for seizures
REFERENCES Alvarado M, Bass HN, Caldwell S, et al.: Miller-Dieker syndrome: Detection of a cryptic chromosome translocation using in situ hybridization in a family with multiple affected offspring. Am J Dis Child 147:1291–1294, 1993. Cardoso C, Leventer RJ, Dowling JJ, et al.: Clinical and molecular basis of classical lissencephaly: mutations in the LIS1 gene (PAFAH1B1). Hum Mutat 19:4–15, 2002. Chitayat D, Toi A, Babul R, et al.: Omphalocele in Miller-Dieker syndrome: Expanding the phenotype. Am J Med Genet 69:293–298, 1997. De Rijk-van Andel JF, Arts WF, Barth PG, et al.: Diagnostic features and clinical signs of 21 patients with Lissencephaly type I. Dev Med Child Neurol 32:707–717, 1990. Dieker H, Edwards RH, ZuRhein G, et al.: The lisssencephaly syndrome. Birth Defects Original Article Series V(2):53–64, 1969. Dobyns WB, Stratton RF, Parke JT, et al.: Miller-Dieker syndrome: Lissencephaly and monosomy 17p. J Pediatr102:552–558, 1983. Dobyns WB, Stratton RF, Greenberg F: Syndromes with lissencephaly I: Miller-Dieker and Norman-Robert syndromes and isolated lissencephaly. Am J Med Genet 18:509–526, 1984. Dobyns WB, Pagon RA, Armstrong D, et al.: Diagnostic criteria for WalkerWarburg syndrome. Am J Med Genet 32:195–210, 1989. Dobyns WB, Curry CJR, Hoyme HE, et al.: Clinical and molecular diagnosis of Miller-Dieker syndrome. Am J Hum Genet 48:584–594, 1991. Dobyns WB, Elias ER, Newlin AC, et al.: Causal heterogeneity in isolated lissencephaly. Neurology 42:1375–1388, 1992. Dobyns WB, Reiner O, Carrozzo R, et al.: Lissencephaly. A human brain malformation associated with deletion of the LIS1 gene located at chromosome 17p13. J Am Med Assoc 270:2838–2842, 1993. Fukuyama Y, Osawa M, Suzuki H: Congenital progressive muscular dystrophy of the Fukuyama type-clinical, genetic and pathological considerations. Brain Dev 3:1–29, 1981.
MILLER-DIEKER SYNDROME Jones KL, Gilbert EF, Kaveggia EG, et al.: The Miller-Dieker syndrome. Pediatrics 66:277–281, 1980. Ledbetter SA, Kuwano A, Dobyns WB, et al.: Microdeletions of chromosome 17p13 as a cause of isolated lissencephaly. Am J Hum Genet 50:182–189, 1992. Miller JQ: Lissencephaly in 2 siblings. Neurology 13:841–850, 1963. Miny P, Holzgreve W, Horst J: Genetic factors in lissencephaly syndromes: a review. Child’s Nerv Syst 9:413–417, 1993. Norman MG, Roberts M, Sirois J, et al.: Lissencephaly. Can J Neurol Sci 3:39–46, 1976. Pilz DT, Quarrell OWJ: Syndromes with lissencephaly. J Med Genet 33:319–323, 1996. Pilz DT, Macha ME, Precht KS, et al.: Fluorescence in situ hybridization analysis with LIS1 specific probes reveals a high deletion mutation rate in isolated lissencephaly sequence. Genet Med 1:29–33, 1998.
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Pollin TI, Dobyns WB, Crowe CA, et al.: Risk of abnormal pregnancy outcome in carriers of balanced reciprocal translocations involving the MillerDieker syndrome (MDS) critical region in chromosome 17p13.3. Am J Med Genet 85:369–375, 1999. Santavuori P, Somer H, Sainio K, et al.: Muscle-eye-brain disease (MEB). Brain Dev 11:147–153, 1989. Stratton RF, Dobyns WB, Airhart SD, et al.: New chromosomal syndrome: MillerDieker syndrome and monosomy 17p13. Hum Genet 67:193–200, 1984. Toyo-oka K, Shionoya A, Gambello MJ, et al.: 14-3-3Ó is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome. Nat Genet 34:274–285, 2003. Van Zelderen-Bhola SL, Breslau-Siderius EJ, Beverstock GC, et al.: Prenatal and postnatal investigation of a case with Miller-Dieker syndrome due to a familial cryptic translocation t(17;20)(p13.3;q13.3) detected by fluorescence in situ hybridization. Prenat Diagn 17:173–179, 1997
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Fig. 1. A child with Miller-Dieker syndrome showing high forehead, frontal bossing, bilateral temporal narrowing, small nose with anteverted nares, prominent upper lip, micrognathia, and a surgically repaired omphalocele.
Fig. 2. A child with Miller-Dieker syndrome showing characteristic facial traits like the previous child. The MRI of the brain showed diffuse and complete type I lissencephaly. FISH revealed one chromosome 17 lacked a signal at 17p13 indicating the presence of a deletion.
Möbius Syndrome viii. Trauma ix. Misoprostol (a synthetic prostaglandin analogue used in the therapy of upper gastrointestinal ulceration or self-administered by the mothers in Brazil as an abortifacient) 2. An etiopathologic classification a. Type I (central lesion in the brainstem nuclei due to congenital origin) b. Type II (primary peripheral nerve involvement) c. Type III (central lesion in the brainstem nuclei due to an anoxic-infectious cause) d. Type IV (wasting of skeletal muscle tissue due to myopathic cause) 3. Possible etiologies a. A primary metameric defect in the brain-stem nuclei in the region of the tegmentum b. An ischemic process resulting from an interruption of the vascular supply of the brainstem and other structures during early fetal development
Möbius syndrome (MBS) is a rare congenital disorder characterized by complete or partial facial diplegia accompanied by other cranial nerve palsies and musculoskeletal anomalies.
GENETICS/BASIC DEFECTS 1. Multifactorial etiology a. The term “Möbius sequence” represents a pattern of multiple anomalies due to multiple etiologies, compared with the designation “syndrome” implies a single cause b. Usually a sporadic occurrence c. Genetic heterogeneity i. Familial cases usually without associated anomalies ii. Low incidence of familial cases with associated anomalies such as limb defects and mental retardation iii. Autosomal dominant inheritance a) Autosomal dominant Möbius syndrome has been linked to markers on 3q21-q22 in a large Dutch family b) A second gene for autosomal dominant Möbius syndrome is localized to chromosome 10q in a second large Dutch family iv. Autosomal recessive inheritance v. X-linked recessive inheritance d. Four genetic loci for MBS have been described to date i. MBS1 on chromosome 13q12.2-q13, based on the following observations: a) A reciprocal translocation of 13q12.2-q13 cosegregating with the disease in a three generation MBS family b) A MBS patient with a deletion of chromosome 13q12.2 ii. MBS2 on chromosome 3q21-q22 iii. MBS3 on chromosome 10q21 iv. MBS4 on chromosome 1p22, based on a) A t(1;11)(p22;p13) in a patient with Mobius syndrome b) A t(1;2)(p22.3;q21.1) in a patient with Mobius-like syndrome e. Ischemia: vascular disruption in the subclavian artery territory f. Teratogens i. Thalidomide ii. Alcohol iii. Benzodiazepines iv. Cocaine v. Ergotamine vi. Infections vii. Hyperthermia
CLINICAL FEATURES
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1. Congenital onset 2. Complete or partial facial diplegia (essential for the diagnosis of Möbius syndrome), often accompanied by other cranial nerve palsies a. Signs and symptoms i. Incomplete eyelid closure during sleep ii. Drooling iii. Difficulty in sucking iv. Inability to smile v. Lack of facial movement when crying (masklike facies) vi. Asymmetry of the angles of the mouth vii. Indistinct speech secondary to the inability to close the lips leading to labial sounds b. Involved cranial nerves i. Facial nerve (VII) palsy (all cases), resulting in mask-like facies and flattened facial expression ii. Abducens nerve (VI) palsy (75%), less commonly oculomotor (III) and trochlear (IV) nerve palsies, resulting in marked internal strabismus, lateral gaze paralysis, and ophthamoplegia iii. Hypoglossal nerve (VII) palsy (25%), leading to paralysis, hypoplasia, and atrophy of the tongue iv. Paresis of cranial nerves V (trigeminal), IX (glossopharyngeal), and X (vagus), leading to bulbar weakness (swallowing and speech difficulties due to velopharyngeal insufficiency) 3. Involvement of cerebellum, hypothalamus, and pituitary gland 4. Oculofacial abnormalities a. Mask-like facial appearance: may create profound difficulties in social interactions with other people,
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5.
6.
7. 8. 9.
10.
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especially strangers who are unfamiliar with the syndrome b. Epicanthal folds c. Ptosis d. Strabismus e. Nystagmus f. Micrognathia g. Tongue abnormalities i. A common anomaly ii. A small asymmetric tongue with irregular atrophic areas: characteristic of Möbius syndrome iii. Impaired motility and fasciculations h. At risk for caries and periodontal disease i. Impaired speech i. A severe and disabling condition ii. Factors affecting speech development a) Cognitive and language skills b) Hearing c) Communication ability d) Orofacial anatomy e) Oral motor function iii. Dysarthria caused by cranial nerve dysfunction, worsened by orofacial anomalies, mental retardation and autism Frequent occurrence of limb malformations a. Reduction malformation of limbs b. Hypoplasia to aplasia of digits c. Brachydactyly d. Syndactyly e. Ectrodactyly f. Talipes deformities (club foot) g. Clinodactyly h. Polydactyly i. Joint contractures Other musculoskeletal features a. Rib defects b. Klippel-Feil anomaly c. Aplasia of muscles Mental retardation (10%) Autistic behavior (30–40%) Association with other anomalies or syndromes a. Poland syndrome i. Hypoplasia/aplasia of pectoralis major muscle ii. Generally unilateral iii. Associated with mammary hypoplasia of the same side iv. Poland syndrome, Möbius syndrome, and Poland-Möbius syndrome may be a spectrum of the same condition b. Hyoglossia-hypodactyly c. Arthrogryposis multiplex congenita d. Dextrocardia e. Robin syndrome f. Corey-Fineman-Ziter syndrome (congenital non progressive myopathy with Möbius and Robin sequence) g. Kallmann syndrome (association with anosmia and hypogonadotropic hypogonadism) Several similar syndromes a. Oromandibular-limb hypogenesis syndrome i. Characteristic features a) Micrognathia
b) Cranial nerve palsies c) Limb anomalies d) Sometimes combined with aplasia of the pectoral muscle (Poland anomaly) ii. Entities included: a) Möbius syndrome b) Hanhart syndrome c) Hypoglossia–hypodactyly (aglossia/adactyly) d) Glossopalatinus ankylosis b. Terminal transverse defects with orofacial malformations i. Orofacial features a) Micrognathia b) Cleft palate c) Tongue anomalies d) Ear anomalies e) Dental anomalies ii. Limb malformations a) Syndactyly b) Clubfeet c) Toe deformities d) Symbrachydactyly e) Absent digits (ectrodactyly) f) Amputation-type defects of the limbs
DIAGNOSTIC INVESTIGATIONS 1. CT of the head: normal in most patients a. Medial deviation of the eyes b. Hypoplastic or dysplastic brainstem c. Hypoplastic cerebellum consistent with DandyWalker variant malformation d. Bilateral calcifications adjacent to the fourth ventricle floor at the level of the VIth cranial nerve nuclei 2. Autopsies in patients with normal CT studies a. Focal necrosis and calcifications b. Hypoplasia to agenesis of the respective cranial nerve nuclei 3. MRI of the brain a. Calcification in the pons within the abducens nuclei b. Hypoplasia of the brainstem c. Hypoplasia of the cerebellum 4. Neurophysiological studies: may be helpful in locating the site of the lesion a. Abnormal nerve conduction studies b. Electromyography (EMG) of facial muscles i. Reveal multifocal chronic neurogenic changes ii. Indicate a brain stem process predominantly affecting the facial nuclei and their internuclear connections rather than a supranuclear or muscular site of involvement c. Abnormal brain stem evoked potential
GENETIC COUNSELING 1. Recurrence risk a. Lower recurrence risk (2%) for Möbius syndrome with congenital 6th and 7th nerve paralysis with skeletal defects b. Higher recurrence risk (25–30%) for Möbius syndrome with isolated facial palsy, deafness, ophthalmoplegia, and digital contractures without skeletal defects
MÖBIUS SYNDROME
c. Autosomal recessive inheritance i. Patient’s sib: 25% ii. Patient’s offspring: not increased unless the spouse is a carrier d. Autosomal dominant inheritance i. Patient’s sib: 50% if a parent is affected; otherwise not increased ii. Patient’s offspring: 50% e. X-linked recessive inheritance i. Patient’s sib: 50% affected in the brothers if the mother is a carrier; otherwise not increased ii. Patient’s offspring: 50% carrier risk in the daughters 2. Prenatal diagnosis possible in the Möbius-Poland spectrum 3. Management a. Supportive care b. Intervention programs i. Physical therapy useful for congenital orthopedic problems or postoperative orthopedic intervention ii. Occupational therapy to help activities of daily living, especially in patients with absent hands or digits iii. Speech therapy for patients affected by severe facial nerve paralysis or lower cranial nerve deficit c. Dental hygiene d. Treat corneal ulcerations or abrasions secondary to exposure keratitis and conjunctivitis secondary to incomplete eyelid closure e. Splints, prostheses for congenital limb anomalies f. Surgical care i. Clubfoot ii. Tracheotomy to support the airway and permit tracheobronchial clearing when airway functions are compromised iii. Feeding gastrostomy tube required in some cases iv. Ocular surgical procedures in some cases
REFERENCES Abramson DL, Cohen MM, Jr., Mulliken JB: Mobius syndrome: classification and grading system. Plast Reconstr Surg 102:961–967, 1998. Baraitser M: Genetics of Möbius syndrome. J Med Genet 14:415–417, 1977. Bavinck JN, Weaver DD: Subclavian artery supply disruption sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil, and Mobius anomalies. Am J Med Genet 23:903–918, 1986. Beerbower J, Chakeres DW, Larsen PD, et al.: Radiographic findings in Moebius and Moebius-like syndromes. AJNR Am J Neuroradiol 7:364–365, 1986. Blanchard K, Winikoff B, Ellertson C: Use of misoprostol during pregnancy and Mobius’ syndrome in infants. N Engl J Med 339:1553–1554, 1998. Bouwes-Bavinck JN, Weaver DD: Subclavian artery supply disruption sequence: hypothesis for a vascular aetiology for Poland, Klippel-Feil, and Möbius anomalies. Am J Med Genet 23:903–918, 1986. Calder AJ, Keane J, Cole J, et al.: Facial expression recognition by people with Mobius syndrome. Cognitive Neuropsychol 17:73–87, 2000. Charles SS, Diario FJ, Grunnet MJ: Möbius sequence: further in vivo support for the subclavian artery supply disruption sequence. Am J Med Genet 47:289–293, 1993. Collins DL, Schimke RN: Moebius syndrome in a child and extremity defect in her father. Clin Genet 22:312–314, 1982. Criado GR, Aytes AP: Mobius sequence, hypogenitalism, cerebral, and skeletal malformations in two brothers. Am J Med Genet 86:492–496, 1999. Cronemberger MF, de Castro Moreira JB, Brunoni D, et al.: Ocular and clinical manifestations of Mobius’ syndrome. J Pediatr Ophthalmol Strabismus 38:156–162, 2001.
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D’Cruz OF, Swisher CN, Jaradeh S, et al.: Mobius syndrome: evidence for a vascular etiology. J Child Neurol 8:260–265, 1993. Donahue SP, Wenger SL, Steele MW, et al.: Broad-spectrum Mobius syndrome associated with a 1;11 chromosome translocation. Ophthalmic Paediatr Genet 14:17–21, 1993. Gadoth N, Biedner B, Torok G: Mobius syndrome and Poland anomaly: case report and review of the literature. J Pediatr Ophthalmol Strabismus 16:374–376, 1979. Ghabrial R, Versace P, Kourt G, et al.: Mobius’ syndrome: features and etiology. J Pediatr Ophthalmol Strabismus 35:304–311; quiz 327–308, 1998. Gillberg C, Steffenburg S: Autistic behaviour in Möbius syndrome. Acta Pediatr Scand 78:314–316, 1989. Jaradeh S, D’Cruz O, Howard JF, et al.: Möbius syndrome: electrophysiologic studies in seven cases. Muscle Nerve 19:1148–1153, 1996. Johansson M, Wentz E, Fernell E, et al.: Autistic spectrum disorders in Mobius sequence: a comprehensive study of 25 individuals. Dev Med Child Neurol 43:338–345, 2001. Kremer H, Kuyt LP, van den Helm B, et al.: Localization of a gene for Mobius syndrome to chromosome 3q by linkage analysis in a Dutch family. Hum Mol Genet 5:1367–1371, 1996. Kuhn MJ, Clark HB, Morales A, et al.: Group III Moebius syndrome: CT and MR findings. Am J Neuroradiol 11:903–904, 1990. Kumar D: Moebius syndrome. J Med Genet 27:122–126, 1990. Legum C, Godel V, Nemet P: Heterogeneity and pleiotropism in the Möbius syndrome. Clin Genet 20:254–259, 1981. Lengyel D, Zaunbauer W, Keller E, et al.: Mobius syndrome: MRI findings in three cases. J Pediatr Ophthalmol Strabismus 37:305–308, 2000. MacDermot KD, Winter RM, Taylor D, et al.: Oculofacial bulbar palsy in mother and son: review of 26 reports of familial transmission within the “Mobius spectrum of defects”. J Med Genet 28:18–26, 1991. Meyerson MD, Foushee DR: Speech, language and hearing in Moebius syndrome: a study of 22 patients. Dev Med Child Neurol 20:357–365, 1978. Möbius PJ: Ueder angeborenen doppelseitge abducens-facialis lahmung. Munch med wochenschr 35:91–94, 1888. Nishikawa M, Ichiyama T, Hayashi T, et al.: Mobius-like syndrome associated with a 1;2 chromosome translocation. Clin Genet 51:122–123, 1997. Palmer CA: Möbius syndrome. Emedicine, 2001. Emedicine, 2001. http://www.emedicine,com Pastuszak AL, Schuler L, Speck-Martins CE: Use of misoprostol during pregnancy and Möbius syndrome in infants. N Engl J Med 338:1881–1885, 1998. Pedraza S, Gamez J, Rovira A, et al.: MRI findings in Möbius Syndrome: Correlation with clinical features. Neurology 55:1058–1060, 2000. Sherer DM, Spafford P: Prenatal sonographic evidence supporting an in utero developmental etiology of Mobius sequence. Am J Perinatol 11:157–159, 1994. Slee JJ, Smart RD, Viljoen DL: Deletion of chromosome 13 in Moebius syndrome. J Med Genet 28:413–414, 1991. Strömland K, Sjögreen L, Miller M, et al.: Möbius sequence-a Swedish multidiscipline study. Eur J Paediatr Neurol 6:35–45, 2002. Sugarman GI, Stark HH: Möbius syndrome with Poland’s anomaly. J Med Genet 10:192–196, 1973. Terzis JK, Noah EM: Mobius and Mobius-like patients: etiology, diagnosis, and treatment options. Clin Plast Surg 29:497–514, 2002. Terzis JK, Noah EM: Dynamic restoration in Mobius and Mobius-like patients. Plast Reconstr Surg 111:40–55, 2003. Towfighi J, Marks K, Palmer E, et al.: Moebius syndrome. Neuropathologic observations. Acta Neuropathol 48:11–17, 1979. Van Der Zwaag B, Verzijl HT, Beltran-Valero De Bernabe D, et al.: Mutation analysis in the candidate Mobius syndrome genes PGT and GATA2 on chromosome 3 and EGR2 on chromosome 10. J Med Genet 39:E30, 2002. Verzijl HT, van den Helm B, Veldman B, et al.: A second gene for autosomal dominant Mobius syndrome is localized to chromosome 10q, in a Dutch family. Am J Hum Genet 65:752–756, 1999. Verzijl HT, van der Zwaag B, Cruysberg JR, et al.: Mobius syndrome redefined: a syndrome of rhombencephalic maldevelopment. Neurology 61:327–333, 2003. Wilmore HP, Smith MJ, Wilcox SA, et al.: SOX14 is a candidate gene for limb defects associated with BPES and Mobius syndrome. Hum Genet 106:269–276, 2000. Ziter FA, Wiser WC, Robinson A: Three-generation pedigree of a Mobius syndrome variant with chromosome translocation. Arch Neurol 34:437– 442, 1977.
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Fig. 2. A child with Möbius syndrome showing mask-like facies, epicanthal folds, strabismus, and limb defect.
Fig. 1. A child with Möbius syndrome showing mask-like facies, epicanthal folds, strabismus, and facial palsy.
Fig. 3. A child with Möbius-Poland syndrome showing mask-like facies, strabismus, and ptosis, associated with right arm defect and absence of right pectoralis major muscle.
MÖBIUS SYNDROME
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Fig. 4. An adult with Möbius syndrome showing mask-like facies, ptosis, strabismus, and digital anomaly.
Fig. 6. Three children with Poland anomaly showing unilateral absence of pectoralis major muscle associated with ipsilateral limb defect.
Fig. 5. An adult with Möbius-Poland syndrome showing mask-like facies, ptosis, absence of left pectoralis major muscle and limb defect, which were illustrated in the patient”s earlier radiographs.
Mucolipidosis II (I-Cell Disease) f. Generalized hypotonia g. Ocular abnormalities i. Corneal clouding ii. Glaucoma iii. Megalocornea 4. Older patients a. Predominant features i. Skeletal deformities (dysostosis multiplex) ii. Progressive failure to thrive iii. Developmental delay with variable mental retardation b. Other features i. Short stature ii. Craniosynostosis iii. Progressive stiffness of all joints, first apparent in the shoulders iv. Variable hepatosplenomegaly v. Congestive heart failure vi. Recurrent pulmonary infections 5. Natural history a. Slowly progressive course b. Fatal outcome usually before 4 years of age
I-cell disease, or mucolipidosis II, is a rare inherited storage disorder of lysosomal enzyme localization.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. N-acetylglucosamine-1-phosphotransferase a. An enzyme that transfers phosphate groups onto oligosaccharide units of lysosomal enzyme precursors b. Deficient in mucolipidosis II (and also in mucolipidosis III) c. Consequences of the enzyme deficiency i. Not generating common phosphomannosyl recognition marker of acid hydrolases ii. The enzymes not targeting to the lysosomes iii. Secretion of the enzymes into the extracellular space (high activities found in the serum of the patients) iv. Considerable reduction of the enzyme levels inside the cells (fibroblasts) d. The term “I-cell disease”: derived from the observation that fibroblasts from affected individuals show dense inclusions filled with storage material
DIAGNOSTIC INVESTIGATIONS
CLINICAL FEATURES 1. A wide range of inter- and intrafamilial variability a. Age of onset: present at birth or appear in the first few months of life b. Organ manifestation c. Radiological findings d. Unusual findings in some patients i. Pericardial effusion ii. Profound brain atrophy 2. Features evident in affected newborn a. Coarse facial (gargoyle-like) features i. Puffy eyelids with slight exophthalmia ii. Excessive prominence of the epicanthal folds iii. Depressed nasal bridge iv. Full cheeks exhibiting multiple fine telangiectasia v. Gingival hyperplasia and alveolar enlargement with buried teeth vi. Thick tongue b. Restricted joint mobility c. A tight, thickened skin 3. Early clinical features a. Low birth weight b. Congenital hip dislocation c. Pes equinovarus d. Joint contractures e. Inguinal hernias 660
1. Elevated activities of multiple lysosomal enzymes in serum or plasma, including the following enzymes: a. Arylsulphatase A b. α-mannosidase c. β-glucuronidase d. β-hexosaminidase 2. Deficient enzyme activities in cultured fibroblasts, including the following enzymes: a. β-galactosidase b. Arylsulfatase A c. β-hexosaminidase d. β-glucuronidase e. α-L-iduronidase 3. Primary biochemical defect: decreased or absent Nacetylglucosamine-1-phosphotransferase in cultured fibroblasts and leukocytes 4. Normal excretion of urinary mucopolysaccharide 5. Radiography a. Fetal radiography i. Diffuse decrease in bone mineralization ii. A coarse, lacy, trabecular pattern iii. Overall shortening and under-modelling of the long bones iv. Subperiosteal bone deficiency in the diaphysis giving the appearance of periosteal new bone (cloaking) v. Retarded ossification of the vertebral bodies vi. Hypoplasia of the anterior superior aspect of the upper lumbar vertebral bodies
MUCOLIPIDOSIS II (I-CELL DISEASE)
6. 7. 8. 9.
vii. Broad ribs viii. Abnormal pelvis with squared iliac wings and flattened acetabular roofs ix. Brachyphalangy x. Mild tapering of the proximal ends of the metacarpals xi. A small irregular calcaneal “ossification center” b. Radiographic findings in early infancy i. Diffuse demineralization ii. Metaphyseal cupping and fraying iii. Excessive periosteal new bone formation iv. Diaphyseal expansion of the long tubular bones v. Irregular trabeculation without differentiation between the cortical and medullary zones vi. Mild anteriosuperior hypoplasia of he upper lumbar bodies vii. Pelvic dysplasia viii. Occasional punctate calcifications and bone defects following intrauterine calcific deposits ix. Skeletal changes in the neonatal I-cell disease resembling those of rickets, osteomyelitis and hyperparathyroidism c. Dysostosis multiplex i. Neurocranium a) Long and thick b) Thickened and sclerotic cranial base ii. Widened ribs iii. Kyphoscoliosis iv. Anterior beaking and wedging of the vertebral bodies v. Lumbar gibbus deformity vi. Cloaking appearance of the long tubular bones vii. Proximal pointing of the metacarpals viii. Bullet-shaped phalanges ix. Claw hand deformities Slit lamp examination to demonstrate corneal clouding Echocardiography for valve thickening and valve insufficiency MRI or CT scan: mild brain atrophy in most cases Light microscopy and electron microscopy a. Inclusion bodies in peripheral lymphocytes in blood smear b. An increased number of empty, large vacuoles that may fill the cytoplasm of cultured skin fibroblast cells c. Presence of numerous intracytoplasmic inclusions in cells of mesenchymal origin i. Membrane-bound vacuoles filled with fibrillogranular material ii. Appear to contain a variety of lipids, mucopolysaccharides, and oligosaccharides d. Cytoplasmic inclusions also observed in various types of cells in fetal I-cell disease
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not surviving to reproductive age 2. Prenatal diagnosis a. Ultrasonography
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i. Intrauterine growth retardation ii. Short tubular bones b. Measuring the levels of lysosomal enzymes (elevated activity of several lysosomal hydrolases) in cell-free amniotic fluid or cultured amniocytes c. Assay of the transferase activity (deficient) in cultured CVS cells and amniocytes d. Electron microscopy of chorionic villus biopsy tissue for detection of inclusion bodies 3. Management a. Supportive care b. Bone marrow transplant from an HLA-identical carrier sibling i. Neurodevelopmental gains ii. Prevention of cardiopulmonary complications iii. No alteration to the course of musculoskeletal disease
REFERENCES Abe K, Matsuda I, Arashima S, et al.: Ultrastructural studies in fetal I-cell disease. Pediatr Res 10:669–676, 1976. Aula P, Rapola J, Autio S, et al.: Prenatal diagnosis and fetal pathology of I-cell disease (mucolipidosis type II). J Pediatr 87:221–226, 1975. Aynaci FM, Cakir E, Aynaci O: A case of I-cell disease (mucolipidosis II) presenting with craniosynostosis. Childs Nerv Syst 18:707–711, 2002. Babcock DS, Bove KE, Hug G, et al.: Fetal mucolipidosis II (I-cell disease): radiologic and pathologic correlation. Pediatr Radiol 16:32–39, 1986. Beck M, Barone R, Hoffmann R, et al.: Inter- and intrafamilial variability in mucolipidosis II (I-cell disease). Clin Genet 47:191–199, 1995. Ben-Yoseph Y, Mitchell DA, Nadler HL: First trimester prenatal evaluation for I-cell disease by N-acetyl-glucosamine 1-phosphotransferase assay. Clin Genet 33:38–43, 1988. Besley GTN, Broadhead DM, Nevin NC, et al.: Prenatal diagnosis of mucolipidosis II by early amniocentesis. Lancet 335:1164–1165, 1990. Blank E, Linder D: I-cell disease (mucolipidosis II): a lysosomopathy. Pediatrics 54:797–805, 1974. Carey WF, Richardson JM, Fong BA, et al.: Prenatal diagnosis of mucolipidosis II. Electron microscopy and biochemical evaluation. Prenat Diagn 19:252–256, 1999. Cipolloni C, Boldrini A, Donti E, et al.: Neonatal mucolipidosis II (I-cell disease): clinical, radiological and biochemical studies in a case. Helv Paediatr Acta 35:85–95, 1980. Grewal S, Shapiro E, Braunlin E, et al.: Continued neurocognitive development and prevention of cardiopulmonary complications after successful BMT for I-cell disease: a long-term follow-up report. Bone Marrow Transplantation 32:957–960, 2003. Lee W, O’Donnell D: Severe gingival hyperplasia in a child with I-cell disease. Int J Paediatr Dent 13:41–45, 2003. Lees C, Homfray T, Nicolaides KH: Prenatal ultrasound diagnosis of Leroy I cell disease. Ultrasound Obstet Gynecol 18:275–276, 2001. Leroy JG, Spranger JW: I-cell disease. N Engl J Med 283:598–599, 1970. Leroy JG, Spranger JW, Feingold M, et al.: I-cell disease: a clinical picture. J Pediatr 79:360–365, 1971. Leroy JG, Ho MW, MacBrinn MC, et al.: I-cell disease: biochemical studies. Pediatr Res 6:752–757, 1972. Leroy JG, Martin JJ: Mucolipidosis II (I-cell disease): present status of knowledge. Birth Defects Orig Artic Ser 11:283–293, 1975. Patriquin HB, Kaplan P, Kind HP, et al.: Neonatal mucolipidosis II (I-cell disease): clinical and radiologic features in three cases. AJR Am J Roentgenol 129:37–43, 1977. Poenaru L, Castelnau L, Dumez Y, et al.: First-trimester prenatal diagnosis of mucolipidosis II (I-cell disease) by chorionic biopsy. Am J Hum Genet 36:1379–1385, 1984. Rapola J, Autio S, Aula P, et al.: Lymphotic inclusions in I-cell disease. J Pediatr 85:88–90, 1974. Sensenbrenner JA: Mucolipidosis II (I-cell disease). Birth Defects Orig Artic Ser 10:470–477, 1974. Sprigz RA, Doughty RA, Spackman TJ, et al.: Neonatal presentation of I-cell disease. J Pediatr 93:954–958, 1978.
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Fig. 1. An 8-year-old girl with I-cell disease. She had severe growth retardation (67 cm), coarse facial features, claw hands, severe skeletal dysplasia, marked gingival hypertrophy, cardiomegaly with marked thickening and deformity of mitral and tricuspid valves, and bilateral duplication of ureters. Histological investigations showed foam cell infiltration in renal glomeruli, splenic corpuscles, atrioventricular valves, and thymus.
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Fig. 2. Radiographs showed generalized dysplastic changes in the chest, upper and lower extremities. The ribs were extremely wide (A). Some vertebral bodies were slightly hook-shaped. The pedicles were long and there was slight gibbus. Mid-shafts of the humerus, radius, and ulna were wide and the neck of the humerus in varus position (B). Widening of the mid-shafts of the lower extremities was less marked than in the upper extremities (C). Metacarpals and phalanges were wide but distal phalanges were short and thin (D). Metacarpal bones pointed proximally. Carpal bones were hypoplastic.
Fig. 4. Foam cells were present in the renal glomeruli, mitral valve, and chondrocytes of cartilage.
Fig. 3. Mitral valve was thickened and deformed.
Fig. 5. The foamy material was reactive with colloidal iron stain (renal glomeruli) and sympathetic ganglion (Alcian blue stain), indicating the presence of mucopolysaccharide.
Mucolipidosis III (Pseudo-Hurler Polydystrophy) 7. Orthopedic problems a. Stiffness of the hands progressing to claw hand deformities by 6 years of age in all patients b. Slow progression of the skeletal dysplasia during school years, the resulting physical disability most apparent in the hands, hips, elbows, and shoulders c. Generalized joint stiffness (limited joint mobility) d. Spine abnormalities i. Kyphosis ii. Lordosis iii. Gibbus e. Hip pain f. Hip dysplasia g. Carpal tunnel syndrome further complicates the claw hand deformities h. Recurrent intermittent triggering of the fingers 8. Natural course of the illness: survive beyond the 5–6th decade
In 1966, Maroteaux and Lamy first described four girls with pseudo-Hurler polydystrophy, a condition milder in severity than the Hurler syndrome and similar to the Scheie syndrome but without hepatosplenomegaly, cloudy cornea or mucopolysacchariduria. In 1970, Spranger and Wiedemann designated pseudo-Hurler polydystrophy as mucolipidosis III because of Hurler-like features and vacuolated bone marrow cells.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Basic defect a. Resulting from deficiency of the enzyme UDP-Nacetylglucosamine: lysosomal protein precursor N-acetyl glucosamine L-phosphate transferase (C1cNAcPT) (mucolipidosis II also caused by deficiency of the same enzyme) b. Genetic complementation analysis of cultured fibroblasts derived from patients with mucolipidosis III identified complementation groups A, B, and C c. Inability to form the correct recognition marker on lysosomal enzymes resulting in a marked intracellular deficiency of most lysosomal enzymes in various tissues, impairment of many lysosomal catabolic processes, and concomitant increase in lysosomal enzymes in plasma 3. Recent finding of molecular basis for mucolipidosis IIIC (variant pseudo-Hurler polydystrophy): a mutation, ins C at codon 167, in the γ subunit of the C1cNAcPT in mucolipidosis IIIC
DIAGNOSTIC INVESTIGATIONS
CLINICAL FEATURES 1. Onset of disease a. Usually appear at 2–4 years of age b. Progress slowly c. First sign: stiffness in the hands and shoulders 2. Short stature 3. Mild Hurler-like facial dysmorphism, usually apparent after age 6 years 4. Ophthalmologic abnormalities a. Constant ocular features i. Corneal opacities consisting of fine, peripheral infiltrates ii. Hyperoptic astigmatism b. Optic nerve head swelling c. Surface wrinkling maculopathy d. Retinal vascular tortuosity 5. Mild mental retardation 6. Valvular heart disease 664
1. Radiography showing dysostosis multiplex a. Pelvis i. Flaring of the iliac wings ii. Constriction of the iliac bodies iii. Oblique acetabular roofs b. Vertebral bodies i. Moderately flattened ii. Presenting as a roughly ovoid contour iii. Underdevelopment of posterior parts in the dorsal spine iv. Hypoplasia of anterior third in the lumbar spine v. Irregular endplates vi. Scoliosis secondary to vertebral abnormalities c. Tubular bones i. Shortened and wide ii. The most striking changes observed in the proximal femur a) A small, flattened and irregular epiphysis b) Coxa valga deformity of the neck c) Subluxation iii. Hands a) Short first metacarpals b) Mild proximal pointing of the metacarpals c) Mild to moderate claw-hand deformities d) Relatively wide diaphysis of some phalanges iv. Retarded bone age d. Skull: normal despite the presence of craniostenosis in some patients 2. Nerve conduction test and electromyography to confirm the carpal tunnel syndrome 3. Slit lamp examination for cornea opacification
MUCOLIPIDOSIS III (PSEUDO-HURLER POLYDYSTROPHY)
4. Normal urinary excretion of acid mucopolysaccharides 5. Presence of cytoplasmic inclusions within cultured fibroblasts as demonstrated by phase-contrast or darkfield microscopy 6. Bone marrow: large, vacuolated plasmocytes 7. Biochemical studies a. Normal activity of multiple lysosomal enzymes in white blood cells b. A marked rise of multiple lysosomal enzymes in serum c. Low levels of multiple lysosomal enzymes in cultured fibroblast cells d. Abnormal radioactive sulfate kinetics (accumulations in cultured fibroblasts of radioactive sulfate several times that of normal fibroblasts) 8. Molecular analysis for a mutation, ins C at codon 167, in the γ subunit of the G1NAcPT in mucolipidosis IIIC
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased unless the spouse is a carrier 2. Prenatal diagnosis a. Diagnosis confirmed by markedly reduced lysosomal enzyme activities in cultured chorionic villi b. Identification of the disease-causing mutation in fetal DNA in newly recognized large BedouinMoslem kindred, allowing prenatal diagnosis, carrier detection, and identification of couples at risk 3. Management a. Physiotherapy b. Padded insoles for clawing of toes c. Carpal tunnel decompression for the median nerve entrapment d. Pelvic osteotomy for severe hip dysplasia
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REFERENCES Falik-Zaccai TC, Zeigler M, Bargal R, et al.: Mucolipidosis III type C: firsttrimester biochemical and molecular prenatal diagnosis. Prenat Diagn 23:211–214, 2003. Freisinger P, Padovani JC, Maroteaux P: An atypical form of mucolipidosis III. J Med Genet 29:834–836, 1992. Herd JK, Dvorak AD, Wiltse HE, et al.: Mucolipidosis type III. Multiple elevated serum and urine enzyme activities. Am J Dis Child 132:1181–1186, 1978. Hetherington C, Harris NJ, Smith TW: Orthopaedic management in four cases of mucolipidosis type III. J R Soc Med 92:244–246, 1999. Honey NK, Mueller OT, Little LE, et al.: Mucolipidosis III is genetically heterogeneous. Proc Natl Acad Sci USA 79:7420–7424, 1982. Kelly TE, Thomas GH, Taylor HA, et al.: Mucolipidosis III: clinical and laboratory findings. Birth Defects Orig Artic Ser 11:295–299, 1975. Kelly TE, Thomas GH, Taylor HA Jr, et al.: Mucolipidosis III (pseudo-Hurler polydystrophy): Clinical and laboratory studies in a series of 12 patients. Johns Hopkins Med J 137:156–175, 1975. Little LE, Mueller OT, Honey NK, et al.: Heterogeneity of N-acetylglucosamine 1-phosphotransferase within mucolipidosis III. J Biol Chem 261:733–738, 1986. Maroteaux P, Lamy M: La pseudo-polydystrophie de Hurler. Presse Med 74:2889–2892, 1966. Melhem R, Dorst JP, Scott CI Jr, et al.: Roentgen findings in mucolipidosis III (Pseudo-Hurler polydystrophy). Radiology 106:153–160, 1973. Mueller OT, Honey NK, Little LE, et al.: Mucolipidosis II and III. The genetic relationships between two disorders of lysosomal enzyme biosynthesis. J Clin Invest 72:1016–1023, 1983. Raas-Rothschild A, Cormier-Daire V, Bao M, et al.: Molecular basis for variant pseudo-Hurler polydystrophy (mucolipidosis IIIC). J Clin Invest 105:673–681, 2000. Robinow M: Mucolipidosis III. Birth Defects Orig Artic Ser 10:267–273, 1974. Robinson C, Baker N, Noble J, et al.: The osteodystrophy of mucolipidosis type III and the effects of intravenous pamidronate treatment. J Inherit Metab Dis 25:681–693, 2002. Spranger JW, Wiedemann HR: The genetic mucolipidoses. Diagnosis and differential diagnosis. Humangenetik 9:113–139, 1970. Traboulsi EI, Maumenee IH: Ophthalmologic findings in mucolipidosis III (pseudo-Hurler polydystrophy). Am J Ophthalmol 102:592–597, 1986. Tylki-Szymanska A, Czartoryska B, Groener JE, et al.: Clinical variability in mucolipidosis III (pseudo-Hurler polydystrophy). Am J Med Genet 108:214–218, 2002. Umehara F, Matsumoto W, Kuriyama M, et al.: Mucolipidosis III (pseudoHurler polydystrophy); clinical studies in aged patients in one family. J Neurol Sci 146:167–172, 1997.
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Fig. 1. Patient 1 (9-year-old boy) with mucolipidosis III showing short stature, mild coarse facial features, flexion contractures of knees, hips, elbows, wrists, and fingers. Fibroblast lysosomal acid hydrolase study revealed β-galactosidase o.o6 (control: 0.36 “moles/hr/mg protein), β-glucuronidase 0.05 (0.21), β-glucosaminidase 0.03 (3.9), α-L-iduronidase 0.12 (0.87), and aryl-sulfatase A 0.10 (0.67).
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Fig. 2. Radiographs of patient 1. Lateral lumbar spines showed severe hypoplasia with characteristic “beaked” configuration along their inferior aspects. Iliac bones were narrow and the basilar portions were hypoplastic with slanting acetabular roofs. Coxa valga deformity was present. Mild claw hand deformities with retarded bone age were evident.
Fig. 3. Patient 2 (sister of the patient 1) at age 7 years and 6 months showing similar clinical findings.
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MUCOLIPIDOSIS III (PSEUDO-HURLER POLYDYSTROPHY)
Fig. 4. Radiographs of patient 2 showing similar radiographic findings.
Fig. 5. Two sisters (ages 10 years and 9 years) with mucolipidosis III showing developing delay, coarse facial features, claw hands, and more severe joint contractures. Radiographs (not shown) revealed bullet-shaped proximal phalanges, small carpal bones, and misshapen femoral heads.
Mucopolysaccharidosis I (MPS I) (α-L-Iduronidase Deficiency): Hurler (MPS I-H), Hurler-Scheie (MPS I-H/S), and Scheie (MPS I-S) Syndromes b. Alleles associated with severe phenotype i. Two common severe mutations (W402X and Q70X) always confer a severe phenotype whether present in a homozygous state or in a compound heterozygous state ii. Additional mutations (474-2a-g, A327P, P533R, A75T, L218P) c. Alleles associated with mild phenotype i. 678-7a-g ii. R89Q 5. Pathophysiology a. Underlying molecular defect leads to a loss or marked reduction in α-L-iduronidase, a lysosomal enzyme involved in the degradation of glycosaminoglycans heparan sulfate and dermatan sulfate b. Because of the enzyme deficiency, excessive accumulation of acid mucopolysaccharides (glycosaminoglycans) in the tissue occurs, leading to wide effect on various systems and remarkable changes in the morphogenesis
Mucopolysaccharidosis I consists of three clinical entities with varying degree of clinical manifestations, all due to the same lysosomal enzyme deficiency, α-L-iduronidase. Hurler (MPS I-H) and Scheie (MPS I-S) syndromes represent phenotypes at the two ends of the clinical spectrum; the HurlerScheie syndrome (MPS I-H/S) represents a phenotype of intermediate clinical severity. In most instances, the subtype of MPS I can only be assigned on the basis of clinical criteria, including the rate of progression of symptoms. The incidences for MPS I-H, MPS I-H/S, and MPS I-S are estimated to be 1/76,000–1/144,000, 1/280,000, and 1/840,000–1/1,300,000 live births, respectively.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. The IDUA gene a. Localized to chromosome 4p16.3, close to the Huntington disease gene b. Spans 19 kb including 14 exons 3. Caused by mutations in the α-L-iduronidase (IDUA) gene a. Two major alleles (W402X and Q70X) and a minor allele (P533R) accounting for over half the MPS I alleles in the Caucasian population b. No functional enzymes produced by above mentioned alleles, giving rise to the severe form of α-Liduronidase deficiency (MPS I-H) c. Limited mutations expected to cause the attenuated clinical phenotypes of MPS I-S or MPS I-H/S d. One of a mutation resulting in Scheie syndrome is a base substitution in intron 7 that creates a new splice site and produces a frameshift. Since the old splice site is not obliterated, some normal enzyme still can be made to overcome the worst features of MPS I e. Most other alleles that lead to MPS I-S or MPS I-H/S carry missense mutations f. In the Japanese population studied, MPS I-H/S results from compound heterozygosity of two mutations (704ins5 and R89Q), which, in homozygous form, would give rise to MPS I-H and MPS I-S, respectively 4. Genotype–phenotype correlations a. General principle i. Any combination of two severe alleles leads to severe MPSI. A severe allele is one that produces the severe phenotype in either the homozygous state or compound heterozygous state ii. Intermediate and mild MPSI: usually associated with one severe allele and another allele that permits production of some residual enzyme activity
CLINICAL FEATURES
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1. Hurler syndrome (MPS I-H) a. General clinical characteristics i. The prototype of MPS representing the severe end of clinical spectrum ii. A progressive disorder with multiple organ and tissue involvement, leading to death in childhood iii. Normal phenotype at birth and in early infancy but deteriorates progressively afterward iv. Diagnosis usually made between 4–18 months of age v. Short stature (linear growth stops at 2–3 years of age) vi. Developmental delay by age 12–24 months, with a maximum functional age at the level of 2–4 years, followed by progressive mental deterioration b. Coarse facial features (one of the earliest signs) i. Ocular hypertelorism ii. Prominent eyes iii. Bushy eyebrows iv. Depressed nasal bridge v. Wide nostrils vi. Large and thickened lips vii. Large tongue viii. Hypertrophy of the gum and the bony alveolar ridge
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MPS I (HURLER-SCHEIE SYNDROME)
c. Other craniofacial features i. A large scaphocephalic head with frontal bossing ii. Communicating hydrocephalus common after age 2–3 years. Shunting procedures may be beneficial for relieving increased intracranial pressure for some children iii. Noisy breathing with persistent nasal discharge (chronic rhinorrhea) iv. Upper respiratory and ear infections d. Ophthalmologic features i. Progressive clouding of the cornea (the hallmark of the syndrome) beginning at the first year of life, leading to impaired vision ii. Open-angle glaucoma iii. Retinal degeneration resulting in decreased peripheral vision iv. Night blindness e. Auditory features i. Frequent sensorineural or mixed deafness ii. Contributing factors: a) Frequent middle ear infection from Eustachian tube dysfunction, caused by storage of glycosaminoglycans within the oropharynx b) Dysostosis of the ossicles of the middle ear c) Scarring of the tympanic membrane d) Damage to the eighth nerve f. Cardiovascular features i. Cardiac valvular disease resulting from storage of mucopolysaccharide in the mitral, aortic, tricuspid, or pulmonary valves, leading to congestive heart failure ii. Thickened coronary artery valves, leading to angina pectoris and myocardial infarction iii. Possible fatal cardiomyopathy as a presenting feature for some MPS I infants less than 1 year old. Endocardial fibroelastosis has been noted postmortem in these patients g. Gastrointestinal features i. Protuberant abdomen ii. Progressive hepatosplenomegaly h. Skeletal abnormalities: dysostosis multiplex i. Short neck ii. Characteristic kyphoscoliosis when on attempt to sit iii. Ultimate frank gibbus deformity iv. Stiff joints with limited mobility v. Claw hands (flexed stubby fingers and broad hands) i. Connective tissue abnormalities i. Inguinal and umbilical hernias: common findings and usually present at birth ii. Thick skin j. Prognosis i. Bedridden before the end of the juvenile period ii. Early demise prior to 10 years of age iii. Usual causes of death a) Obstructive airway disease b) Respiratory infection c) Cardiac complications
2. Scheie syndrome (MPS I-S) a. The mildest form of MPS I b. Normal stature c. Normal intelligence d. Onset of significant signs usually after 5 years e. Diagnosis commonly made between 10 and 20 years of age f. Coarse facial features g. Deafness in some patients h. Joint stiffness i. Claw hands ii. Stiff painful foot i. Carpal-tunnel syndrome j. Pes cavus k. Genu valgum l. Ocular manifestations i. Corneal clouding ii. Glaucoma iii. Retinal degeneration m. Aortic valvular disease (stenosis and regurgitation due to mucopolysaccharide deposits in the valves and chordae tendineae) n. Obstructive airway disease with sleep apnea in some patients o. Mild hepatosplenomegaly p. Mild dysostosis multiplex q. Less common pachymeningitis cervicalis (compression of the cervical cord by thickened dura) than MPS I-H/S r. Potential normal life span 3. Hurler-Scheie compound (MPS I-H/S) a. Clinical phenotype intermediate between Hurler and Scheie syndromes b. Progressive somatic involvement, including dysostosis multiplex, with little or no intellectual dysfunction c. Age of onset: usually between 3 and 8 years d. Survival to adulthood common e. Deafness f. Craniofacial features i. Coarse facial features less obvious ii. Micrognathia in some patients iii. Broad mouth iv. Square jaw v. Short neck g. Ophthalmologic features i. Corneal clouding in all patients ii. Glaucoma iii. Retinal degeneration iv. Optic atrophy h. Valvular heart disease (mitral valve insufficiency) developing by the early to mid-teens i. Skeletal features i. Short stature ii. Small thorax iii. Severe joint involvement (stiffness) iv. Kyphoscoliosis v. Back pain vi. Characteristic claw hand deformity vii. Carpal tunnel syndrome
MPS I (HURLER-SCHEIE SYNDROME)
j. Gastrointestinal features i. Varying degree of hepatomegaly ii. Hernias k. Pachymeningitis cervicalis (compression of the cervical cord due to mucopolysaccharide accumulation in the dura) l. Communicating hydrocephalus uncommon in patients who have normal intelligence m. Spondylolisthesis of the lower spine, leading to spinal cord compression n. Causes of death (around teens and 20s) i. Upper airway obstruction ii. Cardiac involvement
DIAGNOSTIC INVESTIGATIONS 1. 2. 3. 4. 5.
Developmental assessment Ophthalmologic examination ECG and echocardiography for cardiac status Cranial ultrasound for hydrocephalus Skeletal survey a. Dysostosis multiplex b. Skull i. Large, thickened calvarium ii. Premature closure of lambdoidal and sagittal sutures iii. Shallow orbits iv. Enlarged J-shaped sella v. Abnormally spaced teeth with dentigerous cysts c. Ribs i. Oar-shaped, narrowed at the vertebral ends ii. Flat/broad at the sternal ends d. Vertebra i. Beaked anteriorly (anterior hypoplasia) of lumbar vertebrae with kyphosis (an early sign) ii. Scalloped posteriorly iii. Thoracolumbar gibbus, resulting from anterior wedging of the vertebrae iv. Hypoplasia of the odontoid, leading to atlantoaxial subluxation e. Pelvis i. Poorly formed pelvis ii. Small femoral heads iii. Coxa valga f. Long bones i. Widened diaphysis of the long bones ii. Lack of normal modeling and tabulation iii. Irregular metaphysis iv. Poorly developed epiphyseal centers v. Distal ends of the radius and ulna angulate toward each other vi. Claw hands vii. Thickened and bullet-shaped phalanges viii. Coarsening of the trabeculae of the phalanges and metacarpals ix. Proximal narrowing of the metacarpals x. Marked irregularity and retarded ossification of the carpal bones g. Other bones i. Short, thickened, and irregular clavicles ii. Shortened and trapezoid-shaped phalanges with widened diaphyses
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6. Biochemical/molecular studies for MPS I-H, MPS I-HS, and MPS I-S a. Excessive urinary excretion of glycosaminoglycans (dermatan and heparan sulfates): a useful preliminary test b. Metachromatic staining of fibroblasts and leukocyte inclusions (nonspecific lab findings) c. Enzyme assay: deficient α-L-iduronidase in WBC, serum, cultured fibroblast, and CSF d. Accumulation of glycosaminoglycans in cultured fibroblasts correctable by uptake of α-L-iduronidase e. Mutation analysis or sequence analysis of IUDA gene: possible to identify both IDUA mutations in 95% of patients with MPS I f. Characterization of gene mutation: worthwhile for phenotype prediction and genetic counseling 7. Carrier testing a. Measurement of α-L-iduronidase enzyme activity: not a reliable method, requiring testing of obligatory carriers within the family first to determine if their levels of IDUA enzyme activity can be distinguishable from the normal b. Molecular genetic testing of IUDA to identify carriers among at-risk family members when both mutation alleles have been identified in an affected family member
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% chance of being affected b. Patient’s offspring: i. MPS I-S: not increased unless the spouse is a carrier ii. MPS I-H and MPS I-H/S: not surviving to reproductive age 2. Prenatal diagnosis from samples of CVS, amniocentesis, and feta blood a. Enzyme assays (deficient α-L-iduronidase) and increased level of 35S-sulphate incorporation measured in cultured cells obtained from amniocentesis or CVS for pregnancy at risk b. Mutation analysis of the IDUA gene in fetal DNA extracted from cells obtained by CVS or amniocentesis if both mutant IDUA alleles have been identified in a previously affected sib or in the parents of the atrisk fetus 3. Management a. Early infant stimulation programs b. Eye care: corneal transplantation successful but donor grafts eventually becoming cloudy c. Range of motion exercises to preserve joint function d. Physical therapy e. Orthopedic surgery i. Surgical decompression of the median nerve for carpal tunnel syndrome resulting in various restoration of motor hand activity ii. Trigger digits iii. Genu valgum iv. Kyphoscoliosis
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f.
g. h.
i.
j. k. l.
m.
n.
v. Acetabular dysplasia vi. Atlanto-occipital stabilization Ventriculoperitoneal shunting for hydrocephalus i. Generally palliative ii. May improve quality of life Tracheotomy or high pressure continuous positive airway pressure with supplemental oxygen Tonsillectomy and adenoidectomy to correct Eustachian tube dysfunction and to decrease upper airway obstruction Cardiovascular care i. Bacterial endocarditis prophylaxis ii. Valve replacement surgery Surgical repair of inguinal hernias Early surgical intervention to prevent severe complications from progressive compression of the spinal cord Major anesthetic risks exhibited by patients with MPS I i. Avoid hyperextension of the neck since dysostosis multiplex can lead to instability of the spine including the atlantoaxial joint ii. Difficulty in induction of anesthesia due to inability to maintain an adequate airway iii. Require fiberoptic laryngoscopy for intubation iv. Slow recovery from anesthesia v. Common postoperative airway obstruction Allogenic bone marrow transplantation from an unaffected, HLA-compatible donor i. Beneficial effect: replacement of deficient macrophages by marrow-derived donor macrophages to provide ongoing source of normal enzyme capable of gaining access to the various sites of storage ii. Slows the course of congnitive decline if the therapy starts before the developmental delay is evident iii. Improves survival, reducing facial coarseness, hepatosplenomegaly, hearing, and normal cardiac function iv. Skeletal manifestations and corneal clouding continue to progress despite successful transplantation. Surgeries will be required for the persistent orthopedic problems v. Significantly limited by the availability of donors. The immunosuppressive therapy for the prevention of rejection carries significant toxicity vi. The procedure of the transplantation carries a high risk of morbidity and mortality. Failure to achieve stable engraftment and development of graft-versus-host disease are significant barriers to successful bone marrow transplantation for many children vii. Hematopoietic stem cell transplantation: the treatment of choice for a child with Hurler syndrome who is younger than two years of age and has minimal or no central nervous system disease Cord-blood transplantation: i. Use cord-blood transplants from partially HLAmatched, unrelated donors ii. Donors readily available iii. An excellent source of stem cells for transplantation
iv. Sustained engraftment can be achieved without total-body irradiation in young children v. Low incidence for acute graft-versus-host disease (GVHD) vi. Absence of extensive chronic GVHD vii. As effective as bone marrow transplantation o. Enzyme replacement therapy i. An etiology-specific treatment that seeks to address the underlying pathophysiology of MPSI by delivering sufficient IDUA activity to reverse and prevent glycosaminoglycans accumulation ii. Effectiveness depending on the ability of recombinant enzymes injected intravenously to enter cells and localize to the lysosome, the appropriate intracellular site iii. Use of recombinant human α-L-iduronidase (Laronidase: Aldurazyme) a) Significant reduction in liver size b) Increase in height and weight c) Decrease in joint restriction d) Improvement in breathing (respiratory function) and sleep apnea e) Decreased glycosaminoglycan storage f) Recommended for patients with the milder or attenuated forms of MPSI. Infusions of recombinant enzyme are a safer alternative for treating the somatic disease and improving the quality of life of such patients. Intravenously administered enzyme is not expected to cross the blood-brain barrier and affect central nervous system disease
REFERENCES Beesley CE, Meaney CA, Greenland G, et al.: Mutational analysis of 85 mucopolysaccharidosis type I families: frequency of known mutations, identification of 17 novel mutations and in vitro expression of missense mutations. Hum Genet 109:503–511, 2001. Bunge S, Kleijer WJ, Steglich C, et al.: Mucopolysaccharidosis type I: identification of 8 novel mutations and determination of the frequency of the two common alpha-L-iduronidase mutations (W402X and Q70X) among European patients. Hum Mol Genet 3:861–866, 1994. Fensom AH, Benson PF: Recent advances in the prenatal diagnosis of the mucopolysaccharidoses. Prenat Diagn 14:1–12, 1994. Fratantoni JC, Neufeld EF, Uhlendorf BW, et al.: Intrauterine diagnosis of the Hurler and Hunter syndromes. N Engl J Med 280:686–688, 1969. Guffon N, Souillet G, Maire I, et al.: Follow-up of nine patients with Hurler syndrome after bone marrow transplantation. J Pediatr 133:119–125, 1998. Ikeno T, Minami R. Wagatsuma K et al.: Prenatal diagnosis of Hurler’s syndrome— biochemical studies on the affected fetus. Hum Genet 59:353–359, 1981. Kaibara N, Eguchi M, Shibata K, et al.: Hurler-Scheie phenotype: a report of two pairs of inbred sibs. Hum Genet 53:37–41, 1979 Kajii T, Matsuda I, Osawa T, et al.: Hurler/Scheie genetic compound (mucopolysaccharidosis IH/IS) in Japanese brothers. Clin Genet 6:394–400, 1974. Kakkis ED: Enzyme replacement therapy for the mucopolysaccharide storage disorders. Expert Opin Investig Drugs 11:675–685, 2002. Kakkis ED, Muenzer J, Tiller GE, et al.: Enzyme-replacement therapy in mucopolysaccharidosis I. N Enl J Med 344:182–188, 2001. Lee-Chen GJ, Wang TR: Mucopolysaccharidosis type I: identification of novel mutations that cause Hurler/Scheie syndrome in Chinese families. J Med Genet 34:939–941, 1997. Lee-Chen GJ, Lin SP, Tang YF, et al.: Mucopolysaccharidosis type I. Characterization of novel mutations affecting α-L-iduronidase activity. Clin Genet 56:66–70, 1999. McKusick VA: Heritable Disorders of Connective Tissue. St. Louis, MO, CV Mosby, 1972.
MPS I (HURLER-SCHEIE SYNDROME) McKusick VA, Howell RR. Hussels IE et al.: Allelism, nonallelism and genetic compounds among the mucopolysaccharidoses. Lancet I: 993–996, 1972. Moores C, Rogers JG, McKenzie IM, et al.: Anaesthesia for children with mucopolysaccharidoses. Anaesth Intensive Care 24:459–463, 1996. Muenzer J: Mucopolysaccharidoses. Adv Pediatr 33:269–302, 1986. Muenzer J: The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr 144:S27–S34, 2004. Muenzer J, Fisher A: Advances in the treatment of mucopolysaccharidosis type I. N Engl J Med 350:1932–1934, 2004. Mueller OT, Shows TB. Opitz JM: Apparent allelism of the Hurler, Scheie, and Hurler/Scheie syndromes. Am J Med Genet 18:547–556, 1984. Nelson J, Shields MD, Mulholland HC: Cardiovascular studies in the mucopolysaccharidoses. J Med Genet 27:94–100, 1990. Neufeld EF, Muenzer J: The Mucopolysaccharidosis. In Scriver CR, Beaudet al., Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001, Chapter 136, pp 3421–3452. Peters C, Balthazor M, Shapiro EG, et al.: Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. Blood 87:4894–4902, 1996. Peters C, Shapiro EG, Anderson J, et al.: Hurler syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty- four children. The Storage Disease Collaborative Study Group. Blood 91:2601–2608, 1998. Portigal CL, Clarke LA: Mucopolysaccharidosis type I. Gene Reviews, 2003. http://www.genetests.org Roubick M, Gehler J, Spranger J: The clinical spectrum of α-L-iduronidase deficiency. Am J Med Genet 20:471–481, 1985. Scott HS, Ashton LJ, Eyre HJ, et al.: Chromosomal localization of the human αL-iduronidase gene (IDUA) to 4p16.3. Am J Hum Genet 47:802–807, 1990. Scott HS, Guo XH, Hopwood JJ, et al.: Structure and sequence of the human α-L-iduronidase gene. Genomics 13:1311–1313, 1992. Scott HS, Litjens T, Nelson PV, et al.: Identification of mutations in the alphaL-iduronidase gene (IDUA) that cause Hurler and Scheie syndromes. Am J Hum Genet 53:973–786, 1993. Scott HS, Bunge S, Gal A, et al.: Molecular genetics of mucopolysaccharidosis type I: diagnostic, clinical, and biological implications. Hum Mutat 6:288–302, 1995.
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Shapiro J, Strome M, Crocker AC: Airway obstruction and sleep apnea in Hurler and Hunter syndromes. Ann Otol Rhinol Laryngol 94:458–461, 1985. Staba SL, Escolar ML, Poe M, et al.: Cord-blood transplants from unrelated donors in patients with Hurler”s syndrome. N Engl J Med 350:1960–1968, 2004. Tandon V, Williamson JB, Cowie RA, et al.: Spinal problems in mucopolysaccharidosis I (Hurler syndrome). J Bone Joint Surg Br 78:938–944, 1996. Van Heest AE, House J, Krivit W, et al.: Surgical treatment of carpal tunnel syndrome and trigger digits in children with mucopolysaccharide storage disorders. J Hand Surg [Am] 23:236–243, 1998. Vellodi A, Young EP, Cooper A, et al.: Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centres. Arch Dis Child 76:92–99, 1997. Walker RW, Darowski M, Morris P, et al.: Anaesthesia and mucopolysaccharidoses. A review of airway problems in children. Anaesthesia 49:1078–1084, 1994. Watts RW, Spellacy E, Kendall BE, et al.: Computed tomography studies on patients with mucopolysaccharidoses. Neuroradiology 21:9–23, 1981. Whitley CB, Belani KG, Chang PN, et al.: Long-term outcome of Hurler syndrome following bone marrow transplantation. Am J Med Genet 46:209–218, 1993. Whitley CB: The mucopolysaccharidoses, in Beighton P (ed): McKusick’s Heritable Disorders of Connective Tissue, 5th ed. St. Louis, CV Mosby, 1993, pp 367. Wraith JE: The mucopolysaccharidoses: A clinical review and guide to management. Arch Dis Child 72:263–267, 1995. Wraith JE, Clarke LA, Beck M, et al.: Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human a-L-iruronidase (Laronidase). J Pediatr 144:581–588, 2004. Yamagishi A, Tomatsu S, Fukuda S, et al.: Mucopolysaccharidosis type I: identification of common mutations that cause Hurler and Scheie syndromes in Japanese populations. Hum Mutat 7:23–29, 1996. Young EP: Prenatal diagnosis of Hurler disease by analysis of alphaiduronidase in chorionic villi. J Inherit Metab Dis 15:224–230, 1992.
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MPS I (HURLER-SCHEIE SYNDROME)
Fig. 1. A child with Hurler syndrome showing a large head with frontal bossing, coarse facial features, ocular hypertelorism, cloudy (steamy) cornea, depressed nasal bridge, large tongue, short neck, protuberant abdomen, umbilical hernia, stiff joints, and claw hands.
Fig. 3. Radiographs showing oar-shaped ribs with relatively narrow proximal portion, narrow iliac bodies and flaring wings, shallow acetabula, coxa valga, anterior wedging of the lumbar vertebrae, decreased AP diameter of the vertebral bodies with posterior scalloping, and the marked thoracolumbar gibbus.
Fig. 2. Claw hand. The radiographs show thick bullet-shaped phalanges, proximal narrowing of the metacarpals, poorly ossified carpal bones, and angulating toward each other of the distal ends of the radius and the ulnar.
MPS I (HURLER-SCHEIE SYNDROME)
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Fig. 7. Metachromasia of the cultured fibroblasts.
Fig. 4. Radiograph of the upper extremities show the lack of normal modeling and tabulation of the diaphyses, leading to short tubular bones. The radial and ulnar articular surfaces are angulated toward each other. Marked irregularity and retarded ossification of the carpal bones are noted. The findings in the lower extremities are less marked.
Fig. 8. Positive MPS spot test.
Fig. 5. Skull radiograph showing a large scaphocephalic calvarium with early appearance of the J-shaped sella turcica.
Fig. 6. Post-mortem findings of the brain showing cloudy leptomeninges secondary to cloudy CSF.
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MPS I (HURLER-SCHEIE SYNDROME)
Fig. 9. A 14-month-old boy with Hurler syndrome showing a large head, coarse facies, protuberant abdomen, umbilical hernia, a lumbar gibbus, and claw hands. The radiographs showed cardiomegaly, thickened ribs, and beaked vertebral body (L2). The α-iduronidase enzyme level was 0.0 (87.10–190.50 nmol/mg/hr).
Fig. 10. A 14-year-old boy with Hurler-Scheie compound showing, short stature, semi-crouching stance, joint stiffness (A), coarse facies (B) and claw hands (C). When he was 3 years old, he started to complain difficulty in raising his arms above his head and difficulty in moving his hands and fingers because of bent fingers and joint contractures. He was noted to have dwarfism, coarse thickened skin, hirsutism, a big head with frontal bossing, coarse facies with hypertelorism, cloudy cornea, large lips and large tongue, short neck, short trunk with a mild kyphosis, hepatomegaly, claw hands, anteriorly converted shoulders, protuberant abdomen, flexion contractures of elbows, wrists, and knees , and crouching stance. The urine for mucopolysaccharide was positive and the blood for metachromasia was positive. Skin fibroblasts was deficient in α-L-iduronidase.
MPS I (HURLER-SCHEIE SYNDROME)
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Fig. 11. Radiographs. Skull (A) show macrocephaly, frontal bossing, small and airless mastoids, and anterior pocketing of the sella turcica (“shoe-shaped” or “J-shaped” sella). Clavicles (B) are short with widened medial aspects of both clavicles. Ribs are oar-shaped and wide in their lateral and anterior portions with moderate narrowing of the paravertebral portions of the lower ribs (C). Vertebral bodies have concaved anterior and posterior margins and decreased in sagittal diameters. The second lumbar vertebra was hypoplastic with anterior inferior beaking forming almost a hook-shaped deformity. Claw hands were present with tapering of both distal ends of radius and ulnar to form “V-shaped” (D). Carpal bones were small, irregular, and crowded together. Metacarpals and phalanges were wide and short with proximal pointing of metacarpals. Bone age was retarded. Pes cavus was present.
Mucopolysaccharidosis II (Hunter Syndrome) In 1917, Hunter described the syndrome in two brothers. Hunter syndrome is an X-linked recessive form of the mucopolysaccharidosis. Severe and mild forms of the syndrome are caused by the same enzyme deficiency, iduronate sulfatase. The estimated incidence is approximately 1 in 100,000 births.
GENETICS/BASIC DEFECTS 1. Inheritance a. X-linked recessive inheritance from pedigree data b. The gene for iduronate sulfatase mapped to Xq28 2. Primary biochemical defect and pathophysiology a. Deficient iduronate-2-sulfatase (IDS), the enzyme required for cleavage of sulfate from iduronic acid moieties of dermatan and heparan sulfates b. Excessive intracellular accumulation of acid mucopolysaccharides (dermatan sulfate and heparan sulfate) due to deficient iduronate sulfatase activity, leading to multiple organ system involvement, including the musculoskeletal, integumentary, cardiovascular, pulmonary, and ocular systems 3. Molecular defect a. Mutations of IDS gene i. Missense and nonsense mutations ii. Mutations affecting splicing iii. Small insertions and deletions iv. Partial gene deletions v. Deletions or rearrangements of the whole IDS gene b. Major structural alterations and gross deletions of the IDS gene result in the most severe forms of Hunter syndrome c. Single-base substitutions causing diminished but not obliterated enzyme activity is observed in mild disease 4. Hunter syndrome in females: an exceedingly rare event possibly due to the following mechanisms: a. As the offspring of a carrier female and affected male or an unaffected male whose sperm carries a new mutation b. Uniparental disomy of the mutant X-chromosome from a heterozygous female or an affected male c. Genetic rearrangement: e.g, translocation or deletion resulting in nonrandom lyonization toward expression of a mutant allele
CLINICAL FEATURES 1. Clinical presentation showing a spectrum of mild to severe forms as a result of different mutations in the functional gene 2. Severe Hunter syndrome (MPS IIA) a. Onset: usually between 2 and 4 years of age with progressive neurologic and somatic involvement b. More common than the mild form 678
c. Short stature not pronounced d. Coarse facial features i. Frontal bossing ii. Depressed nasal bridge iii. Wide nostrils iv. Thick lips v. Hypertrophic gums vi. A large tongue e. Skeletal deformities i. Kyphosis ii. Digital contractures iii. Claw hands iv. Joint stiffness v. Absence of gibbus f. Mental retardation g. Hydrocephalus h. Retinal degeneration i. Absence of corneal clouding j. Hearing loss k. Respiratory difficulties i. Upper airway obstruction due to adenoid hypertrophy, nasal congestion, and thick rhinorrhea ii. Mouth breathing secondary to choanal stenosis iii. Sonorous breathing, frank obstructive sleep apnea, and even death secondary to adenoid hypertrophy, tongue enlargement, and supraglottic swelling l. Cardiovascular disorders i. Cardiac valvular involvement leading to congestive heart failure, the leading cause of death in affected individuals ii. Mild thickening and shortening of the chordae tendineae contributing to the regurgitant valve dysfunction m. Gastrointestinal problems i. Chronic diarrhea secondary to autonomic nervous system involvement and mucosal dysfunction ii. Hepatosplenomegaly iii. Umbilical and inguinal hernias n. Thick skin often with nodular skin lesions over the scapular area or arms o. Carpal tunnel syndrome secondary to median nerve compression p. Additional features of most severely affected patients, caused by large deletions that include iduronate sulfate sulfatase and contiguous genes i. Hurler-like symptoms ii. Early onset of seizures iii. Ptosis q. Prognosis: typically advancing to cachexia and death before 15 years 3. Mild Hunter syndrome (MPS IIB) a. Diagnosed slightly later than the severe form b. Much less frequent than the severe form
MPS II (HUNTER SYNDROME)
c. d. e. f. g. h. i.
Preservation of normal intelligence No central nervous system involvement Somatic involvement less progressive Hearing impairment Cardiovascular disorders Joint stiffness Cervical myopathy due to a narrowed spinal canal and cord compression j. Carpal tunnel syndrome more frequent and severe compared to the severe form k. Loss of hand function resulting from joint stiffness and carpal tunnel syndrome l. Prognosis i. Longer survival ii. Typically surviving to adulthood iii. Possible death in early adulthood or even in the late teens due to airway obstruction and cardiac failure
DIAGNOSTIC INVESTIGATIONS 1. Echocardiography 2. Electrocardiography 3. Radiographic features a. Kyphosis b. Claw hands c. Thick cortex of the bones progressively becoming thinner as the marrow cavities expand d. Large calvarium with shoe-shaped sella e. Broad and spatulate lower ribs f. Hypoplasia and beaking of the lumbar vertebrae 4. Biochemical/molecular studies a. Measurement of mucopolysaccharides in the urine. Abnormal excretion of a large amount of dermatan sulfate and heparin sulfate in the urine b. Deficient iduronate sulfatase in leukocytes and fibroblasts c. Excessive intracellular accumulation of dermatan sulfate and heparin sulfate d. Peripheral lymphocytes, when stained with toluidine blue, exhibit metachromatic granules within vacuoles e. Mutation analysis 5. Heterozygote detection a. Carrier detection by enzyme analysis is unreliable b. Identification of IDS gene mutations
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Carrier mother: 50% of brothers affected, 50% of brothers normal; 50% of sisters carriers, 50% of sisters normal ii. Noncarrier mother (mother of a sporadic case): recurrence possible due to presence of gonadal mosaicism b. Patient’s offspring i. Severe form: not surviving to reproduction ii. Mild form: none of the sons affected; all daughters carriers 2. Prenatal diagnosis a. Maternal serum analysis
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i. Consistent increase of iduronate sulfate sulfatase in the serum of pregnant women from prepregnancy levels toward the end of pregnancy ii. No change in the serum enzyme levels of heterozygous mothers until the affected fetuses are aborted b. Amniocentesis i. Reduced enzyme activity in the amniotic fluid ii. Low enzyme levels in cultured amniotic cells iii. Abnormal 35SO4 incorporation into cultured amniotic fluid cells iv. Karyotyping for fetal sex v. Direct detection of IDS gene mutation c. CVS i. Diminished enzyme activity in uncultured chorionic villi of affected male fetuses. This may be seen in female carrier fetuses ii. Karyotyping for fetal sexing iii. Direct detection of IDS gene mutation d. Umbilical fetal blood sampling: severe deficiency of iduronate sulfate sulfatase in the plasma of affected male fetuses 3. Management a. Tympanostomy, adenoidectomy, and provision of hearing aids for management of otologic complications b. Symptomatic management of airway obstruction (sleep apnea) c. Ventriculoperitoneal shunting for hydrocephalus, a relatively rare complication of Hunter syndrome d. Difficulties during anesthesia secondary to the following factors: i. Rigid thoracic cage ii. Abdominal distention iii. Macroglossia iv. Temporomandibular ankylosis v. Atlantoaxial instability vi. Short and wide neck e. Prophylactic antibiotics for at-risk procedures in patient with mucopolysaccharidosis f. Surgical repair of inguinal and umbilical hernias g. Surgical release to preserve apposition of the thumbs at the earliest sign of an electrophysical evidence of progressive median nerve compression h. Musculoskeletal complications i. Shoe orthotics and ankle braces well tolerated and useful in maintaining mobility ii. Achilles tendon release in some patients with advanced disease iii. Surgical stabilization of the spine rarely indicated for kyphoscoliosis which is only mildly progressive and not usually resulting in spinal cord compression i. Bone marrow transplantation i. Possible reduction in hepatosplenomegaly, improvement in airway disease and reduction in urinary glycosaminoglycan excretion ii. Long term prognosis for longevity, cardiac complications and neurologic outcome after marrow transplantation still remained to be determined
680
MPS II (HUNTER SYNDROME)
REFERENCES Archer IM, Kingston HM, Harper PS: Prenatal diagnosis of Hunter syndrome. Prenat Diagn 4:195–200, 1984. Archer IM, Young ID, Rees DW, et al.: Carrier detection in Hunter syndrome. Am J Med Genet 16:61–69, 1983. Bergstrom SK, Quinn JJ, Greenstein R, et al.: Long-term follow-up of a patient transplanted for Hunter’s disease type IIB: a case report and literature review. Bone Marrow Transplant 14:653–658, 1994. Broadhead DM, Kirk JM, Burt AJ, et al.: Full expression of Hunter’s disease in a female with an X-chromosome deletion leading to non-random inactivation. Clin Genet 30:392–398, 1986. Bunge S, Steglich C, Zuther C, et al.: Iduronate-2-sulfatase gene mutations in 16 patients with mucopolysaccharidosis type II (Hunter syndrome). Hum Mol Genet 2:1871–1875, 1993. Bunge S, Steglich C, Lorenz P, et al.: Prenatal diagnosis and carrier detection in mucopolysaccharidosis type II by mutation analysis. A 47,XXY male heterozygous for a missense point mutation. Prenat Diagn 14:777–780, 1994. Cooper A, Thornley M, Wraith JE: First-trimester diagnosis of Hunter syndrome: very low iduronate sulphatase activity in chorionic villi from a heterozygous female fetus. Prenat Diagn 11:731–735, 1991. Fensom AH, Benson PF: Recent advances in the prenatal diagnosis of the mucopolysaccharidoses. Prenat Diagn 14:1–12, 1994. Froissart R, Blond JL, Maire I, et al.: Hunter syndrome: gene deletions and rearrangements. Hum Mutat 2:138–140, 1993. Froissart R, Maire I, Bonnet V, et al.: Germline and somatic mosaicism in a female carrier of Hunter disease. J Med Genet 34:137–140, 1997. Froissart R, Maire I, Millat G, et al.: Identification of iduronate sulfatase gene alterations in 70 unrelated Hunter patients. Clin Genet 53:362–368, 1998. Goldenfum SL, Young E, Michelakakis H, et al.: Mutation analysis in 20 patients with Hunter disease. Hum Mutat 7:76–78, 1996. Keulemans JL, Sinigerska I, Garritsen VH, et al.: Prenatal diagnosis of the Hunter syndrome and the introduction of a new fluorimetric enzyme assay. Prenat Diagn 22:1016–1021, 2002. Kleijer WJ, Moody PD, Liebaers I, et al.: Prenatal monitoring for the Hunter syndrome: the heterozygous female fetus. Clin Genet 15:113–117, 1979. Lichtenstein JR, Bilbrey GL, McKusick VA: Clinical and probable genetic heterogeneity within mucopolysaccharidosis. II. Report of a family with a mild form. Johns Hopkins Med J 131:425–435, 1972. Liebaers I, Di Natale P, Neufeld EF: Iduronate sulfatase in amniotic fluid: an aid in the prenatal diagnosis of the hunter syndrome. J Pediatr 90:423–425, 1977. Liebaers I, Neufeld E: Iduronate sulfatase activity in serum, lymphocytes, and fibroblasts—simplified diagnosis of the Hunter syndrome. Pediatr Res 10:733–736, 1976. Lissens W, Seneca S, Liebaers I: Molecular analysis in 23 Hunter disease families. J Inherit Metab Dis 20:453–456, 1997. Lissens W, Van Lierde M, Decaluwe J, et al.: Prenatal diagnosis of Hunter syndrome using fetal plasma. Prenat Diagn 8:59–62, 1988. McKinnis EJ, Sulzbacher S, Rutledge JC, et al.: Bone marrow transplantation in Hunter syndrome. J Pediatr 129:145–148, 1996. Muenzer J: Mucopolysaccharidoses. Adv Pediatr 33:269–302, 1986.
Neufeld EF, Muenzer J: The Mucopolysaccharidosis. In: Scriver CR, Beardet al., Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited disease Vol II, 7th ed, New York: McGraw-hill, 1995: 2465–2494. Pannone N, Gatti R, Lombardo C, et al.: Prenatal diagnosis of Hunter syndrome using chorionic villi. Prenat Diagn 6:207–210, 1986. Rathmann M, Bunge S, Beck M, et al.: Mucopolysaccharidosis type II (Hunter syndrome): mutation “hot spots” in the iduronate-2-sulfatase gene. Am J Hum Genet 59:1202–1209, 1996. Timms KM, Bondeson ML, Ansari-Lari MA, et al.: Molecular and phenotypic variation in patients with severe Hunter syndrome. Hum Mol Genet 6:479–486, 1997. Timms KM, Edwards FJ, Belmont JW, et al.: Reassessment of biochemically determined Hunter syndrome carrier status by DNA testing. J Med Genet 35:646–649, 1998. Upadhyaya M, Sarfarazi M, Bamforth JS, et al.: Localisation of the gene for Hunter syndrome on the long arm of X chromosome. Hum Genet 74:391–398, 1986. Vafiadaki E, Cooper A, Heptinstall LE, et al.: Mutation analysis in 57 unrelated patients with MPS II (Hunter’s disease). Arch Dis Child 79:237–241, 1998. Whitley CB: The mucopolysaccharidoses, in Beighton P (ed): McKusick’s Heritable Disorders of Connective Tissue, 5th ed. St. Louis, CV Mosby, 1993, pp 367. Wilson PJ, Morris CP, Anson DS, et al.: Hunter syndrome: isolation of an iduronate-2-sulfatase cDNA clone and analysis of patient DNA. Proc Natl Acad Sci USA 87:8531–8535, 1990. Wilson PJ, Suthers GK, Callen DF, et al.: Frequent deletions at Xq28 indicate genetic heterogeneity in Hunter syndrome. Hum Genet 86:505–508, 1991. Wraith JE, Cooper A, Thornley M, et al.: The clinical phenotype of two patients with a complete deletion of the iduronate-2-sulphatase gene (mucopolysaccharidosis II—Hunter syndrome). Hum Genet 87:205– 206, 1991. Yatziv S, Erickson RP, Epstein CJ: Mild and severe Hunter syndrome (MPS II) within the same sibships. Clin Genet 11:319–326, 1977. Yoskovitch A, Tewfik TL, Brouillette RT, et al.: Acute airway obstruction in Hunter syndrome. Int J Pediatr Otorhinolaryngol 44:273–278, 1998. Young ID, Harper PS: Long-term complications in Hunter’s syndrome. Clin Genet 16:125–132, 1979. Young ID, Harper PS: Psychosocial problems in Hunter’s syndrome. Child Care Health Dev 7:201–209, 1981. Young ID, Harper PS: Mild form of Hunter’s syndrome: clinical delineation based on 31 cases. Arch Dis Child 57:828–836, 1982. Young ID, Harper PS: The natural history of the severe form of Hunter’s syndrome: a study based on 52 cases. Dev Med Child Neurol 25:481–489, 1983. Young ID, Harper PS, Archer IM, et al.: A clinical and genetic study of Hunter’s syndrome. 1. Heterogeneity. J Med Genet 19:401–407, 1982. Young ID, Harper PS, Newcombe RG, et al.: A clinical and genetic study of Hunter’s syndrome. 2. Differences between the mild and severe forms. J Med Genet 19:408–411, 1982. Zlotogora J, Bach G: Heterozygote detection in Hunter syndrome. Am J Med Genet 17:661–665, 1984. Zlotogora J, Bach G: Hunter syndrome: prenatal diagnosis in maternal serum. Am J Hum Genet 38:253–260, 1986.
MPS II (HUNTER SYNDROME)
Fig. 1. A boy with MPS II showing mild short stature, coarse facial features, and claw hands.
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Mucopolysaccharidosis III (Sanfilippo Syndrome) g) Talking in sleep h) Body rocking i) Chewing bedclothes viii. Poor attention span ix. Marked mood swings x. Self injury d. Progressive motor difficulties due to spasticity and joint stiffness, starting about 10 years of age (marking the 3rd stage) e. Severe hearing loss common in the moderate to severely affected patient f. Severe neurologic degeneration occurring in most patients by 6 to 10 years of age, accompanied by rapid deterioration of social and adaptive skills (mental deterioration) g. Progressive dementia resulting in withdrawal and losing contact with the environment h. Seizures: uncommon 2. Mild somatic disease a. Coarse hair (hirsutism): hypertrichosis often present, especially on the back b. Macrocephaly c. Copious nasal discharge d. Repeated upper respiratory tract infections e. Cardiac signs and symptoms much lesser degree compared to other types of mucopolysaccharidosis f. Mild hepatosplenomegaly g. Joint stiffness h. Recurrent and sometimes severe diarrhea, usually improves in later childhood i. Early onset of puberty 3. Prognosis a. Type A i. The most severe type ii. Earlier onset iii. More rapid progression of symptoms iv. Shorter survival: death usually by late teens b. Type B: known to remain functional into the third or even fourth decades c. Type C: clinically heterogeneous d. Type D i. Least common type ii. Clinically heterogeneous
In 1962 and 1963, Sanfilippo et al. described eight children with mental retardation and heparin sulfate mucopolysacchariduria and delineated the syndrome which now bears his name. Earlier in 1961, Harris reported a 6-year-old girl with hepatosplenomegaly, a normal skeletal survey and excretion of large amounts of heparin sulfate in the urine. Sanfilippo syndrome is one of the most common mucopolysaccharidoses (1/24,000–1/200,000). Sanfilippo syndrome is comprised of four biochemically heterogeneous types, which are clinically indistinguishable. Because the deficiency of these four various lysosomal enzymes involved the same breakdown of heparin sulfate, their clinical phenotype are similar.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Failure to degrade heparan sulfate may result from deficiency of one of the following four lysosomal enzymes: a. MPS IIIA caused by deficient haparan N-sulfatase b. MPS IIIB caused by deficient α-N-acetylglucosaminidase c. MPS IIIC caused by deficient Acetyl-CoA:α-glucosaminide-N-acetyltransferase d. MPS IIID caused by deficient N-acetyl-α-glucosamine6-sulfatase 3. Four subtypes of MPS III a. Clinically indistinguishable b. Each characterized by deficiency of a different enzyme c. MPS IIIA mapped to 17q25.3 d. MPS IIIB mapped to 17q21 e. MPS IIIC: mapping location not yet defined f. MPS IIID mapped to 12q14
CLINICAL FEATURES 1. Severe CNS involvement a. Developmental milestones near normal prior to age 3–4 years b. Developmental delay, especially in speech (1st stage) c. Behavioral problems (second stage) i. Aggressiveness ii. Hyperactivity iii. Attention deficit iv. Temper tantrums v. Destructive behavior vi. Physical aggression vii. Sleep disturbance a) Setting difficulties b) Night walking c) Sometimes awake all night d) Crying out e) Wandering around house f) Entering parents’ bed
DIAGNOSTIC INVESTIGATIONS
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1. Increased urinary excretion of heparan sulfate 2. Imaging features a. Radiography: mild degree of dysostosis multiplex b. Echocardiography for rare cardiac abnormalities c. CT i. Mild to moderate cortical atrophy at onset ii. Severe cortical atrophy at late stage
MPS III (SANFILIPPO SYNDROME)
d. MRI i. Cortical atrophy ii. Corpus callosum atrophy iii. Abnormal or delayed myelination iv. MRI findings may precede the onset of overt neurological symptoms 3. Biochemical analysis a. Deficient haparan N-sulfatase (type A) b. Deficient N-acetylglucosaminidase (type B) c. Deficient α-glucosamine-N-acetyltransferase (type C) d. Deficient N-acetyl-α-glucosamine-6-sulfatase (type D) 4. Mutation studies a. MPS IIIA i. Missense mutations (most common) ii. Premature termination mutations iii. Small deletion mutations b. MPS IIIB i. Great molecular heterogeneity ii. Most mutations: private mutations c. MPS IIIC: no mutation analysis available currently d. MPS IIID: Frameshift and premature termination mutation
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not reproducing due to mental retardation 2. Prenatal diagnosis a. Fetuses at risk for MPS IIIA i. Measuring sulphamidase activity using radioactive assay in CVS and amniocytes ii. Using fluorimetric sulphamidase assay in CVS and amniocytes iii. Molecular diagnosis in characterized families b. Fetuses at risk for MPS IIIB i. Assay of α-N-acetylglucosaminidase activity in cultured amniocytes and CVS ii. Increased level of heparan sulphate in amniotic fluid by two-dimensional electrophoresis of glycosaminoglycans: used as an adjunctive method in prenatal diagnosis iii. Molecular diagnosis in characterized families c. Fetuses at risk for MPS IIIC i. Assay of Acetyl-CoA:α-glucosamine-N-acetyltransferase in amniocytes and CVS ii. Molecular diagnosis in characterized families d. Fetuses at risk for MPS IIID i. Spectrophotometric assay for the N-acetyl-αglucosamine-6-sulfatase activity ii. Molecular diagnosis in characterized families 3. Management a. Supportive treatments i. Antibiotics for otitis media and respiratory tract infections ii. Anticonvulsants for seizure activities b. Muscle relaxants for painful spasms c. Gastrostomy to maintain adequate nutrition
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d. Special education program e. Behavioral management to allow the family to function as near normal as possible i. Alteration to the physical environment within home ii. Drug treatment to control hyperactivity and aggression f. Physical therapy to maintain joint mobility g. Wheel chair for transportation h. Respite care: availability of suitable respite accommodation i. Identify professional and community resources j. Bone marrow transplantation i. Biochemical correction readily achievable ii. Disappointing intellectual outcome
REFERENCES Barone R, Nigro F, Triulzi F, et al.: Clinical and neuroradiological follow-up in mucopolysaccharidosis type III (Sanfilippo syndrome). Neuropediatrics 30:270–274, 1999. Beesley CE, Young EP, Vellodi A, et al.: Identification of 12 novel mutations in the alpha-N-acetylglucosaminidase gene in 14 patients with Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB). J Med Genet 35:910–914, 1998. Beesley CE, Young EP, Vellodi A, et al.: Mutational analysis of Sanfilippo syndrome type A (MPS IIIA): identification of 13 novel mutations. J Med Genet 37:704–707, 2000. Beesley CE, Burke D, Jackson M, et al.: Sanfilippo syndrome type D: identification of the first mutation in the N-acetylglucosamine-6-sulphatase gene. J Med Genet 40:192–194, 2003. Blanch L, Weber B, Guo XH, et al.: Molecular defects in Sanfilippo syndrome type A. Hum Mol Genet 6:787–791, 1997. Bunge S, Ince H, Steglich C, et al.: Identification of 16 sulfamidase gene mutations including the common R74C in patients with mucopolysaccharidosis type IIIA (Sanfilippo A). Hum Mutat 10:479–485, 1997. Bunge S, Knigge A, Steglich C, et al.: Mucopolysaccharidosis type IIIB (Sanfilippo B): identification of 18 novel alpha-N-acetylglucosaminidase gene mutations. J Med Genet 36:28–31, 1999. Chabas A, Montfort M, Martinez-Campos M, et al.: Mutation and haplotype analyses in 26 Spanish Sanfilippo syndrome type A patients: possible single origin for 1091delC mutation. Am J Med Genet 100:223– 228, 2001. Cleary MA, Wraith JE: Management of mucopolysaccharidosis type III. Arch Dis Child 69:403–406, 1993. Di Natale P, Pannone N, D’Argenio G, et al.: First-trimester prenatal diagnosis of Sanfilippo C disease. Prenat Diagn 7:603–605, 1987. Di Natale P, Annelia T, Daniele A, et al.: Biochemical diagnosis of mucopolysaccharidoses. Experience of 297 diagnosis in a fifteen year period (1977–1991). J Inher Metab Dis 16:473–483, 1993. Di Natale P, Villani GR, Esposito S, et al.: Prenatal diagnosis of Sanfilippo type A syndrome in a family with S66W mutant allele. Prenat Diagn 19:993–994, 1999. Di Natale P, Villani G, Di Domenico C, et al.: Analysis of Sanfilippo A gene mutations in a large pedigree. Clin Genet 63:314–318, 2003. He W, Voznyi YaV, Huijmans JG, et al.: Prenatal diagnosis of Sanfilippo disease type C using a simple fluorometric enzyme assay. Prenat Diagn 14:17–22, 1994. Jones MZ, Alroy J, Rutledge JC, et al.: Human mucopolysaccharidosis IIID: Clinical, biochemical, morphological and immunohistochemical characteristics. J Neuropathol Exp Neurol 56:1158–1167, 1997. Karpova EA, Voznyi Ya V, Keulemans JL, et al.: A fluorimetric enzyme assay for the diagnosis of Sanfilippo disease type A (MPS IIIA). J Inherit Metab Dis 19:278–285, 1996. Kleijer WJ, Huijmans JG, Blom W, et al.: Prenatal diagnosis of Sanfilippo disease type B. Hum Genet 66:287–288, 1984. Kleijer WJ, Karpova EA, Geilen GC, et al.: Prenatal diagnosis of Sanfilippo A syndrome: experience in 35 pregnancies at risk and the use of a new flu-
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MPS III (SANFILIPPO SYNDROME)
orogenic substrate for the heparin sulphamidase assay. Prenat Diagn 16:829–835, 1996. Lee-Chen GJ, Lin SP, Ko MH, et al.: Identification and characterization of mutations underlying Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA). Clin Genet 61:192–197, 2002. Lee-Chen GJ, Lin SP, Lin SZ, et al.: Identification and characterisation of mutations underlying Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB). J Med Genet 39:E3, 2002. Maire I, Epelbaum S, Piraud M, et al.: Second trimester prenatal diagnosis of Sanfilippo syndrome type C. [Journal Article] J Inher Metabol Dis 16(3):584–586, 1993. Minelli A, Danesino C, Lo Curto F, et al.: First trimester prenatal diagnosis of Sanfilippo disease (MPSIII) type B. Prenat Diagn 8:47–52, 1988. Mossman J, Young EP, Patrick AD, et al.: Prenatal tests for Sanfilippo disease type B in four pregnancies. Prenat Diagn 3:347–350, 1983. Muenzer J: Mucopolysaccharidoses. Adv Pediatr 33:269–302, 1986. Neufeld EF, Muenzer J: The Mucopolysaccharidosis. In: Scriver CR, Beardet al., Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited disease Vol II, 7th ed, New York: McGraw-hill, 1995: 2465–2494. Nidiffer FD, Kelly TE: Developmental and degenerative patterns associated with cognitive, behavioural and motor difficulties in the Sanfilippo syndrome: an epidemiological study. J Ment Defic Res 27 (Pt 3):185–203, 1983.
Nowakowski RW, Thompson JN, Taylor KB: Sanfilippo syndrome, type D: a spectrophotometric assay with prenatal diagnostic potential. Pediatr Res 26:462–466, 1989. Sivakumur P, Wraith JE: Bone marrow transplantation in mucopolysaccharidosis type IIIA: a comparison of an early treated patient with his untreated sibling. J Inher Metab Dis 22:849–850, 1999. Toone JR, Applegarth DA: Carrier detection in Sanfilippo A syndrome. Clin Genet 33:401–403, 1988. Thompson JN, Huffman P, McConkie-Rosell A, et al.: Prenatal diagnosis of Sanfilippo syndrome type A by early amniocentesis. Biochem Mol Biol Int 29:793–797, 1993. Van de Kamp JJ, Neirmeijer MF, Von Figura K, et al.: Genetic heterogeneity and clinical variability in the Sanfilippo syndrome (type A, B and C). Clin Genet 20:152–160, 1981. Vance JM, Conneally PM, Wappner RS, et al.: Carrier detection in Sanfilippo syndrome type B: report of six families. Clin Genet 20:135–140, 1981. Vellodi A, Young E, New M, et al.: Bone marrow transplantation for Sanfilippo disease type B. J Inherit Metab Dis 15:911–918, 1992. Yogalingam G, Hopwood JJ: Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. Hum Mutat 18:264–281, 2001. Zhao HG, Li HH, Bach G, et al.: The molecular basis of Sanfilippo syndrome type B. Proc Natl Acad Sci USA 93:6101–6105, 1996.
MPS III (SANFILIPPO SYNDROME)
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Fig. 2. A 32-year-old male with Sanfilippo syndrome type A showing mental retardation and severe behavioral problems. Molecular genetic analysis revealed heparan sulfamidase (SGSH) gene mutations. A C > T substitution was detected at nucleotide 892 resulting in a serine being replaced by a proline at amino acid 298 (S298P). A second nucleotide change resulted in insertion of a cysteine at nucleotide 1028 which creates a frameshift and premature truncation of protein (1028insC). The detection of 2 mutations in the heparan sulfamidase gene is associated with Sanfilippo A syndrome.
Fig. 1. A child with MPS IIIA at 8 months and 3 years.
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MPS III (SANFILIPPO SYNDROME)
Fig. 3. A child with MPS IIIB at 3 years of age. The radiographs show mild degree of dysostosis multiplex.
Mucopolysaccharidosis IV (Morquio Syndrome) In 1929, Morquio and Brailsford independently described cases of what is now believed to be Morquio syndrome. The exact incidence is unknown but is estimated to be 1 in 75,000 to 1 in 200,000.
GENETICS/BASIC DEFECTS 1. Genetic inheritance: autosomal recessive 2. Two forms of MPS IV a. MPS IVA i. Deficient N-acetyl-galactosamine 6-sulphate sulfatase (GALNS) gene, which is mapped to 16q24.3 ii. Wide spectrum of clinical manifestations b. MPS IVB i. Deficient β-galactosidase (GLB1) gene ii. Wide spectrum of clinical manifestations 3. Pathogenesis a. Defective degradation of keratan sulfate secondary to deficiency of either N-acetyl-galactosamine-6-sulfate sulfatase (GALNS gene) in MPS IVA or β-galactosidase (GLB1 gene) in MPS IVB b. Cartilage and cornea: the major organs affected in Morquio syndrome since keratan sulfate is predominantly found in these tissues
CLINICAL FEATURES 1. MPS IVA a. Classic form i. The most common form ii. Appear normal at birth iii. Skeletal symptoms occurring between 1 and 3 years of age iv. Clinical diagnosis usually not made until 3–15 years of age v. Skeletal manifestations a) Marked dwarfism b) Waddling gait with tendency to fall c) Short neck d) Hypoplasia or absence of the odontoid process of the axis with risk of resulting in life-threatening atlantoaxial subluxation e) Cervical myelopathy f) Gibbus g) Restrictive chest wall movement h) Pectus carinatum i) Kyphoscoliosis j) Genu valgum k) Semi-crouching stance l) Progressive skeletal deformities frequently resulting in neurologic compromise vi. Joint manifestations a) Hypermobile due to ligamentous laxity 687
b) Decreased mobility in large joints (e.g., hips, knees, elbows) vii. Unusual facial appearance a) Coarse facies b) Prognathism c) Broad mouth viii. Eye manifestations a) Mild corneal clouding b) Glaucoma c) Cataract ix. Dental features a) Abnormally thin enamel b) Spade-shaped incisors c) Pointed cusps d) Pitted buccal surfaces e) Frequent caries formation x. Cardiac manifestations a) Aortic valve insufficiency or stenosis b) Mitral valve thickening and stenosis c) Cardiac failure xi. Progressive deafness xii. Hepatomegaly xiii. Upper airway obstruction a) Obstructive sleep apnea b) Nocturnal dyspnea xiv. Intelligence usually normal, rarely with progressive mental regression b. Mild form i. Almost normal stature ii. Mild skeletal abnormalities a) Odontoid dysplasia but without atlantoaxial instability b) Pectus carinatum deformity c) Dysplastic hips d) Waddling gait e) Kyphoscoliosis f) Deformity of femoral heads g) Platyspondyly h) Limitation of joint movement i) Deformities of metacarpals iii. Enamel hypoplasia iv. Mild corneal clouding v. Absent keratosulfaturia 2. MPS IVB a. Severe form: clinical manifestations as severe as MPS IVA b. Mild form i. Less severe progression of skeletal dysplasia ii. Less severe short stature 3. Prognosis a. Atlantoaxial instability and subsequent cervical myelopathy
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MPS IV (MORQUIO SYNDROME)
b. c.
d. e.
i. Cord transection and subsequent quadriparesis or death secondary to a minor fall or extension of the neck ii. Bowel and bladder dysfunction and apnea secondary to cervical myelopathy iii. Prolonged periods of hypoxia, pulmonary hypertension, and even death from obstructive sleep apnea iv. Airway obstruction secondary to thickening of tissue in the upper airway from mucopolysaccharide deposition Predisposition to pulmonary infection because of progressive truncal deformity and immobility Early-onset coronary heart disease and valve thickening (aortic and mitral) with resultant cardiac dysfunction Visual disturbance and photophobia secondary to corneal clouding Predisposition to dental caries secondary to enamel abnormalities
DIAGNOSTIC INVESTIGATIONS 1. Urine MPS spot tests: associated with false-positive and false-negative results 2. Excessive urinary excretion of keratin sulfate: determination by spectrophotometric assays with dimethylmethylene blue 3. Metachromatic granules in cultured fibroblasts 4. Diagnosis confirmed by direct enzymatic assay in leukocytes or fibroblasts a. N-acetylgalactosamine-6-sulfatase deficiency (classic form) b. β-galactosidase deficiency (mild form) 5. Radiographic features a. Short trunk dwarfism b. Dysostosis multiplex c. Spondyloepiphyseal dysplasia (the hallmark of the syndrome) d. Odontoid hypoplasia e. Sternal protrusion f. Platyspondylia g. Kyphosis h. Hyperlordosis i. Scoliosis j. Ovoid deformities of the thoracic vertebrae k. Hook-shaped lumbar bodies l. Long pelvic configuration m. Coxa valga n. Genu valgum o. Ulnar deviation of the wrist p. Valgus deformity of the elbow q. Inclinations of distal ends of radius and ulna toward each other r. Metacarpal deformities s. Short phalanges t. Epiphyseal deformities of the tubular bones u. Wide metaphysis v. Osteoporosis 6. CT and MRI of the brain and cervical spine for evaluation of odontoid hypoplasia and cord compression
7. Echocardiography for cardiac involvement a. Aortic valve insufficiency or stenosis b. Mitral valve thickening and stenosis c. Ventricular hypertrophy 8. Slit-lamp examination for corneal clouding 9. Mutation analysis
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased unless the spouse is a carrier in which case there will be 50% of offspring affected 2. Prenatal diagnosis a. Demonstration of GalNac-6S or Gal-6S sulphatase deficiency in cultured amniotic fluid cells or chorionic villi b. Abnormal glycosaminoglycans electrophoretic pattern in amniotic fluid c. Mutation analysis in amniocytes or chorionic villi 3. Management a. Orthopedic management i. Surgery to stabilize the upper cervical spine, usually by spinal fusion, can be lifesaving for spinal cord compression ii. Bilateral osteotomies to correct the knock-knee deformity (severe coxa valgum) b. Anesthetic difficulties i. Difficult endotracheal intubation due to odontoid hypoplasia and atlanto-axial instability ii. Compression of the cord during hyperextension of the neck iii. Reduction in vital capacity, functional residual capacity, and total lung capacity due to chest cage dysfunction (kyphoscoliosis and pectus carinatum) c. Infection control d. Medications for glaucoma e. Cornea transplant not very helpful f. Hearing aids helpful g. Hernia repairs h. Cardiac management i. Aortic regurgitation ii. Endocarditis prophylaxis iii. Cardiac valve replacement historically not considered for these patients i. Potential strategies for treatment including enzyme replacement, gene therapy, and allogenic bone marrow transplantation in which engrafted cells provide the normal enzyme
REFERENCES Bagshaw RD, Zhang S, Hinek A, et al.: Novel mutations (Asn 484 Lys, Thr 500 Ala, Gly 438 Glu) in Morquio B disease. Biochim Biophys Acta 1588:247–253, 2002. Baker E, Guo XH, Orsborn AM, et al.: The Morquio A syndrome (mucopolysaccharidosis IVA) gene maps to 16q24.3. Am J Hum Genet 52:96–98, 1993. Bartz HJ, Wiesner L, Wappler F: Anaesthetic management of patients with mucopolysaccharidosis IV presenting for major orthopaedic surgery. Acta Anaesthesiol Scand 43:679–683, 1999. Beck M, Braun S, Coerdt W, et al.: Fetal presentation of Morquio disease type A. Prenat Diagn 12:1019–1029, 1992.
MPS IV (MORQUIO SYNDROME) Beck M, Glossl J, Grubisic A, et al.: Heterogeneity of Morquio disease. Clin Genet 29:325–331, 1986. Beck M, Petersen EM, Spranger J, et al.: Morquio’s disease type B (beta-galactosidase deficiency) in three siblings. S Afr Med J 72:704–707, 1987. Blaw ME, Langer LO: Spinal cord compression in Morquio-Brailsford’s disease. J Pediatr 74:593–600, 1969. Braverman N, Hoover-Fong J: Mucopolysaccharidosis type IV. Emedicine, 2003. http://www.emedicine.com Brailsford JF: Chondro-osteo-dystrophy, roentgenographic and clinical features of a child with dislocation of vertebrae. Am J Surg 7:404–407, 1929. Bunge S, Kleijer WJ, Tylki-Szymanska A, et al.: Identification of 31 novel mutations in the N-acetylgalactosamine-6-sulfatase gene reveals excessive allelic heterogeneity among patients with Morquio A syndrome. Hum Mutat 10:223–232, 1997. Chih-Kuang C, Shuan-Pei L, Shyue-Jye L, et al.: MPS screening methods, the Berry spot and acid turbidity tests, cause a high incidence of false-negative results in sanfilippo and morquio syndromes. J Clin Lab Anal 16:253–258, 2002. Cole DE, Fukuda S, Gordon BA, et al.: Heteroallelic missense mutations of the galactosamine-6-sulfate sulfatase (GALNS) gene in a mild form of Morquio disease (MPS IVA). Am J Med Genet 63:558–565, 1996. Figura K von, van de Kamp JJ, Niermeijer MF: Prenatal diagnosis of Morquio’s disease type A (N-acetylgalactosamine 6-sulphate sulphatase deficiency). Prenat Diagn 2:67–69. 1982. Giugliani R, Jackson M, Skinner SJ, et al.: Progressive mental regression in siblings with Morquio disease type B (mucopolysaccharidosis IV B). Clin Genet 32:313–325, 1987. Hollister DW, Cohen AH, Rimoin DL, et al.: The Morquio syndrome (mucopolysaccharidosis IV): morphologic and biochemical studies. Johns Hopkins Med J 137:176–183, 1975. Holzgreve W, Grobe H, von Figura K, et al.: Morquio syndrome: clinical findings in 11 patients with MPS IVA and 2 patients with MPS IVB. Hum Genet 57:360–365, 1981. Kleijer WJ, Geilen GC, Garritsen V, et al.: First-trimester diagnosis of Morquio disease type A. Prenat Diagn 20:183–185, 2000. Langer LO, Jr., Carey LS: The roentgenographic features of the KS mucopolysaccharidosis of Morquio (Morquio-Brailsford’s disease). Am J Roentgenol Radium Ther Nucl Med 97:1–20, 1966. Lipson SJ: Dysplasia of the odontoid process in Morquio’s syndrome causing quadriparesis. J Bone Joint Surg Am 59:340–344, 1977. Masuno M, Tomatsu S, Nakashima Y, et al.: Mucopolysaccharidosis IV A: assignment of the human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) gene to chromosome 16q24. Genomics 16:777–778, 1993. Mikles M, Stanton RP: A review of Morquio syndrome. Am J Orthop 26:533–540, 1997. Morgan KA, Rehman MA, Schwartz RE: Morquio’s syndrome and its anaesthetic considerations. Paediatr Anaesth 12:641–644, 2002. Morquio L: Sur une forme de dystrophie ossuese familiale. Arch Med Enfants 32:129–140, 1929. Morris CP, Guo XH, Apostolou S, et al.: Morquio A syndrome: cloning, sequence, and structure of the human N-acetylgalactosamine 6-sulfatase (GALNS) gene. Genomics 22:652–654, 1994. Mossman J, Patrick AD: Prenatal diagnosis of mucopolysaccharidosis by twodimensional electrophoresis of amniotic fluid glycosaminoglycans. Prenat Diagn 2:169–176, 1982.
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Muenzer J: Mucopolysaccharidoses. Adv Pediatr 33:269–302, 1986. Nelson J, Broadhead D, Mossman J: Clinical findings in 12 patients with MPS IV A (Morquio’s disease). Further evidence for heterogeneity. Part I: Clinical and biochemical findings. Clin Genet 33:111– 120, 1988. Nelson J, Kinirons M: Clinical findings in 12 patients with MPS IV A (Morquio’s disease). Further evidence for heterogeneity. Part II: Dental findings. Clin Genet 33:121–125, 1988. Nelson J, Thomas PS: Clinical findings in 12 patients with MPS IV A (Morquio’s disease). Further evidence for heterogeneity. Part III: Odontoid dysplasia. Clin Genet 33:126–130, 1988. Neufeld EF, Muenzer J: The Mucopolysaccharidosis. In: Scriver CR, Beardet al., Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited disease Vol II, 7th ed, New York: McGraw-hill, 1995: 2465–2494. Northover H, Cowie RA, Wraith JE: Mucopolysaccharidosis type IVA (Morquio syndrome): a clinical review. J Inherit Metab Dis 19:357–365, 1996. Ogawa T, Tomatsu S, Fukuda S, et al.: Mucopolysaccharidosis IVA: screening and identification of mutations of the N-acetylgalactosamine-6-sulfate sulfatase gene. Hum Mol Genet 4:341–349, 1995. Paschke E, Milos I, Kreimer-Erlacher H, et al.: Mutation analyses in 17 patients with deficiency in acid beta-galactosidase: three novel point mutations and high correlation of mutation W273L with Morquio disease type B. Hum Genet 109:159–166, 2001. Ransford AO, Crockard HA, Stevens JM, et al.: Occipito-atlanto-axial fusion in Morquio-Brailsford syndrome. A ten-year experience. J Bone Joint Surg Br 78:307–313, 1996. Rigante D, Antuzzi D, Ricci R, et al.: Cervical myelopathy in mucopolysaccharidosis type IV. Clin Neuropathol 18:84–86, 1999. R¯lling I, Clausen N, Nyvad B, et al.: Dental findings in three siblings with Morquio’s syndrome. Int J Paediatr Dent 9:219–224, 1999. Sukegawa K, Nakamura H, Kato Z: Biochemical and structural analysis of missense mutations in N-acetylgalactosamine-6-sulfate sulfatase causing mucopolysaccharidosis IVA phenotypes. Hum Mol Genet 9:1283–1290, 2000. Spranger JW: Beta galactosidase and the Morquio syndrome. Am J Med Genet 1:207–209, 1977. Suzuki Y, Oshima A, Nanba E: Beta-galactosidase deficiency (beta-galactosidosis): GM1 gangliosidosis and Morquio B disease. In: Scriver CR, Beaudet al., Sly WS, eds. The Metabolic and Molecular Basis of Inherited Disease. 8th ed. New York: McGraw-Hill, 3775–3809, 2001. Tylki-Szymanska A, Czartoryska B, Bunge S, et al.: Clinical, biochemical and molecular findings in a two-generation Morquio A family. Clin Genet 53:369–374, 1998. Whitley CB: The mucopolysaccharidoses, in Beighton P (ed): McKusick’s Heritable Disorders of Connective Tissue, 5th ed. St. Louis, CV Mosby, 1993, pp 367–499. Yuen M, Fensom AH: Diagnosis of classical Morquio’s disease: N-acetylgalactosamine 6-sulphate sulphatase activity in cultured fibroblasts, leukocytes, amniotic cells and chorionic villi. J Inherit Metab Dis 8:80–86, 1985. Zhao H, Van Diggelen OP, Thoomes R, et al.: Prenatal diagnosis of Morquio disease type A using a simple fluorometric enzyme assay. Prenat Diagn 10:85–91, 1990.
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MPS IV (MORQUIO SYNDROME)
Fig. 2. Lateral view of the spine showing platyspondyly, anterior beaking of vertebral bodies, and lumbar gibbus similar to those seen in Hurler syndrome.
Fig. 1. A boy with MPS IVB showing coarse facial appearance and short trunk.
MPS IV (MORQUIO SYNDROME)
Fig. 3. Radiographic studies showing dysostosis multiplex with proximal conical metacarpals and angling of the ulna toward the radius with dysplastic ulnar and radial growth plates.
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Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome) Mucopolysaccharidosis VI was first recognized by Maroteaux and coworkers in 1963 as a Hurler-like syndrome, but with preservation of intelligence and excretion of dermatan sulfate unaccompanied by heparan sulfate. Milder forms of MPS VI have been recognized since the initial description of the disorder. The estimated birth incidence of MPS VI ranges from 1 in 100,000 to 1 in 1,300,000 in various populations.
GENETICS/BASIC DEFECTS 1. Genetic inheritance: autosomal recessive 2. Cause a. Deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B) which: i. Is deficient in both mild and severe forms ii. Involves in the degradation of dermatan sulphate and chondroitin 4-sulphate iii. Causes intralysosomal storage and urinary excretion of the glycosaminoglycan, dermatan sulfate b. The gene encoding N-acetylgalactosamine 4-sulfatase (ARSB) mapped to chromosome 5q13-q14 c. Mutations: the vast majority of MPS VI mutant alleles are either unique to a patient or are present in a small number of patients i. Null mutations a) Frameshift mutations b) Nonsense mutations ii. Missense mutation giving rise to: a) Severe disease b) Intermediate disease c) Mild disease d. Genotype/phenotype correlation for missense mutations in MPS VI: not reliable enough for prognosis or counseling
d. e.
f.
g. h. i.
j.
CLINICAL FEATURES 1. Variable clinical phenotype (mild to severe) causing considerable difficulty in recognition and diagnosis of the syndrome 2. The severe form (MPS IVA) a. Somatic involvement similar to that in Hurler syndrome b. Growth i. Normal growth for the first few years of life ii. Growth retardation (short stature) first noted at the age of 2–3 years iii. Ultimate height of 110–140 cm in severely affected patients c. Other skeletal involvement i. An enlarged head at birth ii. Deformed chest at birth 692
k.
iii. Joint stiffness (knee, hip, and elbow) developing in the first years of life iv. Progressively restricted articular movements v. Crouching stance vi. Shortened limbs vii. Claw hand deformities secondary to flexion contractures of the fingers viii. Carpal tunnel syndrome contributing to the hand abnormality ix. Shortened trunk x. Anterior sternal protrusion xi. Lumbar gibbus xii. Prominent lumbar lordosis/kyphosis xiii. Genu valgum Mental development usually normal The facies i. Mild coarseness of facies in some patients ii. Coarse facies characteristic of Hurler syndrome in other patients Ocular findings i. Corneal opacities (clouding) developing early, resulting in significant visual impairment ii. Glaucoma iii. Pigmented retinopathy Dentigerous cysts Upper airway obstruction Cardiovascular involvement i. Thickened atrioventricular valves of the heart ii. Endomyocardial fibroelastosis iii. Dilated cardiomyopathy Associated neurologic complications i. Not typically associated with progressive impairment of mental status, although physical limitations may impact learning and development ii. Hydrocephalus iii. Spinal cord compression secondarily to: a) Atlantoaxial subluxation associated with craniovertebral canal stenosis b) Hypertrophy of the posterior longitudinal ligament c) Dural thickening secondary to the deposition of glycosaminoglycans iv. Spastic paraplegia resulting from compressive myelopathy v. Arachnoid cysts vi. Pachymeningitis vii. Nerve entrapment syndromes, particularly of the carpal tunnel viii. Occasional hearing loss due to recurrent otitis media Abdomen and visceral involvement i. Hepatomegaly always present after the age of 6 years ii. Splenomegaly in 50% of patients
MPS VI (MAROTEAUX-LAMY SYNDROME)
iii. Prominent abdomen iv. Inguinal/umbilical hernias common l. Skin i. Tightness ii. Hirsutism m. Most reported patients with the severe form died from heart failure in the second to third decades 3. The mild to intermediate form (MPS IVB) a. Clinical recognition often delayed till 5 years of age b. Mildly affected c. Minimal dysostosis multiplex d. Aortic and mitral valvular dysfunction i. Primarily due to calcified thickened and stenotic valves ii. The most prominent cardiac involvement in the milder phenotypes e. Spinal cord compression from thickening of the dura in the upper cervical spinal canal with resultant myelopathy: a frequent occurrence in patients with the milder forms f. Compression myelopathy associated with a kyphoscoliotic deformity of thoracolumbar spine
DIAGNOSTIC INVESTIGATIONS 1. Increased urinary excretion of glycosaminoglycans a. Dermatan sulfate (70–90% of excreted glycosaminoglycans) b. Heparan sulfate (remainder) 2. Biochemical diagnosis: demonstration of deficient Nacetylgalactosamine-4-sulfatase (arylsulfatase B) in cultured skin fibroblasts or leucocytes 3. Slit-lamp examination for corneal opacities 4. Radiographic features a. Skeletal changes similar to radiographic findings of Hurler syndrome in the severe form b. Striking examples of dysostosis multiplex, particularly severe pelvic changes i. Acetabulum hypoplasia ii. Small flared iliac wings c. Macrocephaly with a large sella d. Vertebrae i. Ovoid deformity of vertebral bodies ii. A hood-shaped deformity or blunt anterior hypoplasia of vertebral bodies of L1 or L2 iii. Epiphyseal dysplasia of the proximal femur iv. An elongated femoral neck in a valgus position v. Irregular diaphyseal distension of tubular bones vi. Vertebral subluxation, especially atlantoaxial joint 5. Mutation analysis
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased unless the spouse is a carrier 2. Prenatal diagnosis a. Demonstration of deficient N-acetylgalactosamine-4sulfatase (arylsulfatase B) in amniotic-fluid cells from the pregnancy at risk
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b. Mutation analysis of amniocytes and CVS in characterized families 3. Management a. Keratoplasty for progressive opacification of the cornea b. Surgery to improve common nerve entrapment syndromes, particularly of the carpal tunnel c. Successful single and double (aortic and mitral) valve replacements have been reported in MPS d. Substantial improvement following laminectomy and excision of the markedly thickened dura in myelopathy due to spinal canal stenosis e. Bone marrow transplantation in patients with the severe form of MPS VI i. Efficacy a) Arylsulfatase B activity increased to normal levels in peripheral lymphocytes and granulocytes b) Decreased urinary excretion of acid mucopolysaccharide c) Decreased inclusions in the liver d) Improved cardiopulmonary function e) Improved visual acuity and joint mobility ii. Not universally performed due to lack of a suitable donor and is associated with significant morbidity and mortality f. Allogeneic CD34 selected peripheral stem cell transplant with rapid haemopoietic and biochemical reconstitution g. Clinical trials of enzyme replacement therapy with human recombinant N-acetylgalactosamine 4-sulfatase (rhASB) i. Well tolerated ii. Reduces lysosomal storage as evidenced by a dose-dependent reduction in urinary glycosaminoglycan iii. Clinical responses present in all patients a) An increase in distance walked b) Stair-climbing ability c) Shoulder range of motion d) Decrease in pain and arthritis iv. The largest gains occurred in patients with advanced disease receiving high-dose rhASB.
REFERENCES Akhtar S, Tullo A, Caterson B, et al.: Clinical and morphological features including expression of betaig-h3 and keratan sulphate proteoglycans in Maroteaux-Lamy syndrome type B and in normal cornea. Br J Ophthalmol 86:147–151, 2002. Alvaro F, Toogood I, Fletcher JM, et al.: Allogeneic CD34 selected peripheral stem cell transplant for Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI): rapid haemopoietic and biochemical reconstitution. Bone Marrow Transplant 21:419–421, 1998. Bacchus H, Peterson DI: Pregnancy complicated by myelopathy due to Maroteaux-Lamy syndrome. Am J Obstet Gynecol 136:259–260, 1980. Bartz HJ, Wiesner L, Wappler F: Anaesthetic management of patients with mucopolysaccharidosis IV presenting for major orthopaedic surgery. Acta Anaesthesiol Scand 43:679–683, 1999. Black SH, Pelias MZ, Miller JB, et al.: Maroteaux-Lamy syndrome in a large consanguineous kindred: biochemical and immunological studies. Am J Med Genet 25:273–279, 1986. Bradford TM, Litjens T, Parkinson EJ, et al.: Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome): a Y210C mutation causes either altered
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protein handling or altered protein function of N-acetylgalactosamine 4sulfatase at multiple points in the vacuolar network. Biochemistry 41:4962–4971, 2002. Cantor LB, Disseler JA, Wilson FM, II: Glaucoma in the Maroteaux-Lamy syndrome. Am J Ophthalmol 108:426–430, 1989. Di Ferrante N, Hyman BH, Klish W, et al.: Mucopolysaccharidosis VI (Maroteaux-Lamy disease). Clinical and biochemical study of a mild variant case. Johns Hopkins Med J 135:42–54, 1974. Dorfman A, Arbogast B, Matalon R: The enzymic defects in Morquio and Maroteaux-Lamy syndrome. Adv Exp Med Biol 68:261–276, 1976. Gardner DG: The dental manifestations of the Morquio syndrome (mucopolysaccharidosis type IV). A diagnostic aid. Am J Dis Child 129:1445–1448, 1975. Giugliani R, Jackson M, Skinner SJ, et al.: Progressive mental regression in siblings with Morquio disease type B (mucopolysaccharidosis IV B). Clin Genet 32:313–325, 1987. Goldberg MF, Scott CI, McKusick VA: Hydrocephalus and papilledema in the Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI). Am J Ophthalmol 69:969–975, 1970. Groebe H, Krins M, Schmidberger H, et al.: Morquio syndrome (mucopolysaccharidosis IV B) associated with beta-galactosidase deficiency. Report of two cases. Am J Hum Genet 32:258–272, 1980. Harmatz P, Whitley CB, Waber L, et al.: Enzyme replacement therapy in mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). J Pediatr 144:574–580, 2004. Hayflick S, Rowe S, Kavanaugh-Mchugh A, et al.: Acute infantile cardiomyopathy as a presenting feature of mucopolysaccharidosis VI. J Pediatr 120:269–272, 1992. Herskhovitz E, Young E, Rainer J, et al.: Bone marrow transplantation for Maroteaux-Lamy syndrome (MPS VI): long-term follow-up. J Inherit Metab Dis 22:50–62, 1999. Hollister DW, Cohen AH, Rimoin DL, et al.: The Morquio syndrome (mucopolysaccharidosis IV): Morphologic and biochemical studies. Johns Hopkins Med J 137:176–183, 1975. Hopwood JJ, Elliott H, Muller VJ, et al.: Diagnosis of Maroteaux-Lamy syndrome by the use of radiolabelled oligosaccharides as substrates for the determination of arylsulphatase B activity. Biochem J 234:507–514, 1986. John RM, Hunter D, Swanton RH: Echocardiographic abnormalities in type IV mucopolysaccharidosis. Arch Dis Child 65:746–749, 1990. Karageorgos L, Harmatz P, Simon J, et al.: Mutational analysis of mucopolysaccharidosis type VI patients undergoing a trial of enzyme replacement therapy. Hum Mutation 23:229–233, 2004. Kleijer WJ, Wolffers GM, Hoogeveen A, et al.: Letter: Prenatal diagnosis of Maroteaux-Lamy syndrome. Lancet 2:50, 1976. Krivit W, Pierpont ME, Ayaz K, et al.: Bone-marrow transplantation in the Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI). Biochemical and clinical status 24 months after transplantation. N Engl J Med 311:1606–1611, 1984.
Lee V, Li CK, Shing MM, et al.: Umbilical cord blood transplantation for Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI). Bone Marrow Transplant 26:455–458, 2000. Litjens T, Hopwood JJ: Mucopolysaccharidosis type VI: structural and clinical implications of mutations in N-acetylgalactosamine-4-sulfatase. Hum Mutat 18:282–295, 2001. Masuno M, Tomatsu S, Nakashima Y, et al.: Mucopolysaccharidosis IV A: assignment of the human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) gene to chromosome 16q24. Genomics 16:777–778, 1993. Matalon R, Arbogast B, Dorfman A: Deficiency of chondroitin sulfate Nacetylgalactosamine 4-sulfate sulfatase in Maroteaux-Lamy syndrome. Biochem Biophys Res Commun 61:1450–1457, 1974. Miller G, Partridge A: Mucopolysaccharidosis type VI presenting in infancy with endocardial fibroelastosis and heart failure. Pediatr Cardiol 4:61– 62, 1983. Muenzer J: Mucopolysaccharidoses. Adv Pediatr 33:269–302, 1986. Neufeld EF, Muenzer J: The Mucopolysaccharidosis. In: Scriver CR, Beardet AL, Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited disease Vol II, 7th ed, New York: McGraw-hill, 1995: 2465–2494. Paterson DE, Harper G, Weston HJ, et al.: Maroteaux-Lamy syndrome, mild form’MPS vi b. Br J Radiol 55:805–812, 1982. Rigante D, Antuzzi D, Ricci R, et al.: Cervical myelopathy in mucopolysaccharidosis type IV. Clin Neuropathol 18:84–86, 1999. Spranger JW, Koch F, McKusick VA, et al.: Mucopolysaccharidosis VI (Maroteaux-Lamy’s disease). Helv Paediatr Acta 25:337–362, 1970. Tan CT, Schaff HV, Miller FA Jr, et al.: Valvular heart disease in four patients with Maroteaux-Lamy syndrome. Circulation 85:188–195, 1992. Thorne JA, Javadpour M, Hughes DG, et al.: Craniovertebral abnormalities in Type VI mucopolysaccharidosis (Maroteaux-Lamy syndrome). Neurosurgery 48:849–852; discussion 852–843, 2001. Van Dyke DL, Fluharty AL, Schafer IA, et al.: Prenatal diagnosis of Maroteaux-Lamy syndrome. Am J Med Genet 8:235–242, 1981. Varssano D, Cohen EJ, Nelson LB, et al.: Corneal transplantation in Maroteaux-Lamy syndrome. Arch Ophthalmol 115:428–429, 1997. Vestermark S, Tonnesen T, Andersen MS, et al.: Mental retardation in a patient with Maroteaux-Lamy. Clin Genet 31:114–117, 1987. Voskoboeva E, Isbrandt D, von Figura K, et al.: Four novel mutant alleles of the arylsulfatase B gene in two patients with intermediate form of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Hum Genet 93:259–264, 1994. Vougioukas VI, Berlis A, Kopp MV, et al.: Neurosurgical interventions in children with Maroteaux-Lamy syndrome. Case report and review of the literature. Pediatr Neurosurg 35:35–38, 2001. Wald SL, Schmidek HH: Compressive myelopathy associated with type VI mucopolysaccharidosis (Maroteaux-Lamy syndrome). Neurosurgery 14:83–88, 1984. Young R, Kleinman G, Ojemann RG, et al.: Compressive myelopathy in Maroteaux-Lamy syndrome: clinical and pathological findings. Ann Neurol 8:336–340, 1980.
MPS VI (MAROTEAUX-LAMY SYNDROME)
Fig. 1. A boy with MPS VI showing dwarfism, short trunk with protruding sternum, and crouching stance.
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Fig. 2. A girl with MPS VI showing dwarfism, short trunk with sternal protrusion, and craw hands. The patient’s radiographs illustrate dysostosis multiplex.
Multiple Epiphyseal Dysplasia Multiple epiphyseal dysplasia is a type of short-limbed dwarfism characterized by impaired enchondral ossification affecting multiple epiphyses and premature degenerative joint disease.
GENETICS/BASIC DEFECTS 1. Inheritance: genetically heterogeneous a. Autosomal dominant i. Multiple epiphyseal dysplasia type I (EDM1) ii. Multiple epiphyseal dysplasia type II (EDM2) iii. Multiple epiphyseal dysplasia type III (EDM3) iv. Multiple epiphyseal dysplasia type V (EDM5) v. Multiple epiphyseal dysplasia type VI (EDM6) b. Autosomal recessive: multiple epiphyseal dysplasia type IV (EDM4) 2. Causes: a. EDM1: mutations in the gene (COMP) encoding cartilage oligomeric matrix protein (COMP) on the centromeric region of 19p (19p13.1-p12), same locus as (allelic to) pseudoachondroplasia (the disease that shares some clinical features with multiple epiphyseal dysplasia) b. EDM2: mutations in the type IX collagen, alpha-1 polypeptide gene (COL9A1) on 6q13 c. EDM3: mutations in the type IX collagen, alpha-2 polypeptide gene (COL9A2) on 1p33-p32.3 d. EDM4: mutations in the diastrophic dysplasia sulphate transporter gene (DTDST) on 5q32-q33.1 e. EDM5: mutations in the gene (MATN3) encoding matrilin-3 on 2p24-p23 f. EDM6: mutations in the type IX collagen, alpha-3 polypeptide gene (COL9A3) on 20q13.3 3. Mutations in extracellular matrix proteins, COMP, types II and IX collagens, and matrilin-3 a. Produce a spectrum of mild to severe chondrodysplasias characterized by epiphyseal and vertebral abnormalities b. Disrupt protein processing and excessive accumulation of some of these proteins in the rER that appears to compromise cellular function 4. Genotype–phenotype correlations a. Patients with COMP mutations i. Significant involvement at the capital femoral epiphyses ii. Irregular acetabuli b. Patients with type IX collagen defects i. More severe involvement of the knees ii. Relative sparing of the hips c. Patients with MATN3 mutations i. Abnormalities similar to those in patients with COL9A2 mutations: more severe hip abnormalities ii. More intra/interfamilial variability
CLINICAL FEATURES 1. Broad historical classification a. Ribbing: milder form with flat epiphyses and minimal involvement of the hands and feet b. Fairbank: more severe form with late appearing epiphyses and greater involvement of the hands and feet 2. Onset: usually in childhood a. Waddling gait b. Easy fatigue c. Joint pain after exercise d. Limp, pain, and stiffness in hip, knee, and ankle joints 3. Mild to moderate short stature with normal body proportion 4. Mild short-limb dwarfism 5. Stubby hands and feet 6. Osteoarthritis: severe osteoarthritis of the hip develops in early childhood 7. Limited joint motions 8. Hip pain 9. Proximal muscle weakness with mild variability in muscle fiber size in EDM3 10. Association with diabetes mellitus in early infancy (Wolcott-Rallison syndrome) 11. Prognosis a. Normal life expectancy b. Joint deformities resulting from abnormal epiphyseal ossification frequently leading to early degenerative arthroses
DIAGNOSTIC INVESTIGATIONS
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1. Radiography a. Radiographic abnormalities may be present before the onset of physical symptoms b. Predominantly epiphyseal involvement i. Initial stage: delayed appearance of epiphyseal ossification ii. Later stage in the appearance of epiphysis a) Usually small ossification centers b) Sometimes fragmented ossification centers with irregular contours c) Adjacent metaphyseal borders may be slightly abnormal iii. Adulthood a) Flattened and dysplastic articular surfaces b) Presence of early features of osteoarthrosis iv. Characteristic epiphyseal involvement a) Epiphyses of the hips and knees: most affected b) Ivory epiphyses in the hands c) Schmorl nodes in the spine d) Double-layered patella c. Vertebrae i. Ovoid vertebral bodies ii. Mildly irregular vertebral endplates
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d. Limbs i. Late ossifying epiphyses ii. Small, irregular, fragmented, and in some cases flattened epiphyses iii. Osteoarthritis iv. Short femoral neck v. Markedly dysplastic capital femoral epiphyses vi. Often initially diagnosed as Legg-Perthes disease (avascular necrosis of femoral head) vii. Genu varum or valgum viii. Short metacarpals and phalanges with irregular epiphyses ix. Small, irregular carpal and tarsal bones x. Normal metaphyses e. Irregular acetabuli f. Patella i. Doubled-layered ii. Dislocation or subluxation g. Absence of severe spinal involvement and minimal metaphyseal defects allows differentiating multiple epiphyseal dysplasia from other disorders with similar clinical features such as spondyloepimetaphyseal dysplasia and spondyloepiphyseal dysplasia 2. Histology: chondrocytic inclusion (ultrastructurally, a dilated rER containing accumulated material) 3. Mutation analyses: available on clinical basis a. Mutations in the COMP gene b. Mutations in the COL9A1 gene c. Mutations in the COL9A2 gene d. Mutations in the COL9A3 gene e. Mutations in the MATN3 gene f. Mutations in the DTDST gene
GENETIC COUNSELING 1. Recurrence risk a. Autosomal dominant inheritance i. Patient’s sib a) 50% if one of the parent is affected b) Not increased if parents are normal ii. Patient’s offspring: 50% b. Autosomal recessive inheritance i. Patient’s sib: 25% ii. Patient’s offspring: not increased unless the spouse is also carrying the gene 2. Prenatal diagnosis for pregnancies at risk for COMP and other mutations is possible if the disease-causing allele of an affected family member has been identified a. Amniocentesis b. CVS 3. Management a. Initial aims of management i. Control pain a) Can be difficult b) Combination of analgesics and physiotherapy including hydrotherapy ii. Limit joint destruction and the development of osteoarthritis b. Weight control
c. Avoid exercise that causes repetitive strain on affected joints d. Realignment osteotomy and/or acetabular osteotomy to slow the progression of symptoms e. Total joint arthroplasty in some cases f. Psychosocial support to address issues of short stature, disability, and employment
REFERENCES Ballhausen D, Bonafé L, Superti-Furga A: Multiple epiphyseal dysplasia, recessive. Gene Reviews, 2002. http://www.genetests.org Ballo R, Briggs MD, Cohn DH, et al.: Multiple epiphyseal dysplasia, Ribbing type: a novel point mutation in the COMP gene in a South African family. Am J Med Genet 68: 396–400, 1997. Berg PK: Dysplasia epiphysialis multiplex: a case report and review of the literature. Am J Roentgen 97: 31–38, 1966. Briggs MD, Hoffman SMG, King LM, et al.: Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nature Genet 10: 330–336, 1995. Briggs MD, Mortier Genome Res, Cole WG, et al.: Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasiamultiple epiphyseal dysplasia disease spectrum. Am J Hum Genet 62:311–319, 1998. Briggs MD, Wright MJ, Mortier, GR: Multiple epiphyseal dysplasia, dominant. Gene Reviews, 2005. http://www.genetests.org. Chapman KL, Briggs MD, Mortier GR: Review: clinical variability and genetic heterogeneity in multiple epiphyseal dysplasia. Pediatr Pathol Mol Med 22:53–75, 2003. Czarny-Ratajczak M, Lohiniva J, Rogala P, et al.: A mutation in COL9A1 causes multiple epiphyseal dysplasia. Further evidence for locus heterogeneity in MED. Am J Hum Genet 69:969–980, 2001. Deere M, Blanton SH, Scott CI, et al.: Genetic heterogeneity in multiple epiphyseal dysplasia. Am J Hum Genet 56: 698–704, 1995. Deere M, Sanford T, Francomano C, et al.: Identification of nine novel mutations in cartilage oligomeric matrix protein in patients with pseudoachondroplasia and multiple epiphyseal dysplasia. Am J Med Genet 85:486–490, 1999. Fairbank HAT: Dysplasia epiphysealis multiplex. Proc Roy Soc Med 39: 315–317, 1945. Hoefnagel D, Sycamore LK, Russell SW, et al.: Hereditary multiple epiphysial dysplasia. Ann Hum Genet 30: 201–210, 1967. Hunt DD, Ponseti IV, Pedrini-Mille A, et al.: Multiple epiphyseal dysplasia in two siblings. J Bone Joint Surg 49A: 1611–1627, 1967. Ikegawa S, Ohashi H, Nishimura G, et al.: Novel and recurrent COMP (cartilage oligomeric matrix protein) mutations in pseudoachondroplasia and multiple metaphyseal dysplasia. Hum Genet 103:633–638, 1998. Jacobs PA: Dysplasia epiphysialis multiplex. Clin Orthop 58: 117–128, 1968. Leeds NE: Epiphysial dysplasia multiplex. Am J Roentgen 84: 506–510, 1960. Mäkitie O, Mortier GR, Czarny-Ratajczak M, et al.: Clinical and radiographic findings in multiple epiphyseal dysplasia caused by MATN3 mutations: description of 12 patients. Am J Med Genet 125A:278–284, 2004. Maudsley RH: Dysplasia epiphysialis multiplex: a report of fourteen cases in three families. J Bone Joint Surg 37B: 228–240, 1955. Mortier GR, Chapman K, Leroy JL, et al.: Clinical and radiographic features of multiple epiphyseal dysplasia not linked to the COMP or type IX collagen genes. Europ J Hum Genet 9: 606–612, 2001. Muragaki Y, Mariman ECM, van Beersum SEC, et al.: A mutation in the gene encoding the alpha-2 chain of the fibril-associated collagen IX, COL9A2, causes multiple epiphyseal dysplasia (EDM2). Nature Genet 12: 103–105, 1996. Murphy MC, Shine I, Stevens DB: Multiple epiphyseal dysplasia: report of a pedigree. J Bone Joint Surg 55A: 814–820, 1973. Oehlmann R, Summerville GP, Yeh G, et al.: Genetic linkage mapping of multiple epiphyseal dysplasia to the pericentromeric region of chromosome 19. Am J Hum Genet 54: 3–10, 1994. Paassilta P, Lohiniva J, Annunen S, et al.: COL9A3: A third locus for multiple epiphyseal dysplasia. Am J Hum Genet 64: 1036–1044, 1999. Sheffield E. G: Double-layered patella in multiple epiphyseal dysplasia: a valuable clue in the diagnosis. J Pediatr Orthop 18: 123–128, 1998.
MULTIPLE EPIPHYSEAL DYSPLASIA Stanescu R, Stanescu V, Muriel M.-P, et al.: Multiple epiphyseal dysplasia, Fairbank type: morphologic and biochemical study of cartilage. Am J Med Genet 45: 501–507, 1993. Superti-Furga A, Neumann L, Riebel T, et al.: Recessively inherited multiple epiphyseal dysplasia with normal stature, clubfoot, and double layered patella caused by a DTDST mutation. J Med Genet 36: 621–624, 1999. Superti-Furga A, Spbetzko D, Hecht JT, et al.: Recessive multiple epiphyseal dysplasia (rMED: MIM 226900): phenotype delineation in twelve individuals homozygous for DTST mutation R279W. Am J Hum Genet 67 (Suppl 2):379, 2000. Thornton CM, Carson DJ, Stewart FJ: Autopsy findings in the Wolcott-Rallison syndrome. Pediatr Pathol Lab Med 17:487–496, 1997.
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Unger S, Hecht JT: Pseudoachondroplasia and multiple epiphyseal dysplasia: new etiologic developments. Am J Med Genet (Semin Med Genet) 106:244–250, 2001. Unger SL, Briggs MD, Holden P, et al.: Multiple epiphyseal dysplasia: radiographic abnormalities correlated with genotype. Pediatr Radiol 31:10–18, 2001. Villarreal T, Carnevale A, Mayen DG, et al.: Anthropometric studies in five children and their mother with a severe form multiple epiphyseal dysplasia. Am J Med Genet 42: 415–419, 1992. Watt JK: Multiple epiphyseal dysplasia: report of four cases. Brit J Surg 39: 533–535, 1952. Waugh W: Dysplasia epiphysialis multiplex in three sisters. J Bone Joint Surg 34B: 82–87, 1952.
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Fig. 1. A boy with multiple epiphyseal dysplasia showing short stature and epiphyseal dysplasia in the wrists, hips, and knee joints.
Fig. 2. A girl and an adult female with multiple epiphyseal dysplasia showing mild short stature with normal body proportion.
MULTIPLE EPIPHYSEAL DYSPLASIA
Fig. 3. Radiograph of the pelvis of a 12-year-old boy with multiple epiphyseal dysplasia showing poorly developed acetabular fossae and flat, fragmented femoral heads.
Fig. 4. Radiographs of another patient with multiple epiphyseal dysplasia showing poorly formed acetabular fossae, poorly ossified femoral heads, and flattened epiphyses of the knees and ankles.
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Multiple Pterygium Syndrome Multiple pterygium syndrome is a distinct syndrome consisting of a constellation of congenital anomalies characterized by pterygia of the neck, antecubital, popliteal and intercrural areas, numerous flexion contractures of the joints, growth retardation, ptosis, antimongoloid slant with or without epicanthal folds, cleft palate, scoliosis, vertebral anomalies, rocker bottom deformity of the feet, and genital anomalies.
CLINICAL FEATURES 1. Short stature 2. Cutaneous and musculoskeletal a. Pterygia involving the following areas: i. Neck ii. Axillary iii. Antecubital iv. Popliteal v. Digital vi. Intercrural b. Multiple joint contractures c. Rib or vertebral anomalies d. Scoliosis/lordosis e. Rocker-bottom feet with vertical talus 3. Standing with a crouching or semi-crouching stance 4. Orofacial features a. A flat, sad, motionless facial appearance b. Epicanthal folds c. Ptosis d. Antimongoloid palpebral fissure e. Long philtrum f. Pointed, receding chin g. Down-turned angles of the mouth h. Cleft lip +/– palate i. Apparent low-set ears 5. Genitalia a. Males i. Small penis and scrotum ii. Cryptorchidism b. Females i. Apparent aplasia of the labia majora ii. A small clitoris
GENETICS/BASIC DEFECTS 1. Inheritance: genetic heterogeneity a. Autosomal recessive inheritance in most cases b. Autosomal dominant inheritance in some cases 2. Phenotypic analysis a. Multiple congenital pterygia, joint contractures and severe foot defects: deformation sequence secondary to reduced frequency of fetal movement b. Micrognathia: resulting from reduced use and represents “disuse hypotrophy” c. Cleft palate: a mechanical disruption due to presumed inter-position of tongue between palatine shelves d. Neck pterygia i. Able to exert a downward pull on facial structures ii. Responsible for the following effects: a) Down-turned angles of the mouth b) Long philtrum c) Anti-mongoloid slant of palpebral fissures d) Low posterior hairline e) Anteversion and apparently low-set position of auricles f) Often with strikingly abnormal directional hair patterning in posterior and posterior-lateral areas of scalp iii. Short neck due to: a) Lateral cervical pterygia b) Secondary fusion of upper vertebrae e. Congenital scoliosis: secondary to abnormal prenatal position, movement, and/or muscle pull f. Genital anomalies i. Small scrotum and apparently absent or hypoplastic labia majora: resulting from the pull of the intercrural pterygia which affects a flattening of these structures ii. Cryptorchidism: representing mechanical obstruction of the processus vaginalis from pull of intercrural web or some intrinsic defect of the gubernaculums testis which is unable to effect descent of the gonads 3. Pathogenesis: the underlying pathogenesis of the secondary deformities and distortions, hypotrophies, disruptions, bony fusions, and incomplete or impeded morphogenetic movements is unknown
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Multiple joint contractures b. Fusion of cervical vertebrae c. Scoliosis/lordosis d. Flexion contractures of fingers e. Rocker-bottom feet with vertical talus 2. Pathological evaluations of muscle and nerve tissue: no consistent abnormality
GENETIC COUNSELING
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1. Recurrence risk a. Patient’s sib i. Autosomal recessive inheritance: 25% ii. Autosomal dominant inheritance: not increased unless a parent is also affected
MULTIPLE PTERYGIUM SYNDROME
b. Patient’s offspring i. Autosomal recessive inheritance: not increased unless the spouse is a carrier ii. Autosomal dominant inheritance: 50% 2. Prenatal diagnosis possible by ultrasonography for the family at risk a. Micrognathia b. Low-set ears c. Hypertelorism d. Cystic hygroma colli e. Rocker-bottom feet 3. Management a. Correction of the hand deformities i. Attention given to any deformities in the shoulder and elbow to maximize function of the limb before initiating correction of hand deformities ii. Intensive physiotherapy and occupational therapy preferable to surgery for management of the upper extremity and hand anomalies b. Correction of mild hip flexion contractures of <30° due to inguinal webbing and crouched stance: responding well to active and passive stretching programs c. Correction of popliteal webbing i. Physiotherapy ii. Traction iii. Popliteal skin web Z-plasty with serial casting or with cable grafting the sciatic nerve (to achieve further knee extension and independent ambulation) iv. Arthrodesis v. Amputation vi. Excision of a significant fibrous band extending from the ischium to the calcaneus allows significant improvement in extension d. Correction of knee flexion contracture <25° without severe ambulatory limitations: conservative, consisting of a stretching program and night splints e. Correction of knee flexion contracture of 25° to 90° i. Physiotherapy followed by popliteal Z-plasty, fibrous band excision, and lengthening of all tense structures that are not neurovascular ii. Postoperative serial casting iii. Cable grafting or femoral shortening for neurovascular compromised cases f. Correction of knee flexion contracture of >90° which poses significant ambulatory difficulty i. Arthroses in extension ii. Disarticulation g. Correction of vertical talus i. Children 6 years or younger: treated with soft tissue procedures and/or Grice subtalar arthodeses ii. Children over 6 years: undergo triple arthrodesis at age 12
REFERENCES Angle B, Hersh JH, Yen F, et al.: XY gonadal dysgenesis associated with a multiple pterygium syndrome phenotype. Am J Med Genet 68:7–11, 1997. Aslan Y, Erduran E, Kutlu N: Autosomal recessive multiple pterygium syndrome: a new variant? Am J Med Genet 93:194–197, 2000.
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Chen H, Chang CH, Misra RP, et al.: Multiple pterygium syndrome. Am J Med Genet 7:91–102, 1980. Di Gennaro GL, Greggi T, Parisini P: Scoliosis in Escobar syndrome (multiple pterygium syndrome). Description of two cases. Chir Organi Mov 81:317–323, 1996. Escobar V, Bixler D, Gleiser S, et al.: Multiple pterygium syndrome. Am J Dis Child 132:609–611, 1978. Fryns JP, Vandenberghe K, Moerman P, et al.: Cystic hygroma and multiple pterygium syndrome. Ann Genet 27:252–253, 1984. Fryns JP, Volcke P, van den Berghe H: Multiple pterygium syndrome type Escobar in two brothers. Follow-up data from childhood to adulthood. Eur J Pediatr 147:550–552, 1988. Gillin ME, Pryse-Davis J: Pterygium syndrome. J Med Genet 13:249–251, 1976. Goh A, Lim KW, Rajalingam V: Multiple pterygium syndrome (Escobar syndrome)—a case report. Singapore Med J 35:208–210, 1994. Hall JG, Reed SD, Rosenbaum KN, et al.: Limb pterygium syndromes: a review and report of eleven patients. Am J Med Genet 12:377–409, 1982. Holtmann M, Woermann FG, Boenigk HE: Multiple pterygium syndrome, bilateral periventricular nodular heterotopia and epileptic seizures “a syndrome” Neuropediatrics 32:264–266, 2001. Kok JG, Gabreels FJ, Renier WO, et al.: Multiple pterygium syndrome. A report of two unrelated cases. Clin Neurol Neurosurg 86:101–105, 1984. Kuzma PJ, Calkins MD, Kline MD, et al.: The anesthetic management of patients with multiple pterygium syndrome. Anesth Analg 83:430–432, 1996. Lembet A, Oktem M, Yilmaz Z, et al.: Prenatal diagnosis of multiple pterygium syndrome associated with Klinefelter syndrome. Prenat Diagn 23:728–730, 2003. Liu DC, Tsai FJ, Chen HW, et al.: Multiple pterygium syndrome: report of one case. Acta Paediatr Taiwan 40:192–194, 1999. MacArthur CJ, Pereira S: Otolaryngologic manifestations of multiple pterygium syndrome. Int J Pediatr Otorhinolaryngol 34:135–140, 1996. Madhuri V, Bose A, Danda S, et al.: Chromosomes 6/7 translocation t(6:7)(q15;32) presenting as multiple pterygium syndrome. Indian Pediatr 38:194–197, 2001. McCall RE, Budden J: Treatment of multiple pterygium syndrome. Orthopedics 15:1417–1422, 1992. McKeown CM, Harris R: An autosomal dominant multiple pterygium syndrome. J Med Genet 25:96–103, 1988. Naguib KK, Teebi AS, Al-Awadi SA, et al.: Multiple pterygium syndrome in five Arab sibs. Ann Genet 30:122–125, 1987. Ohkubo M, Ino T, Shimazaki S, et al.: Multicore myopathy associated with multiple pterygium syndrome and hypertrophic cardiomyopathy. Pediatr Cardiol 17:53–56, 1996. Ozkinay FF, Ozkinay C, Akin H, et al.: Multiple pterygium syndrome. Indian J Pediatr 64:113–116, 1997. Papadia F, Longo N, Serlenga L, et al.: Progressive form of multiple pterygium syndrome in association with nemalin-myopathy: report of a female followed for twelve years. Am J Med Genet 26:73–83, 1987. Penchaszadeh VB, Salszberg B: Multiple pterygium syndrome. J Med Genet 18:451–455, 1981. Ramer JC, Ladda RL, Demuth WW: Multiple pterygium syndrome. An overview. Am J Dis Child 142:794–798, 1988. Robinson LK, O’Brien NC, Puckett MC, et al.: Multiple pterygium syndrome: a case complicated by malignant hyperthermia. Clin Genet 32:5–9, 1987. Stoll C, Levy JM, Kehr P, et al.: Familial pterygium syndrome. Clin Genet 18:317–320, 1980. Teebi AS: Not a new variant of the autosomal recessive multiple pterygium syndrome but the Bartsocas-Papas syndrome. Am J Med Genet 101:78–79, 2001. Teebi AS, Daoud AS: Multiple pterygium syndrome: a relatively common disorder among Arabs. J Med Genet 27:791, 1990. Thompson EM, Donnai D, Baraitser M, et al.: Multiple pterygium syndrome: evolution of the phenotype. J Med Genet 24:733–749, 1987. Wee AS, Bock HG, Bobo H: Multiple pterygium syndrome: neuromuscular findings in a case. J Miss State Med Assoc 31:327–330, 1990. Willems PJ, Colpaert C, Vaerenbergh M, et al.: Multiple pterygium syndrome with body asymmetry. Am J Med Genet 47:106–111, 1993. Zeitune M, Fejgin MD, Abramowicz J, et al.: Prenatal diagnosis of the pterygium syndrome. Prenat Diagn 8:145–149, 1988.
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MULTIPLE PTERYGIUM SYNDROME
Fig. 1. Two Honduran siblings (a 5-year-old girl and a 9-year-old boy) with multiple pterygium syndrome showing multiple pterygia involving neck, axillary, antecubital, popliteal, and intercrural areas. In addition, they had multiple joint contractures affecting hips, elbows, interphalangeal, and popliteal joints, semi-crouching stance, and rocker bottom feet due to vertical tali. Vigorous physiotherapy was performed initially for both upper and lower extremity contractures. Popliteal Z-plasty with release of the posterior capsule and excision of a fibrous band extending from the ischial tuberosity to the calcaneus resulted in better knee extension, but further correction was limited by tight neurovascular structures. Vertical tali were addressed surgically with triple arthrodeses on the boy at age 12 and soft tissue release combined with a Grice subtalar arthrodesis on the girl at age 6. Both children attained painless plantigrade feet at discharge.
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Fig. 2. Three Nicaraguan siblings (parents are third cousins) with multiple pterygium syndrome showing similar features. Radiographs showed rocker bottom feet with vertical talus and the fusion of cervical vertebrae. Patient 1 (7-year-old boy) had motionless facial appearance, cleft palate, multiple flexion contractures, and severe webbing at the antecubital and popliteal fossae, and interphalangeal regions. He also had severe foot deformities with calcaneus heels and vertical talus. Patient 2 (9-year-old girl) crawled at 4 years of age but had never walked. She was much more severely affected. Patient 3 (11year-old boy) walked with difficulty but much less severely affected than younger brother and sister. Digital deformities were addressed surgically with some recurrence of original deformities. Hip flexion contractures were addressed with an active stretching program and prone positioning resulting in satisfactory resolution. Popliteal webbing was treated by either physiotherapy alone and/or operative procedures. Bilateral congenital tali were treated by either bilateral talectomy or arthrodesis with partial talectomies.
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Fig. 3. A boy with a sporadic case of multiple pterygium syndrome showing multiple pterygia, long philtrum, receding chin, cleft palate, low-set ears, and multiple contractures.
Myotonic Dystrophy Type I iii. Relation of cardiac abnormalities and CTGrepeat size in myotonic dystrophy a) Increased cardiac involvement with increasing CTG-repeat size in patients age 21–50 b) The number of CTG-repeats needed to develop a reasonable cardiac involvement is higher in young patients than in older patients
Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy affecting adults with an estimated incidence of 1 in 8000 among Caucasians.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal dominant 2. Molecular genetic perspective a. Considerable variability of phenotype between affected individuals even within the same family b. An association of myotonic dystrophy with specific haplotypes in the population, indicating that most cases have resulted from a small number of genetic events c. Multi-systemic nature of the phenotype d. An apparent increase in severity of symptoms and reduction in age at onset that is observed during transmission of the gene within families 3. Genetic defect: caused by an expanded CTG (cytosinethymine-guanine)-repeat in the dystrophia myotonica phosphokinase (DMPK) gene a. Encodes for a serine-threonine protein kinase b. Mapped on chromosome 19q13.3 4. CTG triplet repeat a. Transcribed and located in the 3’ untranslated region of an mRNA that is expressed in tissues affected by myotonic dystrophy b. Repeat size i. Highly variable in the normal population (5–36 triplets) ii. Undergoing expansion in myotonic dystrophy patients (50-several thousand copies) a) Expansion of at least 50 repeats in patients who are minimally affected b) Expansion of up to several kilobase pairs in more severely affected patients c. Intergenerational instability (unstable CTG expansion at mitotic and meiotic levels with a bias towards length increase in the successive generations) i. Accounting for anticipation (the CTG-repeat size increases in successive generations in parallel with increasing severity of the disease) ii. Accounting for somatic instability and mosaicism (the CTG-repeat size varies considerably among different tissues and organs with coexistence in the same subject of cell lines with different CTG-repeats) d. Genotype–phenotype correlations i. Size of the CTG trinucleotide repeats generally correlated with the age of onset and clinical severity of the disease ii. Longer CTG repeat expansions correlate, in general, with an earlier age of onset and more severe disease
CLINICAL FEATURES
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1. Highly variable phenotypic expression and age of onset a. The mildest form i. Seen in middle or old age ii. Characterized by cataracts and baldness with little or no muscle involvement iii. Occasionally difficult to diagnose: the pleomorphic manifestations, due to a dynamic mutation in the length of CTG repeat, lead to difficulty in clinical identification of asymptomatic or mildly affected patients b. The classic (juvenile or adult) form i. The more common form ii. Usually becoming evident between the ages of 15 and 35 years iii. Phenotypically variable iv. Characteristic clinical features a) Myotonia b) Muscle weakness c) Cardiac arrhythmias d) Male balding e) Hypogonadism f) Psychocognitive dysfunction g) Glucose intolerance c. The most severe (congenital) form i. Recognized at birth or in the neonatal period ii. Pregnancy a) Maternal polyhydramnios b) Reduced fetal movement c) Breech presentation d) Prematurity iii. Associated with generalized muscular hypotonia iv. Respiratory distress a) Aspiration pneumonia b) Recurrent bronchitis c) Hypoventilation d) Sleep apnea e) Bronchiectasis v. Feeding difficulties vi. Dysphagia vii. Nasal regurgitation viii. Facial diplegia with a “tented-shaped” mouth ix. Delayed motor development
MYOTONIC DYSTROPHY TYPE I
x. xi. xii. xiii.
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Joint deformities Mental retardation High neonatal mortality Those survived invariably exhibiting the classical form of the disease in late childhood or adolescence xiv. Almost all congenital cases are exclusively maternally transmitted xv. The phenomenon of anticipation often most strikingly manifested in a family producing a congenitally affected child Neurologic manifestations a. Myotonia (delayed relaxation of muscles after an initial contraction) (100%) b. Muscle weakness and atrophy i. Muscles most prominently affected a) Superficial facial muscles b) Levator palpebrae superioris c) Temporalis d) Sternocleidomastoids e) Distal muscles of forearm f) Dorsiflexors of foot ii. Other muscles commonly affected a) Quadriceps b) Diaphragm and intercostals c) Intrinsic muscles of hand and feet d) Palate and pharyngeal muscles e) Tongue f) External ocular muscles c. Percussion myotonia and voluntary myotonia aggravated by cold d. Dysarthria e. Slow nasal indistinct speech f. Foot drop g. Step page gait h. Contractures of the Achilles tendon i. Diminished deep tendon reflexes j. Cognitive and behavioral abnormalities Craniofacial appearance a. Long thin face b. Flat, sagging, sad, and expressionless face c. Frontal bossing d. Hollow temple secondary to atrophy of temporalis e. Bilateral facial weakness (facial diplegia) f. Tented mouth g. Micrognathia h. Swan neck appearance (sternocleidomastoid muscle wasting) Ocular findings a. Cataracts (>85%) b. Ptosis c. Extraocular weakness d. Peripheral retinal changes e. Coloboma of retina/choroid f. Optic atrophy g. Blepharospasms h. Decreased ocular pressure Cardiac involvement (76%) a. An integral part of myotonic dystrophy targeting: i. Almost selectively the conduction system ii. Less specifically the myocardium
6.
7.
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b. Electrocardiographic conduction abnormalities i. Manifesting with or without ventricular tachyarrhythmias or brady-arrhythmias ii. The first-degree atrioventricular (AV) block (most common) iii. Intraventricular conduction abnormalities (premature ventricular complexes like couplets and triplets) iv. Atrial arrhythmias (atrial fibrillation and flutter) c. A high incidence of sudden death d. Possible cardiomyopathy e. Congestive heart failure (6%) Gastrointestinal findings a. Achalasia b. Gastroparesis c. Constipation d. Megacolon e. Gallstones Genitourinary findings a. Dysuria b. Urinary retention c. Polycystic kidneys d. Testicular atrophy Endocrine findings a. Hypogonadism b. Male infertility secondary to testicular atrophy c. Hypothyroidism d. Goiter/hyperparathyroidism e. Multiple endocrine neoplasia type 2A (pheochromocytoma and amyloid-producing medullary thyroid carcinoma) f. Dysmenorrhea g. Postprandial hyperinsulinemia Joint deformities a. Arthrogryposis b. Talipes Female patients a. Decreased total reproductive rate b. Higher rate of spontaneous abortions Occasional accompanying benign or malignant neoplasms a. Pilomatrixoma b. Parathyroid adenoma c. Small bowel carcinoma d. Neurofibromatosis e. Thymoma f. Pleomorphic adenoma of the parotid gland g. Pituitary adenoma h. Ovarian cancer i. Ovarian cyst j. Laryngeal cancer Natural history a. Usually progressive b. Usually leading to severe disability within 15–20 years c. Greatly reduced life expectancy, particularly in the case of an early disease onset and proximal muscle involvement d. The high mortality rate reflecting an increase in deaths due to: i. Respiratory diseases ii. Cardiovascular diseases
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iii. Neoplasms iv. Sudden deaths induced by cardiac arrhythmias 13. Differential diagnosis a. Myotonic dystrophy type 2 (DM2) i. Reported by Day et al. (1999): a five-generation family from Minnesota with an unusual form of myotonic dystrophy ii. Clinical characteristics similar to those of DM1 a) Myotonic b) Distal weakness c) Frontal balding d) Polychromatic cataracts e) Infertility f) Cardiac arrhythmias iii. Molecular genetic analysis a) No CTG expansion associated with DM1 b) No linkage of the disease locus to the DM1 region on chromosome 19 c) Exclusion of a disease locus from the chromosomal regions containing the gene of muscle sodium and chloride channels, both of which are involved in other myotonic disorders d) The disease locus in this family mapped to a 10-centimorgan region of chromosome 3q iv. Sharing many clinical features of previously reported proximal myotonic myopathy (PROMM) but distinguished by the presence of significant early distal weakness and severe cardiac arrhythmias b. Proximal myotonic myopathy i. Autosomal dominant disorder ii. Clinical features a) Proximal muscle weakness b) Myotonia c) Cataracts d) Symptoms usually appearing between 30 and 40 years of age e) No infantile form comparable to severe congenital DM1 observed iii. Molecular genetic analysis: a normal size of the [GTG]n repeat in the DM1 gene c. Proximal myotonic dystrophy (PDM) i. Reported by Udd et al. in 1977: a 4-generation family from Finland’s Vasa region ii. An autosomal dominant disorder iii. Clinical features a) Late-onset proximal muscular dystrophy b) Electrophysiological myotonia c) Cataracts d) Late-onset deafness e) Male hypogonadism iv. Differential diagnosis from PROMM a) Similarities: prominent proximal weakness, inconstant clinical and electrical myotonia, and cataracts b) Differences: more severe muscle involvement (atrophy of the affected muscles and dystrophic changes on muscle biopsy and computed tomography scan) and hearing loss
v. Molecular genetic testing a) No expansion of the unstable [CTG]n trinucleotide repeat on chromosome 19q13.3 b) Exclusion of the linkage with three known myotonia loci: DMPK, CLCN1, and SCN4
DIAGNOSTIC INVESTIGATIONS 1. Clinical examination to search muscle and nonmuscle manifestations 2. Lab: mildly elevated serum creatine kinase 3. Electromyography to identify subclinical myotonia 4. Slit-lamp examination to detect characteristic cataracts 5. Muscle biopsy a. Diagnostic but not indicated or useful for routine clinical evaluation b. Atrophic small type I fibers c. An increase in central nuclei d. Ringed fibers 6. Radiography a. Kyphosis of cervical spine b. Thin ribs observed in neonates suffering from myotonic dystrophy 7. Electrocardiogram abnormalities (60–70%) a. ST abnormalities b. AV block I c. Increased QTc-interval d. Tall R and/or S-waves e. Left anterior hemi-block f. Supraventricular ectopic beats g. T-wave abnormalities h. Pace-maker i. Missing R-progression j. Abnormal U-wave k. Left bundle branch block 8. Echocardiography a. Septal thickness >11 mm b. Posterior wall thickness >11 mm c. Fractional shortening <30% d. E/A ratio >1 e. Left ventricular end-diastolic diameter >57 mm f. Valve abnormalities 9. DNA testing for CTG repeat size a. Gold standard for the diagnosis of DM1 b. CTG repeat size in various phenotype i. Normal: 5–37 ii. Premutation: 38–49 iii. Mild: 50–150 iv. Classical: 100–1500 v. Congenital: 1000 ≥ 2000 10. Presymptomatic carrier testing a. Leukocyte DNA analysis: provides an earlier opportunity to diagnose DM1 in family members at risk who are clinically asymptomatic b. Providing more aggressive monitoring program to detect: i. Early cardiac conduction disturbance ii. Cataract formation iii. Respiratory difficulties iv. At risk of developing anesthetic complications, especially delayed-onset apnea
MYOTONIC DYSTROPHY TYPE I
GENETIC COUNSELING 1. Recurrence risk a. General principle for genetic counseling i. A normal molecular analysis excludes the risk of developing or transmitting myotonic dystrophy in essentially all situations ii. For women who have had a child with congenital myotonic dystrophy, almost all subsequently affected pregnancies are likely to be severely affected iii. Clinically affected women, in general, have around a 30 percent chance that an affected child would have congenital or severe childhood myotonic dystrophy. The risk of a congenitally affected child is related to maternal repeat size iv. The risk for the healthy sib of a congenitally affected patient developing the disorder after childhood is low v. For the adult healthy sib of an adult onset case, the risk of carrying the mutation is also low (around 10%), with about half of this developing clinically significant disease b. Patient’s sib: recurrence risk depending on the genetic status of the parents i. Not increased if both parents are normal ii. 50% risk if the mother is affected iii. Minimal risk (<1%) if the father is affected c. Patient’s offspring i. Offspring of an individual with an expanded allele (>37 CTG repeats) have a 50% chance of inheriting the mutant allele ii. Disease-causing alleles may expand in length during gametogenesis, resulting in the transmission of longer CTG trinucleotide repeat alleles that may be associated with earlier onset and more severe disease than that observed in the parent 2. Prenatal diagnosis a. Prenatal ultrasonography in congenital myotonic dystrophy i. Polyhydramnios ii. Talipes iii. Decreased fetal movements reflecting the neuromuscular failure of swallowing and movement b. Prenatal diagnosis possible by using mutation analysis and detection of the CTG repeat expansion with the DMPK gene in amniocytes or chorionic villi c. More challenging by using the CTG repeat test to determine whether the fetus is at risk for the severe form of myotonic dystrophy i. Generally, in amniocytes, congenital myotonic dystrophy is association with CTG repeat expansion larger than that of the affected mother ii. CTG repeat size may change over time in CVS or amniocentesis, providing different CTG repeat size at different gestational ages d. Counseling of pregnant patients affected with myotonic dystrophy i. An explanation of the risk associated with anticipation, which is the tendency toward large inter-
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generational expansion of the CTG repeat during maternal transmission resulting in offspring with congenital myotonic dystrophy ii. CTG repeat number provides only an approximate guide to prognosis or to pregnancy outcome. Most cases with over 2000 repeats will have congenital or severe childhood onset disease; most individuals with 50 to 100 repeats will not have significant neuromuscular disease iii. An intergenerational contraction of the CTG fragment observed in approximately 7% of cases. Clinical anticipation was seen despite the reduced CTG repeat size, resulting in congenital myotonic dystrophy in the offspring 3. Management a. No specific treatment available for the progressive weakness that is responsible for most of the disability in patients with myotonic dystrophy b. To alleviate myotonia by drugs i. Quinine, quinidine, dilantin, carbamazepine, procainamide, diamox to alleviate myopia not universally successful ii. Encouraging results with mexiletine and tocainide c. Avoid cold which may induce myotonia d. Prescription for orthoses, wheelchairs, or other assisted devices e. Treat cataracts, diabetes mellitus, hypothyroidism, and sleep apnea f. Avoid surgery and anesthesia (sensitive to narcotics and sedatives)
REFERENCES Amorosi B, Giustini S, Rossi A, et al.: Myotonic dystrophy (Steinert disease): a morphologic and biochemical hair study. Int J Dermatol 38:434–438, 1999. Bird TD: Myotonic dystrophy. Gene Reviews, 2004. http://www.genetests.org. Brook JD, McCurrach ME, Harley Hum Genet, et al.: Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3’ end of a transcript encoding a protein kinase family member. Cell 68:799–808, 1992. Bundley S: Clinical evidence for heterogeneity in myotonic dystrophy. J Med Genet 19:341–348, 1982. Day JW, Roelofs R, Leroy B, et al.: Clinical and genetic characteristics of a five-generation family with a novel form of myotonic dystrophy (DM2). Neuromuscul Disord 9:19–27, 1999. Day JW, Ricker K, Jacobsen JF, et al.: Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology 60:657–664, 2003. Delaporte C: Personality patterns in patients with myotonic dystrophy. Arch Neurol 55:635–640, 1998. Dufour P, Berard J, Vinatier D, et al.: Myotonic dystrophy and pregnancy. A report of two cases and a review of the literature. Eur J Obstet Gynecol Reprod Biol 72:159–164, 1997. Finsterer J, Gharehbaghi-Schnell E, Korschineck I, et al.: Phenotype and CTGrepeat size in myotonic dystrophy: a study of 26 patients and 55 relatives. J Neurogenet 13:181–190, 1999. Finsterer J, Gharehbaghi-Schnell EG, Stöllberger C, et al.: Relation of cardiac abnormalities and CTG-repeat size in myotonic dystrophy. Clin Genet 59:350–355, 2001. Geifman-Holtzman O, Fay K: Prenatal diagnosis of congenital myotonic dystrophy and counseling of the pregnant mother: case report and literature review. Am J Med Genet 78:250–253, 1998. Gennarelli M, Novella G, Andreasi Bassi F, et al.: Prediction of myotonic dystrophy clinical severity based on the number of intragenic (CTG)n trinucleotide repeats. Am J Med Genet 65:342–347, 1996.
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Gharehbaghi-Schnell E, Finsterer J, Korschineck I, et al.: Genotype-phenotype correlation in myotonic dystrophy. Clin Genet 53:20–26, 1998. Hageman AT, Gabreels FJ, Liem KD, et al.: Congenital myotonic dystrophy; a report on thirteen cases and a review of the literature. J Neurol Sci 115:95–101, 1993. Harper PS: Congenital myotonic dystrophy in Britain. I. Clinical aspects. Arch Dis Child 50:505–513, 1975. Harper PS: Congenital myotonic dystrophy in Britain. II. Genetic aspects. Arch Dis Child 50:514–521, 1975. Harper PS: Myotonic Dystrophy. Saunders, Philadelphia. 1989. Harper PS, Keith J: Myotonic dystrophy. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001. International Myotonic Dystrophy Consortium (IDMC): New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1). Neurology 54:1218–1221, 2000. Joseph JT, Richards CS, Anthony DC, et al.: Congenital myotonic dystrophy pathology and somatic mosaicism. Neurology 49:1457–1460, 1997. Koch MC, Grimm T, Harley HG, et al.: Genetic risks for children of women with myotonic dystrophy. Am J Hum Genet 48:1084–1091, 1991. Magee AC, Hughes AE, Kidd A, et al.: Reproductive counselling for women with myotonic dystrophy. J Med Genet 39:E15, 2002. Mathieu J, Allard P, Gobeil G, et al.: Anesthetic and surgical complications in 219 cases of myotonic dystrophy. Neurology 49:1646–1650, 1997.
Mathieu J, Allard P, Potvin L, et al.: A 10-year study of mortality in a cohort of patients with myotonic dystrophy. Neurology 52:1658–1662, 1999. Meola G: Clinical and genetic heterogeneity in myotonic dystrophies. Muscle Nerve 23:1789–1799, 2000. Meola G, Sansone V: A newly described myotonic disorder (proximal myotonic myopathy-PROMM): personal experience and review of the literature. It J Neurol Sci 17:347–353, 1996. Osanai R, Kinoshita M, Hirose K, et al.: CTG triplet repeat expansion in a laryngeal carcinoma from a patient with myotonic dystrophy. Muscle Nerve 23:804–806, 2000. Pearse RG, Howeler CJ: Neonatal form of dystrophic myotonica: five cases in preterm babies and a review of earlier reports. Arch Dis Child 54:331–338, 1979. Simmons Z, Thornton CA, Seltzer WK, et al.: Relative stability of a minimal CTG repeat expansion in a large kindred with myotonic dystrophy. Neurology 50:1501–1504, 1998. Thornton C: The myotonic dystrophies. Sem Neurol 19:25–32, 1999. Timchenko LT, Tapscott SJ, Cooper TA, et al.: Myotonic dystrophy: discussion of molecular basis. Adv Exp Med Biol 516:27–45, 2002. Udd B, Krahe R, Wallgren-Pettersson C, et al.: Proximal myotonic dystrophy—a family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: heterogeneity of proximal myotonic syndromes’ Neuromuscul Disord 7:217–228, 1997.
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Fig. 1. An adult (A) with myotonic dystrophy showing hard to release after shaking hand (B) and thenar myotonia after tapping (C).
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Fig. 2. An adult with myotonia dystrophy showing long thin face with frontal bossing and thenar myotonia after tapping.
Fig. 3. A 23-year-old mother and her 21-month-old daughter with myotonia congenita type 1. The mother has myotonia (hard to relax after shaking hand), thenar myotonia after tapping, and absent tendon reflexes. The pregnancy was complicated by polyhydramnios, feeble fetal movement, and breech presentation. After scheduled cesarean section, the baby breathed only once and needed intubation for 5 days. She was very floppy and just started to walk about 2 month prior to the clinic visit. She chokes easily and does not chew and talk. On physical examination, in addition to hypotonia, there is a long and sagging face with marked tented-mouth. Molecular genetic testing of the daughter showed CTG repeats of 1050.
Netherton Syndrome 2. Prognosis: poor a. Frequent life-threatening complications during the neonatal period i. Hypernatremic dehydration ii. Hypothermia iii. Extreme weight loss iv. Recurrent infections v. Bronchopneumonia vi. Sepsis b. Failure to thrive common during childhood resulting from: i. Malnutrition ii. Metabolic disorders iii. Chronic erythroderma iv. Persistent cutaneous infections v. Severe enteropathy with villous atrophy vi. Growth retardation c. Other abnormalities i. Renal failure ii. Aminoaciduria iii. Congenital heart defects iv. Hydroureter v. Infantile pyloric stenosis vi. Increased susceptibility to skin cancer a) Squamous cell carcinoma b) Vulvar cancer
Netherton syndrome is a rare hereditary disorder of keratinization. It was described by Comèl in 1949 and Netherton in 1958. The syndrome is sometimes called Comèl-Netherton syndrome. The incidence is about 1 in 200,000.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Defective gene in Netherton syndrome a. Serine protease inhibitor, Kazal-type 5 (SPINK5) mapped on chromosome 5q31 b. The protein encoded by SPINK5 is highly expressed in thymus and mucous epithelia, thereby termed LEKT1 for lympho-epithelial Kazal-type related inhibitor i. LEKT1 possibly plays a role in anti-inflammatory and/or antimicrobial protection of mucous epithelia ii. LEKT1 possibly have similar function in the epidermis
CLINICAL FEATURES 1. Clinical triad a. Congenital ichthyosis i. Extent of involvement: highly variable ii. Natural course a) At birth: usually normal appearing skin b) Within a few weeks of age: skin becomes erythematous and develops serpiginous double-edged scales typical of ichthyosis linearis circumflexa or ichthyosiform erythroderma b. Hair abnormality i. Trichorrhexis invaginata/nodosa a) Sparse and brittle scalp hair with a characteristic “bamboo” shape under light microscope due to invagination of the distal part of the hair shaft to its proximal part b) The major diagnostic sign (considered pathognomonic) but may be difficult to detect in infancy and early childhood c) May not affect all hair and can be limited to the lateral part of the eyebrows ii. Pili torti iii. Eyelashes and eyebrows may be affected c. Atopic manifestations i. Eczema-like rashes ii. Atopic dermatitis iii. Pruritus iv. Allergic rhinitis v. Asthma vi. Urticaria/angioedema
DIAGNOSTIC INVESTIGATIONS 1. Clinical laboratory a. Increased serum immunoglobulin E levels b. Hypereosinophilia c. No consistent or significant abnormalities of immune function d. IgG abnormalities (both hypo- and hyper-IgG) e. T-cell and neutrophil defects may also occur f. Selective humoral deficiency to bacterial polysaccharide antigens has been described g. Specific IgE antibodies against airborne and food allergens frequently present 2. Histology and ultrastructural studies of skin sections a. Incomplete keratinization or defective cornification of the epidermis b. Dermal lymphocytic infiltrate 3. Molecular genetic testing a. Mutation analysis of patients b. Carrier testing
GENETIC COUNSELING
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1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased unless the spouse is a carrier of the gene
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2. Prenatal diagnosis a. Ultrastructural examination of fetal skin biopsies for defective cornification of the epidermis not reliable, since fetal skin keratinization does not begin until the 24th week of gestation whereas in utero fetal skin biopsy is usually performed between 19 and 22 weeks b. DNA-based prenatal diagnosis on fetal DNA obtained from amniocentesis or CVS i. SPINK5 mutation detection ii. Indirect genotype analysis at the SPINK5 locus using linkage analysis a) This approach is reliable since there is no evidence of locus heterogeneity b) Presence of a large number of SPINK5 intragenic restriction fragment length polymorphisms (RFLPs) showing a high percentage of heterozygosity 3. Management a. No specific treatment available b. Emollients c. Keratolytics d. Antibiotics for recurrent infections e. Topical corticosteroids f. Topical (Protopic) g. Medium dose of psoralen-UVA1 phototherapy may be effective and tolerated in adult
REFERENCES Ansai S, Itsuhashi U, Sasaki K: Netherton’s syndrome in siblings. Br J Dermatol 141:1097–1100, 1999. Bitoun E, Bodemer C, Amiel J, et al.: Prenatal diagnosis of a lethal form of Netherton syndrome by SPINK5 mutation analysis. Prenat Diagn 22:121–126, 2002. Bitoun E, Chavanas S, Irvine AD, et al.: Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families. J Invest Dermatol 118:352–361, 2002. Bitoun E, Micheloni A, Lamant L, et al.: LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome. Hum Mol Genet 12:2417–2430, 2003. Capezzera R, Venturini M, Bianchi D, et al.: UVA1 phototherapy of Netherton syndrome. Acta Derm Venereol 84:69–70, 2004. Chao SC, Tsai YM, Lee JY: A compound heterozygous mutation of the SPINK5 gene in a Taiwanese boy with Netherton syndrome. J Formos Med Assoc 102:418–423, 2003.
Chavanas S, Bodemer C, Rochat A, et al.: Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet 25:141–142, 2000. Chavanas S, Garner C, Bodemer C, et al.: Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosity mapping. Am J Hum Genet 66:914–921, 2000. De Felipe I, Vazquez-Doval FJ, Vicente J: Comel-Netherton syndrome. A diagnostic challenge. Br J Dermatol 137:468–469, 1997. Hausser I, Anton-Lamprecht I: Severe congenital generalized exfoliative erythroderma in newborns and infants: a possible sign of Netherton syndrome. Pediatr Dermatol 13:183–199, 1996. Hedberg CL, Hogan DJ, Bahna SL: An infant with generalized rash and abnormal hair. Ann Allergy Asthma Immunol 91:1–6, 2003. Jones SK, Thomasson LM, Surbrugg SK, et al.: neonatal hypernatraemia in two siblings with Netherton’s syndrome. Br J Dermatol 114:741–743, 1986. Judge MR, Morgan G, Harper JI: A clinical and immunological study of Netherton’s syndrome. Br J Dermatol 131:615–621, 1994. Krasagakis K, Ioannidou DJ, Stephanidou M, et al.: Early development of multiple epithelial neoplasms in Netherton syndrome. Dermatology 207:182–184, 2003. Müller FB, Hausser I, Berg D, et al.: Genetic analysis of a severe case of Netherton syndrome and application for prenatal testing. Br J Dermatol 146:495–499, 2002. Netherton EW: A unique case of Trichorrhexis invaginata ‘bamboo hair’. Arch Dermatol 78:483–487, 1958. Powell J: Increasing the likelihood of early diagnosis of Netherton syndrome by simple examination of eyebrow hairs. Arch Dermatol 136:423–424, 2000. Sahari S, Wollery-Lloyd H, Nouri K: Squamous cell carcinoma in a patient with Netherton’s syndrome. Br J Dermatol 144:415–416, 2002. Seraly MP, Sheehan M, Collins M, et al.: Netherton syndrome revisited. Pediatr Dermatol 11:61–64, 1994. Smith DL, Smith JG, Womg SW, et al.: Netherton’s syndrome: a syndrome of elevated IgE and characteristic skin and hair findings. J Allergy Clin Immunol 95:116–123, 1995. Sprecher E, Chavanas S, DiGiovanna JJ, et al.: The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis. J Invest Dermatol 117:179–187, 2001. Stevanovic DV: Multiple defects of the hair shaft in Netherton’s disease. Br J Dermatol 81:851–857, 1969. Stoll C, Alembik Y, Tchomakov D, et al.: Severe hypernatremic dehydration in an infant with Netherton syndrome. Genet Couns 12:237–243, 2001. Stryk S, Siegfried EC, Knutsen AP: Selective antibody deficiency to bacterial polysaccharide antigens in patients with Netherton syndrome. Pediatr Dermatol 16:19–22, 1999. Van Gysel D, Koning H, Baert MR, et al.: Clinico-immunological heterogeneity in Comel-Netherton syndrome. Dermatology 202:99–107, 2001.
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Fig. 1. A neonate (A) with Netherton syndrome showing erythroderma. The patient had markedly elevated serum total IgE levels of 409 IU/mL at age 8 months and 285 IU/mL at 14 months of age. Molecular genetic analysis of SPINK5 showed a compound heterozygote with a mutation 316DelGA in exon 5 inherited from the mother and a mutation 2441+1delGTGA in exon 25 inherited from the father. The same patient at age 3 years (B) showed generalized erythroderma and marked growth retardation (height age of 7 months and weight age of 4 months). Microscopic analysis of the hair (C and D, lower and higher magnification) showed trichorrhexis invaginata/nodosa (bamboo hair) (pink arrows), pili torti (yellow arrow), and fractured hair shaft at the site of invagination (blue arrow).
Neu-Laxova Syndrome c. Flexion deformity d. Severe edema of the hands and feet e. Syndactyly f. Rocker-bottom feet 7. Other features a. Short broad neck b. Cystic hygroma c. Subcutaneous edema d. Small thorax e. Hypoplastic or atelectatic lungs f. Small abdomen g. Hypoplastic genitalia h. Short umbilical cord i. Absence of hair j. Muscle atrophy 8. Classification proposed by Curry (1982): may represent heterogeneity of the condition or different grades of severity a. Group I i. Joint contractures ii. Partial syndactyly iii. Thin scaly skin iv. Mild ichthyosis v. Poor mineralization of bones b. Group II i. Massive swelling of hands and feet ii. Ichthyosis iii. Undermineralized bones c. Group III i. Hypoplastic digits ii. Severe ichthyosis (harlequin-like fetus) iii. Short limbs iv. Stick-like long bones 9. Prognosis a. Stillborn b. Die shortly after birth
The Neu-Laxova syndrome is a lethal disorder characterized by multiple congenital malformations. Microcephaly, lissencephaly, absence of corpus callosum, facial anomalies (notably absent eyelids), short broad neck, peripheral edema, ichthyosis, limb anomalies and other malformations are common findings. The syndrome was described first by Neu et al. in 1971 and Laxova et al. in 1972.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive inheritance 2. Pathogenesis: unknown
CLINICAL FEATURES 1. Considerable intrafamilial and interfamilial variation in clinical features 2. Prenatal history a. Severe intrauterine growth retardation b. Polyhydramnios 3. Spectrum of skin lesions a. Edema over the dorsum of foot and hand, often associated with hypoplastic phalanges b. Thick, waxy, and stretched in appearance c. Peeling of skin, scaling, and extensive plaque formation over scalp, face, neck, back, and arm d. Translucent flexible membrane covering most of the skin e. Varying degree of lamellar ichthyosis 4. Craniofacial features a. Receding forehead b. Ocular hypertelorism c. Exophthalmos (protruding eyes) d. Absence of the eyelids e. Flat, abnormal nose f. Eclabium g. Cataract h. Micrognathia i. Cleft palate/lip j. Hypodontia k. Low-set, malformed ears 5. CNS abnormalities a. Microcephaly b. Lissencephaly c. Hypoplastic or abnormal cerebellum d. Agenesis or dysgenesis of the corpus callosum e. Decreased or absent gyri f. Dilatation or abnormal ventricles g. Dandy-Walker malformation h. Choroid plexus cysts 6. Limb anomalies a. Deformed digits b. Deformed limbs
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1. Radiography a. Multiple contractures b. Hemivertebrae c. Kyphoscoliosis 2. Histopathology of the skin a. Hyperkeratosis i. With or without parakeratosis ii. Associated with abundant subcutaneous tissue and excess of fat b. Myxomatous connective tissue associated with excess subcutaneous adipose tissue c. Epidermal and dermal atrophy 3. Ultrasound of the brain for CNS anomalies 4. Normal chromosomes
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GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: a lethal entity not surviving to reproductive age 2. Prenatal ultrasonography a. Severe growth retardation: a major feature b. Polyhydramnios c. Microcephaly/deficient calvarial ossification d. CNS abnormalities e. Abnormal facies including receding forehead f. Exophthalmos g. Cataract h. Cystic hygromas i. Pulmonary hypoplasia j. Contractures k. Excessive edema of the hands and feet l. Syndactyly m. Clubbing of the feet n. Absence of breathing movements, sucking, swallowing, or normal isolated arm and leg movements o. Restricted fetal movement 3. Management a. No specific treatment for the uniformly lethal disorder b. Mainly supportive with initial management of ventilatory, thermal, and nutritional support
REFERENCES Abdel Meguid N, Temtamy SA: Neu Laxova syndrome in two Egyptian families. Am J Med Genet 41:30–31, 1991. Aslan H, Gul A, Polat I, et al.: Prenatal diagnosis of Neu-Laxova syndrome: a case report. BMC Pregnancy Childbirth 2:1–4, 2002. Curry CJ: Further comments on the Neu-Laxova syndrome. Am J Med Genet 13:441–444, 1982. Driggers RW, Isbister S, McShane C, et al.: Early second trimester prenatal diagnosis of Neu-Laxova syndrome. Prenat Diagn 22:118–120, 2002. Durr-e-Sabih, Khan AN, Sabih Z: Prenatal sonographic diagnosis of NeuLaxova syndrome. J Clin Ultrasound 29:531–534, 2001. Ejeckam GG, Wadhwa JK, Williams JP, et al.: Neu-Laxova syndrome: report of two cases. Pediatr Pathol 5:295–306, 1986. Fitch N: Comments on Dr. Curry’s classification of the Neu-Laxova syndrome. Am J Med Genet 15:515–517, 1983.
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Fitch N, Resch L, Rochon L: The Neu-Laxova syndrome: comments on syndrome identification. Am J Med Genet 13:445–452, 1982. Gulmezoglu AM, Ekici E: Sonographic diagnosis of Neu-Laxova syndrome. J Clin Ultrasound 22:48–51, 1994. Hickey P, Piantanida E, Lentz-Kapua S, et al.: Neu-Laxova syndrome: a case report. Pediatr Dermatol 20:25–27, 2003. Hirota T, Hirota Y, Asagami C, et al.: A Japanese case of Neu-Laxova syndrome. J Dermatol 25:163–166, 1998. Horn D, Muller D, Thiele H, et al.: Extreme microcephaly, severe growth and mental retardation, flexion contractures, and ichthyotic skin in two brothers: a new syndrome or mild form of Neu-Laxova syndrome? Clin Dysmorphol 6:323–328, 1997. Kainer F, Prechtl HF, Dudenhausen JW, et al.: Qualitative analysis of fetal movement patterns in the Neu-Laxova syndrome. Prenat Diagn 16:667–669, 1996. King JAC, Gardner V, Chen H, et al.: Neu-Laxova syndrome: pathological evaluation of a fetus and review of the literature. Pediatr Pathol Lab Med 15:57–79, 1995. Laxova R, Ohdra PT, Timotthy JAD: A further example of a lethal autosomal recessive condition in sibs. J Ment Defic Res 16:139–143, 1972. Lazjuk GI, Lurie IW, Ostrowskaja TI, et al.: Brief clinical observations: the Neu-Laxova syndrome—a distinct entity. Am J Med Genet 3:261–267, 1979. Meguid NA, Temtamy SA: Neu-Laxova syndrome in two Egyptian families. Am J Med Genet 41:30–31, 1991. Monaco R, Stabile M, Guida F, et al.: Echographic, radiological and anatomopathological evaluation of a foetus with Neu-Laxova syndrome. Australas Radiol 36:51–53, 1992. Mueller RF, Winter RM, Naylor CP: Neu-Laxova syndrome: two further case reports and comments on proposed subclassification. Am J Med Genet 16:645–649, 1983. Muller LM, de Jong G, Mouton SC, et al.: A case of the Neu-Laxova syndrome: prenatal ultrasonographic monitoring in the third trimester and the histopathological findings. Am J Med Genet 26:421–429, 1987. Neu RL, Kajii T, Gardner LI, et al.: A lethal syndrome of microcephaly with multiple congenital anomalies in three siblings. Pediatrics 47:610–612, 1971. Rode ME, Mennuti MT, Giardine RM, et al.: Early ultrasound diagnosis of Neu-Laxova syndrome. Prenat Diagn 21:575–580, 2001. Russo R, D’Armiento M, Martinelli P, et al.: Neu-Laxova syndrome: pathological, radiological, and prenatal findings in a stillborn female. Am J Med Genet 32:136–139, 1989. Scott CI, Louro JM, Laurence KM, et al.: Comments on the Neu-Laxova syndrome and CAD complex. Am J Med Genet 9:165–175, 1981. Shapiro I, Borochowitz Z, Degani S, et al.: Neu-Laxova syndrome: prenatal ultrasonographic diagnosis, clinical and pathological studies, and new manifestations. Am J Med Genet 43:602–605, 1992. Shivarajan MA, Suresh S, Jagadeesh S, et al.: Second trimester diagnosis of Neu Laxova syndrome. Prenat Diagn 23:21–24, 2003.
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Fig. 2. Radiographs showing hemivertebrae, kyphoscoliosis and 11 pairs of ribs.
Fig. 1. An infant with Neu-Laxova syndrome showing severe ichthyosis, characteristic facial features (absent eyelids, flattened nose, round gaping mouth, low-set ears with poorly developed pinnae), short broad neck, flexion contractures of the limbs, and short, small-caliber umbilical cord. Photomicrographs of skin (not shown) demonstrated a prominent hyperkeratosis of the epidermis and a thick layer of subcutaneous adipose tissue due to edema.
Neural Tube Defects Neural tube defects (NTDs) are among the most common severe congenital malformations of the central nervous system. Approximately 1 in 500 to 1 in 1000 pregnancies result in NTDs. About 4000 fetuses are affected each year in the US. The incidence varies with geographic areas and ethnic groups. The incidence, however, appears to be decreasing recently.
GENETICS/BASIC DEFECTS 1. Caused by a defect in closure of the neural tube, which is normally closed by 28 days 2. Multifactorial trait: environmental and genetic factors play a role in the causation of NTDs 3. Specific causes are identified in less than 10% of affected infants a. Chromosomal abnormalities b. Single gene mutations c. Teratogens 4. Defects in the neural tube closure linked to 5,10 methylenetetrahydrofolate reductase deficiency and defects in the metabolism of folic acid 5. Mildly elevated homocysteine in some pregnant women who subsequently give birth to infants with NTDs 6. A specific mutation known as C677T polymorphism a. More common in parents of children affected with NTDs b. This polymorphism affects the enzyme methylenetetrahydrofolate reductase (MTHFR), causing it to require more folic acid to work properly 7. Low erythrocyte folate in the first trimester of pregnancy: associated with an increased risk of neural tube defects
CLINICAL FEATURES There are several morphologic types of NTDs: open NTDs (anencephaly, cranial or spinal rachischisis, iniencephaly, meningomyelocele, cranioectomesodermal hypoplasia), closed NTDs (cranial meningocele, cranial encephalocele, spinal meningocele alone or with spinal cord abnormality), and myelocystocele. 1. Anencephaly a. Refers to an absence of the brain and the calvarium covering the brain b. The most severe form of NTDs c. Incidence: about 1/1000 live births d. Responsible for about 50% of all NTDs e. Infants with anencephaly i. Stillborn ii. Die shortly after birth f. Anterior pituitary, eyes, and brainstem usually spared g. Remaining tissue covering the basal cranium: a highly vascular and friable membrane referred to as area cerebrovasculosa 721
h. Striking craniofacial appearance i. Absent cranial vault ii. An angiomatous membranous mass lying on the floor of the cranium iii. An absent or backward sloping of the forehead iv. Frog-like eyes (ocular proptosis) v. Puffy eye-lids vi. A flattened nose vii. Large folded-down ears viii. Often an open mouth ix. A short neck i. Syndromes associated with anencephaly i. Chromosomal disorders [e.g., r(13), trisomy 18, del(13q)] ii. Monogenic disorder (e.g., Meckel syndrome) iii. Disruptive sequences (e.g., amniotic bands, maternal hyperthermia) iv. Associations (e.g., spina bifida, holoprosencephalic face syndrome, craniofacial duplication) 2. Craniorachischisis or spinal rachischisis a. Rachischisis: refers to anencephaly with a contiguous spinal defect involving at least the cervical spine region and extending for varying degrees down the spinal column b. The area cerebrovasculosa and the area medullovasculosa fill the skeletal defects of the cranium and of the spinal column c. Short neck d. Upward-turned face e. Ears touching the shoulders f. Frequent polyhydramnios g. Frequently stillborn h. Neurologic involvement i. Primarily limited to brainstem and spinal reflexes ii. Occasional seizures resembling infantile spasms 3. Iniencephaly a. The name iniencephaly derived from an abnormality of the neck (inion) and the brain (cephaly) b. Triad i. Deficient cranial bone ii. Cervical dysraphism (rachischisis) iii. Fixed retroflexion of the fetal head and severe lordosis of the cervicothoracic spine c. Closed or open lesions i. A closed lesion when the occipital bone is not malformed ii. An open lesion when the occipital bone is hypoplastic d. Site of the neural tube lesion: at the level of the cervical spine
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e. Severity of lesion i. Spina bifida with intact skin ii. Meningomyeloencephalocele iii. Open rachischisis f. Associated CNS malformations i. Anencephaly ii. Encephalocele iii. Microcephaly iv. Hydrocephaly v. Holoprosencephaly vi. Posterior fossa defects vii. Spinal defects such as cervical dysraphism viii. Fixed cervical hyperlordosis g. Other associated malformations i. Diaphragmatic hernia ii. Omphalocele iii. Thoracic cage deformities iv. Hypoplastic lungs v. Genitourinary malformations vi. Cyclopia vii. Cleft lip and palate viii. Imperforate anus ix. Clubfoot x. Single umbilical artery h. Die within a few hours in most newborns 4. Cranium bifidum occultum a. The most benign type b. Generally asymptomatic c. Skull defects often close over time d. Persistent parietal foramina (sometimes called “Caitlin marks” after the family for which it was described; transmitted as an autosomal dominant trait via a gene located on 11p) e. Persistent wide fontanelle 5. Cranial meningocele a. Associated with a defect in the skull b. Associated with protrusion of the leptomeninges 6. Encephalocele a. A type of cephalocele (a herniation of cranial contents through a skull defect) that contains brain b. Incidence: 1/10,000 live births c. Occurring most frequently in the occipital region (80–90%) and commonly associated with a variety of syndromes, notably Meckel-Gruber syndrome and Walker-Warburg syndrome d. Anterior encephaloceles: found more commonly in Roberts syndrome e. An isolated malformation of frontal encephalocele: more commonly seen in southeast Asia f. Outcome depending on the position of the defect and on the associated anomalies g. Chromosome syndromes associated with encephalocele i. Trisomy 13 ii. Trisomy 18 iii. Del(13q) iv. Del(2)(q21 → q24) v. Dup(1q) vi. Dup(6) (q21 → qter) vii. Dup(7)(qter → p11) viii. Dup(8)(q23 → qter) ix. Turner syndrome
h. Monogenic disorders associated with encephalocele i. Meckel syndrome ii. Cryptophthalmos syndrome iii. Silverman-Handmaker type and RollandDesbuquiois type of dyssegmental dysplasias iv. Knobloch syndrome v. Chemke syndrome vi. Roberts syndrome vii. Walker-Warburg syndrome viii. Van Voss-Cherstovy syndrome i. Disruptive sequences associated with encephalocele i. Maternal hyperthermia ii. Warfarin embryopathy iii. Amniotic bands j. “Associations” associated with encephalocele i. Absent corpus callosum ii. Dandy-Walker malformations iii. Arnold-Chiari malformation iv. Holoprosencephaly v. Craniosynostosis vi. Ectrodactyly vii. Frontonasal dysplasia viii. Hypothalamic-pituitary dysfunction ix. Klippel-Feil anomaly x. Iniencephaly xi. Myelomeningocele xii. Oculoauriculovertebral spectrum 7. Spina bifida cystica (the most common lesion) a. Myelomeningoceles (meningomyeloceles) i. A herniation of the spinal cord and/or nerves through a bony defect of spine ii. Usually open defects in which meninges and/or neural tissue is exposed to the environment associated with leaking CSF iii. The most common type of spina bifida cystica (about 90%) iv. Approximately 20% of affected infants have additional congenital anomalies, such as gastrointestinal, cardiac, and urogenital malformations v. Surviving infants with spina bifida likely have severe, life-long disabilities, and psychosocial maladjustment vi. Medical problems a) Paralysis b) Hydrocephalus c) Arnold-Chiari type II malformation (herniation of the cerebellar vermis and brainstem below the foramen magnum) d) Endocrine abnormalities e) Tethered cord f) Syringomyelia (cavitation of the spinal cord whose walls are comprised of glial tissue) g) Syringobulbia h) Deformed limbs and spine i) Bladder/bowel/sexual dysfunction j) Learning disabilities vii. Neonates with Arnold-Chiari malformation presenting with: a) Stridor secondary to vocal cord paralysis b) Central apnea
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b.
c.
d.
e.
c) Aspiration d) Dysphagia e) Hypotonia f) Progressive brainstem dysfunction g) Myelopathy h) Quadriparesis i) Nystagmus j) Strabismus k) Poor sucking l) Swallowing difficulties Meningoceles i. A saccular herniation of meninges and CSF through a bony defect of spine and usually covered by normal skin ii. No herniation of the spinal cord or nerve roots into the dorsal dural sac iii. A cystic mass full of cerebrospinal fluid iv. Without associated neurologic problems such as hydrocephalus and Chiari II malformation Lipomeningocele or lipomyelomeningocele i. A lipomatous mass herniating through the bony defect and attaching to the spinal cord, tethering the cord and often its nerve roots ii. Presentation with a skin-covered mass above the buttocks and eventual neurologic deficits iii. Absent associated hydrocephalus Myelocystocele i. A large terminal cystic dilatation of the spinal cord secondary to hydromyelia giving rise to a large terminal skin-covered sac ii. Constituting 4–6.5% of the skin-covered masses overlying the lower spine iii. The majority of cases are dorsally located; only rarely (about 0.5%) are ventral in location iv. The ventral type is an anterior sacral meningocele, most often presenting as a pelvic mass in females v. Cervical myelocystocele vi. Lumbar myelocystocele vii. Terminal myelocystoceles accompanying midline abdominal and pelvic defects such as part of the OEIS (omphalocele-exstrophy of the bladder-imperforate anus-spinal defects) complex viii. Chiari malformation less frequent since the lesion is covered by dura with regular hydrodynamics of the cerebrospinal fluid ix. Other associate malformations a) Genitourinary tract anomalies b) Intestinal malrotation c) Club feet x. Differential diagnoses a) Meningomyelocele b) Lumbosacral and sacrococcygeal teratomas c) Lipomas d) Lipomyelomeningoceles e) Hamartomas Life-long disability risks in infants with spina bifida i. At risk for psychosocial maladjustment ii. Medical problems resulting from the neurologic defects or from its repair a) Paralysis b) Hydrocephalus
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c) Arnold-Chiari malformation d) Endocrine abnormalities e) Tethered cord f) Syringomyelia g) Syringobulbia iii. Medical problems as sequelae of the neurologic deficits a) Deformations of the limbs and spine b) Bowel, bladder, and sexual dysfunction c) Learning disabilities 8. Spina bifida occulta a. A bony defect of spine occurs most often at S1 and/or S2 and is covered by normal skin (a closed lesion). b. No herniation of the meninges through the bony defect c. Without associated hydrocephalus or Chiari II malformations d. Paraspinal cutaneous lesions with high index of suspicion pointing towards the underlying spina bifida i. Hypertrichosis or hairy patches ii. Lumbosacrococcygeal dimples and sinuses iii. Acrochordons (skin tags): a small, flesh-colored to dark brown, sessile or pedunculated lesion consisting of a hyperplastic epidermis enclosing a dermal stalk of connective tissue iv. True tails: a caudal midline appendage capable of spontaneous or reflex motion consisting of skin covering muscle, adipose, connective tissue, blood vessels, and nerves but lack vertebrae and abnormal tissue v. Pseudotails: a caudal protrusion composed of adipose (lipoma), teratomatous elements, or cartilage vi. Lipomas vii. Hemangiomas: indicator for tethered-cord syndrome viii. Aplasia cutis congenita (congenital absence of skin) or scar ix. Dermoid cyst or sinus: 12–35% of children with spina bifida occulta have sacrococcygeal dermoid cysts or sinuses, which rarely connect with the intraspinal canal. Lesions above these levels along the spine are more likely to connect with the intraspinal canal and increasingly associated with spina bifida occulta e. Paraspinal cutaneous lesions with low index of suspicion i. Telangiectasia ii. Capillary malformation (port-wine stain) iii. Hyperpigmentation (lentigines or cafè-au-laitlike lesions) iv. Melanocytic nevi v. Teratomas: most common in the sacrococcygeal region in infancy f. Neurologic deficits i. Weakness of leg or legs ii. Leg atrophy or asymmetry iii. Loss of sensation iv. Painless sores v. Hyperreflexia vi. Unusual back pain vii. Abnormal gait viii. Radiculopathy
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ix. Neurogenic bladder x. Incontinence
DIAGNOSTIC INVESTIGATIONS 1. Neurological examination of neonates a. Size, site and level of the lesion b. Motor and sensory level c. Presence of associated hydrocephalus d. Presence of associated symptomatic hindbrain herniation such as Chiari II malformation e. Presence of associated orthopedic deformity 2. Neonatal cranial ultrasonography to demonstrate hydrocephalus 3. Radiography a. Occult spinal disorders in children i. Lamina defects ii. Hemivertebrae iii. Scoliosis iv. Widening of interpedicular distance v. Butterfly vertebrae b. Generally to detect bony defects 4. CT a. Cranial defects b. Spinal defects 5. MRI: provide exquisite detail of both the cranial defect and the herniated contents a. Cranial defects b. Cerebral defects i. Hydrocephalus ii. Gray matter heterotopia iii. Schizencephaly iv. Gyral abnormalities v. Agenesis and thinning of the corpus callosum vi. Abnormal thalami vii. Abnormal white matter c. Herniated contents in Chiari malformations d. Associated lesions i. Diastematomyelia ii. Syringomyelia iii. Hydromyelia iv. Tethered cord
GENETIC COUNSELING 1. Recurrence risk a. Affected first-degree relatives i. 1 sib affected (5%) ii. 2 sibs affected (10%) iii. 3 sibs affected (21%) iv. 1 parent affected (3–4.5%) b. Affected second-degree relative: uncle/aunt; half sib (2%) c. Third-degree relative: first cousin (1% or less) 2. Prenatal diagnosis a. Measurement of maternal serum alpha-fetoprotein (MSAFP): a useful tool for mass screening of pregnant women for NTDs b. All cases of anencephaly and about 65% of cases of spina bifida are identified by measurement of MSAFP and ultrasonography
c. The most significant risk factor: a history of having a previous child affected with neural tube defect d. Ultrasonography i. Used both as a screening test and as a follow-up test after positive results on MSAFP screening ii. Direct demonstration of the spinal defect iii. Indirect signs a) Lemon sign (referring to a symmetrical bifrontal narrowing of the skull) b) Banana sign (cerebellar abnormality) e. Prenatal diagnosis of iniencephaly by careful sonography i. Marked fixed retroflexion of the head and neck ii. Rachischisis iii. Extreme lordosis of the fetus f. Amniotic fluid alpha-fetoprotein (AFAFP) and amniotic fluid acetylcholinesterase (AFAChE): confirmatory tests for spina bifida 3. Management: complex and challenging a. Prevention i. Folic acid supplementation of 0.4 mg/day to all woman capable of becoming pregnant: decrease the first occurrence of NTDs by at least 40% ii. Folic acid supplementation of 4 mg/day in families with previous children born with NTDs: decrease risk of recurrence by 70% iii. Periconceptional use of folic acid supplementation will prevent 50–70% of NTDs b. Medical management i. Antibiotic prophylaxis to prevent meningitis and ventriculitis ii. Urological management iii. Management of rectal incontinence iv. Preventable conditions a) Urinary tract infections b) Calculi c) Skin ulcerations d) Latex allergy and sensitization c. Surgical treatment i. Closing all but the prognostically worst cases ii. Concurrent shunting of co-existing hydrocephalus often necessary iii. Decompression of the posterior fossa and/or cervical cord in Chiari II malformations iv. Spina bifida occulta: prophylactic surgical repair more effective than waiting for patients to experience a significant neurologic deficit such as a neurogenic bladder or leg weakness from these occult spinal lesions v. Orthopedic management of scoliosis vi. Several reports of intrauterine repair of meningomyelocele with benefits to motor function and a decreased incidence of shunt-dependent hydrocephalus and hindbrain herniations d. Rehabilitation programs i. Physical therapy ii. Occupational therapy iii. Speech therapy iv. Recreational therapy
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REFERENCES American Academy of Pediatrics. Committee on Genetics. Folic acid for the prevention of neural tube defects. Pediatrics 104:325–327, 1999. Balci S, Aypar E, Altmok G, et al.: Prenatal diagnosis in three cases of iniencephaly with unusual postmortem findings. Prenat Diagn 21:558–562, 2001. Botto LD, Moore CA, Khoury MJ, et al.: Neural-tube defects. N Engl J Med 341:1509–1519, 2000. Bruner JP, Tulpan N, Paschall RL, et al.: Fetal surgery for myelomeningocele and the incidence of shunt-dependent hydrocephalus. J Am Med Assoc 282:1819–1825, 1999. Budorick NE, Pretorius DH, McMahan JP, et al.: Cephalocele detection in utero: Sonographic and clinical features. Ultrasound Obstet Gynecol 5:77–85, 1995. Campbell J, Gilbert WM, Nicolaides KH, et al.: Ultrasound screening for spina bifida: Cranial and cerebellar signs in a high-risk population. Obstet Gynecol 70:247–250, 1987. Centers for Disease Control and Prevention: Surveillance for anencephaly and spina bifida and the impact of prenatal diagnosis. United States, 1985–1994. MMWR 44(SS-4):1–13, 1996. Cohen MM Jr: Malformations of the craniofacial region: Evolutionary, embryonic, genetic, and clinical perspectives. Am J Med Genet (Semin Med Genet) 115:245–268, 2002. Cohen MM Jr, Lemire RJ: Syndromes with cephaloceles. Teratology 24:161–172, 1982. Czeizel AE, Dudas I: Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 327:1832–1835, 1992. Doˇgan MM, Ekiki E, Yapar EG, et al.: Iniencephaly: sonographic-pathologic correlation of 19 cases. J Perinat Med 24:501–511, 1996. Drolet BA: Cutaneous signs of neural tube dysraphism. Pediatr Clin N Am 47:813–823, 2000. Ellenbeugen RG: Neural tube defects in the neonatal period. Emedicine 2001. http://www.emedicine.com Erdincler P, Kaynar MY, Canbaz B et al.: Iniencephaly: neuroradiological and surgical features. Case report and review of the literature. J Neurosurg 89:317–320, 1998. Golden JA, Bonnemann CG: Developmental Structural Disorders. In Goetz (ed): Textbook of Clinical Neurology. 1st Ed. WB Saunders, 1999, Ch 28, pp 510–537. Gorlin RJ, Cohen MM Jr, Henneckan RCM: Syndromes of the Head and Neck. 4th edition. New York: Oxford Univ Press, 2001. Hall JG, Soelhdin F: Genetics of neural tube defects. Ment Retard Dev Disabil 4:269–281, 1999. Hunter AGW: Brain and spinal cord. In Stevenson RE, Hall JG, Goodman RM (eds): Human Malformations and Related anomalies. Vol 2: New York: Oxford Univ Press, 1993, pp 109–137. Iqbal MM: Prevention of neural tube defects by periconceptional use of folic acid. Pediatr Rev 21:58–66, 2000. Kjaer I, Mygind H, Hansen BF: Notochordal remnants in human iniencephaly suggest disturbed dorsoventral axis signaling. Am J Med Genet 84:425–432, 1999. Kölble N, Houseman TAGM, Stallmach T, et al.: Prenatal diagnosis of a fetus with lumbar Myelocystocele. Ultrasound Obstet Gynecol 18:536– 539, 2001.
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Kulaylat NA, Narchi H: Iniencephaloy: An uncommon neural tube defect. J Pediatr 136:414, 2000. Lemire RJ, Graham CB, Beckwith JB: Sin-covered sacrococygeal masses in infants and children. J Pediatr 79:948–954, 1971. Lemire RJ, Beckwith JB, Warkany J: Anencephaly. New York: Raven Press, 1978. Lindfors KK, McGahan JP, Tennant FP, et al.: Midtrimester screening for open neural tube defects: Correlation of sonography with amniocentesis results. Am J Roentgenol 149:141–145, 1987. Manning SM, Jennings R, Madsen JR: Pathophysiology, prevention, and potential treatment of neural tube defects. Ment Retard Dev Disabil Res Rev 6:6–14, 2000. McAtee-Smith J, Hebert AA, Rapini RP, et al.: Skin lesions of the spinal axis and spinal dysraphism. Fifteen cases and a review of the literature. Arch Pediatr Adolesc Med 148:740–748, 1994. Milunsky A, Jick H, Jick SS, et al.: Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 262:2847–2852, 1989. Molloy AM, Mills JL, Kirke PN: Folate status and neural tube defects. Biofactors 10:291–294, 1999. Morocz I, Szeifert GT, Molnar P, et al.: Prenatal diagnosis and pathoanatomy of iniencephaly. Clin Genet 30:81–86, 1986. Naldich TP, Altman NR, Braffman BH, et al.: Cephaloceles and related malformations. Am J Neuroradiol 13:655–690, 1992. Nicolaides KH, Gabbe S, Camphell S, et al.: Ultrasound screening for spina bifida, cranial and cerebellar signs. Lancet 12:72–74, 1986. Norman MG, McGillivray BC, Kalousek DK, et al.: Congenital Malformations of the Brain. Pathologic, Embryologic, Clinical, Radiologic and Genetic Aspects. New York, Oxford University Press, 1995. Put van der NMJ, Steegers-Theunissen RP, et al.: Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lance 346:1070–1071, 1995. Rintoul NE, Sutton LN, Hubbard AM, et al.: A new look at myelomeningoceles: functional level, vertebral level, shunting, and the implications for fetal intervention. Pediatrics 109:409–413, 2002. Robinson HP, Hood VD, Adam AH, et al.: Diagnostic ultrasound: early detection of fetal neural tube defects. Obstet Gynecol 56:705–710, 1980. Sahid SK Sepulveda W, Dezerega V, et al.: Iniencephaly: prenatal diagnosis and management. Prenat Diagn 20:202–205, 2000. Smithells RW, Nevin NC, Seller MJ, et al.: Further experience of vitamin supplementation for prevention of neural tube defect recurrences. Lancet 1:1027–1031, 1983. Stone DH: The declining prevalence of anencephalus and spina bifida: its nature, causes and implications. Div Med Child Neuro 29:541–549, 1987. Talipan N, Bruner JP, Hernanz-Schulman M, et al.: Effect of intrauterine myelomeningocele repair on central nervous system structure and function. Pediatr Neurosurg 31:183–188, 1999. Talipan N, Hernanz-Schulman M, Lowe LH, et al.: Intrauterine myelomeningocele repair reverses preexisting hindbrain herniation. Pediatr Neurosurg 31:137–142, 1999. Van den Hof M, Nicolaides KH, Campbell J, et al.: Evaluation of the lemon and banana signs in one hundred thirty fetuses with open spina bifida. Am J Obstet Gynecol 162:322–327, 1990. Warkany J, Lemire RJ, Cohen MM Jr: Mental Retardation and Congenital Malformations of the Central Nervous System. Chicago: Year Book Medical Publishers, 1981.
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Fig. 1. Inward scalloping of the frontal bones, known as “lemon sign” (short arrows) and “banana” configuration of the cerebellum (long arrows), in a fetus with open spina bifida.
Fig. 2. A paraspinal unilocular cyst (arrow) in a fetus with lumbosacral meningocele.
Fig. 3. Ventriculomegaly (arrows) observed in a fetus with lumbar meningomyelocele.
NEURAL TUBE DEFECTS
Fig. 4. A stillbirth with classic anencephaly showing absent cranial vault, an angiomatous mass on the skull base, an absent forehead, protuberant, puffy “frog-like” eyes, an open mouth, large foldeddown ears, and a short neck. Radiographs show the absent calvarium.
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Fig. 5. A newborn with anencephaly/meningocele showing the presence of a meningeal sac above the base of the skull without containing the brain tissue, illustrated by transillumination and MRI of the brain with or without contrast.
Fig. 7. Newborns with an occipital encephalocele.
Fig. 6. Another neonate with anencephaly/meningocele showing similar craniofacial anomalies.
Fig. 8. Encephalocele associated with amniotic band syndrome.
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Fig. 10. A fetus with trisomy 18 and open lumbosacral spina bifida.
Fig. 9. Newborns with a lumbosacral myelomeningocele.
Fig. 11. Two infants with a large lumbosacral myelocystocele covered with skin.
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Fig. 12. A stillborn with iniencephaly showing deficient cranium, short neck, cervical rachischisis, fixed retroflexion of the head, and severe lordosis of the cervicothoracic spine.
Fig. 13. A stillborn with caniorachischisis showing anencephaly with a contiguous spinal defect involving cervical spine region and extending down the spinal column, short neck, upward-turned face, and ears touching the shoulders.
Neurofibromatosis I Neurofibromatosis I (NF1) was described in 1882 by von Recklinghausen who gave the disease its first full description, including recognition that the tumors arose from the fibrous tissue surrounding small nerves, leading to his designation of these tumors as “neurofibromas”. Thus, it is also called von Recklinghausen disease. It is one of the most common dominantly inherited genetic disorders affecting about 1 in 3000 newborns and 1,000,000 people worldwide.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant b. High spontaneous mutation rate i. One of the highest in humans (1 × 10–4 per gamete per generation) ii. 50% of the cases are due to new mutations iii. Most patients are expected to have different mutations due to the high mutation rate at the NF1 locus c. Full penetrance: essentially 100% in adults after careful examination by a slit-lamp examination d. Widely variable e. Highly pleiotropic 2. The NF1 gene a. Mapped to pericentromeric region of 17q11.2 b. Entire sequence of the expressed NF1 gene has been identified by a positional cloning strategy c. A large size of the gene spanning over 350 kb of genomic DNA d. Consisting of at least 60 exons e. Translated into a 240 kDa protein, neurofibromin 3. Neurofibromin a. Acting as GTPase activating protein (GAP) b. Negatively regulating a cellular proto-oncogen, p21-ras c. Normally functions as a tumor suppressor, the loss of which produces increased mitogenic signaling leading to uncontrolled cell growth or tumor formation 4. Mutations of the NF1 gene a. Most described mutations are unique to a particular family b. Type of mutations (over 250 different mutations described) i. Stop codon ii. Substitutions iii. Deletions of only one or a few base pairs, multiple exons, or the entire gene iv. Insertions v. Intronic changes affecting splicing vi. Alterations of the 3′ untranslated region of the gene vii. Gross chromosomal rearrangements 731
c. Severe truncation of the gene product in about 70% of the germline mutations d. NF1 gene usually classified as a tumor suppressor gene since mutations in both NF1 alleles are detectable in malignant tumors associated with NF1 and in benign tumors, such as neurofibromas 5. Knudson two-hit hypothesis also applicable to explain the mechanism by which the manifestations of NF1 occur a. A mutated tumor-suppressor gene (the first hit) i. Inherited from a parent ii. Presents in every cell of the body b. A second mutation (hit) in some somatic cells of the individual i. Knocks out the other copy of the gene ii. Resulting in complete loss of the gene product and unregulated cell growth/division iii. Resulting in a predisposition to cancer in the cells 6. Marked heterogeneity in NF1 a. Whole-gene-deletion with distinctive phenotype i. Early onset of cutaneous neurofibromas ii. Facial anomalies a) Macrocephaly b) Hypertelorism c) Ptosis d) Down-slanting palpebral fissures e) Short nose f) Low set ears g) Micrognathia iii. Developmental delay iv. Other standard features of NF1 b. Alternate forms of NF1 (conditions with incomplete/ atypical features) i. Mixed neurofibromatosis ii. Localized neurofibromatosis a) Segmental neurofibromatosis (occasional localized café-au-lait spots, segmental distribution of dermal neurofibromas, no systemic manifestations, uncommon internal manifestations of neurofibromas) b) Gastrointestinal neurofibromatosis c) Familial spinal neurofibromatosis (multiple café-au-lait spots and neurofibromas involving spinal cord, lack dermal neurofibromas and Lisch nodules) d) Familial café-au-lait spots (autosomal dominant café-au-lait spots in rare multi-generation families, lack of neurofibromas, axillary freckling and Lisch nodules) c. Related forms of NF1 (conditions with additional features) i. Neurofibromatosis /Noonan syndrome (may or may not fit the criteria of NF1 but with features of Noonan syndrome)
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ii. Watson syndrome a) Multiple café-au-lait spots b) Pulmonary stenosis c) Intertriginous freckling d) Short stature e) Low intelligence 7. Variable expressivity (one of the hallmarks of NF1) a. Intrafamilial variability (marked phenotypic differences may be observed within the same family) b. Interfamilial variability (full spectrum of the disease, mild to severe form, may be present in different families in which affected individuals have the same NF1 mutation) 8. Prototype of a pleiotropic congenital multiple dysplasia syndrome involving CNS, vascular and skeletal systems, and a predilection for hamartomas, dysplasia, and malignancies 9. Mosaicism resulting from somatic mutations a. Early somatic mutation gives rise to generalized disease, clinically indistinguishable from nonmosaic form b. Late somatic mutation gives rise to localized disease often described as segmental form c. Individuals with the mosaic form i. Less likely to have severe disease even with a generalized phenotype ii. Lower offspring recurrence risk than individuals with the nonmosaic form
CLINICAL FEATURES 1. Extreme interfamilial and intrafamilial clinical variability 2. Often not diagnosed at birth, especially a new mutation case 3. Cutaneous manifestations a. Café-au-lait spots (analogy of the color to coffee with milk) i. Present in nearly all patients ii. Round or oval, discrete, well circumscribed, uniformly light brown-pigmented, macular lesions iii. Usually present at birth but continue to increase in number and size during the first decade iv. 6 or more café-au-lait spots exceeding 0.5 cm in diameter in prepubertal children or exceeding 1.5 cm in broadest diameter in postpubertal individuals: the pathognomonic sign for NF1 b. Hyperpigmentation patches: may be associated with underlying plexiform neurofibromas, which are congenital in origin and which may lead to extensive localized hypertrophy c. Freckles in the axillary, groin, and intertriginous areas (almost 90%): a helpful diagnostic feature d. Dermal neurofibromas, usually present in adults with NF1 e. Xanthogranulomas (2–5%) f. Hemangiomas (5–10%) 4. Lisch nodules (asymptomatic pigmented iris hamartomas) a. An extremely important diagnostic feature i. A characteristic sign of NF1 present in 97% of postpubertal patients ii. Lesions typically not detected before 5 years of age iii. Often appear before development of neurofibromas
b. Best observed with slit lamp examination c. Raised, often pigmented nodules of the iris, pathologically representing hamartomas d. Never resulting in significant disease e. Often appear before development of neurofibromas 5. Peripheral neurofibromas a. Benign histologically b. May involve viscera, such as bowel, bladder, and liver, causing bleeding and obstruction c. May result in functional compromise and cosmetic disfigurement d. Increase in size and number during puberty and pregnancy 6. Gross forms of neurofibromas a. Localized cutaneous neurofibromas (nodular or polypoid): the most common form of neurofibromas. Numerous localized cutaneous neurofibromas are the hallmark of NF1 b. Localized intraneural neurofibromas (causing fusiform enlargement of the affected nerve) c. Plexiform neurofibromas (25%) i. Diffuse lesion involving nerve, muscle, connective tissue, vascular elements, and overlying skin ii. Commonly leading to overgrowth of surrounding tissues during childhood iii. Usually congenital iv. Almost invariably apparent by 4 or 5 year of age v. One of the most common and debilitating complications of NF1 vi. Account for substantial morbidity, including disfigurement, functional impairment, and life threatening complications vii. Subject to transformation into malignant peripheral nerve sheath tumor (2–5%) d. Diffuse neurofibromas involving skin and subcutaneous tissue e. Massive soft-tissue neurofibromas (extreme neurofibromatous growth producing massive, diffuse infiltration of soft tissue of a body part, often a distal extremity, leading to localized gigantism, cape formation, or, at the extreme end of the spectrum, formation of disfiguring redundant soft-tissue masses) 7. Certain selected clinical features of NF1 in different age groups a. Infancy i. Pseudarthrosis ii. Seizures iii. Constipation iv. Congenital glaucoma v. Deafness vi. Optic gliomas b. Childhood: i. Optic gliomas ii. Other brain tumors iii. Kyphoscoliosis iv. Genu valgum v. Seizures vi. Congnitive disorders a) Developmental delay b) Learning disabilities c) Mental retardation
NEUROFIBROMATOSIS I
vii. Speech impediments viii. Short stature ix. Macrocephaly x. Early puberty xi. Hypertension xii. Embryonal tumors xiii. Leukemia d. Preadolescence and adolescence: worsening of previous problems such as: i. Scoliosis ii. Cosmetic disfigurement iii. Major psychologic burden iv. Malignancy (neurofibrosarcoma) e. Early adulthood: i. Increase in the number and size of cutaneous, subcutaneous, and plexiform neurofibromas ii. Cosmetic disfigurement iii. Functional compromise a) Pain b) Paralysis c) Gastrointestinal hemorrhage d) Renovascular hypertension f. Adulthood i. An increased risk of developing a specific cancer (2–5% of patients with NF1) ii. Neurofibrosarcoma and malignant peripheral nerve sheath tumor commonly arise in a plexiform neurofibroma in a young adult with symptoms of pain or rapid growth 10. Skeletal involvement (50% of cases) a. Short stature (30%) b. Scoliosis i. Observed in approximately 20% of children with NF1 ii. The most common skeletal defect iii. With or without classic dystrophic features such as vertebral scalloping and rib penciling c. Kyphosis d. Cervical spine abnormalities e. Spondylolisthesis f. Congenital pseudarthroses (3%), frequently with bowing of the tibia and fibula (2–5%) i. A peculiar and uncommon complication ii. First noted as bowing, particularly of the tibia and fibula, in young children iii. May progress to thinning of the cortex, pathologic fracture, and severe difficulties with nonunion of the fragments iv. May go on to form a pseudarthrosis, or false joint, leaving the limb severely compromised g. Macrocephaly (40%) h. Skull bony defects i. Posterosuperior orbital wall bony defect ii. Overgrowth of cranial bones iii. Craniofacial asymmetry iv. Sphenoid wing dysplasia (5–10%) i. Ocular hypertelorism j. Hemihyperplasia of a limb or digit k. Spina bifida l. Absent patella
733
m. Elevated scapulas n. Congenital dislocation (hip, radius, ulna) o. Club foot p. Syndactyly q. Complete or partial absence of the limb bones 11. Endocrine abnormalities a. Sexual precocity (2–5%, the most common endocrine abnormality) b. Hypopituitarism c. Hypogonadism d. Gigantism e. Acromegaly f. Delayed sexual development g. Obesity h. Hypoglycemia i. Diabetes insipidus j. Goiter k. Myxedema l. Hyperparathyroidism 12. Cardiovascular diseases a. Vasculopathy i. Asymptomatic throughout life in many patients ii. Symptomatic vasculopathy: uncommon iii. Affects vessels, from aorta to small arterioles, result in vascular stenosis, occlusion, aneurysm, pseudoaneurysm, rupture, or fistula formation iv. Renal arteries: the most frequently involved site v. NF1-associated cerebrovascular disease in children: presents with weakness, involuntary movements, headaches, or seizures as a result of cerebral ischemia vi. NF1-related cerebrovascular disease in adults: similar symptoms and signs as a result of intracranial hemorrhage b. Hypertension i. Extremely common in adult patients with NF1 (33%) ii. Causes a) Essential hypertension b) Renal artery stenosis c) Pheochromocytomas c. Congenital heart disease (0.4–6.4%) i. Pulmonary stenosis (recognized feature of Watson syndrome, NF1-noonan syndrome, and individuals with large deletions of the NF1 gene) ii. Left heart obstruction (aortic stenosis or coarctation) iii. Other CHD 13. Neuropsychological impairment a. Cognitive impairments (30–65%) b. Learning disabilities (30–60%) i. Easy distractibility ii. Impulsiveness iii. Deficient visual-motor coordination iv. Language and vocabulary deficits c. Mental retardation (4–8%) d. Behavioral difficulties e. Hydrocephalus (5%) f. Neurosensory hearing loss (5%)
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14. Miscellaneous complications a. Headache (10–20%) i. Bothersome but usually not a disabling complaint ii. Headache possibly indicates the presence of an intracranial tumor but no identifiable etiology in many patients b. Generalized itching or itching localized to newly developing neurofibromas experienced by many individuals c. Constipation observed especially in patients with plexiform neurofibromas in the pelvic area which interfere with autonomic innervation of the colon and produce both bowel and bladder problems 15. Pathological manifestations of NF1 a. Epidermis (pigmented macule or café-au-lait spot) b. Iris (Lisch nodule, optic glioma) c. Skeleton (malformations) d. Blood vessels (mesodermal vascular dysplasias): Intrinsic lesions of arterial walls (vasculopathy) are important manifestations of NF1. It appears to contribute to excess mortality of young patients with NF1 i. Asymmetric ii. Renal artery stenosis with consequent hypertension iii. Occlusion resulting in cerebral or visceral infarcts iv. Aneurysms resulting in hemorrhage v. Arterio-venous fistulae e. Brain i. Glial hamartomas ii. Astrocytomas f. Adrenal (pheochromocytoma) g. Intestine i. Somatostatinoma ii. Gastrointestinal autonomic nerve tumor h. Peripheral nerve sheath i. Neurofibromas ii. Malignant peripheral nerve sheath tumors 16. NIH Diagnostic Criteria. National Institutes of Health consensus development conference identified seven important components of neurofibromatosis. Two or more of these components must be present for a diagnosis of neurofibromatosis: a. Six or more café-au-lait spots, which are more than 5 mm in diameter in prepubertal patients and more than 15 mm in diameter in postpubertal individuals b. Two or more neurofibromas of peripheral nerves of any type or one plexiform neurofibroma c. Freckling in the axillary or inguinal region d. Optic glioma (age of presentation at preschool years) e. Two or more Lisch nodules (hamartomas of the iris) f. A distinctive bony lesion such as dysplasia of the sphenoid at the base of the skull or pseudarthrosis or thinning of long bone cortex, with or without complete interruption of the bone g. A first-degree relative (parent, sib, or offspring) affected with neurofibromatosis type 1 which was diagnosed according to the preceding criteria 17. Syndromes related to NF1 a. Neurofibromatosis type 2 (bilateral vestibular neurofibromatosis)
i. ii. iii. iv.
Clinically and genetically distinct from NF1 NF2 gene is mapped to chromosome 22 Inheritance: autosomal dominant Often with a small number of café-au-lait spots (rarely more than six) v. Often with one or two peripheral neurofibromas (usually not more) vi. Occasionally with Lisch nodules vii. Posterior subcapsular cataracts detected by ophthalmologic examination in a sizable proportion of patients viii. The hallmark of NF2: development of bilateral eighth cranial nerve tumors, properly called vestibular schwannomas rather than acoustic neuromas (by age 30 years in 95% of patients) ix. Other tumors of cranial and cervical nerve roots common x. NF2 much less common than NF1, affecting approximately 1 in 40,000 individuals b. Segmental or mosaic NF1 i. Presence of NF1 features (café-au-lait spots, freckling, and peripheral or plexiform neurofibromas, and Lisch nodules) in an individual with a segment of the body affected ii. Family history with invariably normal parents who, on rare occasions, can have a child with classic NF1 iii. Presence of strong circumstantial evidence suggests somatic mutation of the NF1 gene early in embryogenesis so that derivatives of that mutant line display the features of NF1 iv. May transmit the disease if the mosaicism involves the germ line v. Germ-line mosaicism for an NF1 gene mutation has been observed in a clinically unaffected father of a child with new onset NF1 vi. Somatic mosaicism for an NF1 gene deletion has been detected in an individual with NF1 vii. Possibility of demonstrating similar somatic mosaicism if cases of segmental NF1 are analyzed c. Watson syndrome i. Pulmonary stenosis with café-au-lait spots ii. Dull intelligence iii. Short stature iv. A small number of neurofibromas v. Lisch nodules vi. Deletions present in the NF1 gene in at least two families: no distinguishing aspect between the deletions causing Watson syndrome and those associated with more classic NF1 d. Neurofibromatosis 1-Noonan syndrome i. A Noonan syndrome phenotype in patients with NF1 (about 12%) ii. Clinical features in addition to NF1 a) Ocular hypertelorism b) Down-slanting palpebral fissures c) Low-set ears d) Webbed neck e) Pulmonic stenosis f) Pectus excavatum
NEUROFIBROMATOSIS I
g) Mild hypertelorism h) Short stature iii. Relatives affected with NF1 present with or without concomitant features of Noonan syndrome iv. Current understanding: the phenotype of NF1 can include features overlapping with those described in Noonan syndrome, but these disorders are probably genetically distinct e. Predominance of spinal tumors and relatively few peripheral neurofibromas identified in rare families i. Locus heterogeneity ii. Not representing a distinct subtype of NF 18. Prognosis of NF1 a. Progression of the disease with time b. Pregnancies in women with NF1 i. Normal pregnancies in most patients but serious complications have been noted in some patients ii. Rapid increase in the number and size of neurofibromas during pregnancy iii. First onset of hypertension or marked exacerbation of preexisting hypertension during pregnancy iv. Delivery complicated by large pelvic or genital neurofibromas often necessitates cesarean section in pregnant women with NF1 c. Anesthetic risk i. Intraoral lesions compromising the airway (5%) ii. Coexisting kyphoscoliosis (2%) and fibrosing alveolitis (20%) complicating the perioperative period iii. Careful regional anesthesia to monitor the existence of neurofibromas affecting peripheral nerves and nerve roots iv. Possible long-term muscular blockade following the use of suxamethonium and nondepolarizing muscle relaxants d. Average life expectancy overall reduced by at least 15 years i. Malignancy and hypertension contributing to increased morbidity in adults with NF1 ii. Risk for neurofibromatosis-related malignancy (8%) iii. Most common malignancy: malignant peripheral nerve sheath tumors iv. Better prognosis in patients with only mild and cosmetic symptoms of the disease
DIAGNOSTIC INVESTIGATIONS 1. Diagnosis of neurofibromatosis 1 based largely on clinical criteria despite progress in defining the molecular genetics of the disorder 2. Slit-lamp examination of the eyes to detect Lisch iris nodules 3. Radiography to detect bony abnormalities a. Skull i. Macrocephaly ii. Absence of the greater and lesser wings of the sphenoid iii. Absence of the orbital floor iv. Hypoplasia of the lesser wings of the sphenoid v. Enlarged orbits vi. Enlargement of cranial foramina
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vii. Enlargement of orbital margins viii. Sclerosis in the vicinity of the optic foramen (optic nerve sheath meningioma) ix. Facial asymmetry x. Hypoplasia of the paranasal sinuses xi. Mandibular abnormalities xii. Mandibular hypoplasia with flattening of the external contour xiii. Thinning of the ramus xiv. Coronoid hyperplasia xv. Widening of the lateral and medial coronoid spaces xvi. Calvarial defects adjacent the left lambdoid suture xvii. Osseous defects associated with multiple frontonasal osseomeningeal defects causing cerebrospinal fluid (CSF) rhinorrhea b. Chest i. Inferior rib notching ii. Twisted ribbon-like ribs in the upper thoracic cage iii. Posterior mediastinal masses secondary to intrathoracic meningoceles iv. Mediastinal and lung masses secondary to neurofibromas v. Dumbbell neurofibromas vi. Progressive pulmonary interstitial fibrosis leads to formation of bullae and honeycomb lung vii. Increased incidence of spontaneous pneumothorax and hemothorax viii. Dilatation/enlargement of the central pulmonary arteries and peripheral pruning of vessels secondary to changes of interstitial lung disease and pulmonary hypertension c. Spine i. A sharply angled kyphoscoliosis centered at the thoracolumbar junction in 50% of patients ii. Enlargement of the intervertebral foramina iii. Scalloping of the vertebral bodies (anterior, posterior, lateral) iv. Hypoplasia of the vertebral pedicles v. Wedged-shaped vertebrae vi. Spondylolisthesis vii. Spinal clefts viii. Osteolysis ix. Spindling of the transverse processes d. Appendicular skeleton i. Bowing of long bones ii. Hyperplasia or hypoplasia of long and short bones iii. Pseudarthrosis iv. Erosions v. Periosteal dysplasia vi. Intramedullary longitudinal osteosclerotic streaks vii. Single or multiple cystic bone lesions viii. Focal gigantism ix. Protrusio acetabuli x. Dislocation of the hip xi. Dislocation of the radius and ulna xii. Absence of a patella xiii. Neuropathic arthropathy of the knee
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4. 5.
6.
7.
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e. Gastrointestinal i. Neurofibromas within the stomach, small and large bowels, and rectum ii. Intussusception of the bowel presenting with intestinal obstruction iii. Bowel obstruction simulating Hirschsprung disease secondary to plexiform neurofibroma of the colon iv. Pseudoobstruction v. Biliary strictures and bile duct intraluminal neurofibromas rarely reported f. Urinary tract i. Renal collecting system and bladder intrinsically involved or extrinsically compressed or displaced by neurofibromas ii. Intravenous urogram providing useful information regarding the nature and site of obstruction and function Echocardiography for pulmonic stenosis, aortic coarctation, or other CHD CT imaging a. Solid fusiform masses i. Present in the distribution of nerves, with central areas of low attenuation and calcification ii. May present in the paravertebral, laryngeal, mediastinal, abdominal, and pelvic/ischiorectal fossae b. Plexiform neurofibromas seen as widespread sheets of nodular tissue c. Paraspinal neurofibromas seen at every level, vary in size, may be dumbbell shaped, or may comprise fusiform/spherical soft tissue masses d. Mesenteric plexiform neurofibromas trap mesenteric fat within an entangled network e. Nonneoplastic cerebral and cerebellar calcification and choroid plexus calcification on cranial CT scans f. Hydrocephalus in NF1 results from benign aqueduct stenosis or a glioma of the tectum/tegmentum of the mesencephalon g. Intracranial nerve sheath tumors with associated bone erosions h. Meningiomas with associated changes in the calvarium/skull i. Extrinsic bladder involvement, intrinsic infiltrative processes, or extrinsic compression of the renal collecting system by a neurofibroma j. A role in the investigation of thoracic, abdominal, and pelvic complications of NF1 MRI imaging a. Brain i. T2 hyperintensities (60–70%) ii. Hamartomas in the brain iii. Optic nerve pathology b. Internal lesions i. Mediastinal masses ii. Spinal cord tumors iii. Deep plexiform neurofibromas iv. Neurofibromas of the brachial or sacral plexus Histopathology a. Confirmation of neurofibromas i. Arisen from cells in the peripheral nerve sheath
8. 9.
10.
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ii. Consist of a mixture of cell types, including Schwann cells, fibroblasts, mast cells, and vascular elements b. Verification of malignant transformation to neurofibrosarcoma Linkage analyses using polymorphic markers that segregate with the disease in familial cases Either FISH, loss of heterozygosity or Southern blotting analyses reveal 5% of patients with large deletions of NF1 gene encompassing part or the whole NF1 gene Mutation analysis in sporadic and familial cases a. Protein truncation test based on the detection of truncated proteins via in vitro transcription and translation from RT-PCR fragments spanning the entire NF1 cDNA i. NF1 mutations detected a) Nonsense mutations b) Frameshift mutations c) Splicing mutations ii. Method of exploring the RNA for changes that are compatible with mutations in the gene iii. Positive in 80% of the cases b. Gene sequencing: specific search of exon by exon for the mutation Multi-step protocol a. Testing methods i. Optimized protein truncation testing ii. Sequence analysis iii. FISH iv. Long-range RT-PCR v. Southern blot analysis vi. Cytogenetic analysis b. NF1 mutations detected i. Nonsense mutations ii. Frameshift mutations iii. Splicing mutations iv. Missense mutations v. Deletions vi. Other rearrangements c. Mutation detection rate in patients with a clinical diagnosis of NF1: >95% Presymptomatic/preconceptional genetic testing: molecular characterization in familial and in sporadic cases
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sibling i. Risk not increased unless a parent is affected or has gonadal mosaicism ii. Possibility of germ-line mosaicism in a clinically normal parent: recurrence risk based on the percentage of the germ-line mosaicism b. Patient’s offspring i. Risk: 50% of inheriting the disease with extremely variable disease manifestations ii. Risk of having a child with NF1 in a patient affected with segmental NF1: small but greater than the general population risk. Segmental neurofibromatosis is believed to be due to
NEUROFIBROMATOSIS I
somatic mosaicism for a mutation in the NF gene. The mutation occurred postconceptionally and present in the limited population of cells. Gonadal cells may or may not have a mutation 2. Prenatal diagnosis a. Influence of knowledge of the disease in the reproductive decisions of affected individuals i. Interest in prenatal test by 41% of the subjects considering becoming pregnant ii. Only 10% considering terminating an affected pregnancy b. Prenatal diagnosis of NF1 difficult to be made in the past due to the following reasons i. Large size of the NF1 gene ii. Lack of any hotspots where the mutations arise iii. Variable expression even within members of a family with NF1 iv. Lack of a tight genotype–phenotype correlation v. High spontaneous mutation rate c. Currently available prenatal diagnosis i. Direct characterization of the mutation from a parent affected by NF1 ii. Analysis of the genomic DNA mutation from the fetus either by amniocentesis or CVS iii. Indirect linkage analysis to familial cases using informative polymorphic markers iv. Protein truncation test v. Fluorescence in situ hybridization d. Molecular diagnosis, unfortunately, cannot predict clinical expression of the disease in the fetus 3. Management a. Developmental assessment in children b. Medical management for itching, pain, depression, and other psychological and social problems c. Treatment of hypertension depending on the etiology i. Pheochromocytomas ii. Renal artery stenosis d. Surgical resection of tumors i. Resection of neurofibromas pressing on vital structures, obstructing vision, or rapidly growing lesions causing irritation, discomfort, and pain ii. Plexiform neurofibromas: extremely difficult to approach surgically and often recur after resection because of residual cells resting deeply in the soft tissues iii. Resection of spinal cord tumors: quite difficult but often is necessary to prevent progressive paraplegia or quadriplegia e. Surgical treatment of disfigurement i. Excision of multiple neurofibromas ii. Reconstructive surgery for plexiform neurofibromas f. Orthopedic care indicated for rapidly progressive scoliosis and for some severe bony defects g. Treatment of congenital pseudarthrosis of the tibia: challenging i. Bracing mainly of early treatment before fracture develops
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ii. A knee-ankle-foot-orthosis when weight bearing iii. Intramedullary rod fixation, often in combination with autogenous bone grafting of the pseudarthrosis site h. Complications of genetic counseling i. Intrafamilial variability (wide variation of phenotype even between members of the same family) ii. Presence of gonadal mosaicism in a phenotypically normal parent i. Advise high-risk pregnancy care to pregnant patient with neurofibromatosis i. Maternal hypertension ii. Aggravating features of neurofibromatosis
REFERENCES American Academy of Pediatrics Committee on Genetics: Health supervision for children with neurofibromatosis. Pediatrics 96:368–372, 1995. Ars E, Kruyer H, Gaona A, et al.: Prenatal diagnosis of sporadic neurofibromatosis type 1 (NF1) by RNA and DNA analysis of a splicing mutation. Prenat Diagn 19:739–742, 1999. Barker D, Wright E, Nguyen K, et al.: Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Science 236:1100–1102, 1987. Benjamin CM, Colley A, Donnai D, et al.: Neurofibromatosis type 1 (NF1): knowledge, experience, and reproductive decisions of affected patients and families. J Med Genet 30:567–574, 1993. Blickstein I, Lancet M, Shoham Z: The obstetric perspective of neurofibromatosis. Am J Obstet Gynecol 158:385–388, 1988, Comment in 161:501, 1989. Brasfield RD, DasGupta TK: Van Recklinghausen’s disease. A clinicopathological study. Ann Surg 175:86–104, 1972. Carey J: Health supervision and anticipatory guidance for children with genetic disorders (including specific recommendations for trisomy 21, trisomy 18, and neurofibromatosis I). Pediatr Clin North Am 39:25–53, 1992. Carey JC, Laub JM, Hall BD: Penetrance and variability in neurofibromatosis: A genetic study of 60 families. Birth Defects 15(5B):271, 1979. Carey JC, Baty BJ, Johnson JP, et al.: The genetic aspects of neurofibromatosis. Ann New York Acad Sci 486:45–56, 1986. Cnossen MH, Moon KGM, Garssen MPJ, et al.: Minor disease features in neurofibromatosis type 1 (NF1) and their possible value in diagnosis of NF1 children <6 years and clinically suspected of having NF1. J Med Genet 35:624–627, 1998. Cohen MM Jr: Overgrowth syndromes: An update. Adv Pediatr 40:441–491, 1999. Colman SD, Rasmussen SA, Ho VT, et al.: Somatic mosaicism in a patient with neurofibromatosis type 1. Am J Hum Genet 58:484, 1996. DeBella K, Szudek J, Friedman JM: Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics 105:608–614, 2000. Dohil MA, Baugh WP, Eichenfield LF: Vascular and pigmented birthmarks. Pediatr Clin N Am 47:783–812, 2000. Dugoff L, Sujansky E: Neurofibromatosis type 1 and pregnancy. Am J Med Genet 66:7–610, 1996. Es SV, North KN, McHugh K, et al.: MRI findings in children with neurofibromatosis type 1: a prospective study. Pediatr Radiol 26:478–487, 1996. Friedman JM: Epidemiology of neurofibromatosis type 1. Am J Med Genet 89:1–6, 1999. Friedman JM: Neurofibromatosis 1. Gene Reviews, 2002. Friedman JM, Birch PH: Type 1 neurofibromatosis: a descriptive analysis of the disorder in 1,728 patients. Am J Med Genet 70:138–143, 1997. Friedman JM, Gutmann DH, MacCollin M, Riccardi VM (eds): Neurofibromatosis: Phenotype, Natural History and Pathogenesis, 3rd ed. Baltimore: Johns Hopkins University Press, 1999. Goldberg Y, Dibbern K, Klein J, et al.: Neurofibromatosis type 1—an update and review for the primary pediatrician. Clin Pediatr 35:545–561, 1996. Gutmann DH: Recent insights into neurofibromatosis type 1: clear genetic progress. Arch Neurol 55:778–780, 1998.
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Gutmann DH, Collins FS: Neurofibromatosis 1. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001. Gutmann DH, Aynsworth A, Carey JC, et al.: The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278:51–57, 1997. Hamilton SJ, Friedman JM: Insights into the pathogenesis of neurofibromatosis 1 vasculopathy. Clin Genet 58:341–344, 2000. Huson SM, Hughes RAC: The Neurofibromatoses: A Pathogenetic and Clinical Overview. London, Chapman and Hall, 1994. Kayl AE, Moore BD III: Behavioral phenotype of neurofibromatosis, type 1. Ment Retard Dev Disabil Res Rev 6:117–124, 2000. Khan AN, Turnbull I: Neurofibromatosis type I. eMedicine 2002. Korf BR: Plexiform neurofibromas. Am J Med Genet (Semin Med Genet) 89:31–37, 1999. Korf BR: Malignancy in neurofibromatosis type 1. Oncologist 5:477–485, 2000. Korf BR, Carey JC: Molecular genetics of neurofibromatosis, in Rubenstein AE, Korf BR (eds): Neurofibromatosis: A Handbook for Patients, Families, and Health-Care Professionals. New York, Thieme, 1990, pp 178. Lakkis MM, Tennekoon GI: Neurofibromatosis type 1. I. General overview. J Neurosci Res 62:755–763, 2000. Landau M, Krafchik BR: The diagnostic value of cafè-au-lait macules. J Am Acad Dermatol 6:877–890, 1999. Liebermann F, Korf BR: Emerging approaches toward the treatment of neurofibromatoses. Genet Med 1:158–64, 1999. Messiaen L, Callens T, Mortier G, et al.: Towards an efficient and sensitive molecular genetic test for neurofibromatosis type 1 (NF1). Eur J Hum Genet 9:314, 2001. National Institutes of Health: Neurofibromatosis. National Institutes Consensus Development Conference Statement. Arch Neurol 45:575–578, 1988. Neville HL, Seymour-Dempsey K, Slopis J, et al.: The role of surgery in children with neurofibromatosis. J Pediatr Surg 36:25–9, 2001. North K: Neurofibromatosis type 1. Am J Med Genet (Semin Med Genet) 97:119–127, 2000. Opitz JM, Weaver DD: The neurofibromatosis-Noonan syndrome. Am J Med Genet 21:477, 1985. Ozonoff S: Cognitive impairment in neurofibromatosis type 1. Am J Med Genet (Semin Med Genet) 89:45–52, 1999. Park VM, Pivnick EK: Neurofibromatosis type 1 (NF1): a protein truncation assay yielding identification of mutations in 73 per cent of patients. J Med Genet 35:813–820, 1998. Poyhonen M, Niemela S, Herva R: Risk of malignancy and death in neurofibromatosis. Arch Pathol Lab Med 121:139–143, 1997. Rasmussen SA, Friedman JM: NF1 gene and neurofibromatosis 1. Am J Epidemiol 151:33–40, 2000. Riccardi VM: Von Recklinghausen neurofibromatosis. N Enl J Med 305:1617–1627, 1981.
Riccardi VM: Type 1 neurofibromatosis and the pediatric patient. Curr Probl Pediatr 22:66–106, discussion in 107, 1992. Riccardi VM: Neurofibromatosis. Phenotype, Natural History, and Pathogenesis. 2nd ed. Baltimore, Johns Hopkins Univ Press, 1992. Ruggieri M: The different forms of neurofibromatosis. Childs Nerv Syst 15:295–308, 1999. Ruggieri M, Huson SM: The clinical and diagnostic implications of mosaicism in the neurofibromatosis. Neurology 56(11): June 12, 2001. Seashore MR, Cho S, Desposito F, et al.: Health supervision for children with neurofibromatosis. Pediatrics 96:368–372, 1995. Shen MH, Harper PS, Upadhyaya M: Molecular genetics of neurofibromatosis type 1 (NF1). J Med Genet 33:2–17, 1996. Sloan JB, Fretzin DF, Bovenmyer DA: Genetic counseling in segmental neurofibromatosis. J Ann Med Acad Dermatol 22:461–467, 1990. Sorenson SA, Mulvhill JT, Nielsen A: Long-term follow up of von Recklinghausen neurofibromatosis: survival and malignant neoplasms. N Engl J Med 314:1010, 1986. Stumpf D, Alksne J, Annegers J, et al.: Neurofibromatosis conference statement. Arch Neurol 45:575–578, 1988. Tinschert S, Naumann I, Stegmann E, et al.: Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (NF1) gene. Eur J Hum Genet 8:455–459, 2000. Upadhyaya M, Fryer A, MacMillan J, et al.: Prenatal diagnosis and presymptomatic detection of neurofibromatosis type 1. J Med Genet 29:180–183, 1992. Viskochil DH (ed): Neurofibromatosis 1. Am J Med Genet (Semin Med Genet) 89:1–52, 1999. Viskochil D: Neurofibromatosis type 1. In: Cassidy SB, Allanson JE (eds): Management of Genetic Syndromes. New York: Wiley-Liss, 2001. Vitale MG, Guha A, Skaggs DL: Orthopaedic manifestations of neurofibromatosis in children: An update. Clin Orthop Rel Res 401:107–118, 2002. Von Recklinghausen FD: Ueber die multiplen fibrome der Hautund inhre beziehung zu den multiplen neuromen. Berlin, Hirschwald, 1882. Woodruff JM: Pathology of tumors of the peripheral nerve sheath in type 1 neurofibromatosis. Am J Med Genet (Semin Med Genet) 89:23–30, 1999. Wu BL, Austin MA, Schneider GH, et al.: Deletion of the entire NF1 gene detected by the FISH: four deletion patients associated with severe manifestations. Am J Med Genet 59:528–535, 1995. Wu BL, Boles RG, Yaari H, et al.: Somatic mosaicism for deletion of the entire NF1 gene identified by FISH. Hum Genet 99:209–213, 1997. Zhu Y, Parada LF: Neurofibromin, a tumor suppressor in the nervous system. Exp Cell Res 264:19–28, 2001. Zoller M, Rembeck B, Akesson HO, et al.: Life expectancy, mortality and prognostic factors in neurofibromatosis type 1. A twelve-year follow-up of an epidemiological study in Goteborg, Sweden. Acta Derm Venereol 75: 136–140, 1995.
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Fig. 1. Typical café-au-lait spots in different patients.
Fig. 2. Axillary freckles in a child and an adult.
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Fig. 3. Café-au-lait spots and numerous localized cutaneous neurofibromas in three different patients.
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Fig. 4. Diffuse cutaneous neurofibromas (nodular and polypoid shapes) in four patients affecting skin and subcutaneous tissue resulting in marked cosmetic disfigurements and functional disturbances.
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Fig. 5. Neurofibromas involving vessels of the face and subcutaneous tissue of the fingers.
Fig. 6. Macrocephaly with prominent forehead and depressed nasal bridge.
Fig. 7. Pseudoarthrosis of right tibia manifesting as bowed leg.
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Fig. 8. Localized intraneural neurofibromas of a median nerve, causing fusiform enlargement of the affected nerve.
Fig. 10. Massive soft-tissue neurofibromas affecting two patients. Extreme neurofibromatous growth producing massive, diffuse infiltration of soft tissue of the thigh producing disfiguring redundant softtissue masses.
Fig. 11. Tanish white iris Lesch nodules in a patient with NF1.
Fig. 9. Plexiform neurofibromas affecting left orbital region in different ages.
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Fig. 12. MRI of the brain showing a hamartomatous lesion of the right globus pallidus. This patient has numerous cutaneous café-au-lait spots of varying size and typical axillary freckles. He was shown to have a truncating mutation in the segment 3 of the neurofibromin (NF1) gene.
Fig. 13. A 26-year-old female with segmental neurofibromatosis showing axillary freckles (A), multiple small neurofibromas and hyperpigmentation (C,D), all involving the right side of the body. Left side of the body is spared, including left axilla which showed no freckles (B).
Noonan Syndrome iv. v. vi. vii.
Noonan syndrome (NS) is a relatively common but genetically heterogeneous autosomal dominant malformation syndrome. The incidence of Noonan syndrome is estimated to be 1 in 1000 to 1 in 2500 live births.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant inheritance b. Many affected individuals with de novo mutations c. Affected parent recognized in 30–70% of families 2. Caused by mutation in the gene PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11), mapped on 12q24.1, encoding the protein tyrosine phosphatase SHP-2 a. Heterozygous point mutations in the gene PTPN11 identified in: i. Families showing linkage to the NS1 locus in 12q24 ii. Some sporadic cases with NS b. All mutations detected to date: missense mutations c. The majority of mutations found in exons 3 and 8, which correspond to the interacting regions of the N-SH2 and protein tyrosine phosphatase domains of the gene 3. Genotype–phenotype correlation a. Increased frequency of PTPN11 mutations observed in individuals with Noonan syndrome with pulmonary stenosis (70%) b. Infrequent frequency of PTPN11 mutations observed in individuals with hypertrophic cardiomyopathy (6%)
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CLINICAL FEATURES 1. Clinical features a. Growth i. Average length at birth: 47 cm ii. Generally normal birth weight but can be high due to subcutaneous edema iii. Prepubertal growth parallel the 3rd centile (40%) with a relatively normal growth velocity iv. Pubertal growth spurt often reduced or absent b. Craniofacial features: change with age (see below) c. Ocular abnormalities (observed up to 95% of cases) i. Strabismus ii. Refractive errors iii. Amblyopia iv. Nystagmus v. Anterior segment and fundal changes d. Congenital heart defects (2/3rd of cases) i. Pulmonary valvular stenosis (50%) ii. Hypertrophic cardiomyopathy (20–30%): may be present at birth or appears in infancy or childhood iii. Atrial septal defect (10%) 744
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Asymmetrical septal hypertrophy (10%) Ventricular septal defect (5%) Persistent ductus arteriosus (3%) Other cardiac defects a) Pulmonary artery branch stenosis b) Mitral valve prolapse c) Ebstein anomaly d) Single ventricles Genitourinary abnormalities i. Males: ranging from normal prepubertal virilization to delayed fertility and inadequate secondary sexual development associated with deficient spermatogenesis secondary to earlier cryptorchidism (60%) ii. Females: normal or delayed puberty but fertile in majority of cases Skeletal abnormalities i. Characteristic pectus deformity (see detail description below) ii. Common features a) Cubitus valgus (50%) b) Hand anomalies including clinobrachydactyly and blunt fingertips (30%) c) Vertebral and sternal anomalies (25%) d) Dental malocclusion (35%) Ectodermal abnormalities i. Various skin manifestations a) Café-au-lait patches (10%) b) Pigmented nevi (25%) c) Lentigines (2%) d) Keratosis pilaris atrophicans faciei ii. Several instances of neurofibromatosis and the Noonan phenotype documented Bleeding diathesis (about 1/3rd of cases with a coagulation defect) i. Factor XI deficiency ii. Von Willebrand disease iii. Platelet dysfunction which may be associated with trimethylaminuria Lymphatic abnormalities i. Congenital dysplasia, hypoplasia, or aplasia of lymphatic channels (20%) ii. General lymphedema iii. Peripheral lymphedema iv. Pulmonary lymphangiectasia v. Intestinal lymphangiectasia vi. Hydrops fetalis vii. Cystic hygroma Rare associated features i. Autoimmune thyroiditis ii. Pheochromocytoma iii. Ganglioneuroma iv. Malignant schwannomas
NOONAN SYNDROME
v. Congenital contractures vi. Chiari malformation with syringomyelia vii. Skin and oral xanthomas viii. Odontogenic keratosis k. Behavioral and developmental abnormalities i. Failure to thrive in infancy (40%) ii. Motor developmental delay (26%) iii. Learning disability with specific visual-constructional problems and verbal-performance discrepancy (15%) iv. Language delay (20%) secondary to perceptual motor disabilities, mild hearing loss (12%), or articulation abnormalities (72%) v. Intelligence a) IQ: 64-127 with a median of 102 b) IQ: 10 points below that of unaffected family members c) Mild mental retardation reported in up to 35% of cases 2. Changing phenotype with age a. Newborn period i. Marked edema a) Contributing to a normal-to-high birth weight b) Rapid reduction after birth simulating failure to thrive ii. Excess nuchal skin iii. Sloping and broad forehead iv. Apparent ocular hypertelorism v. Downslanting palpebral fissures vi. A deep philtrum vii. Mild retrognathia viii. Posteriorly angulated ears with a thick helix b. Neonatal period to 2 years i. Head a) Relatively large appearance b) Flat malar eminence c) Bitemporal narrowing accentuated by lateral supraorbital fullness d) “Coarse” and occasional asymmetric facial appearance ii. Eyes a) Prominent and round b) Ocular hypertelorism c) Telecanthus d) Lessening down slanting of the palpebral fissures e) Occasional strabismus f) Thick eyelid hooding the upper iris g) Sharp arched eyebrows iii. Nose a) Depressed nasal root b) Low nasal bridge c) Wide nasal base d) Bulbous nasal tip e) Anteverted nares f) Short columella iv. Deep philtrum v. Arched upper lip with high and wide peaks of the vermilion border
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vi. Ears a) Posteriorly rotated b) Occasionally small or square vii. Neck a) Short b) Less excess skin than in the newborn period c) A low posterior hairline viii. Often failure to thrive and hypotonia ix. Occasional hepatosplenomegaly, swarthy skin, and wispy hair x. 12–18 months of age a) Changing body shape with stocky and square upper body b) Occasional presence of an umbilical hernia or diastasis recti c) The limbs becoming relatively longer and thinner secondary to resolving edema d) Blunt finger tips c. Childhood i. Face a) Appearance remaining coarse b) Becoming more triangular as the chin lengthens c) Forehead becoming lower and may be bossed d) Flatter malar eminence ii. Eyes a) Less prominent eyes with reduced epicanthus b) Increasing ptosis c) Increasing lateral supraorbital fullness d) Higher nasal root and bridge iii. Full lips with sublabial protrusion iv. Neck a) Appearing longer b) Accentuating webbing c) Prominent trapezius v. Thorax a) Broad b) An inverted pyramid shape c) Increasing pectus d) Upper chest length increases with relatively low-set nipples and axillary webbing which persist to adulthood vi. Scapula a) Round shape b) Winged scapulae vii. Limbs a) Thin b) Marked cubitus valgus c) Flat feet viii. Skin a) Lentigines b) Nevi c) Café-au-lait spots ix. Often markedly curly or woolly hair d. Teenage and young adulthood i. Facial shape becoming increasingly triangular ii. Facial features becoming sharper iii. Less prominent eyes with occasional ptosis
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iv. Nose a) Thinner b) A pinched root c) Higher bridge d) Wide base e) Pointed tip f) A longer columella v. Eyebrows becoming sparse e. Older adulthood i. Prominent nasolabial folds ii. Higher anterior hairline iii. Occasional sloping forehead iv. Transparent wrinkled skin f. Prominent abnormalities at all ages i. Striking blue or blue-green irides ii. Increased number of fingertip whorls iii. Posteriorly angulated ears with a thick helix iv. Characteristic pectus deformity a) Pectus carinatum superiorly b) Pectus excavatum inferiorly
DIAGNOSTIC INVESTIGATIONS 1. Growth curves for males and females with Noonan syndrome now available 2. Echocardiography for previously described congenital heart defects 3. Electrocardiography a. A wide QRS complex b. Left axis deviation c. Giant Q wave d. A negative pattern in the left precordial leads 4. Radiography: pectus deformity 5. Renal ultrasound for renal anomalies 6. Coagulation studies when needed 7. Chromosome analysis: normal karyotype 8. Molecular genetic testing available clinically a. Mutations in the gene PTPN11 identified in 50% of patients (familial and sporadic cases) b. Germline mutations i. Detected in 59% of patients with familial Noonan syndrome ii. Detected in 37% of individuals with sporadic Noonan syndrome
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. 50% if a parent is affected ii. Low risk (<1%) if parents are not affected unless gonadal mosaicism is present in a parent b. Patient’s offspring: 50% affected 2. Prenatal diagnosis a. Ultrasonography for pregnancies at 50% risk: no definitive ultrasonographic diagnostic criteria early in gestation i. Septated cystic hygroma ii. Scalp edema iii. Polyhydramnios iv. Facial features
a) Posteriorly angulated, apparently low-set ears b) Depressed nasal bridge v. Pleural and pericardial effusions vi. Cardiac defects a) Pulmonic stenosis b) Hypertrophic cardiomyopathy vii. Ascites viii. Hydrops fetalis b. Molecular genetic testing of fetal DNA extracted from amniocentesis or CVS for PTPN11 mutations. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed 3. Management a. Plotting of growth parameters on growth charts for Noonan syndrome b. Ophthalmological care c. Cardiac management of congenital heart defects and hypertrophic cardiomyopathy d. Hearing evaluation and management e. Physical and occupational therapies for hypotonia f. Speech therapy for articulation deficiencies g. Infant stimulation program for developmental delay h. Multidisciplinary developmental intervention program i. Hearing aids for sensorineural hearing loss j. Orthopedic management of musculoskeletal abnormalities k. Growth hormone treatment of short stature: final height not improved substantially in most patients l. Successful pregnancy possible in women with Noonan syndrome
REFERENCES Abuelo DN, Meryash DL: Neurofibromatosis with fully expressed Noonan syndrome. Am J Med Genet 29:937–941, 1988. Achiron R, Heggesh J, Grisaru D, et al.: Noonan syndrome: a cryptic condition in early gestation. Am J Med Genet 92:159–165, 2000. Allanson JE: Noonan syndrome. J Med Genet 24:9–13, 1987. Allanson JE: Noonan syndrome. In Cassidy SB, Allanson JE (eds): Management of Genetic Syndromes. New York: Wiley-Liss, 2001. pp 253–268. Allanson JE: Noonan syndrome. Gene Reviews 2003. http://www.genetests.org Allanson JE, Hall JG, Hughes HE, et al.: Noonan syndrome: the changing phenotype. Am J Med Genet 21:507–514, 1985. Burch M, Sharland M, Shinebourne E, et al.: Cardiologic abnormalities in Noonan syndrome: phenotypic diagnosis and echocardiographic assessment of 118 patients. J Am Coll Cardiol 22:1189–1192, 1993. Collins E, Turner G: The Noonan syndrome—a review of the clinical and genetic features of 27 cases. J Pediatr 83:941–950, 1973. Kirk JM, Betts PR, Butler GE, et al.: Short stature in Noonan syndrome: response to growth hormone therapy. Arch Dis Child 84:440–443, 2001. Kosaki K, Suzuki T, Muroya K, et al.: PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome. J Clin Endocrinol Metab 87:3529–3533, 2002. Maheshwari M, Belmont J, Fernbach S, et al.: PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13. Hum Mutat 20:298–304, 2002. Mendez HM, Opitz JM: Noonan syndrome: a review. Am J Med Genet 21:493–506, 1985. Musante L, Kehl HG, Majewski F, et al.: Spectrum of mutations in PTPN11 and genotype–phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome. Eur J Hum Genet 11:201–206, 2003. Noonan JA: Noonan syndrome. An update and review for the primary pediatrician. Clin Pediatr (Phila) 33:548–555, 1994.
NOONAN SYNDROME Noonan JA, Raaijmakers R, Hall B: Adult height in Noonan syndrome. Am J Med Genet 123A:68–71, 2003. Nora JJ, Nora AH, Sinha AK, et al.: The Ullrich-Noonan syndrome (Turner phenotype). Am J Dis Child 127:48–55, 1974. Ogata T, Sato S, Hasegawa Y, et al.: Lymphstasis in a boy with Noonan syndrome: implication for the development of skeletal features. Endocr J 50:319–324, 2003. Opitz JM: The Noonan syndrome. Am J Med Genet 21:515–518, 1985. Patton MA: Noonan syndrome: a review. Growth Horm 10:1–3, 1994. Ranke MB, Heidemann P, Knupfer C, et al.: Noonan syndrome: growth and clinical manifestations in 144 cases. Eur J Pediatr 148:220–227, 1988. Romano AA, Blethen SL, Dana K, et al.: Growth hormone treatment in Noonan syndrome: the National Cooperative Growth Study experience. J Pediatr 128:S18–S21, 1996. Sharland M, Morgan M, Smith G, et al.: Genetic counselling in Noonan syndrome. Am J Med Genet 45:437–440, 1993.
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Tartaglia M, Kalidas K, Shaw A, et al.: PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype–phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 70:1555–1563, 2002. Tartaglia M, Mehler EL, Goldberg R, et al.: Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29:465–468, 2001. Witt DR, Hoyme HE, Zonana J, et al.: Lymphedema in Noonan syndrome: clues to pathogenesis and prenatal diagnosis and review of the literature. Am J Med Genet 27:841–856, 1987. Witt DR, Keena BA, Hall JG, et al.: Growth curves for height in Noonan syndrome. Clin Genet 30:150–153, 1986. Witt DR, McGillivray BC, Allanson JE, et al.: Bleeding diathesis in Noonan syndrome: a common association. Am J Med Genet 31:305–317, 1988. Zenker M, Buheitel G, Rauch R, et al.: Genotype–phenotype correlations in Noonan syndrome. J Pediatr 144:368–374, 2004.
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Fig. 1. Two boys (A-D;E-F) with Noonan syndrome showing various features: down slanting palpebral fissures, hypertelorism, short and webbed neck with a low posterior hair line, pectus, and cubitus valgus.
NOONAN SYNDROME
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Fig. 3. Familial Noonan syndrome in a mother and a daughter.
Fig. 2. A boy with Noonan syndrome showing characteristic facial features and webbed neck.
Oblique Facial Cleft Syndrome i. Whole stretch from the lip through the nose to the eyelid and orbit ii. Nasolacrimal duct always involved iii. Defective and upwardly dislocated ala nasi b. Oro-ocular clefts i. Type I (medial): cleft medial to infra-orbital region of the naso-labial groove to end in the inner canthus or the lower eyelid ii. Type II (lateral): cleft extending from the angle of the mouth upwards to the orbit ending in the lateral canthus or in a coloboma in the mid-portion of the lower eyelid iii. Twice as frequent as the naso-ocular types c. Bilateral clefts in 20–35% of cases d. Presence of complete or incomplete forms e. Possible involvement of palate and extending into the temporal region 3. Concordant clinical signs a. Short stature b. Sparse eyebrows c. Sparse eyelashes d. Lower lid coloboma e. Abnormal nose f. Involvement of the nasolacrimal duct g. Malar hypoplasia 4. Other variable clinical signs a. Mental retardation b. Anophthalmia/microphthalmia c. Hemimelia (possibly resulting from in utero vascular accident in some cases) 5. Associated anomalies a. Amniotic bands i. Amniotic band affecting premaxillary-nasalocular areas of the midface producing oblique tissue disruptions ii. Intrauterine amputation iii. Constriction rings iv. Distal lymphedema v. Distal pseudosyndactyly vi. Remnant of amniotic band still attached to the lesion b. CNS abnormalities i. Encephalocele ii. Hydrocephaly c. Cutis aplasia congenita d. Talipes equinovarus
Oblique facial clefts are extremely rare congenital anomalies occurring in about 1/100 to 12/1000 of facial clefts.
GENETICS/BASIC DEFECTS 1. Genetic heterogeneity a. Sporadic in most cases b. A disruptive event resulting from amniotic band rupture sequence considered as a main etiological agent i. 26% of nonsyndromal craniofacial cleft display congenital limb anomalies ii. 13% of nonsyndromal craniofacial cleft show evidence of limb ring constrictions c. Occasional association with malformation syndrome (e.g., Fryns anophthalmia-microphthalmia-oblique clefting syndrome) d. Rare autosomal recessive inheritance 2. Classification of facial clefts a. American Association for Cleft Palate Rehabilitation (1962) divided facial clefts into four major groups according to the anatomic location: i. Mandibular process clefts ii. Naso-ocular clefts iii. Oro-ocular clefts iv. Oro-aural clefts b. Boo-Chai (1970) proposed a subdivision of the oroocular group into: i. Medial (Type I) ii. Lateral (Type II) c. Tessier (1976) presented an anatomic classification of the facial clefts by using numbers 0–14 anticlockwise to point the location of the cleft when the orbit is used as the central point i. Proven validity in analyzing complex facial deformities ii. Careful examination in confirming the diagnosis and in managing the patients 3. Oblique clefts a. Considered as late or secondary defects resulting from outgrowth of one or more bone centers in membranous bones b. Including certain types of Tessier classification (1976): oblique clefts corresponding to the numbers 3 to 6 distally or “south-wards” and 8 to 11 proximally or “northwards” from the orbit in the extreme forms c. Arbitrary classification in some instances d. Presence of intermediate forms of facial clefts
DIAGNOSTIC INVESTIGATIONS 1. Radiography for craniofacial anomalies 2. Three-dimensional CT scan for visualization of the extent and location of the cleft 3. MRI of the brain for CNS anomalies 4. Blood for chromosome analysis to rule out chromosome etiology
CLINICAL FEATURES 1. Clinical variability 2. Oblique facial clefts a. Naso-ocular clefts 751
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OBLIQUE FACIAL CLEFT SYNDROME
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Recurrence risk not increased since most cases are sporadic, especially in a case where amniotic band rupture sequence is considered to be the etiologic factor ii. Recurrence risk possibly increased in occasional cases of autosomal recessive inheritance b. Patient’s offspring: not increased 2. Prenatal diagnosis: possible by ultrasonographic documenting oblique facial cleft associated with other commonly associated anomalies (CNS anomaly, anophthalmia, and findings of amniotic band disruption sequence) 3. Management a. Early orthopedic treatment i. To achieve both the proper alignment of the maxillary segments and a reduction of cleft width in cases of unilateral cleft lip, alveolus, and palate ii. Presurgical orthopedic devices to approximate the distorted segments and to facilitate lip closure in the treatment of maxillary clefts b. Surgical repair of facial cleft i. General principle a) Accurate approximation of each tissue layer b) Meticulous layer closure to prevent loss of anatomical continuity and a depressed scar along the site of the operative procedure c) Multiple Z-plasty when the repair crosses lines of minimal skin tension or when there is loss of length ii. Closure of the cleft and reconstruction of the underlying bony deficiencies at a very early age iii. Followed by subsequent correction of orbital hypertelorism between the ages of 2–5 years iv. Followed by orthognathic correction of maxillary and mandibular deformities in the teens c. Multidisciplinary approach to early intervention
REFERENCES Boo-Chai K: The oblique facial cleft. A report of 2 cases and a review of 41 cases. Br J Plast Surg 23:352–359, 1970. Boo-Chai K: The oblique facial cleft: a 20-year follow-up. Br J Plast Surg 43:355–358, 1990. Butow KW, de Witt TW: Bilateral oblique facial cleft—tissue expansion with primary reconstruction. J Dent Assoc S Afr 45:507–511, 1990. Chiong AT, Guevarra ES Jr, Zantua RV: Oblique facial cleft. Arch Otolaryngol 107:59–62, 1981. Coady MSE, Moore MH, Wallis K: Amniotic band syndrome: the association between rare facial clefts and limb ring constrictions. Plast Reconstr Surg 101:640–648, 1998. Dasouki M, Barr M Jr, Erickson RP, et al.: Translocation (1;22) in a child with bilateral oblique facial clefts. J Med Genet 25:427–431, 1988.
Darzi MA, Chowdri NA: Oblique facial clefts: a report of Tessier numbers 3, 4, 5, and 9 clefts. Cleft Palate Craniofacial J 30:414–415, 1993. David DJ, Moore MH, Cooter RD: Tessier clefts revisited with a third dimension. Cleft palate J 26:163–184, 1989. Dey DL: Oblique facial clefts. Plast Reconstr Surg 52:258–263, 1973. Ecker HA: An unusual bilateral oblique facial cleft: report of case. J Oral Surg 28:619–620, 1970. Eppley BL, David L, Li M, et al.: Amniotic band facies. J Craniofac Surg 9:360–365, 1998. Kara IG, Ocsel H: The Tessier number 5 cleft with associated extremity anomalies. Cleft Palate Craniofacial J 38:529–532, 2001. Kawamoto HK: The kaleidoscopic world of rare craniofacial clefts: Order out of chaos (Tessier classification). Clin Plast Surg 5:529–572, 1976. Kubaˇcek V, P˘enkava J: Oblique clefts of the face. Acta Chir Plast (Praha) 16:152–163, 1974. MacKinnon CA, David DJ: Oblique facial clefting associated with unicoronal synostosis. J Craniofac Surg 12:227–231, 2001. Mavili E, Gursu G, Ercal MD, et al.: Three cases of oblique facial cleft: etiology, tomographic evaluation and reconstruction. Clin Dysmorphol 1:229–234, 1992. Mayou BJ, Fenton OM: Oblique facial clefts caused by amniotic bands. Plast Reconstr Surg 68:675–681, 1981. Mishima K, Sugahara T, Mori Y, et al.: Three cases of oblique facial cleft. J Craniomaxillofac Surg 24:372–377, 1996. Miyajima K, Natsume N, Kawai T, et al.: Oblique facial cleft, cleft palate, and supernumerary teeth secondary to amniotic bands. Cleft Palate Craniofac J 31:483–486, 1994. Ranta R, Rintala A: Oblique lateral oro-ocular facial cleft. Case report. Int J Oral Maxillofac Surg 17:186–189, 1988. Richieri-Costa A, Gorlin RJ: Oblique facial clefts: report on 4 Brazilian patients. Evidence for clinical variability and genetic heterogeneity. Am J Med Genet 53:222–226, 1994. Rintala A, Leisti J, Liesmaa, et al.: Oblique facial clefts. Scand J Plast Reconstr Surg 14:291–297, 1980. Rowsell AR: The amniotic band disruption complex. The pathogenesis of oblique facial clefts; an experimental study in the foetal rat. Br J Plast Surg 42:291–295, 1989. Sakurai EH, Mitchell DF, Holmes LA: Bilateral oblique facial clefts and amniotic bands: a report of two cases. Cleft palate J 3:181–185, 1966. Sano S, Tani T, Nishimura Y: Bilateral oblique facial cleft. Ann Plast Surg 11:434–437, 1983. Schlenker JD, Ricketson G, Lynch JB: Classification of oblique facial clefts with microphthalmia. Plast Reconstr Surg 63:680–688, 1979. Schweckendiek W: Nasal abnormalities in facial clefts. J Maxillofac Surg 4:141–149, 1974. Stellzig A, Basdra EK, Muhling J, et al.: Early maxillary orthopedics in a child with an oblique facial cleft. Cleft Palate Craniofac J 34:147–150, 1997. Tessier P: Anatomical classification of facial, cranio-facial and latero-facial clefts. J Maxillofac Surg 4:69–92, 1976. Tolarová MM, Cervenka J: Classification and birth prevalence of Orofacial clefts. Am J Med Genet 75:126–137, 1998. Tsur H, Winkler E, Kessler A: Oblique facial cleft with anophthalmia in a mentally normal child. Ann Plast Surg 26:449–455, 1991. Van der Meulen JC: Oblique facial clefts: pathology, etiology, and reconstruction. Plast Reconstr Surg 76:212–224, 1985. Warburg M, Jensen H, Prause JU, et al.: Anophthalmia-microphthalmiaoblique clefting syndrome: confirmation of the Fryns anophthalmia syndrome. Am J Med Genet 73:36–40, 1997. Wilson LF, Musgrave RH, Garrett W, et al.: Reconstruction of oblique facial clefts. Cleft palate J 9:109–114, 1972. Yang SS: ADAM sequence and innocent amniotic band: manifestations of early amnion rupture. Am J Med Genet 37:562–568, 1990. Zimmer ET, Taub E, Sova Y, et al.: Tetra-amelia with multiple malformations in six male fetuses in one kindred. Eur J Pediatr 144:412–414, 1985.
OBLIQUE FACIAL CLEFT SYNDROME
Fig. 1. An infant with oblique facial cleft syndrome (at birth and postoperative) showing unilateral oro-ocular cleft with cleft beginning at the angle of the mouth and ending in a coloboma of the lower eyelid and corneal opacity.
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Fig. 2. An infant with oblique facial cleft syndrome showing extensive unilateral oro-naso-ocular cleft and encephalocele.
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OBLIQUE FACIAL CLEFT SYNDROME
Fig. 3. A newborn with oblique facial cleft syndrome associated with amniotic band syndrome and cutis aplasia congenita of the scalp showing bilateral frontonasal clefts, scalp defect, pseudotail, hypertelorism, anophthalmia, club hands, digital amputation, constriction bands, and an amniotic band still attached to the left finger. The infant also had hydrocephalus, atrial septal defect and clubfoot.
Oligohydramnios Sequence ii. One twin stucked because of severe oligohydramnios and compressed by the significant polyhydramnios associated with its co-twin iii. Perinatal mortality associated with severe oligohydramnios/polyhydramnios sequence in a monochorionic twin pregnancy before 28 weeks: 70–100% e. Intrauterine growth retardation f. Intrauterine fetal demise g. Postmaturity possibly caused by a decline in placental function h. Rupture of membranes: the most common cause of oligohydramnios i. Preterm ii. Prolonged iii. Idiopathic 3. Dynamic of amniotic fluid a. Presence of amniotic fluid throughout gestation i. Enables normal development of the fetal respiratory, gastrointestinal, and urinary tracts and musculoskeletal system ii. Continued fetal growth in a nonrestricted, sterile, and thermally controlled environment iii. Amniotic fluid volume is gestational-age dependent b. Factors contributing to the formation and removal of amniotic fluid i. Formation a) Fetal urination b) Tracheal secretions c) Intramembranous pathway including transfers between amniotic fluid and fetal blood perfusing the fetal surface of the placenta, fetal skin, and umbilical cord d) Transmembranous pathway involving direct exchange across the fetal membranes between amniotic fluid and maternal blood within the uterus ii. Removal: fetal swallowing c. Significance of oligohydramnios i. A sign of potential fetal compromise ii. Associated with an increased incidence of adverse perinatal morbidity and mortality, especially in conjunction with the following: a) Structural fetal anomalies b) Fetal growth restriction c) Post dates pregnancies d) Maternal disease
Oligohydramnios is defined as deficiency of amniotic fluid, i.e., decrease in the volume of amniotic fluid. It may result from decreased urinary production or excretion, or fluid loss from rupture of membranes. The incidence is estimated to be 0.5-8% of all pregnancies.
GENETICS/BASIC DEFECTS 1. Associated maternal conditions a. Ureteroplacental insufficiency i. Antiphospholipid antibodies ii. Chronic hypertension iii. Collagen vascular diseases iv. Diabetic vasculopathy v. Maternal hypovolemia vi. Preeclampsia/pregnancy-induced hypertension b. Drugs i. Prostaglandin synthetase inhibitors ii. Angiotensin converting enzyme inhibitors c. Placental i. Abruption ii. Twin-to-twin transfusion d. Maternal hydration status 2. Associated fetal conditions a. Renal malformations i. Bilateral agenesis ii. Bilateral cystic dysplasia iii. Unilateral cystic dysplasia/agenesis iv. Meckel syndrome v. Infantile polycystic kidneys vi. Renal tubular dysgenesis vii. Posterior urethral valves viii. Renal hypoplasia ix. Horseshoe kidney b. Other congenital anomalies i. Amniotic band syndrome ii. Branchio-oto-renal syndrome iii. Cystic hygroma iv. Encephalocele v. Endocardial fibroelastosis vi. Holoprosencephaly vii. Hypophosphatasia (homozygous dominant form) viii. MURCS association ix. Sacral agenesis (caudal regression) x. Sirenomelia xi. VATER association xii. Others c. Chromosome abnormalities i. Trisomy 13 ii. Trisomy 18 d. Twin-to-twin transfusion syndrome (‘stuck twin syndrome’) i. A complication of monochorionic diamniotic twinning
CLINICAL FEATURES
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1. Consequences of severe fetal constraints secondary to early and prolonged oligohydramnios
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OLIGOHYDRAMNIOS SEQUENCE
a. Potter facies: associated with renal agenesis and any other cause of severe oligohydramnios i. Hypertelorism ii. Deep crease under the eyes iii. Epicanthal folds iv. Flat nose v. Receding chin vi. Low-set, aberrantly folded ears b. Lung hypoplasia i. Respiratory insufficiency ii. Death c. Limb positional anomalies i. Arthrogryposis ii. Spade-like hands iii. Talipes equinovarus d. Intrauterine growth retardation: one of the most common complications associated with sever oligohydramnios 2. Presence of fetal abnormalities in cases associated with severe oligohydramnios a. 50.7% in the second trimester b. 22.1% in the third trimester c. Rate of aneuploidy: at least 4.4% 3. Correlation of the rate of survivors and the gestation when the severe oligohydramnios is diagnosed a. 10.2% survivors in the second trimester b. 85.6% survivors in the third trimester
DIAGNOSTIC INVESTIGATIONS 1. Ultrasonography a. Ultrasonographic modalities to assess oligohydramnios i. Single deepest vertical pocket (range: <0.5 cm to <3 cm) ii. Two-diameter pocket (vertical X horizontal <15cm) iii. Amniotic fluid index (AFI) (range: <5 cm to <8 cm) b. Defines oligohydramnios i. Amniotic fluid index less than 7 cm ii. Absence of a fluid pocket of 2–3 cm in depth c. Assesses fetal growth d. Visualizes fetal kidneys, collecting system, and bladder e. Improves fetal structures by amnioinfusion 2. Chromosome analysis for aneuploidy 3. Autopsy for verification of etiology
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: depends on etiology b. Patient’s offspring: depends on etiology 2. Prenatal diagnosis a. Ultrasonography b. Amniocentesis 3. Management a. Maternal bed rest b. Maternal hydration
c. Serial amnioinfusions to prevent pulmonary hypoplasia (complications including preterm labor, amnionitis, and perinatal deaths) d. The risks of maintaining the fetus in utero must be weighed against the morbidities and mortalities of premature delivery.
REFERENCES Barss VA, Benacerraf BR, Frigoletto FD Jr: Second trimester oligohydramnios, a predictor of poor fetal outcome. Obstet Gynecol 64:608–610, 1984. Bianchi DW, Crombleholme TM, D’Alton ME: Fetology. Diagnosis & Management of the Fetal Patient. New York, McGraw-Hill, 2000. Bromley B, Frigoletto FD Jr, Estroff JA, et al.: The natural history of oligohydramnios/polyhydramnios sequence in monochorionic diamniotic twins. Ultrasound Obstet Gynecol 2:317–320, 1992. Bronshtein M, Blumenfeld Z: First- and early second-trimester oligohydramnios: A predictor of poor fetal outcome except in iatrogenic oligohydramnios post chorionic villus biopsy. Ultrasound Obstet Gynecol 1:245–249, 1991. Fisk NM, Ronderos-Dumit D, Soliani A, et al.: Diagnostic and therapeutic transabdominal amniofusion in oligohydramnios. Obstet Gynecol 78:270–278, 1991. Hill LM, Breckle R, Gehrking WC: The variable effects of oligohydramnios on the biparietal diameter and the cephalic index. J Ultrasound Med 3:93–95, 1984. Horsager R, Nathan L, Leveno KJ: Correlation of measured amniotic fluid volume and sonographic predictions of oligohydramnios. Obstet Gynecol 83:955–958, 1994. Laudy JAM, Wladimiroff JW: The fetal lung 2: pulmonary hypoplasia. Ultrasound Obstet Gynecol 16:482–494, 2000. Mahony BS, Petty CN, Nyberg DA, et al.: The ‘stuck twin’ phenomenon: ultrasonographic findings, pregnancy outcome, and management with serial amniocenteses. Am J Obstet Gynecol 163:1513–1522, 1990. Mandel J, Peters CA, Estroff JA, et al.: Late onset severe oligohydramnios associated with genitourinary abnormalities. J Urol 148:515–518, 1992. Mercer LJ, Brown LG: Fetal outcome with oligohydramnios in the second trimester. Obstet Gynecol 67:840–842, 1986. Moore TR, Longo J, Leopold Genome Res, et al.: The reliability and predictive value of an amniotic fluid scoring system in severe second-trimester oligohydramnios. Obstet Gynecol 73:739–742, 1989. Newbould MJ, Barson AJ: Oligohydramnios sequence: the spectrum of renal malformations. Br J Obstet Gynaecol 101:598–604, 1994. Peipert JF, Donnenfeld AE: Oligohydramnios: a review. Obstet Gynecol Surv 46:325–339, 1991. Potter EL: Facial characteristics of infants with bilateral renal agenesis. Am J Obstet Gynecol 51:885–888, 1946. Rotschild A, Ling EW, Puterman ML, et al.: Neonatal outcome after prolonged preterm rupture of the membranes. Am J Obstet Gynecol 162:46–52, 1990. Rib DM, Sherer DM, Woods JR Jr: Maternal and neonatal outcome associated with prolonged premature rupture of membranes below 26 weeks’ gestation. Am J Perinatol 10:369–373, 1993. Sherer DM: A review of amniotic fluid dynamics and the enigma of isolated oligohydramnios. Am J Perinatol 19:253–266, 2002. Sherer DM, Langer O: Oligohydramnios: use and misuse in clinical management. Shipp TD, Bromley B, Pauker S, et al.: Outcome of singleton pregnancies with severe oligohydramnios in the second and third trimesters. Ultrasound Obstet Gynecol 7:108–113, 1996. Spong CY: Preterm premature rupture of the fetal membranes complicated by oligohydramnios. Clin Perinatol 28:753–759, 2001. Thomas IT, Smith DW: Oligohydramnios, a cause of the non-renal features of Potter’s syndrome, including pulmonary hypoplasia. J Pediatr 84:811–814, 1974. Vergani P, Ghidini A, Locatelli A, et al.: Risk factors for pulmonary hypoplasia in second-trimester premature rupture of membranes. Am J Obstet Gynecol 170(5 Pt 1):1359–1364, 1994.
OLIGOHYDRAMNIOS SEQUENCE
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Fig. 1. An infant with renal agenesis and oligohydramnios showing characteristic Potter facies.
Fig. 2. Multicystic/dysplastic kidneys (arrows) causing oligohydramnios.
Fig. 3. An infant with caudal regression showing Potter facies, anal atresia, arthrogryposis, and talipes equinovarus.
Omphalocele vi. vii. viii. ix. x. xi.
Omphalocele is a congenital herniation of viscera into the base of the umbilical cord, covered by a membranous sac. The incidence of omphalocele is approximately 1 in 4000 births.
GENETICS/BASIC DEFECTS 1. Embryogenesis: failure of the cranial, caudal, and lateral folds to fuse before myotome invasion is the most likely explanation for the failure of physiologically herniated midgut returning to the abdomen during the first trimester 2. Inheritance a. Usually sporadic b. Single gene disorders associated with omphalocele i. Autosomal recessive disorders a) Agonadism with multiple internal malformation b) Agonadism, XY, with mental retardation, short stature, retarded bone age, and multiple extragenital malformations c) Craniostenosis-mental retardation syndrome of Lin and Gettig d) Hydrocephalus with associated malformation e) Hydrolethalus syndrome f) Malpuech facial clefting syndrome g) Omphalocele-exstrophy-imperforate anusspinal defects (OEIS) h) Omphalocele-cleft palate i) Opitz C syndrome ii. Autosomal dominant disorders a) Beckwith-Wiedemann syndrome b) Omphalocele c) Shprintzen syndrome iii. X-linked recessive disorders a) Cranioorodigital syndrome b) Melnick-Needles osteodysplasty c) Omphalocele d) Simpson-Golabi Behmel syndrome e) Thoracoabdominal syndrome c. Other malformation syndromes associated with omphalocele i. Caudal regression ii. Cornelia de Lange syndrome iii. Amniotic band syndrome iv. Limb body wall complex v. Megacystic microcolon vi. Schisis association vii. Skeletal dysplasias d. Chromosome disorders associated with omphalocele (25%) i. Trisomy 1q ii. Trisomy 3q iii. Trisomy 13 iv. Trisomy 18 v. Trisomy 21
Trisomy 16 add(15) Turner syndrome Del(18p) Del(21p) Diploid-triploid mixoploidy
CLINICAL FEATURES
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1. General features a. Prematurity b. IUGR 2. Herniated sac a. Size ranging from 2 to 10 cm b. Covering avascular sac consists of fused layers of peritoneum and amnion c. Contents of hernia include thoracic and abdominal viscera i. Liver ii. Large intestine iii. Small intestine iv. Stomach v. Gall bladder vi. Urinary bladder vii. Pancreas viii. Spleen ix. Internal genitalia d. The sac may be torn or ruptured (10–20%) e. Necrotizing enterocolitis and malabsortion only if sac is ruptured 3. Umbilical cord inserting into the apex of the sac 4. At increased risk for associated anomalies or syndromes (45–67%) a. Cleft lip/palate b. Gastrointestinal abnormalities i. Diaphragmatic hernia ii. Midgut volvulus iii. Meckel diverticulum iv. Intestinal atresia v. Intestinal duplication vi. Intestinal malrotation vii. Colonic agenesis viii. Imperforate anus c. Congenital heart defects d. Neural tube defects e. Genitourinary i. Exstrophy of the bladder f. Limb defects: absent radial ray g. Beckwith-Wiedemann syndrome i. Macroglossia ii. Hypoglycemia iii. Organomegaly iv. Gigantism
OMPHALOCELE
h. Epigastric omphalocele associated with pentalogy of Cantrell i. Cardiac abnormalities a) Ventricular septal defect most common b) Occasional diverticulum of the left ventricle ii. Sternal cleft iii. Omphalocele iv. Anterior diaphragmatic hernia v. Ectopia cordis 5. Prognosis depending on: a. Size of the omphalocele i. Better prognosis with smaller defects ii. Intractable respiratory insufficiency in newborns with large omphaloceles b. Presence or absence of the associated anomalies c. Presence of chromosome anomalies
DIAGNOSTIC INVESTIGATIONS 1. 2. 3. 4. 5. 6.
Routine blood work Abdominal radiography Abdominal ultrasound Echocardiography Chromosome analysis Initiate studies for associated single gene disorder or malformation syndrome
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ii. CVS iii. Fetal blood sampling 3. Management a. Mode of delivery: currently no evidence to support a policy of cesarean delivery for infants with abdominal wall defects b. Attempts at primary repair difficult due to a small abdominal cavity resulting from extra-abdominal location of the viscera in utero c. Emergency care i. Insertion of an orogastric tube a) To decompress the stomach b) To prevent swallowed air from causing bowel distention ii. Cover the intact omphalocele sac with a sterile dressing and protect it from injury iii. Administer intravenous fluids and parenteral antibiotics iv. Assess cardiorespiratory status and additional anomalies d. Direct primary closure of the abdominal wall for small omphalocele (2 cm) e. Staged closure, using a Dacron-reinforced Silastic silo as a temporary housing for the bowel for medium to large omphalocele
REFERENCES GENETIC COUNSELING 1. Recurrence risk: depends on the mode of transmission and associated chromosome anomalies 2. Prenatal Diagnosis a. Elevated maternal serum alpha-fetoprotein b. Prenatal 2D ultrasonography i. Maternal polyhydramnios ii. A circumscribed mass containing liver and/or intestines at the cord insertion site iii. Covering sac composed of amnion and peritoneum iv. Ruptured omphalocele: a rare complication v. Identifies other malformations and allows diagnosis of recognizable syndromes such as pentalogy of Cantrell and prune-belly syndrome c. Prenatal 3D ultrasonography i. A useful complement to 2D ultrasonography ii. Improved definition of omphalocele iii. Identifies other malformations and allows diagnosis of recognizable syndromes such as pentalogy of Cantrell and prune-belly syndrome iv. Allows isolation and better evaluation of the anomalous structure of interest when there is oligohydramnios or fetal contact with the uterine wall or placenta d. Fetal echocardiography for evaluation of cardiac anomalies e. Amniocentesis i. Elevated amniotic fluid alpha-fetoprotein ii. Positive acetylcholinesterase f. Chromosome analysis i. Amniocentesis
Baird PA, MacDonald EC: An epidemiologic study of congenital malformations of the anterior abdominal wall in more than half a million consecutive live births. Am J Hum Genet 33:470–478, 1981. Barisic I, Clement M, Häusler M, et al.: Evaluation of prenatal ultrasound diagnosis of fetal abdominal wall defects by 19 European registries. Ultrasound Obstet Gynecol 18:309–316, 2001. Benacerraf BR, Saltzman DH, Estroff JA, et al.: Abnormal karyotype of fetuses with omphalocele: prediction based on omphalocele contents. Obstet Gynecol 75:317–321, 1990. Bonilla-Musoles F, Machado LE, Bailao LA, et al.: Abdominal wall defects: two-versus three-dimensional ultrasonographic diagnosis. J Ultrasound Med 20:379–389, 2001. Calzolari E, Volpato S, Bianchi F, et al.: Omphalocele and gastroschisis: A collaborative study of the Italian congenital malformation registries. Teratology 47:47–55, 1993. Chen H, Gershanik JJ, Mailhes JB, et al.: Omphalocele and partial trisomy 1q syndrome. Hum Genet 53:1–4, 1979. Chitayat D, Toi A, Babul R, et al.: Omphalocele in Miller-Dieker syndrome: Expanding the phenotype. Am J Med Genet 69:293–298, 1997. Colombani PM, Cunningham MD: Perinatal aspects of omphalocele and gastroschisis. Am J Dis Child 131:1386–1388, 1977. Cooney D: Defects of the abdominal wall. Pediatr Surg 2:1045–1070, 1998. De Vries P: The pathogenesis of gastroschisis and omphalocele. J Pediatr Surg 15:245–249, 1980. Duhamel B: Embryology of exomphalos and allied malformations. Arch Dis Child 38:142–147, 1963. Dykes EH: Prenatal diagnosis and management of abdominal wall defects. Semin Pediatr Surg 5:90–94, 1996. Forrester MB, Merz RD: Epidemiology of abdominal wall defects, Hawaii, 1986–1997. Teratology 60:117–123, 1999. Glasser JG: Omphalocele and gastroschisis. Emedicine, 2001. http://emedicine.com Havalad S, Noblett H, Speidel BD: Familial occurrence of omphalocele, suggesting sex-linked inheritance. Arch Dis Child 54:142–145, 1979. Kanagawa SL, Begleiter ML, Ostlie DJ, et al.: Omphalocele in three generations with autosomal dominant transmission. J Med Genet 39:184–185, 2002. Keppler-Noreuil KM: OEIS complex (omphalocele-exstrophy-imperforate anusspinal defects): a review of 14 cases. Am J Med Genet 99:271–279, 2001.
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Kilby MD, Lander A, Usher-Somers M: Exomphalos (omphalocele). Prenat Diagn 18:1283–1288, 1998. Kitchanan S, Patole SK, Muller R, et al.: Neonatal outcome of gastroschisis and exomphalos: A 10-year review. J Paediatr Child Health 36: October 2000. Langer JC: Gastroschisis and omphalocele. Semin Pediatr Surg 5:124–128, 1996. Lin HJ, Schaber B, Hashimoto CH, et al.: Omphalocele with absent radial ray (ORR): a case with diploid-triploid mixoploidy. Am J Med Genet 75:235–239, 1998. Loder RT, Guiboux JP: Musculoskeletal involvement in children with gastroschisis and omphalocele. J Pediatr Surg 28:584–590, 1993. Lowry RB, Baird PA: Familial gastroschisis and omphalocele. Am J Hum Genet 34:517–519, 1982. Mayer T: Gastroschisis and omphalocele: an eight year review. Ann Surg 192:783–785, 1980. Nicolaides KH, Snijders RJM, Chen HH, et al.: Fetal gastrointestinal and abdominal wall defects: Associated malformations and chromosomal abnormalities. Fetal Diagn Ther 7:102–115, 1992. Nyberg DA, Fitzsimmons J, Mack LA, et al.: Chromosomal abnormalities in fetuses with omphalocele: significance of omphalocele contents. J Ultrasound Med 8:299–308, 1989. Paidas MJ, Crombleholme TM, Robertson FM: Prenatal diagnosis and management of the fetus with an abdominal wall defect. Semin Perinatol 18:196–214, 1994.
Palomski GE, Hill LE, Knight GJ: Second-trimester maternal serum alphafetoprotein levels in pregnancies associated with gastroschisis and omphalocele. Obstet Gynecol 71:906, 1988. Shanske AL, Pande S, Aref K, et al.: Omphalocele-exstrophy-imperforate anusspinal defects (OEIS) in triplet pregnancy after IVF and CVS. Birth Defects Res Part A Clin Mol Teratol 67:467–471, 2003. Segel SY, Marder SJ, Parry S, et al.: Fetal abdominal wall defects and mode of delivery: a systematic review. Obstet Gynecol 98:867–873, 2001. Tucci M, Bard H: The associated anomalies that determine prognosis in congenital omphaloceles. Am J Obstet Gynecol 163:1646–1649, 1990. Vermeij-Keers C, Hartwig NG, van der Werff JF: Embryonic development of the ventral body wall and its congenital malformations. Semin Pediatr Surg 5:82–89, 1996. Weber RR, Au-Fliegner M, Downard CD, et al.: Abdominal wall defects. Curr Opin Pediatr 14:491–497, 2002. Yang P, Beaty TH, Khoury MJ, et al.: Genetic-epidemiologic study of omphalocele and gastroschisis: Evidence for heterogeneity. Am J Med Genet 44:668–675, 1992. Yatsenko SA, Mendoza-Londono R, Belmont JW, et al.: Omphalocele in trisomy 3q: further delineation of phenotype. Clin Genet 64:404–413, 2003. Yazbeck S, Ndoye M, Khan AD: Omphalocele: A 25 year experience. J Pediatr Surg 21:761–763, 1986.
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Fig. 3. A fetus with omphalocele showing the umbilical cord attaching to the apex of the sac.
Fig. 1. Two infants with omphalocele showing a sac containing bowel and other abdominal contents.
Fig. 4. A neonate with a large ruptured omphalocele. The remnant of omphalocele sac is visible between the herniated viscera and the abdominal wall. The infant had body stalk anomaly.
Fig. 2. A 16-week-old fetus with omphalocele showing a sac containing bowel.
Osteogenesis Imperfecta Osteogenesis imperfecta (OI) is a generalized, hereditary disorder of connective tissue involving bone, tendon, ligament, fascia, and dentin. OI affects about 1 in 10,000 individuals.
2.
GENETICS/BASIC DEFECTS
3.
1. A heterogeneous disorder comprising at least four clinically distinct conditions, resulting from mutations affecting the amount or structure of type I collagen a. OI I i. Autosomal dominant disorder ii. Fresh mutation in 15% of cases iii. The mildest of osteogenesis imperfecta iv. Estimated prevalence at between 1 in 10,000 and 1 in 25,000, or may be more frequent because of its relatively mild presentation and the possibility of underdiagnosis b. OI II i. Autosomal dominant disorder (new mutations in almost all instances) ii. Autosomal recessive disorder (rare) iii. Further subdivided into IIA, IIB (same as type III), and type IIC iv. Estimated frequency of 1 in 20,000 to 1 in 60,000 births c. OI III i. Autosomal dominant disorder ii. Autosomal recessive disorder (uncommon) iii. The rarest form of OI iv. Known as the progressive deforming form d. OI IV i. Autosomal dominant ii. Represents the moderately severe spectrum of OI iii. Marked intra/interfamilial variability of expression e. Rare variants of OI i. OI type V: a group of individuals with osteoporosis, interosseous membrane ossification of the forearms and legs, and a high frequency of hypertrophic calluses ii. Osteoporosis-pseudoglioma syndrome: bone fragility and blindness attributable to mutations of the gene encoding the low density lipoprotein receptor-related protein 5 iii. Syndrome of osteopenia with radiolucent lesions of the mandible iv. Cole-Carpenter syndrome: bone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features v. Bruck syndrome: an autosomal recessive condition caused by mutations in the bone specific collagen type I telopeptide lysyl hydroxylase enzyme
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4.
5.
and characterized by bone fragility and congenital joint contractures Sillence Type I to Type IV categories represent approximately 80–90% of patients. The etiologies of the remaining cases are unclear Molecular basis a. Type I collagen i. Found in the skin, bone, tendons, and ligaments ii. Composed of three α chains (two α1 chains and one α2 chain) iii. Each α chain forms a helix which consists of three amino acids per turn iv. The chains are held together by disulfide bonds at the C-terminal ends of the protein v. There are three amino acids per turn in the helix vi. Every third amino acid is glycine, giving a repeat of Gly-X-Y, where X and Y represent other amino acid residues a) About 10% of the X residues are proline b) About 10% of the Y residues are hydroxyproline vii. A mutant collagen is produced by missense mutations that result in a substitution of the glycine residue by another amino acid b. OI I i. Affected individuals produce only 50% of the normal amount of type I collagen, produced by the normal allele ii. Mechanisms a) Splicing in α1 gene b) Null mutation in α1 gene c. OI II, OI III, and OI IV i. Affected individuals produce only 25% of the normal amount of type I collagen and 75% of mutant or defective collagen ii. Mechanism: a missense mutation arises in the α1 gene resulting in a defective α1 chain which is incorporated into the final collagen molecule and destroys its function iii. Severity of the disease a) Related to the position of the missense mutation within the gene and the amino acid substitution that occurs b) Generally, the disease is more severe when the mutation is closer to the C-terminal end of the protein Very few individuals or families share the same mutation, although more than hundreds of unique mutations of the type I collagen genes have been identified Phenotypic variations among different families and within same family
OSTEOGENESIS IMPERFECTA
CLINICAL FEATURES 1. OI type I (mild type) a. Fractures i. Rarely fracture in utero or in the perinatal period ii. Usual onset of fractures: when the child begins to walk iii. A few to more than 50 fractures before puberty iv. Number of fractures gradually decreases after puberty v. Involve any bones of the body, but primarily long bones of the arms and legs, ribs, and small bones of hands and feet vi. Increasing fractures often after menopause in affected women and in the 6th or 8th decades in affected men vii. Healing rapidly with evidence of good callus formation and without deformity b. Cranial features i. Soft thin calvarium ii. Wide fontanels iii. Wormian bones iv. Frontal and temporal bulging v. Occipital flattening c. Blue sclera (secondary to a thin sclera allowing partial visualization of the choroid) i. Readily apparent at birth ii. Gradually lighten to blue-grey in the adulthood d. Other ocular features i. Occasional embryotoxon (opacity in the peripheral cornea) ii. Occasional keratoconus or megalocornea e. Teeth abnormalities i. Rare dentinogenesis imperfecta ii. Hypoplasia of pulp iii. Yellow or grey teeth iv. Susceptible to caries v. Irregular placement vi. Late eruption f. Hearing loss i. Early-onset in about 50% of families beginning in late teens ii. Gradually leading to profound hearing loss in the end of 4th or 5th decades secondary to otosclerosis iii. Primarily conductive hearing loss in the early phase secondary to fractured and fused bones of the middle ear iv. Early hearing loss typically of the high-frequency type resulting in a characteristic bifid compliance curve by tympanometry v. Later hearing loss becoming mixed in type and surgical intervention may be less successful g. Skin and joint abnormalities i. Mild joint hypermobility ii. Easy bruising iii. Thinner translucent skin iv. Capillary fragility v. Inguinal or umbilical hernia vi. Flat feet
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vii. Joint dislocation viii. Poorly developed muscles ix. Decreased thrombocyte function leading to increased bleeding h. Cardiovascular abnormalities i. Mitral valve prolapse ii. Aortic valvular insufficiency iii. Slightly larger than normal aortic root diameter without significant risk of progression to dissection, identified in a small number of patients iv. Increased bleeding tendency secondary to increased capillary fragility i. Prognosis i. Usually normal stature but may loose some height in later decades due to spine involvement ii. In general, with good orthopedic cares, fractures heal quickly without deformities iii. No decrease in fertility or longevity in affected individuals 2. OI type II (perinatal lethal type) a. Lethality during perinatal period resulting from: i. Pulmonary insufficiency ii. Congestive heart failure iii. Infection b. Prenatal history i. Intrauterine growth retardation (dwarfism, low birth weight) ii. Prematurity iii. Nonimmune hydrops c. Short-limbed dwarf d. Characteristic craniofacial features i. Extremely soft calvarium ii. Dark blue sclerae iii. Beaked nose iv. Micrognathia e. Chest i. Very small ii. Beaded ribs iii. Lung hypoplasia f. Extremities i. Short and deformed limbs ii. Bowed legs g. Hip: flexed and abducted (frog-position) h. Prognosis: death resulting from pulmonary insufficiency, congestive heart failure, or infection i. Usually during the first few hours of life ii. More than 60 percent of infants with OI type II during the first day iii. 80 percent within the first month iv. Rare survival beyond a year 3. OI type III (progressively deforming type) a. Dwarfism and moderate deformities resulting from in utero fractures b. Craniofacial features i. Typical triangular faces ii. Relatively large cranium c. Fractures i. Very common ii. Progressive long bone deformities with growth iii. Marked deformities of most bones
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d. Significant kyphoscoliosis leading to cardiopulmonary insufficiency, a major cause of early death in these individuals e. Sclerae i. Often pale blue at birth ii. Generally becomes normal hue by puberty f. Abnormal dentinogenesis involving both primary and permanent teeth: common g. Hearing loss: common h. Prognosis i. Death resulting from cardiac decompensation, pulmonary insufficiency or basilar impression with compression of the brain stem ii. Long term survival possible with multiple fractures and deformities iii. Primary objective to lead a satisfying and productive life iv. Major limitations (severe bone fragility and deformity, muscle weakness, joint contractures that develop from inactivity, progressive scoliosis resulting in life-threatening cardiopulmonary decompensation, marked short stature) 4. OI type IV (moderately severe type) a. Significant intrafamilial and interfamilial phenotypic variation b. Fractures i. Occurring in utero, during labor and delivery, or in the newborn period ii. Fractures at birth, not observed in all affected infants iii. Some affected infants with only mild femoral bowing iv. Early recognition of these fractures essential to prevent accusation of child abuse when the first fractures occur and the previous, now healed, fracture(s) is/are detected by routine skeletal survey c. Variable short stature d. Normal white or greyish sclera e. Occasional hearing loss f. Common dentinogenesis imperfecta g. Mild to moderate bone deformity h. Severe kyphoscoliosis may compromise cardiopulmonary function i. Prognosis i. Life span near normal in the absence of severe cardiopulmonary complications ii. Treatment objectives (to minimize the long-term complications of kyphoscoliosis and to assure independence and mobility)
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. OI type I i. None to multiple fractures with little bone deformities ii. Fractures primarily in long bones (may occur with minimal trauma, decreased dramatically in puberty, increase at later ages, normal healing with callus formation)
iii. Osteopenia (generalized demineralization) which can be documented by densitometry iv. Thin bones (cortices) v. Little trabeculae with fragility vi. Bowing vii. Platyspondyly viii. Retarded ossification of the cranial vault with multiple Wormian bones ix. Flattening of vertical axis x. Widening in transverse axis of the skull xi. Small facial bones xii. Susceptible to osteoporosis and compression fractures of the vertebrae xiii. Pectus carinatum/excavatum b. OI type II i. Short-limbed dwarfism ii. Rhizomelic limb shortening iii. Severely retarded (virtual absence) calvarial mineralization iv. Generalized osteoporosis v. Multiple fractures with callus formation vi. Small chest vii. Beaded and broad ribs viii. Shortened crumpled long bones especially compressed (“telescoped” or “accordion-like”) femurs and/or humeri ix. Externally rotated and abducted femurs x. Bowed lower legs xi. Angulated tibiae xii. Usually flexed and abducted hip (frog-leg position) xiii. Flattened acetabulae and iliac wings xiv. Platyspondyly xv. Type IIA: short and squared tubular bones, continuous beading of the ribs xvi. Type IIB/III: thicker tubular bones, compressed vertebrae, better ossification of the cranial bones, more normally appearing ribs and scapulae xvii. Type IIC: thin, deformed tubular bones, severely twisted long tubular bones c. OI type III i. Undermineralized calvarium with a large fontanelle and Wormian bones ii. Initially normal or mildly shortening long bones iii. Fractures present at birth or during the first year of life with evidence of deformity iv. Thin gracile ribs prone to fracture v. Gracile long bones showing evidence of intrauterine fractures with callus formation vi. Marked angulation or bowing of long bones (especially tibias and femurs reducing the efficiency of weight bearing and increasing the likelihood of fracture) vii. “Accordion-like” short and deformed femurs viii. Later metaphyseal and diaphyseal widening with “popcorn” calcification appearance of cystic metaphyses ix. Codfish appearance of vertebrae x. Fractures with minimal trauma and progressive deformities xi. Severe and generalized osteopenia
OSTEOGENESIS IMPERFECTA
2.
3.
4.
5.
d. OI type IV i. Bowed femurs in the newborn period but tend to straighten with time ii. Osteopenia/osteoporosis iii. Thin bones iv. Fractures with deformities v. Scoliosis Bone density analysis a. Still experimental b. Dual energy X-ray absorptiometry (DEXA) Bone histology a. Thin cortices b. Decreased trabecular bone volume c. Smaller apatite crystals d. Defective microvascular system e. Defective collagen fibril diameter Collagen synthesis analyses by cultured fibroblasts from skin biopsy. In OI type I, about half the normal amount of type I procollagen is synthesized. Direct mutation analyses from blood or cultured skin fibroblasts
GENETIC COUNSELING 1. Recurrence risk for OI I a. Patient’s sib: not increased unless a parent is affected or with gonadal mosaicism b. Patient’s offspring i. 50% affected if an affected parent marrying a normal spouse ii. 25% homozygously affected infant (likely to be perinatally lethal or severely affected) if both parents are affected with OI Type I 2. Recurrence risk for OI II a. Patient’s sib: An empiric recurrence risk of 2–3% to 6–7% among siblings resulting from parental mosaicism for the mutation that is lethal in the infant who is heterozygous for the same mutation or due to the rare recessive form b. Patient’s offspring: none surviving beyond infancy 3. Recurrence risk for OI III (also called type IIB) a. Patient’s sib i. Autosomal dominant form: not increased unless a parent is affected or with gonadal mosaicism ii. Autosomal recessive form: 25% iii. An empiric recurrence risk of 7–8% (germinal mosaicism, homozygosity of COL1A2 mutations and autosomal recessive inheritance) b. Patient’s offspring i. Autosomal dominant form: 50% ii. Autosomal recessive form: not increased unless a spouse is a carrier or affected 4. Recurrence risk for OI IV a. Striking intrafamilial variability making clinical classification difficult for OI IV, OI III, or OI I b. Patient’s sib: not increased unless a parent carries gonadal mosaicism c. Patient’s offspring i. 50% when an affected parent marrying a normal spouse
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ii. Rare possibility of having children with lethal OI phenotype by a parent with OI IV as a consequence of parental mosaicism for the lethal mutations 5. Prenatal diagnosis a. OI type I i. Identification of the mutant allele including segregation studies with an appropriate family structure (CVS at 11–12 weeks gestation) ii. Identification of the nonexpressed allele in mRNA from the fetus iii. Direct identification of the mutation (CVS at 11–12 weeks gestation) iv. Recognition of fracture or bowing of long bones by ultrasound b. Type II i. Diagnosis by prenatal ultrasonography accomplished between 14–18 weeks gestation (short femurs, fractures, small thoracic cage, minimal calvarial mineralization, or polyhydramnios) ii. Analysis of chorionic villi for the presence of abnormal collagens iii. Analysis of collagens synthesized by cells grown from chorionic villi iv. Direct mutation analysis in families of an identified DNA mutation in a previously affected infant c. Type III i. Diagnosis by prenatal ultrasonography not feasible until 20–22 weeks gestation ii. Direct mutation analysis of collagens synthesized by chorionic villus cells or DNA isolated directly from the tissue d. Type IV i. Linkage analysis with COL1A2 polymorphisms in the dominant families ii. Direct mutation analysis iii. Analysis of proteins produced by cells grown from CVS biopsies iv. Little value of ultrasound analysis because of the late appearance of short or deformed bones 6. Management a. Improving bone mass i. Use of bisphosphonates (cyclic intravenous Pamidronate) to decrease the resorption of bone and to increase the formation of bone. Hopefully, early commencement of bisphosphnate treatment will prevent serious deformities ii. Use of bone marrow transplantation as means of introducing normal mesenchymal stromal cells that have the capacity to differentiate into normal osteoblasts b. Fractures i. Meticulous orthopedic care ii. Corrective osteotomies iii. Intramedullary roddings to improve mobility, prevent fractures, and correct and prevent progressive deformity iv. Avoid unnecessary immobilization v. Avoid malunions
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c. Progressive scoliosis in adolescence require spinal fusion with instrumentation d. Orthotics i. To stabilize lax joints such as the ankle and subtalar joints ii. To prevent progressive deformities and fractures iii. Commonly used devices include ankle-foot, knee-ankle-foot, and forearm orthoses e. Recognition and management of hearing loss f. Care of dentinogenesis imperfecta 7. Importance of diagnosis in the newly affected infant for whom there is no family history a. To facilitate genetic counseling b. To reassure the family about prognosis c. To remove the concern of child abuse in some families (Steiner et al., 1996) i. Fractures considered “highly specific” for child abuse: present in 33% (2/6) of cases with OI a) Metaphyseal fractures b) Posterior rib fractures c) Scapular spinous process d) Sternal fractures ii. Fractures considered “moderately specific” for abuse: present in 50% (3/6) of cases with OI a) Multiple fractures, especially bilateral b) Fractures of different ages c) Epiphyseal separations d) Digital fractures e) Complex skull fractures iii. Fractures considered “low specificity” for child abuse: present in 17% (1/6) cases of OI a) Clavicular fractures b) Long bone shaft c) Linear skull fractures d. General signs of child abuse i. Multiple fractures as described ii. Clinical findings highly indicative of child abuse a) Retinal hemorrhage b) Cephalohematoma c) Subdural hemorrhage d) Evidence of bodily abuse (bruises, lacerations, burns) e) Evidence of sexual abuse iii. Incompatible history with physical examination iv. History of domestic violence, corporal punishment, and child maltreatment e. Useful for families to have a letter from the child’s physician stating the diagnosis of the osteogenesis imperfecta
REFERENCES Andersen PE Jr, Hauge M: Osteogenesis imperfecta: a genetic, radiological, and epidemiological study. Clin Genet 36:250–255, 1989. Bembi B, Parma A, Bottega M, et al.: Intravenous pamidronate treatment in osteogenesis imperfecta. J Pediatr 131:622–625, 1997. Beyers PH: Osteogenesis imperfecta. In Royce PM, Steinmann B: Connective Tissue and Its Heritable Disorders. Molecular, Genetic, and Medical Aspects. New York, Wiley-Liss, 1993. Beyers PH: Disorders of collagen biosynthesis and structure. In Scriver CR, Beaudet al., Sly WS, Valle D (eds): The Metabolic & Molecular Bases of
Inherited Disease. 8th ed. New York: McGraw-Hill, Chapter 205, pp 5241–5285, 2001. Beyers PH, Wallis GA, Willing MC: Osteogenesis imperfecta: translation of mutation to phenotype. J Med Genet 28:433–442, 1991. Binder HB, Conway A, Hason S, et al.: Comprehensive rehabilitation of the child with osteogenesis imperfecta. Am J Med Genet 45:265–269, 1993. Byers PH: Osteogenesis imperfecta: an update. Growth Genet Horm 4:1–5, 1988. Byers PH: Osteogenesis imperfecta. In Royce PM, Steinman B (eds): Connective Tissue and its Heritable Disorders. Wiley-Liss, New York, 2002. Byers PH, Barsh GS, Holbrook KA: Molecular pathology in inherited disorders of collagen metabolism. Hum Path 13:89–95, 1982. Cohn DH, Starman BJ, Blumberg B, et al.: Recurrence of lethal osteogenesis imperfecta due to parental mosaicism for a dominant mutation in a human type I collagen gene (COLIAI). Am J Hum Genet 46:591–601, 1990. Cole WG: Orthopaedic treatment of osteogenesis imperfecta. Ann New York Acad Sci 543:157–166, 1988. Cole WG: Early surgical management of severe forms of osteogenesis imperfecta. Am J Med Genet 45:270–274, 1993. Cole WG: The molecular pathology of osteogenesis imperfecta. Clin Orthop 343:235–248, 1997. Cole WG: Advances in osteogenesis imperfecta. Clin Orthop Rel Res 401:6–16, 2002. Cole WG, Carpenter TO: Bone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features: a newly recognized type of osteogenesis imperfecta. J Pediatr 110:76–80, 1987. Cole WG, Dalgleish R: Perinatal lethal osteogenesis imperfecta. J Med Genet 32:284–289, 1995. Cubert R, Cheng EY, Mack S, et al.: Osteogenesis imperfecta: mode of delivery and neonatal outcome. Obstet Gynecol 97:66–69, 2001. De Vos A, Sermon K, Van de Velde, et al.: Two pregnancies after preimplantation genetic diagnosis for osteogenesis imperfecta type I and type IV. Hum Genet 106:605–613, 2000. Glorieux FH: Bisphosphonate therapy for severe osteogenesis imperfecta. J Pediatr Endocrinol Metab 13 (Suppl):989–992, 2000. Glorieux FH, Bishop NJ, Plotkin H, et al.: Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. New Eng J Med 339:947–952, 1998. Glorieux FH, Rauch F, Plotkin H, et al.: Type V osteogenesis imperfecta: A new form of brittle bone disease. J Bone Miner Res 15:1650–1658, 2000. Horwitz EM, Prockop DJ, Gordon PL, et al.: Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Blood 97:1227–1231, 2001. Kleinman PK: Diagnostic imaging in infant abuse. AJR Am J Roentgenol 155:703–712, 1990. Lee Y-S, et al.: Cyclic pamidronate infusion improves bone mineralisation and reduces fracture incidence in osteogenesis imperfecta. Eur J Pediatr 160:641–644, 2001. Lund AM, Schwartz M, Skovby F: Genetic counselling and prenatal diagnosis of osteogenesis imperfecta caused by paternal mosaicism. Prenat Diagn 16:1032–1038, 1996. Lynch JR, Ogilvie D, Priestly L, et al.: Prenatal diagnosis of osteogenesis imperfecta by identification of the concordant collagen 1 allele. J Med Genet 28:145–150, 1991. Minch CM, Kruse RW: Osteogenesis imperfecta: a review of basic science and diagnosis [published erratum appears in Orthopedics 21:842, 1998]. Orthopedics 21:558–567, 1998. Namikawa C, Suzumori K, Fukushima Y, et al.: Recurrence of osteogenesis imperfecta because of paternal mosaicism: Gly862—>Ser substitution in a type I collagen gene (COL1A1). Hum Genet 95:666–670, 1995. Nuytinck L, Sayli BS, Karen W, et al.: Prenatal diagnosis of osteogenesis imperfecta type I by COL1A1 null-allele testing. Prenat Diagn 19:873–875, 1999. Pattekar MA, Cacciarelli A: Osteogenesis imperfecta. eMed J 2(5), 2001. Pepin M, Atkinson M, Starman BJ, et al.: Strategies and outcomes of prenatal diagnosis for osteogenesis imperfecta: a review of biochemical and molecular studies completed in 129 pregnancies. Prenat Diagn 17:559–570, 1997. Plotkin H, Rauch F, Bishop NJ, et al.: Pamidronate treatment of severe osteogenesis imperfecta in children under 3 years of age. J Clin Endocrinol Metab 85:1846–1849, 2000. Prockop DJ, Kivirikko KI: Heritable diseases of collagen. New Eng J Med 311:376–386, 1984.
OSTEOGENESIS IMPERFECTA Ricci LR, Botash AS: Pediatric, child abuse. eMed J 2(6), 2001. Sillence DO: Osteogenesis imperfecta nosology and genetics. Ann NY Acad Sci 543:1–15, 1988. Sillence DO: Disorders of bone density, volume, and mineralization. In Rimoin DL, Connor JM, Pyeritz RE, Korf BR (eds): Emery and Rimoin’s Principles and766 Practice of Medical Genetics. 4th ed. Ch 153, pp 4116–4145, 2002. Sillence DO, Rimoin DL, Danks DM: Clinical variability in osteogenesis imperfecta-variable expressivity or genetic heterogeneity. Birth Defects Original Article Series 15:113–129, 1979. Sillence DO: Osteogenesis imperfecta: An expanding panorama of variants. Clin Orthop Related Res 159:11–25, 1981. Sillence DO, Senn A, Danks DM: Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 16:101–116, 1979. Sillence DO, Barlow KK, Garber AP, et al.: Osteogenesis imperfecta type II: Delineation of the phenotype with reference to genetic heterogeneity. Am J Med Genet 17:407–423, 1984. Sillence DO, Barlow KK, Cole WG, et al.: Osteogenesis type III: Delineation of phenotype with reference to genetic.
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Spranger J, Maroteaux P: The lethal osteochondrodysplasias. Advances in Human Genetics. New York, Plenum Press, 1990. Spranger J, Cremin B, Beighton P: Osteogenesis imperfecta congenita: features and prognosis of a heterogeneous condition. Pediatr Radiol 12:21–27, 1982. Spranger JW, Brill PW, Poznanski A: Bone Dysplasias. An Atlas of Genetic Disorders of Skeletal Development. 2nd ed. Oxford: Oxford University Press, 2002. Steiner RD, Pepin M, Byers PH: Studies of collagen synthesis and structure in the differentiation of child abuse from osteogenesis imperfecta. J Pediatr 128:542–547, 1996. Thompson EM, Young IK, Hall CM, et al.: Recurrence risks and prognosis in severe sporadic osteogenesis imperfecta. J Med Genet 24:390–405, 1987. Willing MC, Pruchno CJ, Byers PH: Molecular heterogeneity in osteogenesis imperfecta type I. Am J Med Genet 45:223–227, 1993. Willing MC, Deschenes SP, Scott DA, et al.: Osteogenesis imperfecta type I: molecular heterogeneity for COL1A1 null alleles of type I collagen. Am J Hum Genet 55:638–47, 1994. Young ID, Thompson EM, Hall CM, et al.: Osteogenesis imperfecta type IIA: evidence for dominant inheritance. J Med Genet 24:386–389, 1987.
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Fig. 1. A boy with osteogenesis imperfecta type I showing blue sclera.
Fig. 3. A 22-month-old boy with osteogenesis imperfecta type I showing blue sclera. He has heterozygous mutation Arg75Stop of the COL1A1 gene by molecular genetic analysis.
Fig. 2. Familial osteogenesis imperfecta type I in two sibs. Radiographs show fracture of a femur in the boy and that of humerus in the girl. Their father is also affected. Molecular testing revealed c.578^579insC of COL1A1 gene mutation in this family.
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Fig. 5. Another case of osteogenesis imperfecta type II showing the similar features.
Fig. 4. An infant with osteogenesis imperfecta type II showing severe dwarfism, characteristic craniofacial features, short and deformed limbs, and bowed legs. Radiographs showed short-limb dwarfism, rhizomelic limb shortening, severely retarded calvarial mineralization, multiple fractures with callus formation, beaded and broad ribs, and “telescoped” femurs and humeri. Fig. 6. Photomicrograph of rib of another case with type II osteogenesis imperfecta. The columns of cartilage in the metaphysis are covered by minimal amounts of basophilic primitive woven bone. Normal ossification is absent. The physeal growth zone is moderately disorganized.
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Fig. 7. A neonate with osteogenesis type III showing short-limbed dwarfism, large head, short neck, short thigh and curbed lower legs. Radiographs showed generalized osteopenia, poor mineralization of the skull, thin ribs with sixth, seventh, and eighth rib fractures with callus formation, short limbs, and bowed femurs with multiple fractures with callus formation. Molecular study showed heterozygous mutation of COL1A2 gene [del of 3 base pairs (GTT) at cDNA position c.763–765]. This mutation has been reported in patients with osteogenesis imperfecta type III.
OSTEOGENESIS IMPERFECTA
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Fig. 8. Three other infants with osteogenesis imperfecta type III showing dwarfism, moderate deformities resulting from in utero fractures, and typical triangular face with relatively large cranium. Radiographs showed undermineralized calvarium with a large fontanelle, and marked angulation or bowing of long bones, especially tibias and femurs.
Fig. 9. An infant girl with osteogenesis imperfecta type IV.
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Fig. 10. A girl with Cole-Carpenter syndrome showing ocular proptosis, craniosynostosis, and bone fragility with fractures.
Osteopetrosis Osteopetrosis is a heterogeneous group of sclerosing bone diseases due to impaired bone and cartilage resorption, resulting from absence or defective function of osteoclasts.
iii.
GENETICS/BASIC DEFECTS 1. Inheritance of recognized subtypes of human osteopetrosis a. Malignant infantile osteopetrosis: autosomal recessive inheritance b. More benign osteopetrosis primarily affecting adults: two subtypes based on radiographic features i. Autosomal dominant osteopetrosis type I (locus 11q12-13) ii. Autosomal dominant osteopetrosis type II (Albers-Schönberg disease) (dominant negative CLCN7 mutations) (locus chromosome 16p13.3) c. Intermediate forms i. An autosomal recessive disease with milder mutations ii. Early diagnoses of the more severe end of the autosomal dominant spectrum d. Carbonic anhydrase isoenzyme type II deficiency (CAII): autosomal recessive e. Vacuolar proton pump deficiency (ATP6i/TCIRG1) (locus 11q13.3-q13.5): autosomal recessive f. CLC-7 chloride pump deficiency (loss of function CLCN7 mutations) (locus 16p13.3): autosomal recessive g. Neuronopathic osteopetrosis (osteopetrosis and infantile neuroaxonal dystrophy): autosomal recessive h. Osteopetrosis with agenesis of corpus callosum: autosomal recessive i. Dysosteosclerosis i. Autosomal recessive ii. X-linked also reported 2. Basic defects: absence or defective function of osteoclasts results in defective remodeling of bone with partial or complete obliteration of marrow cavities, producing bone which is dense but has an increased tendency to fracture
CLINICAL FEATURES
iv.
v.
vi.
vii.
viii.
ix.
1. Malignant infantile osteopetrosis a. Usually diagnosed during the first year of life b. Signs and symptoms i. Presenting signs a) Blindness b) Failure to thrive c) Seizures due to hypocalcemia d) Infections e) Pathologic fractures ii. Neurovascular involvement: the most serious consequences of the osteopetrosis are cranial nerves, blood vessels and the spinal cord compression by 773
x.
either gradual occlusion or lack of growth of skull foramina Visual impairment a) Optic atrophy: some degree of optic atrophy are present in most patients. Blindness is observed in many children with severe forms of autosomal recessive osteopetrosis b) Nystagmus c) Strabismus d) Proptosis e) Limited extraocular movement Compression of facial and trigeminal nerves a) Produce paralysis, spasm or neuralgia b) Involvement of the trigeminal nerve tend to occur in type I autosomal dominant osteopetrosis c) Involvement of the facial nerve predominant in type II disease Hearing loss a) Poor drainage of the middle ear b) Narrowing of the internal acoustic meatus c) Osteosclerosis Blood vessel compression a) Stenosis of arterial supply (internal carotid artery, vertebral artery) b) Stenosis of venous supply Craniofacial features a) Macrocephaly b) Frontal bossing c) Hypertelorism d) Exophthalmos e) Flat nasal bridge f) Chronic rhinitis g) Jaw: a frequent site of osteomyelitis h) Obligate mouth breathing in most children secondary to obstruction of the upper airway Compromised nutritional state due to difficulty in eating and breathing resulting from limited posterior nasophrynx from bony overgrowth Psychomotor retardation a) Secondary to hydrocephalus b) Secondary to apnea due to upper airway obstruction c) Common in carbonic anhydrase isoenzyme type II deficiency Bone marrow failure a) Results from bone marrow encroachment b) Leads to extramedullary hematopoiesis and hepatosplenomegaly (abdominal protuberance) c) Frequently progresses to hypersplenism and pancytopenia
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2.
3.
4.
5.
6.
OSTEOPETROSIS
d) Signs secondary to thrombocytopenia (petechiae, ecchymoses, epistaxis, melena, gingival bleeding, intracerebral hemorrhages) e) Carries a high mortality Autosomal dominant osteopetrosis type I a. Chronic bone pain b. Cranial nerve palsies c. Hearing loss d. Not associated with increased fracture rate Autosomal dominant osteopetrosis type II (AlbersScho˝nberg disease) a. Originally described by Albers-Scho˝nberg in 1904 b. The most common form of osteopetrosis c. The prevalence: 5.5 in 100,000 d. The term “benign osteopetrosis”: a misnomer for autosomal dominant osteopetrosis type II because of the possibility of severe clinical complications e. Most prominent symptoms i. Bone pain ii. Multiple fractures: frequent (78%), perhaps due to the reduced elasticity of the brittle bone iii. Mandibular osteomyelitis f. Other signs i. Hip osteoarthritis ii. Thoracic or lumbar scoliosis iii. Hearing loss iv. Visual loss v. Optic atrophy vi. Facial palsy vii. Multiple dental abscesses “Intermediate” form of osteopetrosis a. Usually diagnosed during the first decade and survive into adulthood b. Short stature c. Frontal bossing d. Mild hepatosplenomegaly Carbonic anhydrase isoenzyme type II deficiency a. Most cases have been reported from Middle East or the Mediterranean region b. Osteopetrosis with renal tubular acidosis (usually distal type) c. Short stature d. Fractures e. Psychomotor retardation f. Cranial nerve compression (>50%) g. Optic atrophy and visual loss h. Cerebral calcifications i. Minor hematological impairment j. Craniofacial features i. Micrognathia ii. Narrow prominent nose iii. Poorly developed philtrum k. Abnormal dentition i. Peg-shaped carious teeth with malocclusion ii. Delayed eruption of the teeth iii. Retained primary dentition l. Visual failure m. Episodic hypokalemic paralysis in some patients Vacuolar proton pump deficiency a. Visual failure
7. 8.
9. 10.
11.
b. Symptomatic hypocalcemia in the first month (50%) i. Early or late neonatal convulsions ii. Irritability iii. Jittering episodes c. Fractures d. Mild to severe hematological impairment e. Hepatosplenomegaly f. Failure to thrive g. Poor growth h. Reduced life span ClC-7 chloride pump deficiency: severe osteopetrosis Neuronopathic osteopetrosis a. Causing rapid neurodegeneration and death within the first year b. Widespread axonal spheroids and accumulation of ceroid lipofuscin c. Often accompanied by severe hematological impairment d. Gross hepatosplenomegaly e. Severe anemia/thrombocytopenia f. High arched palate g. Gum hypertrophy h. Hyperreflexia i. Clonus j. Opisthotonos k. Fisting l. Poor head control m. Irritability n. Early death Osteopetrosis with agenesis of corpus callosum: possible variant to neuronopathic osteopetrosis Dysosteosclerosis a. Bone fractures b. Developmental delay with occasional mental retardation c. Cranial nerve impingement i. Visual loss (optic atrophy) ii. Hearing loss iii. Facial nerve paralysis d. Osteomyelitis of the mandible e. Macular atrophy of the skin f. Flattened fingernails Differential diagnosis a. Hyperostosis corticalis generalisata (van Buchem syndrome) i. Diffuse/widespread sclerosis of the cortex, usually sparing spine ii. Hyperphosphatasemia b. Oculo-dento-osseous dysplasia i. An autosomal dominant disorder ii. Enlarged mandible iii. Focal osteosclerosis in the pelvis iv. Other findings a) Microphthalmia b) Large jaw c) Hypoplasia of tooth enamel c. Osteitis deformans (Paget disease) i. Localized osteosclerosis in one or a few regions of the skeleton ii. Local pain iii. Bone marrow biopsy finding
OSTEOPETROSIS
d. Progressive diaphyseal dysplasia (Camurati-Engelmann disease) i. An autosomal dominant disorder with variable expression ii. Caused by domain-specific mutations of the TGFB gene located on chromosome 19q13 encoding transforming growth factor β-1 iii. Major clinical features a) Leg pain b) Muscular weakness c) Waddling gait d) Failure to thrive iv. Major radiographic features a) Fusiform sclerosis of cortical surfaces and subendosteum b) Sclerosis of the skull base e. Pyknodysostosis i. An autosomal recessive disorder ii. Generalized osteosclerosis iii. Open fontanel iv. Associated with mental retardation and dwarfism f. Heavy metals (lead, bismuth) i. Presence of radiodense lines (Harris lines) ii. Elevated levels of heavy metals g. Mastocytosis i. Poorly demarcated sclerosis in the pelvis, ribs, vertebrae, skull, and proximal long bones ii. Not uniformly symmetric iii. Elevated histamine level h. Renal osteodystrophy i. Widespread sclerosis of the skeleton ii. Increased density less clear iii. Elevated serum parathyroid hormone iv. Elevated renal function test i. Metastatic carcinomas (breast, prostate, lung, kidney, and thyroid) i. Dispersed in random fashion ii. Bone marrow biopsy often diagnostic j. Osteosclerosis or myelofibrosis i. Diffuse increased bone density with a smooth and even density ii. Bone marrow biopsy finding
DIAGNOSTIC INVESTIGATIONS 1. Blood work-up for infantile malignant osteopetrosis a. Anemia b. Leukopenia c. Thrombocytopenia d. Reticulocytosis e. Pancytopenia f. Hypocalcemia g. Inconsistent hypophosphatemia h. Defective superoxide generation in peripheral leukocytes 2. Radiographic features a. Malignant infantile osteopetrosis i. Increased density of the entire skeleton ii. Complete absence of the medullary canal in severe cases
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iii. Lack of remodeling gives rise to metaphyseal widening or a “club-shaped” appearance of the long bones iv. “Bone within a bone” phenomena or “endobones” seen especially in the pelvis, vertebrae, hands, and feet v. Transverse radiolucent bands within the metaphyseal regions of the long bones: attributed to periodic variations in the ability to resorb bone vi. Longitudinal striations in the long bones: attributed to periosteal elevation by trauma or microfractures vii. Increasingly thickened skull with a “hair-onend” appearance viii. Common occurrence of fractures a) Especially epiphyseal separations and femur fractures b) Diaphyseal and metaphyseal fractures: usually transverse or short oblique pattern b. Various subtypes of osteopetrosis i. Vacuolar proton pump deficiency a) Generalized increased bone density b) Bone-within-bone appearance due to periosteal new bone formation c) Modeling deformities d) Pseudorickets (widened and irregular metaphyses) e) Metaphyseal lucencies in some children f) Fractures: common particularly affecting acromial processes, long bones, posterior ribs, and pubic bones ii. Carbonic anhydrase isoenzyme type II deficiency a) Thick sclerotic skull base b) Generalized osteopetrosis c) Faulty modeling of metaphyses d) Transverse striations in metaphyses e) Arcuate striations in iliac bones f) Bone-within-bone appearance g) Sandwich vertebrae h) Intracranial calcifications iii. Neuronopathic osteopetrosis a) Typical findings of severe malignant infantile osteopetrosis b) Mild to severe cerebral atrophy iv. Osteopetrosis with agenesis of the corpus callosum a) As with neuronopathic osteopetrosis b) Absence of the corpus callosum v. Dysosteosclerosis a) Thickening and sclerosis of cranial vault, base of skull, ribs, and clavicle b) Sclerotic long bones with splayed submetaphyseal clear zones c) Platyspondyly d) Retarded white matter myelination e) Intracerebral calcifications c. Autosomal dominant osteopetrosis type I i. Generalized/diffuse osteosclerosis affects especially the cranial vault ii. Sclerotic skull base iii. Vertebral bodies comparatively normal but the vertebral arches appearing dense
776
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d. Autosomal dominant osteopetrosis type II (AlbersScho˝nberg disease) i. A spectacular radiological appearance with the segmental distribution of dense bone ii. Characterized by diffuse osteosclerosis, predominantly involving spine, pelvis, and skull base a) Thickened vertebral end-plates (“sandwich vertebrae”, Rugger-Jersey spine) b) Classic “bone-within-bone” appearance/ endobone structures (especially in pelvis) c) Thickened (dense) skull base iii. Common sclerotic bands in the metaphyses iv. Fractures a) Common (78%) b) Heal slowly v. Mandibular osteomyelitis vi. Hip osteoarthritis (27%) vii. Thoracic or lumbar scoliosis (24%) viii. Cranial nerve encroachment leading to hearing loss, bilateral optic atrophy, and/or facial palsy (16%) 3. Major pathologic features a. General features for malignant infantile osteopetrosis i. Obliteration of the marrow spaces by unresorbed primary trabecular bone and calcified cartilage ii. The cartilage cores not remodeled despite an increased number of osteoclasts iii. Absent or diminished ruffled border of the osteoclast by electron microscopy b. Vacuolar proton pump deficiency: increased osteoclasts c. ClC-7 chloride pump deficiency: normal numbers of osteoclasts (in mice) d. Neuronopathic osteopetrosis i. Autofluorescent neuronal ceroid lipofuscin ii. Widespread eosinophilic neuroaxonal spheroids e. Autosomal dominant osteopetrosis type I: normal appearance of trabecular bone remodeling f. Autosomal dominant osteopetrosis type II (AlbersScho˝nberg disease) i. Defective trabecular bone remodeling ii. Increased number of osteoclasts iii. Frequent delayed healing of fractures iv. Increased total acid phosphatases probably reflects the increased number of osteoclast that are unable to resorb bone v. Observation of large multinucleated osteoclasts suggests a defect in osteoclast function rather than differentiation, as in infantile osteopetrosis g. Intermediate form i. Mild to marked increased bone density of the axial skeleton and long bones ii. Defects of modeling seen especially at the distal femurs which may have “Erlenmeyer flask” deformity iii. Frequent coxa vara and pathologic long bone fractures iv. Problematic dental malocclusion and caries
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal recessive disorder: 25% ii. Autosomal dominant disorder: low unless one of the parent is affected b. Patient’s offspring i. Autosomal recessive disorder: low unless the spouse is a carrier ii. Autosomal dominant disorder: 50% 2. Prenatal diagnosis a. Prenatal radiography i. Made at the 25th week of pregnancy at risk for autosomal recessive osteopetrosis ii. Fetal radiographic findings a) Marked sclerosis of osteopetrotic bone b) Metaphyseal splaying and clubbing of both femurs b. Prenatal diagnosis available for pregnancies with a 25% risk for fetuses affected with malignant osteopetrosis i. By amniocentesis or CVS ii. Using linked micro-satellite markers in the region of chromosome 11q12-13 c. DNA mutation analysis of fetal DNA for the pregnancy at risk for malignant autosomal recessive osteopetrosis by amniocentesis or CVS when the mutation is previously characterized in the family 3. Management a. Supportive care b. Blood transfusion for anemia secondary to a failure of bone marrow development c. Risk of recurrent infections viewed as an indication for bone marrow transplantation d. Optical nerve decompression in mildly affected older children e. Early insertion of ventilatory “grommet” tube for hearing impairment secondary to a combination of bony compression of the nerve, sclerosis of the middle ear ossicles, and/or chronic middle ear effusion f. Nasal gastric feeding for children with chronic anemia and feeding problems caused by bulbar nerve involvement, nasal congestion, and recurrent infections g. A high risk of anesthetic morbidity and mortality in patients with malignant osteopetrosis primarily related to airway and respiratory factors h. Manage osteomyelitis i. Pus drainage ii. Appropriate antibiotic therapy iii. Surgical debridement iv. Reconstruction if indicated i. Orthopedic cares for fractures j. Corticosteroids and calcitriol with some short term initial benefit but with debatable long-term benefit k. Recombinant human gamma interferon i. Enhances bone resorption and leukocyte function ii. Effects on morbidity and survival remain unclear l. Bone marrow or peripheral blood stem cell transplantation
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i. Rational: Osteoclasts are derived from hematopoietic stem cells ii. Long-term disease-free survival has been achieved in approximately 70% of infants receiving transplants from matched sibling donors a) Repopulating the bones with functioning osteoclasts by successful infusion of donor marrow b) Beginning the process of remodeling and restoration of normal calcium homeostasis c) Radiographic changes of osteopetrosis expected to gradually returning to normal four months to two years following bone marrow transfusion d) Improvement and resolution of the rachitic changes: the first observation after bone marrow transplantation e) Immune recovery f) Improved growth m. Improving results with the use of high-dose peripheral blood stem cell grafts for infantile osteopetrosis from alternative donors, including those from parents mismatched for up to one-half of their HLA-type (haploidentical)
REFERENCES Armstrong DG, Newfield JT, Gillespie R: Orthopedic management of osteopetrosis: results of a survey and review of the literature. J Pediatr Orthop 19:122–132, 1999. Bénichou O, Cleiren E, Gram J, et al.: Mapping of autosomal dominant osteopetrosis type II (Albers-Schonberg disease) to chromosome 16p13.3. Am J Hum Genet 69:647–654, 2001. Bénichou OD, Benichou B, Copin H, et al.: Further evidence for genetic heterogeneity within type II autosomal dominant osteopetrosis. J Bone Miner Res 15:1900–1904, 2000. Bénichou OD, Laredo JD, de Vernejoul MC: Type II autosomal dominant osteopetrosis (Albers-Schonberg disease): clinical and radiological manifestations in 42 patients. Bone 26:87–93, 2000. Campos-Xavier AB, Saraiva JM, Ribeiro LM, et al.: Chloride channel 7 (CLCN7) gene mutations in intermediate autosomal recessive osteopetrosis. Hum Genet 112:186–189, 2003. Carolino J, Perez JA, Popa A: Osteopetrosis. Am Fam Physician 57:1293–1296, 1998. Cheow HK, Steward CG, Grier DJ: Imaging of malignant infantile osteopetrosis before and after bone marrow transplantation. Pediatr Radiol 31:869–875, 2001.
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Cleiren E, Benichou O, Van Hul E, et al.: Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet 10:2861–2867, 2001. de Vernejoul MC, Benichou O: Human osteopetrosis and other sclerosing disorders: recent genetic developments. Calcif Tissue Int 69:1–6, 2001. Driessen GJ, Gerritsen EJ, Fischer A, et al.: Long-term outcome of haematopoietic stem cell transplantation in autosomal recessive osteopetrosis: an EBMT report. Bone Marrow Transplant 32:657–663, 2003. Eapen M, Davies SM, Ramsay NK, et al.: Hematopoietic stem cell transplantation for infantile osteopetrosis. Bone Marrow Transplant 22:941–946, 1998. el-Tawil T, Stoker DJ: Benign osteopetrosis: a review of 42 cases showing two different patterns. Skeletal Radiol 22:587–593, 1993. Felix R, Hofstetter W, Cecchini MG: Recent developments in the understanding of the pathophysiology of osteopetrosis. Eur J Endocrinol 134:143–156, 1996. Frattini A, Pangrazio A, Susani L, et al.: Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis. J Bone Miner Res 18:1740–1747, 2003. Kapelushnik J, Shalev C, Yaniv I, et al.: Osteopetrosis: a single centre experience of stem cell transplantation and prenatal diagnosis. Bone Marrow Transplant 27:129–132, 2001. Key LL Jr, Rodriguiz RM, Willi SM, et al.: Long-term treatment of osteopetrosis with recombinant human interferon gamma. N Engl J Med 332:1594–1599, 1995. Kocher MS, Kasser JR: Osteopetrosis. Am J Orthop 32:222–228, 2003. Kornak U, Kasper D, Bosl MR, et al.: Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell 104:205–215, 2001. Kornak U, Schulz A, Friedrich W, et al.: Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis. Hum Mol Genet 9:2059–2063, 2000. Manusov EG, Douville DR, Page LV, et al.: Osteopetrosis (‘marble bone’ disease). Am Fam Physician 47:175–180, 1993. Og˘ur G, Og˘ur E, Celasun B, et al.: Prenatal diagnosis of autosomal recessive osteopetrosis, infantile type, by X-ray evaluation. Prenat Diagn 15:477–481, 1995. Schulz AS, Classen CF, Mihatsch WA, et al.: HLA-haploidentical blood progenitor cell transplantation in osteopetrosis. Blood 99:3458–3460, 2002. Shalev H, Mishori-Dery A, Kapelushnik J, et al.: Prenatal diagnosis of malignant osteopetrosis in Bedouin families by linkage analysis. Prenat Diagn 21:183–186, 2001. Sobacchi C, Frattini A, Orchard P, et al.: The mutational spectrum of human malignant autosomal recessive osteopetrosis. Hum Mol Genet 10:1767–1773, 2001. Steward CG: Neurological aspects of osteopetrosis. Neuropathol Appl Neurobiol 29:87–97, 2003. Van Hul E, Gram J, Bollerslev J, et al.: Localization of the gene causing autosomal dominant osteopetrosis type I to chromosome 11q12-13. J Bone Miner Res 17:1111–1117, 2002. Waguespack SG, Koller DL, White KE, et al.: Chloride channel 7 (ClCN7) gene mutations and autosomal dominant osteopetrosis, type II. J Bone Miner Res 18:1513–1518, 2003. Wilson CJ ,Vellodi A: Autosomal recessive osteopetrosis: diagnosis, management, and outcome. Arch Dis Child 83:449–452, 2000.
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Fig. 1. Radiographs of a girl with Albers-Scho˝ngberg syndrome at 3 years (arm, pelvis, and foot) and at 10 years (arm and chest) showing sclerotic bones with loss of corticomedullary differentiation, fracture at the left humerus, and endobone appearance of phalanges of the hands and feet.
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Fig. 2. A 14-year-old boy with osteopetrosis showing sclerotic bones with loss of corticomedullary differentiation and multiple fractures, illustrated by a series of radiographs.
Pachyonychia Congenita Pachyonychia congenita is a group of rare genetically inherited diseases characterized by nail dystrophy and by varying features of ectodermal dysplasias. There are two major clinical subtypes recognized: type I with oral leukokeratosis and type II with multiple pilosebaceous cysts.
GENETICS/BIRTH DEFECTS 1. Inheritance a. Type I pachyonychia congenita (Jadassohn-Lewandowsky type) i. Autosomal dominant inheritance ii. Possible autosomal recessive inheritance b. Type II pachyonychia congenita (Jackson-Lawler type): autosomal dominant 2. Etiology a. Type I: caused by mutations in genes encoding one of the paired keratins of specialized epidermis, K6a/ K16, resulting in: i. Fragility of specific epithelia ii. Phenotypes of pachyonychia congenita I or focal non-epidermolytic palmoplantar keratoderma with insignificant nail changes b. Type II: caused by mutations in genes encoding one of the paired keratins of specialized epidermis, K6b/K17 i. Linkage analysis mapped pachyonychia congenita type II phenotype within the type I keratin gene cluster on chromosome 17q12-21 ii. A germline mutation has been identified in keratin 17 gene (K17) iii. Colocalization of K17 with keratin 6b 3. Genotype-phenotype correlation a. Differences in type I and type II phenotypes: largely explainable by the difference in expression patterns between the K6a/K16 and k6b/K17 expression pairs b. K6b/K17 expresses at higher levels in the pilosebaceous unit than K6a/K16: responsible for the pilosebaceous cysts in type II c. Conversely, K6a/K16 more widely expressed in oral epithelia: responsible for the greater predominance of oral leukokeratosis in type I
CLINICAL FEATURES 1. Presence of intra- and interfamilial phenotypic variation 2. Pachyonychia congenita type I (56.2% of cases) a. The most common subtype b. Onset in infancy c. Severe nail dystrophy affecting all the nails symmetrically i. The best hallmark of the disease ii. Thickened wedge-shaped nails iii. Proximal portions of the nails: smooth and normally attached to the lateral nail folds 781
iv. Distal portions of the nails: may increase to many times the normal thickness, producing a subungual keratinous mass that pushes the nail plate upward, arching it transversally, folding it longitudinally, and elevating it distally v. Nails commonly shed and regrow with similar but more severe changes vi. Projections from the nail beds make the nails susceptible to trauma with consequent chronic paronychial infections d. With or without following associated anomalies i. Focal nonepidermolytic palmoplantar keratoderma (predominantly a feature of type I) ii. Follicular keratoses observed on: a) Temple b) Eyebrows c) Extensor aspect of the proximal parts of the extremities iii. Hyperkeratosis of palms, soles, knees and elbows iv. Localized foot blistering v. Oral leukokeratosis: a prominent sign vi. Neonatal teeth vii. Blister formation on palms and soles viii. Hoarse voice due to laryngeal involvement (leukokeratosis) ix. Plantar hyperhidrosis 3. Pachyonychia congenita type II (24.9% of cases) a. Nail dystrophy b. Less pronounced or absent palmoplantar keratoderma and oral changes c. Follicular keratoses d. Oral leukokeratosis e. Multiple pilosebaceous cysts (most useful distinguishing feature for type II but usually occurring at puberty) i. Epidermoid or infundibular cysts (arising from the hair follicle infundibulum) ii. Eruptive vellus hair cysts and multiple steatocystomas (characteristic of type II) (arising from the sebaceous duct epithelium) f. Bullae of palms and soles g. Palmar and plantar hyperhidrosis h. Natal or neonatal teeth i. Pili torti in children j. Bushy eyebrows k. Hidradenitis suppurativa 4. Pachyonychia congenita type III (Schafer-Brunauer type) (11.7%) a. Features of type I and type II b. Angular cheilosis c. Leukokeratosis of the cornea d. Cataracts
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5. Pachyonychia congenita tarda (type IV) (7.2%) a. A rare form of pachyonychia congenita b. Features of type I, type II, and type III c. Laryngeal lesions d. Hoarseness e. Mental retardation f. Hair anomalies g. Alopecia h. Nail changes occurring in the second or third decade i. Abnormal painful nails j. Palmoplantar kertoderma 6. Pachyonychia congenita with early onset nail changes in the absence of other associated features
DIAGNOSTIC INVESTIGATIONS 1. Histology and ultrastructure of cutaneous and oral lesions: suggest a keratin disorder 2. Molecular analyses of mutations in genes encoding one of the paired keratins of specialized epidermis, K6a/K16 and K6b/K17
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal dominant inheritance: not increased unless a parent is affected ii. Autosomal recessive inheritance: 25% b. Patient’s offspring i. Autosomal dominant inheritance: 50% ii. Autosomal recessive inheritance: not increased unless the spouse is a carrier 2. Prenatal diagnosis: genomic mutation detection possible in prenatal diagnosis of pachyonychia congenita type I (K6a/K16) or type II (K6b/K17) by CVS or amniocentesis 3. Management a. No ideal treatment for the thickened nail plate available b. Vigorous use of topical lubricants and keratolytics c. Antiseptic wet dressings for secondarily infected areas d. Systemic treatment with acitretin producing variable and inconsistent results with caution of side effects (teratogenicity and hyperostosis) e. Custom-fitted footwear for protective support of painful fissures and blisters on the soles f. Simple avulsion of the distorted nails inadequate because the dystrophic nail regrows g. Curettage and electrofulguration or surgical excision of the nail matrix and bed can improve function and appearance
h. Surgical excision of a focal, hyperplastic epithelial mass results in improvement of hoarseness due to laryngeal obstruction by laryngeal lesions. Additional microsurgery may be necessary for the recurrence of the laryngeal lesions
REFERENCES Çelebi JT, Tanzi EL, Yao YJ, et al.: Identification of a germline mutation in keratin 17 in a family with pachyonychia congenita type 2. Mutat Report 113:848–850, 1999. Dahl PR, Daoud MS, Su WP: Jadassohn-Lewandowski syndrome (pachyonychia congenita). Semin Dermatol 14:129–134, 1995. Dogra S, Handa S, Jain R: Pachyonychia congenita affecting only the nails. Pediatr Dermatol 19:91–92, 2002. Feng Y-G, Xiao S-X, Ren X-R, et al.: Keratin 17 mutation in pachyonychia congenita type 2 with early onset sebaceous cysts. Br J Dermatol 148:452–455, 2003. Feinstein A, Friedman J, Schewach M: Pachyonychia congenita. J Am Acad Dermatol 19:705–711, 1988. Haber RM, Rose TH: Autosomal recessive pachyonychia congenita. Arch Dermatol 122:919–923, 1986. Hannaford RS, Stapleton K: Pachyonychia congenita tarda. Austral J Dermatol 41:175–177, 2000. Irvine AD, McLean WHI: Human keratin diseases: increasing spectrum of disease and subtlety of phenotype–genotype correlation. Br J Dermatol 140:815–828, 1999. Kansky A: Pachyonychia congenita. 2002. http://www.emedicine.com Lucker G, Steijlen P: Pachyonychia congenita tarda. Clin Exp Dermatol 20:226–229, 1995. McLean WHI, Rugg EL, Lunny DP, et al.: Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nat Genet 9:273–278, 1995. Moon SE, Lee YS, Youn JI: Eruptive vellus hair cyst and steatocystoma multiplex in a patient with pachyonychia congenita. J Am Acad Dermatol 30:275–276, 1994. Mouaci-Midoun N, Cambiaghi S, Abimelec P: Pachyonychia congenita tarda. J Am Acad Dermatol 35:334–335, 1996. Munro CS: Pachyonychia congenita: mutations and clinical presentations. Br J Dermatol 144:929–930, 144. Munro CS, Carter S, Bryce S, et al.: A gene for pachyonychia congenita is closely linked to the keratin gene cluster on 17q12–q21. J Med Genet 31:675–678, 1994. Smith FJD, Corden LD, Rugg EL, et al.: Missense mutations in keratin 17 cause either pachyonychia congenita type 2 or a phenotype resembling steatocystoma multiplex. J Invest Dermatol 108:220–223, 1997. Smith FJD, Jonkman MF, van Goor H, et al.: A mutation in human keratin K6b produces a phenocopy of the K17 disorder pachyonychia congenita type 2. Hum Mol Genet 7:1143–1148, 1998. Smith FJD, McKenna KE, Irvine AD, et al.: A mutation detection strategy for the human K6A gene and novel mutations in two cases of pachyonychia congenita type 1. Exp Dermatol 8:109–114, 1999. Smith FJD, McKusick VA, Nielsen K, et al.: Cloning of multiple keratin 16 genes facilitates prenatal diagnosis of pachyonychia congenita type 1. Prenat Diagn 19:941–946, 1999. Su WPD, Chun S, Hammond DE, et al.: Pachyonychia congenita: a clinical study of 12 cases and review of the literature. Pediatr Dermatol 7:33–38, 1990. Terrinoni A, Smith FJD, Didona B, et al.: Novel and recurrent mutations in the genes encoding keratins K6a, K16 and K17 in 13 cases of pachyonychia congenita. J Invest Dermatol 117:1391–1396, 2001.
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Fig. 1. Characteristic nail changes in a 8-month-old girl with pachyonychia congenita type I showing smooth proximal ends and thick distal ends of the nails, producing a subungual keratinous mass that pushes the nail bed upward, arching it transversally, folding it longitudinally, and elevating it distally. The patient also has oral leukokeratosis.
Pallister-Killian Syndrome Pallister-Killian syndrome is a rare sporadic cytogenetic abnormality, first described in three adults by Pallister et al. in 1977 and followed by report of a child by Teschler-Nicola and Killian in 1981. The syndrome is also known as TeschlerNicola/Killian syndrome, Pallister mosaic aneuploidy syndrome, or isochromosome 12p mosaicism. It is the most frequent autosomal tetrasomy in humans.
GENETICS/BASIC DEFECTS 1. Genetics a. Always reported as sporadic b. Appears to be associated with increased maternal age 2. Basic cytogenetic defect a. Caused by tetrasomy 12p b. Generally a mosaic c. Frequently undetectable by standard cytogenetic analysis of peripheral blood
CLINICAL FEATURES 1. Normal or large birth weight 2. Craniofacial dysmorphism a. Brachycephaly b. High and broad forehead with frontal bossing c. Temporal alopecia d. Sparse eyebrows and eyelashes e. Hypertelorism f. Short nose with anteverted nares g. A thick philtrum h. A large mouth with down slanting corners i. Full cheeks j. Cleft lip/palate k. High-arched palate l. Micrognathia m. Macroglossia n. Oral frenulae o. Delayed dental eruption p. Dental anomalies q. Low-set and posteriorly rotated ears r. Hypertrophy of anthelix crux s. Thick earlobes 3. Short neck 4. Diaphragmatic hernia with or without lung hypoplasia 5. Imperforate anus 6. CNS/neurologic abnormalities a. Severe hypotonia b. Mental retardation c. Dilated ventricles d. Bifrontal cortical atrophy e. Absent speech f. Poor vision g. Epilepsy
7. Congenital heart defects a. Ventricular septal defect: the most frequent single malformation b. Coarctation of the aorta c. Patent ductus arteriosus d. Atrial septal defect e. Aortic stenosis 8. Limb defects a. Talipes b. Broad and short hands and fingers c. Hypoplastic nails d. Abnormal palmar creases e. Lymphedema 9. Skin anomalies a. Loose/excess skin b. Pigmentary dysplasia c. Mild hyperkeratosis d. Dry skin e. Sweating abnormalities 10. Occasional internal organ malformations a. Umbilical hernia b. Malrotation of the gut c. Omphalocele d. Abnormalities of urogenital tract including cystic or dysplastic kidneys e. Genital anomalies in males i. Cryptorchidism ii. Small scrotum f. Occasional genital anomalies in females i. Ambiguous external genitalia ii. Hypoplasia of the labia majora iii. Absence of the upper vagina and uterus 11. Majority of patients die prenatally, perinatally or early postnatally, and may die even after 10 or 15 years. 12. Phenotype in older children and young adults: marked phenotypic changes occurring during childhood and adolescence a. Coarse and flat facies b. Macroglossia c. Prognathia d. Everted lower lip e. Muscular hypertonia f. Contractures g. Severe psychomotor retardation
DIAGNOSTIC INVESTIGATIONS 1. Cytogenetic studies a. Demonstration of a supernumerary isochromosome of 12p b. Confirmation of 12p tetrasomy by FISH techniques i. Using centromere probe on chromosome 12 ii. Using whole chromosome 12 painting probe 784
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2.
3. 4. 5.
c. Cytogenetic studies of several tissues because of mosaicism i. Circulating lymphocytes: mosaicism as low as 1–3% ii. Amniocytes, chorionic cells and skin fibroblasts: mosaicism ranging from 6–100% Radiography a. Asymmetry of diaphyseal length b. Short humerus or femur c. Radial notch d. Diaphyseal irregularities e. Costo-vertebral defect Echocardiography for congenital heart defect EEG for seizure activities Postmortem pathologic examinations a. Malpositioned feet b. Diaphragmatic defect c. Hypoplastic nails d. Genital malformation e. Imperforate or anteriorly placed anus f. Supernumerary spleen g. Heart valvular dysplasia h. Hypoplasia of the fibula
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: low recurrence risk (all cases are sporadic with only one preliminary case report of recurrence) b. Patient’s offspring: not surviving to reproductive age or severely handicapped by profound mental retardation 2. Prenatal diagnosis a. Ultrasound anomalies i. Hydramnios (84%) ii. Diaphragmatic hernia (16%) iii. Short limbs, predominantly rhizomelic type of micromelia (10%) iv. Hydrops fetalis (6%) v. Cystic hygroma (3%) vi. Increased nuchal translucency (3%) vii. Fetal overgrowth (3%) viii. Ventriculomegaly (3%) ix. Dilatation of cavum pellucidum (3%) x. Absence of visualization of the stomach (3%) xi. Presence of a sacral appendix (3%) xii. Cardiac malformation xiii. Hypertelorism xiv. Short neck xv. Other congenital anomalies b. Cytogenetic studies on amniocytes, cells from CVS, or fetal blood cells from cordocentesis i. Conventional karyotyping ii. FISH using chromosome 12 centromeric and whole chromosome painting probes
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a) Interphase cells b) Metaphase cells 3. Management a. Supportive treatment b. Surgical repair of diaphragmatic hernia or other congenital anomalies in non-lethal cases
REFERENCES Bernert J, Bartels I, Gatz G, et al.: Prenatal diagnosis of the Pallister-Killian mosaic aneuploidy syndrome by CVS. Am J Med Genet 42:747–750, 1992. Bresson JL, Arbez-Gindre F, Peltie J, et al.: Pallister Killian-mosaic tetrasomy 12 p syndrome. Another prenatally diagnosed case. Prenat Diagn 11:271–275, 1991. Bulter MG, Dev VG: Pallister-Killian syndrome detected by fluorescence in situ hybridization. Am J Med Genet 57:498–500, 1995. Buyse ML, Korf BR: “Killian Syndrome”, Pallister mosaic syndrome, or mosaic tetrasomy 12P?—an analysis. J Clin Dysmorphol 1:2–5, 1983. Chiesa J, Hoffet M, Rousseau O, et al.: Pallister-Killian syndrome [i(12p)]: first pre-natal diagnosis using cordocentesis in the second trimester confirmed by in situ hybridization. Clin Genet 54:294–302, 1998. Doray B, Girard-Lemaire F, Gasser B, et al.: Pallister-Killian syndrome: difficulties of prenatal diagnosis. Prenat Diagn 22:470–477, 2002. Genevieve D, Cormier-Daire V, Sanlaville D, et al.: Mild phenotype in a 15year-old boy with Pallister-Killian syndrome. Am J Med Genet 116A:90–93, 2003. Hall BD: Mosaic tetrasomy 21 is mosaic tetrasomy 12p some of the time. Clin Genet 27:284–286, 1985. Horneff G, Majewski F, Hildebrand B, et al.: Pallister-Killian syndrome in older children and adolescents. Pediatr Neurol 9:312–315, 1993. Hunter AG, Clifford B, Cox DM: The characteristic physiognomy and tissue specific karyotype distribution in the Pallister-Killian syndrome. Clin Genet 28:47–53, 1985. Mathieu M, Piussan C, Thepot F, et al.: Collaborative study of mosaic tetrasomy 12p or Pallister-Killian syndrome (nineteen fetuses or children). Ann Genet 40:45–54, 1997. Pallister PD, Meisner LF, Elejalde BR, et al.: The Pallister mosaic syndrome. Birth Defects Original Article Series XIII(3B):103–110, 1977. Peltomaki P, Knuutila S, Ritvanen A, et al.: Pallister-Killian syndrome: cytogenetic and molecular studies. Clin Genet 31:399–405, 1987. Quarrell OW, Hamill MA, Hughes HE: Pallister-Killian mosaic syndrome with emphasis on the adult phenotype. Am J Med Genet 31:841–844, 1988. Reynolds JF, Daniel A, Kelly TE, et al.: Isochromosome 12p mosaicism (Pallister mosaic aneuploidy or Pallister-Killian syndrome): report of 11 cases. Am J Med Genet 27:257–274, 1987. Schinzel A: Tetrasomy 12p (Pallister-Killian syndrome). J Med Genet 28:122–125, 1991. Shivashankar L, Whitney E, Colmorgen C, et al.: Prenatal diagnosis of tetrasomy 47,XY,+i(12p) confirmed by in situ hybridization. Prenat Diagn 8:85–91, 1988. Soukup S, Neidich K: Prenatal diagnosis of Pallister-Killian syndrome. Am J Med Genet 35:526–528, 1990. Speleman F, Leroy JG, Van Roy N, et al.: Pallister-Killian syndrome: characterization of the isochromosome 12p by fluorescent in situ hybridization. Am J Med Genet 41:381–387, 1991. Teschler-Nicola M, Killian W: Case report 72: Mental retardation, unusual facial appearance, abnormal hair. Synd Ident 7:6–7, 1981. Warburton D, Anyana-Yeboa K, Francke U: Mosaic tetrasomy 12p: Four new cases, and confirmation of the chromosomal origin of supernumerary chromosome in one of the original Pallister-mosaic syndrome cases. Am J Med Genet 27:275–283, 1988. Wenger SL, Steele MW, Yu W-D: Risk effect of maternal age in Pallister i(12p) syndrome. Cg 34:181–184, 1988. Young ID, Duckett DP, O’Reilly KM: Lethal presentation of mosaic tetrasomy 12p (Pallister-Killian) syndrome. Ann Genet 32:62–64, 1989.
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Fig. 3. FISH of an interphase cell with centromere specific probe for chromosome 12 showing 3 signals.
Fig. 1. Postmortem picture of a neonate with prenatally diagnosed mosaic i(12p). Amniocentesis was performed because of ultrasonographic finding of diaphragmatic hernia. Fig. 4. FISH of a metaphase chromosome spread with a whole chromosome probe specific for chromosome 12 showing two chromosome 12s and the i(12p) (arrow).
Fig. 2. A G-banded karyotype showing a supernumerary i(12p) (arrow). Fig. 5. FISH of a metaphase chromosome spread with a centromere probe specific for chromosome 12 showing two chromosome 12s and the i(12p) (arrow).
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Fig. 6. Another child with Pallister-Killian syndrome confirmed by cytogenetic studies showing prominent forehead, flat nasal bridge, sparse eyebrows, bitemporal alopecia, and everted lower lip.
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Phenylketonuria (PKU) Classical phenylketonuria (PKU) is a rare metabolic disorder, resulting from a deficiency of a liver enzyme, phenylalanine hydroxylase. The deficiency of the enzyme leads to elevated phenylalanine (Phe) levels in the blood and various tissues including the brain. The incidence in Caucasians is approximately 1 in 10,000, giving a heterozygote frequency of 1 in 50 to 1 in 70. About one in 15,000 infants is born with PKU in the United States.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal recessive b. Parents: obligatory carriers 2. Basic defect a. Deficient activity of the enzyme phenylalanine hydroxylase (PAH), resulting in hyperphenylalaninemia. PAH, a liver specific enzyme, catalyzes the conversion of phenylalanine to tyrosine, using tetrahydrobiopterin as a cofactor. Chromosomal locus of the PAH gene is on 12q24.1. b. Identification of more than 400 different mutations in the PAH gene i. Deletions ii. Insertions iii. Missense mutations iv. Splicing defects v. Nonsense mutations c. Compound heterozygotes in most PKU patients, contributing to the clinical heterogeneity and biochemical heterogeneity d. Consequences of accumulation of phenylalanine (Phe) and other amino acids in the CNS i. Irreversible brain damage from the first few weeks of life ii. Severe learning disabilities and associated behavioral and psychological problems
CLINICAL FEATURES 1. Treated patients a. Symptom-free on strict metabolic control using a low phenylalanine diet for the infants detected by newborn screenings b. Normal development with a normal life span when diagnosed early in the newborn period and treated effectively with life-long dietary control 2. Untreated patients a. Profound mental retardation b. Psychomotor handicaps c. Microcephaly d. Delayed speech e. Seizures f. Light hair and eyes and fair skin secondary to decreased formation of melanin pigment because of compromised tyrosine formation 788
g. Musty body or urine odor secondary to excretion of phenylacetic acid into the sweat and the urine h. Vomiting i. Irritability j. Eczema k. Subtle neurologic findings, sometimes noted even in treated individuals i. Hypertonic reflexes ii. Intention tremor l. Behavior problems i. Autistic-like behaviors ii. Hyperactivity iii. Agitation iv. Aggression 3. Maternal PKU a. Background information i. Loss of dietary compliance frequently starting during mid-childhood ii. Noncompliance on special diet by many affected adolescent females, capable of reproduction, with blood phenylalanine levels above the current recommended therapeutic range iii. Loss of follow-up of such females despite effort to identifying them iv. Teratogenic effect of elevated phenylalanine levels during pregnancy v. Fetal anomalies preventable by dietary therapy starting before conception and throughout pregnancy on women with PKU b. Abnormalities in the children of women with uncontrolled PKU during pregnancy i. Psychomotor retardation (92%) ii. Intrauterine growth retardation (40%) iii. Microcephaly iv. Congenital heart defects (10%) v. Postnatal growth retardation vi. Neurologic deficits vii. Mild craniofacial dysmorphic features viii. The frequency of abnormalities directly related to the degree of elevation of maternal phenylalanine levels during pregnancy ix. Abnormalities more likely to occur if maternal phenylalanine levels are not controlled during critical periods of embryogenesis and organogenesis early in pregnancy c. Currently, the control of phenylalanine levels during pregnancy is recommended at 2–6 mg/dL or 1–4 mg/dL: at least as strict, if not more strict, than that currently recommended for PKU treatment during early childhood d. Women with mild forms of PKU having relatively mild elevations of the phenylalanine are at risk of adversely affecting the fetuses if the mothers are
PHENYLKETONURIA (PKU)
unmonitored and untreated during pregnancies. Because placental gradient favors the fetus, the levels of Phe are higher in the fetus than in the mother e. Effects of uncontrolled maternal PKU occur regardless of the genetic PKU status of the fetus
DIAGNOSTIC INVESTIGATIONS 1. Universal newborn screening from a heel stick bloodspot for PKU (since the 1960s) for early detection and treatment of the disorder a. Guthrie bacterial inhibition assay i. Inexpensive ii. Simple iii. Reliable b. Fluorometric analysis i. Quantitative and automated test ii. Fewer false positive c. Tandem mass spectrometry i. Quantitative and automated test ii. Fewer false positive iii. Measurements of tyrosine iv. Identification of other metabolic disorders on a single sample 2. Plasma quantitative amino acid analysis especially phenylalanine and tyrosine levels a. Phe concentrations persistently >2mg/dL in the untreated state b. Recommended blood Phe levels in US clinics i. 2–6 mg/dL for age <12 year ii. 2–10 mg/dL for age >12 year c. Frequent monitoring of blood Phe levels i. During 1st year: once a week to once a month ii. After 1st year: once a month to once every 3 months d. Recommended blood Phe levels in pregnant maternal PKU i. <6mg/dL achieved at least 3 months before conception ii. 2–6mg/dL during pregnancy 3. MRI of the brain a. Hypoplasia of the corpus callosum: a marker for adverse brain development in maternal PKU b. Areas of demyelination 4. Molecular genetic testing a. Primary purpose i. Confirmatory diagnostic testing ii. Determine carrier status of at-risk relatives iii. For prenatal diagnosis b. Methodology i. Mutation analysis ii. Mutation scanning iii. Sequencing iv. Linkage analysis
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. 25% affected ii. 50% carrier iii. 25% normal
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b. Patient’s offspring i. Not increased unless the spouse is also a carrier in which case there will be a 50% risk of having affected offspring and a 50% of having carrier offspring ii. All offspring of PKU mothers a) Carry at least 1 abnormal gene at the PAH locus inherited from their homozygous affected mothers (obligatory heterozygotes) b) Approximately 1 in 120 (1/4 × 1/30) offspring will be affected by inheriting two abnormal PAH genes from both parents depending on the PKU carrier status of the father 2. Prenatal diagnosis a. Fetal ultrasonography in noncompliant maternal PKU i. Intrauterine growth retardation ii. Microcephaly iii. Congenital heart disease b. DNA mutation analysis on fetal cells by amniocentesis or CVS i. Provided the disease-causing mutations in the PAH gene identified in an affected family members ii. Informative markers available for linkage analysis 3. Management a. Dietary phenylalanine restriction: the only known strategy of preventing neurological impairment and mental retardation in patients with PKU i. Natural history of the disease modified by a lowphenylalanine diet ii. Early strict restriction of phenylalanine intake resulting in normal intelligence iii. Phenylalanine restricted diet required for life iv. Special medical foods devoid of or low in phenylalanine supplemented with tyrosine v. Restricted diet worth trying in most individuals with previously untreated PKU with possible benefits in the areas of concentration, alertness, mood, irritability and adaptive behavior b. Counseling for maternal PKU i. Genetic and nutritional evaluation and counseling, optimally before contemplating pregnancy ii. Benefits of dietary phenylalanine restriction in pregnant women with hyperphenylalaninemia: decrease the incidence of following fetal effects a) Mental retardation b) Microcephaly c) Congenital heart disease d) Intrauterine growth retardation iii. Assistance of women with hyperphenylalaninemia, who are unable or unwilling to maintain blood phenylalanine levels in the range for optimum pregnancy outcome, to obtain adequate means for birth control, including tubal ligation if requested iv. Counseling of women with hyperphenylalaninemia who conceive with blood phenylalanine levels greater than 4–6 mg/dL concerning risks to the fetus: offer detailed ultrasonography to detect fetal abnormalities such as growth retardation and congenital heart defects
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v. Close monitoring of serum phenylalanine levels at 2–6 mg/dL during pregnancy of PKU mother and intake of vitamins (folic acid and vitamin B12, in particular) and other nutrients vi. Blood testing for hyperphenylalaninemia indicated to children born to women with features of maternal PKU fetal effects without a known cause
REFERENCES American Academy of Pediatrics Committee on Genetics: Maternal phenylketonuria. Pediatrics 107:427–428, 2001. Brown MCJ, Guest JF: Economic impact of feeding a phenylalanine-restricted diet to adults with previously untreated phenylketonuria. J Intellect Disab Res 43:30–37, 1999. Centerwall SA, Centerwall WR: The discovery of phenylketonuria: the story of a young couple, two retarded children, and a scientist. Pediatrics 105:89–103, 2000. Clarke TR: The maternal phenylketonuria: a summary of progress and challenges for the future. Pediatrics 112:1584–1587, 2003. Di Meglio G: Phenylketonuria. Pediatr Rev 19:214–215, 1998. Dougherty FE, Levy HL: Present newborn screening for phenylketonuria. Ment Retard Dev Disab Res Rev 5:144–149, 1999. Dyer CA: Pathophysiology of phenylketonuria. Ment Retard Dev Disab Res Rev 5:104–112, 1999. Eisensmith RC, Martinez DR, Kuzmin AI, et al.: Molecular basis of phenylketonuria and a correlation between genotype and phenotype in a heterogeneous Southeastern US population. Pediatrics 97:512–516, 1996. Fitzgerald B, Morgan J, Keene N, et al.: An investigation into diet treatment for adults with previously untreated phenylketonuria and severe intellectual disability. J Intellect Disabil Res 44:53–59, 2000. Güttler F, Azen C, Guldberg P, et al.: Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: Report from the Maternal Phenylketonuria Collaborative Study. Pediatrics 104:258–262, 1999. Güttler F, Guldberg P, Eisensmith RC, et al.: Molecular genetics and outcome in PKU. Ment Retard Dev Disab Res Rev 5:113–116, 1999. Güttler F, Azen C, Guldberg P, et al.: Impact of the phenylalanine hydroxylase gene on maternal phenylketonuria outcome. Pediatrics 112:1530–1533, 2003. Hanley WB, Platt LD, Bachman RP, et al.: Undiagnosed maternal phenylketonuria: the need for prenatal selective screening or case finding. Am J Obstet Gynecol 180:986–994, 1999. Hellekson KL: NIH consensus statement on phenylketonuria. Am Fam Physician 63:1430–1432, 2001. Howell RR, Chakravarti A, Dawson G, et al.: National Institutes of Health Consensus Development Conference Statement: Phenylketonuria: Screening and Management, October 16–18, 2000. Pediatrics 108 (4): October 2001. Kalsner LR, Rohr FJ, Strauss KA, et al.: Tyrosine supplementation in phenylketonuria: diurnal blood tyrosine levels and presumptive brain influx of tyrosine and other large neutral amnio acids. J Pediatr 139:421–427, 2001. Koch RK: Issues in newborn screening for phenylketonuria. Am Fam Physician 605:1462–1466, 1999.
Koch R, Hanley W, Levy H, et al.: The maternal phenylketonuria international study: 1984–2002. Pediatrics 112:1523–1529, 2003. Landolt MA, Nuoffer J-M, Steinmann B, et al.: Quality of life and psychologic adjustment in children and adolescents with early treated phenylketonuria can be normal. J Pediatr 140:516–521, 2002. Levy HL, Ghavami M: Maternal phenylketonuria: a metabolic teratogen. Teratology 53:176–184, 1996. Levy HL, Lobbregt D, Barnes PD, et al.: Maternal phenylketonuria: magnetic resonance imaging of the brain in offspring. J Pediatr 128:770–775, 1996. Levy HL, Lobbregt D, Platt LD, et al.: Fetal ultrasonography in maternal PKU. Prenat Diagn 16:599–604, 1996. Mabry CC: Phenylketonuria: contemporary screening and diagnosis. Ann Clin Lab Sci 20:393–397, 1990. Matalon R, Michals K: Phenylketonuria: screening, treatment and maternal PKU. Clin Biochem 24:337–342, 1991. Maternal Phenylketonuria Collaborative Study (MPKUCS) offspring: facial anomalies, malformations, and early neurological sequelae. Am J Med Genet 69:89–95, 1997. Meglio GD: Phenylketonuria. Pediatr Rev 19:214–215, 1998. Moats RA, Scadeng M, Nelson MD Jr: MR imaging and spectroscopy in PKU. Ment Retard Dev Disab Res Rev 5:132–135, 1999. National Institutes of Health: Phenylketonuria (PKU): Screening and Management. NIH Consensus Statement 17:1–33, 2000. Pietz J, Fatkenheuer B, Burgard P, et al.: Psychiatric disorders in adult patients with early-treated phenylketonuria. Pediatrics 99:345–350, 1997. Platt LD, Koch R, Hanley WB, et al.: The international study of pregnancy outcome in women with maternal phenylketonuria: Report of a 12-year study. Am J Obstet Gynecol 182:326–333, 2000. Restrepo S, Aguero H, Jayakar P, et al.: Clinical findings in untreated classic phenylketonuria. Int Pediatr 14:232–234, 1999. Rouse B, Azen C, Koch R, et al.: Maternal phenylketonuria collaborative study (MPKUCS) offspring: facial anomalies, malformations, and early neurological sequelae. Am J Med Genet 69:89–95, 1997. Rouse B, Matalon R, Koch R, et al.: Maternal phenylketonuria syndrome: congenital heart defects, microcephaly, and developmental outcomes. J Pediatr 136(1): Jan 2000. Ryan S, Scriver CR: Phenylalanine hydroxylase deficiency. Gene Reviews, 2002. http://www.genetests.org Schoonheyt WE, Clarke JT, Hanley WB, et al.: Feto-maternal plasma phenylalanine concentration gradient from 19 weeks gestation to term. Clin Chim Acta 225:165–169, 1994. Scriver CR, Kaufman S: Hyperphenylalaninemia: Phenylalanine hydroxylase deficiency. In Scriver CR, Beaudet al., Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001, Chapter 77, pp 1667–1724. Sinai LN, Kim SC, Casey R, et al.: Phenylketonuria screening: Effect of early newborn discharge. Pediatrics 96:605–608, 1995. U.S. Preventive Services Task Force: Screening for phenylketonuria. In Guidelines from Guide to Clinical Preventive Services (2nd ed), Section I. Screening, Part G. Congenital disorders. 1996. Waisbren SE: Developmental and neuropsychological outcome in children born to mothers with phenylketonuria. Ment Retard Dev Disab Res Rev 5:125–131, 1999. Yannicelli S, Ryan A: Improvements in behaviour and physical manifestations in previously untreated adults with phenylketonuria using a phenylalanine-restricted diet: a national survey. J Inherit Metab Dis 18:131–134, 1995.
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Fig. 1. Normal color urine (left) and deep green color change after adding ferric chloride due to the presence of phenylpyruvic acid (right).
Fig. 2. Two successfully treated girls and an adult with PKU.
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Fig. 3. Six adults with untreated PKU showing varying degree of mental retardation.
Fig. 4. Noncompliant PKU mother and her infant with microcephaly and mental retardation.
Pierre Robin Sequence vi. Unknown cause: a) CHARGE syndrome b) Femoral dysgenesis c) Moebius sequence d) Robin/amelia association 3. Pathogenetically and phenotypically variable (Robin sequences and complexes) a. Malformation sequence based on intrinsic mandibular hypoplasia that prevents the normal descent of the tongue interfering with palatal fusion. For example: i. Treacher-Collins syndrome ii. Del(22q) syndrome b. Deformation sequence based on extrinsic mandibular hypoplasia caused by intrauterine constraint i. Oligohydramnios (reduced amniotic fluid results in compression of the chin against the sternum restricting mandibular growth and impacting the tongue between the palatal shelves) ii. Mandibular catch-up growth expected after birth when intrauterine deforming forces are no longer acting since micrognathia is based upon intrauterine molding c. Neurogenic hypotonia leading to lack of mandibular exercise d. Connective tissue dysplasia: Stickler dysplasia complex e. Spondyloepiphyseal dysplasia congenita complex
Pierre Robin described a group of patients with cleft palate, micrognathia, and glossoptosis in 1923. The meticulous documentation of the triad of findings led to the recognition of the sequence that bears his name. Pierre Robin sequence is estimated to affect approximately 1 in 8500 births.
GENETICS/BASIC DEFECTS 1. Inheritance a. Sporadic in most instances b. May be familial with autosomal dominant mode of inheritance 2. Genetic basis a. Isolated form i. Genetic basis unknown ii. A report of unbalanced t(2;21) with an interstitial deletion of 2q32.3-q33.2 provides a candidate Pierre Robin sequence locus in chromosomal region 2q32.3-q33.2 iii. A report of a family over three generations with isolated Pierre Robin sequence cosegregates with a balanced reciprocal t(2;17) (q24.1;q24.3), suggesting that the translocation has disrupted a putative gene or a regulatory element of one or both translocation breakpoints b. Syndromic form: etiologically heterogeneous i. Monogenic a) Stickler syndrome (common cause) b) Beckwith-Wiedemann syndrome c) Camptomelic syndrome d) Cerebrocostomandibular syndrome e) Congenital myotonic dystrophy f) Distal arthrogryposis-Robin syndrome g) Mandibulofacial dysostosis h) Miller-Dieker syndrome i) Otopalatodigital syndrome II j) Robin-oligodactyly syndrome ii. Chromosomal a) Del(22q) velocardiofacial syndrome (common cause) b) Del(4q) syndrome c) Del(6q) syndrome d) Dup(11q) syndrome iii. Teratogenic a) Fetal alcohol syndrome b) Fetal hydantoin syndrome c) Fetal trimethadione syndrome iv. Deformation a) Oligohydramnios b) Uterine structural anomalies c) Amniotic band syndrome v. Disruption: amniotic band disruption
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1. Classic triads a. Posterior, U-shaped cleft palate b. Micrognathia/retrognathia c. Glossoptosis (observed tendency of the tongue to move posteriorly obstructing the oropharynx) 2. Pierre robin sequence using different criteria a. Mandibular deficiency b. Cleft palate c. Upper airway obstruction 3. Respiratory difficulty a. Often the first signs causing concern relating to feeding b. May not necessarily be present at birth c. Upper airway obstruction and apnea i. Glossoptosis associated with retrognathia ii. Upper airway collapse secondary to: a) Hypotonic pharynx b) Laryngomalacia c) Laryngeal cleft d) Laryngeal web d. Complications of continuing airway obstruction i. Failure to thrive ii. Pectus excavatum iii. Decreased pulmonary function iv. Sudden death
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4. Failure to thrive 5. Developmental delay a. Usually not present in isolated Robin sequence b. May be present depending on the underlying syndrome 6. Middle ear diseases associated with cleft palate a. Otitis media (80%) b. Auricular anomalies (75%) c. Hearing loss, mostly conductive (60%) 7. Cleft palate associated problems a. Speech defects b. Velopharyngeal insufficiency 8. “Catch-up growth” of the mandible a. Normal mandibular growth in patients with Robin sequence secondary to mechanical constraint b. Deficient mandibular growth in patients with intrinsic mandibular anomalies 9. Other signs and symptoms and associated anomalies depending on the underlying conditions
DIAGNOSTIC INVESTIGATIONS 1. Assess respiratory sounds with stethoscope during feeding and at rest 2. Monitor developmental milestone achievement 3. Pulse oximetry monitoring to document drops in oxygen saturation 4. Flexible fiber optic nasopharyngoscopy a. To identify exact mechanism of upper airway obstruction b. To assess pharyngeal, palatal, lingual, and laryngeal morphology and function during feeding and swallowing 5. Identify the underlying cause of the micrognathia 6. Orthodontic assessment 7. Hearing assessment 8. Cephalometric radiographs a. Deformation sequence i. Mandible a) Short body b) Short ramus c) Increased gonial angle d) Incomplete catch-up growth ii. Cranial base angle: decreased b. Treacher-Collin syndrome i. Mandible a) Short body b) Short ramus c) Characteristic shape d) Severely affected growth ii. Cranial base angle: decreased c. Del(22q11.2) syndrome i. Mandible a) Retrognathia b) Essentially normal in shape ii. Cranial base angle: increased d. Stickler dysplasia complex i. Mandible a) Short ramus b) Antegonial notching of body ii. Cranial base angle: decreased e. Spondyloepiphyseal dysplasia congenita complex: short body of mandible
10. Chromosome analysis: del(22q11.2) 11. Molecular diagnosis a. Treacher-Collins syndrome: mutations in TCOF1 b. Stickler dysplasia complex i. Mutations in COL2A1 ii. Mutations in COL11A1 c. Spondyloepiphyseal dysplasia congenita complex: mutations in COL2A1
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: rare unless Pierre Robin sequence is a part of a syndrome b. Patient’s offspring: rare unless Pierre Robin sequence is a part of a syndrome 2. Prenatal diagnosis by ultrasonography demonstrating micrognathia/retrognathia and cleft palate 3. Management a. Prone positioning of infants believed to help prevent the tongue and mandible from obstructing the airway, leading to generally improved oxygen saturation b. Nasogastric tube placement for early feeding c. Occupational therapy directed toward management of the palatal abnormality d. Surgical intervention for airway obstruction i. Glossopexy to bring tongue forward and attach it to an anterior structure to prevent the tongue from falling back into the airway ii. Tracheotomy needed only in cases where conservative treatments fail iii. Mandibular distraction involving surgical incision of the mandible followed by the application of traction to stimulate new bone growth iv. Repair of cleft palate e. Treat middle ear infections i. Antibiotics ii. Placement of tympanostomy tubes f. Speech therapy
REFERENCES Argamaso RV: Glossopexy for upper airway obstruction in Robin sequence. Cleft Palate Craniofacial J 29:232–238, 1992. Bath AP, Bull PD: Management of upper airway obstruction in Pierre Robin sequence. J Laryngol Otol 111:1155–1157, 1997. Bush P, Williams A: Incidence of the Robin anomalad. Br J Plast Surg 36:434–437, 1983. Caouette-Laberge L, Bayet B, Larocque Y: The Pierre Robin sequence: review of 125 cases and evolution of treatment modalities. Plast Reconstruct Surg 93:934–941, 1994. Carey J, Fineman R, Ziter F: The robin sequence as a consequence of malformation, dysplasia, and neuromuscular syndromes. J Pediatr 101:858–864, 1982. Cohen MM Jr: The Robin anomalad—its nonspecificity and associated syndromes. J Oral Surg 34:587–593, 1976. Cohen MM Jr: The Child with Multiple Birth Defects. New York: Raven Press, 1982. Cohen MM Jr: Robin sequences and complexes: causal heterogeneity and pathogenetic/phenotypic variability. Am J Med Genet 84:311–315, 1999. Hanson JW, Smith DW: U-shaped palatal defect in the Robin anomaly: developmental and clinical relevance. J Pediatr 87:30, 1975. Heaf D, Jelms P, Dinwiddie R, et al.: Nasopharyngeal airways in Pierre Robin syndrome. J Pediatr 100:698–703, 1982. Holder-Espinasse M, Abadie V, Cormier-Daire V, et al.: Pierre Robin sequence: a series of 117 consecutive cases. J Pediatr 139:588–590, 2001.
PIERRE ROBIN SEQUENCE Hsieh Y-Y, et al.: The prenatal diagnosis of Pierre Robin sequence. Prenat Diagn 19:567–569, 1999. Jamshidi N, Macciocca I, Dargaville PA, et al.: Isolated Robin sequence associated with a balanced t(2;17) chromosomal translocation. J Med Genet 41:e1-e5, 2004. Marques I, Barbieri M, Bettiol H: Etiopathogenesis of isolated Robin sequence. Cleft palate Craniofac J 35:517–525, 1998. Myer CM III, Reed JM, Cotton RT, et al.: Airway management in Pierre Robin sequence. Otolaryngol Head Neck Surg 118:630–635, 1998. Pilu G, Rombero R, Reece A, et al.: The prenatal diagnosis of Robin anomalad. Am J Obstet Gynecol 154:630–632, 1986. Randall P, Krogman WM, Jahina S: Pierre Robin and the syndrome that bears his name. Cleft palate J 2:237–244, 1965. Robin P: la chute de la base de la langue considérée comme une nouvelle cause de gene dans la respiration naso-pharyngienne. Bull Acad Natl Med (Paris) 89:37–41, 1923. Sheffield LJ, et al.: A genetic follow-up study of 64 patients with the Pierre Robin complex. Am J Med Genet 28:25–37, 1987. Sher AE: Mechanisms of airway obstruction in Robin sequence: Implications for treatment. Cleft Palate-Craniofacial J 29:224–231, 1992. Shprintzen RJ: Pierre Robin, micrognathia, and airway obstruction: the dependency of treatment on accurate diagnosis. Int Anesthesiol Clin 26:64–71, 1988.
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Shprintzen RJ: The implications of the diagnosis of Robin sequence. Cleft Palate-Craniofacial J 29:205–209, 1992. Shprintzen RJ: Robin sequence. In Cassidy SB, Allanson JE (eds): Management of Genetic Syndromes. New York: Wiley-Liss, 2001, pp 323–336. Shprintzen RJ, Siegel-Sadewitz VL, Amato J, et al.: Anomalies associated with cleft lip, cleft palate, or both. Am J Med Genet 20:585–596, 1985. Sidhu SS, Deshmukh RN: Pierre Robin syndrome: autosomal dominant inheritance with pleiotropic effect. Indian J Pediatr 56:413–417, 1989. Snead M, Yates J: Clinical and molecular genetics of Stickler syndrome. J Med Genet 36:353–359, 1999. Spranger JW, Benirschke K, Hall JG, et al.: Errors of morphogenesis: concepts and terms. J Pediatr 100:160–165, 1982. William A: The Robin anomalad-a follow-up study. Arch Dis Child 56:663–668, 1981. Taylor MRG: The Pierre Robin sequence: a concise review for the practicing pediatrician. Pediatr Rev 22:125–130, 2001. Tewfik TL, Trinh N: Pierre Robin syndrome. E-Med J January, 2003. Van den Elzen APM, Semmekrot BA, Bongers EMHF, et al.: Diagnosis and treatment of the Pierre Robin sequence: results of a retrospective clinical study and review of the literature. Eur J Pediatr 160:47–53, 160. Vegter F, Hage JJ, Mulder JW: Pierre Robin syndrome: mandibular growth during the first year of life. Ann Plast Surg 42:154–157, 1999.
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Fig. 1. Three infants with typical Pierre Robin sequence.
Polycystic Kidney Disease, Autosomal Dominant Type c. Polycstin-1 i. Predicted to have a receptor-like structure ii. May be involved in cell-cell/matrix interactions iii. May have a regulatory role over a polycystin channel d. Polycystin-2 i. Similar to and functioning as an ion channel subunit ii. Causes nonselective cation permeability e. Basic defect in ADPKD: could be in polycystinregulated intracellular Ca++ levels 5. Disease characteristics a. Principal ductal organs with cyst formation i. Kidneys ii. Liver b. Consequences of cyst enlargement i. Progressive destruction of normal renal tissue ii. End-stage renal failure in >50% of patients by age 60 c. Systemic involvement i. Arterial hypertension developing early and observed in >50% of patients ii. Vascular aneurysms iii. Cardiac valve defects iv. Colonic diverticula
Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of polycystic kidney disease with an estimated incidence of approximately 1/400 to 1/1000 individuals worldwide. It roughly accounts for 10% of patients with chronic renal failure requiring hemodialysis or transplantation.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant with almost complete penetrance b. Negative family history in 40% of cases 2. Genetically heterogeneous with at least three different genes now known to cause ADPKD. All three types of ADPKD present with an identical profile of extrarenal manifestations (including liver cysts and aneurysms) a. Type I (85–90% of cases): caused by mutations in PKD1 gene, which is: i. Mapped on chromosome 16p13.3 ii. The most severe form with a lower median survival and a higher risk of progressing to endstage renal disease iii. Closely linked to TSC2, a gene responsible for a major form of tuberous sclerosis b. Type II (most of the remaining cases): caused by mutations in PKD2 gene, which is: i. Mapped on chromosome 4q21-q23 ii. Identified by positional cloning iii. Producing milder disease but otherwise phenotypically identical with the PKD1 disease c. A small number of familial cases reported to be unlinked to both the PKD1 and PKD2 loci, suggesting the existence of at least one more proposed gene (PKD3) which has not been identified d. Patients with mutations in both the PKD1 and PKD2 genes (transheterozygotes) have a more severe clinical course than those with mutations in only one of the genes 3. Mechanism of cyst formation: somatic second-hit model a. A germline mutation in one PKD allele in all cells in ADPKD b. A random somatic mutation (second hit) occurring in the normal allele causing increased cell proliferation, leading to cyst formation 4. Molecular basis of ADPKD a. Protein products of the disease gene forming a macromolecular signaling structure, the polycystin complex, that regulates fundamental aspects of renal epithelial development and cell biology b. Protein products of PKD1 and PKD2 (polycystin-1 and polycystin-2, respectively) i. Share sequence homology ii. May form components of a receptor/channel complex
CLINICAL FEATURES
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1. Intrafamilial and interfamilial variability in the onset, phenotype, and progression of the disease a. Due to genetic heterogeneity i. More common PKD1 (accounting for approximately 85% of cases associated with more severe disease) ii. Evidence of significant intrafamilial phenotypic variation suggesting modifying factors (such as the angiotensin-converting enzyme insertion/deletion polymorphism) as well as environmental factors that influence the clinical course iii. Association of the position of the PKD1 mutation with earlier end-stage renal disease b. Age of onset i. Presenting at any age ii. Generally presenting in the 4th and 5th decades of life iii. Occasionally presenting in the fetal or neonatal period 2. Onset of disease in the childhood in children who carry PKD1 gene a. Frequency of children with renal cysts detectable by ultrasound i. 60% by five years of age ii. 75–80% among children aged 5–18 years
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b. Number of renal cysts at 11 years i. 1–10 in 60% of children ii. More than 10 cysts in 40% of children 3. Age at the time of diagnosis and progression of the disease a. Diagnosis in utero or in the first year of life (intrauterine or infantile onset) i. Manifesting unusually severe disease ii. End-stage renal disease during childhood in 18% of cases b. Diagnosis after the first year of life i. Increase in the number of cysts over a mean interval of 3.7 years ii. Systolic hypertension in 9% of cases iii. None with decreased renal function 4. Renal manifestations a. Development of bilateral renal cysts i. Primary renal manifestation ii. Leading to functional changes (impaired renal concentrating capacity, hypertension) iii. Leading to various clinical manifestations b. Flank or back pain (about 60%) c. Acute pain i. Infected cyst ii. Ruptured cyst (associated with gross hematuria) iii. Nephrolithiasis (20–36%) d. Urinary tract infection (40–68%) e. Hematuria f. Mild proteinuria g. End-stage renal disease 5. Extrarenal manifestations a. Liver involvement i. Most common extrarenal manifestation ii. Liver cysts uncommon before 16 years of age iii. Liver cysts observed in about 75% of patients older than 60 years iv. No liver symptoms in most patients with ADPKD v. Occasionally encountered liver changes a) Congenital hepatic fibrosis b) Segmental dilation of the biliary tract vi. Liver cysts responsible for most of the hepatic complications vii. Acute complications a) Cyst infection b) Cyst hemorrhage c) Cyst rupture d) Cyst torsion viii. Chronic complications related to progressive increase of the polycystic liver a) Abdominal mass b) Ascites c) Hepatic venous outflow obstruction (BuddChiari syndrome) d) Portal hypertension with variceal bleeding e) Inferior vena cava compression f) Bile duct compression g) Jaundice ix. Intrahepatic biliary cysts a) More common in women b) Exacerbated by pregnancy b. Other rare cystic involvement i. Pancreatic cysts (10%)
ii. Arachnoid cysts (5%) iii. Ovarian cysts c. Cardiovascular manifestations not uncommon i. Intracranial berry aneurysms (5–10%) ii. Dolichoectatic arteries iii. Aortic root dilatation iv. Dissections of intracerebral, coronary, thoracic, iliac, aortic, and splenic arteries reported v. Cardiac valve defects d. Other noncystic involvement i. Colonic diverticula (80% of patients with endstage renal disease) ii. Hernias (25%) 6. Clinical course in children a. Clinical spectrum ranging from severe neonatal manifestations mimicking autosomal recessive polycystic kidney disease to renal cysts noted on ultrasound in asymptomatic children b. Diagnosis made in utero by ultrasound: massively enlarged cystic kidneys c. Newborn presenting with Potter phenotype and death from pulmonary hypoplasia d. Newborn with large abdominal masses e. After neonatal period i. Hypertension ii. Abdominal pain iii. Palpable abdominal mass iv. Hematuria v. Renal insufficiency only rarely vi. Renal infections f. Rare extrarenal manifestations i. Liver cysts ii. Cerebral vessel aneurysms g. Prognosis i. Severe symptoms in neonatal or infantile cases ii. Milder symptoms in late childhood cases 7. Risk factors precipitating faster progression of the disease a. The PKD-1 gene b. Male gender c. Earlier onset of symptoms i. Renal enlargement ii. Hematuria iii. Proteinuria iv. Incipient renal failure v. Hypertension d. Having >10 renal cysts before age 12 years e. Having blood pressures above the 75th percentile for age, height, and gender f. Polycystic liver disease i. Frequently associated with autosomal dominant polycystic kidney disease ii. Develops later than renal cysts iii. Develops earlier and more severe in women than in men
DIAGNOSTIC INVESTIGATIONS 1. Urinalysis a. Hematuria b. Mild proteinuria c. Evidence of infection
POLYCYSTIC KIDNEY DISEASE, AUTOSOMAL DOMINANT TYPE
2. Sonography a. Prenatal presentation i. Large hyperechogenic kidneys ii. Variable size iii. Mixtures of small and large cysts iv. Exceptionally uncommon oligohydramnios b. Postnatal presentation: invariably large cysts 3. Renal ultrasound and IVP a. Enlarged kidneys b. Macrocysts and distortion of the collecting system 4. CT scan and/or MRI for renal, hepatic, pancreatic and ovarian cysts 5. CT scan and/or MRI angiography for intracranial aneurysm 6. Renal function tests 7. Renal ultrasound to assess carrier status a. A painless and relatively noninvasive procedure b. Detection rate in asymptomatic subjects from families with known ADPKD i. 22% of cases in the first decade ii. 66% of cases by the second decade iii. 86% by age 25 8. Molecular genetic testing a. Linkage analysis i. Linkage analysis with microsatellite markers ii. Requires a relatively large number of affected family members in order to establish which one of the two possible genes is responsible within each family b. Direct DNA analysis difficult to perform due to: i. Large size and complexity of PKD1 and PKD2 genes ii. Marked allelic heterogeneity c. Mutation screening in the research laboratory i. Mutation detection rates of 50–70% for PKD1 ii. Mutation detection rates of about 75% for PKD2 d. Mutation screening of entire coding region by denaturing high-performance liquid chromatography recently available clinically 9. Screening for mutations of PKD1 gene: complicated by the genomic structure of the 5′-duplicated region encoding 75% of the gene
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Not increased in de novo case ii. 50% if one of the parent is affected b. Patient’s offspring i. 50% risk of acquiring the disease ii. Both sexes of offspring affected equally 2. Carrier testing for family members at risk a. Ultrasound and radiography b. Molecular mutation analysis of PKD1 and PKD2 genes 3. Prenatal diagnosis a. Prenatal ultrasonography i. Enlarged kidneys with or without cysts ii. Absence of urine in the bladder iii. May not be evident until the third trimester
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b. Molecular mutation analysis of PKD1 and PKD2 genes on fetal DNA obtained from amniocentesis or CVS, provided the mutation has been identified in the affected family members or linkage has been established in the family 4. Management a. No treatment currently directed at the disease process b. Monitoring of presymptomatic patients with ADPKD i. Monitor blood pressure ii. Test renal function iii. Advantages a) Prevent or control hypertension b) Prevent or control infection c) Identify potential kidney donors from among the family d) Offer advise on reproduction e) Provide prenatal diagnosis c. Treatment of polycystic kidney disease i. Narcotic analgesics for pain ii. Antibiotics for infection iii. Treatment of nephrolithiasis a) Potassium citrate for uric acid lithiasis, hypocitric calcium oxalate nephrolithiasis, and distal acidification defects b) Extracorporeal shock-wave lithotripsy c) Percutaneous nephrostolithotomy iv. Needle aspiration of dominant cysts v. Laparoscopic cyst decortication vi. Open renal cyst decortication vii. Therapeutic intervention aimed at slowing the progression of renal failure a) Control of hypertension b) Control of hyperlipidemia c) Dietary protein restriction d) Control of acidosis e) Prevention of hyperphosphatemia viii. Renal dialysis ix. Renal transplantation for end stage renal disease d. Treatment of massive polycystic liver disease i. Aspiration of cyst fluid ii. Stenting iii. Cyst fenestration iv. Liver resection v. Liver transplantation e. Treatment of intracranial aneurysms i. Asymptomatic aneurysm a) Observation and yearly follow-up b) Surgery for enlarging aneurysm ii. Ruptured or symptomatic aneurysm: surgical clipping at its neck f. Management of aortic dissection i. Aortic root dilatation a) Yearly follow-up b) Strict blood pressure control with β-blockade ii. Surgery for aortic root greater than 55–60 mm
REFERENCES Ariza M, Alvarez V, Marin R, et al.: A family with a milder form of adult dominant polycystic kidney disease not linked to the PKD1 (16p) or PKD2 (4q) genes. J Med Genet 34:587–589, 1997.
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Arnaout MA: Molecular genetics and pathogenesis of autosomal dominant polycystic kidney disease. Annu Rev Med 52:93–123, 2001. Bear JC, McManamon P, Morgan J, et al.: Age at clinical onset and at ultrasonographic diction of adult polycystic kidney disease: Data for genetic counselling. Am J Med Genet 18:45–53, 1984. Chauvear D, Fakhouri F, Grünfeld J-P: Liver involvement in autosomal-dominant polycystic kidney disease: therapeutic dilemma. J Am Soc Nephrol 11:1767–1775, 2000. Chen M-F: Surgery for adult polycystic liver disease. J Gastroenterol Hepatol 15:1239–1242, 2000. Daoust MC, Reynolds DM, Biche TDG, et al.: Evidence for a third genetic locus for autosomal dominant polycystic kidney disease. Genomics 25:733–736, 1995. Edwards OP, Baldinger S: Prenatal onset of autosomal dominant polycystic kidney disease. Urology 34:265–270, 1989. Fick GM, Gabow PA: Natural history of autosomal dominant polycystic kidney disease. Annu Rev Med 45:23–29, 1994. Fick GM, Johnson AM, Strain JD, et al.: Characteristics of very early onset autosomal dominant polycystic kidney disease. J Am Soc Nephrol 3:1863–1870, 1993. Fick GM, Duley IT, Johnson AM, et al.: The spectrum of autosomal dominant polycystic kidney disease in children. J Am Soc Nephrol 4:1654–1660, 1994. Fick-Brosnahan GM, Tran ZV, Johnson AM, et al.: Progression of autosomaldominant polycystic kidney disease in children. Kidney Int 59: 1654–1662, 2001. Gabow PA, Johnson AM, Kaehny WD, et al.: Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease. Kidney Int 41:1311–1319, 1992. Grantham JJ: The etiology, pathogenesis, and treatment of autosomal dominant polycystic kidney disease: recent advances. Am J Kidney Dis 28:788–803, 1996. Gupta S, Seith A, Dhiman RK, et al.: CT of liver cysts in patients with autosomal dominant polycystic kidney disease. Acta Radiologica 40:444–448, 1999.
Hateboer N, Lazarou LP, Williams AJ, et al.: Familial phenotype differences in PKD1. Kidney Int 56:34–40, 1999. Hateboer N, van Dijk MA, Bogdanova N, et al.: Comparison of phenotypes of polycystic kidney disease types 1 and 2. Lancet 353:103–107, 1999. Hemal AK: Laparoscopic management of renal cystic disease. Urol Clin N Amer 28:115–126, 2001. Harris PC, Torres VE: Autosomal dominant polycystic kidney disease. Gene Reviews, 2002. http://www.genetests.org Kimberling WJ, Kumar S, Gabow PA, et al.: Autosomal dominant polycystic kidney disease: localization of the second gene to chromosome 4q13-q23. Genomics 18:467–472, 1993. McDonald RA, Avner ED: Inherited polycystic kidney disease in children. Semin Nephrol 11:632–642, 1991. Pei Y, Paterson AD, Wang KR, et al.: Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease. Am J Hum Genet 68:355–363, 2001. Perrone RD: Extrarenal manifestations of ADPKD. Kidney Int 51:2022–2036, 1997. Pirson Y, Chauveau D, Torres V: Management of cerebral aneurysms in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 13:269–276, 2002. Rossetti S, Strmecki L, Gamble V, et al.: Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications. Am J Hum Genet 68:46–63, 2001. Rossetti S, Burton S, Strmecki L, et al.: The position of the polycystic kidney disease 1 (PKD1) gene mutation correlates with severity of renal disease. J Am Soc Nephrol 13:1230–1237, 2002. Rossetti S, Chauveau D, Walker D, et al.: A complete mutation screen of the ADPKD genes by DHPLC. Kidney Int 61:1588–1599, 2002. Torres VE, Wilson DM, Hattery RR, et al.: Renal stone disease in autosomal dominant polycystic kidney disease. Am J Kidney Dis 22:513–519, 1993. Wilson PD: Polycystic kidney disease. N Engl J Med 350:151–164, 2004.
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Fig. 1. A lady (A) with autosomal dominant polycystic kidney disease and with family history of multiple affected family members. Her liver was markedly enlarged as shown by a pencil mark on the patient’s photo. The ultrasonography of the kidney (B) showed numerous cysts with minimal residual normal appearing cortex. The right kidney (shown on ultrasound image) measured 11 cm with the largest cyst measuring 2.9 cm. The left kidney measured 13.3 cm in length with the largest cyst measuring 3.8 cm. The abdominal CT scan (C) showed marked hepatomegaly \which occupies the entire abdomen. Numerous hepatic cysts and renal cysts were evident. Numerous cysts of different sizes were also detected in her brother’s enlarged kidneys by ultrasonography (the left kidney is shown here).
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POLYCYSTIC KIDNEY DISEASE, AUTOSOMAL DOMINANT TYPE
Fig. 3. Appearance of the gross and cut section of a kidney (745 gm) surgically removed from in a 43-year-old female with autosomal dominant polycystic kidney disease.
Fig. 4. Multiple hepatic cysts of a patient with autosomal dominant polycystic kidney disease. Fig. 2. Three CT scans of an adult patient with polycystic kidney disease with and without contrast showing multiple cysts in the kidneys and liver.
Polycystic Kidney Disease, Autosomal Recessive Type Autosomal recessive polycystic kidney disease (ARPKD) or polycystic kidney and hepatic disease 1 (PKHD1) is an oftendevastating form of polycystic kidney disease. It is also known as infantile polycystic kidney disease. The incidence of ARPKD is estimated to be 1 in 20,000 live births and the frequency of the heterozygous carrier state 1 in 70.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. No clear evidence of genetic heterogeneity 3. Molecular cause a. Mutations in the PKHD1 gene on chromosome 6p21.1-p12, encoding a putative receptor protein, fibrocystin (or polyductin) b. The full spectrum of phenotypic variants appears to involve mutations in this gene c. Characterization of disease-causing mutations providing new insights into the molecular basis for the phenotypic variability with the recent identification of the PKHD1 gene 4. Genotype-phenotype correlations: All patients carrying two truncating mutations displayed a severe phenotype with perinatal or neonatal demise
CLINICAL FEATURES 1. The most common heritable cystic renal disease manifesting in infancy and childhood 2. A wide variable clinical spectrum, ranging from severe renal impairment and a high mortality rate in infancy to older children and adolescents with minimal renal disease and complications of congenital hepatic fibrosis, cholangitis and portal hypertension 3. Principal manifestations a. Fusiform dilatation of renal collecting ducts and distal tubuli b. Dysgenesis of the hepatic portal triad 4. Clinical characteristics at presentation a. 0–1 month i. Prenatal diagnosis made ii. Positive family history iii. Pneumothorax iv. Flank mass v. Hypertension vi. Renal insufficiency b. >1 month to 1 year i. Frank mass ii. Hepatomegaly iii. Hypertension iv. Urinary tract infection c. >1 year to 5 years i. Hepatomegaly ii. Portal hypertension 803
d. >5 year i. Hepatomegaly ii. Hypertension iii. Renal insufficiency iv. Portal hypertension e. Predominance of renal abnormalities in younger children f. Predominance of hepatic disease in older children and adolescents g. Tendency of inverse relative degrees of kidney and liver involvement i. Children with severe renal disease usually with milder hepatic disease ii. Children with severe hepatic disease with milder renal impairment 5. “Potter” phenotype developed in affected fetuses a. Pulmonary hypoplasia, often incompatible with life b. Characteristic face i. Short and snubbed nose ii. Deep eye creases iii. Micrognathia iv. Low-set flattened ears c. Deformities of the spine and limbs (clubfoot) 6. Renal manifestations a. Frequent loss of concentrating ability of the kidney b. Common recurrent urinary tract infections c. Proteinuria d. Hematuria e. Creatinine clearance improving early but declining progressively during adolescence f. Hypertension early in life but usually regresses g. Enlarged kidneys h. End-stage renal disease 7. Hepatic manifestations a. Congenital hepatic fibrosis i. Invariably present but only occasionally do hepatic symptoms predominate ii. Two predominant features characterizing the liver in ARPKD a) Bile ducts: abnormally/irregularly formed, often increased in number, and dilated intrahepatic bile ducts b) Portal tracts: enlarged and fibrotic iii. Normal hepatic parenchyma iv. Hepatocellular function almost always normal in affected patients, even when they have relatively severe portal tract disease v. Not by itself a diagnostic (not pathognomonic) sign. Congenital hepatic fibrosis has been observed in the following situations: a) Meckel-Gruber syndrome b) Vaginal atresia c) Tuberous sclerosis
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d) Juvenile nephronophthisis e) Rarely autosomal dominant polycystic kidney disease b. Caroli disease i. Congenital hepatic fibrosis accompanied by a non-obstructive dilation of the intrahepatic bile ducts ii. Clinical risk of secondary complications a) Stone formation b) Recurrent cholangitis: may result from ectatic bile ducts c) Hepatic abscesses d) Rare cholangiocarcinoma c. Hepatomegaly d. Portal hypertension i. The most common sequelae of congenital hepatic fibrosis ii. Splenomegaly iii. Variceal bleeding iv. Hypersplenism a) Leukopenia b) Thrombocytopenia c) Anemia d) Increased susceptibility to infections resulting from leukopenia associated with splenic sequestration e. Ascending cholangitis i. Presumably caused by entry of nonsterile gastrointestinal contents into the dilated intrahepatic bile ducts ii. Common in patients with macroscopically dilated bile ducts iii. Clinical features a) Abdominal pain b) Fever c) Elevation in levels of hepatic enzymes iv. Tends to recur v. May lead to hepatic abscess formation, sepsis, and death 8. Cerebral aneurysm, a common feature of ADPKD, reported in an adult with ARPKD 9. Prognosis a. 30–50% of affected neonates die shortly after birth in respiratory insufficiency due to pulmonary hypoplasia b. Recent trend with improved prognosis c. 67% of children who survive the newborn period with life-sustaining renal function at 15 years of age
DIAGNOSTIC INVESTIGATIONS 1. Radiography in neonates and infants with moderate to severe renal disease a. Smoothly enlarged kidneys because of the numerous dilated collecting ducts b. Abdominal distension c. Gas-filled bowel loops often deviated centrally d. Pulmonary hypoplasia and small thorax in the baby with severe kidney disease e. Pneumothorax common at birth following assisted ventilation
2. Ultrasonography a. Absence of renal cysts in both parents as demonstrated by ultrasound examination b. Neonatal ultrasonography with more marked renal cystic disease i. Massive enlarged kidneys ii. Increased echogenicity of entire parenchyma iii. Loss of corticomedullary differentiation iv. Loss of central echo complex v. Small macrocysts vi. Usually small bladder vii. Increased hepatic echogenicity, mainly in medulla c. Ultrasonography in children with more prominent hepatic fibrosis i. Massive kidney enlargement ii. Increased hepatic echogenicity, mainly in medulla iii. Macrocysts a) Less than 2 cm in diameter b) Tend to become larger and more numerous over time iv. Enlarged echogenic liver v. Hepatic cysts vi. Pancreatic cysts vii. Splenomegaly secondary to portal hypertension viii. Hepatofugal-flow duplex and color-flow Doppler 3. CT scan a. Nonenhanced CT: smooth, enlarged, and low attenuating kidneys, likely the reflection of the large fluid volume in the dilated ducts b. CT with contrast i. Kidneys with a striated pattern representing accumulation of contrast material in the dilated tubules ii. Linear opacifications representing retention of contrast medium in dilated medullary collecting ducts iii. Macrocysts appearing as well-circumscribed rounded lucent defects iv. Time of delay in visualizing the contrast medium in the kidneys, proportionate to the severity of renal impairment 4. Ultrasonography and magnetic resonance cholangiography to investigate the presence of an extent of Caroli disease in children with autosomal recessive polycystic kidney disease 5. MRI of affected children (perinatal, neonatal and infantile course) a. Kidney appearance i. Enlarged, humpy but still reniform in shape ii. Homogeneously grainy parenchyma b. Signal intensity i. Hypointense on T1-W spin-echo sequences ii. Hyperintense on T2-W turbo-spin-echo sequences c. RARE (rapid acquisition with relaxation enhancement)-MR-urography i. Hyperintense, linear radial pattern seen in the cortex and medulla representing the characteristic microcystic dilatation of collecting ducts ii. Possible few circumscribed small subcapsular cysts
POLYCYSTIC KIDNEY DISEASE, AUTOSOMAL RECESSIVE TYPE
6. Histopathology of the kidney a. Radially arranged cylindrical and fusiform ducts are present throughout renal medulla and cortex, due to a generalized dilatation of collecting ducts b. The portal tracts of the liver are enlarged and contain abundant fibrous tissue and many cistern-like dilated bile ducts. The abnormal changes are the result of ductal plate malformation 7. Molecular diagnosis a. Linkage analysis of the affected family using 6p21 markers demonstrating linkage to the ARPKD1 gene with the affected proband b. 33 different mutations detected on 57 alleles (Rossetti et al., 2003) i. 51.1% in ARPKD ii. 32.1% in congenital hepatic fibrosis/Caroli disease) iii. Two frequent truncating mutations a) 9689delA (9 alleles) b) 589insA (8 alleles) iv. Mutation detection rate a) High in severely affected patients (85%) b) Lower in moderate severe ARPKD (41.9%) c) Low, but significant, in adults with congenital hepatic fibrosis/Caroli disease (323.1%) v. Complications for the prospects for gene-based diagnostics a) Large gene size b) Marked allelic heterogeneity c) Clinical diversity of the ARPKD phenotype c. Direct DNA analysis available clinically
b. c. d.
e. f.
g.
h.
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased (theoretical risk 0.7%) 2. Prenatal diagnosis a. Ultrasonography in most severely affected fetuses i. Enlarged, echogenic kidneys ii. Dilated collecting ducts iii. Characteristic hepatic ductal plate malformation iv. A small or nonvisualized bladder v. Oligohydramnios attributable to poor fetal renal output vi. Unreliable especially in early pregnancy b. Mutation scanning of PKHD1 is available clinically by analysis of fetal DNA obtained from amniocentesis or CVS. Both disease-causing alleles of an affected family member must be identified or likage has been established in the family before prenatal testing can be performed. The ARPKD locus mapped to proximal chromosome 6p allowing haplotype-based prenatal diagnosis in “at-risk” family with a previously affected child in whom prior family studies have identified informative linked markers. An absolute prerequisite for these studies is an accurate diagnosis of ARPKD in the previously affected sib 3. Management a. Initial management of affected infants to focus on stabilization of respiratory function. Mechanical ventilation
i.
j.
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may be necessary to treat both pulmonary hypoplasia and respiratory compromise from massively enlarged kidneys Water and electrolyte balance Peritoneal dialysis may be required for neonates with oliguria or anuria within the first days of life Vigorous treatment of systemic hypertension with antihypertensive agents i. ACE inhibitors ii. Calcium channel blockers iii. Beta-blockers iv. Judicious use of diuretics (eg, thiazides, loop diuretics) Antibiotics for treatment of urinary tract infections Management of renal osteodystrophy in children with ARPKD and chronic renal insufficiency i. Calcium supplements ii. Phosphate binders iii. 1,25-dihydroxyvitamin D3 to suppress parathyroid hormone (PTH) iv. Erythropoietin (EPO) a) Increases hemoglobin levels b) Improves the overall well-being of the child Potential use of recombinant human growth hormone therapy to improve the growth of children with uremia Therapeutic options available for the treatment of portal hypertension in children i. Conservative management ii. Control of variceal bleeding a) Sclerotherapy effective in controlling bleeding b) Banding of varices c) Placement of portosystemic shunts occasionally necessary to reduce bleeding and the formation of additional varices iii. Prompt management with antibiotics and, when indicated, surgical drainage to help reduce morbidity and mortality associated with ascending cholangitis iv. Splenectomy for hypersplenism v. Liver transplantation in patients with severe hepatic dysfunction or chronic cholangitis Replacement therapy for renal failure i. Renal dialysis ii. Renal transplant Combined liver/kidney transplantation
REFERENCES Bergmann C, Senderek J, Sedlacek B, et al.: Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1). J Am Soc Nephrol 14:76–89, 2003. Dell KM: Autosomal recessive polycystic kidney disease. Gene Reviews; 2003. http://genetests.org. Guay-Woodford LM, Desmond RA: Autosomal recessive polycystic kidney disease: the clinical experience in North America. Pediatrics 111:1072–1080, 2003. Herrin JT: Phenotypic correlates of autosomal recessive (infantile) polycystic disease of kidney and liver: criteria for classification and genetic counseling. Prog Clin Biol Res 305:45–54, 1989. Jamil B, McMahon LP, Savige JA, et al.: A study of long-term morbidity associated with autosomal recessive polycystic kidney disease. Nephrol Dial Transplant 14:205–209, 1999.
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Jung G, Benz-Bohm G, Kugel H, et al.: MR cholangiography in children with autosomal recessive polycystic kidney disease. Pediatr Radiol 29:463–466, 1999. Kern S, Zimmerhackl LB, Hildebrandt F, et al.: Rare-MR-urography—a new diagnostic method in autosomal recessive polycystic kidney disease. Acta Radiol 40:543–544, 1999. Lederman HM, Hurth PJ: Polycystic kidney disease. http://www.emedicine.com Lieberman E, Salinas-Madrigal L, Gwinn JL, et al.: Infantile polycystic disease of the kidneys and liver: clinical, pathological and radiological correlations and comparison with congenital hepatic fibrosis. Medicine 50:277–318, 1971. Lilova M, Kaplan BS, Meyers KE: Recombinant human growth hormone therapy in autosomal recessive polycystic kidney disease. Pediatr Nephrol 18:57–61, 2003. Lonergan GJ, Rice RR, Suarez ES: Autosomal recessive polycystic kidney disease: radiologic-pathologic correlation. Radiographics 20:837–855, 2000. Pèrez L, Torra R, Badenas C, et al.: Autosomal recessive polycystic kidney disease presenting in adulthood. Molecular diagnosis of the family. Nephrol Dial Transplant 13:1273–1276, 1998. Rossetti S, Torra R, Coto E, et al.: A complete mutation screen of PKHD1 in autosomal-recessive polycystic kidney disease (ARPKD) pedigrees. Kidney Int 64:391–403, 2003.
Roy S, Dillon MJ, Trompeter RS, et al.: Autosomal recessive polycystic kidney disease: long-term outcome of neonatal survivors. Pediatr Nephrol 11:302–306, 1997. Stein-Wexler R, Jain K: Sonography of macrocysts in infantile polycystic kidney disease. J Ultrasound Med 22:105–107, 2003. Sumfest JM, Burns MW, Mitchell ME: Aggressive surgical and medical management of autosomal recessive polycystic kidney disease. Urology 42:309–312, 1993. Zerres K, Becker J, Mucher G, et al.: Autosomal recessive polycystic kidney disease. Contrib Nephrol 122:10–16, 1997. Zerres K, Hansmann M, Mallmann R, et al.: Autosomal recessive polycystic kidney disease. Problems of prenatal diagnosis. Prenat Diagn 8:215–229, 1988. Zerres K, Mucher G, Bachner L, et al.: Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome 6p21-cen. Nat Genet 7:429–432, 1994. Zerres K, Mucher G, Becker J, et al.: Prenatal diagnosis of autosomal recessive polycystic kidney disease (ARPKD): molecular genetics, clinical experience, and fetal morphology. Am J Med Genet 76:137–144, 1998. Zerres K, Rudnik-Schoneborn S, Senderek J, et al.: Autosomal recessive polycystic kidney disease (ARPKD). J Nephrol 16:453–458, 2003. Zerres K, Rudnik-Schoneborn S, Steinkamm C, et al.: Autosomal recessive polycystic kidney disease. J Mol Med 76:303–309, 1998.
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Fig. 2. Photomicrograph of a kidney of a neonate (37 weeks gestation) with ARPKD showing markedly dilated collecting ducts in the medulla (top) and the cortex (bottom). The infant also had intrahepatic bile duct proliferation and mild cystic changes, and pulmonary hypoplasia.
Fig. 3. Photomicrograph of the liver of a 2-year-old girl with congenital hepatic fibrosis, consistent with ARPKD. Note the irregularly dilated branching bile ducts. There is abundant fibrous connective tissue in this enlarged portal tract.
Fig. 1. A newborn with ARPKD showing Potter facies. The spongy appearing cut surface of a kidney from the same patient is due to generalized dilatation of the collecting ducts in both cortex and medulla.
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Fig. 4. Two neonates with ARPKD showing markedly distended abdomen.
Fig. 5. Kidneys in another neonate with ARPKD.
Prader-Willi Syndrome Prader-Willi syndrome is a neurogenetic disorder characterized by hypotonia and feeding difficulties in infancy, followed by hyperphagia, hypogonadism, mental retardation, and short stature. It was the first recognized microdeletion syndrome identified with high-resolution chromosome analysis, the first recognized human genomic imprinting disorder, and the first recognized disorder resulting from uniparental disomy. The incidence of Prader-Willi syndrome is approximately 1/10,000 to 1/15,000 individuals.
GENETICS/BASIC DEFECTS 1. Inheritance a. Usually sporadic events (de novo deletions of 15q11-q13) b. Rare familial transmission (balanced translocations involving 15q11-q13) (<1%) 2. A contiguous gene syndrome involving multiple paternally expressed genes 3. Caused by the lack of expression of normally active paternally inherited genes at chromosome 15q11-q13 because of a phenomenon called genomic imprinting a. The relevant region on chromosome 15q11-q13: normally expressed on the paternally derived chromosome and imprinted on maternally derived chromosome b. The imprinted maternal allele is unable to produce functional protein since the normally expressed paternal copy is often deleted in Prader-Willi syndrome 4. Molecular subclassification of Prader-Willi syndrome: all involving loss of paternal gene expression from chromosome 15q11-q13 a. Paternal deletion 15q11-q13 (70% of cases): microdeletion of the actively transcribed segment on the paternally derived chromosome 15q11-q13 b. Maternal uniparental disomy (UPD15) (25–30% of cases) i. Inheritance of two copies of the maternal chromosome without paternal contribution ii. In normal individuals, the paternally donated chromosome expresses multiple genes in the Prader-Willi syndrome region while the maternal chromosome is largely silent iii. In case of maternal uniparental disomy, without the presence of a chromosome donated from the father, normal imprinting on the 2 maternally donated chromosomes leads to the absence of gene expression in this region c. Mutation in the imprinting control center i. Deletion of the imprinting center (1–2% of the cases) of the SNRPN (small nuclear ribonucleoprotein polypeptide N) gene causing inability to establish the normal methylation status ii. Without imprinting center deletion (1–2% of cases)
CLINICAL FEATURES 1. Neonatal presentation a. Central hypotonia in infancy b. Poor feeding/sucking c. Poor weight gain (failure to thrive) d. Genital hypoplasia/hypogonadism e. Diminished deep tendon reflexes f. Abnormal squeaky weak cry g. History of fetal inactivity (in utero hypotonia) 2. Developmental delay 3. Mild dysmorphic features a. Almond-shaped eyes b. Dolichocephaly c. Narrow bifrontal diameter d. Narrow nasal bridge e. Small mandible f. Small mouth g. High-arched palate h. Down-turned lips i. Thick viscous saliva 4. Hyperphagia after the 1st-2nd postnatal years 5. Severe obesity without significant intervention 6. Retinal hypopigmentation 7. Small hands and feet (acromicria) 8. Mild to moderate mental retardation 9. Hypothalamic insufficiency suggested by several autonomic dysfunctions that affect appetite regulation, growth, pubertal development, control of breathing, and alertness 10. Behavioral and psychiatric difficulties a. Excessive food-seeking behaviors b. Obsessions c. Compulsions d. Mood lability e. Depression 11. Other manifestations a. Infantile lethargy b. Sleep disturbance and/or sleep apnea c. Short stature d. Hypopigmentation e. Skin sores from constant picking f. Esotropia/myopia g. Speech articulation defects h. High pain threshold i. Ineffective thermoregulation j. Early adrenarche k. Osteoporosis l. Kyphoscoliosis 12. Prognosis a. Obesity: the major cause of morbidity and mortality b. Cardiopulmonary compromise (Pickwickian syndrome) resulting from excessive obesity
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13. Diagnostic criteria (adapted from Holm et al., 1993): 5 points for children under 3 years (3 from major criteria); 8 points for children above 3 years (4 from major criteria) a. Major Criteria (1 points each) i. Infantile central hypotonia ii. Infantile feeding problems/failure to thrive iii. Rapid weight gain between 1 and 6 years iv. Characteristic facial features v. Hypogonadism (genital hypoplasia, pubertal deficiency) vi. Developmental delay/mental retardation b. Minor Criteria (1/2 point each) i. Decreased fetal movement and infantile lethargy ii. Typical behavioral problems iii. Sleep disturbance/sleep apnea iv. Short stature for the family by age 15 years v. Hypopigmentation vi. Small hands and feet for height age vii. Narrow hands with straight ulnar border viii. Esotropia/myopia ix. Thick viscous saliva x. Speech articulation defects xi. Skin picking c. Supportive Criteria (no points) i. High pain threshold ii. Decreased vomiting iii. Temperature control problems iv. Scoliosis/kyphosis v. Early adrenarche vi. Osteoporosis vii. Unusual skill with jigsaw puzzles viii. Normal neuromuscular studies
DIAGNOSTIC INVESTIGATIONS 1. Cytogenetic studies a. Microscopic or submicroscopic del(15)(q11-q13) confirmed by fluorescence in situ hybridization (FISH probe for SNRPN) (60–80%) b. Paternally derived chromosome 15 that is deleted c. De novo events in most cases with cytogenetically normal father’s chromosomes d. Balanced chromosomal rearrangement with break in 15q11-q13 (<1%) 2. Molecular analyses a. Uniparental disomy identified by using microsatellite repeat sequences of chromosome 15 in the patient and both parents i. Maternal uniparental disomy for chromosome 15 in most of non-deletion cases (20–40%) ii. Inheriting both copies of chromosome 15 from the mother iii. Absence of the paternally inherited copy of chromosome 15q11-q13 b. Rare familial Prader-Willi syndrome: associated with very small mutations in 15q11-q13 region leading to the loss of expression of multiple genes from the paternal chromosome c. DNA methylation analyses (by Southern blotting and PCR) of the SNRPN or PW71 (D15S63) loci to detect
absence of paternal methylation patterns on the basis of deletion, uniparental disomy, or defective methylation: detects over 99% of cases and is highly specific
GENETIC COUNSELING 1. Recurrence risks a. De novo deletion or maternal uniparental disomy in an affected child: a low recurrence risk ≤1% due to possible paternal balanced insertion or gonadal mosaicism) b. Imprinting center mutation in an affected child: recurrence risk up to 50% c. Presence of a parental balanced chromosomal rearrangement: up to 25% recurrence risk 2. Prenatal diagnosis a. High risk pregnancies i. Parents who have had a previous child with Prader-Willi syndrome, caused by deletion or uniparental disomy, for assurance purpose ii. Parents who have had a previous child with Prader-Willi syndrome, caused by a defect in the imprinting control center, because of the high recurrence risk iii. Inherited translocation involving chromosome 15 and resulting in a deletion, because of the theoretical 25% risk of Prader-Willi syndrome in the offspring b. Low risk pregnancies in which no family history of Prader-Willi syndrome exists c. Cytogenetic study to detect del(15q11-q13) from amniocytes or CVS cells, complemented by FISH probe d. Molecular studies of uniparental disomy 15 using microsatellite dinucleotide polymorphism analysis of amniocytes and parental DNA e. DNA methylation analysis of amniocytes 3. Management a. Manage feeding problems with special nipples or gavage feeding if needed to assure adequate nutrition, to avoid failure to thrive, and to improve hypotonia b. Early intervention programs with speech, physical, and occupational therapies after careful educational, behavioral, and psychological assessments c. Dietary control i. Monitoring of weight and nutritional counseling ii. Low-calorie and well-balanced diet combined with a regular exercise program iii. Limit access to food iv. Close supervision to minimize food stealing d. Management of endocrine problems i. Growth hormone replacement in patients with deficient growth hormone ii. Testosterone treatment in males to improve changes in voice and body hair, beard growth, genital size, body mass and strength, and selfimage iii. Treatment with estrogen, cycling hormones or birth control pills in females has resulted in increasing breast size and menstrual periods
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e. Management of scoliosis as in the general population f. Behavioral management i. Firm limit setting and enforcement ii. Consult with a behavioral psychologist or other behavior specialist for behavioral management programs g. Psychiatric management i. Psychosis ii. Manic-depressive illness iii. Obsessive-compulsive disorder h. Treatment of complications resulting from excessive obesity i. Cardiopulmonary compromise ii. Type II diabetes mellitus iii. Thrombophlebitis iv. Management of skin picking, chronic skin changes, and peripheral edema
REFERENCES Åkefeldt A, Törnhage CJ, Gillberg C: A woman with Prader-Willi syndrome gives birth to a healthy baby girl. Dev Med Child Neurol 41:789–790, 1999. American Society for Human Genetics: Diagnostic testing for Prader-Willi and Angelman syndromes: Report of the ASHG/ACMG Test and Technology Transfer Committee. Am J Hum Genet 58:1085–1088, 1996. Ashley CT Jr, Warren ST: Trinucleotide repeat expansion and human disease. Annu Rev Genet 29:703–728, 1995. Aughton DJ, Cassidy SB: Physical features of Prader-Willi syndrome in neonates. Am J Dis Child 144:1251–1254, 1990. Brannan CI, Bartolomei MS: Mechanisms of genomic imprinting. Curr Opin Genet Dev 9:164–170, 1999. Bray G, Dahms W, Swerdloff R, et al.: The Prader-Willi syndrome: A study of 40 patients and a review of the literature. Medicine 62:59–80, 1983. Buiting K, Saitoh S, Gross S, et al.: Inherited microdeletions in the Angelman and Prader-Willi syndrome define an imprinting centre on human chromosome 15. Nat Genet 9:395–400, 1994. Buiting K, Dittrich B, Gross S, et al.: Sporadic imprinting defects in PraderWilli syndrome and Angelman syndrome: implications for imprint-switch models, genetic counseling, and prenatal diagnosis. Am J Hum Genet 63:170–180, 1998. Buiting K, Farber C, Kroisel P, et al.: Imprinting center in two PWS families: implications for diagnostic testing and genetic counseling. Clin Genet 58: 284–290, 2000. Burd L, Vesely B, Martsolf J, et al.: Prevalence study of Prader-Willi syndrome in North Dakota. Am J Med Genet 37:97–99, 1990. Buttler MG: Prader-Willi syndrome: Current understanding of cause and diagnosis. Am J Med Genet 35:319–332, 1990. Butler MG: Molecular diagnosis of Prader-Willi syndrome: comparison of cytogenetic and molecular genetic data including parent of origin dependent methylation DNA patterns. Am J Med Genet 61:188–190, 1996. Butler MG, Palmer CG: Parental origin of chromosome 15 deletion in PraderWilli syndrome. Lancet 1:1285–1286, 1983. Cassidy SB: Prader-Willi syndrome. Curr Probl Pediatr 14:1–55, 1984. Cassidy SB: Recurrence risk in Prader-Willi syndrome. Am J Med Genet 28:59–60, 1987. Cassidy SB: Aging in Prader-Willi syndrome: 22 patients over age 30 years. Proc Greenwood Genet Ctr 13:102–103, 1994. Cassidy SB: Prader-Willi syndrome. J Med Genet 34:917–923, 1997. Cassidy SB: Prader-Willi and Angelman syndromes: sister imprinted disorders. Am J Med Genet 97:136–146, 2000. Cassidy SB: Prader-Willi syndrome. In: Cassidy SB, Allanson JE (eds): Management of Genetic Syndromes. New York: Wiley-Liss, 2001. Cassidy SB, Schwartz S: Prader-Willi and Angelman syndromes: Disorders of genomic imprinting. Medicine 77:140–151, 1998. Cassidy SB, Schwartz S: Prader-Willi syndrome. Gene Reviews, 2000. Christian SL, Smith ACM, Macha M, et al.: Prenatal diagnosis of uniparental disomy 15 following trisomy 15 mosaicism. Prenat Diagn 16:323–332, 1996.
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Curfs LM, Fryns JP: Prader-Willi syndrome: a review with special attention to the cognitive and behavioral profile. Birth Defects Original Article Series 28:99–104, 1992. Delach JA, Rosengren SS, Kaplan L, et al.: Comparison of high resolution chromosome banding and fluorescence in situ hybridization (FISH) for the laboratory evaluation of Prader-Willi syndrome and Angelman syndrome. Am J Med Genet 52:85–91, 1994. Driscoll DJ, Waters MF, Williams CA, et al.: A DNA methylation imprint, determined by the sex of the parent, distinguishes the Angelman and Prader-Willi syndromes. Genomics 13:917–924, 1992. Dykens EM, Leckman JF, Cassidy SB: Obsessions and compulsions in PraderWilli syndrome. J Child Psychol Psychiatry 37:995–1002, 1996. Dykens EM, Cassidy SB, King BH: Prader-Willi syndrome: Genetic, behavioral and treatment issues. Child Adolesc Clinics of N Am 5:913–27, 1996. Einfeld SL, Smith A, Durvasula S, et al.: Behavior and emotional disturbance in Prader-Willi syndrome. Am J Med Genet 82:123–127, 1999. Everman DB, Cassidy SB: Genetics of childhood disorders: XII. Genomic imprinting: breaking the rules. J Am Acad Child Adolesc Psychiatry 39:386–389, 2000. Fridman C: Origin of uniparental disomy 15 in patients with Prader-Willi or Angelman syndrome. Am J Med Genet 94:249–253, 2000. Gillessen-Kaesbach G, Gross S, Kaya-Westerloh S, et al.: DNA methylation based testing of 450 patients suspected of having Prader-Willi syndrome. J Med Genet 32:88–92, 1995. Glenn CC, Saitoh S, Jong MT, et al.: Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene. Am J Hum Genet 58:335–346, 1996. Glenn CC, Driscoll DJ, Yang TP, et al.: Genetic imprinting: Potential function and mechanisms revealed by the Prader-Willi and Angelman syndromes. Mol Hum Reprod 3:321–333, 1997. Glenn CC, Deng G, Michaelis RC, et al.: DNA methylation analysis with respect to prenatal diagnosis of the Angelman and Prader-Willi syndromes and imprinting. Prenat Diagn 20:300–306, 2000. Greally JM, State MW: Genetics of childhood disorders: XIII. Genomic imprinting: the indelible mark of the gamete. J Am Acad Child Adolesc Psychiatry 39:532–535, 2000. Greenswag LR: Adults with Prader-Willi syndrome. A survey of 22 cases. Dev Med Child Neurol 29:145–152, 1987. Greenswag LR, Alexander RC (eds): Management of Prader-Willi syndrome. 2nd ed. New York: Springer-Verlag, 1995. Hanel ML, Wevrick R: The role of genomic imprinting in human developmental disorders: lessons from Prader-Willi syndrome. Clin Genet 59:156–164, 2001. Hart PS: Salivary abnormalities in Prader-Willi syndrome. Ann New York Acad Sci 842:125–131, 1998. Hertz G, Cataletto M, Feinsilver SH, et al.: Developmental trends of sleepdisordered breathing in Prader-Willi syndrome: the role of obesity. Am J Med Genet 56:188–90, 1995. Holm VA, Pipes PL: Food and children with Prader-Willi syndrome. Am J Dis Child 130:1063–1067, 1976. Holm VA, Cassidy SB, Butler MG, et al.: Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics 91:398–402, 1993. Horsthemke B, Dittrich B, Buiting K: Imprinting mutations on human chromosome 15. Hum Mutat 10:329–337, 1997. Hulten M, Armstrong S, Challinor P, et al.: Genomic imprinting in Adv Neurol Angelman and Prader-Willi translocation family. Lancet 338:638–639, 1991. Kennerknecht I: Differentiated recurrence risk estimations in the Prader-Willi syndrome. Clin Genet 41:303–308, 1992. Knoll J, Nicholls R, Magenis R, et al.: Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion. Am J Med Genet 32:285–290, 1989. Kubota T, Sutcliffe JS, Aradhya S, et al.: Validation studies of SNPRN methylation as a diagnostic test for Prader-Willi syndrome. Am J Med Genet 66:77–80, 1996. Kubota T, Aradhya S, Macha M, et al.: Analysis of parent of origin specific DNA methylation at SNRPN and PW71 in tissues: implication for prenatal diagnosis. J Med Genet 33:1011–1014, 1996. Kuslich Clin Dysmorphol: Prader-Willi syndrome is caused by disruption of the SNRPN gene. Am J Hum Genet 64:70–76, 1999. Lai LW, Erickson RP, Cassidy SB: Clinical correlates of chromosome 15 deletions and maternal disomy in Prader-Willi syndrome. Am J Dis Child 147:1217–1223, 1993.
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Lalande M: Parental imprinting and human disease. Annu Rev Genet 30:173–195, 1996. Le Bris-Quillevere MJ, Riviere D, Pluchon-Riviere E, et al.: Prenatal diagnosis of del(15)(q11q13). Prenat Diagn 10:405–411, 1990. Ledbetter DH, Engel E: Uniparental disomy in humans. Development of an imprinting map and its implications for prenatal diagnosis. Hum Mol Genet 4:1757–1764, 1995. Ledbetter D, Riccardi V, Airhart S, et al.: Deletions of chromosome 15 as a cause of the Prader-Willi syndrome. New Engl J Med 304:235–239, 1981. Lindgren AC, Barkeling B, Hagg A, et al.: Eating behavior in Prader-Willi syndrome, normal weight, and obese control groups. J Pediatr 137:50–55, 2000. Malcolm S: Microdeletion and microduplication syndromes. Prenat Diagn 16:1213–1219, 1996. Mannens M, Alders M: Genomic imprinting: concept and clinical consequences. Ann Med 31:4–11, 1999. Martin A, State M, Koenig K, et al.: Prader-Willi syndrome. Am J Psychiatry 155:1265–1273, 1998. Mascari MJ, Gottlieb W, Rogan PK, et al.: The frequency of uniparental disomy in Prader-Willi syndrome. Implication for molecular diagnosis. New Engl J Med 326:1599–1607, 1992. McEntagart ME, Webb T, Hardy C, et al.: Familial Prader-Willi syndrome: case report and a literature review. Clin Genet 58:216–223, 2000. Miller SP, Riley P, Shevell MI: The neonatal presentation of Prader-Willi syndrome revisited. J Pediatr 134:226–228, 1999. Morison IM, Reeve AE: A catalogue of imprinted genes and parent-of-origin effects in humans and animals. Hum Mol Genet 7:1599–1609, 1998. Nicholls RD: Genomic imprinting and uniparental disomy in Angelman and Prader-Willi syndromes: a review. Am J Med Genet 46:16–25, 1993. Nicholls RD: New insights reveal complex mechanisms involved in genomic imprinting [editorial; comment] Am J Hum Genet 54:733–740, 1994. Nicholls RD, Knoll JH, Butler MG, et al.: Genetic imprinting suggested by maternal heterodisomy in nondeletion Prader-Willi syndrome. Nature 342:281–285, 1989. Nicholls R, Saitoh S, Horsthemke B: Imprinting in Prader-Willi and Angelman syndromes. Trends Genet 14:194–200, 1998. Ohta T, Gray TA, Rogan PK, et al.: Imprinting mutation mechanisms in PraderWilli syndrome. Am J Hum Genet 64:397–413, 1999. Orstavik KH, Tangsrud SE, Kiil R, et al.: Prader-Willi syndrome in a brother and sister without Cytogenetic or detectable molecular genetic abnormality at chromosome 15q11q13. Am J Med Genet 44:534–538, 1992. Ozcelik T, Leff S, Robinson W, et al.: Small nuclear ribonucleoprotein polypeptide N (SNRPN), an expressed gene in the Prader-Willi syndrome critical region. Nat Genet 2:265–269, 1992. Prader A, Labhart A, Willi H: Ein Syndrom von Adipositas, Kleinwuchs, Kryptorchismus und Oligophrenie nach Myatonieartigem Zustand im Neugeborenenalter. Schweiz Med Wschr 86:1260–1261, 1956. Reis A, Dittrich B, Greger V, et al.: Imprinting mutations suggested by abnormal DNA methylation patterns in familial Angelman and Prader-Willi syndromes Am J Hum Genet 54:741–747, 1994.
Ritzen EM, Lindgren AC, Hagenas L, et al.: Growth hormone treatment of patients with Prader-Willi syndrome. Swedish Growth Hormone Advisory Group. J Pediatr Endocrinol Metab 12 (Suppl 1):345–349, 1999. Roberts E, Stevenson K, Cole T, et al.: Prospective prenatal diagnosis of Prader-Willi syndrome due to maternal disomy for chromosome 15 following trisomic zygote rescue. Prenat Diagn 17:780–783, 1997. Robinson WP, Bottani A, Yagang X, et al.: Molecular, cytogenetic and clinical investigations of Prader-Willi syndrome patients. Am J Hum Genet 49:1219–1234, 1991. Saitoh S, Buiting K, Cassidy SB, et al.: Clinical spectrum and molecular diagnosis of Angelman and Prader-Willi syndrome imprinting mutation patients. Am J Med Genet 68:195–206, 1997. Scheimann A: Prader-Willi syndrome. eMedicine J 2002. Schinzel A: Approaches to the prenatal diagnosis of the Prader-Willi syndrome. Hum Genet 74:327, 1986. Schluter B, Buschatz D, Trowitzsch E, et al.: Respiratory control in children with Prader-Willi syndrome. Eur J Pediatr 156:65–68, 1997. Slater HR, Vaux C, Pertile M, et al.: Prenatal diagnosis of Prader-Willi syndrome using PW71 methylation analysis-Uniparental disomy and the significance of residual trisomy 15. Prenat Diagn 17:109–113, 1997. Smeets DFCM, Hamel BCJ, Nelen MR, et al.: Prader-Willi syndrome and Angelman syndrome in cousins from a family with a translocation between chromosomes 6 and 15. N Engl J Med 326:807–811, 1992. Soper RT, Mason EE, Printen KJ, Zellweger H: Gastric bypass for morbid obesity in children and adolescents. J Pediatr Surg 10:51–58, 1975. State MW, Dykens EM: Genetics of childhood disorders: XV. Prader-Willi syndrome: genes, brain, and behavior. J Am Acad Child Adolesc Psychiatry 39:797–800, 2000. State MW, Lombroso PJ, Pauls DL, et al.: The genetics of childhood psychiatric disorders: a decade of progress. J Am Acad Child Adolesc Psychiatry 39:946–962, 2000. Stephenson JBP: Neonatal presentation of Prader-Willi syndrome in neonates. Am J Dis Child 142:151–152, 1992. Surth LC, Wang H, Hunter AGW: Deletion and uniparental disomy involving the same maternal chromosome 15. N Engl J Med 330:572–573, 1994. Sutcliffe JS, Nakao M, Christian S, et al.: Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nat Genet 8:52–58, 1994. Swaab DF, Purba JS, Hofman MA: Alterations in the hypothalamic paraventricular nucleus and its oxytocin neurons (putative satiety cells) in PraderWilli and “Prader-Willi-like” syndromes: a study of five cases. J Clin Endocrinol Metab 80:573–579, 1995. Wevrick R, Francke U: Diagnostic test for the Prader-Willi syndrome by SNRPN expression in blood. Lancet 348:1068–1069, 1996. Wharton RH, Loechner KJ: Genetic and clinical advances in Prader-Willi syndrome. Curr Opin Pediatr 8:618–624, 1996. Zeschnigk M, Lich C, Buiting K, et al.: A single-tube PCR test for the diagnosis of Angelman and Prader-Willi syndrome based on allelic methylation differences at the SNRPN locus. Eur J Hum Genet 5:94–98, 1997.
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Fig. 1. A 10-month old girl with Prader-Willi syndrome showing severe hypotonia, strabismus, and small hands and feet. Parent-of-origin specific DNA methylation studies at 15q11-q13 for Prader-Willi syndrome revealed the presence of maternal 4.2 kb hybridization band only but not paternal 0.9 kb band consistent with Prader-Willi syndrome. Uniparental disomy DNA analysis revealed that the patient has only maternal alleles based on the Mendelian inheritance of 2 informative markers (D15S205 and D15S1002) and 2 partial informative markers (D15S130 and D15S1007), indicative of uniparental disomy for chromosome 15.
Fig. 2. An infant with Prader-Willi syndrome [del(15)(q11-q13)] showing hypotonia and failure to thrive.
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Fig. 3. A girl with Prader-Willi syndrome [del(15)(q11-q13)] showing obesity, short stature, almond-shaped eyes, and small hands and feet.
Fig. 4. A boy with Prader-Willi syndrome [del(15)(q11-q13)] showing almond-shaped eyes, bitemporal narrowing, obesity, hypogenitalism, and small hands and feet.
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Fig. 6. Sore on the hand in a patient with Prader-Willi syndrome [del(15)(q11-q13)] (shown by partial karyotypes and ideogram) and trimethylaminuria.
Fig. 5. A girl with Prader-Willi syndrome [del(15)(q11-q13)] showing extreme obesity, characteristic facial appearance, small hands and feet, and multiple skin sores from constant picking.
Fig. 7. A woman with Prader-Willi syndrome [del(15)(q11-q13)] and neurofibromatosis 1 showing obesity and axillary freckles.
Progeria b. Hutchinson-Gilford progeria syndrome gene localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q and one case with a 6megabase paternal interstitial deletion c. Increased hyaluronic acid production by progeric fibroblasts postulated as the underlying metabolic abnormality in progeria i. Urinary excretion of hyaluronic acid found to be increased in some patients ii. Elevated levels of hyaluronic acid may result in growth failure and accelerated senescence by inhibiting the growth of blood vessels d. Accumulation of type IV collagen due to an interaction between activated T lymphocytes and fibroblasts e. Current results of microarray analysis: further support the notion that patients with progeria experience an accelerated form of aging f. Reduced growth capacity in vitro in the skin fibroblasts from progeria patients with conflicting evidence on whether progeric cells can repair single-strand DNA breaks induced by X- or gamma-irradiation g. Fibroblasts from progeric tissue i. Inability to subculture ii. Having short telomeres iii. Uncertain as to whether aging is the consequence of shortened telomeres with reduced cell replication, impaired telomerase activity, or the culmination of the effects of reactive oxygen species h. Del(1)(q23) reported in a patient with HutchinsonGilford progeria i. Inv ins(1;1)(q32;q44q23) reported in the postmortem skin biopsy specimens from identical twins raising the possibility that a gene for progeria may be located at the break point site of the inserted chromosome segment
In 1886, Hutchinson described a boy with congenital alopecia, wrinkled atrophic skin, an odd facies, joint contractures, and normal intelligence. Subsequently in 1904, Gilford reported a second patient with similar features and suggested the term progeria, from the Greek word geras meaning old age, to describe the premature senile characteristics of the patients. Thus, the syndrome is also known as Hutchinson-Gilford progeria syndrome (HGPS). Progeria is an extremely rare condition with characteristic clinical findings of premature and accelerated aging. Its incidence was estimated to be 1 per 8 million live births in the United States. Males to females ratio is about 1.5 to 1. Most reported patients are Caucasians.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal dominant inheritance a. Advanced paternal age effect observed b. Germinal mosaicism responsible for rare instances of affected sibs 2. Basic defects a. Caused by mutations in lamin A (LMNA) gene i. LMNA gene encodes two protein products, lamin A/C (lamin A and lamin C), representing major constituent of the inner nuclear membrane lamina ii. Mutations in LMNA a) About 90% of patients have an identifiable mutation b) Most common mutation: a de novo singlebase substitution, G608G (GGC>GGT) in exon 11. G608G mutation responsible for the majority of progeria arises in the paternal germline c) A second mutation in the same codon, G608S (GGC>AGC) d) E145K (exon 2) observed in a phenotypically unusual HGPS iii. Mutations in LMNA also cause the following different recessive and dominant disorders: a) Emery-Dreifuss muscular dystrophy type 1 (EMD1) (autosomal dominant) b) Emery-Dreifuss muscular dystrophy type 2 (EMD2) (autosomal recessive) c) A familial dilated cardiomyopathy and conduction system defects (CMD1A) (autosomal dominant) d) Dunnigan type familial partial lipodystrophy (FPLD) (autosomal dominant) e) Limb girdle muscular dystrophy type 1B (LGMD1B) (autosomal dominant) f) Charcot-Marie-Tooth disorder type 2B1 (CMT2B1) (autosomal recessive axonal neuropathy) g) Mandibuloacral dysplasia (MAD) (autosomal recessive)
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1. General features a. Normal appearance at birth b. Normal intelligence and personality c. High-pitched voice 2. Growth a. Profound growth failure/failure to thrive starting around 6 month to one year of age b. Extreme short stature c. No rapid growth during puberty d. Markedly diminished subcutaneous fat, especially on the face and limbs e. Absent sexual maturation 3. Skin a. Unremarkable at birth b. Generalized non-pitting edema suggestive of scleroderma shortly after birth
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c. “Sclerodermatous” skin over lower abdomen and proximal thighs, in which irregular bumps give appearance of lipodystrophy d. Becoming thin, dry, taut, and shiny in some areas, but lax and wrinkled in others, most commonly over the fingers and toes, by the second year e. Striking loss of subcutaneous tissue f. Prominent venous pattern g. Easy bruising h. Diminished eccrine sweating in some cases i. Progressive freckle-like hyperpigmentation (most evident in sun-exposed areas) and thickened sclerotic areas (usually on the lower parts of the trunk or thighs) after several years Hair a. Partial alopecia progressing to generalized alopecia often beginning at birth or in the first year and becoming prominent by the end of the second year b. Few remaining hairs: white or blond, fine, and fuzzy c. Body hair as well as scalp and facial hair: equally affected Nails a. Short, thin, and dystrophic fingernails and toenails b. Koilonychia (spoon nails) c. Onychogryphosis (deformed overgrowth of the nails) A striking facies after few months of life a. Typical “plucked-bird” appearance related to disproportionate craniofacial growth b. Disproportionately large cranium c. Relatively small face d. Prominent eyes e. Prominent scalp veins f. Sparse to absent scalp hair (alopecia, balding, hypotrichosis) g. Absent eyebrows and eyelashes h. Thin lips i. Circumoral cyanosis j. Protruded ears with absent earlobes k. “Beaked”, pinched nose with sculptured tip l. Micrognathia Teeth a. Anodontia/hypodontia, especially permanent teeth b. Delayed and incomplete dentition c. Discoloration (yellowish brownish) d. Crowded, rotated, displaced, overlapped, and maloccluded, especially the anterior teeth e. High incidence of caries f. Poor oral hygiene/gingivitis g. Irregularity in size and shape of the odontoblasts h. Delayed in ossification of the crown of the permanent teeth i. Narrow pulp chambers and root canals j. Reticular atrophy of pulp k. Calcification along the nerve fibers and the vascular walls l. Irregular width of predentin, secondary dentin and cemetum m. Osteoclastic resorption at apical portion n. Incompletely formation of roots of deciduous molars
8. Endocrine manifestations a. Incomplete sexual maturation b. Occasional hypoplastic nipples 9. Cardiovascular disease. a. Premature severe atherosclerosis b. Premature coronary artery disease c. Death from coronary artery disease frequent and may occur before 10 years of age d. Angina pectoris e. Myocardial infarction f. Congestive heart failure g. Epidural hematoma formation after a mild head injury possibly due to progressive atherosclerosis of intracranial vessels 10. Musculoskeletal abnormalities a. Generalized osteoporosis with pathologic fractures b. Marked delay in bone-healing after fractures c. Short/dystrophic clavicles d. Coxa valga e. Arthropathy f. Avascular necrosis of the femoral capital epiphysis g. Distal phalangeal osteolysis h. Delayed closure and persistently patent anterior fontanelle i. Joint contractures with contracted hands, elbows, and knees j. Dislocation of the hip k. Mild flexion of the knees resulting in a wide-gaited horse-riding stance and wide-based shuffling gait l. Short, tapered distal phalanges m. Thin limbs n. Muscle atrophy 11. Prognosis a. Absence of other factors associated with aging such as cancers, cataracts, and senility (not considered to be a phenocopy of normal aging) b. Death due to cardiovascular abnormalities in approximately 75% of patients c. Main cause of death due to cardiovascular complications i. Myocardial infarction ii. Congestive heart failure d. Other causes of death i. Marasmus ii. Inanition iii. Convulsions iv. Accidental head trauma due to thinned cortical bones e. Average life expectancy: 13 years (7–27 years)
DIAGNOSTIC INVESTIGATIONS 1. Histopathology a. Skin lesions indistinguishable from scleroderma i. Progressive hyalinization of dermal collagen (hyaline fibrosis) ii. Loss of subcutaneous tissue iii. Decreased sebaceous and sweat glands and hair follicles
PROGERIA
b. Bone lesions i. Osteoporosis ii. Osteolysis prominent in distal phalanges and clavicles iii. Skeletal dysplasia manifesting as coxa plana, coxa valga, and attenuated diaphyses with dystrophic metaphyses iv. Avascular hip necrosis v. Nonunion of fractures vi. Hip dislocations c. Cardiovascular lesions i. Severe, progressive atherosclerosis with widely variable age of clinical manifestation ii. Presence of atherosclerotic plaques in the large and small arteries iii. Calcifications in the mitral and aortic valves as well as aorta, coronary, cerebral, subclavian, and axillary arteries iv. Myocardial ischemia and infarction resulting from the coronary artery disease v. Diffuse interstitial myocardial fibrosis vi. Ventricular dilatation and hypertrophy d. Increased lipofuscin in the brain, adrenal cortex, kidney, testis, liver, and heart e. Gonads i. Aspermatogenesis in males ii. Presence of primordial follicles and corpora albicans in females with evidence of ovulation f. Arterial biopsy i. Premature atherosclerosis ii. Subintimal fibrosis 2. Radiography a. Widespread degenerative changes of bone in the first or second year of life b. Skull and facial bones i. Craniofacial disproportion ii. Patent fontanelles iii. Wormian bones with fractures iv. Facial bone hypoplasia v. Mandibular hypoplasia with dental crowding vi. Delayed and abnormal dentition c. Thorax i. Clavicular resorption ii. Rib tapering d. Long bones i. Indentations ii. Attenuated cortices iii. Widened metaphyses iv. Coxa valga v. Genu valgum e. Phalanges i. Distal resorption, one of the hallmarks of the disease ii. Radiolucent terminal phalanges (acro-osteolysis) f. Other i. Osteoporosis ii. Fish-mouthed vertebral bodies iii. Soft-tissue loss 3. Blood chemistry for hyperlipidemia a. Increased low-density lipoprotein levels
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b. Increased β-lipoprotein and pre-β-lipoprotein levels of high-density lipoprotein c. Increased serum cholesterol levels Metabolic work-up: inconsistent results a. Insulin resistance b. Abnormal collagen formation c. Increased metabolic rate: could be the cause of the failure to thrive seen in progeria d. Elevated growth hormone levels Urine test a. Excessive excretion of glycosaminoglycans b. Excessive excretion of hyaluronic acid (unreliable) Cultured skin fibroblasts a. Exhibit 76.1% DNA repair capacity compared to normal b. Decreased cell growth in culture c. Short telomeres d. Whether aging is the consequence of shortened telomeres with reduced cell replication, impaired telomerase activity, or the culmination of the effects of reactive oxygen species is uncertain Immunofluorescence of cultured fibroblasts with antibodies directed against lamin A demonstrating visible abnormalities of the nuclear membrane in many cells Molecular genetic analysis: polymerase chain reaction amplification of all of the exons of the LMNA gene, followed by direct sequencing
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. The lamin A gene mutations not found in patient’s parents suggesting that it occurs spontaneously in each patient and does not pass from parent to child ii. Recurrence risk very low, estimated at 1 in 500 with each subsequent pregnancy due to germ line mutations iii. Rare reports of siblings with progeria from consanguineous or nonconsanguineous marriages iv. Reported cases of monozygous twins with progeria b. Patient’s offspring: inability of patients to reproduce 2. Prenatal diagnosis: possible in families in which the diseasecausing mutation has been identified in a family member 3. Management a. Regular diet b. Combined nutritional treatment and growth hormone treatment i. Improve growth ii. Increase the levels of growth factors iii. Paradoxically result in a decreased BMR iv. Response decreases over time v. Do not prevent the progression of atherosclerotic disease c. Early and definitive surgical intervention for symptomatic oral pathosis i. Abnormal facial morphology ii. Dermal inelasticity
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iii. Potential anaesthetic difficulties iv. Progressive ongoing deterioration in the medical condition d. Orthopedic cares for musculoskeletal abnormalities i. Routine treatment of fractures ii. Conservative treatment for hip dislocation. Avoid surgery if possible iii. Routine physical therapy to maintain joint range of motion e. Management of cardiovascular complications i. Routine anticongestive therapy for congestive heart failure ii. Nitroglycerin for angina iii. Low doses of aspirin help delay heart attacks and strokes
REFERENCES Abdenur JE, Brown WT, Friedman S, et al.: Response to nutritional and growth hormone treatment in progeria. Metabolism 46:851–856, 1997. Ackerman J, Gilbert-Barness E: Hutchinson-Gilford progeria syndrome: a pathologic study. Pediatr Pathol Mol Med 21:1–13, 2002. Arai T, Yamashita M: An abnormal dentition in progeria. Paediatr Anaesth 12:287, 2002. Badame AJ: Progeria. Arch Dermatol 125:540–544, 1989. Baker PB, Baba N, Boesel CP: Cardiovascular abnormalities in progeria: case report and review of the literature. Arch Pathol Lab Med 105:384–386, 1981. Batstone MD, Macleod AW: Oral and maxillofacial surgical considerations for a case of Hutchinson-Gilford progeria. Int J Paediatr Dent 12:429–432, 2002. Beauregard S, Gilchrest BA: Syndromes of premature aging. Dermatol Clin 5:109–121, 1987. Brown WT, Gordon LB, Collins FS: Hutchinson-Gilford progeria syndrome. Gene Reviews, 2004. http://www.genetests.org Cao H, Hegele RA: LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090). J Hum Genet 48:271–274, 2003. Cooke JV: The rate of growth in progeria. J Pediatr 42:26–37, 1953 Danes BS: Progeria: a cell culture study on aging. J Clin Invest 50:2000–2003, 1971. De Sandre-Giovannoli A, Bernard R, Cau P, et al.: Lamin a truncation in Hutchinson-Gilford progeria. Science 300:20–55, 2003. DeBusk FL: The Hutchinson-Gilford progeria syndrome. Report of 4 cases and review of the literature. J Pediatr 80:697–724, 1972. Delahunt B, Stehbens WE, Gilbert-Barness E, et al.: Progeria kidney has abnormal mesangial collagen distribution. Pediatr Nephrol 15:279–285, 2000. Eriksson M, Brown WT, Gordon LB, et al.: Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293–298, 2003. Faivre L, Van Kien PK, Madinier-Chappat N, et al.: Can Hutchinson-Gilford progeria syndrome be a neonatal condition? Am J Med Genet 87:450–452; discussion 453–454, 1999. Fossel M: Human aging and progeria. J Pediatr Endocrinol Metab 13 Suppl 6:1477–1481, 2000. Fukuchi K, Katsuya T, Sugimoto K, et al.: LMNA mutation in a 45 year old Japanese subject with Hutchinson-Gilford progeria syndrome. J Med Genet 41:e67, 2004. Gabr M: Progeria Review of the literature with report of a case. Arc Pediatr 71:35–46, 1954. Gabr M, Hashem N, Hashem M, et al.: Progeria, a pathologic study. J Pediatr 57:70–77, 1960. Giannotti A, Digilio C, Mingarelli R, et al.: Progeroid syndrome with characteristic facial Appearance and hand anomalies in father and son. Am J Med Genet 73:227–229, 1997.
Gilford H: Progeria: a form of senilism. Practitioner 73:188–217, 1904. Gillar PJ, Kaye CI, McCourt JW: Progressive early dermatologic changes in Hutchinson-Gilford progeria syndrome. Pediatr Dermatol 8:199–206, 1991. Guarente L: Link between aging and the nucleolus. Genes Dev 11:2449–2455, 1997. Hamer L, Kaplan F, Fallon M: The musculoskeletal manifestations of progeria. A literature review. Orthopedics 11:763–769, 1988. Ishii T: Progeria: autopsy report of one case, with a review of pathologic findings reported in the literature. J Am Geriatr Soc 24:193–202, 1976. Jansen T, Romiti R: Progeria infantum (Hutchinson-Gilford syndrome) associated with scleroderma-like lesions and acro-osteolysis: a case report and brief review of the literature. Pediatr Dermatol 17:282–285, 2000. Jimbow K, Kobayashi H, Ishii M, et al.: Scar and keloid like lesions in progeria. An electron-microscopic and immunohistochemical study. Arch Dermatol 124:1261–1266, 1988. Khalifa MM: Hutchinson-Gilford progeria syndrome: report of a Libyan family and evidence of autosomal recessive inheritance. Clin Genet 35:125–132, 1989. Liessmann CD: Anaesthesia in a child with Hutchinson-Gilford progeria. Paediatr Anaesth 11:611–614, 2001. Luengo WD, Martinez AR, Lopez RO, et al.: Del(1)(q23) in a patient with Hutchinson-Gilford progeria. Am J Med Genet 113:298–301, 2002. Makous N, Friedman S, Yakovac W, et al.: Cardiovascular manifestations in progeria. Report of clinical and pathologic findings in a patient with severe arteriosclerotic heart disease and aortic stenosis. Am Heart J 64:334–346, 1962. Miki T, Morishima AK, Nakura J: The genes responsible for human Progeroid syndromes. Intern Med 39:327–328, 2000. Moen C: Orthopaedic aspects of progeria. J Bone Joint Surg Am 64:542–546, 1982. Monu JU, Benka-Coker LB, Fatunde Y: Hutchinson-Gilford progeria syndrome in siblings. Report of three new cases. Skeletal Radiol 19:585–590, 1990. Mounkes LC, Kozlov S, Hernandez L, et al.: A Progeroid syndrome in mice is caused by defects in A-type lamins. Nature 423:298–301, 2003. Nguyen NH, Mayhew JF: Anaesthesia for a child with progeria. Paediatr Anaesth 11:370–371, 2001. O’Brien ME, Weiss AS: A novel β(1–4) galactosyltransferase gene silent mutation (594C>T) associated with Hutchinson-Gilford progeria. Hum Mutat 17:355, 2001. Ozonoff MB, Clemett AR: Progressive osteolysis in progeria. Am J Roentgenol Radium Ther Nucl Med 100:75–79, 1967. Park WY, Hwang CI, Kang MJ, et al.: Gene profile of replicative senescence is different from progeria or elderly donor. Biochem Biophys Res Commun 282:934–939, 2001. Parkash H, Sidhu SS, Raghavan R: Hutchinson-Gilford progeria: familial occurrence. Am J Med Genet 36:431–433, 1990. Reichel W, Garcia-Bunuel R: Pathologic findings in progeria: myocardial fibrosis and lipofuscin pigment. Am J Clin Pathol 53:243–253, 1970. Rodríguez JI, Péez-Alonso P, Funes R, et al.: Lethal neonatal HutchinsonGilford progeria syndrome. Am J Med Genet 82:242–248, 1999. Rodriguez JI, Perez-Alonso P: Diagnosis of progeria syndrome is the only one possible. Am J Med Genet 87:453–454, 1999. Rosenbloom AL, Kappy MS, DeBusk FL, et al.: Progeria: insulin resistance and hyperglycemia. J Pediatr 102:400–402, 1983. Runge P, Asnis MS, Brumley GW, et al.: Hutchinson-Gilford progeria syndrome. South Med J 71:877–879, 1978. Sarkar PK, Shinton RA: Hutchinson-Guilford progeria syndrome. Postgrad Med J 77:312–317, 2001. Shiraishi I, Hayashi S, Hirai E, et al.: Fatal pulmonary hypertension associated with an atypical case of Hutchinson-Gilford progeria. Pediatr Cardiol 22:530–533, 2001. Talbot NB, Butler AM, Pratt EL, et al.: Progeria. Clinical, metabolic and pathologic studies on a patient. Am J Dis Child 69:267–279, 1945 Thomson J, Forfar JO: Progeria report of a case and review of the literature. Arch Dis Child 25:224–234, 1950. Yu QX, Zeng LH: Progeria: report of a case and review of the literature. J Oral Pathol Med 20:86–88, 1991.
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Fig. 1. A boy with progeria showing short stature, senile appearance, small face in comparison with large cranial vault (craniofacial disproportion), alopecia with prominent scalp veins, absent eyelashes and eyebrows, prominent eyes, beaklike nose, mandibular hypoplasia, absent earlobes, contracted hands, elbows, and knees, short tapered terminal phalanges, enlarged joints, and dry brittle hypoplastic nails.
Prune Belly Syndrome 2. Pathogenesis: abdominal wall hypoplasia as a nonspecific lesion resulting from fetal abdominal distension of various causes 3. Terminologies a. Prune belly: a descriptive term for a wrinkled and flaccid abdominal wall secondary to stretched skin, soft tissues, and muscles of the abdomen b. Prune-belly syndrome generally used to indicate the condition having prune belly, cryptorchidism, and abnormalities of the urinary tract 4. Causes of urine flow impairment/obstruction a. Renal causes i. Pelvi-ureteric junction anomaly ii. Vesico-ureteric junction anomaly iii. Posterior urethral valves iv. Duplex systems v. Ureterocele/ectopic ureter vi. Urethral atresia vii. Cloacal anomaly viii. Vesico-ureteric reflux ix. Megaureter x. Megacystis microcolon xi. Hypoperistalsis syndrome b. Extrarenal causes i. Sacrococcygeal teratoma ii. Hydrometacolpos iii. Other pelvic masses
In 1895, Parker described the congenital triad of deficient abdominal musculature, cryptorchidism, and urinary tract abnormalities. Subsequently, the term “prune-belly syndrome” was coined for this condition based on the characteristic wrinkled appearance of the abdomen. The incidence of the syndrome is estimated to be 1 in 35,000 to 1 in 50,000 live births.
GENETICS/BASIC DEFECTS 1. Etiologies a. Questionable genetic inheritance i. Questionable autosomal dominant inheritance ii. Autosomal recessive inheritance suggested by some authors b. Fetal abdominal distension caused by urinary tract obstruction i. The most common cause of prune-belly syndrome ii. Urethral obstruction causing dilatation of the fetal bladder and upper tracts thereby attenuating the abdominal musculature iii. Spontaneous relief of the urethral obstruction in some cases prenatally decompresses the abdomen producing the shriveled, prune-like appearance of the baby’s abdomen iv. Persistent urethral obstruction causing huge distention of the urinary bladder, bilateral hydronephrosis and hydroureter complicated by oligohydramnios in more severe cases c. Fetal ascites from whatever cause: abdominal decompression during intrauterine life leading to prune belly appearance of the abdomen d. Prostatic hypoplasia resulting in a functional urethral obstruction leading to development of the prune-belly syndrome e. Primary mesodermal defect simultaneously affecting the formation of abdominal musculature and abnormalities in the lower urinary tract f. Rare association of chromosome abnormalities i. Trisomy 13 ii. Trisomy 18 iii. Turner syndrome with fetal ascites (pathogenetic mechanism thought to involve abdominal distention by ascites rather than by urinary obstruction) iv. Ring X chromosome lacking XIST v. Cat-eye syndrome vi. Rarely with trisomy 21 vii. Mosaic unbalanced chromosome constitution of chromosome 16 viii. Presence of a small additional chromosome fragment ix. Interstitial deletion of chromosome 1 [del(1) (q25q32)]
CLINICAL FEATURES
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1. Broad spectrum in severity 2. Nearly 95% of cases occurring in males 3. Abdomen a. Partial or complete absence of the abdominal musculature b. Thin/lax protruding abdominal wall c. Wrinkled abdominal skin d. Visible intra-abdominal intestinal patterns through thin abdominal wall 4. Genitourinary anomalies a. Bilateral cryptorchidism in males b. Urethral obstruction c. Dilated/hypertrophic bladder d. Dilated urethra, particularly the prostatic urethra e. Dilated/tortuous ureters f. Renal dysplasia/hypoplasia with cystic changes g. Hydronephrosis h. Absence or hypoplasia of the prostate i. Ventral body wall defects i. Cloacal exstrophy ii. Bladder exstrophy iii. Hypo/epispadias
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j. Potter sequence i. Oligohydramnios ii. Potter face iii. Pulmonary hypoplasia iv. Other deformations 5. Secondary malformations a. Gastrointestinal obstruction i. Malrotation ii. Atresia iii. Stenosis iv. Volvulus v. Splenic torsion vi. Imperforate anus vii. Anorectal agenesis b. Limb and other skeletal abnormalities believed to be the direct result of oligohydramnios with resultant fetal crowding i. Talipes equinovarus ii. Metatarsus adductus iii. Vertical talus iv. Hip dislocation v. Arthrogryposis vi. Pectus excavatum/carinatum vii. Congenital muscular torticollis viii. Infantile scoliosis ix. Severe leg maldevelopment a) Generalized hypoplasia b) Complete absence c) Terminal defects c. Cardiac malformations i. Tetralogy of Fallot ii. Ventriculoseptal defect d. Cleft lip e. Spina bifida f. Association with diverse chromosome syndromes i. Trisomy 13 ii. Trisomy 18 iii. Turner syndrome iv. Cat-eye syndrome v. Trisomy 21 vi. Others 6. Prognosis a. High mortality although compatible with long-term survival i. Stillbirth or death by one moth of age in 20% of cases ii. Death by the second year for additional 30% of cases b. Causes of death i. Renal failure secondary to renal dysplasia present at birth ii. Pulmonary complications including lung hypoplasia iii. Infection associated with urinary stasis or operative interventions
DIAGNOSTIC INVESTIGATIONS 1. Renal and bladder ultrasound 2. Contrast voiding cystourethrogram 3. Radiography
a. Hypoplastic lungs with flared lower ribs secondary to the distended abdomen b. Diffusely distended flanks c. Dilated/dysplastic calyces of the kidneys d. Markedly dilated/tortuous ureters e. Vertical and trabeculated bladder f. A wide and long posterior urethra g. Cryptorchidism 4. Histology of the abdominal wall a. Muscle atrophy (degeneration of already formed muscle), not of primitive muscle b. The finding supports the theory that the abdominal muscle hypoplasia is a nonspecific lesion, resulting from fetal abdominal distension of various causes 5. Chromosome analysis for multiple congenital anomalies
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless in autosomal recessive inheritance (which is still unclear) b. Patient’s offspring: not increased 2. Prenatal diagnosis by ultrasonography a. Signs of fetal abdominal laxity (characteristic abdominal appearance) associated with fetal urinary tract abnormalities i. Amniotic fluid wave produced by fetal movement ii. Sinusoidal undulation of the fetal anterior abdominal wall produced by tapping the maternal abdomen b. A distended bladder (megacystis) and ureters c. Cryptorchidism d. Oligohydramnios e. Fetal ascites f. Lung hypoplasia g. Associated anomalies i. Other renal anomalies (25%) ii. Extra-renal abnormalities (12%) a) Anorectal anomalies b) VATER syndrome c) Esophageal atresia d) Pattern compatible to specific chromosomal abnormality 3. Management a. Orchidopexy for cryptorchidism b. Treatment of vesicoureteral dysfunction i. Temporary diversion ii. Ureteral reconstruction c. Treatment of vesicourethral dysfunction i. Reduction cystoplasty ii. Internal urethrotomy iii. Megalourethra repair d. Abdominal wall reconstruction e. Vesico-amniotic shunt placement for suspected prenatal obstructive uropathy: remains controversial
REFERENCES Amacker EA, Grass FS, Hickey DE, et al.: An association of prune belly anomaly with trisomy 21. Am J Med Genet 23:919–923, 1986. Beckman H, Rehder H, Rauskolb R: Prune belly sequence associated with trisomy 13. Am J Med Genet 19:603–604, 1984.
PRUNE BELLY SYNDROME Bosman G, Reuss A, Nijman JM, et al.: Prenatal diagnosis, management and outcome of fetal uretero-pelvic junction obstruction. Ultrasound Med Biol 17:117–120, 1991. Burton BK, Dillerd RG: Prune belly syndrome: Observation supporting the hypothesis of abdominal over distention. Am J Med Genet 17:669–672, 1984. Christopher CR, Spinelli A, Severt D: Ultrasonic diagnosis of prune-belly syndrome. Obstet Gynecol 59:391–394, 1982. Cooperberg PL, Romalis G, Wright V: Megacystis (prune-belly syndrome): sonographic demonstration in utero. J Can Assoc Radiol 30:120–121, 1979. Drake DP, Stevens P, Eckstein HB: Hydronephrosis secondary to uretero-pelvic obstruction in children: a review of 14 years’ experience. J Urol 119:649–651, 1978. Eagle JF, Barret GS: Congenital deficiency of abdominal musculature with associated genitourinary anomalies: A syndrome. Report of 9 cases. Pediatrics 6:721–736, 1950. Freedman AL, Bukowski TP, Smith CA, et al.: Fetal therapy for obstructive uropathy: specific outcomes diagnosis. J Urol 156:720–724, 1996. Frydman M, Magenis RE, Mohandas TK, et al.: Chromosome abnormalities in infants with prune belly anomaly: Association with trisomy 18. Am J Med Genet 15:145–148, 1983. Genest DR, Driscoll SG, Bieber FR: Complexities of limb anomalies: the lower extremity in the “prune belly” phenotype. Teratology 44:365–371, 1991. Green NE, Lowery ER, Thomas R: Orthopaedic aspects of prune belly syndrome. J Pediatr Orthop 13:496–501, 1993. Harley LM, Chen Y, Rattner WH: Prune belly syndrome. J Urol 108:174–176, 1972. Ives EJ: The abdominal muscle deficiency triad syndrome-experience with ten cases. Birth Defects Original Article Series 10:127–135, 1974. Lattimer JK: Congenital deficiency of abdominal musculature and associated genitourinary anomalies. J Urol 79:343–352, 1958. Leeners B, Sauer I, Schefels J, et al.: Prune-belly syndrome: therapeutic options including in utero placement of a vesicoamniotic shunt. J Clin Ultrasound 28:500–507, 2000. Lubinsky M, Doyle K, Trunca C: The association of “prune-belly” with Turner’s syndrome. Am J Dis Child 134:1171–1172, 1980. Moerman P, Fryns JP, Goddeeris P: Prune belly syndrome, a secondary urethral functional obstruction due to prostatic hypoplasia. J Genet Hum 32:141–143, 1984.
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Moerman P, Fryns J-P, Goddeeris P, et al.: pathogenesis of the prune-belly syndrome: a functional urethral obstruction caused by prostatic hypoplasia. Pediatrics 73:470–475, 1984. Monie IW, Monie BJ: Prune belly syndrome and fetal ascites. Teratology 19:111–117, 1979. Mouriquand PDE, Whitten M, Pracros J-P: Pathophysiology, diagnosis and management of prenatal upper tract dilatation. Prenatal Diagn 21:942–951, 2001. Nunn IN, Stephens FD: The triad syndrome: A composite anomaly of the abdominal wall, urinary system, and testes. J Urol 86:782–784, 1961. Pagon RA, Smith DW, Shepard TH: Urethral obstruction malformation complex: a cause of abdominal muscle deficiency and the “prune belly”. J Pediatr 94:900–906, 1979. Parker RW: Absence of abdominal muscles in an infant-extensive degenerating nevus of bladder-gastric ulcer treated by laparotomy. Lancet 1:1252–1254, 1895. Osler W: Congenital absence of abdominal muscle with distended and hypertrophied urinary bladder. Bull Johns Hopkins Hosp 12:331, 1901. Pramanik AK, Altshuler G, Light IJ, et al.: Prune-belly syndrome associated with Potter (renal nonfunction) syndrome. Am J Dis Child 131:672–674, 1977. Qazi QH, Kaufman S, Sher J, et al.: Chromosomal anomaly in prune belly syndrome. Hum Genet 20:265–267, 1978. Rogers LW, Ostrow PT: The prune belly syndrome. Report of 20 cases and description of a lethal variant. J Pediatr 83:786–793, 1973. Scarbrough PR, Files B, Carroll AJ, et al.: Interstitial deletion of chromosome 1 [del(1)(q25q32)] in an infant with prune belly sequence. Prenat Diagn 8:169–174, 1988. Shimada K, Hosokawa S, Tohda A, et al.: Histology of the fetal prune belly syndrome with reference to the efficacy of prenatal decompression. Int J Urol 7:161–166, 2000. Stevenson RE, Schroer RJ, Collins J, et al.: Fetal ascites: the underlying cause for prune belly. Proc Greenwood Genet Ctr 6:16–21, 1987. Straub E ,Spranger J: Etiology and pathogenesis of the prune belly syndrome. Kidney Int 20:695–699, 1981. Tuch BA, Smith TK: Prune-belly syndrome. A report of twelve cases and review of the literature. J Bone Joint Surg 60A:109–111, 1978 Welch KJ, Kearney GP: Abdominal musculature deficiency syndrome: prune belly. J Urol 111:693–700, 1974. Woodhouse CR, Ransley PG, Innes-Williams D: Prune belly syndrome— report of 47 cases. Arch Dis Child 57:856–859, 1982.
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Fig. 1. A premature male neonate with prune-belly syndrome due to urethral atresia. He lived for 2 hours. There was a massive dilation and hypertrophy of the urinary bladder. Mild hydronephrosis was seen in one kidney but the second kidney was hypoplastic. The anterior abdominal wall showed muscle deficiency. Additional anomalies included imperforate anus with vesicorectal fistula, secundum type atrial septal defect of the heart, mild coarctation of the aorta, and bilateral talipes equinovarus.
Fig. 2. A male fetus with prune belly syndrome due to severe urethral stenosis. There were marked dilatation of the proximal urethra, bladder and bilateral ureters. Mild hydronephrosis and cystic renal dysplasia were seen in both kidneys. There were no other anomalies.
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Fig. 3. An infant with prune belly syndrome showing thin, flaccid abdominal wall through which intra-abdominal intestinal patterns are visible.
Fig. 5. A neonate with prune belly syndrome showing wrinkling abdominal wall due to multicystic kidneys. The infant also has duplicated great toes.
Fig. 4. A postmortem infant with prune belly syndrome showing flaccid and wrinkling abdominal wall with visible intestinal patterns.
Pseudoachondroplasia d. Chronic compression myelopathy secondary to habitual atlantoaxial dislocation 7. Extremities a. Bowing of the long bones b. Deformities of the lower limbs i. Secondary to ligamentous laxity ii. Ranging from genu varum (bowed legs), genu valgum (knock knees), and genu recurvatum iii. A “wind-swept deformity” (bow-leg on one side and knock-knee on the other side) c. Markedly shortened hands (without trident configuration) and feet d. Ulnar deviation of the wrist e. Flexion contractures of the elbow and knees f. Brachydactyly g. “Telescoping” fingers 8. Joint a. Lax ligament b. Premature osteoarthritis c. Contractures of the hips 9. Prognosis a. Good survival b. Early arthrosis, notably in the hip and knee joints c. Possible myelopathy secondary to atlantoaxial dislocations
Pseudoachondroplasia is a type of short-limbed dwarfism, deriving its name from phenotypic similarity to achondroplasia. It is characterized by normal facies, short-limbed dwarfism, joint laxity, and epiphyseal and metaphyseal abnormalities in the growing child.
GENETICS/BASIC DEFECTS 1. Inheritance a. Pseudoachondroplasia: autosomal dominant with complete penetrance b. Pseudoachondroplasia types II: autosomal recessive (small percentage of cases from parental gonadal mosaicism) 2. Cause a. Mutations in the gene encoding cartilage oligomeric matrix protein (COMP) on the centromeric region of 19p (19p13.1-p12) i. Deletions: Approximately 40–50% of cases of pseudoachondroplasia have deletion mutations in exon 13 of the COMP gene. ii. Specific base substitutions iii. Duplications b. Allelic to multiple epiphyseal dysplasia, which is also caused by COMP mutations c. All mutations associated with pseudoachondroplasia and multiple epiphyseal dysplasia: found in exons encoding the type III repeat region or C-terminal domain of COMP d. Mutations in extracellular matrix proteins, COMP, types II and IX collagens, and matrilin-3 i. Producing a spectrum of mild to severe chondrodysplasias characterized by epiphyseal and vertebral abnormalities ii. Disruption of protein processing and excessive accumulation of some of these proteins in the rough endoplasmic reticulum that appears to compromise cellular function
DIAGNOSTIC INVESTIGATIONS
CLINICAL FEATURES 1. 2. 3. 4.
Normal at birth Normal intelligence Normal craniofacial appearance Waddling gait and diminished linear growth at about 2 years of age 5. Rhizomelic short-limbed dwarfism a. Body proportion resembling achondroplasia b. Usually detectable at age 2–4 years 6. Spine a. Accentuated lumbar lordosis b. Scoliosis c. Kyphosis 826
1. Radiography a. Tubular bones i. Irregularities and fragmentations of the developing epiphyses ii. Shortened tubular bones iii. Brachydactyly iv. Delayed epiphyseal ossification (delayed bone age) v. Small phalangeal epiphyses (miniepiphyses) vi. Small, irregular carpal bones vii. Irregular, widened (frayed), mushroomed metaphyses viii. Coxa vara b. Pelvis i. Delayed ossification of the capital femoral epiphyses, which become flattened and small when ossified ii. Commonly observed sclerosis and irregularity of the acetabular roof c. Vertebrae i. Characteristic anterior beaking or tonguing (in lateral view of the lumbar spines) a) Due to delayed ossification of the annular epiphyses b) Vertebrae becoming more normal in appearance after puberty
PSEUDOACHONDROPLASIA
i. Characteristic platyspondyly in childhood ii. Kyphoscoliosis iii. Lumbar lordosis iv. Odontoid hypoplasia v. Atlantoaxial dislocations d. Ribs: spatulate 2. Histology of growth plates a. Irregular arrangement of chondrocytes without column formation b. Irregular provisional calcification c. Intracytoplasmic inclusions in chondrocytes 3. EM of chondrocytes a. Showing distinctive giant rough endoplasmic reticulum cisternae filled with punctuate material b. The material composed of alternating electron-lucent and electron-dense layers in a unique lamellar appearance 4. Molecular diagnosis a. Techniques i. Mutation screening in exons of the COMP gene using SSCP and sequence analysis ii. COMP mutation screening in RNA isolated from skin fibroblast cell line b. Particularly useful in adult patients where radiological diagnosis can be difficult
GENETIC COUNSELING 1. Recurrence risk a. Autosomal dominant inheritance i. Patient’s sibs a) 50% if one of the parent is affected b) Not increased if parents are normal ii. Patient’s offspring: 50% b. Autosomal recessive inheritance i. Patient’s sibs a) 25% for true autosomal recessive inheritance b) Slightly increased risk in case of parental gonadal mosaicism (depending on the degree of mosaicism) ii. Patient’s offspring: not increased unless the spouse is also carrying the gene 2. Prenatal diagnosis a. Prenatal ultrasonography unlikely to detect the skeletal changes, which will not manifest until about 2 years of age b. Prenatal diagnosis possible in the family at risk and the disease-causing COMP mutation has been characterized in an affected individual 3. Management a. Supportive b. Surgical correction of the leg deformities c. Hip replacement for severe hip contractures d. Cervical stabilization procedures for cervical cord compression with progressive neurologic symptoms and signs
REFERENCES Beck M, Lingnau K, Spranger J: Newly synthesized proteoglycans in pseudoachondroplasia. Bone 9:367–370, 1988. Briggs MD, Hoffman SMG, King LM, et al.: Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nature Genet 10:330–336, 1995.
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Briggs MD, Rasmussen IM, Weber JL, et al.: Genetic linkage of mild pseudoachondroplasia (PSACH) to markers in the pericentromeric region of chromosome 19. Genomics 18:656–660, 1993. Briggs MD, Mortier GR, Cole WG, et al.: Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia-multiple epiphyseal dysplasia disease spectrum. Am J Hum Genet 62:311–319, 1998. Briggs MD, Chapman KL: Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations. Hum Mutat 19:465–478, 2002. Byers PH: Molecular heterogeneity in chondrodysplasias. (Editorial) Am J Hum Genet 45:1–4, 1989. Cohn DH, Briggs MD, King LM, et al.: Mutations in the cartilage oligomeric matrix protein (COMP) gene in pseudoachondroplasia and multiple epiphyseal dysplasia. Ann N Y Acad Sci 785:188–194, 1996. Cooper RR, Ponseti IV, Maynard JA: Pseudoachondroplastic dwarfism. A rough-surfaced endoplasmic reticulum storage disorder. J Bone Joint Surg 55A:475–484, 1973. Cranley RE, Williams BR, Kopits SE, et al.: Pseudoachondroplastic dysplasia: five cases representing clinical, roentgenographic and histologic heterogeneity. Birth Defects Original Article Series 11(6):205–215, 1975. Deere M, Sanford T, Ferguson HL, et al.: Identification of twelve mutations in cartilage oligomeric matrix protein (COMP) in patients with pseudoachondroplasia. Am J Med Genet 80:510–513, 1998. Dennis NR, Renton P: The severe recessive form of pseudoachondroplasia. Pediatr Radiol 3:169–175, 1975. Ferguson Hl, Deere M, Evans R, et al.: Mosaicism in pseudoachondroplasia. Am J Med Genet 70:287–201, 1997. Hall JG: Pseudoachondroplasia. Birth Defects Orig Artic Ser 11:187–202, 1975. Hall JG, Dorst JP: Pseudoachondroplastic SED, recessive Maroteaux-Lamy type. Birth Defects Orig Art Ser V(4):254–259, 1969. Hall JG, Dorst JP, Rotta J, McKusick VA: Gonadal mosaicism in pseudoachondroplasia. Am J Med Genet 28:143–151, 1987. Hecht JT, Nelson LD, Crowder E et al.: Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia. Nature Genet 10:325–329, 1995. Heselson NG, Cremin BJ, Beighton P: Pseudoachondroplasia: a report of 13 cases. Brit J Radiol 59:473–482, 1977. Ikegawa S, Ohashi H, Nishimura G, et al.: Novel and recurrent COMP (cartilage oligomeric matrix protein) mutations in pseudoachondroplasia and multiple metaphyseal dysplasia. Hum Genet 103:633–638, 1998. Kopits SE, Lindstrom JA, McKusick VA: Pseudoachondroplastic dysplasia: pathodynamics and management. In: Bergsma D (ed.): Skeletal Dysplasias. Amsterdam: Excerpta Medica (pub.) 1974, pp 341–| 352. Langer LO Jr, Schaefer GB, Wadsworth DT: Patient with double heterozygosity for achondroplasia and pseudoachondroplasia, with comments on these conditions and the relationship between pseudoachondroplasia and multiple epiphyseal dysplasia, Fairbank type. Am J Med Genet 47: 772–781, 1993. Maroteaux P, Stanescu R, Stanescu V, et al.: The mild form of pseudoachondroplasia. Eur J Pediatr 133:227–231, 1980. McKeand J, Rotta J, Hecht JT: Natural history study of pseudoachondroplasia. Am J Med Genet 63:406–410, 1996. Newman B, Donnah D, Briggs MD: Molecular diagnosis is important to confirm suspected pseudoachondroplasia. J Med Genet 37:64–65, 2000. Song HR, Lee KS, Li QW, et al.: Identification of cartilage oligomeric matrix protein (COMP) gene mutations in patients with pseudoachondroplasia and multiple epiphyseal dysplasia. J Hum Genet 48:222–225, 2003. Wynne-Davis R, Hall CM, Young ID: Pseudoachondroplasia: clinical diagnosis at different ages and comparison of autosomal dominant and recessive types: a review of 32 patients (26 kindreds). J Med Genet 23:425–434, 1986. Young ID, Moore JR: Severe pseudoachondroplasia with parental consanguinity. J Med Genet 22:150, 1985.
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Fig. 1. A girl with pseudoachondroplasia at 2 and half years (upper) with normal craniofacial appearance, mild short stature, and waddling gate and at 6 years (lowers) with short limbs, accentuated lumbar lordosis, and short stature.
Fig. 2. Radiographs of the spine show characteristic anterior beaking of the lumbar spine and mild scoliosis.
PSEUDOACHONDROPLASIA
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Fig. 3. Radiographs of the pelvis and lower extremities showing irregular, horizontal acetabular roof, delayed epiphyseal ossification, and wide mushroom-shape metaphyses. Fig. 5. Radiographs of the hands and feet show grossly disturbed metaphyseal and epiphyseal ossification, short and stubby tubular bones, somewhat widened metacarpals and metatarsals, and small and markedly irregular carpal and tarsal bones.
Fig. 4. Radiograph of the upper extremities showing markedly widened and defective metaphyseal and epiphyseal ossifications in the proximal humerus, distal radius and ulna.
R(18) Syndrome In 1962, Wang et al. reported the first observation of the ring chromosome 18.
GENETICS/BASIC DEFECTS 1. Caused by the presence of a ring chromosome 18 or mosaic ring chromosome 18 with a loss of 18p segment and a loss of 18q segment 2. Phenotypic variability depends on the extent of the deleted chromosome 8 segments 3. Rare occurrence of a ring chromosome 18 together with a duplication of a segment of chromosome 18 or with a marker chromosome
CLINICAL FEATURES 1. Clinical features of r(18) syndrome a. Growth and development i. Mental retardation ii. Hypotonia iii. Short stature b. Head/brain i. Microcephaly ii. Dolichocephaly iii. Holoprosencephaly iv. Cebocephaly v. Arhinencephaly c. Midface: flat d. Ears i. Asymmetric ii. Low-set iii. Atretic external ear canals iv. Prominent anti-helix e. Eyes i. Deep-set ii. Hypertelorism iii. Down slanting palpebral fissures iv. Epicanthal folds v. Nystagmus vi. Strabismus vii. Ptosis viii. Coloboma f. Nose i. Broad base ii. Depressed nasal bridge iii. Broad tip g. Mouth i. Micrognathia ii. Carp-like down-turned corners iii. Thin upper and lower lips iv. High/narrow palate v. Dental caries
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h. Neck: short i. Chest i. Pectus excavatum ii. Wide-spaced nipples j. Congenital heart defect i. PDA ii. PS iii. VSD iv. AS k. Abdomen i. Umbilical hernia ii. Inguinal hernia l. Genitourinary i. Male genitalia a) Cryptorchidism b) Hypoplastic scrotum c) Micropenis ii. Female genitalia: hypoplastic labia minora m. Musculoskeletal i. Spine: scoliosis ii. Hands a) Clinodactyly b) Camptodactyly c) Short fingers d) Long tapering fingers e) Proximally placed thumbs f) Single transverse palmar crease iii. Legs/feet a) Club feet (varus) b) Over-riding toes c) Long/broad toes d) Genu valgum n. Other features i. Hypothyroidism ii. Hypoparathyroidism iii. Growth hormone deficiency o. Atypical features i. Van der Woude syndrome ii. Insulin-dependent diabetes mellitus iii. Agammaglobulinemia 2. Most patients share the features of del(18q) syndrome, which are highly variable depending on the extent of the terminal or interstitial 18q deletion: a. Mental retardation b. Hypotonia c. Microcephaly d. Short stature e. Flat midface f. Carp-shaped mouth g. Prominent antihelix and antitragus h. Atretic/stenotic ear canals
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i. Proximally placed thumbs j. Long tapering digits k. Foot deformity l. Abnormal male genitalia 3. Some patients share the features of del(18p) syndrome, which are highly variable depending on the extent of the terminal or interstitial 18p deletion: a. Mental retardation b. Speech delay c. Hypotonia d. Short stature e. Midface defects including holoprosencephaly f. Ptosis of eyelids g. Small mandible h. Dental caries i. Short neck j. IgA deficiency 4. Some patients share the combined features of del(18p) syndrome and del(18q) syndrome
DIAGNOSTIC INVESTIGATIONS 1. Conventional cytogenetic studies a. Nonmosaic r(18) b. Mosaic r(18) 2. Molecular cytogenetic studies using fluorescence in situ hybridization (FISH) technique a. Ring chromosome positive for chromosome 18 centromeric probe b. Absence of 18q subtelomeric probe 3. Microdissection followed by FISH to determine the origin of the marker chromosome 4. Using a number of microsatellite markers to determine the parental origin and possible mode of formation of the r(18) 5. Low IgA
GENETIC COUNSELING 1. Recurrence risk a. Patient sibling: not increased in cases of de novo instances (majority of cases) b. Patient’s offspring i. Vertical transmission of ring chromosome 18 from a mother to her offspring reported ii. Mosaic monosomy 18 with familial ring chromosome 18 reported 2. Prenatal diagnosis by chromosome analysis from amniocentesis, CVS, and fetal blood 3. Management a. Mainly supportive b. Multidisciplinary team approach with physical, occupational, and speech therapies
c. Supportive treatment for chronic sinopulmonary infections associated with IgA deficiency d. Treat endocrine dysfunction, if present
REFERENCES Baumer A, Uzielli MLG, Guarducci S, et al.: Meiotic origin of two ring chromosomes 18 in a girl with developmental delay. Am J Med Genet 113:101–104, 2002. Christensen KR, et al. Ring chromosome 18 in mother and daughter. J Ment Defic Res 14:49–67, 1970. Cody JD, Ghidoni PD, DuPont BR, et al.: Congenital anomalies and anthropometry of 42 individuals with deletions of chromosome 18q. Am J Med Genet 85:455–462, 1999. De Grouchy J: The 18p-, 18q- and 18r-syndromes. Birth Defects Orig Artic Ser V(5):74–87, 1969. Donlan MA, Dolan CR: Ring chromosome 18 in a mother and son. J Med Genet 24:171–174, 1986. Eiben B, Unger M, Stoltenberg G, et al.: Prenatal diagnosis of monosomy 18 and ring chromosome 18 mosaicism. Prenat Diagn 12:945–950, 1992. Grouchy J de: The 18p-, 18q-, and 18r-syndromes. Birth Defects Original Article Series V(5):74–87, 1969. Jenderny J, Caliebe A, Beyer C, et al.: Transmission of a ring chromosome 18 from a mother with 46,XX/47,XX,+r(18) mosaicism to her daughter, resulting in a 46,XX,r(18) karyotype. J Med Genet 30:964–965, 1993. Karda SI, Wirth J, Mazurczak T, et al.: Clinical and molecular-cytogenetic studies in seven patients with ring chromosome 18. Am J Med Genet 101:226–239, 2001. Litzman J, Brysova V, Gaillyova R, et al.: Agammaglobulinaemia in a girl with a mosaic of ring 18 chromosome. J Paediatr Child Health 34:92–94, 1998. Los FJ, van den berg C, Braat PG, Ring chromosome 18 in a fetus with only facial anomalies. Am J Med Genet 66:216–220, 1996. Miller K, Pabst B, Ritter H, et al.: Chromosome 18 replaced by two ring chromosomes of chromosome 18 origin. Hum Genet 112:343–347, 2003. Schaub RL, Leach RJ, Cody JD: Reevaluation of frequencies of selected features in patients with the 18p syndrome. Am J Hum Genet 63 (Suppl A342): 1931, 1999. Stankiewicz P, Brozek I, Hélias-Rodzewicz Z, et al.: Clinical and molecularcytogenetic studies in seven patients with ring chromosome 18. Am J Med Genet 101:226–239, 2001. Stewart J, Go S, Ellis E, et al.: Absent IgA and deletions of chromosome 18. J Med Genet 7:11–19, 1970. Strathdee G, Zackai EH, Shapiro R, et al.: Analysis of clinical variation seen in patients with 18q terminal deletions. Am J Med Genet 59:476–483, 1995. Thies U, Bartels I, von Beust G, et al.: Prenatal diagnosis and fetopathological findings in a fetus with ring chromosome 18. Fetal Diagn Ther 13:315–320, 1998. Wertelecki W, Gerald PS: Clinical and chromosomal studies of the 18q- syndrome. J Pediatr 78:44–52, 1971. Wilson MG, Towner JW, Forsman I, et al.: Syndromes associated with deletion of the long arm of chromosome 18[del(18q)]. Am J Med Genet 3:155–174, 1979. Yardin C, Esclaire F, Terro F, et al.: First familial case of ring chromosome 18 and monosomy 18 mosaicism. Am J Med Genet 104:257–259, 2001. Zumel RM, Darnaude MT, Delicado A, et al.: The 18p-syndrome. Report of five cases. Ann Génét 32:160–163, 1989.
R(18) SYNDROME
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Fig. 2. Chromosome analysis of the patient showed 46,XY,r(18), illustrated by a G-banded karyotype, a partial karyotype with idiograms, and FISH with whole chromosome 18 painting probe.
Fig. 1. A 4-year-old boy with de novo r(18) syndrome showing growth deficiency (prenatal and postnatal), speech delay, hypertelorism, downward slanting of the palpebral fissures, strabismus, slightly lowset ears, mild pectus carinatum, clinodactyly of the 5th fingers, and syndactyly of toes. He also has IgA deficiency.
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Fig. 4. A boy with del(18q) showing hypotonia, ptosis of the eyelids, and carp-like mouth.
Fig. 3. A girl with del(18p) showing hypotonia, ptosis of the eyelids, and small mandible. The G-banded karyotype shows deletion of the short arm of a chromosome 18.
Retinoid Embryopathy 2. Teratogenicity a. Isotretinoin i. Teratogenic during the first trimester fetal exposure within the therapeutic dose range ii. Has a short elimination half-life of about 20 hours iii. Recommended contraception period after cessation of therapy: one month iv. Risk of teratogenicity for isotretinoin a) Exposure within first trimester: about 28% b) Pregnancy occurring within one month after cessation of treatment: about 4% c) Pregnancy occurring after 1 month: The risk of fetal malformations returns to baseline (isotretinoin is no longer detectable in the maternal circulation) b. Etretinate i. Readily absorbed into adipose tissue and slowly released from it ii. Has a long elimination half-life (≥120 days) iii. Recommended contraception period after therapy: 2 years iv. Risk for teratogenicity for exposure to etretinate a) During pregnancy: about 26% b) Within 2 years of treatment cessation: about 2% c. Acitretin i. A shorter elimination half-life of 50 hours ii. Recommendation of a two-year contraception period after therapy for acitretin, as in some women there is conversion of acitretin to etretinate during therapy
Oral retinoids, isotretinoin (Accutane) and etretinate, uniquely effective in the treatment for severe cystic and keratinization disorders, are potent human teratogens.
GENETICS/BASIC DEFECTS 1. Synthetic retinoids (isotretinoin, etretinate, acitretin) a. Closely resemble naturally occurring vitamin A, which is essential for the maintenance of visual and reproductive function and for proliferation and differentiation of epithelial tissues b. Isotretinoin and etretinate i. Released in the United States and Europe in 1982 ii. Isotretinoin: uniquely effective in severe cystic acne iii. Etretinate (and acitretin): uniquely effective in severe psoriasis and other keratinization disorders which proved recalcitrant to all other therapies, account for their availability on prescription despite their teratogenicity c. Acitretin released later to replace etretinate as it is more rapidly eliminated from the body d. Adverse reactions i. Commonly reported adverse reactions: largely dose-related, of early onset, and reversible on discontinuation a) Dryness of the lips, mouth, and eyes b) Hair loss c) Pruitis ii. Less common and more severe, idiosyncratic reactions a) Altered vision b) Headache c) Joint and muscle pain d) Abnormally raised serum transaminases levels e) Serum lipid changes f) Increased serum triglyceriode and cholesterol levels g) An increase in low density/high density lipoprotein ratio iii. Rare reactions a) Mental depression b) Severe hepatitis c) Diffuse hyperostosis of the spine d) Benign intracranial hypertension e. Teratogenicity of retinoids i. Foreshadowed by animal studies with strong warnings against exposure during pregnancy ii. Believed to interfere with the activity and migration of cranial neural crest cells during development and thus cause craniofacial, thymic conotruncal heart and CNS malformations iii. Intellectual deficits
CLINICAL FEATURES
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1. Isotretinoin embryopathy a. Craniofacial abnormalities i. Microtia/anotia ii. Agenesis or marked stenosis of external ear canals iii. Hypertelorism iv. Depressed nasal bridge v. Micrognathia vi. Cleft palate vii. Low-set ears b. Central nervous system abnormalities i. Hydrocephalus ii. Dandy-Walker malformation iii. Microcephaly iv. Microophthalmia v. Cerebellar defects a) Hypoplasia b) Microdysgenesis vi. Cortical defects vii. Cortical blindness
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viii. Facial nerve palsy ix. Optic nerve hypoplasia x. Retinal defects xi. Spina bifida xii. Mental retardation c. Cardiovascular abnormalities i. Conotruncal malformations a) Transposition of the great vessels b) Tetralogy of Fallot c) Truncus arteriosus d) Double-outlet right ventricle e) Ventricular septal defect f) Atrial septal defect ii. Coarctation of the aorta iii. Interrupted aortic arch iv. Hypoplastic left ventricle v. Retroesophageal right subclavian artery d. Other abnormalities i. Thymic abnormalities a) Ectopia b) Hypoplasia c) Aplasia ii. Nystagmus iii. Decreased muscle tone iv. Hepatic abnormality v. Hydroureter vi. Simian crease vii. Limb reduction viii. An increased risk of spontaneous abortions (about 15%) but no long-term effects on fertility 2. Retinate embryopathy a. Craniofacial abnormalities i. Microtia ii. Micrognathia iii. Low set ears b. Central nervous system abnormalities i. Menigomyelocele ii. Anophthalmia iii. Brain defect c. Skeletal abnormalities i. Syndactyly ii. Shortened or absent digits iii. Club foot iv. Multiple synostosis
DIAGNOSTIC INVESTIGATIONS 1. 2. 3. 4.
Sonogram/CT/MRI of the brain for CNS anomalies Radiography/CT for auditory canal malformations Echocardiography for congenital heart defects Audiological assessment by brainstem auditory evoked response 5. Visual and somatosensory evoked potential to detect cortical response 6. Electroencephalography
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless the mother exposes to retinoid again during the pregnancy
b. Patient’s offspring: not increased unless exposure to retinoid during pregnancy 2. Prenatal diagnosis a. History of maternal exposure to retinoid b. Prenatal ultrasonography i. Craniofacial anomalies a) Microtia/anotia b) Anophthalmia/microphthalmia c) Other facial abnormalities ii. CNS anomalies a) Microcephaly b) Dandy-Walker malformation c) Hydrocephalus iii. Cardiac defects by fetal echocardiography iv. Skeletal abnormalities 3. Management a. Pregnancy Prevention Program, developed by the manufacturer and the US Food and Drug Administration since 1988, to prevent fetal exposure to the drug Accutane i. Distribute printed material to prescribing physicians to be used in educating their female patients about the serious teratogenic effects ii. Instruct physicians to delay therapy until the second or third day of the patient’s next normal menstrual period iii. Stress to patients the importance of using 2 forms of contraception concurrently iv. A consent form to be signed by female patients a) Acknowledging that they have been instructed through the program b) Aware of the need to use 2 forms of contraception during isotretinoin therapy c) Agree to undergo pregnancy testing before, during and after the therapy b. Adhere to strict prescription guidelines, but exposure during pregnancy still occurs. The most common reasons for unwanted or mistimed pregnancies with isotretinoin therapy are: i. Unsuccessful attempts at abstinence ii. Use of ineffective contraception iii. Inconsistent use of contraception iv. Unexpected sexual activity v. Contraceptive failure c. Surgical shunting for hydrocephalus d. Surgical repair of congenital heart defects e. Surgical reconstruction of the external ear canal and middle ear f. Orthopedic management of limb reduction g. Multi-disciplinary approach to multiple handicapped conditions
REFERENCES Atanackovic G, Koren G: Fetal exposure to oral isotretinoin: failure to comply with the Pregnancy Prevention Program. Canad Med Assoc J 160:1719–1720, 1999. Atanackovic G, Koren G: Young women taking isotretinoin still conceive. Role of physicians in preventing disaster. Can Fam Physician 45:289–292, 1999. Braun JT, Franciosi RA, Mastri AR, et al.: Isotretinoin dysmorphic syndrome. Lancet 1:506–507, 1984.
RETINOID EMBRYOPATHY Brinker A, Trontell A, Beitz J: Pregnancy and pregnancy rates in association with isotretinoin (Accutane). J Am Acad Dermatol 47:798–799, 2002. Chan A, Hanna M, Abbott M, et al.: Oral retinoids and pregnancy. Med J Aust 165:164–167, 1996. Dai WS, Hsu MA, Itri LM: Safety of pregnancy after discontinuation of isotretinoin. Arch Dermatol 125:362–365, 1989. Dai WS, LaBraico JM, Stern RS: Epidemiology of isotretinoin exposure during pregnancy. J Am Acad Dermatol 26:599–606, 1992. de la Cruz E, Sun S, Vangvanichyakorn K, et al.: Multiple congenital malformations associated with maternal isotretinoin therapy. Pediatrics 74:428–430, 1984. Ellis CN, Krach KJ: Uses and complications of isotretinoin therapy. J Am Acad Dermatol 45:S150–S157, 2001. Fernhoff PM, Lammer EJ: Craniofacial features of isotretinoin embryopathy. J Pediatr 105:595–597, 1984. Hansen RC: Accutane (isotretinoin) revisited: severe birth defects from acne therapy. Ariz Med 42:363–365, 1985. Holmes SC, Bankowska U, Mackie RM: The prescription of isotretinoin to women: is every precaution taken? Br J Dermatol 138:450–455, 1998. Jahn AF, Ganti K: Major auricular malformations due to Accutane (isotretinoin). Laryngoscope 97:832–835, 1987. Jones KL, Adams J, Chambers CD, et al.: Isotretinoin and pregnancy. JAMA 285:2079–2081, 2001. Kassis I, Sunderji S, Abdul-Karim R: Isotretinoin (Accutane) and pregnancy. Teratology 32:145–146, 1985. Koren G, Pastuszak A: How to ensure fetal safety when mothers use isotretinoin (Accutane). Can Fam Physician 43:216–219, 1997. Lammer EJ, Schunior A, Hayes AM, et al.: Isotretinoin dose and teratogenicity. Lancet 2:503–504, 1988. Lancaster PA: Teratogenicity of isotretinoin. Lancet 2:1254–1255, 1988.
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Mitchell AA, Van Bennekom CM: Accutane and pregnancy. J Am Acad Dermatol 49:1201–1202, 2003. Mitchell AA, Van Bennekom CM, Louik C: A pregnancy-prevention program in women of childbearing age receiving isotretinoin. N Engl J Med 333:101–106, 1995. Nau H: Teratogenicity of isotretinoin revisited: species variation and the role of all-trans-retinoic acid. J Am Acad Dermatol 45:S183–S187, 2001. Pastuszak A, Koren G, Rieder MJ: Use of the Retinoid Pregnancy Prevention Program in Canada: patterns of contraception use in women treated with isotretinoin and etretinate. Reprod Toxicol 8:63–68, 1994. Perlman SE, Leach EE, Dominguez L, et al.: “Be smart, be safe, be sure”. The revised Pregnancy Prevention Program for women on isotretinoin. J Reprod Med 46:179–185, 2001. Pochi PE, Ceilley RI, Coskey RJ, et al.: Guidelines for prescribing isotretinoin (Accutane) in the treatment of female acne patients of childbearing potential. Acne Subgroup, Task Force on Standards of Care. J Am Acad Dermatol 19:920, 1988. Rappaport EB, Knapp M: Isotretinoin embryopathy-a continuing problem. J Clin Pharmacol 29:463–465, 1989. Rizzo R, Lammer EJ, Parano E, et al.: Limb reduction defects in humans associated with prenatal isotretinoin exposure. Teratology 44:599–604, 1991. Shear NH: Oral isotretinoin: prescribers beware. Canad Med Assoc J 160:1723–1724, 1999. Stashower ME: Pregnancy rates associated with isotretinoin (Accutane) and the FDA. J Am Acad Dermatol 49:1202–1203, 2003. Strauss JS, Cunningham WJ, Leyden JJ, et al.: Isotretinoin and teratogenicity. J Am Acad Dermatol 19:353–354, 1988. Strauss JS, Leyden JJ, Lucky AW, et al.: Safety of a new micronized formulation of isotretinoin in patients with severe recalcitrant nodular acne: A randomized trial comparing micronized isotretinoin with standard isotretinoin. J Am Acad Dermatol 45:196–207, 2001.
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Fig. 1. An infant with isotretinoin embryopathy. The mother took accutane in the first trimester. Prenatal ultrasound examinations revealed intrauterine growth retardation, apparent ocular hypertelorism and flat nasal bridge, and Tetralogy of Fallot. Parents elected to continue the pregnancy. The infant was born with dysmorphic craniofacial features (microcephaly, hypertelorism, flat nasal bridge, microretrognathia, cleft palate, absent ear canals and anotia, duplicated thumb on the left hand, anteriorly placed anus, and Tetralogy of Fallot (illustrated in a drawing).
Rett Syndrome Rett syndrome, a neurodevelopmental disorder affecting girls almost exclusively, was first described by Rett in 1966. The disorder now bears his name and became widely known after a report of 35 cases by Hagberg et al. in 1983. The prevalence is estimated to be 1/10,000 ~ 1/15,000 female births; over 95% of cases arise de novo due to the fact that most females with Rett syndrome do not reproduce. Rett syndrome is considered to be one of the most common genetic causes of mental retardation in girls, second only to Down syndrome.
GENETICS/BASIC DEFECTS 1. Inheritance a. Sporadic cases (99.5%), occurring almost exclusively in females i. A de novo mutation in the child with Rett syndrome ii. Disease-causing mutation inherited from one parent who has somatic or germline mosaicism b. Several reports of familial recurrence support X-linked dominant inheritance with lethality in hemizygous males 2. The region of interest has been localized to Xq28 by linkage analysis from available familial cases 3. Caused by mutations in the MECP2 (methyl-CpG-binding protein 2) gene in Xq28 a. Result in a loss of function by either disrupting the methylated DNA-binding properties of the protein or interfering with its association with transcriptional co-repressors b. MECP2 mutations in sporadic or atypical cases i. Up to 80% of sporadic affected females ii. One third of the clinically atypical cases c. MECP2 mutations in familial cases (lower incidence) i. Germline mosaic mothers ii. Asymptomatic carrier mothers due to nonrandom patterns of X-inactivation. The pattern of X-inactivation most likely protects the mutation carriers from expression of the disease by preferential inactivation of the mutant MECP2 allele 4. Males with MECP2 mutations may suffer from severe neonatal encephalopathy and die from breathing difficulties before their second year. The almost absence of men with classic Rett syndrome suggests a lethal effect of the MECP2 mutation in hemizygous affected men. However, males with Rett syndrome are not always lethal, although neurologic impairment is slowly progressive and much more severe in men than in women a. Affected men have been reported in association with Klinefelter syndrome and somatic mosaicism b. Most MECP2 mutations have originated in the paternal germline. The paternal X MECP2 never passed on from father to their sons
c. Only way for a male to have Rett syndrome is a de novo mutation of a maternal X or inheritance of a MECP2 gene mutation from his mother d. Caution: some reported MECP2 mutations may actually represent genetic variant rather than true pathogenetic novel mutations in the MECP2 gene in males
CLINICAL FEATURES 1. Normal prenatal and perinatal history 2. Appropriate head circumference 3. Apparently normal psychomotor development until about 6 to 18 months of life in affected girls 4. Developmental milestones afterwards beginning to slow down and regress with loss of skills already achieved a. Deterioration of communicative skills b. Social withdrawal c. Loss of purposeful hand movement 5. Continued deterioration over the next few years a. Loss of language b. Poor motor function (truncal and gait apraxia/ataxia) c. Stereotypic hand movements (hand wringing and flapping) d. Deceleration of head growth (acquired microcephaly) e. Autistic behavior 6. Period of stabilization a. Severe psychomotor dysfunction b. Some patients may make small recoveries in contact and communication skills 7. Breathing difficulties a. Periodic apnea b. Hyperventilation c. Breath holding d. Forced explosion of air/saliva e. Bruxism 8. Swallowing difficulties 9. Dystonia and hand and foot deformities as affected girls grow older 10. Later development of scoliosis 11. Osteoporosis at risk for fractures 12. Seizures (epilepsy) in 50% affected females 13. Possible survival into adulthood without further deterioration 14. An increased risk for sudden, unexplained death a. Longer corrected QT intervals b. T-wave abnormalities c. Reduced heart rate 15. Rett syndrome variants (<10% of cases) a. Patients with a milder clinical course (‘forme fruste’ phenotype): considered to be the most common variant of nonclassical Rett syndrome i. Less dramatic regression ii. Mild learning disability iii. Milder mental retardation
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iv. v. vi. vii. viii.
Preserved speech Ability to walk Some hand use Usually without seizures No apparent symptoms observed in a few women who demonstrate skewed X chromosome inactivation b. Patients with a severe phenotype i. Lack of normal postnatal developmental period ii. Congenital hypotonia iii. Infantile spasms c. Patients with late regression d. Male patients with Rett syndrome i. Males with XXY (Klinefelter syndrome) ii. Males with somatic mosaicism iii. Males with XY (normal karyotype) 16. Clinical stages in classic Rett syndrome a. Stagnation stage (6–18 months) i. Developmental arrest ii. Deterioration of eye contact and possible loss of communication b. Rapid destructive stage (1–4 years) i. Developmental deterioration ii. Loss of purposeful hand use iii. Stereotyped hand movements iv. Autistic features v. Gait ataxia and apraxia vi. Irregular breathing-hyperventilation c. Pseudostationary stage (preschool-early school years) i. Mental retardation ii. Decreased autistic features iii. Prominent gait ataxia and apraxia iv. Gross motor dysfunction v. Seizures d. Late motor deterioration stage (5–25 years) i. Decreased mobility ii. Spasticity iii. Improved emotional contact iv. Scoliosis v. Cachexia and growth retardation vi. Staring, unfathomable gaze 17. Relatively restrictive international diagnostic criteria (Rett syndrome Diagnostic Criteria Work Group, 1988) a. Apparently normal prenatal and perinatal period* b. Normal head circumference at birth c. Apparently normal development through age six months* d. Deceleration of head growth occurring anytime between ages three months and 48 months e. Loss of acquired hand skills and purposeful hand use between ages five months and 30 months, with subsequent development of stereotyped hand movements f. Severe impairment of expressive and receptive language together with severe psychomotor retardation g. Development of gait apraxia and truncal ataxia between ages 12 months and 48 months *Clinical criteria “a” and “c” may not be applicable to severely affected females; other criteria will not apply to those who are mildly affected and are identified as having mutations in MECP2.
18. Modified diagnostic criteria (proposed by Clarke in 1996) a. Necessary criteria i. Normal prenatal and perinatal development ii. Loss of acquired skills such as communication and speech iii. Normal head circumference at birth with acquired microcephaly iv. Marked developmental delay v. Loss of hand skills vi. Autistic features vii. Gait apraxia viii. Stereotypic hand movements b. Supportive criteria i. Seizures ii. Abnormal EEG iii. Apnea iv. Hyperventilation v. Breathing dysfunction with breath holding vi. Scoliosis vii. Growth retardation viii. Cold feet ix. Spasticity with muscle wasting 19. Wide spectrum of clinical features associated with an MECP2 mutation a. Male patients with early-onset lethal encephalopathy b. Adult cases with severe mental retardation c. Female cases i. Asymptomatic ii. Mildly mentally retarded iii. Severe variant of Rett syndrome with congenital onset
DIAGNOSTIC INVESTIGATIONS 1. Mutational analyses of MECP2 gene a. Sequence analysis and mutation scanning b. Mutations detected in 35–90% of patients (detected in almost every patient with classical Rett syndrome) c. Wide spectrum of mutations of the MECP2 gene d. Mutations extending to phenotypes that are not easily recognized as Rett syndrome e. No significant correlation exists between the clinical course and mutation type f. MECP2 mutations have been identified in patients previously diagnosed with the following conditions: i. Autism ii. Mild learning disability iii. Clinically suspected but molecularly unconfirmed Angelman syndrome iv. Mental retardation with spasticity or tremor 2. X-chromosome inactivation pattern: not tested routinely 3. EEG: not specific 4. CT and MRI a. Cortical atrophy predominantly in the frontal area b. No abnormalities in the white matter, basal ganglia, thalamus, or hippocampus c. Narrowing of the brain stem in some patients 5. Photon emission CT a. Lower cerebral blood flow in the prefrontal and temporoparietal association regions with sparing of the sensorimotor regions
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b. The flow distribution in Rett patients i. Similar to that observed in infants of a few months of age ii. Suggesting a neurodevelopmental abnormality rather than a neurodegenerative process
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. 50% risk to sibs of inheriting MECP2 allele from the carrier mother ii. Low risk to sibs when a mutation present in the proband is not identified in a parent, provided germline mosaicism is not present in either parent b. Patient’s offspring i. Unlikely to have offspring due to mental retardation and other handicaps ii. Reproduction reported in mildly affected females a) Each offspring of a carrier female with 50% risk of inheriting the disease-causing mutation b) Daughters who inherit the mutation are at high risk of developing classic Rett syndrome, although skewed X chromosome inactivation may result in a milder phenotype c) Sons who inherit the mutation may suffer a severe neonatal encephalopathy or severe mental retardation in those who survive beyond the first year of age iii. Healthy sisters of a girl with Rett syndrome a) Possibility of being carriers of the MECP2 mutation but with little or no symptoms because of favorable skewed X chromosome inactivation b) At risk of transmitting the disease-causing MECP2 mutation to their own children iv. No male with a MECP2 mutation known to reproduce 2. Prenatal diagnosis a. Amniocentesis or chorionic villus sampling available to pregnancies at risk for women with a known MECP2 mutation identified in a family member b. Appropriate to offer prenatal diagnosis to couples who have had a child with Rett syndrome or mental retardation due to a MECP2 mutation, whether or not the disease-causing mutation has been identified in a parent, since germline mosaicism cannot be excluded in either parent c. A male fetus with the mutation i. May suffer from a severe neonatal encephalopathy ii. May survive with a severe mental retardation syndrome d. A female fetus with the mutation i. Difficult to predict the phenotype in a female fetus with a MECP2 mutation which can range from apparently normal to severely affected ii. At high risk of developing classic Rett syndrome, although skewed X chromosome inactivation may result in a milder phenotype
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3. Management a. No treatment is known to improve the neurologic outcome of Rett patients b. Supportive and symptomatic therapies i. Anticonvulsants for seizures ii. Chloral hydrate for agitation iii. Carbidopa and levodopa for rigidity iv. Melatonin for sleep disturbances v. Nutritional management to insure adequate caloric and fiber intake vi. Management of gastroesophageal reflux a) Antireflux agents b) Smaller and thickened feedings c) Positioning c. Occupational and physical therapies i. Maintain function ii. Prevent scoliosis and deformities d. Augmentative communication e. Therapeutic horseback riding, swimming, and music therapy
REFERENCES Amir RE. Zoghbi HY: Rett syndrome: methyl-CpG-binding protein 2 mutations and phenotype-genotype correlations. Am J Med Genet 97(2):147–152, 2000. Amir RE, Van den Veyver IB, Wan M, et al.: Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188, 1999. Amir RE, Van den Veyver IB, Schultz R, et al.: Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes. Ann Neurol 47:670–679, 2000. Auranen M, Vanhala R, Vosman M, et al.: MECP2 gene analysis in classical Rett syndrome and in patients with Rett-like features. Neurology 56:611–617, 2001. Bienvenu T, Carrie A, de Roux N, et al.: MECP2 mutations account for most cases of typical forms of Rett syndrome. Hum Mol Genet 9:1377–1384, 2000. Brandt BL, Zoghbi HY: Rett syndrome. Gene Reviews. www.genetest.org Budden SS: Rett syndrome: habilitation and management reviewed. Eur Child Adolesc Psychiatry 6 [Suppl 1]:103–107, 1997. Buyse IM, Fang P, Hoon KT, et al.: Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MeCP2 gene: identification of several novel mutations and polymorphisms. Am J Hum Genet 67:1428–1436, 2000. Chelly J: MRX review. Am J Med Genet 94:364–366, 2000. Clarke A: Rett syndrome. J Med Genet 33:693–699, 1996. Clayton-Smith J, Watson P, Ramsden S, et al.: Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males. Lancet 356:830–832, 2000. Couvert P, Bienvenu T, Aquaviva C, et al.: MECP2 is highly mutated in X-linked mental retardation. Hum Mol Genet 10:941–946, 2001. De Bona C, Zappella M, Hayek G, et al.: preserved speech variant is allelic of classic Rett syndrome. Eur J Hum Genet 8:325–330, 2000. Dotti MT, Orrico A, De Stefano N, et al.: A Rett syndrome MECP2 mutation that causes mental retardation in men. Neurology 58:226–230, 2001. Ellaway C, Christodoulou J: Rett syndrome: clinical update and review of recent genetic advances. J Paediatr Child Health 35:419–426, 1999. Hagberg B: Clinical delineation of Rett syndrome variants. Neuropediatrics 26:62, 1995. Hagberg B: Rett syndrome: clinical peculiarities, diagnostic approach, and possible cause. Pediatr Neurol 5:75–83, 1989. Hagberg BA, Skjeldal OH: Rett variants: a suggested model for inclusion criteria. Pediatr Neurol 11:5–11, 1994. Hagberg B, Aicardi J, Dias K, et al.: A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: report of 35 cases. Ann Neurol 14:471–479, 1983. Hampson K, Woods Clin Genet, Latif F, et al.: Mutations in the MeCP2 gene in a cohort of girls with Rett syndrome. J Med Genet 37:610–612, 2000.
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Heilstedt HA, Shahbazian MD, Lee B: Infantile hypotonia as a presentation of Rett syndrome. Am J Med Genet 111:238–242, 2002. Hoffbuhr K, Devaney JM, LaFleur B, et al.: Neurology 56:1486–1495, 2001. Huppke P, Laccone F, Kramer N, et al.: Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum Mol Genet 9:1369–1375, 2000. Imessaoudene B, Bonnefont JP, Royer G, et al.: MECP2 mutation in nonfatal, non-progressive encephalopathy in a male. J Med Genet 38:171–174, 2001. Jan MM, Dooley JM, Gordon KE: Male Rett syndrome variant: application of diagnostic criteria. Pediatr Neurol 20:238–240, 1999. Kozinetz CA, Skender ML, MacNaughton N, et al.: Epidemiology of Rett syndrome: a population-based registry. Pediatrics 91:445–450, 1993. Laccone F, Zoll B, Huppke P, et al.: MECP2 gene nucleotide changes and their pathogenicity in males: proceed with caution. J Med Genet 39:586–588, 2002. Lombroso PJ: Genetics of childhood disorders: XIV. A gene for Rett syndrome: new flash. J Am Acad Child Adolesc Psychiatry 39:671–674, 2000. Meloni I, Bruttini M, Longo I, et al.: A mutation in the Rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males. Am J Hum Genet 67:982–985, 2000. Naidu S: Rett syndrome: a disorder affecting early brain growth. Ann Neurol 42:3–10, 1997. Obata K, Matsuishi T, Yamashita Y, et al.: Mutation analysis of methyl=CpG binding protein 2 gene (MeCP2) in patients with Rett syndrome. J Med Genet 37:608–610, 2000. Orrico A, Lam C, Galli L, et al.: MECP2 mutation in male patients with nonspecific mental retardation. REBS Lett 481:285–288, 2000. Percy AK: Rett syndrome. Curr Opin Neurol 8:156–160, 1995. Rett A: Über ein zerebral-atrophisches Syndrome bei Hyperammonemie. Vienna, Austria: Bruder Hollinek, 1966. Schwartzman JS, De Souza Ann Med, Faiwichow G, et al.: Rett phenotype in patient with XXY karyotype: case report. Arq Neuropsiquiatr 56: 824–828, 1998.
Shahbazian MD. Zoghbi HY. Molecular genetics of Rett syndrome and clinical spectrum of MECP2 mutations. Current Opinion in Neurology. 14(2):171–176, 200. Schanen C, Francke U: A severely affected male born into a Rett syndrome kindred supports X-linked inheritance and allows extension of the exclusion map. Am J Hum Genet 63:267–269, 1998. Singer HS: Rett syndrome “We’ll keep the genes on for you.” Neurology 56:582–584, 2001. Sirianni N, Naidu S, Pereira J, et al.: Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28. Am J Hum Genet 63:1552–1558, 1998. The Rett Syndrome Diagnostic Criteria Work Group: Diagnostic criteria for Rett syndrome. Ann Neurol 23:425–428, 1988. Trappe R, Laccone F, Cobilanschi J, et al.: MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin. Am J Hum Genet 68:1093–1101, 2001. Villard L, Kpebe A, Cardoso C, et al.: Two affected boys in a Rett syndrome family. Neurology 55:1188–1193, 2000. Wan M, Lee SS, Zhang X, et al.: Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet 65:1520–1529, 1999. Webb T, Latif F: Rett syndrome and the MECP2 gene. J Med Genet 38:217–223, 2001. Webb T, Clarke A, Hanefeld F, et al.: Linkage analysis in Rett syndrome families suggests that there may be a critical region at Xq28. J Med Genet 35:997–1003, 1998. Xiang F, Buervenich S, Nicolao P, et al.: Mutation screening in Rett syndrome patients. J Med Genet 37:250–255, 2000. Yusufzai TM, Wolffe AP: Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res 28:4172–4179, 2000. Zoghbi HY, Francke U: Rett syndrome. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001. Zoghbi HY. Gage FH. Choi DW. Neurobiology of disease. Current Opinion in Neurobiology. 10(5):655–660, 2000.
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Fig. 1. A girl with Rett syndrome.
Fig. 2. A girl with Rett syndrome who has MECP2 mutation (R106W).
Fig. 3. A 33-year-old female with Rett syndrome showing severe psychomotor retardation and hand wringing so severe that the part of the hand and fingers are red, rough, and swollen from constant irritation by stereotypic hand movement. She was normal developmentally until about 18 months of age when she started to have hand washing/ wringing, tip toe walking, fell easily, and lost the skills she already attained. Shortly after, she started to loose eye contact with people and have seizures. DNA sequence analysis identify a nucleotide change of 763C>T in one copy of the MECP2 gene which predicts an amino acid change of arginine to a premature translation stop at codon 255 (R255X). This nonsense mutation was previously identified in multiple Rett syndrome patients as a disease-causing MECP2 mutation.
Rickets Normal bone mineralization requires adequate supplies of calcium and phosphate and normal vitamin D metabolism. Defective supply or function of any of these factors can cause rickets and osteomalacia.
GENETICS/BASIC DEFECTS 1. Causes a. Younger than 6 months of age i. Hypophosphatasia ii. Prematurity iii. Primary hyperparathyroidism iv. Maternal factors a) Vitamin D deficiency b) Poorly controlled hyperparathyroidism c) Poorly controlled renal insufficiency b. Older than 6 months of age i. Nutritional rickets in children a) Inadequate levels (deficiency) of vitamin D due to either inadequate oral intake or insufficient exposure to sunlight b) With resultant decreased calcium absorption in the small intestine c) Thereby decreasing the available calcium for epiphyseal cartilage and skeletal mineralization d) Secondary hyperparathyroidism due to limited calcium availability and attendant renal phosphate losses contributes to the bone and growth plate pathophysiology that lead to the clinical manifestations of rickets ii. Liver disease (impaired 25-vitamin D formation) a) Chronic liver diseases (extrahepatic biliary atresia, total parenteral nutrition, tyrosinemia) b) Anticonvulsant therapy iii. Malabsorption a) Celiac disease b) Inflammatory bowel disease c) Pancreatic insufficiency iv. Renal tubular insufficiency (hypophosphatemia) a) Vitamin D resistant rickets b) Vitamin D dependent rickets c) Fanconi syndrome d) Lowe syndrome e) Cystine storage disease v. Chronic renal disease (renal osteodystrophy) a) Pyelonephritis b) Polycystic kidney disease c) Chronic glomerulonephritis d) Renal tubular acidosis 844
2. Vitamin D deficiency rickets: caused by low endogenous vitamin D a. Selected pediatric populations at high risk for vitamin D deficiency i. Dietary factors (breast-fed infants with marginal calcium stores due to low levels of vitamin D in breast milk) ii. Skin pigmentation (African American children due to dark skin absorbing ultraviolet radiation less available for vitamin D production) iii. Sun screen application iv. Insufficient sun exposure (far northern latitudes, during the winter months, cultural traditions) b. Other predisposing factors i. Severe liver failure ii. Nephrotic syndrome iii. Severe malnutrition iv. Gastrointestinal diseases leading to malabsorption, including impaired fat absorption or enterohepatic recirculation 3. Familial hypophosphatemic rickets: caused by defect in reabsorption of phosphate in the proximal tubule, resulting in hypophosphatemia, defective bone mineralization, normocalcemic rickets and short stature a. Dominant X-linked hypophosphatemic rickets (also called vitamin D-resistant rickets) i. The gene locus: mapped to Xp22.1 ii. The gene responsible: phosphate regulating (PHEX) gene with homologies to endopeptidases in the X chromosome iii. Complete penetrance b. Autosomal dominant hypophosphatemic rickets i. The gene locus: mapped to 12p13 ii. Incomplete penetrance 4. Vitamin D-dependent rickets: caused by reduced activity of 25(OH)1-alphahydroxylase a. Vitamin D-dependent rickets type I (1-alpha-hydroxylase mutation): also known as hereditary pseudovitamin D deficiency rickets i. Autosomal recessive disorder ii. Commonly found in the French Canadian population iii. The gene locus mapped to chromosome 12q14 iv. Caused by mutation in the vitamin D 1-alphahydroxylase gene v. Impaired 1 alpha-hydroxylation in the renal proximal tubule that converts 25(OH)D to 1,25(OH)2D b. Vitamin D-dependent rickets type II (receptor mutation): also known as hereditary vitamin D-resistant rickets i. Autosomal recessive inheritance ii. Caused by mutations in the vitamin D receptor (VDR) that result in end-organ resistance to
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active vitamin D (1,25-dihydroxyvitamin D) [1,25-(OH)2D3] iii. Major defect caused by the mutant VDR: a decrease of intestinal calcium and phosphate absorption which leads to decreased bone mineralization and rickets iv. The major biochemical distinction between type I and type II a) Low circulating 1,25(OH)2D levels in patients with type I b) High circulating 1,25(OH)2D levels in patients with type II
CLINICAL FEATURES 1. Rickets vs osteomalacia a. Rickets: occur only before fusion of the epiphyses b. Osteomalacia: occur in adults deficient in calcium, phosphate, or vitamin D 2. Signs of rickets in osseous tissues a. Craniotabes in newborn baby and young infant i. Softening of skull bones ii. May be present but not pathognomonic b. Frontal bossing in early infancy i. Expansion of cranial bones relative to facial bones ii. Also possibly due to hydrocephalus (“rickets hydrocephalus”) c. Fontanelle i. Delayed closure ii. Occasional intracranial hypertension d. Wrists: an apparent bracelet of bone around the wrist (specificity 81%) e. Rickety rosary: swollen costochondral junctions of ribs (specificity 64%) f. Skeletal deformities i. Particularly “bow legs” once the child is walking ii. Genu valgum generally not due to rickets iii. Spinal curvature most likely due to nonrickets cause iv. Narrowed pelvic outlet used to cause obstructed labor g. Brown tumor: rare fibrous-cystic osteitis associated with the secondary hyperparathyroidism h. Limb pain i. Bone pain and pseudoparalysis uncommon ii. Osteomalacia and the subperiosteal hematoma of scurvy: more likely causes of pain i. Teeth i. Delayed eruption of teeth ii. Enamel hypoplasia: greater susceptibility to caries in the first dentition 3. Nonosseous effect of vitamin D deficiency a. Symptomatic hypocalcemia with convulsions: particularly in young infants less than 6 months of age born to mothers with untreated osteomalacia, many of whom are subclinical cases b. Myopathy i. Proximal myopathy in infants and adolescents ii. Heart failure simulating cardiomyopathy with severe hypocalcemia iii. Responding to treatment for rickets and inotropes
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c. Myelofibrosis i. With pancytopenia or microcytic hypochromic anemia ii. Returning to normal when treated with vitamin D d. Possible link between early vitamin D deficiency and other disorders in later life i. Type I diabetes ii. Multiple sclerosis iii. Schizophrenia iv. Hear disease e. Intrauterine and infant growth: vitamin D supplement in the last trimester of pregnancy improves growth in utero and during infancy in some studies 4. Vitamin D deficiency rickets a. Not clinically apparent before 6 months of age because of prenatal stores of vitamin D imparted by the mother b. Decreased linear growth/short stature c. Poor weight gain/small for age d. Delayed development e. Incidental finding on radiograph or physical examinations f. Nonspecific musculoskeletal complaints g. Bowing of the legs h. Seizures i. Tetany j. Weakness k. Drowsiness l. Development of secondary hyperparathyroidism due to increasing severity of vitamin D deficiency, progressing to frank osteomalacia and fractures 5. Hereditary hypophosphatemic rickets a. X-linked dominant hypophosphatemic rickets i. Disease severity similar in males and females but differs among individuals (some patients with isolated hypophosphatemia; others with disabling severe bone disease) ii. The disease may persists into adulthood iii. Short stature iv. Rickets with resultant lower-extremity deformities v. Bone pain vi. Enthesopathy (calcification of tendons, ligaments, and joint capsules) vii. Dental abscesses viii. Cranial abnormalities and spinal stenosis in some severely affected individuals b. Autosomal dominant hypophosphatemic rickets i. Isolated renal phosphate wasting ii. Short stature iii. Impressive windswept deformity (valgus on one side and varus on the other side) iv. Marked tendency for fracture with or without trauma v. Delayed onset of disease in some patients vi. Patients who present as adults: osteomalacia with bone pain, weakness, and fractures 6. Vitamin D-dependent rickets a. Vitamin D-dependent rickets type I (hereditary pseudovitamin D deficiency rickets) i. Clinical presentation within the first few months of life
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ii. First clinical sign: acute or chronic hypocalcemia because the major physiologic role of 1,25-dihydroxyvitamin D is to promote intestinal calcium absorption iii. Hypocalcemic seizures as early as 4 weeks of age or usually before 2 years of age iv. Growth retardation v. Bowing of the extremities vi. Bone pain secondary to rickets and osteomalacia vii. Enamel hypoplasia and oligodentia viii. Hypocalcemia accompanied by secondary hyperparathyroidism resulting in hypophosphatemia and occasional aminoaciduria b. Vitamin D-dependent rickets type II (hereditary vitamin D-resistant rickets) i. Onset of disease: infancy or childhood ii. Major clinical findings: hypocalcemia and rickets due to defective intestinal calcium absorption leading to impaired mineralization of newly forming bone and preosseous cartilage iii. Rickets a) Often severe b) Usually exhibits within months of birth iv. Bone pain v. Muscle weakness vi. Hypotonia vii. Occasional convulsions from hypocalcemia viii. Often growth retarded ix. Enamel hypoplasia, oligodentia, and severe dental caries x. Hypocalcemia accompanied by secondary hyperparathyroidism results in hypophosphatemia and occasional aminoaciduria. xi. Pneumonia secondary to severe rickets of the chest wall and poor respiratory effort causes death in some infants xii. Alopecia a) Sparse body hair in many patients b) Alopecia totalis observed in some kindreds, including eyebrows and in some cases eyelashes
DIAGNOSTIC INVESTIGATIONS 1. Vitamin D deficiency rickets a. Decreased levels of 25-OH vitamin D (best screening test for vitamin D stores in otherwise healthy individuals) b. Normal or increased levels of 1,25 (OH)2 vitamin D c. Increased levels of parathyroid hormone d. Decreased levels of calcium (hypocalcemia) e. Decreased levels of phosphate (hypophosphatemia) 2. Vitamin D-resistant rickets a. Renal tubular phosphate leakage and subsequent hypophosphatemia in all affected individuals b. Normal levels of 25-OH vitamin D c. Normal or decreased levels of 1,25 (OH)2 vitamin D d. Normal or increased levels of parathyroid hormone e. Normal levels of calcium f. Decreased phosphate (hypophosphatemia)
3. Vitamin D-dependent rickets a. Elevated or normal levels of 25-OH vitamin D b. Low levels of 1,25 (OH)2 vitamin D in type I and elevated levels in type II c. Normal or increased levels of parathyroid hormone d. Normal or decreased levels of calcium e. Decreased levels of phosphorous (hypophosphatemia) f. Elevated serum alkaline phosphatase activity 4. Radiographic findings a. Cupping, fraying and widening of the metaphyses: a requirement for diagnosis of rickets b. Rachitic rosary (enlargement of the wrists, knees, and rib ends) c. Bowing of the lower extremities in the newly ambulating child d. Widening and irregularity of all the physes e. Osteopenia (decreased mineralization of the bone matrix) with blurred or nonapparent cortical outlines of the epiphyseal ossification centers f. Rib flaring g. Multiple fractures in various stages of healing h. Deformities caused by softening of bone or poor muscle tone i. Femoral bowing ii. Tibial bowing iii. Genu valgum (knock knees) i. Pelvis i. Coxa valga ii. Protrusio acetabuli j. Thorax: hourglass shape k. Skull i. Postural molding ii. Frontal bossing l. The zone of provisional calcification appearing as a dense metaphyseal band due to calcium deposit in response to vitamin D therapy i. Seen as early as 2–3 weeks after initiation of therapy in children with nutritional rickets ii. Seen after 2–3 months in children with renal rickets iii. Persistence of deformities caused by bone softening despite successful treatment 5. Histological findings a. Primary metabolic abnormality at the zone of provisional calcification b. Diminished calcification of cartilage columns in the metaphysis c. Continued osteoid production by osteoblasts, but ossification of the osteoid tissue is impaired because of insufficient calcium deposition d. Widened, irregularly calcified physis resulting from resorption of osteoid and calcium because of impaired osteoclast function e. Metaphyseal broadening or “cupping” likely caused by stress at sites of ligament attachment f. Splaying of cartilage cells peripherally g. Microfractures of the primary spongiosa by herniation of cartilage into this area 6. Molecular genetic diagnosis a. X-linked dominant hypophosphatemic rickets: sequencing of entire coding region
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b. Autosomal dominant hypophosphatemic rickets: sequencing of entire coding region c. Pseudovitamin D deficiency rickets i. Sequencing of entire coding region ii. Sequencing of select exons d. Rickets-alopecia syndrome: sequencing of entire coding region
GENETIC COUNSELING 1. Recurrence risk: depend on the etiology a. Vitamin D deficiency rickets: recurrence risk high if conditions leading to vitamin D deficiency exist b. Autosomal recessive inheritance i. Patient’s sib: 25% ii. Patient’s offspring: not increased unless the spouse is a carrier or affected c. Autosomal dominant inheritance i. Patient’s sib: not increased unless a parent is affected ii. Patient’s offspring: 50% d. X-linked dominant inheritance i. Patient’s sib: not increased unless a parent is affected ii. Patient’s offspring a) Affected female: 50% of daughters and 50% of sons will be affected b) Affected male: All daughters will be affected and all sons will be normal 2. Prenatal diagnosis a. Fetal radiography, particularly in mothers with osteomalacia i. Poorly mineralized fetal bones ii. Thin cortices of the limb bones and penciled outlines of the vertebral bodies iii. Cupped tibial/radial metaphysis with indistinct border to the epiphyseal aspect b. Fetal echocardiography i. Atrial flutter with heart failure reported in a fetus affected with X-linked dominant hypophosphatemic rickets ii. Causal relationship in this case remained unknown c. Prenatal diagnosis by molecular analysis of cultured fetal cells obtained from CVS and amniocentesis in pregnant women from high-risk families to look for disease-causing mutation, previously identified in an affected individual i. X-linked dominant hypophosphatemic rickets: sequencing of entire coding region ii. Autosomal dominant hypophosphatemic rickets: sequencing of entire coding region iii. Pseudovitamin D deficiency rickets: sequencing of entire coding region and select exons iv. Hereditary vitamin D-resistant rickets a) [3H]1,25-(OH)2D3 binding b) Induction of 24-hydroxylase activity c) RFLP analyses v. Rickets-alopecia syndrome: sequencing of entire coding region
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3. Management a. Hypocalcemia and ‘simple rickets’ i. Hypocalcemia (early infancy) a) IV calcium gluconate to control continuing seizures b) Oral calcium daily c) Oral calciferol daily d) Look for evidence of rickets in the baby (radiographs of the knees and wrists) e) Look for maternal osteomalacia (elevated maternal alkaline phosphatase) f) Slowly withdraw treatment when the plasma calcium is normal g) Continue prophylactic vitamin D thereafter ii. Rickets without hypocalcemia (early infancy): oral calciferol daily for 2–4 months iii. Older infants, toddlers, and adolescents a) Oral calciferol b) Add oral calcium if dietary deficiency may be a factor c) Phosphorus not needed in simple rickets since phosphorus is abundant in the diet d) Necessary to supplement phosphorus for very preterm babies and in the phosphatewasting causes of rickets b. Vitamin D deficiency rickets i. Increase dietary intake of vitamin D a) The new recommended adequate intake of vitamin D by the National Academy of Sciences to prevent vitamin D deficiency in normal infants, children, and adolescents is 200 IU per day b) An intake of at least 200 IU per day of vitamin D will prevent physical signs of vitamin D deficiency and maintain serum 25hydroxy-vitmin D at or above 27.5 nmol/L ii. Increased sun exposure iii. Prevent other predisposing factors c. Vitamin D-resistant rickets i. Increase dietary intake of vitamin D ii. Increased sun exposure iii. Prevent other predisposing factors d. Vitamin D-dependent rickets: life-long treatment with 1-alpha-hydroxyvitamin D or 1,25-dihydroxyvitamin D e. Dominant X-linked hypophosphatemic rickets: treat bone lesions and impaired longitudinal growth i. Vitamin D supplement ii. Oral phosphate supplement: risks of stimulating secondary hyperparathyroidism
REFERENCES Al-Khenaizan S, Vitale P: Vitamin D-dependent rickets type II with alopecia: two case reports and review of the literature. Int J Dermatol 42:682–685, 2003. Begum R, Continho ML, Dormandy TL: Maternal malabsorption presenting congenital rickets. Lancet 1:1048–1052, 1968. Bishop N: Rickets today-children still need milk and sunshine. N Engl J Med 341:602–603, 1999. Carpenter TO: New perspectives on the biology and treatment of x-linked hypophosphatemic rickets. Pediatr Clin N Am 44:443–466, 1997. Currarino GD, Neuhauser EBD, Reyersbach Genet Counsel, et al.: Hypophosphatasia. Am J Roentgenol 78:392–419, 1957.
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DeLucia MC, Mitnick ME, Carpenter TO: Nutritional rickets with normal circulating 25-hydroxyvitamin D: a call for reexamining the role of dietary calcium intake in North American infants. J Clin Endocrinol Metab 88:3539–3545, 2003. DiMeglio LA, Econs MJ: Hypophosphatemic rickets. Rev Endocr Metab Disord 2:165–173, 2001. DiMeglio LA, White KE, Econs MJ: Disorders of phosphate metabolism. Endocrinol Met Clin 29:591–609, 2000. Econs MJ, Francis F: Positional cloning of the PEX gene: new insights into the pathophysiology of X-linked hypophosphatemic rickets. Am J Physiol 273:F489–F498, 1997. Felman KW, Marcuse EK, Springer DA: Nutritional rickets. Am Fam Physician 42:1311–1318, 1990. Gartner LM, Greer FR: Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake. Pediatrics 111:908–910, 2003. Glorieux FH, Scriver CR, Reade TM, et al.: Use of phosphate and vitamin D to prevent dwarfism and rickets in X-linked hypophosphatemia. N Engl J Med 287:481–487, 1972. Greer FR: Osteopenia of Prematurity. Annu Rev Nutr 14:169–185, 1994. Institute of Medicine, Food and Nutrition Board, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Vitamin D. In: Dietary Reference Intakes for Calcium, phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press; 1997: 250–287. Joiner TA, Foster C, Shope T: The many faces of vitamin D deficiency rickets. Pediatr Rev 21:296–302, 2000. Kreiter SR, Schwartz RP, Kirkman HN Jr, et al.: Nutritional rickets in African American breast-fed infants. J Pediatr 137:153–157, 2000. Kruse K: Pathophysiology of calcium metabolism in children with vitamin Ddeficiency rickets. J Pediatr 126:736–741, 1995. Landing BH, Kamoshita S: Congenital hyperparathyroidism secondary to maternal hypoparathyroidism. J Pediatr 77:842–847, 1970. Levin TL, States L, Greig A, et al.: Maternal renal insufficiency: a cause of congenital rickets and secondary hyperparathyroidism, Pediatr Radiol 22:315–316, 1992.
Malloy PJ, Pike JW, Feldman D: The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. Endocr Rev 20:156–188, 1999. Mancrieff H, Fadahunsi T: Congenital rickets due to maternal vitamin D deficiency. Arch Dis Child 49:810–811, 1974. Norman ME: Vitamin D in bone disease. Pediatr Clin N Am 229:947–971, 1982. Pitt MJ: Rachitic and osteomalacic syndromes. Radiol Clin N Amer 19:581–599, 1981. Pitt MJ: Rickets and osteomalacia are still around. Radiol Clin North Am 29:97–118, 1991. Russell JG, Hill LF: True fetal rickets. Br J Radiol 47:732–734, 1974. Schmitt CP, Mehls O: The enigma of hyperparathyroidism in hypophosphatemic rickets. Pediatr Nephrol 19:473–477, 2004. Schneider R: Radiologic methods of evaluating generalized osteopenia. Orthop Clin N Amer 15:631–651, 1984. Smith R: The pathophysiology and management of rickets. Orthop Clin North Am 3:601–621, 1972. States LJ: Imaging of metabolic bone disease and marrow disorders in children Teitelbaum SL: Pathological manifestations of osteomalacia and rickets. Clin Endocrinol Metab 9:43–62, 1980. Thakker RV, Davies KE, Read AP, et al.: Linkage analysis of two cloned DNA sequences, DXS197 and DXS207, in hypophosphatemic rickets families. Genomics 8:189–193, 1990. The HYP Consortium: A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet 11:130–136, 1995. Thomas MK, Demay MB: Vitamin D deficiency and disorders of vitamin D metabolism. Endocrinol Metab Clin 29:611–627, 2000. Vintzileos AM, Campbell WA, Soberman SM, et al.: Fetal atrial flutter and X-linked dominant vitamin D-resistant rickets. Obstet Gynecol 65:39S–44S, 1985. Wharton B, Bishop N: Rickets. Lancet 362:1389–1400, 2003. Weisman Y, Jaccard N, Legum C, et al.: Prenatal diagnosis of vitamin D-dependent rickets, type II: response to 1,25-dihydroxyvitamin D in amniotic fluid cells and fetal tissues. J Clin Endocrinol Metab 71: 937–943, 1990.
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Fig. 2. A boy with vitamin D resistant rickets showing short stature. The radiograph shows widening, cupping, and fraying of the distal radius and ulna. Fig. 1. An infant with healing nutritional rickets. The radiograph shows femoral bowing and a healing fracture with callus formation in the right femur.
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Fig. 4. Radiograph from a patient with renal rickets shows widening, cupping, and fraying of the distal radius and ulna.
Fig. 3. Another boy with vitamin D resistant rickets.
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Fig. 6. Three sisters with hypophosphatemic rickets showing short stature and bowed legs. They have an affected father.
Fig. 5. Photomicrograph of the humerus (top) and the rib (bottom) of a female neonate who lived 43 minutes. Broad cartilage columns with many large chondrocytes are present in the metaphysis. They have broad osteoid seams and are poorly ossified. The abnormal area corresponds to the radiographic metaphyseal irregular lucency. The findings are similar to those of hypophosphatasia, though the changes are milder. The cause of congenital rickets in this case is unknown. The mother did not have history of malabsorption, vitamin D intake deficiency, renal failure or preeclampsia.
Fig. 7. Two sisters and a brother with hypophosphatemic rickets showing short stature. The brother had severe short stature and bowed legs. The oldest sister had surgeries on her legs to correct the lower leg deformities. The middle sister was mildly affected. Their mother was affected.
Roberts Syndrome Roberts syndrome is a rare hereditary disorder characterized by symmetrical reduction of all limbs and a unique cytogenetic abnormality of premature centromere separation, which disrupts the process of chromatid pairing.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Associated with unique cytogenetic abnormality: premature centromere separation a. Disrupts the process of chromatid pairing b. Responsible for the development of multiple structural anomalies observed in Roberts syndrome 3. Caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion
CLINICAL FEATURES 1. Craniofacial malformations: marked variability a. Bilateral cleft lip and cleft palate in severe cases b. No clefting of the lip or palate in some cases c. Hypertelorism secondary to widely spaced obits d. Ophthalmic manifestations i. Exophthalmos due to shallow orbits ii. Microphthalmia iii. Peter anomaly iv. Cloudy cornea v. Cataracts e. Wide nasal bridge f. Hypoplastic nasal alae g. Hemangiomata of the lip, nose, face, or forehead h. Micrognathia i. Dark scalp hair becomes thin and silvery blond 2. Limb defects a. Phenotype varies from a complete absence of arms and legs with rudimentary digits to mild growth reduction in the limbs. b. Limb reduction defects tend to be symmetric and more severely involved in the upper extremities than the lower extremities. c. Presence of phocomelia i. Tetraphocomelia: a prominent characteristic of the syndrome ii. Two deficient limbs in 11% of cases iii. No phocomelia in 2% of cases d. Often reduced number of fingers (oligodactyly) e. Radial aplasia or dysplasia common f. Lack of 1st metacarpal, thumb, or first phalanx 3. Other associated anomalies a. CNS anomalies i. Mental retardation ii. Microcephaly 852
iii. Hydrocephalus iv. Absent olfactory lobes v. Calcification of the basal ganglia vi. Encephalocele vii. Cranial nerve paralysis viii. Seizures b. Congenital heart defects i. Atrial septal defect ii. Patent ductus arteriosus iii. Pulmonic stenosis iv. Aortic stenosis v. AV canal defect c. Renal anomalies i. Polycystic kidneys ii. Dysplastic kidneys iii. Horseshoe kidney iv. Hydronephrosis v. Renal agenesis d. Gastrointestinal obstruction e. Splenogonadal fusion f. Cryptorchidism g. Enlarged phallus h. Failure to thrive i. Neoplasms i. Sarcoma botryoides ii. Malignant melanoma 4. Prognosis a. Severe cases i. Often resulting in spontaneous abortions or stillbirths ii. Few cases survive past one month of life b. Phenotypically milder cases i. Requiring minimal to full time care depending on the degree of mental retardation ii. May require surgical interventions to correct craniofacial and limb anomalies 5. Differential diagnosis a. SC phocomelia i. Clinical characteristics a) Tetraphocomelia b) Silvery blond hair c) Facial hemangioma d) Hypoplastic nasal alae ii. Originally thought to differ from Roberts syndrome by: a) Usual absence of midfacial clefting b) Prolonged survival c) Lesser degree of mental and physical retardation d) Relatively milder degree of phocomelia iii. Now considered to be the same entity as Roberts syndrome (Roberts-SC phocomelia syndrome)
ROBERTS SYNDROME
b. TAR syndrome i. Absent radii with thumbs present ii. Hypomegakaryocytic thrombocytopenia iii. Absent cleft palate
DIAGNOSTIC INVESTIGATIONS 1. Cytogenetics a. Distinctive abnormality of the constitutive heterochromatin (the RS effect): premature centromere separation (PCS) i. Detected in: a) Fibroblasts and lymphocytes in neonates b) Chorionic villi and amniocytes in the fetus ii. Consists of “puffing” or “repulsion” of the constitutive heterochromatin a) Chromosome puffing most obvious at the large heterochromatic regions of chromosomes 1, 9, and 16 b) Chromosome repulsion most evident at the short arms of the acrocentrics and the distal long arm of the Y chromosome iii. A “rail-road-track” or “tram-track” appearance of the sister chromatids due to the absence of a constriction at the centromere in several other chromosomes a) This phenomenon, called heterochromatin repulsion, is observed in cells of different tissue origin with several chromosomes in each metaphase showing a visible abnormality b) Most evident in chromosomes containing the largest amount of heterochromatin b. Sporadic aneuploidy noted with the pattern of aneuploidy different in each patient. The possible relationship between centromere “splaying” and aneuploidy has yet to be determined c. Normal karyotypes lacking any microdeletion or chromosomal rearrangement from either leukocytes or fibroblasts in about a fifth of all cases 2. Radiography for phocomelia evaluation a. Absence of the radius and fibula: the most common skeletal abnormalities in the upper and lower limbs b. Absent, short, deformed and /or hypoplastic ulna and tibia: the second most common bone defects c. Absent, short, deformed or hypoplastic humerus and femur: the third and least common abnormalities 3. Echocardiography for congenital heart defect 4. Renal ultrasound for renal anomalies 5. MRI of the brain for CNS anomalies
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased (not surviving to reproduction in severe cases) 2. Prenatal diagnosis for pregnancies at risk a. Ultrasonography i. Intrauterine growth retardation ii. Bilateral phocomelia (tetraphocomelia in majority of cases) of varying degree
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iii. Cleft lip and palate iv. Associate anomalies a) Hydrocephalus b) Congenital heart defects c) Renal anomalies b. Confirmed by characteristic disjunction of centromeres in amniocytes or CVS 3. Management a. Special education b. Cornea grafting c. Corrective surgery i. Cleft lip/palate ii. Limb defects d. Prosthetic devices i. For underdeveloped or missing limbs ii. Used to increase independence
REFERENCES Benzacken B, Savary JB, Manouvrier S, et al.: Prenatal diagnosis of Roberts syndrome: two new cases. Prenat Diagn 16:125–130, 1996. Concolino D, Sperli D, Cinti R, et al.: A mild form of Roberts/SC phocomelia syndrome with asymmetrical reduction of the upper limbs. Clin Genet 49:274–276, 1996. de Ravel TJ, Seftel MD, Wright CA: Tetra-amelia and splenogonadal fusion in Roberts syndrome. Am J Med Genet 68:185–189, 1997. Freeman MV, Williams DW, Schimke RN, et al.: The Roberts syndrome. Birth Defects Orig Artic Ser 10:87–95, 1974. Freeman MV, Williams DW, Schimke RN, et al.: The Roberts syndrome. Clin Genet 5:1–16, 1974. Fryns JP, Kleczkowska A, Moerman P, et al.: The Roberts tetraphocomelia syndrome: identical limb defects in two siblings. Ann Genet 30:243–245, 1987. German J: Roberts’ syndrome. I. Cytological evidence for a disturbance in chromatid pairing. Clin Genet 16:441–447, 1979. Herrmann J, Opitz JM: The SC phocomelia and the Roberts syndrome: nosologic aspects. Eur J Pediatr 125:117–134, 1977. Holden KR, Jabs EW, Sponseller PD: Roberts/pseudothalidomide syndrome and normal intelligence: approaches to diagnosis and management. Dev Med Child Neurol 34:534–539, 1992. Holmes-Siedle M, Seres-Santamaria A, Crocker M, et al.: A sibship with Roberts/SC phocomelia syndrome. Am J Med Genet 37:18–22, 1990. Hwang K, Lee DK, Lee SI, et al.: Roberts syndrome, normal cell division, and normal intelligence. J Craniofac Surg 13:390–394, 2002. Jabs EW, Tuck-Muller CM, Cusano R, et al.: Centromere separation and aneuploidy in human mitotic mutants: Roberts syndrome. Prog Clin Biol Res 318:111–118, 1989. Jabs EW, Tuck-Muller CM, Cusano R, et al.: Studies of mitotic and centromeric abnormalities in Roberts syndrome: implications for a defect in the mitotic mechanism. Chromosoma 100:251–261, 1991. Karabulut AB, Aydin H, Erer M, et al.: Roberts syndrome from the plastic surgeon’s viewpoint. Plast Reconstr Surg 108:1443–1445, 2001. Keppen LD, Gollin SM, Seibert JJ, et al.: Roberts syndrome with normal cell division. Am J Med Genet 38:21–24, 1991. Lenz WD, Marquardt E, Weicker H: Pseudothalidomide syndrome. Birth Defects 10:97–107, 1974. Lopez-Allen G, Hutcheon RG, Shaham M, et al.: Picture of the month. Roberts-SC phocomelia syndrome. Arch Pediatr Adolesc Med 150:645–646, 1996. Louie E, German J: Roberts’s syndrome. II. Aberrant Y-chromosome behavior. Clin Genet 19:71–74, 1981. Mann NP, Fitzsimmons J, Fitzsimmons E, et al.: Roberts syndrome: clinical and cytogenetic aspects. J Med Genet 19:116–119, 1982. Maserati E, Pasquali F, Zuffardi O, et al.: Roberts syndrome: phenotypic variation, cytogenetic definition and heterozygote detection. Ann Genet 34:239–246, 1991. Ota˜no L, Matayoshi T, Gadow EC: Roberts syndrome: first-trimester prenatal diagnosis. Prenat Diagn 16:770–771, 1996. Paladini D, Palmieri S, Lecora M, et al.: Prenatal ultrasound diagnosis of Roberts syndrome in a family with negative history. Ultrasound Obstet Gynecol 7:208–210, 1996.
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Parry DM, Mulvihill JJ, Tsai S, et al.: SC phocomelia syndrome, premature centromere separation, and congenital cranial nerve paralysis in two sisters, one with malignant melanoma. Am J Med Genet 24:653–672, 1986. Qazi OH, Kassner EG, Masakawa A, et al.: The SC phocomelia syndrome: report of two cases with cytogenetic abnormality. Am J Med Genet 4:231–238, 1979. Roberts JB: A child with double cleft of lip and palate, protrusion of the intermaxillary portion of the upper jaw and imperfect development of the bones of the four extremities. Ann Surg 70:252–253, 1919. Robins DB, Ladda RL, Thieme GA, et al.: Prenatal detection of Roberts-SC phocomelia syndrome: report of 2 sibs with characteristic manifestations. Am J Med Genet 32:390–394, 1989. Römke C, Froster-Iskenius U, Heyne K, et al.: Roberts syndrome and SC phocomelia. A single genetic entity. Clin Genet 31:170–177, 1987. Sherer DM, Shah YG, Klionsky N, et al.: Prenatal sonographic features and management of a fetus with Roberts-SC phocomelia syndrome (pseudothalidomide syndrome) and pulmonary hypoplasia. Am J Perinatol 8:259–262, 1991.
Sinha AK, Verma RS, Mani VJ: Clinical heterogeneity of skeletal dysplasia in Roberts syndrome: a review. Hum Hered 44:121–126, 1994. Stioui S, Privitera O, Brambati B, et al.: First-trimester prenatal diagnosis of Roberts syndrome. Prenat Diagn 12:145–149, 1992. Stoll C, Levy JM, Beshara D: Roberts’s syndrome and clonidine. J Med Genet 16:486–487, 1979. Tomkins D, Hunter A, Roberts M: Cytogenetic findings in Roberts-SC phocomelia syndrome(s). Am J Med Genet 4:17–26, 1979. Tomkins DJ: Premature centromere separation and the prenatal diagnosis of Roberts syndrome. Prenat Diagn 9:450–452, 1989. Urban M, Opitz C, Bommer C, et al.: Bilaterally cleft lip, limb defects, and haematological manifestations: Roberts syndrome versus TAR syndrome. Am J Med Genet 79:155–160, 1998. Van Den Berg DJ, Francke U: Roberts syndrome: a review of 100 cases and a new rating system for severity. Am J Med Genet 47:1104–1123, 1993. Vega H, Waisfisz Q, Gordillo M, et al.: Roberts syndrome is caused by mutation in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion. Nature Genet Online 10 April 2005, pp. 1–3.
ROBERTS SYNDROME
Fig. 1. The G-banded metaphase spread from fibroblast culture of a male infant with Roberts syndrome showing characteristic heterochromatin separation: puffing of the centromeric heterochromatin of some chromosomes and splaying of the Yqh region (arrows). The patient had profound psychomotor retardation, corneal clouding, and tetraphocomelia.
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Fig. 2. A newborn with Roberts syndrome variant showing bilateral cleft lip and cleft palate, phocomelia, club hands with an appendage-like thumb on the right and a missing thumb on the left. The infant also had intrauterine growth retardation, hydrocephalus, cloudy cornea, AV canal heart defect, and normal lower extremities. Cytogenetic studies revealed no premature centromere separation. The mother took Diflucan during pregnancy and the teratogenic etiology was a possibility.
Robinow Syndrome In 1969, Robinow et al. described a new dwarfing syndrome characterized by mesomelic shortening of extremities, hemivertebrae, genital hypoplasia, and “fetal facies”. The incidence is estimated to be approximately 1 in 500,000.
2.
GENETICS/BASIC DEFECTS 1. Autosomal recessive form a. Phenotype tends to be more severe than the autosomal dominant form b. Caused by different homozygous missense, nonsense, and frameshift mutations of the ROR2 gene c. ROR2 gene i. Mapped to chromosome 9q22 ii. Encoding an orphan receptor tyrosine kinase 2 with orthologues in mouse and other species iii. Allelic to dominant brachydactyly type B (characterized by terminal deficiency of fingers and toes) 2. Autosomal dominant form: uncertain whether it is caused by mutations in ROR2 or caused by mutations in a different gene
3.
4.
CLINICAL FEATURES 1. Characteristic craniofacial appearance a. Early childhood i. Midfacial hypoplasia ii. Occasional midline capillary hemangioma iii. Eyes a) Marked hypertelorism b) Prominent eyes giving appearance of exophthalmos (pseudoexophthalmos) iv. A short upturned nose v. Mouth a) “Tented” upper lip having an inverted V appearance with tethering in the center b) Midline clefting of the lower lip c) Gum hypertrophy at birth d) Dental crowding/irregular teeth e) “Tongue tie” (ankyloglossia) resembling a bifid tongue when the tongue tie is marked vi. Ears a) Low set b) Simple c) Deformed pinna vii. Resemblance to a fetal face a) Relatively small face b) Laterally displaced eyes c) Forward pointing alae nasi d) “Fetal facies” becomes less prominent over time b. Adulthood i. Loss of fetal facial proportions 856
5.
6.
ii. Absent midfacial hypoplasia iii. Persistent hypertelorism with a broad nasal root and broad forehead Short stature a. Reduced birth length b. Not an universal finding with some reports of normal growth Limb abnormalities a. Mesomelic or acromesomelic limb shortening b. Shortening of the forearms more striking than the shortening of the legs c. Occasional Madelung deformity d. Hands/feet i. Brachydactyly with shortening of the distal phalanx and nail hypoplasia or dystrophy ii. Thumbs a) Displaced b) Occasionally bifid c) Partial cutaneous syndactyly d) Ectrodactyly (especially patients reported from Turkey) Other skeletal abnormalities a. Chest deformities b. Kyphoscoliosis c. Vertebral anomalies d. Rib defects e. Pectus excavatum f. Acrodysostosis g. Delayed bone age Genital hypoplasia a. Genital abnormalities: may be present at birth causing concern regarding gender assignment i. Males a) Micropenis b) Normal scrotum and testes ii. Females a) Reduced clitoral size b) Hypoplasia of the labia minor c) Associated vaginal atresia and hematocolpos iii. Onset of puberty normal in both sexes iv. Several reports of both male and female patients having normal children Congenital heart defects (15%) a. Severe pulmonary stenosis or atresia (the most common cardiac abnormalities) b. Atrial septal defect c. Ventricular septal defect d. Coarctation of the aorta e. Bicuspid aortic valve f. Tetralogy of Fallot g. Tricuspid atresia h. Double outlet right ventricle i. Patent ductus arteriosus
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7. Renal abnormalities a. Hydronephrosis (relatively common) b. Cystic dysplasia of the kidney 8. Developmental delay but intelligence is usually normal 9. Dermatoglyphics a. Absent interphalangeal creases b. Bilateral transverse creases c. Hypothenar whorl pattern 10. Clinical characteristics of recessive Robinow syndrome: more frequently manifests orthopedic involvement (vertebral/rib anomalies and more severe mesomelic brachymelia) than the dominant form a. Short stature b. Mesomelic and acromelic brachymelia c. Thick abnormally modeled radius and ulna d. Characteristic face i. Hypertelorism ii. Wide palpebral fissures iii. Broad based nose with everted nares iv. Large mouth v. Gum hypertrophy vi. Irregular and crowded teeth e. Costovertebral anomalies f. Endocrine dysfunction i. Empty sella ii. Partial insensitivity of Leydig cells to HCG iii. Low basal testosterone in prepubertal boys iv. Defective sex-steroid feedback mechanism g. Micropenis in males 11. Differential diagnosis of mesomelic dwarfism a. With Madelung deformity: dyschondrosteosis b. With malformations of long bones depending on various distribution/severity patterns and types of transmission i. Ulno-fibular a) With mild triangular deformity b) With extreme variety: Boomerang bone disease ii. Radio-tibial with “normal” fibula iii. Ulno-fibular-mandibular (Langer type, homozygous dyschondrosteosis) iv. Ulno-radio-fibular-tarsal with square, triangular or rhomboid tibia v. Ulno-radio-tibial with absent fibula c. With associated malformations of spine i. Robinow syndrome ii. Wegmann syndrome iii. Campallia and Martinelli syndrome iv. “Spondylo-epiphyso-metaphyseal” d. With acrodysplasia i. Acromesomelic dwarfism ii. Ellis-van Creveld syndrome iii. Grebe achondrogenesis
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Skull i. Macrocephaly ii. Prominent forehead iii. Hypertelorism
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iv. Hypoplastic mandible v. Dental anomalies b. Spine/ribs: widespread fusion of thoracic vertebrae with frequent hemivertebrae and fusion of the ribs, resembling Jarcho-Levin syndrome (spondylocostal dysostosis) in severe cases (autosomal recessive form) i. Hemivertebrae and vertebral fusions ii. Fusion of ribs iii. Shortened interpeduncular distance c. Extremities (long bones): mesomelic shortening i. Upper extremities ii. Lower extremities iii. Ulna shorter than radius iv. Luxation of the radius d. Hands and feet i. Brachymesophalangism of fifth digits ii. Clinodactyly of the fifth digits iii. Shortening of other phalanges iv. Brachymetacarpism v. Fusion of carpal bones vi. Bifid terminal phalanges (splitting of one or more distal phalanges) vii. Fusion of phalanges viii. Retarded bone age Renal ultrasound for renal anomalies Echocardiography for congenital heart disease Growth hormone assay for possible growth hormone deficiency DNA mutation analysis by sequencing of entire coding region of ROR2 gene
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal dominant inheritance: not increased unless a parent is affected ii. Autosomal recessive inheritance: 25% b. Patient’s offspring i. Autosomal dominant inheritance: 50% ii. Autosomal recessive inheritance: not increased unless the spouse is a carrier 2. Prenatal diagnosis possible by ultrasonography: measure the length of the long bones and the ulna/humerus ratio for the fetus at risk. Prenatal diagnosis is also possible by sequencing of entire coding region of ROR2 gene on fetal DNA obtained by amniocentesis or CVS, provided disease-causing alleles have been previously identified in the proband. 3. Management a. Anticipate difficult intubation because of midfacial hypoplasia b. Orthopedic care for vertebral anomalies and hip dislocation c. Orthodontics for dental malalignment d. Surgery for cleft lip and palate, inguinal hernia and undescended testes e. Growth hormone therapy if associated with growth hormone deficiency f. Testosterone therapy for micropenis not proven useful g. Psychologic support
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REFERENCES Afzal AR, Rajab A, Fenske C, et al.: Linkage of recessive Robinow syndrome to a 4 cm interval on chromosome 9q22. Hum Genet 106:351–354, 2000. Afzal AR, Rajab A, Fenske C, et al.: Autosomal recessive Robinow syndrome is allelic to dominant brachydactyly type B and caused by loss of function mutations in ROR2. Nat Genet 25:419–422, 2000. Afzal AR, Jeffery S: One gene, two phenotypes: ROR2 mutations in autosomal recessive Robinow syndrome and autosomal dominant brachydactyly type B. Human Mutat 22:1–11, 2003. Al-Ata J, Paquet M, Teebi AS. Congenital heart disease in Robinow syndrome. Am J Med Genet 77:332–333, 1998. Atalay S, Ege B, Imamoglu A, et al.: Congenital heart disease and Robinow syndrome. Clin Dysmorphol 2:208–210, 1993. Butler MG, Wadlington WB: Robinow syndrome: report of two patients and review of literature. Clin Genet 31:77–85, 1987. Castells S, Chakurkar A, Qazi Q, et al.: Robinow syndrome with growth hormone deficiency: treatment with growth hormone. J Pediatr Endocrinol Metab 12:565–571, 1999. Giedion A, Battaglia GF, Bellini F, et al.: The radiological diagnosis of the fetal-face (= Robinow) syndrome (mesomelic dwarfism and small genitalia). Report of 3 cases. Helv Paediatr Acta 30:409–423, 1976. Kantaputra PN, Gorlin RJ, Ukarapol N, et al.: Robinow (fetal face) syndrome: report of a boy with dominant type and an infant with recessive type. Am J Med Genet 84:1–7, 1999. Kawai M, Yorifuji T, Yamanaka C, et al.: A case of Robinow syndrome accompanied by partial growth hormone insufficiency treated with growth hormone. Horm Res 48:41–43, 1997. Lee PA, Migeon CJ, Brown TR, et al.: Robinow’s syndrome. Partial primary hypogonadism in pubertal boys, with persistence of micropenis. Am J Dis Child 136:327–330, 1982.
Lovero G, Guanti G, Caruso G, et al.: Robinow’s syndrome: prenatal diagnosis. Prenat Diagn 10:121–126, 1990. Patton MA, Afzal AR: Robinow syndrome. J Med Genet 39:305–310, 2002. Percin EF, Guvenal T, Cetin A, et al.: First-trimester diagnosis of Robinow syndrome. Fetal Diagn Ther 16:308–311, 2001. Robinow M, Silverman FN, Smith HD. A newly recognized dwarfing syndrome. Am J Dis Child 117:645–651, 1969. Robinow M. The Robinow (fetal face) syndrome: a continuing puzzle. Clin Dysmorphol 2:189–198, 1993. Schorderet DF, Dahoun S, Defrance I, et al.: Robinow syndrome in two siblings from consanguineous parents. Eur J Pediatr 151:586–589, 1992. Soliman AT, Rajab A, Alsalmi I, et al.: Recessive Robinow syndrome: with emphasis on endocrine functions. Metabolism 47:1337–1343, 1998. Teebi AS: Autosomal recessive Robinow syndrome. Am J Med Genet 35:64–68, 1990. van Bokhoven H, Celli J, Kayserili H, et al.: Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome. Nat Genet 25:423–426, 2000. (Erratum in Nat Genet 26:383, 2000.) Wadlington WB, Tucker VL, Schimke RN: Mesomelic dwarfism with hemivertebrae and small genitalia (the Robinow syndrome). Am J Dis Child 126:202–205, 1973. Webber SA, Wargowski DS, Chitayat D, et al.: Congenital heart disease and Robinow syndrome: coincidence or an additional component of the syndrome? Am J Med Genet 37:519–521, 1990. Wiens L, Strickland DK, Sniffen B, et al.: Robinow syndrome: report of two patients with cystic kidney disease. Clin Genet 37:481–484, 1990. Wilcox DT, Quinn FM, Ng CS, et al.: Redefining the genital abnormality in the Robinow syndrome. J Urol 157:2312–2314, 1997.
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Fig. 1. A child with Robinow syndrome showing prominent forehead, ocular hypertelorism, short upturned nose, pectus excavatum, penile hypoplasia, and acromesomelic shortening of the limbs.
Rubinstein-Taybi Syndrome In 1963, Rubinstein and Taybi described a new syndrome characterized by broad thumbs and toes, facial abnormalities, and mental retardation. The prevalence of Rubinstein-Taybi syndrome is estimated to be 1 in 100,000 to 125,000 live births in the Netherlands.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal dominant 2. Caused by deletions or heteroallelic mutations of CREBBP, the gene for cAMP responsive element binding (CREB) protein, which resides on chromosome 16p13.3. CREBBP is a large nuclear protein involved in transcription regulation, chromatin remodeling, and the integration of several different signal transduction pathways. The following mutations of CREBBP were reported in patients with RubinsteinTaybi syndrome: a. Chromosomal translocations/inversions b. Deletions at the microscopic and submicroscopic level c. Molecular mutations 3. Mutations in the CREBBP gene are responsible for: a. Rubinstein-Taybi syndrome b. t(8;16)-associated acute myeloid leukemia 4. No clear phenotypic differences observed between patients in which microdeletions or truncating mutations were found
CLINICAL FEATURES 1. Characteristic craniofacial features a. Microcephaly (35–94%) b. Prominent forehead c. Down-slanting palpebral fissures d. Apparent ocular hypertelorism e. High-arched or heavy eyebrows f. Long eyelashes g. Epicanthal folds h. Prominent nose with columella (lower margin of the nasal septum) below the alae nasi i. Malpositioned ears with dysplastic helices j. Grimacing smile k. Hypoplastic maxilla l. Mild retrognathia m. High arched palate 2. Skeletal abnormalities a. Thumbs i. Broad terminal phalanges ii. Severe radial angulation deformity (“hitch-hiker thumbs”) with abnormal shape of proximal phalanx, which prevents opposition and functional gripping strength b. Great toes i. Broad terminal phalanges 860
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ii. Angulation deformity with abnormal shape of proximal phalanx or first metatarsal iii. Duplicated proximal phalanx iv. Duplicated distal phalanx c. Short stature (78%) d. 5th finger clinodactyly e. Overlapping toes f. Broad terminal phalanges of other fingers g. Pelvic anomalies i. Flat acetabular angles ii. Flaring of the ilia iii. Notch in the ischia h. Stiff gait i. Lax ligaments j. Hyperextensible joints k. Vertebral anomalies i. Spina bifida ii. Kyphosis iii. Lordosis iv. Scoliosis l. Sternal or rib anomalies i. Premature fusion ii. Simian sternum iii. Pectus excavatum or carinatum iv. Forked ribs v. Cervical ribs vi. Fusion of the first and second ribs History of maternal polyhydramnios (39%) Hypotonia Developmental delay Variable mental retardation a. Severe in some patients b. Moderate degree in many patients c. Mild in some patients Behavioral/psychiatric disorders a. Childhood i. Short attention span ii. Impulsiveness iii. Clinically nonsignificant stereotype iv. Withdrawal v. Nonspecific ‘maladaptive behavior’ vi. Repetitive motions vii. Resistance to change viii. Distractibility ix. Aggressive outbursts x. Difficulty in sleeping b. Adulthood i. Mood disorders ii. Chronic motor tic disorder iii. Obsessive compulsive disorder iv. Depressive disorder v. Bipolar disorder vi. Tourette disorder
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vii. Trichotillomania viii. Pervasive developmental disorder ix. Self-injurious behaviors x. Autistic features Seizures (27–28%) Ophthalmologic problems a. Strabismus (60–71%) with subsequent risk of amblyopia b. Refractive errors (41–56%) c. Lacrimal duct obstructions (38–47%) d. Ptosis (29–32%) e. Coloboma (9–11%) f. Duane retraction syndrome (8%) g. Ghost vessels h. Peters anomaly i. Optic nerve hypoplasia j. Cataracts k. Corneal opacities l. Congenital glaucoma m. Retinal abnormalities Dental manifestations (67%) a. Talon cusps of secondary dentition b. Crowding and malpositioned teeth c. Anterior and posterior crossbites secondary to a narrow palate or jaw size discrepancy d. Natal teeth e. Gingivitis f. Hypo/hyperdontia g. Increased rate of carries Upper airway obstruction during sleep due to: a. Hypotonia b. Anatomy of the oropharynx and airway i. Small nasal passages ii. Retrognathia iii. Micrognathia iv. Hypertrophy of the tonsils and adenoids v. Obesity Gastrointestinal problems a. Significant gastroesophageal reflux b. Feeding difficulties c. Constipation Congenital heart disease (24–38%) a. ASD b. VSD c. PDA d. Coarctation of the aorta e. Pulmonary stenosis f. Bicuspid aortic valve g. Pseudotruncus h. Aortic stenosis i. Hypoplastic left heart syndrome j. Complex congenital heart defects k. Dextrocardia l. Vascular rings m. Conduction problems Renal anomalies (52%) a. Hydronephrosis b. Duplications c. Vesicoureteral reflux d. Urinary tract infections
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e. Renal stones f. Nephrotic syndrome g. Neurogenic bladder 15. Cutaneous manifestations a. Tendency of keloid and hypertrophic scar formation b. Ingrown toenails c. Toenail paronychia (44%) d. Fingernail paronychia (9%) e. Pilomatrixomas f. Capillary hemangioma i. Forehead ii. Nape of the neck iii. Back g. Supernumerary nipples h. Hirsutism i. Transverse palmar creases j. Deep plantar crease between the first and second toes 16. Orthopedic problems a. Hypotonia b. Lax ligaments c. Tight heel cords d. Elbow abnormalities e. Legg-Perthes disease (3%) f. Dislocated patella (2.5%) g. Congenital hip dislocation (1.4%) h. Slipped capital femoral epiphysis (0.6%) i. Congenital or acquired scoliosis, kyphosis, and lordosis j. An increased risk of associated thickened filum terminale, tethering of the cord, and lipoma k. An increased risk of fractures 17. An increased risk of having benign and malignant tumors as well as leukemia and lymphoma a. Oligodendroglioma b. Medulloblastoma c. Neuroblastoma d. Meningioma e. Pheochromocytoma f. Nasopharyngeal rhabdomyosarcoma g. Leiomyosarcoma h. Seminoma i. Embryonal carcinoma j. Odontoma k. Choristoma l. Dermoid cyst m. Pilomatrixomas
DIAGNOSTIC INVESTIGATIONS 1. 2. 3. 4. 5. 6. 7. 8.
Developmental evaluation Echocardiography for cardiac defects Ophthalmologic examination Renal ultrasound Voiding cystourethrogram Hearing evaluation EEG abnormalities Radiography a. Hands i. Broad 1st distal phalanx ii. Broad 1st ray iii. Duplicated 1st distal phalanx
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iv. Delta-shaped proximal phalanges of the thumbs v. Mushroom-shaped distal phalanges vi. Angulation of the distal phalanges vii. Thin tubular bones viii. Delayed bone age (74%) b. Feet i. Broad 1st distal phalanx ii. Broad 1st ray iii. Duplicated 1st distal phalanx iv. Duplicated 1st proximal and distal phalanx v. Delta-shaped 1st proximal phalanx. A duplicated longitudinal bracketed epiphysis (“kissing delta” phalanx) always involve the proximal phalanx of the great toe vi. Angulation deformity of the hallux vii. Mushroom-shaped distal phalanges viii. Very small distal phalanges ix. Thin tubular bones x. Protruding calcaneus xi. Synostosis of cuneiform ossicles xii. Proximally split 5th metatarsal bone c. Limbs i. Thin tubular bones ii. Fractures iii. Patella luxations d. Spine i. Cervical hyperkyphosis ii. Lumbar hyperlordosis iii. Scoliosis iv. Spina bifida occulta: cervical or lumbosacral v. Spondylolisthesis vi. Irregular thoracic endplates e. Skull i. Microcephaly ii. Absent sinus frontalis iii. Deviated nasal septum iv. Steep skull base v. Abnormally-shaped sella turcica vi. Foramina parietale permagna vii. Prominent digital marking f. Thorax i. Narrow thoracic aperture ii. 11 ribs iii. Fusion of ribs iv. High diaphragm g. Pelvis i. Small iliac wings ii. Flaring iliac wings iii. Irregularly formed acetabulum iv. Symphysiolysis 9. Diagnosis of Rubinstein-Taybi syndrome a. Made primarily by clinical examination b. Confirmed by the presence of microdeletion 10. Cytogenetic analysis a. FISH analysis with cosmids from the CBP region to detect chromosome 16p13.3 b. Chromosome abnormalities i. t(2;16)(p13.3;p13.3) ii. t(7;16)(q34;p13.3) iii. Inv(16)(p13.3q13)
11. Mutation analysis of CREBBP gene a. SSCP b. Genomic sequencing c. Protein truncation test (10% of cases) d. Fluorescent in situ hybridization (FISH) probes i. Specific for chromosome region 16p13.3 ii. Containing regions of the cyclic AMP-responsive element-binding protein gene (CBP gene) iii. Microdeletions identified in approximately 10% of patients by five cosmid probes containing almost the entire gene
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 0.1% based on empiric data b. Patient’s offspring: as high as 50%, particularly in individuals with deletions 2. Prenatal diagnosis: possible for fetuses at risk using FISH on fetal cells obtained by amniocentesis or chorionic villus sampling, provided the FISH has identified a deletion in an affected family member 3. Management a. Early intervention programs i. Physical therapy ii. Occupational therapy iii. Speech therapy b. Management of gastroesophageal reflux c. Prophylaxis for subacute bacterial endocarditis for patients at risk d. Require assistance and training in self-help skills but can become self-sufficient in most self-help areas such as feeding, dressing, and toileting e. Special education f. Behavioral modification g. Surgery to correct a delta phalanx deformity h. Caution with general anesthesia in children i. Challenging to intubate due to airway anomalies a) Relatively anterior position of the larynx b) Easily collapsible laryngeal wall ii. Important to intubate due to the high risk of aspiration during induction and emergence iii. Presence of skeletal anomalies iv. Cardiac arrhythmia may result from use of cardioactive drugs a) Atropine b) Neostigmine c) Succinylcholine d) Suxamethonium
REFERENCES Allanson JE: Rubinstein-Taybi syndrome: the changing face. Am J Med Genet Suppl 6:38–41, 1990. Bartsch O, Wagner A, Hinkel GK, et al.: FISH studies in 45 patients with Rubinstein-Taybi syndrome: deletions associated with polysplenia, hypoplastic left heart and death in infancy. Eur J Hum Genet 7:748–756, 1999. Bartsch O, Locher K, Meinecke P, et al.: Molecular studies in 10 cases of Rubinstein-Taybi syndrome, including a mild variant showing a missense mutation in codon 1175 of CREBBP. J Med Genet 39:496–501, 2002. Baxter G, Beer J: Rubinstein-Taybi syndrome. Psychol Rep 70:451–456, 1992. Berry AC: Rubinstein-Taybi syndrome. J Med Genet 24:562–566, 1987.
RUBINSTEIN-TAYBI SYNDROME Blough RI, Petrij F, Dauwerse JG, et al.: Variation in microdeletions of the cyclic AMP-responsive element-binding protein gene at chromosome band 16p13.3 in the Rubinstein-Taybi syndrome. Am J Med Genet 90:29–34, 2000. Breuning MH, Dauwerse HG, Fugazza G, et al.: Rubinstein-Taybi syndrome caused by submicroscopic deletions within 16p13.3. Am J Hum Genet 52:249–254, 1993. Cantani A, Gagliesi D: Rubinstein-Taybi syndrome. Review of 732 cases and analysis of the typical traits. Eur Rev Med Pharmacol Sci 2:81–87, 1998. Carey JC, Curry CJR: Rubinstein-Taybi syndrome: new look at an “old” syndrome. Am J Med Genet (Suppl 6):2, 1990. Coupry I, Roudaut C, Stef M, et al.: Molecular analysis of the CBP gene in 60 patients with Rubinstein-Taybi syndrome. J Med Genet 39:415–421, 2002. Filippi G: The Rubinstein-Taybi syndrome. Report of 7 cases. Clin Genet 3:303–318, 1972. Giles RH, Petru F, Dauwerse HG, et al.: Constructions of a 1.2-Mb contig surrounding, and molecular analysis of the human CREB-binding protein (CBP/CREBBP) gene on chromosome 16p13.3. Genomics 42:96–114, 1997. Gotts EE, Liemohn WP: Behavioral characteristics of three children with the broad thumb-hallux (Rubinstein-Taybi) syndrome. Biol Psychiatry 12: 413–423, 1977. Hellings JA, Hossain S, Martin JK, et al.: Psychopathology, GABA, and the Rubinstein-Taybi syndrome: a review and case study. Am J Med Genet 114:190–195, 2002. Hennekam RC: Bibliography on Rubinstein-Taybi syndrome. Am J Med Genet Suppl 6:77–83, 1990. Hennekam RC: Rubinstein-Taybi syndrome: a history in pictures. Clin Dysmorphol 2:87–92, 1993. Hennekam RC, Baselier AC, Beyaert E, et al.: Psychological and speech studies in Rubinstein-Taybi syndrome. Am J Ment Retard 96:645–660, 1992. Hennekam RC, Lommen EJ, Strengers JL, et al.: Rubinstein-Taybi syndrome in a mother and son. Eur J Pediatr 148:439–441, 1989. Hennekam RC, Van Doorne JM: Oral aspects of Rubinstein-Taybi syndrome. Am J Med Genet Suppl 6:42–47, 1990. Hennekam RC, Stevens CA, Van de Kamp JJ: Etiology and recurrence risk in Rubinstein-Taybi syndrome. Am J Med Genet (Suppl 6):56–64, 1990. Hennekam RC, Van Den Boogaard MJ, Sibbles BJ, et al.: Rubinstein-Taybi syndrome in The Netherlands. Am J Med Genet (Suppl 6):17–29, 1990. Hennekam RC, Tilanus M, Hamel BC, et al.: Deletion at chromosome 16p13.3 as a cause of Rubinstein-Taybi syndrome: clinical aspects. Am J Hum Genet 52:255–262, 1993. Imaizumi K, Kuroki Y: Rubinstein-Taybi syndrome with de novo reciprocal translocation t(2;16)(p13.3;p13.3). Am J Med Genet 38:636–639, 1991. Imaizumi K, Kurosawa K, Masuno M, et al.: Chromosome aberrations in Rubinstein-Taybi syndrome. Clin Genet 43:215–216, 1993. Lacombe D, Saura R, Taine L, et al.: Confirmation of assignment of a locus for Rubinstein-Taybi syndrome gene to 16p13.3. Am J Med Genet 44:126–128, 1992. Levitas AS, Reid CS: Rubinstein-Taybi syndrome and psychiatric disorders. J Intellect Disabil Res 42 (Pt 4):284–292, 1998. Masuno M, Imaizumi K, Kurosawa K, et al.: Submicroscopic deletion of chromosome region 16p13.3 in a Japanese patient with Rubinstein-Taybi syndrome. Am J Med Genet 53:352–354, 1994. McGaughran JM, Gaunt L, Dore J, et al.: Rubinstein-Taybi syndrome with deletions of FISH probe RT1 at 16p13.3: two UK patients. J Med Genet 33:82–83, 1996.
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Miller RW, Rubinstein JH: Tumors in Rubinstein-Taybi syndrome. Am J Med Genet 56:112–115, 1995. Partington MW: Rubinstein-Taybi syndrome: a follow-up study. Am J Med Genet Suppl 6:65–68, 1990. Petrij F, Giles RH, Dauwerse HG, et al.: Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 376:348–351, 1995. Petrij F, Dauwerse HG, Blough RI, et al.: Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations. J Med Genet 37:168–176, 2000. Petrij F, Dorsman JC, Dauwerse HG, et al.: Rubinstein-Taybi syndrome caused by a De Novo reciprocal translocation t(2;16)(q36.3;p13.3). Am J Med Genet 92:47–52, 2000. Petrij F, Giles RH, Breuning MH, et al.: Rubinstein-Taybi syndrome. In: Scriver CR, Beaudet al., Valle D, Sly WS, eds. The metabolic and molecular bases of inherited disease. 8th ed. Chapter 248, New York: McGrawHill, 2001:6167–6182. Rubinstein JH: The broad thumbs syndrome-Progress report 1968. Birth Defects Original Article Series 5(2):25–41, 1969. Rubinstein JH: Broad thumb-hallux (Rubinstein-Taybi) syndrome 1957-1988. Am J Med Genet Suppl 6:3–16, 1990. Rubenstein JH, Taybi H: Broad thumbs and facial abnormalities. Am J Dis Child 105:588–608, 1963. Rubinstein-Taybi syndrome. Papers presented at the 9th annual David W. Smith Workshop on Malformations and Morphogenesis. Oakland, 1988. Proceedings. Am J Med Genet (Suppl 6):1–131, 1990. Selmanowitz VJ, Stiller MJ: Rubinstein-Taybi syndrome. Cutaneous manifestations and colossal keloids. Arch Dermatol 117:504–506, 1981. Stevens CA: Rubinstein-Taybi syndrome. Gene Reviews. www.genetests.org Stevens CA, Bhakta MG: Cardiac abnormalities in the Rubinstein-Taybi syndrome. Am J Med Genet 59:346–348, 1995. Stevens CA, Carey JC, Blackburn BL: Rubinstein-Taybi syndrome: a natural history study. Am J Med Genet Suppl 6:30–37, 1990. Stirt JA: Anesthetic problems in Rubinstein-Taybi syndrome. Anesth Analg 60:534–536, 1981. Taine L, Goizet C, Wen ZQ, et al.: Submicroscopic deletion of chromosome 16p13.3 in patients with Rubinstein-Taybi syndrome. Am J Med Genet 78:267–270, 1998. Tommerup N, van der Hagen CB, Heiberg A: Tentative assignment of a locus for Rubinstein-Taybi syndrome to 16p13.3 by a de novo reciprocal translocation, t(7;16)(q34;p13.3). Am J Med Genet 44:237–241, 1992. van Genderen MM, Kinds GF, Riemslag FC, et al.: Ocular features in Rubinstein-Taybi syndrome: investigation of 24 patients and review of the literature. Br J Ophthalmol 84:1177–1184, 2000. Wallerstein R, Anderson CE, Hay B, et al.: Submicroscopic deletions at 16p13.3 in Rubinstein-Taybi syndrome: frequency and clinical manifestations in a North American population. J Med Genet 34:203–206, 1997. Wiley S, Swayne S, Rubinstein JH, et al.: Rubinstein-Taybi syndrome medical guidelines. Am J Med Genet 119A:101–110, 2003. Wood VE, Rubinstein JH: Surgical treatment of the thumb in the RubinsteinTaybi syndrome. J Hand Surg [Br] 12:166–172, 1987. Wood VE, Rubinstein J: Duplicated longitudinal bracketed epiphysis “kissing delta phalanx” in Rubinstein-Taybi syndrome. J Pediatr Orthop 19:603–606, 1999.
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Fig. 1. A patient with Rubinstein-Taybi syndrome at different ages (childhood and adulthood) showing typical facial appearance (prominent beaked nose with the columella below the alae nasi), broad thumbs, and broad/bifid great toes, which are illustrated by radiographs.
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Fig. 3. A young patient with Rubinstein-Taybi syndrome showing characteristic facies, broad thumbs, and great toes.
Fig. 2. An adult with Rubinstein-Taybi syndrome showing the characteristic facies and broad thumbs.
Schizencephaly ii. Type II (open-lip schizencephaly): Presence of a large defect, a holohemispheric cleft in the cerebral cortex filled with cerebral spinal fluid and lined by polymicrogyric grey matter d. Associated malformations commonly accompanying schizencephaly i. Mild hypoplasia of the corpus callosum ii. Total or nearly total absence of cavum septum pellucidum in 70–90% of patients with schizencephaly. 30–50% of patients show associated optic nerve hypoplasia on clinical examination (septo-optic dysplasia with schizencephaly) iii. Focal cortical dysplasia iv. Coloboma of the retina v. Hydrocephalus 4. Syndromes associated with schizencephaly a. Septo-optic dysplasia-schizencephaly syndrome i. Clinical features distinct from isolated septo-optic dysplasia ii. Significant global developmental delay and spastic motor deficits iii. Seizures and visual symptoms rather than with endocrine abnormalities b. Other rare schizencephaly syndromes i. Prenatal cytomegalovirus infection ii. Vascular disruption related to twinning c. Schizencephaly (plus polymicrogyria) as part of multiple congenital anomaly/mental retardation syndromes i. Adam-Oliver syndrome ii. Aicardi syndrome iii. Arima syndrome iv. Delleman (oculocerebrocutaneous ) syndrome v. Galloway-Mowat syndrome vi. Micro syndrome
Schizencephaly is a rare congenital brain malformation characterized by deep clefts of the cerebral mantle that extend from the cortical surface to the lateral ventricles. The conditions are often associated with convolutional anomalies such as polymicrogyria or nodular subependymal heterotopias.
GENETICS/BIRTH DEFECTS 1. Inheritance a. Isolated schizencephaly: mainly sporadic b. Rare reports of familial cases 2. Etiology a. A developmental defect in the blood vessels supplying the cerebral cortex i. Resulting in tissue death and cleft formation due to lack of oxygen (in utero vascular insufficiency) ii. With preferential location in the parasylvian regions following the frontoparietal distribution of the middle cerebral artery b. Mutations in the homeodomain gene Emx2 as a possible cause of some cases of schizencephaly i. At least some schizencephaly cases result from germline mutations ii. Emx2: expressed in restricted areas of the developing mammalian forebrain, including areas that develop into the cerebral cortex iii. Discovery of Emx2 mutations in both sporadic and familial cases of schizencephaly marking an important advance in establishing genetic causes for brain malformations iv. Lack of Emx2 mutations in most schizencephaly patients has increased the likelihood of other genes being involved 3. Schizencephaly a. Refers to gray matter lined clefts that extend through the entire hemisphere from the ependymal lining of the lateral ventricles to the pial covering of the cortex b. Cleft i. A cleft in cerebral mantle which communicates between the subarachnoid space laterally and ventricular system medially a) Unilateral or bilateral cleft b) Symmetric or asymmetric cleft ii. The sides of clefts generally lined with heterotopic gray matter (an abnormal accumulation of neurons) c. Two types of schizencephaly depending on the size of the area involved and the separation of the cleft lips i. Type I (closed-lip schizencephaly) a) Consisting of a fused cleft b) This fused pial-ependymal seam forms a furrow in the developing brain and is lined by polymicrogyric grey matter
CLINICAL FEATURES
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1. Clinical manifestations depend on the size and location of involved brain a. A narrow, unilateral cleft i. Usually present with seizures and mild focal neurological deficits ii. Otherwise developmentally normal b. Bilateral clefts i. Severe developmental delay ii. Early intractable epilepsy iii. Severe motor dysfunction 2. Clinical features a. Mental retardation (varying degree) b. Developmental delay: moderate to severe if the defects are large c. Microcephaly (varying degree) d. Hydrocephalus in some patients e. Hypotonia in the postnatal period
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f. g. h. i. j. k.
Motor difficulties Seizures in most patients Generalized spasticity Hemiparesis or quadriparesis Blindness secondary to optic nerve hypoplasia Prognosis depending on the size of the clefts and the degree of neurological deficits i. Patients with type I abnormalities a) Almost normal b) May have seizures and spasticity ii. Patients with smaller, unilateral clefts (clefts in only one hemisphere) a) Often paralyzed on one side of the body b) May have normal intelligence iii. Patients with type II abnormalities a) Mental retardation b) Seizures c) Hypotonia d) Spasticity e) Inability to walk or speak f) Blindness iv. Patients with bilateral open-lip schizencephaly generally with the worst clinical symptoms
DIAGNOSTIC INVESTIGATIONS 1. Ultrasonography of the brain to demonstrate closed-lip or open-lipped brain cleft communicating with lateral ventricle(s) 2. Magnetic resonance imaging (MRI) or computed tomography (CT) of the brain a. Open-lipped or closed-lipped schizencephaly b. Associated absence of the septum pellucidum and hypoplasia of the optic chiasm 3. Pathology a. Clefts most commonly in the Rolandic fissures b. Frequently associated with pachygyria, polymicrogyria or lissencephaly 4. Molecular genetic testing of EMX2 mutation for familial schizencephaly
GENETIC COUNSELING 1. Recurrence risk: low unless germline mutation is present in one of the parent 2. Prenatal diagnosis with ultrasonography to demonstrate brain clefts connecting to the lateral ventricles and with EMX2 gene mutation analysis of amniocytes and CVS to the end 3. Management a. Physical therapy b. Seizure control c. VP shunt for hydrocephalus
REFERENCES Aniskiewicz AS, Frumkin NL, Brady DE, et al.: Magnetic resonance imaging and neurobehavioral correlates in schinzencephaly. Arch Neurol 47:911–916, 1990. Barkovich AJ, Kjos BO: Schizencephaly: correlation of clinical findings with MR characteristics. Am J Neuroradiol 13:85–94, 1992.
Barkovich AJ, Kuzniecky RI, Jackson GD, et al.: Classification system for malformations of cortical development. Update 2001. Neurology 57:2168, 2001. Brunelli S, Faiella A, Capra V, et al.: Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. Nature Genet 12:94–96, 1996. Byrd SE, Osborn RE, Bohan TP, et al.: The CT and MR evaluation of Migrational disorders of the brain. Part I. Lissencephaly and pachygyria. Pediatr Radiology 19:151–156, 1989. Capra V, De Marco P, Moroni A, et al.: Schizencephaly: Surgical features and new molecular genetic results. Eur J Pediatr Surg 6(Suppl 1):27–29, 1996. Ceccherini AF, Twining P, Variend S: Schizencephaly: antenatal detection using ultrasound. Clin Radiol 54:620–622, 1999. Chamberlain MC, Press GA, Bejar RF: Neonatal schizencephaly: comparison of brain imaging. Pediatr Neurol 6:382–387, 1990. Denis D, Maugey-Laulom B, Carles D, et al.: Prenatal diagnosis of schizencephaly by fetal magnetic resonance imaging. Fetal Diagn Ther 16:354–359, 2001. Denis D, Chateil JF, Brun M, et al.: Schizencephaly: clinical and imaging features in 30 infantile cases. Brain Dev 22:475–483, 2000. Faiella A, Brunelli S, Granata T, et al.: A number of schizencephaly patients including 2 brothers are heterozygous for germline mutations in the homeobox gene EMX2. Eur J Hum Genet 5:186–190, 1997. Granata T, Battaglia G, D’Incerti L, et al.: Schizencephaly: neuroradiologic and epileptologic findings. Epilepsia 37:1185–1193, 1996. Granata T, Farina L, Faiella A, et al.: Familial schizencephaly associated with EMX2 mutation. Neurology 48:1404–1406, 1997. Herman M, Rico S: Schizencephaly: Presentation in a 6-week-old boy with fetal death of co-twin. Int Pediatr 14:32–34, 1999. Haverkamp F, Zerres K, Ostertun B, et al.: Familial schizencephaly: further delineation of a rare disorder. J Med Genet 32:242–244, 1995. Hayashi N, Tsutsumi Y, Barkovich AJ: Morphological features and associated anomalies of schizencephaly in the clinical population: detailed analysis of MR images. Neuroradiology 44:418–427, 2002. Hilburger AC, Willis JK, Bouldin F, et al.: Familial schizencephaly. Brain Dev 15:234–236, 1993. Hosley MA, Abroms IF, Ragland RL: Schizencephaly: Case report of familial incidence. Pediatr Neurol 8:148–150, 1991. Klingensmith WC III, Cioffi-Ragan DT: Schizencephaly: Diagnosis and progression in utero. Radiology 159:617–618, 1986. Komarniski CA, Cyr DR, Mack LA, et al.: Prenatal diagnosis of schizencephaly. J Ultrasound Med 9:305–307, 1990. Kuban KC, Teele RL, Wallman J: Septo-optic-dysplasia-schizencephaly. Radiographic and clinical features. Pediatr Radiol 19:145–150, 1989. Landrieu P, Lacroix C: Schizencephaly, consequence of a developmental vasculopathy? A clinicopathological report. Clin Neuropathol 13:192–196, 1994. Lituania M, Passamonti U, Cordono MS, et al.: Schizencephaly: prenatal diagnosis by computed sonography and magnetic resonance imaging. Prenat Diagn 9:649–655, 1989. Lubinsky MS: Hypothesis: septo-optic dysplasia is a vascular disruption sequence. Am J Med Genet 69:235–236, 1997. Miller SP, Shevell MI, Patenaude Y, et al.: Septo-optic plus: A spectrum of malformations of cortical development. Neurology 54:1701–1703, 2000. Miller GM, Stears IC, Cuggenheim MA, et al.: The clinical and computerized tomographic spectrum of schinzencephaly in six patients. Neurology 32:A218–219, 1982. Miller GM, Stears IC, Cuggenheim MA, et al.: Schizencephaly: a clinical and CT study. Neurology 34:997–1001, 1984. Packard AM, Miller VS, Delgado MR: Schizencephaly: Correlations of clinical and radiologic features. Neurology 48:1427–1434, 1997. Pilu GL, Falco P, Perolo A, et al.: Differential diagnosis and outcome of fetal intracranial hypoechoic lesions: report of 21 cases. Ultrasound Obstet Gynecol 9:229–236, 1997. Robinson RO: Familial schizencephaly. Dev Med Child Neurol 33:1010–1012, 1991. Yakovlev PI, Wadsworth RC: Schizencephalies. A study of the congenital clefts in the cerebral mantle. I. Clefts with fused lips. J Neuropathol Exp Neurol 5:116–130, 1946. Yakovlev PI, Wadsworth RC: Schizencephalies. A study of the congenital clefts in the cerebral mantle. II. Clefts with hydrocephalus and lips separated. J Neuropathol Exp Neurol 5:169–206, 1946. Yoshida M, Suda Y, Matsuo I, et al.: Emx1 and Emx2 functions in development of dorsal telencephalon. Development 124:101–110, 1997.
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Fig. 2. An infant with schizencephaly with global delay and spastic quadriplegia. His MRI of the brain showed bilateral large open-lip schizencephaly in frontotemporal regions.
Fig. 1. An infant with asymmetric open-lip parietal schizencephaly, illustrated by MRI.
Fig. 3. MRI of the brain of another patient showing bilateral open-lip schizencephaly in the parietal regions in communication with a large cavity filled by cerebrospinal fluid.
Schmid Metaphyseal Chondrodysplasia ii. Abnormal distal fibular metaphyses d. Wrist i. Abnormal distal radial metaphyses ii. Abnormal distal ulnar metaphyses e. Ribs: anterior cupping, splaying and sclerosis f. Wide metaphyses with cupping and fraying g. Short and stubby long bones h. Normal metacarpals and phalanges i. Normal spine 2. Histology: variable bone changes a. Mild sharp serrations of the metaphyses with increased density of the provisional zone of calcification b. Irregularity with flaring and fragmentation and widening of the growth plate 3. Molecular genetic analysis of COL10A1 mutation a. Mutation analysis b. Mutation scanning
Schmid metaphyseal chondrodysplasia (SMCD) is a mild hereditary chondrodysplasia resulting from growth plate cartilage abnormalities.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant b. Variable expression 2. Molecular pathogenesis a. SMCD: caused by heterozygous mutations in the gene (COL10A1 mapped to chromosome 6q21-q22) for Type X collagen, a short-chain collagen whose expression is largely restricted to the hypertrophic chondrocytes of growth plate cartilage i. Most mutations reside in the carboxylterminal globular domain (CN1) ii. Two mutations observed in a putative signal peptide cleavage site b. Growth plate abnormalities of SMCD: resulting from collagen X haploinsufficiency, a reduction by 50% in collagen X
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: low recurrence risk unless a parent is affected b. Patient’s offspring: 50% 2. Prenatal diagnosis by amniocentesis or CVS: can be offered to families at-risk for DMCD with a previously characterized disease-causing COL10A1 mutation 3. Management a. Supportive b. Orthopedic management of bowed legs: generally does not require orthopedic surgery
CLINICAL FEATURES 1. 2. 3. 4. 5. 6. 7. 8. 9.
Mild to moderate short-limbed dwarfism Bowed legs Waddling gait, often a presenting sign at second year Coxa vara Genu varum Exaggerated lumbar lordosis Flared anterior rib cage Leg pain during childhood Prognosis a. Radiological changes appearing early with a tendency to heal and change slowly with time, giving rise to mildly dwarfed patients b. Normal intelligence
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Hip i. Abnormal acetabular roofs ii. Enlarged capital femoral epiphyses iii. Coxa vara iv. Femoral bowing v. Abnormal proximal femoral metaphyses b. Knee i. Abnormal distal femoral metaphyses ii. Abnormal proximal tibial metaphyses iii. Abnormal proximal fibular metaphyses c. Ankle i. Abnormal distal tibial metaphyses
REFERENCES Bateman JF, Freddi S, Nattrass G, et al.: Tissue-specific RNA surveillance? Nonsense-mediated mRNA decay causes collagen X haploinsufficiency in Schmid metaphyseal chondrodysplasia cartilage. Hum Mol Genet 12:217–225, 2003. Beluffi G, Fiori P, Notarangelo CD, et al.: Metaphyseal dysplasia type Schmid. Early X-ray detection and evolution with time. Ann Radiol (Paris) 26:237–243, 1983. Beluffi G, Fiori P, Schifino A, et al.: Metaphyseal dysplasia, type Schmid. Prog Clin Biol Res 104:103–110, 1982. Bonaventure J, Chaminade F, Maroteaux P: Mutations in three subdomains of the carboxy-terminal region of collagen type X account for most of the Schmid metaphyseal dysplasias. Hum Genet 96:58–64, 1995. Chan D, Jacenko O: Phenotypic and biochemical consequences of collagen X mutations in mice and humans. Matrix Biol 17:169–184, 1998. Chan D, Ho MS, Cheah KS: Aberrant signal peptide cleavage of collagen X in Schmid metaphyseal chondrodysplasia. Implications for the molecular basis of the disease. J Biol Chem 276:7992–7997, 2001. Chan D, Weng YM, Graham HK, et al.: A nonsense mutation in the carboxylterminal domain of type X collagen causes haploinsufficiency in Schmid metaphyseal chondrodysplasia. J Clin Invest 101:1490–1499, 1998. Dharmavaram RM, Elberson MA, Peng M, et al.: Identification of a mutation in type X collagen in a family with Schmid metaphyseal chondrodysplasia. Hum Mol Genet 3:507–509, 1994.
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SCHMID METAPHYSEAL CHONDRODYSPLASIA Dimson SB: Metaphyseal dysostosis type Schmid. Proc R Soc Med 61:1260–1261, 1968. Lachman RS, Rimoin DL, Spranger J: Metaphyseal chondrodysplasia, Schmid type. Clinical and radiographic delineation with a review of the literature. Pediatr Radiol 18:93–102, 1988. Matsui Y, Yasui N, Kawabata H, et al.: A novel type X collagen gene mutation (G595R) associated with Schmid-type metaphyseal chondrodysplasia. J Hum Genet 45:105–108, 2000. Miller SM, Paul LW: Roentgen observations in familial metaphyseal dysostosis. Radiology 83: 665–673, 1964. Milunsky J, Maher T, Lebo R, et al.: Prenatal diagnosis for Schmid metaphyseal chondrodysplasia in twins. Fetal Diagn Ther 13:167–168, 1998. Sawai H, Ida A, Nakata Y, et al.: Novel missense mutation resulting in the substitution of tyrosine by cysteine at codon 597 of the type X collagen gene
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associated with Schmid metaphyseal chondrodysplasia. J Hum Genet 43:259–261, 1998. Schmid F: Beitrag zur dysostosis enchondralis metaphysaria. Monatsschr Kinderheilk 97:393–397, 1949. Schmid TM, Linsenmayer TF: Immunohistochemical localization of short chain cartilage collagen (type X) in avian tissues. J Cell Biol 100:598–605, 1985. Wallis GA, Rash B, Sweetman WA, et al.: Amino acid substitutions of conserved residues in the carboxyl-terminal domain of the alpha 1(X) chain of type X collagen occur in two unrelated families with metaphyseal chondrodysplasia type Schmid. Am J Hum Genet 54:169–178, 1994. Wallis GA, Rash B, Sykes B, et al.: Mutations within the gene encoding the alpha 1 (X) chain of type X collagen (COL10A1) cause metaphyseal chondrodysplasia type Schmid but not several other forms of metaphyseal chondrodysplasia. J Med Genet 33:450–457, 1996. Warman ML, Abbott M, Apte SS, et al.: A type X collagen mutation causes Schmid metaphyseal chondrodysplasia. Nat Genet 5:79–82, 1993.
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SCHMID METAPHYSEAL CHONDRODYSPLASIA
Fig. 1. Three young children with Schmid metaphyseal chondrodysplasia showing short stature, lumbar lordosis, and bowing of the legs. Radiographs showed genu varum and metaphyseal widening with fraying and cupping. Epiphyses are normal.
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Seckel Syndrome In 1960, Seckel reported two personal cases and 13 cases from the literature of a clinical condition characterized by severe intrauterine and postnatal proportionate dwarfism, severe microcephaly, “bird-headed” profile with receding forehead and chin, large and beaked nose, severe mental retardation and other anomalies. Seckel syndrome (SCKL) is a rare heterogeneous type of primordial dwarfism with frequency of less than 1 in 10,000 live births.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Genetic heterogeneity a. SCKL1: A gene for Seckel syndrome was mapped to human chromosome 3q22.1-q24 in two inbred Pakistani families originating from the same village i. The gene encoding ataxia-telangiectasia and Rad3-related protein (ATR) maps to the critical region to an interval of 5Mbp between markers D3S1316 and D3S1557 ii. A synonymous mutation in affected individuals was identified that alters ATR splicing iii. The mutation confers a phenotype including marked microcephaly and dwarfism b. SCKL2: Another gene locus was mapped to chromosome 18p11.31-q11.2 in one inbred Iraqi family c. SCKL3: A novel locus at 14q23 by linkage analysis in 13 Turkish families. The novel gene locus SCKL3 is 1.18 cM and harbors ménage a trios 1, a gene with a role in DNA repair
CLINICAL FEATURES 1. Broad interfamilial clinical heterogeneity 2. Growth a. Severe proportionate short stature of prenatal onset b. Severe postnatal growth deficiency c. Intrauterine growth retardation d. Low birth weight dwarfism 3. Mental retardation 4. Characteristic craniofacial features a. Cranial manifestations i. Severe microcephaly ii. Premature closure of cranial sutures b. Receding forehead c. “Bird-like” face d. Antimongoloid slant of palpebral fissures e. Large eyes f. Beak-like protrusion of the nose g. Narrow face h. Receding lower jaw (retrognathia) i. Micrognathia j. High-arched or cleft palate 874
k. Ears i. Low-set ii. Hypoplastic lobules l. Dental abnormalities i. Enamel hypoplasia ii. Missing permanent teeth iii. Precocious eruption of teeth iv. Microdontia v. Malocclusion vi. Taurodontism m. “Dysplastic” ears 5. Associated anomalies a. Ocular manifestations i. Severe myopia and astigmatism ii. Severe, early onset, bilateral retinal degeneration iii. Hypotelorism iv. Bilateral ptosis v. Microphthalmos vi. Megacornea vii. Glaucoma viii. Retrolental membrane ix. Macular coloboma x. Optic hypoplasia xi. Strabismus xii. Lens dislocation b. Skeletal defects i. Premature closure of cranial sutures ii. Dislocation of the radial head iii. Clinodactyly of the 5th fingers iv. Hip “dysplasia”/dislocation v. Retardation of ossification vi. Clubfoot vii. Hypoplastic patella viii. Scoliosis c. CNS anomalies i. Small cerebrum with simplified, apelike convolutional pattern (pongidoid micrencephaly) ii. Dysgenesis of cerebral cortex iii. Agenesis of corpus callosum iv. Cerebellar vermis hypoplasia v. Dorsal cerebral cyst vi. Arachnoid cyst vii. Dilated ventricles viii. Pachygyria ix. Agyria x. Intracranial aneurysms d. Endocrine abnormalities i. Pituitary gland abnormalities a) Delayed development b) Decreased adrenocorticotropic hormone production c) Decreased growth hormone production
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d) Absence of adenohypophysis e) Hypophyseal hypoplasia f) Precocious puberty ii. Adrenal hypoplasia iii. Hirsutism e. Hematopoietic abnormalities i. Acute myelogenous leukemia ii. Refractory anemia with excess blasts iii. Pancytopenia iv. Fanconi anemia f. Urogenital abnormalities i. Males a) Cryptorchidism b) Hypoplasia of testis ii. Females a) Clitoromegaly b) Hypoplasia of labia majora g. Features of premature senility i. Receding hair ii. Redundant wrinkled skin on the palms h. Miscellaneous findings i. Congenital heart defects a) Patent ductus arteriosus b) Atrial septal defect c) Ventricular septal defects d) Atrioventricular canal defect ii. Multiple intestinal atresia 6. Seckel-like syndromes a. Microcephalic osteodysplastic primordial dwarfism type I i. Distinguished from Seckel syndrome by: a) Broad, low “dysplastic” pelvis with poor development of the acetabula b) Disproportionately short, broad bowing of humeri and femora with rather unremarkable metaphysis c) Agenesis of the corpus callosum and lissencephaly have also been noted ii. Classified as Seckel syndrome by Majewski and Goecke (1982) b. Microcephalic osteodysplastic primordial dwarfism type II: Differences from the Seckel syndrome include the following (mainly based on X-ray features): i. Short limbs with preferential distal involvement (disproportionate shortness of forearms and legs) in the first years of life ii. Brachymesophalangy iii. Brachymetacarpy I iv. Coxa vara v. Epiphysiolysis vi. Metaphyseal flaring with V-shaped distal femoral metaphyses c. Microcephalic osteodysplastic primordial dwarfism type III i. Alopecia ii. Seckel-like features a) Intrauterine growth retardation b) Microcephaly c) Receding forehead and chin d) Large ears
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e) Large prominent nose f) Platyspondyly g) Long dysplastic clavicles h) Hypoplasia of iliac wing and acetabula i) Broad femora iii. Currently considered to be the same entity as type I d. A variant of osteodysplastic bird-headed dwarfism described by Bangstad et al. (1989) i. Progressive ataxia ii. Primary gonadal insufficiency iii. Endocrine abnormalities a) Insulin-resistant diabetes mellitus b) Goiter e. Chromosome abnormalities i. Chromosome instability/breakage ii. Deletion 1q22–q24.3 iii. Interstitial deletion 2q33.3–q34 iv. Ring chromosome 4 mosaicism
DIAGNOSTIC INVESTIGATIONS 1. Hematological work-up indicated in selected patients a. Anemia b. Pancytopenia c. Acute myeloid leukemia 2. Endocrine work-up for pituitary and adrenal dysfunction 3. Radiography a. Microcephaly with a rather steeply sloping base of the skull b. Premature closure of the cranial sutures c. Delayed bone age d. Hip dysplasia e. Elbow dislocation f. Dislocation of the radial head g. Ivory epiphyses (dense sclerotic areas in the phalanges) h. Cone-shaped epiphyses i. Disharmonic bone development i. Hypoplasia of proximal radii and fibulae ii. Absence of epiphyseal ossification centers in fingers and toes 4. Neuropathology and CT/MRI of the brain a. Microcephaly b. Neuroglial ectopia c. Agenesis of the corpus callosum d. Micropolygyria e. Disproportion of the cerebrum and cerebellum f. Dysgenetic cerebral cortex g. Hypoplasia of the cerebellar vermis h. Dorsal cerebral cyst 5. Growth plate histology a. Normal column formation b. No structural abnormality of chondrocytes c. Decrease in cellularity of chondrocytes
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not likely to have offspring due to severe mental retardation
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2. Prenatal diagnosis possible by serial ultrasonography for families at risk for Seckel syndrome a. Severe intrauterine growth retardation b. Craniofacial abnormalities i. Microcephaly ii. Receding forehead iii. A prominent nose iv. Severe micrognathia c. Short limbs 3. Management a. Symptomatic b. Psychosocial support for mental retardation c. Dental cares d. Orthopedic cares e. Treatments for hematological abnormalities
REFERENCES Abou-zahr F, Bejjani B, Kruyt F AE, et al.: Normal expression of the Fanconi anemia proteins FAA and FAC and sensitivity to mitomycin C in two patients with Seckel syndrome. Am J Med Genet 83:388–391, 1999. Anderson CE, Wallerstein R, Zamerowski ST, et al.: Ring chromosome 4 mosaicism coincidence of oligomeganephronia and signs of Seckel syndrome. Am J Med Genet 72:281–285, 1997. Arnold SR, Spicer D, Kouseff B, et al.: Seckel-like syndrome in three siblings. Pediatr Dev Pathol 2:180–187, 1999. Bangstad HJ, Beck-Nielsen H, Hother-Neilsen O, et al.: primordial bird-headed nanisme associated with progressive ataxia, early onset insulin resistant diabetes, goiter, and primary gonadal insufficiency. A new syndrome. Acta Paediatr Scand 78:488–493, 1989. Bobabilla-Morales L, Corona-Rivera A, Corona-Rivera JR, et al.: Chromosome instability induced in vitro with mitomycin C in five Seckel syndrome patients. Am J Med Genet 123A:148–152, 2003. Børglum AD, Balslev T, Haagerup A, et al.: A new locus for Seckel syndrome on chromosome 18p11.31-q11.2. Eur J Hum Genet 9:753–757, 2001. Butler MG, Hall BD, Maclean RN, et al.: Do some patients with Seckel syndrome have hematological problems and/or chromosome breakage? Am J Med Genet 27:645–649, 1987. D’Angelo VA, Ceddia AM, Zelante L, et al.: Multiple intracranial aneurysms in a patient with Seckel syndrome. Childs Nerv Syst 14:82–84, 1998. De Elejalde MM, Elejalde BR: Visualization of the fetal face by ultrasound. J Craniofac Genet Dev Biol 4:251–257, 1984. Faivre L, Le Merrer M, Lyonnet S, et al.: Clinical and genetic heterogeneity of Seckel syndrome. Am J Med Genet 112:379–383, 2002. Featherstone LS, Sherman SJ, Quigg MH: Prenatal diagnosis of Seckel syndrome. J Ultrasound Med 15:85–88, 1996. Goodship J, Gill H, Carter J, et al.: Autozygosity mapping of a Seckel syndrome locus to chromosome 3q22. 1–q24. Am J Hum Genet 67:498–503, 2000.
Guirgis MF, Lam BL, Howard CW: Ocular manifestations of Seckel syndrome. Am J Ophthalmol 132:596–597, 2001. Harper RG, Orti E, Baker RK: Bird-headed dwarfs (Seckel’s syndrome). A familial pattern of developmental, dental, skeletal, genital, and central nervous system anomalies. J Pediatr 70:799–804, 1967. Kilinç MO, Ninis VN, Ug˘ur SA, et al.: Is the novel SCKL3 at 14q23 the predominant Seckel locus? Eur J Hum Genet 11:851–857, 2003. Majewski F, Goecke T: Studies of microcephalic primordial dwarfism I: approach to a delineation of the Seckel syndrome. Am J Med Genet 12:7–21, 1982. Majewski F, Ranke M, Schinzel A: Studies of microcephalic primordial dwarfism II: the osteodysplastic type II of primordial dwarfism. Am J Med Genet 12:23–35, 1982. Majewski F, Stoeckenius M, Kemperdick H: Studies of microcephalic primordial dwarfism III: an intrauterine dwarf with platyspondyly and anomalies of pelvis and clavicles—osteodysplastic primordial dwarfism type III. Am J Med Genet 12:37–42, 1982. Majewski F: Caroline Crachami and the delineation of osteodysplastic primordial dwarfism type III, and autosomal recessive syndrome. Am J Med Genet 44:203–209, 1992. Majewski F, Goecke TO: Microcephalic osteodysplastic primordial dwarfism type II: report of three cases and review. Am J Med Genet 80:25–31, 1998. Majoor-Krakauer DF, Wladimiroff JW, et al.: Microcephaly, micrognathia, and bird-headed dwarfism: prenatal diagnosis of a Seckel-like syndrome. Am J Med Genet 27:183–188, 1987. McKusick VA, Mahloudji M, Abbott MH, et al.: Seckel’s bird-headed dwarfism. N Engl J Med 277:279–286, 1967. Meinecke P, Passarge E: Microcephalic osteodysplastic primordial dwarfism type I/III in sibs. J Med Genet 28:795–800, 1991. Meinecke P, Schaefer E, Wiedemann HR, et al.: Microcephalic osteodysplastic primordial dwarfism: further evidence for identity of the so-called types I and III. Am J Med Genet 39:232–236, 1991. Nadjari M, Fasouliotis SJ, Ariel I, et al.: Ultrasonographic prenatal diagnosis of microcephalic osteodysplastic primordial dwarfism types I/III. Prenat Diagn 20:666–669, 2000. O’Driscoll M, Ruiz-Perez VL, Woods CG, et al.: A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33:497–501, 2003. Sauk JJ, Litt R, Espiritu CE, et al.: Familial bird-headed dwarfism (Seckel’s syndrome). J Med Genet 10:196–198, 1973. Seckel HPG: “Bird headed dwarfs: Studies in Developmental Anthropology Including Human Proportions.” Springfield, Ill: CC Thomas Publ. 1960. Shanske A, Caride DG, Menasse-Palmer L, et al.: Central nervous system anomalies in Seckel syndrome: report of a new family and review of the literature. Am J Med Genet 70:155–158, 1997. Syrrou M, Georgiou I, Paschopoulos M, et al.: Seckel syndrome in a family with three affected children and hematological manifestations associated with chromosome instability. Genet Couns 6:37–41, 1995. Thompson E, Pembrey M: Seckel syndrome: an overdiagnosed syndrome. J Med Genet 22:192–201, 1985.
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Fig. 2. An adult with Seckel syndrome showing severe short stature, mental retardation, extreme microcephaly, sloping forehead, a beaked nose, and retro/micrognathia.
Fig. 1. A girl with Seckel syndrome showing marked short stature, severe microcephaly, sloping forehead, “bird-headed” face, large eyes, beaked nose, and severe retro/micrognathia.
Severe Combined Immune Deficiency Severe combined immune deficiency (SCID) is a fatal, heterogeneous group of immune disorder, characterized by T-cell lymphopenia, a profound lack of cellular (T-cell) and humoral (B-cell) immunity and, in some cases, decreased NK-cell number and function. The incidence of SCID is estimated to be 1/100,000 live births.
GENETICS/BASIC DEFECTS 1. A heterogeneous syndrome of varied genetic origins a. X-linked type SCID (X-SCID) i. The most common type (50% of all patients with SCIDs) ii. A combined cellular and humoral immunodeficiency resulting from lack of T and natural killer (NK) lymphocytes and nonfunctional B lymphocytes iii. Caused by a mutation in the X-linked gene IL2RG, which encodes the common γ chain, γc (mapped on Xq13), of the leukocyte receptors for interleukin-2 and multiple other cytokines a) Significant frequency of de novo mutations accounting for 1/3rd of the cases b) Occurrence of maternal germline mosaicism iv. Atypical X-SCID: less frequently seen in patients with mutations that result in production of a small amount of gene product or a protein with residual activity b. Autosomal recessive type SCID i. Formerly known as Swiss-type agammaglobulinemia ii. Causes a) Adenosine deaminase deficiency (10–20% of all cases of SCID): the ADA gene mapped on chromosome 20q13.11 b) Purine nucleoside phosphorylase (PNP) deficiency: the PNP gene mapped on 14q13 c) Janus-associated kinase 3 (JAK3) deficiency causing autosomal recessive T–B+ SCID: the JAK3 gene mapped on 19p13 d) Interleukin (IL)-2 deficiency e) ZAP-70 protein tyrosine kinase (PTK) deficiency: ZAP-70 mapped on 2q12 f) Bare lymphocyte syndrome g) Reticular dysgenesis h) Omenn syndrome 2. Pathophysiology a. Varies among various forms of SCID b. Common endpoint in all forms of SCID i. Lack of T-cell function ii. Lack of B-cell function c. Cellular hallmarks differentiating various forms of SCID 878
i. X-linked SCID a) Absence or near absence of T cells (CD3+) and natural killer (NK) cells leading to lymphopenia b) Variable levels of B cells that produce no functional antibodies ii. JAK3 deficiency a) Absence or near absence of T cells (CD3+) and natural killer (NK) cells leading to lymphopenia b) Normal or high levels of B cells that produce no functional antibodies iii. ADA deficiency a) Death of T cells secondary to the accumulation of toxic metabolites in the purine salvage pathway leading to lymphopenia b) Decreased or absence of functional antibodies iv. PNP deficiency a) Death of T cells secondary to the accumulation of toxic metabolites in the purine salvage pathway leading to lymphopenia b) Normal number of circulating B cells with poor B-cell function, evidenced by the lack of antibody formation v. IL-2 deficiency a) Normal or near normal numbers of T cells (both CD4+ and CD8+) b) Decreased production of functional antibody vi. ZAP-70 PTK deficiency a) Absence of CD8+ T cells leading to lymphopenia b) No antibody formation vii. Bare lymphocyte syndrome a) Normal or mildly reduced lymphocyte count b) Decreased CD4+ T cells c) Normal or mildly increased CD8+ T cell numbers d) Normal or mildly decreased B-cell numbers with decreased antibody production viii. Reticular dysgenesis a) Absence of myeloid cells in the bone marrow leading to lymphopenia b) Presence of functioning red blood cells and platelets ix. Omenn syndrome a) Presence of normal or elevated T-cell numbers of maternal origin b) Usually undetectable B cells c) Presence of NK cells d) Markedly low total immunoglobulin level with poor antibody production e) Elevated eosinophils and total serum immunoglobulin E (IgE) level
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3. Molecular defects a. X-linked SCID i. Mutation of the common gamma chain of the IL receptors (IL-2R, IL-4R, IL-7R, IL-9R, IL-15R) resulting in loss of cytokine function ii. Loss of IL-2R function leading to the loss of a lymphocyte proliferation signal iii. Loss of IL-4R function leading to the inability of B cells to class switch iv. Loss of IL-7R function leading to the loss of an antiapoptotic signal resulting in a loss of T-cell selection in the thymus and also associated with the loss of a T-cell receptor v. Loss of IL-15R function leading to the ablation of NK cell development b. JAK3 deficiency i. JAK, a protein tyrosine kinase that associates with the common gamma chain of the IL receptors ii. Deficiency of JAK3 resulting in the same clinical manifestations as those of X-linked SCID c. ADA and PNP deficiencies i. Associated with enzyme deficiencies in the purine salvage pathway ii. Toxic metabolites responsible for the destruction of lymphocytes that cause the immune deficiency d. IL-2 deficiency i. Molecular defect unknown ii. Often associated with other cytokine production defects e. ZAP-70 PTK deficiency: caused by a mutation in the gene coding for this tyrosine kinase, which is important in T-cell signaling and is critical in positive and negative selection of T cells in the thymus f. Bare lymphocyte syndrome i. Deficiency of major histocompatibility complex (MHC) ii. Absent or decreased MHC type I levels iii. Decreased MHC type II levels on mononuclear cells g. Omenn syndrome: believed to be caused by a mutation impairing the function of immunoglobulin and TCR recombinase genes, such as RAG1 and RAG2 genes
CLINICAL FEATURES 1. Age of onset: 3–6 months of life 2. Usual presentation with infections due to lack of T-cell function a. Opportunistic organisms i. Pneumocystis carinii pneumonia ii. Systemic candidiasis iii. Atypical mycobacterium iv. Cryptosporidium v. Pneumococcus b. Recurrent infections c. Persistence of infections despite conventional treatment 3. Failure to thrive 4. Oral or diaper candidiasis 5. Dehydration from chronic diarrhea
6. 7. 8. 9. 10. 11. 12. 13. 14.
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Fevers Rashes Cough and congestion Increased reparatory rate and effort Absence of tonsils and lymph nodes Absence of lymphadenopathy or increased tonsillar tissue despite serious infections Pneumonias Sepsis Disseminated infections a. Salmonella b. Varicella c. Cytomegalovirus d. Epstein-Barr virus e. Herpes simplex virus f. BCG g. Vaccine strain (live) polio virus Recurrent sinopulmonary infections Recurrent skin infections Abscesses Poor wound healing Transplacental transfer of maternal lymphocytes to the infant prenatally or during parturition causing graft-vs-host disease (GVHD), characterized by: a. Erythematous skin rashes b. Hepatomegaly c. Lymphadenopathy ADA deficiency and PNP deficiency with later onset and miler or atypical clinical presentation a. Diagnosis suspected in patients with: i. Unexplained T-cell lymphopenia ii. Late manifestations of immunodeficiency a) Chronic pulmonary insufficiency b) History of autoimmunity and neurologic abnormalities c) Onset during the first two decades of life and even later b. Diagnosis confirmed by finding absent or very low enzyme activity in erythrocytes or in nucleated blood cells Lymphadenopathy or hepatosplenomegaly in Omenn syndrome or bare lymphocyte syndrome Prognosis a. Fatal if untreated b. Bone marrow transplantation or enzyme replacement to reconstitute the immune system compatible with long survival
DIAGNOSTIC INVESTIGATIONS 1. Blood workup a. Complete blood cell count with differential to detect lymphopenia b. Lymphocyte markers to obtain percentages and absolute counts i. CD3+ T cells ii. CD4+ T cells iii. CD8+ T cells iv. CD19+ T cells v. NK cell markers (CD16 and CD56)
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c. Immunoglobulin concentrations i. Low IgA and IgM ii. IgG a) Generally normal at birth b) Declines as maternally transferred IgG disappears by three months of age d. Lymphocyte functional tests i. Absence of responses to vaccines and infectious agents ii. Lacking T-cell responses to mitogens Chest X-ray a. Absent to small thymus shadow b. Pneumonia c. Typical cupping and flaring of the costochondral junction in patients with ADA deficiency Lymph node biopsy a. Paucity of T and B cells b. Lack of germinal centers Consider X-SCID in male infants with: a. Severe recurrent or persistent infections b. Infections not responding to ordinary treatment c. Infections caused by opportunistic pathogens d. Failure to thrive Confirmatory tests a. Determination of the ADA and PNP levels i. Lymphocytes ii. Erythrocytes iii. Fibroblasts b. X-inactivation studies to determine whether the SCID is X-linked c. Molecular genetic testing i. X-SCID a) Sequence analysis of the IL2RG coding region detecting a mutation in >99% of affected individuals b) Mutation analysis Carrier testing of X-SCID a. Testing for known family-specific IL2RG mutations b. Sequence analysis of the IL2RG coding region and splice regions c. Southern blot analysis used to detect large deletions and complex mutations if the family-specific mutation is not known and sequence analysis is uninformative d. X-chromosome inactivation studies on lymphocytes for at-risk females in whom sequence analysis and/or mutation analysis are not an option for carrier testing or are not informative, provided presence of the following two conditions: i. Skewed X-chromosome inactivation in lymphocytes ii. Nonskewed X-chromosome inactivation in another blood lineage such as granulocytes
GENETIC COUNSELING 1. Recurrence risk a. X-SCID i. Female germline mosaicism present if a woman has more than one affected son and the
disease-causing mutation in the IL2RG gene cannot be detected in her leukocytes ii. Over 50% of affected males do not have family history of early deaths in maternal male relatives iii. Patient’s sib if the mother is a carrier a) 50% of males sibs affected b) 50% of females sibs carriers iv. Patient’s sib is still at increased risk even if the disease-causing mutation has not been identified in the mother’s leukocytes since germline mosaicism has been demonstrated in this condition v. Patient’s offspring (offspring of affected males) a) 100% of daughters carriers b) None of sons affected b. Autosomal recessive SCID i. Patient’s sib: 25% ii. Patient’s offspring: not increased unless the spouse is a carrier in which case 25% of the offspring will be affected 2. Prenatal diagnosis a. X-SCID i. Determination on fetal cells obtained by CVS or amniocentesis ii. Analysis of DNA from fetal cells for the known disease-causing mutation, provided: a) Karyotype revealing 46,XY b) The disease-causing IL2RG mutation has been identified in a family member iii. Fetal blood sampling for immunological evaluation when the family-specific mutation is not known a) Lymphocytopenia b) Low numbers of T cells c) Poor T cell blastogenic responses to mitogens b. Autosomal recessive SCID i. JAK3 deficient SCID a) Immunophenotypic evaluation of cord blood cells at 18–20 weeks of gestation b) Direct gene analysis using chorionic villus sampling derived DNA in the first trimester ii. ADA deficiency: prenatal diagnosis established by measuring ADA enzyme activity in amniotic cells or chorionic villi 3. Management a. X-linked SCID and JAK3 PTK deficiency i. Fatal disease unless cured by bone marrow transplantation (BMT) a) The best results achieved by using an HLA-matched sibling as a donor (success rates of 97%) b) Using haploidentical T-cell depleted BMT from a parent (haploidentical family donors resulting in lower success rates of 52%): lifesaving for the majority of X-SCID patients who lack matched sibling ii. Monthly intravenous immunoglobulin replacement therapy required if B cells do not engraft iii. Report of in utero transplantation of hematopoietic progenitor cells allowing immune reconstitution in a fetus
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b.
c.
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iv. Gene therapy a) Using autologous bone marrow stem/progenitor cells retrovirally transduced with a therapeutic gene b) Successful in reconstituting the immune system in patients with X-SCID c) Youngest two of the first ten infants treated in a French study developed leukemia due to retroviral insertional mutagenesis d) Currently a consideration only for those who are not candidates for bone marrow transplantation or have failed bone marrow transplantation ADA deficiency i. Usually fatal unless: a) Keeping affected children in protective isolation, or b) Reconstituting the immune system by bone marrow transplantation from a human leukocyte antigen (HLA)-identical sibling donor (therapy of choice but only available for a minority of patients) ii. Exogenous enzyme replacement primarily with polyethylene glycol-conjugated ADA replacement (PED-ADA) therapy a) Providing noncurative, life-saving treatment for ADA- SCID patients b) Increased peripheral T cell counts providing a source of T cells for gene correction not available without enzyme therapy c) Weight gain and decreased opportunistic infections in most patients d) Improved T cell function as measured by in vitro mitogen responses in most patients e) Recovery of consistent immune responses to specific antigens in fewer patients iii. The first genetic disorder treated by gene therapy: a clinical trial using retroviral mediated transfer of the adenosine deaminase (ADA) gene into the T cells of children with ADA- SCID a) Normalization of the number of blood T cells as well as many cellular and humoral immune responses b) Successful gene transfer into long-lasting progenitor cells, producing a functional multilineage progeny c) Safe and effective addition to treatment for some patients iv. Combined treatment with PEG-ADA and gene therapy PNP deficiency and bare lymphocyte syndrome: primarily with bone marrow transplantation when an appropriate donor is available IL-2 production defects: i. Primarily with intravenous IL-2 replacement ii. Alternatively with bone marrow transplantation when an appropriate donor is available Omenn syndrome i. Primarily with bone marrow transplantation when an appropriate donor is available
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ii. Pretreatment ablative chemotherapy necessary because of maternal cell engraftment Bone marrow transplantation from a related donor: a life-saving and life-sustaining treatment for patients with any type of severe combined immune deficiency, even when there is no HLA-identical donor Two fetuses successfully treated with gene therapy in utero by an injection of haploidentical CD34+ cells for the γ chain deficiency Psychosocial support for the affected family Avoid live vaccines
REFERENCES Antoine C, Muller S, Cant A, et al.: Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968–99. Lancet 361:553–60, 2003. Arredondo-Vega FX, Santisteban I, Daniels S, et al.: Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles. Am J Hum Genet 63:1049–1059, 1998. Belmont JW, Puck JM: T cell and combined immunodeficiency syndromes. In: Scriver DR, Beaudet al., Sly WS (eds) The Metabolic and Molecular Bases of Inherited Disease, 8 ed. McGraw-Hill, New York, 2001, pp 4751–4784. Blaese RM, Culver KW, Miller AD, et al.: T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science 270:475–480, 1995. Bordignon C, Notarangelo LD, Nobili N, et al.: Gene therapy in peripheral blood lymphocytes and bone marrow for ADA-immunodeficient patients. Science 270:470–475, 1995. Buckley RH, Schiff RI, Schiff SE, et al.: Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J Pediatr 130:378–387, 1997. Buckley RH, Schiff SE, Schiff RI, et al.: Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 340:508–516, 1999. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, et al.: Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288:669–673, 2000. Davis J, Puck JM: X-linked severe combined immunodeficiency. http://www. geneclinics.org Fisher A: Severe combined immunodeficiencies. Immunodefic Rev 3:83–100, 1992. Fisher A, Hacein-Bey S, Le Deist F, et al.: Gene therapy for human severe combined immunodeficiencies. Immunity 15:1–4, 2001. French gene therapy group reports on the adverse event in a clinical trial of gene therapy for X-linked severe combined immune deficiency (X-SCID). Position statement from the European Society of Gene Therapy. J Gene Med 5:82–84, 2003. Gansbacher B: Report of a second serious adverse event in a clinical trial of gene therapy for X-linked severe combined immune deficiency (X-SCID). Position of the European Society of Gene Therapy (ESGT). J Gene Med 5:261–262, 2003. Gaspar HB, Gilmour KC, Jones AM: Severe combined immunodeficiencymolecular pathogenesis and diagnosis. Arch Dis Child 84:169–173, 2001. Hershfield MS: Enzyme replacement therapy of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase (PEG-ADA). Immunodeficiency 4:93–97, 1993. Hershfield MS: PEG-ADA replacement therapy for adenosine deaminase deficiency: an update after 8.5 years. Clin Immunol Immunopathol 76:S228–S232, 1995. Hershfield MS: PEG-ADA: an alternative to haploidentical bone marrow transplantation and an adjunct to gene therapy for adenosine deaminase deficiency. Hum Mutat 5:107–112, 1995. Hershfield MS, Mitchell BS: Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. In Scriver CR, Beaudet al., Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001, Chapter 109, pp 2586–2588. Hoogerbrugge PM, van Beusechem VW, Fischer A, et al.: Bone marrow gene transfer in three patients with adenosine deaminase deficiency. Gene Ther 3:179–183, 1996.
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Kalman L, Lindegren ML, Kobrynski L, et al.: Mutations in genes required for T-cell development: IL7R, CD45, IL3RG, JAK3, RAG1, RAG2, ARTEMIS, and ADA and severe combined immunodeficiency: HUGE review. Genet Med 6:16–26, 2004. Myers LA, Patel DD, Puck JM, et al.: Hematopoietic stem cell transplantation for severe combined immunodeficiency in the neonatal period leads to superior thymic output and improved survival. Blood 99:872–8, 2002. Puck JM: Primary immunodeficiency diseases. JAMA 278:1835–1841, 1997. Puck JM, Middelton L, Pepper AE: Carrier and prenatal diagnosis of X-linked severe combined immunodeficiency: mutation detection methods and utilization. Hum Genet 99:628–633, 1997. Puck JM, Nussbaum RL, Conley ME: Carrier detection in X-linked severe combined immunodeficiency based on patterns of X chromosome inactivation. J Clin Invest 79:1395–400, 1987.
Rosen FS: Severe combined immunodeficiency: a pediatric emergency. J Pediatr 130:345–346, 1997. Secord EA: Severe combined immunodeficiency. http://www.emedicine.com. Emedicine 2002. Stephan JL, Vlekova V, Le Deist F, et al.: Severe combined immunodeficiency: a retrospective single-center study of clinical presentation and outcome in 117 patients. J Pediatr 123:564–72, 1993. Ting SS, Leigh D, Lindeman R, et al.: Identification of X-linked severe combined immunodeficiency by mutation analysis of blood and hair roots. Br J Haematol 106:190–194, 1999. Wengler GS, Lanfranchi A, Frusca T, et al.: In-utero transplantation of parental CD34 haematopoietic progenitor cells in a patient with Xlinked severe combined immunodeficiency (SCIDX1). Lancet 348: 1484–1487, 1996.
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Fig. 1. A healthy 9-year-old boy with ADA deficient SCID who has been receiving bi-weekly Adagen (Pegademase) injections since early infancy.
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Short Rib Polydactyly Syndromes Short rib-polydactyly syndromes (SRPS) are a heterogeneous group of recessively inherited lethal skeletal dysplasia. There are four classic subtypes: type I (Saldino-Noonan) (SRPS I), type II (Majewski) (SRPS II), type III (Verma-Naumoff) (SRPS III), and type IV (Beemer-Langer) (SRPS IV).
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive in all four subtypes 2. Different subtypes of SRPS a. A great overlap of anomalies present among different subtypes contributing to diagnostic dilemmas in the short rib-polydactyly syndrome group b. Possibly represent a continuous spectrum with variable expressivity, suggested by some reports
CLINICAL FEATURES 1. SRPS I (Saldino-Noonan) a. Constant findings i. Severely shortened (flipper-like) limbs with postaxial polydactyly ii. Small/narrow thorax with short ribs and hypoplastic lungs iii. Protuberant abdomen iv. Early neonatal death b. Common findings i. Hydrops fetalis ii. Gastrointestinal abnormalities a) Esophageal atresia b) Short small intestine c) Malrotation of the bowel d) Imperforate anus e) Persistent cloaca f) Imperforate anus g) Pancreatic fibrosis and cysts iii. Cardiac malformations a) Transposition of the great vessels b) Coarctation of the aorta or hypoplastic aortic arch c) Ventricular septal defects d) Double-outlet left ventricle c. Occasional findings i. Oligohydramnios ii. Renal dysplasia/cystic disease iii. Abnormal genitalia a) Cryptorchidism b) Hypoplastic penis iv. CNS malformations a) Cerebellar hypoplasia b) Dandy-Walker malformation
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v. Bifid epiglottis vi. Bifid tongue vii. Cleft upper lip 2. SRPS II (Majewski) a. Constant findings i. Extremely short limbs with pre/postaxial polydactyly of the hands and feet ii. Small/narrow chest with short ribs and pulmonary hypoplasia iii. Protuberant abdomen iv. Median cleft lip or pseudo-cleft of the upper and lower lip or cleft palate v. Epiglottis and larynx hypoplasia vi. Short/ovoid tibias with round ends vii. Presence of premature ossification centers viii. Early neonatal death b. Common findings i. Polyhydramnios ii. Hydrops fetalis iii. Ocular hypertelorism iv. Broad and flat nose v. Low-set ears vi. Ambiguous genitalia vii. Renal cystic disease c. Occasional findings i. Short small intestine ii. Malrotation of the bowel iii. Cardiac malformations iv. Dysplastic pancreas 3. SRPS III (Verma-Naumoff) a. Constant findings i. Severely shortened limbs with postaxial polydactyly ii. Small/narrow thorax with short ribs and hypoplastic lungs iii. Early neonatal death b. Common findings i. Hydrops fetalis ii. Short cranial base iii. Bulging forehead iv. Depressed nasal bridge v. Flat occiput vi. Renal cystic dysplasia c. Occasional findings i. Congenital heart defects a) Ventricular septal defect b) Situs inversus ii. Epiglottic hypoplasia iii. Intestinal malrotation iv. Cloacal developmental abnormalities and ambiguous genitalia
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4. SRPS IV (Beemer-Langer) a. Constant findings i. Severely shortened limbs with or without postaxial polydactyly ii. Small/narrow thorax with short ribs and hypoplastic lungs iii. Early neonatal death b. Common findings i. Hydrops fetalis ii. Macrocephaly with frontal bossing iii. Ocular hypertelorism iv. Flat nasal bridge v. Cleft lip and palate vi. Protuberant abdomen c. Occasional findings i. CNS abnormalities a) Holoprosencephaly/absence of the corpus callosum/hydrocephalus b) Dandy-Walker cyst and/or arachnoid cyst c) Hypothalamic hamartomas ii. Lobulated tongue with hamartomas iii. Oral frenula iv. Congenital heart defects v. Malrotation of the intestine vi. Renal malformations a) Renal cystic dysplasia b) Atresia of the ureter with hydronephrosis and hydroureter vii. Omphalocele viii. Inguinal hernia
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. SRPS I (Saldino-Noonan) i. Extreme micromelia with severely dysplastic pointed (or ragged) metaphyses of the long tubular bones, and absence of corticomedullary demarcation ii. Narrow thorax with short/horizontal ribs iii. Deficient ossification in calvarium, vertebrae, pelvis, and bones of the hands and feet iv. Small iliac bones with horizontal acetabulae v. Postaxial polydactyly vi. Short tibiae b. SRPS II (Majewski) i. Extreme micromelia with smooth rounded metaphyses ii. Extremely short horizontal ribs iii. Normal pelvis and vertebrae iv. Disproportionately shortened ovoid-shaped tibiae v. Pre- and post-axial polydactyly, syndactyly, and brachydactyly vi. Advanced skeletal ossification—advanced maturation of the proximal femora and humeri c. SRPS III (Verma-Naumoff) i. Extreme micromelia with severely dysplastic widened metaphyses (bones of the legs) and clear corticomedullary demarcation of the long tubular bones
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Extremely shortened and horizontal ribs Small and malformed vertebral bodies Shortened cranial base Short iliac bones with horizontal trident lower margin vi. Polydactyly d. SRPS IV (Beemer-Langer) i. Extreme micromelia with smooth metaphyseal margins ii. Extremely shortened and horizontal ribs iii. Small, poorly ossified vertebrae and increased intervertebral spaces iv. High clavicles and small scapulae v. Small iliac bones vi. Bowed radii and ulnae vii. Tibiae: well tabulated and longer than fibulae viii. Postaxial polydactyly 2. Histopathology/necropsy a. SRPS I (Saldino-Noonan) i. Markedly retarded and frequently deranged endochondral ossification. A large island of fibrous tissue may occupy the center of physeal growth zone. A premature ossification center may be seen in the epiphyseal resting cartilage. ii. Lungs: hypoplasia which is easily assessed by abnormally small size and low weight iii. Identify associated multiple congenital anomalies listed in the clinical features b. SRPS II (Majewski) i. Markedly retarded endochondral ossification. The chondrocytes in the physeal growth zones are markedly reduced in number and disorderly arranged. ii. Lungs: hypoplasia as in type I iii. Identify associated multiple congenital anomalies listed in the clinical features c. SRPS III (Verma-Naumoff) i. Markedly retarded endochondral ossification as in type II. A single patient showed chondrocytic inclusions which are PAS reactive and diastase resistant. ii. Lung: hypoplasia as in type I iii. Identify associated multiple congenital anomalies which are less common in this type d. SRPS IV (Beemer-Langer) i. Physeal growth zones showing a prominent but disorganized zone of hypertrophy. The vascuolar penetration of physeal cartilage is irregular. ii. Lungs: hypoplasia as in type I iii. Identify associated multiple congenital anomalies listed in the clinical features
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: the patients will not survive to reproductive age 2. Prenatal diagnosis: not always possible to differentiate the subtypes
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a. Ultrasonography for SRPS I (Saldino-Noonan) i. Short fetal limbs ii. Narrow thorax iii. Polydactyly iv. Pointed metaphyses v. Dysplastic cystic kidneys vi. Congenital heart defect vii. Genital anomalies b. Ultrasonography for SRPS II (Majewski) i. With a positive family history of Majewski syndrome a) Presence of short fetal limbs b) Other skeletal findings ii. Without a family history a) Short fetal limbs b) Disproportionately short tibia c) Very narrow fetal chest d) Short ribs e) Bilateral postaxial polydactyly of the hands and feet f) Median cleft lip and palate g) Polyhydramnios h) Hydrops i) Marked shortened humerus and femur j) Severe bowing and deformity of the bones of the lower leg and forearm k) Hypoplastic lungs l) Congenital heart defect m) Enlarged echogenic kidneys n) Genital anomalies c. Ultrasonography for SRPS III (Verma-Naumoff) i. Short fetal limbs ii. Small/narrow thorax iii. Short thin ribs iv. Polydactyly v. Widened metaphyses with marginal spurs vi. Micromelia d. Ultrasonography for SRPS IV (Beemer-Langer) i. Short fetal bones ii. Small/narrow thorax iii. Short thin ribs iv. Polydactyly e. Fetoscopy i. To identify fetus with SRPS phenotype ii. An invasive procedure currently replaced by ultrasonography 3. Management: supportive therapy only for these lethal entities
REFERENCES Beemer FA: Short-rib syndrome classification. Am J Med Genet Suppl 3:209–210, 1987. Beemer FA, Langer LO Jr, Klep-de Pater JM, et al.: A new short rib syndrome: report of two cases. Am J Med Genet 14:115–123, 1983.
Benacerraf BR: Prenatal sonographic diagnosis of short rib-polydactyly syndrome type II, Majewski type. J Ultrasound Med 12:552–555, 1993. Black IL, Fitzsimmons J, Fitzsimmons E, et al.: Parental consanguinity and the Majewski syndrome. J Med Genet 19:141–143, 1982. Chen H, Yang SS, Gonzalez E, Fowler M, Al Saadi A: Short rib-polydactyly syndrome, Majewski type. Am J Med Genet 7:215–222, 1980. Chen H, Mirkin D, Yang S: De novo 17q paracentric inversion mosaicism in a patient with Beemer-Langer type short rib-polydactyly syndrome with special consideration to the classification of short rib polydactyly syndromes. Am J Med Genet 53:165–171, 1994. Cooper CP, Hall CM: Lethal short-rib polydactyly syndrome of the Majewski type: a report of three cases. Radiology 144:513–517, 1982. Corsi A, Riminucci M, Roggini M, et al.: Short rib polydactyly syndrome type III: histopathogenesis of the skeletal phenotype. Pediatr Dev Pathol 5:91–96, 2002. Elçiog˘lu N, Karatekin G, Sezgin B, et al.: Short rib-polydactyly syndrome in twins: Beemer-Langer type with polydactyly. Clin Genet 50:159–163, 1996. Elçiog˘lu NH, Hall CM: Diagnostic dilemmas in the short rib-polydactyly syndrome group. Am J Med Genet 111:392–400, 2002. Golombeck K, Jacobs VR, von Kaisenberg C, et al.: Short rib-polydactyly syndrome type III: comparison of ultrasound, radiology, and pathology findings. Fetal Diagn Ther 16:133–138, 2001. Hennekam RC: Short rib syndrome—Beemer type in sibs. Am J Med Genet 40:230–233, 1991. Martinez-Frias ML, Bermejo E, Urioste M, et al.: Lethal short rib-polydactyly syndromes: further evidence for their overlapping in a continuous spectrum. J Med Genet 30:937–941, 1993. Meizner I, Bar-Ziv J: Prenatal ultrasonic diagnosis of short-rib polydactyly syndrome (SRPS) type III: a case report and a proposed approach to the diagnosis of SRPS and related conditions. J Clin Ultrasound 13:284–287, 1985. Meizner I, Bar-Ziv J: Prenatal ultrasonic diagnosis of short rib polydactyly syndrome, type I. A case report. J Reprod Med 34:668–672, 1989. Meizner I, Barnhard Y: Short-rib polydactyly syndrome (SRPS) type III diagnosed during routine prenatal ultrasonographic screening. A case report. Prenat Diagn 15:665–668, 1995. Motegi T, Kusunoki M, Nishi T, et al.: Short rib-polydactyly syndrome, Majewski type, in two male siblings. Hum Genet 49:269–275, 1979. Naumoff P, Young LW, Mazer J, et al.: Short rib-polydactyly syndrome type 3. Radiology 122:443–447, 1977. Richardson MM, Beaudet AL, Wagner ML, et al.: Prenatal diagnosis of recurrence of Saldino-Noonan dwarfism. J Pediatr 91:467–471, 1977. Sillence DO: Non-Majewski short rib-polydactyly syndrome. Am J Med Genet 7:223–229, 1980. Sillence D, Kozlowski K, Bar-Ziv J, et al.: Perinatally lethal short rib-polydactyly syndromes. 1. Variability in known syndromes. Pediatr Radiol 17:474–480, 1987. Toftager-Larsen K, Benzie RJ: Fetoscopy in prenatal diagnosis of the Majewski and the Saldino-Noonan types of the Short Rib-Polydactyly syndromes. Clin Genet 26:56–60, 1984. Yang SS, Lin CS, Al Saadi A, et al.: Short rib-polydactyly syndrome, type 3 with chondrocytic inclusions: report of a case and review of the literature. Am J Med Genet 7:205–213, 1980. Yang SS, Langer LO Jr, Cacciarelli A, et al.: Three conditions in neonatal asphyxiating thoracic dysplasia (Jeune) and short rib-polydactyly syndrome spectrum: a clinicopathologic study. Am J Med Genet Suppl 3:191–207, 1987. Yang SS, Roth JA, Langer LO Jr: Short rib syndrome Beemer-Langer type with polydactyly: a multiple congenital anomalies syndrome. Am J Med Genet 39:243–246, 1991.
SHORT RIB POLYDACTYLY SYNDROMES
Fig. 1. Radiograph of a neonate with Saldino-Noonan syndrome (SRPS I) showing extremely shortened horizontal ribs, very small and dysplastic vertebral bodies and iliac cones, and very short tubular bones with irregular metaphyses.
Fig. 2. Photomicrograph of femur (SRPS I) shows markedly retarded and disorganized physeal growth zone.
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Fig. 3. Photomicrograph of humerus (SRPS I) shows markedly disrupted physeal growth zone by a large cartilage canal-like vascular fibrous tissue. In addition, there is a large premature ossification center (upper one third of the picture).
Fig. 4. A neonate with Majewski syndrome (SRPS II) showed hydrops, a large head, hairy forehead, small, malformed, and low-set ears, telecanthus, short nose, a flat nasal bridge, a central cleft upper and lower lips, short neck, short and narrow chest, markedly distended abdomen with ascites, extremely short limbs with pre- and postaxial polydactyly, syndactyly, and brachydactyly.
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Fig. 5. Mouth of the neonate in Fig. 4 showing lobulated tongue and mucosal frenular.
Fig. 6. Ambiguous genitalia with a barely visible micropenis (SRPS II).
Fig. 8. Radiographs (SRPS II) showing extremely short, horizontal ribs, high clavicles, unremarkable spine and pelvis, premature ossification of the proximal epiphyses of the humeri, femora, and lateral cuboids. The tubular bones were extremely short, especially the mesomelic segments. The tibiae were disproportionately short and oval in shape.
Fig. 7. Hands and feet showed pre and postaxial polydactyly, syndactyly, and brachydactyly (SRPS II).
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Fig. 11. Photomicrograph of renal cortex showing many dilated glomeruli and mildly cystic renal tubules (SRPS II).
Fig. 9. Respiratory system (necropsy) (SRPS II) showing a small larynx with hypoplastic epiglottis (arrow) and remarkably small and hypoplastic lungs. The patient’s thymus is juxtaposed for comparison.
Fig. 10. Photomicrograph of tibia cartilage (SRPS II) (Hematoxylineosin, ×108) showing a markedly stunted and disorganized physeal growth zone.
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Fig. 12. Radiographs of the skeletal system (SRPS III) showing extremely short and horizontal ribs, small dysplastic vertebral bodies and ilia, short tubular bones with widened metaphyses with longitudinal spurs
Fig. 13. Photomicrograph of the cartilage of the iliac crest (SRPS III) showing retardation and disorganization of physeal growth zone.
Fig. 14. Higher magnification of the chondrocytes in the resting cartilage and the physeal zone of proliferation frequently show cytoplasmic inclusions (PAS after diastase digestion) (SRPS III).
SHORT RIB POLYDACTYLY SYNDROMES
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Fig. 16. Radiograph of another premature neonate (SRPS IV) showing extremely short and horizontal ribs, small dysplastic vertebral bodies, small iliac wings, and short tubular bone.
Fig. 15. A fetus with Beemer-Langer syndrome showing macrocephaly, cystic hygroma, severe micro/retrognathia with cleft palate, low-set and malformed ears, short limbs, narrow thorax, protuberant abdomen with an omphalocele, and polydactyly. The radiographs show short, horizontal ribs, small scapulae, relatively poorly ossified vertebral bodies, small ilia, short tubular bones with absence of metaphyseal spicules, bowed radii and ulnae, and postaxial polydactyly. The ultrasonograph shows porencephalic cyst. The fetus also had a de novo paracentric inversion of chromosome 17q (q12;q25).
Fig. 17. Physeal growth zone of femur showing prominent but disorganized zone of hypertrophy (SRPS IV).
Sickle Cell Disease ii. Hb C iii. Hb DLos Angels iv. Hb E v. Hb Lepore vi. Hb OArab vii. Hb CHarlem viii. Hb Quebec-Chori 4. Pathophysiology of sickle cell disease a. Hemolysis: the shortened survival of SS red blood cells results from the following two apparently independent properties of Hb S: i. Propensity of the concentrated Hb to polymerization resulting in: a) Morphologic sickling b) RBC dehydration c) A marked decrease in RBC deformability ii. Hemoglobin S instability b. Erythropoiesis i. Submaximal erythropoietic response ii. Abnormally low affinity for oxygen of SS cells iii. Response of the red cells’ glycolytic metabolism to hypoxia
Sickle cell disease is the most common single gene disorder in Afro Americans, affecting approximately one in 375 persons of African ancestry. The frequency of sickle cell trait is about 8% in the United States blacks. Sickle blood cells have an increased resistance to malaria. Protection from malaria helps maintain the high prevalence of the sickle gene in areas where malaria is endemic.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Caused by a point mutation at the second nucleotide of codon 6 of the β-globin gene. The base change of A to T causes the amino acid substitution of valine for glutamic acid (GAG to GTG) a. Immediate consequence of the mutation: Deoxygenated hemoglobin S polymerizes and distorts the shape of the red blood cell, causing vaso-occlusion in the small vessels b. Adverse effects of sickle hemoglobin on the red cell membrane i. Oxidative damage ii. Cellular dehydration iii. Abnormal phospholipid asymmetry iv. Increased adherence to endothelial cells c. Results of cellular abnormalities i. Shortened red cell lifespan causing a lifelong hemolytic anemia ii. Intermittent episodes of vascular occlusion causing tissue ischemia and acute and chronic organ dysfunction 3. Sickle cell disease a. Sickle cell anemia (homozygous sickle cell disease, Hb SS) i. Accounts for 60–70% of sickle cell disease in the US ii. The most common form of sickle cell disease iii. Caused by inheritance of hemoglobin S from both parents b. Other clinically significant sickle cell disorders caused by coinheritance of a sickle gene with a gene for: i. β-thalassemia: a) The β-thalassemias are divided into β+thalassemia (in which some β globin chains are produced) and β0-thalassemia (in which there is no β chain synthesis) b) Clinical pictures of patients with hemoglobin S β+-thalassemia and S β0-thalassemia resembles sickle cell disease rather than thalassemia, because the sickle β globin predominates in the presence of underproduction of normal β globin
CLINICAL FEATURES
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1. Infection a. The most immediate risk for infants diagnosed with sickle cell disease b. Prone to many bacterial infections, especially from encapsulated organisms, because of lack of splenic function resulting from progressive infarction of the spleen due to sickling of the red cells 2. Hemolysis a. Chronic anemia: Hemolytic anemia develops around three months of age. b. Jaundice (indirect hyperbilirubinemia) c. Aplastic crises i. Erythrocyte production by the bone marrow may pause temporarily in children with sickle cell disease. ii. Human parvovirus 19 infection responsible for 80% of aplastic crises d. Cholelithiasis i. Prone to develop pigmented gallstones due to large load of bilirubin from hemoglobin breakdown (chronic hemolysis) ii. Presenting symptoms: severe recurrent right upper quadrant pain, episode of cholecystitis, common duct obstruction, or pancreatitis e. Delayed growth and sexual maturation 3. Vaso-occlusion due to occlusion of the microcirculation by rigid red cells and consequent tissue anoxia and infarction
SICKLE CELL DISEASE
a. Recurrent acute pain i. Dactylitis (hand and foot syndrome) occurs in 25–45% of the patients and can be the earliest manifestation of sickle cell disease. The syndrome is rare after 4 years of age. It is believed to be due to infarction of the red marrow and associated periosteal inflammation. The clinical manifestations are fever and painful swelling of the hands or feet or both ii. Musculoskeletal pain iii. Abdominal pain b. Functional asplenia i. The proportion of children with Hb SS who are functionally asplenic: 1 year (28%), 2 years (58%), 3 years (78%), and 5 years (94%) ii. At risk for fulminant septicemia and meningitis with pneumococci and other encapsulated bacteria and death during the first 3 years of life in most patients with Hb SS c. Splenic sequestration (10–30% of children with Hb SS most commonly between 6 months and 3 years of life) i. Sudden massive collection of blood in the spleen due to sickle cells blocking outflow ii. Rapid enlargement of the spleen causing acute fall of the hemoglobin level of more than 2 g/dL, despite a persistently elevated reticulocyte count iii. Mild to moderate thrombocytopenia caused by sequestered platelets iv. Symptoms a) Acute pallor b) Lethargy c) Increased thirst d) Abdominal fullness e) Tachycardia f) Tachypnea v. May be associated with other complications of sickle cell disease, such as acute chest syndrome, vaso-occlusive pain, bacterial infection, stroke, or aplastic crisis vi. Increased tendency of recurrence (50%) vii. High mortality (second leading cause of death in children with sickle cell anemia) d. Acute chest syndrome i. Appearance of a new pulmonary infiltrate on chest radiography ii. Causes a) Infection (bacterial pneumonia, atypical bacterial pneumonia by Mycoplasma or Chlamydia, viral pneumonia, Parvovirus B19) b) Pulmonary vascular occlusion (in situ pulmonary thrombosis, fat embolism, peripheral thromboembolism) c) Hypoventilation/atelectasis (thoracic bony infarction, abdominal pain, opioids) d) Pulmonary edema (intravenous fluids, opioids, pulmonary vascular injury) e) Bronchospasm iii. Presenting with varying degrees of fever, cough, tachypnea, pleuritic chest pain, and/or hypoxemia
e.
f.
g.
h.
i.
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iv. Occurs in more than 50% of pediatric patients with Hb SS v. The second leading cause for hospitalization vi. Predispose to chronic restrictive lung disease with pulmonary hypertension and cor pulmonale (important causes of morbidity and mortality in adulthood) Stroke i. Caused by complete occlusion or severe narrowing of large cerebral vessels ii. Occurs in 7–8% of children with Hb SS after the first year of life, less commonly in children with Hb SC and sickle beta-thalassemia iii. Presenting symptoms a) Hemiparesis b) Monoparesis c) Aphasia d) Dysphasia e) Seizures f) Semicoma g) Coma h) Transient ischemic attack iv. High rate of recurrence (60–90% have a second stroke within 3 years without transfusion therapy) v. Silent cerebral infarctions in 10–20% of children with Hb SS without clinically apparent neurologic event Chronic nephropathy: an important cause of mortality in adult patients i. Hematuria a) Persistent microscopic (asymptomatic) hematuria: one of the most prevalent features of the disease b) Gross hematuria ii. Significant proteinuria (30%) iii. Papillary necrosis iv. Hyposthenuria and enuresis: inability to concentrate urine resulting in a high incidence of enuresis v. Nephrotic syndrome (40%) vi. Renal infarction vii. Pyelonephritis viii. Renal medullary carcinoma ix. Hypertension (2–6% in patients with Hb SS) x. Renal failure (5–18%) Priapism (painful erection) i. Affects about 2/3 of male patients ii. Recurrent attacks eventuate in impotence in 50% of the patients Bone disorders i. Dactylitis (hand-foot syndrome) ii. Bone infarction: manifestations include pain, tenderness, and frequently swelling at the involved site(s) iii. Aseptic necrosis of the long bones: manifestations include pain or limitation of motion in the hip, shoulder, or other joints, and during walking and climbing stairs Proliferative retinopathy
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SICKLE CELL DISEASE
j. Leg ulcers i. Most common cutaneous complication in sickle cell anemia ii. Causing pain, physical disfigurement, social isolation, vocational adversity, and high utilization of health care resources iii. Most common in the ankle area over the medial or lateral malleoli, less common over the dorsum of the foot and near the Achilles tendon iv. Universal secondary infections (Staphylococcus aureus and Pseudomonas aeruginosa most common pathogens) k. Osteomyelitis i. Salmonella (most common cause) ii. Staphylococcus aureus l. Transfusional hemosiderosis 4. Prognosis a. Natural history of sickle cell anemia conducted before mandated newborn screening programs: 15% of children die from acute infections or acute anemic events in the first five years of life b. Hb SC disease i. Clinical manifestations milder than Hb SS disease ii. Mild hemolytic anemia iii. Risk of overwhelming sepsis and death: less than that in Hb SS disease because of the later onset of splenic dysfunction iv. Risk of splenic sequestration up to young adulthood v. Splenomegaly vi. Vaso-occlusion vii. Proliferative retinopathy viii. Aseptic necrosis of femoral head c. Early infectious morbidity and mortality in Hb SS and sickle β0-thalassemia preventable by: i. Presymptomatic diagnosis by neonatal screening ii. Extensive parental education iii. Prophylactic penicillin for infants with Hb SS and Sβ0-thalassemia (125 mg by mouth twice a day begun between 2 months and three years of age and 250 mg twice daily until at least 5 years of age) iv. Timely immunizations (all routine immunizations in a timely fashion; new heptavalent conjugated pneumococcal vaccine administered at 2 months of age; influenza virus vaccines yearly after 6 months of age; meningococcal vaccine for children with splenic dysfunction) v. Prompt medical evaluation and management of febrile illness d. Sickle cell disease and pregnancy: Affected pregnant women are at risk for: i. Crisis ii. Toxemia iii. Pyelonephritis iv. Thrombophlebitis v. Spontaneous abortion e. Progress toward specific therapies i. Transfusion therapy ii. Bone marrow transplantation iii. Hydroxyurea
DIAGNOSTIC INVESTIGATIONS 1. Laboratory studies a. CBC count i. CBC and reticulocyte counts to document anemia and brisk marrow response ii. Peripheral blood smear to document presence of sickled erythrocytes, target cells, and HowellJolly body (indicating functional asplenism) iii. Differential white cell count iv. Arterial blood gases to reflect the severity of pulmonary crises v. Hemoglobin electrophoresis to document Hb SS or Hb S with another mutant hemoglobin in compound heterozygotes vi. Liver function tests, BUN, creatinine, and serum electrolytes vii. Fetal hemoglobin 2. Imaging studies a. Radiography i. Performed in patients with respiratory symptoms ii. To detect areas of infarction for painful bones b. MRI to detect areas of avascular necrosis for the femoral and humeral heads and to distinguish osteomyelitis from bony infarction c. Abdominal sonogram to document spleen size and the presence of biliary stones d. Transcranial Doppler ultrasonography useful in selecting patients at risk for stroke 3. Sickle cell anemia (Hb SS) a. Relative clinical severity i. Markedly severe hemolysis ii. Markedly severe vasoocclusion b. Neonatal screening: hemoglobins FS c. Hemoglobin electrophoresis i. Hb A: 0% ii. Hb S: 80–95% iii. Hb F: 2–20% iv. Hb A2: <3.5% v. Hb C: 0% d. Thin layer isoelectric focusing i. Gives better resolution of hemoglobins other than Hb A, Hb S, Hb C, and Hb F ii. Less experience using this method for screening and more costly e. High-performance liquid chromatography i. Differentiates many Hbs (Hbs F, A, S, C, D, E) ii. Hb S + Hb F + Hb A2 (probable sickle cell disease) iii. Hb A + Hb S + Hb A2 (Sickle cell trait) iv. Hb A + Hb C (Hb C trait) v. Hb C (Hb C disease) vi. Hb S + Hb C (sickle C disease) vii. Is quantitative (can differentiate sickle trait from sickle-β-thalassemia and identify βthalassemia) f. Sickle prep i. Does not distinguish between Heterozygote and homozygote ii. Easy for mass screening iii. Inappropriate for newborn screening
SICKLE CELL DISEASE
4.
5.
6.
7.
8.
g. Solubility test i. Hb S detected by precipitation/turbidity ii. Dows not distinguish sickle cell anemia from other sickle diseases iii. May gives false negative if Hb is low iv. May give false positive if lipidemia is present v. Easy to use for mass screening if only the presence of Hb S is desired vi. Inappropriate for newborn screening h. DNA diagnosis Sickle β0-thalassemia a. Relative clinical severity i. Moderate severe hemolysis ii. Moderate severe vasoocclusion b. Neonatal screening: hemoglobin FS c. Hemoglobin electrophoresis i. Hb A: 0% ii. Hb S: 80–92% iii. Hb F: 2–15% iv. Hb A2: 3.5–7.0% v. Hb C: 0% Sickle hemoglobin C disease (Hb SC) a. Relative clinical severity i. Mild hemolysis ii. Mild vasoocclusion b. Neonatal screening: hemoglobins FSC c. Hemoglobin electrophoresis i. Hb A: 0% ii. Hb S: 45–50% iii. Hb F: 1–5% iv. Hb A2: Quantity of A2 cannot be measured in the presence of Hb C v. Hb C: 45–50% Sickle β+-thalassemia a. Relative clinical severity i. Mild to moderate hemolysis ii. Mild to moderate vasoocclusion b. Neonatal screening: hemoglobins FSA or FS c. Hemoglobin electrophoresis i. Hb A: 5–30% ii. Hb S: 65–90% iii. Hb F: 2–10% iv. Hb A2: 3.5–6.0% v. Hb C: 0% Sickle cell trait a. Relative clinical severity: normal phenotype b. Neonatal screening: hemoglobins FAS c. Hemoglobin electrophoresis i. Hb A: 50–60% ii. Hb S: 35–45% iii. Hb F: <2% iv. Hb A2: <3.5% v. Hb C: 0% Normal a. Relative clinical severity: normal phenotype b. Neonatal screening: hemoglobins FA c. Hemoglobin electrophoresis i. Hb A: 95–98% ii. Hb S: 0% iii. Hb F: <2%
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iv. Hb A2: <3.5% v. Hb C: 0% 9. Newborn hemoglobinopathy screening a. Provided in all 50 states in the US b. The most commonly used screening method: electrophoresis and high performance liquid chromatography c. Fetal hemoglobin present predominantly in young infants d. Positive results to be followed by fetal hemoglobin electrophoresis for confirmation e. Results with only Hb F and S: suggest the infant has either sickle cell anemia or Sickle β0-thalassemia f. Results with Hb F, S, and C: suggest the infant has hemoglobin SC disease g. Results with Hb F, S, and A and the infant has not been transfused i. Hb S > Hb A: most likely Sickle β+-thalassemia ii. Hb A > Hb S: presumed sickle cell trait iii. Hb A ∼ Hb S a) Study the parents to determine if one of them has the thalassemia trait b) Repeat Hb electrophoresis after several months 10. Molecular genetic testing a. Carrier testing i. Most commonly accomplished by high-performance liquid chromatography ii. Isoelectric focusing iii. DNA-based assays b. Prenatal diagnosis: most commonly use DNA-based assays for the detection of the Hb S mutation c. Testing methods i. Mutation analysis a) Hb S (E6V) b) Hb C (E6K) c) Hb D (E121Q) d) Hb O (E121K) ii. Sequence analysis for Hb mutations
GENETIC COUNSELING 1. Recurrence risk a. Homozygous sickle cell disease (Hb SS): The child inherits a sickle (S) gene from each parent i. Risk to patient’s sibs: 25% ii. Risk to patient’s offspring: not increased unless the spouse is a carrier b. Sickle hemoglobin C disease (Hb SC): The child inherits an S gene from one parent and a C gene from the other parent i. Risk to patient’s sibs: 25% if Hb AS in one parent and Hb AC in other parent ii. Risk to patient’s offspring: not increased unless the spouse is either Hb AS or Hb AC carrier c. Sickle β-thalassemias: the child inherits an S gene from one parent and a β-thalassemia gene from the other parent i. Risk to patient’s sibs: 25% if sickle cell carrier in one parent and β-thalassemia carrier in other parent
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ii. Risk to patient’s offspring: not increased unless the spouse is a carrier for either Hb S or βthalassemia gene 2. Prenatal diagnosis a. Possible by analysis of DNA extracted from fetal cells obtained by amniocentesis or CVS b. Both disease-causing hemoglobin alleles of the carrier parents must be identified before prenatal testing c. Formal genetic counseling needed when the mother is a known carrier and the father is unknown and/or unavailable for testing 3. Management a. Preventive care i. Immunizations a) Hemophillus influenzae type b (Hib) vaccine b) 7-valent pneumococcal conjugate vaccine c) 23-valent pneumococcal polysaccharide vaccine d) Consider quadrivalent meningococcal polysaccharide vaccine e) Influenza immunization recommended yearly ii. Prophylactic medications a) Penicillin prophylaxis: effective in preventing 80% of life-threatening episodes of childhood Streptococcus pneumoniae sepsis b) Erythromycin prophylaxis: an alternative for individuals allergic to penicillin c) Consider folic acid supplementation iii. Other preventive strategies a) Transcranial Doppler to screen the presence of abnormal velocity of arterial blood flow (at risk for stroke) b) Screening for pulmonary hypertension, proteinuria, retinopathy, osteonecrosis, neurocognitive dysfunction, liver disease, growth failure, nutritional deficiency, and gallbladder disease b. Acute illness i. Infection/fever a) Broad-spectrum antibiotics (e.g., ceftriaxone) pending culture results b) Vancomycin only for proven or suspected meningitis or other severe illness ii. Painful crisis a) Oral hydration b) Oral analgesics including narcotics, acetaminophen, and ibuprofen c) Hospitalization for more severe pain episodes with parental analgesics and hydration iii. Splenic sequestration a) Emergency transfusion indicated when the signs of cardiovascular instability are present b) Splenectomy for multiple or severe episodes of splenic sequestration iv. Acute chest syndrome a) Treat aggressively with oxygen, analgesics, and antibiotics b) Simple transfusion c) Exchange transfusion
v. Stroke a) Monitor neurologic status b) Aggressive treatment of increased intracranial pressure and seizures c) Exchange transfusion generally indicated with the goal of decreasing Hb S percentage <30% of the total hemoglobin d) A preventive chronic transfusion protocol initiated after a CNS event to prevent a second stroke e) Prophylactic transfusion with folic acid replacement shown to decrease the incidence of vasoocclusive crisis during pregnancy vi. Priapism a) Hydration b) Analgesia administration c) Aspiration and irrigation by a urologist c. Surgical care, limited to treat complications i. Skin graft to help heal chronic leg ulcers ii. Hip replacement or other orthopedic procedures to treat avascular necrosis iii. Surgical draining of the penile corpora for resistant priapism iv. Cholecystectomy for gallstones d. Disease-modulating therapy i. Hydroxyurea a) Principle: the most prescribed therapy causes myelosuppressive-induced Hb F synthesis by decreasing terminal differentiation of erythroid stem cells, resulting in decreased sickling and improved red cell survival b) Effects of therapy: Patients treated have fewer acute episodes of pain crisis and acute chest syndrome, decreased need for transfusion, and improved survival c) Not effective for cerebrovascular complications of sickle cell disease ii. Other medications that increase the percentage of Hb F, currently under investigation a) Short chain fatty acids, such as butyrate or valproic acid b) 5-azacytidine iii. Chronic red blood cell transfusion a) To prevent stroke in patients with an abnormal transcranial Doppler and stroke recurrence b) To treat chronic debilitating pain and pulmonary hypertension c) Goal: to maintain the percentage of Hb S between 30–50% d) Complications: iron overload, alloimmunization, and infection iv. Stem cell transplantation a) Can be curative b) Limited use to a select group of patients with significant complications and a matched sibling stem cell donor v. Gene therapy a) Principle: a single nucleotide substitution in the pathogenesis of sickle cell disease makes
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the presence of the sickle cell allele an ideal candidate for gene therapy b) Question of the safety of this type of approach: development of leukemia in two patients participating in a clinical trial of gene therapy for X-linked severe combined immunodeficiency disease
REFERENCES American Academy of Pediatrics: Health supervision for children with sickle cell disease. Pediatrics 109:526–535, 2002. Bhardwaj U, Zhang YH, Jackson DS, et al.: DNA diagnosis confirms hemoglobin deletion in newborn screen follow-up. J Pediatr 142:346–348, 2003. Bookchin RM, Lew VL: Pathophysiology of sickle cell anemia. Hematol Oncol Clin N Amer 10:1241–1253, 1996. Burnett MW, Bass JW, Cook BA: Etiology of osteomyelitis complicating sickle cell disease. Pediatrics 101:296–297, 1998. Chen H: Genetic testing and counseling for hemoglobinopathies. In Chen H (ed): Ohio Department of Health The Resource Manual for hemoglobinopathies. An Essential Guide for Health Professionals. 1992, pp 97–107. Distenfeld A, Woermann U: Sickle cell anemia. EMedicine. 2003. http:// www.emedicine.com Dugdale M: Anemia. Obstet Gynecol Clin 28(2): June 2001. Eckman JR: Leg ulcers in sickle cell disease. Hematol Oncol Clin North Am 10:1333–1344, 1996. Fixler J, Styles L: Sickle cell disease. Pediatr Clin N Am 49:1193–1210, 2002. Lane PA: Sickle cell disease. Pediatr Clin N Am 43:639–664, 1996. Molitierno JA Jr, Carson CC III: Urologic manifestations of hematologic disease: sickle cell, leukemia, and thromboembolic disease. Urol Clin N Amer 30:49–61, 2003. Pegelow C: Sickle cell anemia. eMedicine. 2003. http://www.emedicine.com Powers DR: Natural history of sickle cell disease: The first ten years. Semin Hematol 12:267, 1975. Powers DR, Johnson CS: Priapism. Hematol Oncol Clin North Am 10:1363–1371, 1996.
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Quinn CT, Buchanan GR: The acute chest syndrome of sickle cell disease. J Pediatr 135:416–422, 1999. Rao SP, Miller ST, Cohen BJ: Transient aplastic crisis in patients with sickle cell disease: B19 parvovirus studies during a 7-year period. Arch J Dis Child 146:1328, 1992. Saborio P, Scheinman JI: Sickle cell nephropathy. J Am Soc Nephrol 10: 187–192, 1999. Sackey K: Hemolytic anemia: Part 2. Pediatr Rev 20:204–208, 1999. Sadowitz PD, Amanullah S, Souid A-K: Hematologic emergencies in the pediatric emergency room. Emerg Med Clin North Am 20(1): Feb 2002. Smith JA: Bone disorders in sickle cell disease. Hematol Oncol Clin North Am 10:1345–1356, 1996. Sun PM, Wilburn W, Raynor Arch Dermatol, et al.: Sickle cell disease in pregnancy: twenty years of experience at Grady Memorial Hospital, Atlanta, Georgia. Am J Obstet Gynecol 184:1127–1130, 2001. Vichinsky EP: Comprehensive care in sickle cell disease: its impact on morbidity and mortality. Semin Hematol 28:220–226, 1991. Vichinsky EP: Hydroxyurea in children: present and future. Semin Hematol 34:22–29, 1997. Vichinsky E: New therapies in sickle cell disease. Lancet 360:629–631, 2002. Vichinsky E, Hurst D, Earles A, et al.: Newborn screening for sickle cell disease: effect on mortality. Pediatrics 81:749–755, 1988. Vichinsky E, Schlis K: Sickle cell disease. Gene Reviews. 2003. http://www.genetests.org Walters MC, Storb R, Patience M, et al.: Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease. Blood 95:1918–1924, 2000. Wethers DL: Sickle cell disease in childhood: Part I. Laboratory diagnosis, pathophysiology and health maintenance. Am Fam Physician 62:1013–1020, 1027–1028, 2000. Wethers DL: Sickle cell disease in childhood: Part II. Diagnosis and treatment of major complications and recent advances in treatment. Am Fam Physician 62:1309–1314, 2000. Zarkowsky HS, Gallagher D, gill FM, et al.: Bacteremia in sickle hemoglobinopathies. J Pediatr 109:579–585, 1986.
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Fig. 3. Peripheral blood smear from another patient with sickle cell disease showing a sickle erythrocyte (short arrow) and target cells (long arrows) (Wright’s Giemsa stain, ×1000).
Fig. 1. A young child with sickle cell anemia showing hand-foot syndrome (dactylitis).
Fig. 2. Peripheral blood smear from a 28 year-old man with hemoglobin SS disease showing several sickle cells (drepanocytes) (short arrows), Howell-Jolly body (White arrow), and target cells (long arrows).
Silver-Russell Syndrome gene underlying the Silver-Russell phenotype in these cases c. The majority of the cases, however, have a normal karyotype
Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder, characterized by severe pre/postnatal growth retardation, characteristic facies, skeletal asymmetry, and other congenital anomalies. The incidence is estimated as 1:50,000–1:100,000 live births.
CLINICAL FEATURES
GENETIC/BASIC DEFECTS 1. Inheritance a. Sporadic occurrence in majority of cases b. 19% of cases with more than one affected individuals in the family, providing evidence for a genetic cause c. A genetically (and clinically) heterogeneous disorder i. Autosomal recessive (17.4%) ii. Autosomal dominant (8.7%) iii. X-linked dominant (74%) 2. Chromosomal basis a. Small number of cases with Silver-Russell syndrome reported in association with numerous chromosomal abnormalities i. R(15) and deletion of 15q ii. Diploid–triploid mixoploidy iii. 45,X/46,XY iv. XXY v. Trisomy 18 mosaicism vi. Del(8)(q11-q13) vii. Del(18p) viii. Dup(1)(q32.1-q42.1) ix. Dup(7p12.1-p13) x. Distal chromosome 17q a) Balanced translocation (17;20)(q25;q13) inherited from clinically normal father b) De novo translocation (1;17)(q31;q25) with breakpoint recently cloned and localized to 17q23.3-q24 c) Heterozygous deletion of the chorionic somatomammotrophin hormone 1 (CSH1) gene located within the growth hormone and CSH gene cluster on 17q24.1. The deletion was inherited from the father who appeared clinically normal but had short stature b. Maternal uniparental disomy (UPD) for chromosome 7 (about 7–10% of cases) i. Inheritance of both chromosomes 7 from the mother ii. A possible novel imprinted region at 7p12-p14, 7q32, and 7q31-ter: UPD can disrupt the balance between imprinted genes and thereby lead to phenotypic manifestations iii. Strong evidence of disruption of imprinted gene expression rather than mutation of a recessive
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1. Diagnostic criteria: Presence of three major features plus one or more minor features is generally required for a positive diagnosis. a. Major criteria i. Low birth weight (intrauterine growth retardation) ii. Proportionate short stature (postnatal growth retardation): mature height about –3.6 standard deviation scores in both sexes iii. Small triangular face iv. Fifth finger clinodactyly b. Minor criteria i. Relative macrocephaly due to sparing of cranial growth ii. Ear anomalies iii. Skeletal asymmetry (face, limb, or body) iv. Brachydactyly of the fifth fingers v. Bilateral camptodactyly with terminal interphalangeal contractures vi. Syndactyly vii. Transverse palmar crease viii. Downward slanting corner of the mouth ix. Muscular hypotrophy/hypotonia x. Motor/neurological delay xi. Irregular spacing of the teeth xii. Café-au-lait spots xiii. Precocious puberty xiv. Squeaky voice xv. Genital abnormalities xvi. Speech delay xvii. Feeding difficulties 2. Other manifestations a. Significant cognitive impairment (50%) b. Gastrointestinal symptoms (77%) i. Gastroesophageal reflux disease (34%) ii. Esophagitis (25%) iii. Food aversion (32%) iv. Failure to thrive (63%) c. Skeletal anomalies i. Large anterior fontanelle (delayed closure) ii. Absence of asymmetry iii. Syndactyly of the toes d. Genitourinary anomalies i. Hypospadias ii. Posterior urethral valves
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e. Cardiac defects f. Various tumors i. Craniopharyngioma ii. Testicular seminoma iii. Hepatocellular carcinoma iv. Wilms tumor g. Essentially normal pattern of puberty and adolescent growth h. Fertility not necessarily impaired, at least in females i. Other features i. Blue sclera ii. Café-au-lait spots iii. Excessive sweating iv. Hypoglycemia
DIAGNOSTIC INVESTIGATIONS 1. Increased serum or urinary gonadotropin levels in the prepubertal age 2. Hypoglycemia 3. Growth hormone studies 4. Metabolic acidosis due to renal tubular acidosis in a few patients 5. Radiography a. Delayed bone age b. Limb asymmetry c. Ivory epiphyses of the distal phalanges d. Clinodactyly of the fifth fingers e. Short fifth middle phalanges f. Pseudoepiphyses at the base of the second metacarpal 6. Chromosome analysis to define chromosome basis 7. UPD study using microsatellite markers on chromosome 7
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sibs i. Not increased in a non-genetic sporadic case ii. Increased depending on the inheritance pattern b. Patient’s offspring i. Not increased in a non-genetic sporadic case ii. Increased depending on the inheritance pattern 2. Prenatal diagnosis by ultrasonography of fetus at risk by family history a. Delayed fetal skeletal growth may not be evident until late second trimester b. Asymmetry of fetal limbs may not be evident until the third trimester 3. Management a. Growth deficiency i. Optimize caloric intake ii. Consider nasogastric or gastrostomy feeding for severe gastroesophageal reflux and failure to thrive iii. Consider growth hormone treatment in patients with documented growth hormone deficiency b. Dental cares for overcrowding of teeth c. Orthopedic management for asymmetry of legs d. Early intervention programs including physical therapy for developmental delay due to hypotonia e. Special education for learning disabilities f. Psychological counseling related to body image and peer relationship
REFERENCES Abramowicz HK, Nitowsky HM: Reproductive ability of an adult female with Silver-Russell syndrome. J Med Genet 14:134–136, 1977. Al-Fifi, Teebi AS, Shevell M: Autosomal dominant Russell-Silver syndrome. Am J Med Genet 61:96–97, 1996. Angehrn V, Zachmann M, Prader A: Silver-Russell syndrome. Observations in 20 patients. Helv Paediat Acta 34:297–308, 1979. Bernard LE, Peñaherrera MS, Van Allen MI, et al.: Clinical and molecular findings in two patients with Russell-Silver syndrome and UPD7: comparison with non-UPD7 cases. Am J Med Genet 87:230–236, 1999. Bianchi M, Arico M, Severi F, et al.: Russell-Silver syndrome and XXY karyotype. Pediatrics 71:669, 1983. Blissett J, Harris G, Kirk J: Feeding problems in Silver-Russell syndrome. Dev Med Child Neurol 43:39–44, 2001. Christensen MF, Nielson J: Deletion short arm 18 and Silver-Russell syndrome. Acta Paediatr Scand 67:101–103, 1978. Curi JFJ, Vanucci RC, Grossman H, et al.: Elevated serum gonadotrophins in Silver’s syndrome. Am J Dis Child 114:658–661, 1967. Donnai D, Thompson E, Allanson J, et al.: Severe Silver-Russell syndrome. J Med Genet 26:447–451, 1989. Duncan PA, Hall JG, Shapiro LR, et al.: Three-generation dominant transmission of the Silver-Russell syndrome. Am J Med Genet 35: 245–250, 1990. Dupont JM, Cuisset L, Cartigny M, et al.: Familial reciprocal translocation t(7;16) associated with maternal uniparental disomy 7 in a Silver-Russell patient. Am J Med Genet 111:405–408, 2002. Eggermann T, Wollman HA, Kuner R, et al.: Molecular studies in 37 SilverRussell syndrome patients: frequency and etiology of uniparental disomy. Hum Genet 100:415–419, 1997. Eggermann T, Eggermann K, Mergenthale S, et al.: Paternally inherited deletion of CSH1 in a patient with Silver-Russell syndrome. J Med Genet 35:784–786, 1998. Eggermann T, Mergenthaler S, Eggermann K, et al.: Segmental uniparental disomy of 7q31-qter is rare in Silver-Russell syndrome. Clin Genet 60:395–396, 2001. Escobar V, Gleiser S, Weaver DD: Phenotypic and genetic analysis of the Silver-Russell syndrome. Clin Genet 13:278–288, 1978. Fernandez BA, et al.: Russell-Silver syndrome: identification of a candidate region on the short arm of chromosome 7. Am J Hum Genet 65S:1653, 1999. Fuleihan DS, DerKaloustian VM, Najjar SS: The Russell-Silver syndrome: report of three siblings. J Pediatr 78:654–657, 1971. Gareis FJ, Smith DW, Summitt RL: The Russell-Silver syndrome without asymmetry. J Pediatr 79:775–781, 1971. Graham JM, Hoehn H, Liu MS, et al.: Diploid-triploid mixoploidy: clinical and cytogenetic aspects. Pediatrics 68:23, 1981. Hall JG: Unilateral disomy as a possible explanation for Russell-Silver syndrome. J Med Genet 27:141–142, 1990. Hannula K, Lipsanen-Nyman M, Kontiokari T, et al.: A narrow segment of maternal uniparental disomy of chromosome 7q31-qter in Silver-Russell syndrome delimits a candidate gene region. Am J Hum Genet 68:247–253, 2001. Herman TE, et al.: Hand radiographs in Russell-Silver syndrome. Pediatrics 79:743–744, 1987. Hitchins MP, Stanier P, Preece MA, et al.: Silver-Russell syndrome: a dissection of the genetic aetiology and candidate chromosomal regions. J Med Genet 38:810–819, 2001. Hitchins MP, Abu-Amero S, Apostolidou S, et al.: Investigation of the GRB2, GRB7, and CSH1 genes as candidates for the Silver-Russell syndrome (SRS) on chromosome 17q. J Med Genet 39,e13, 2002. Joyce CA, Sharp A, Walker JM, et al.: Duplication of 7p12.1–13, including GRB10 and IGFBP1, in a mother and daughter with features of SilverRussell syndrome. Hum Genet 105:273–280, 1999. Lai KYC, Skuse D, Stanhope R, et al.: Congnitive abilities associated with the Silver-Russell syndrome. Arch Dis Child 71:490–496, 1994. Monk D, Bentley L, Hitchins M, et al.: Chromosome 7p disruptions in Silver Russell syndrome: delineating an imprinted candidate gene region. Hum Genet 111:376–387, 2002. Moore GE, Sbu-Amero S, Wakeling E, et al.: The search for the gene for SilverRussell syndrome. Acta Paediatr Suppl 433:42–48, 1999. Nakabayashi K, Fernandez BA, Teshima I, et al.: Molecular genetic studies of human chromosome 7 in Russell-Silver syndrome. Genomics 79:186–196, 2002.
SILVER-RUSSELL SYNDROME Partington MW: X-linked short stature with skin pigmentation: Evidence for heterogeneity of the Russell-silver syndrome. Clin Genet 29:151–156, 1986. Patton MA: Russell-Silver syndrome. J Med Genet 25:557–560, 1988. Preece MA: The genetics of the silver-Russell syndrome. Rev Endocr Metab Disord 3:369–379, 2002. Preece MA, Price SM, Davies V, et al.: Maternal uniparental disomy 7 in Silver-Russell syndrome. J Med Genet 34:6–9, 1997. Preece MA, Abu-Amero SN, Ali Z, et al.: An analysis of the distribution of hetero- and isodisomic regions of chromosome 7 in five mUPD7 SilverRussell syndrome probands. J Med Genet 36:457–460, 1999. Price SM, Stanhope R, Garrett C, et al.: The spectrum of Silver-Russell syndrome: a clinical and genetic study and new diagnostic criteria. J Med Genet 36:837–842, 1999. Ram`irez-Due`oas ML, Medina C, Ocampo-Campos R, et al.: Severe RussellSilver syndrome and translocation (17;20)(q25;q13). Clin Genet 41:51–53, 1992. Ranke MB, Lindberg A: Growth hormone treatment of short children born small for gestational age or with Silver-Russell syndrome: results from KIGS (Kabi International Growth Study), including the first report on final height. Acta Paediatr 417 (Suppl 4):18–26, 1996. Robichaux V, Fraikor A, Favara B, et al.: Silver-Russell syndrome: A family with symmetric and asymmetric siblings. Arch Path Lab Med 105:157–159, 1981. Rogan PK, Seip JR, Driscoll DJ, et al.: Distinct 15q genotypes in Russell-Silver and ring 15 syndrome. Am J Med Genet 62:10–15, 1996.
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Russell A: A syndrome of intra-uterine dwarfism recognizable at birth with cranio-facial synostosis, disproportionately short arms and other anomalies. Proc R Soc Med 47:1040–1044, 1954. Schinzel AA, Robinson WP, Binkert F, et al.: An interstitial deletion of proximal 8q (q11-q13) in a girl with Silver-Russell syndrome-like features. Clin Dysmorphol 3:63–69, 1994. Silver HK, Kiyasu W, George J, et al.: Syndrome of congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins. Pediatrics 12:368–376, 1953. Silver HK: Asymmetry, short stature, and variations in sexual development: a syndrome of congenital malformations. Am J Dis Child 107: 495–515, 1964. Tanner JM, Lejarraga H, Cameron N: The natural history of the Silver-Russell syndrome: a longitudinal study of thirty-nine cases. Pediatr Res 9:611–623, 1975. Teebi AS: Autosomal recessive Silver-Russell syndrome. Clin Dysmorphol 1:151–156, 1992. van Haelst MM, Eussen HJ, Visscher F, et al.: Silver-Russell phenotype in a patient with pure trisomy 1q32.1–q42.1: further delineation of the pure 1q trisomy syndrome. J Med Genet 39:582–585, 2002. Wax JR, Burroughs R, Wright MS: Prenatal sonographic features of RussellSilver syndrome. J Ultrasound Med 15:253–255, 1996. Wilson GN, Sauder SE, Bush M, et al.: Phenotypic delineation of ring chromosome 15 and Russell-Silver syndromes. J Med Genet 22:233–236, 1985. Wollmann HA, Kirchner T, Enders H, et al.: Growth and symptoms in SilverRussell syndrome; review on the basis of 386 patients. Eur J Pediatr 154:958–968, 1995.
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Fig. 2. A girl with Silver-Russell syndrome showing prenatal and postnatal growth deficiency, triangular face, and clinodactyly of the 5th fingers.
Fig. 1. An infant with Silver-Russell syndrome showing prenatal and postnatal growth deficiency, triangular face, and asymmetry of legs.
Fig. 3. A girl with Silver-Russell syndrome showing prenatal and postnatal growth deficiency with brachydactyly and clinodactyly of the 5th fingers.
Sirenomelia Sirenomelia is a rare malformation sequence characterized by a partial or complete fusion of the lower limbs associated with urogenital, anal, lower spine and other anomalies. The term sirenomelia comes from “siren” or “mermaid” because of the characteristic fusion of the lower extremities. Because of its physical resemblance to the mythical mermaid, the topic of sirenomelia has fascinated public for centuries. Sirenomelia occurs in approximately 1 in 60,000 births.
GENETICS/BASIC DEFECTS 1. Sporadic occurrence 2. Incidence of sirenomelia in monozygotic twins markedly increased over dizygotic twins or singletons 3. Cause obscure a. Malformations as developmental field defects, probably arising during blastogenesis. Previously considered a vascular disruption anomaly, sirenomelia is quintessential primary defect of blastogenesis affecting multiple midline primordia during the final stages of granulation at the caudal eminence. b. The fusion theory: The lower extremities develop in lateral contact to each other and subsequently become fused. c. The classical theory: Deficiency of the caudal axial area in the embryo allows the approximation of the side plates where the limbs develop. d. The single umbilical artery theory: Resulting vascular insufficiency does not allow the normal process of lower limb development. e. The vascular steal theory: The sirenomelic malformations result from diversion of the blood flow from caudal structures of the embryo to the placenta. The tissues distal to the diversion receive diminished vascular supply; consequently the development is arrested at some stage during fetal life. f. The extrinsic theory: Any mechanical pressure on the caudal portion of the embryo may impede normal rotation of the limb buds as it has been observed in chick embryos exposed to such influences. g. The neural tube distention theory: Over distention of the neural tube in the caudal region expands the roof plate of the tube, displacing and laterally rotating the mesoderm, which allows the fusion of the limb buds.
CLINICAL FEATURES 1. Fusion of the lower limbs a. The most striking feature of the syndrome b. Fusion of the lower limbs and abnormalities of the feet creating the appearance of a mermaid c. Often with rotated feet d. Posteriorly located patella 903
2. Sirtori’s classification into three types according to the number of the feet a. Sympus apus (absence of both feet) b. Sympus unipus or monopus (presence of only one foot) c. Sympus dipus (presence of both feet) 3. Stocker’s more detailed classification into seven subtypes according to the fused bones a. Type I: paired femora, tibiae, and fibulae b. Type II: a single, fused fibula c. Type III: absent fibula d. Type IV: partially fused femora and a single fibula e. Type V: partially fused femora and absent fibulae f. Type VI: a single femur and tibia g. Type VII: a single femur and absent tibiae and fibulae 4. Oligohydramnios 5. Single umbilical artery a. With hypoplasia of the aorta below the origin of the umbilical artery b. Presents virtually in every cases of sirenomelia 6. Vascular anomalies a. Single umbilical artery b. Persistent vitelline artery c. Hypoplastic distal aorta d. Aberrant femoral arteries 7. Urogenital anomalies a. Unilateral or bilateral renal agenesis (the most common finding) b. Renal cystic dysplasia c. Fusion of the renal pelvis d. Absent bladder e. Urethral atresia f. Ectopic urethra g. Posterior urethral valves h. Male i. Absent external genitalia ii. Small/rudimentary phallus iii. Absent testis i. Females i. Absent/ambiguous external genitalia ii. Absent ovaries iii. Anomalous/rudimentary uterus iv. Anomalous vagina 8. Gastrointestinal anomalies a. Meckel’s diverticulum b. Duodenal atresia c. Absent gallbladder d. Annular pancreas e. Omphalocele f. Intestinal malrotation g. Blind-end colon/rectum h. Colon duplication i. Absent spleen
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SIRENOMELIA
j. Imperforate anus k. Limb-body wall complex Cardiac anomalies a. Tetralogy of Fallot b. Totally anomalous pulmonary venous return c. Ventricular septal defect d. Atrial septal defect e. Truncus arteriosus f. Hypoplastic ventricles g. Mitral atresia h. Transposition of the aorta i. Coarctation of the aorta j. Hypoplastic left heart k. Acardius amorphus Pulmonary anomalies a. Pulmonary hypoplasia b. Tracheo-esophageal fistula c. Laryngeal stenosis and tracheal atresia d. Cystic adenomatoid malformation e. Diaphragmatic hernia f. Abnormal lung lobation g. Pulmonary agenesis associated with acardius amorphus CNS anomalies a. Craniorachischisis b. Holoprosencephaly c. Hydrocephalus d. Arnold-Chiari malformation e. Absent corpus callosum f. Meningomyelocele Pelvis/sacral anomalies a. Dysplastic pelvis b. Sacral agenesis/dysplasia Vertebral anomalies a. Hemivertebrae b. Spina bifida c. Kyphoscoliosis Upper limb anomalies a. Absent radius b. Abnormal thumb c. Absent limb d. Preaxial polydactyly Face a. Potter facies i. Large, floppy low-set ears ii. Flat nose iii. Micrognathia b. Skin tags Prognosis a. Generally lethal i. Stillborn in more than half of cases ii. Remainder of cases most likely die shortly after birth due to severe associated visceral anomalies, incompatible with life b. Occasional long-term survival possible
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Classification based on osseous findings
i. Type I (all bones of thigh and lower leg present and unfused) ii. Type II (fused fibulae) iii. Type III (absent fibulae) iv. Type IV (partially fused femora and fused fibulae) v. Type V (partially fused femora) vi. Type VI (fused femora and fused tibiae) vii. Type VII (fused femora and absent tibiae) b. Rotation of the legs and feet c. Abnormalities of the vertebrae, especially sacral bones d. Deficient bony pelvis 2. Angiography for vascular anomalies 3. Chromosome analysis: normal in most cases
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sibs: negligible b. Patient’s offspring: Affected individuals do not expect to survive to reproduce 2. Prenatal diagnosis a. Ultrasonography i. Inability to demonstrate separate lower limbs ii. Identification of varying degree of a single or “fused” lower limb iii. Lower spine agenesis/dysgenesis iv. CNS, cardiac, GI, and other abnormalities v. A single umbilical artery vi. Oligohydramnios associated with urogenital anomalies, especially renal agenesis/dysgenesis vii. Prenatal diagnosis of sirenomelia difficult to make because of the associated anhydramnios b. Color Doppler imaging i. A simple, non-invasive method to detect vascular abnormalities associated with sirenomelia ii. Two vascular hallmarks of the syndrome in utero a) Persistence of the vitelline artery: a single large artery arising from the high abdominal aorta to become the single umbilical artery, leaving an atretic or absent distal aorta. Such a vascular abnormality is thought to be responsible for a vascular steal phenomenon and poor perfusion distal to the anomalous artery, leading to the sirenomelia sequence. b) Absence of renal vessels 3. Management a. Orthopedic treatment of patients with less severe spectrum of caudal regression i. Soft tissue release ii. Osteotomies iii. Separation of the lower limbs. Long-term functional results of the separation are unknown. iv. Orthotics b. Anticipate extensive reconstruction in the event of survival c. Goal of orthopedic intervention: proper seating and standing, achievable without amputation d. Severe form of sirenomelia: a lethal condition
SIRENOMELIA
REFERENCES Adra A, Cordero D, Mejides A, et al.: Caudal regression syndrome: etiopathogenesis, prenatal diagnosis, and perinatal management. Obstet Gynecol Surv 49:508–516, 1994. Blaicher W, Lee A, Deutinger J, et al.: Sirenomelia: early prenatal diagnosis with combined two- and three-dimensional sonography. Ultrasound Obstet Gynecol 17:542–543, 2001. Chen C-P, Shih S-L, Liu F-F, et al.: Cebocephaly, alobar holoprosencephaly, spina bifida, and sirenomelia in a stillbirth. J Med Genet 34:252–255, 1997. Clark LA, Stringer DA, Fraser GC, et al.: Long term survival of an infant with Sirenomelia. Am J Med Genet 45:292–296, 1993. Goodlaw OG, McCoy-Sibley RI, Allen BG, et al.: Sirenomelia mermaid syndrome. J Natl Med Assoc 80:343–346, 1988. Guidera KJ, Raney E, Ogden JA, et al.: Caudal regression: a review of seven cases, including the mermaid syndrome. J Pediatr Orthop 11:743–747, 1991. Kallen B, Winberg J: Caudal mesoderm pattern of anomalies: from renal agenesis to sirenomelia. Teratology 9:99–112, 1973. Murphy JJ, Fraser GC, Blair GK: Sirenomelia: case of the surviving mermaid. J Pediatr Surg 27:1265–1268, 1992. Opitz JM, Zanni G, Reynolds JF Jr, et al.: Defects of blastogenesis. Am J Med Genet (Semin Med Genet) 115:269–286, 2002. Perez-Aytes A, Montero L, Gomez J, et al.: Single aberrant umbilical artery in a fetus with severe caudal defects: Sirenomelia or caudal dysgenesis. Am J Med Genet 69:409–412, 1997. Raabe RD, Harnsberger HR, Lee TG, et al.: Ultrasonographic antenatal diagnosis of ‘mermaid syndrome’: fusion of fetal lower extremities. J Ultrasound Med 2:463–464, 1983.
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Rodriguez JI, Palacios J Pediatr: Craniorachischisis totalis and Sirenomelia. Am J Med Genet 43:732–736, 1992. Savader DJ, Savader BL, Clark RA: Sirenomelia without Potter syndrome: MR characteristics. J Comput Assist Tomogr 13:689–691, 1989. Sepulveda W, Romero R, Pryde PG, et al.: Prenatal diagnosis of sirenomelia with color Doppler ultrasonography. Am J Obstet Gynecol 170:1377–1379, 1994. Sepulveda W, Corral E, Sanchez J, et al.: Sirenomelia sequence versus renal agenesis: prenatal differentiation with power Doppler ultrasound. Ultrasound Obstet Gynecol 11:445–449, 1998. Sirtori M, Ghidini A, Romero R, et al.: Prenatal diagnosis of sirenomelia. J Ultrasound Med 8:83–88, 1989. Stevenson RE, Jones KL, Phelan MC, et al.: Vascular steal: the pathogenetic mechanism producing sirenomelia and associated defects of the viscera and soft tissues. Pediatrics 78:451–457, 1986. Stocker JT, Heifetz SA: Sirenomelia: A morphological study of 33 cases and review of the literature. Perspect Pediatr Pathol 10:7–50, 1987. Talamo TS, Macpherson TA, Dominínguez R: Sirenomelia: angiographic demonstration of vascular anomalies. Arch Pathol Lab Med 106:347–348, 1982. Twickler D, Budorixk N, Pretorius D, et al.: Caudal regression versus Sirenomelia: Sonographic clues. J Ultrasound Med 12:323–330, 1993. Van Zalen-Sprock MM, Van Vugt JMG, Van der Harten JJ, et al.: Early secondtrimester diagnosis of sirenomelia. Prenat Diagn 15:171–177, 1995. Valenzano M, Paoletti R, Rossi A, et al.: Pathological features, antenatal ultrasonographic clues, and a review of current embryogenic theories. Hum Reprod Update 5:82–86, 1999. Young ID, O’Reilly KM, Kendall CH: Etiological heterogeneity in Sirenomelia. Pediatr Pathol 5:31–43, 1986.
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Fig. 3. A female stillborn (35 weeks gestation) with sirenomelia (monomelia). The infant had a single femur with one bone below knee, agenesis of urinary system (ureters, bladder and urethra), ectopic rudimentary renal tissue, absence of uterus, vagina, and external genitalia, and imperforate anus.
Fig. 1. A stillborn with sirenomelia showing Potter facies, short neck, absent external genitalia, and fused single lower limb with absent feet. This infant also had holoprosencephaly.
Fig. 4. A male premature neonate with sirenomelia showing fused lower extremities and posterior alignment of the knees and feet. The left foot was malformed. Other major anomalies included absence of external genitalia, bilateral renal agenesis, agenesis of the ureters, bladder, urethra, and prostate, esophageal atresia with TE fistula, imperforate anus with absence of the rectum, intestinal malrotation, persistent left superior vena cava, bifid cardiac apex and scoliosis with two hemivertebrae.
Fig. 2. Radiographs of the previous infant showed vertebral segmentation defects, malformed ribs, absent sacrum, dysplastic pelvic bones, a single femur, and absent tibiae/fibulae/tarsal/metatarsals/phalanges.
Smith-Lemli-Opitz Syndrome In 1964, Smith, Lemli, and Opitz reported three patients with a common distinctive facial appearance, microcephaly, broad alveolar ridges, hypospadias, a characteristic dermatoglyphics pattern, severe feeding disorder, and global developmental delay. The incidence of the Smith-Lemli-Opitz syndrome is estimated to be approximately 1 in 10,000 to 1 in 40,000 births based on clinical diagnosis and 1 in 60,000 to 1 in 100,000 births based on biochemical testing. There appears to be strikingly different incidences among various ethnic groups.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Basic defect a. Caused by a defect of cholesterol biosynthesis b. Underlying biochemical defect: deficiency of 7dehydrocholesterol reductase (DHCR7), an enzyme catalyzing the last step of the Kandutsch-Russell cholesterol biosynthesis pathway, resulting in generalized cholesterol deficiency c. Mutations of DHCR7 gene lead to deficient activity of 7-dehydrocholesterol reductase (DHCR7), the final enzyme of the cholesterol biosynthesis pathway. Functional null alleles of the DHCR7 locus results in lethal form of Smith-Lemli-Opitz syndrome. d. Human DHCR7 gene has been cloned and localized to 11q12-13. e. An example of metabolic deficiency as a cause of a dysmorphic syndrome 3. Clues pointing to an underlying biochemical defect of cholesterol metabolism a. Holoprosencephaly, microcephaly, pituitary agenesis, limb defects, and genital anomalies produced by in utero exposure of rat and mouse pups to chemical inhibitors of the cholesterol biosynthetic pathway b. Large adrenal glands with complete absence of lipid in adrenal cortex of patients with Smith-Lemli-Opitz syndrome c. Abnormalities of the pituitary-adrenal axis d. Suppressed fetal estriol production in pregnancies affected with Smith-Lemli-Opitz syndrome e. Neonatal liver disease in severe Smith-Lemli-Opitz syndrome associated with low serum cholesterol level f. Male pseudohermaphroditism not caused by dihydrotestosterone receptor defects g. Observation of two patients with Smith-Lemli-Opitz syndrome with low plasma cholesterol and elevated levels of 7-dehydrocholesterol (7DHC), the immediate precursor of cholesterol in the Kandutsch-Russell biosynthetic pathway, suggesting that this multiple malformation was caused by a simple Garrodian enzymatic defect 907
4. Rutledge multiple congenital anomaly syndrome a. Considered a variant of Smith-Lemli-Opitz syndrome b. Biochemical abnormality of excess 7-dehydrocholesterol and low cholesterol identified in the liver tissue 5. Five additional related human syndromes resulting from impaired cholesterol synthesis a. Desmosterolosis i. Report of a female infant with a lethal syndrome of macrocephaly, thick alveolar ridges, gingival nodules, cleft palate, total anomalous pulmonary venous drainage, ambiguous genitalia, short limbs, and generalized osteosclerosis was found to have markedly increased tissue levels of desmosterol ii. Another report of a child with microcephaly, short stature, and delays in speech and psychomotor development was found to have an increased plasma level of desmosterol and markedly increased levels of desmosterol in cultured lymphoblasts b. X-linked dominant chondrodysplasia punctata type 2 (CDPX2) (Conradi-Hünermann syndrome) i. Typically in females with a variable combination of bilateral and asymmetric shortening of long bones, punctate calcification of epiphyses, trachea, and larynx, segmental cataracts, and patches of ichthyotic skin that typically follow the lines of Blaschko ii. Caused by function-impairing mutations in the sterol-Δ8-isomerase gene, which maps to Xp11.2-3 iii. Lethal to males early in gestation c. CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma/nevus and limb defects) i. X-linked dominant inheritance ii. Cutaneous and bony abnormalities similar to CDPX2 iii. Report of a patient with classic CHILD syndrome a) Manifests the characteristic sterol abnormality of CDPX2 b) Carries a mutation creating a stop codon in the same sterol-Δ8-isomerase associated with CDPX2 d. Greenberg dysplasia (hydrops-ectopic calcificationmoth-eaten skeletal dysplasia) i. Autosomal recessive inheritance ii. A lethal skeletal dysplasia characterized by hydrops fetalis, short-limbed dwarfism, postaxial polydactyly, and abnormal chondro-osseous mineralization iii. Radiologic abnormalities a) Moth-eaten appearing long bones b) Ectopic epiphyseal calcification c) Laryngeal and tracheal calcification d) Platyspondyly iv. Steroid-Δ14-reductase deficiency
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e. Antley-Bixler syndrome i. A skeletal abnormality syndrome primarily affecting head and limbs ii. Also known as multi-synostotic osteodysgenesis with long bone fractures iii. A high incidence of genital ambiguity, an anomaly unlikely due to the FGFR2 mutation, suggesting possible disordered steroidogenesis in early pregnancy iv. Elevated two primary precursors of steroid hormones, pregnenolone and progesterone, as are the classical diagnostic metabolites for 17- and 21-hydroxylase deficiencies, suggesting attenuated steroid hydroxylation (including 17,20lyase activity) at least in the form not associated with FGFR2 mutations
CLINICAL FEATURES 1. General a. Postnatal growth retardation b. Failure to thrive c. Feeding difficulties requiring gavage feeding in many cases d. Abnormal intestinal motility i. Pyloric stenosis ii. Vomiting iii. Gastoresophageal reflux e. Feeding intolerance f. Gastrointestinal irritability g. Allergy h. Initial hypotonia/later hypertonia i. Recurrent otitis media and pneumonias j. Photosensitivity k. Adrenal insufficiency uncommon 2. Craniofacial features a. Congenital microcephaly: very common b. Bitemporal narrowing c. Capillary hemangioma over the glabella d. Eyes i. Epicanthal folds ii. Ptosis (more than 50% of patients, often with asymmetrical or unilateral ptosis) iii. Congenital cataracts iv. Optic nerve hypoplasia e. Broad nasal bridge and short nasal root with anteverted nares f. Micrognathia g. Oral i. Cleft lip/palate ii. High-arched/narrow hard palate iii. Broad/ridged alveolar ridges iv. Redundant sublingual tissues v. Long philtrum h. Low-set and posteriorly rotated ears 3. CNS anomalies a. Global psychomotor retardation b. Microcephaly (almost universal finding) c. Agenesis/hypoplasia of corpus callosum d. Cellebellar hypoplasia
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Enlarged ventricles Decreased size of frontal lobes Pituitary lipoma Cerebellar hypoplasia with hypoplasia or aplasia of the vermis i. Holoprosencephaly sequence (5% of cases) j. Seizures Limb anomalies a. Bilateral or unilateral postaxial polydactyly in the hands or feet b. Short/proximally placed thumb c. Short first metacarpals d. Hypoplastic thenar eminences e. Subtle ‘Zigzag’ alignment of the phalanges of the index finger f. Characteristic Y-shaped cutaneous syndactyly of the 2nd–3rd toes Genital anomalies a. Male (range from normal to the appearance of complete sex reversal) i. External genitalia: normal, hypospadias, female appearing, or ambiguous ii. Internal genitalia: gonads varying from normal testes to ovotestes to normal ovaries or missing gonads; sex reversal including blind vaginal pouch and rudimentary or bicornuate uterus b. Female i. Hypoplasia of labia minora ii. Hypoplasia of labia majora Congenital heart defects (about 50% of cases) a. Endocardial cushion defect (AV canal) b. Septal defect c. Hypoplastic left heart syndrome d. Patent ductus arteriosus e. Aortic coarctation f. Anomalous pulmonary venous return g. Hypertrophic cardiomyopathy Renal anomalies (about 25% of cases) a. Renal hypoplasia/aplasia with oligohydramnios sequence b. Horseshoe kidney c. Renal cortical cysts d. Hydronephrosis e. Renal ectopia f. Ureteral duplication g. Fetal lobation h. Hypoplastic bladder and ureters Adrenal anomalies a. Adrenal hyperplasia b. Adrenal hypoplasia Respiratory tract anomalies a. Laryngomalacia b. Tracheomalacia c. Sleep apnea d. Abnormal pulmonary lobation e. Pulmonary hypoplasia Gastrointestinal/hepatic anomalies a. Pyloric stenosis (prominent clinical problem) b. Hirschsprung disease c. Cholestatic liver disease
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11. Behavioral disorders a. Hypersensitivity with tactile defensiveness (oral, hands, and feet) b. Unusual hyperresponsivity to auditory and visual stimuli c. Aggressiveness and self-injury d. Severe sleep disturbance e. Autistic behavior 12. Prognosis a. Many survive to adulthood. b. Many affected children died in the first year from failure to thrive and infections. 13. So-called Smith-Lemli-Opitz syndrome type II, a lethal syndrome resembling the original Smith-Lemli-Opitz syndrome a. Autosomal recessive disorder b. Lethal in the newborn period from internal malformations c. Most 46,XY “males” with severe hypogenitalism or female appearing external genitalia d. Same sterol pattern in most patients e. Differences in severity between type I and type II Smith-Lemli-Opitz syndrome: due to severity of the mutations according to subsequent molecular genetic studies f. Possibility of genetic heterogeneity of the SmithLemli-Opitz syndrome 14. Clinical criteria for the revised severity score (revised Bialer score) by Kelly and Hennekam (2000). The severity score is obtained based on categories of cerebral, ocular, oral, skeletal, and genital defects identified. Based on the severity score, Smith-Lemli-Opitz syndrome phenotype can be divided into three categories: mild (<20), classical (20–50), and severe (>50). Severity score can be correlated with biochemical parameters and provides a basis for establishing a genotype-phenotype correlation a. Brain i. Score 1: Seizures; qualitative MRI abnormality ii. Score 2: Major CNS malformations; gyral defects b. Oral i. Score 1: Bifid uvula or submucous cleft ii. Score 2: Cleft hard palate or median cleft lip c. Acral i. Score 0: Non-Y-shaped minimal toe syndactyly ii. Score 1: Y-shaped 2–3 toe syndactyly; club foot; upper or lower polydactyly; other syndactyly iii. Score 2: Any two of the above d. Eye i. Score 2: Cataract; frank microphthalmia e. Heart i. Score 0: Functional defects ii. Score 1: Single chamber or vessel defects iii. Score 2: Complex cardiac malformation f. Kidney i. Score 0: Functional defect ii. Score 1: Simple cystic kidney disease iii. Score 2: Renal agenesis; clinically important cystic disease
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g. Liver i. Score 0: Induced hepatic abnormality ii. Score 1: Simple structural abnormality iii. Score 2: Progressive liver disease h. Lung i. Score 0: Functional pulmonary disease ii. Score 1: Abnormal lobation; pulmonary hypoplasia iii. Score 2: Pulmonary cysts; other major malformations i. Bowel i. Score 0: Functional GI disease ii. Score 1: Pyloric stenosis iii. Hirschsprung disease j. Genitalia i. Score 1: Simple hypospadias ii. Score 2: Ambiguous or female genitalia in a 46,XY; frank genital malformation in a 46,XX
DIAGNOSTIC INVESTIGATIONS 1. Diagnostic biochemical hallmarks of the syndrome a. Low serum cholesterol levels (10% of patients with DHCR7 deficiency have normal levels of cholesterol) b. Markedly elevated serum levels of 7-dehydrocholesterol (cholesta-5,7-dien-3beta-ol; 7DHC), precursor of cholesterol 2. DHCR7 enzyme assay 3. Analysis of sterol biosynthesis in cultured cells 4. DHCR7 mutation testing: Seven most frequent mutations described to date, representing two thirds of the mutation in analyzed alleles a. IVS8-1G>C (31.5%) b. T93M (11.2%) c. R404C (10.7%) d. W151X (6.4%) e. V326L (6.3%) f. R352W (3.2%) g. E448K (3.2%)
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sibs: 25% b. Patient’s offspring: not increased 2. Prenatal diagnosis a. Prenatal screening as part of routine triple marker screen for Down syndrome and neural tube defects: abnormally low maternal serum level of unconjugated estriol observed in pregnancies affected with SmithLemli-Opitz syndrome b. Second trimester ultrasonography i. Nuchal edema ii. Renal malformation iii. Polydactyly iv. Ambiguous genitalia v. Cerebral malformation vi. Cardiac malformation vii. Intrauterine growth retardation c. Amniocentesis or CVS i. Increased levels of 7DHC in amniotic fluid (typically a more than 500-fold increase in affected pregnancies)
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ii. Relative increase in 7DHC/total sterol ratio in fetal tissues obtained by chorionic villus sampling at 11–12 weeks of gestation iii. Direct DNA mutation analyses for known parental mutations 3. Management a. Therapeutic trials using dietary supplementation of cholesterol i. Used to treat complications related to the biochemical disturbance. Clinical benefits of this therapy are limited by presence of developmental problems. ii. Currently most patients being treated with pharmaceutical-grade cholesterol suspended in either soybean oil or Ora Plus syrup or alternatively with egg yolks iii. Multiple benefits of dietary cholesterol supplementation a) Improved nutrition and growth b) Decreased irritability c) Increased alertness d) Increased sociability e) Decreased self-abusive and aggressive behavior f) Decreased tactile defensiveness g) Decreased photosensitivity h) Decreased infections i) Improved hearing j) Improved muscle tone and strength iv. Use of bile acids shown no clear benefit b. An alternative therapeutic strategy of treating with Simvastatin (an oral HMG-CoA reductase inhibitor) for a median period of 2 years with impressive overall biochemical effect i. A decrease of 7DHC and 8DHC ii. An increase of cholesterol iii. Promising clinical improvement c. Fresh frozen plasma, which contains cholesterol rich lipoproteins, used to provide cholesterol supplementation in very sick patients and the fetuses
REFERENCES Abuelo DN, Tint GS, Kelley R, et al.: Prenatal detection of the cholesterol biosynthetic defect in the Smith-Lemli-Opitz syndrome by the analysis of amniotic fluid sterols. Am J Med Genet 56:281–285, 1995. Bradley LA, Palomaki GE, Knight GJ, et al.: Levels of unconjugated estriol and other maternal serum markers in pregnancies with Smith-LemliOpitz (RSH) syndrome fetuses. Am J Med Genet 82:355–358, 1999. Cunniff C, Kratz LE, Moser A, et al.: Clinical and biochemical spectrum of patients with RSH/Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism. Am J Med Genet 68:263–269, 1997. Curry CJ, Carey JC, Holland JS, et al.: Smith-Lemli-Opitz syndrome II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality. Am J Med Genet 26:45–57, 1997. Donnai D, Young ID, Owen WG, et al.: The lethal multiple congenital syndrome of polydactyly, sex reversal, renal hypoplasia, and unilobar lungs. J Med Genet 23:64–71, 1986. Elias ER, Irons MB, Hurley AD, et al.: Clinical effects of cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome (SLOS). Am J Med Genet 68:305–310, 1997.
Goldenberg A, Wolf C, Chevy F, et al.: Antenatal manifestations of SmithLemli-Opitz (RSH) syndrome: a retrospective survey of 30 cases. Am J Med Genet 124A:423–426, 2004. Irons M, Elias ER, Abuelo D, et al.: Treatment of Smith-Lemli-Opitz syndrome: results of a multicenter trial. Am J Med Genet 68:311–314, 1997. Irons MB, Nores J, Stewart TL, et al.: Antenatal therapy of Smith-Lemli-Opitz syndrome. Fetal Diagn Ther 14:133–137, 1999. Jira PE, Wevers RA, de Jong J, et al.: Simvastatin. A new therapeutic approach for Smith-Lemli-Opitz syndrome. J Lipid Res 41:1339–1346, 2000. Jira PE, Waterham HR, Wanders RJ, et al.: Smith-Lemli-Opitz syndrome and the DHCR7 gene. Ann Hum Genet 67:269–280, 2003. Kelly RI: Inborn errors of cholesterol biosynthesis. Adv Pediatr 47:1–53, 2000. Kelley RI, Hennekam RCM: The Smith-Lemli-Opitz syndrome. J Med Genet 37:321–335, 2000. Kratz L, Kelley RI: Prenatal diagnosis of the RSH/ Smith-Lemli-Opitz syndrome. Am J Med Genet 82:376–381, 1999. Lin AE, Ardinger HH, Ardinger RH Jr, et al.: Cardiovascular malformations in Smith-Lemli-Opitz syndrome. Am J Med Genet 68:270–278, 1997. Linck LM, Lin DS, Flavell D, et al.: Cholesterol supplementation with egg yolk increases plasma cholesterol and decreases plasma 7-dehydrocholesterol in Smith-Lemli-Opitz syndrome. Am J Med Genet 93:360–365, 2000. Löffler J, Trojovsky A, Casati B, et al.: Homozygosity for the W151X stop mutation in the delta7-sterol reductase gene (DHCR7) causing a lethal form of Smith-Lemli-Opitz syndrome: retrospective molecular diagnosis. Am J Med Genet 95:174–177, 2000. Opitz JM: RSH/SLO (“Smith-Lemli-Opitz”) syndrome: historical, genetic, and developmental considerations. Am J Med Genet 50:344–346, 1994. Opitz JM: RSH (so-called Smith-Lemli-Opitz) syndrome. Curr Opin Pediatr 11:353–362, 1999. Opitz JM, de la Cruz F: Cholesterol metabolism in the RSH/ Smith-LemliOpitz syndrome: summary of an NICHD conference. Am J Med Genet 50:326–338, 1994. Opitz JM, Gilbert-Barness E, Ackerman J, et al.: Cholesterol and development: the RSH (“Smith-Lemli-Opitz”) syndrome and related conditions. Pediatr Pathol Mol Med 21:153–181, 2002. Porter FD: RSH/Smith-Lemli-Opitz syndrome: a multiple congenital anomaly/mental retardation syndrome due to an inborn error of cholesterol biosynthesis. Mol Genet Metab 71:163–174, 2000. Porter FD: Malformation syndromes due to inborn errors of cholesterol synthesis. J Clin Invest 110:715–723, 2002. Rakheja D, Wilson GN, Rogers BB: Biochemical abnormality associated with Smith-Lemli-Opitz syndrome in an infant with features of Rutledge multiple congenital anomaly syndrome confirms that the latter is a variant of the former. Pediatr Dev Pathol 6:270–277, 2003. Rutledge J, Friedman J, Harrod M, et al.: A “new” lethal multiple congenital anomaly syndrome: Joint contractures, cerebellar hypoplasia, renal hypoplasia, urogenital anomalies, tongue cysts, shortens of limbs, eye abnormalities, defects of the heart, gallbladder agenesis, and ear malformations. Am J Med Genet 19:255–264, 1984. Ryan AK, Bartlett K, Clayton P, et al.: Smith-Lemli-Opitz syndrome: a variable clinical and biochemical phenotype. J Med Genet 35:558–565, 1998. Schoen E, Norem C, O’Keefe J, et al.: Maternal serum unconjugated estriol as a predictor for Smith-Lemli-Opitz syndrome and other fetal conditions. Obstet Gynecol 102:167–172, 2003. Shackleton C, Marcos J, Malunowicz EM, et al.: Biochemical diagnosis of Antley-Bixler syndrome by steroid analysis. Am J Med Genet 128A:223–231, 2004. Sharp P, Haan E, Fletcher JM, et al.: First-trimester diagnosis of Smith-LemliOpitz syndrome. Prenat Diagn 17:355–361, 1997. Smith DW, Lemli L, Opitz JA: A newly recognized syndrome of multiple congenital anomalies. J Pediatr 64:210–217, 1964. Tint GS, Irons M, Elias ER, et al.: Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med 330:107–113, 1994. Waterham HR, Wijburg FA, Hennekam RC, et al.: Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene. Am J Hum Genet 63:329–338, 1998. Witsch-Baumgartner M, Fitzky BU, Ogorelkova M, et al.; Mutational spectrum and genotype-phenotype correlation in 84 patients with Smith-LemliOpitz syndrome. Am J Hum Genet 66:402–412, 2000.
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Fig. 1. An infant with Smith-Lemli-Opitz syndrome showing failure to thrive, ptosis, cleft palate, thick alveolar ridge, upturned nares, micrognathia, transverse palmar crease, and syndactyly between the second and third toes.
Fig. 2. A boy with Smith-Lemli-Opitz syndrome showing characteristic facial features (epicanthal folds, ptosis of the eyelids, broad nose with upturned nares, thick alveolar ridges, ambiguous genitalia (hypospadias), umbilical hernia, transverse palmar crease, and talipes equinovarus.
Smith-Magenis Syndrome Smith-Magenis syndrome (SMS) is a complex multiple congenital anomalies and mental retardation syndrome caused by an interstitial deletion of chromosome 17p11.2.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant inheritance in virtually all cases of SMS occurring de novo b. Rare familial chromosome complex rearrangements leading to del(17)(p11.2) and SMS 2. Caused by an interstitial deletion of 17p11.2 a. A common deletion size observed in the majority of patients, derived from nonallelic homologous recombination between low-copy repeat gene clusters during either maternal or paternal gametogenesis b. Either smaller or larger sized deletions in about 20–25% of patients 3. Considered a contiguous gene syndrome a. Haploinsufficiency of multiple functionally unrelated genes located in close proximity is responsible for the phenotype b. Deletion of a common interval spanning an estimated 4–5 Mb in majority of patients 4. Sterol regulatory element binding protein 1 (SREBP1) has been mapped to 17p11.2 within the SMS critical region. Therefore, the patients are hemizygous for the gene encoding SREBP1 leading to hypercholesterolemia. 5. Rare non-deletion cases a. Report of additional patients without a microdeletion, each harbors a mutation in RAI1, which maps within the SMS critical region b. MYO15 clearly associated with a specific phenotypic feature (sensorineural hearing impairment) in a patient with SMS who harbored a recessive mutation on the nondeleted allele
CLINICAL FEATURES 1. 2. 3. 4. 5.
Infantile hypotonia Feeding difficulties Failure to thrive Developmental delay Distinctive craniofacial features a. Brachycephaly b. Broad square-shaped face c. Prominent forehead d. Synophrys e. Epicanthal folds f. Upslanted palpebral fissures g. Deep-set eyes h. Broad nasal bridge i. Marked mid-facial hypoplasia 912
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j. Short full-tipped nose with reduced nasal height k. Micrognathia in infancy changing to relative prognathia with age l. Distinctive appearance of the mouth, with fleshy everted upper lip with a “tented” appearance Otolaryngologic anomalies a. Speech delay b. Hoarse voice c. Velophalangeal insufficiency d. Tracheobronchial problems Ocular anomalies a. Iris anomalies b. Microcornia c. Retinal detachment Skeletal abnormalities a. Short stature b. Scoliosis c. Brachydactyly d. Flat feet Characteristic neurobehavioral phenotype a. Mental retardation (most patients in moderate range) b. Speech delay c. Signs of peripheral neuropathy d. Inattention e. Hyperactivity f. Maladaptive behaviors including frequent outbursts and temper tantrums g. Attention seeking h. Attention deficit i. Impulsivity j. Distractability k. Disobedience l. Aggression m. Toileting difficulties n. Decreased sensitivity to pain o. Self-injurious behaviors i. Self-hitting ii. Self-biting iii. Skin picking iv. Inserting foreign objects into body orifices v. Yanking finger nails and/or toenails (onychotillomania) p. Stereotypic behaviors i. Specific to SMS a) Spasmodic upper-body squeeze or “self hug” b) Hang licking and page flipping (“lick and flip”) ii. Additional stereotypies a) Mouthing objects or insertion of hand in mouth b) Teeth grinding
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c) Body rocking d) Spinning or twirling objects q. Significant sleep disturbance potentially due to circadian rhythm abnormalities of melatonin 10. Other features a. Cardiac defects b. Renal and urinary tract abnormalities c. Thyroid function abnormalities d. Cleft lip/palate e. Hearing loss f. Seizures g. Immune function abnormalities, especially low IgA
DIAGNOSTIC INVESTIGATIONS 1. Cytogenetic studies for detection of an interstitial deletion of 17p11.2 a. G-banded karyotype: may not detect small deletion especially when the indication of cytogenetic study is other than SMS b. Molecular cytogenetic analysis by FISH using a DNA probe specific for the SMS critical region 2. Molecular genetic testing of RAI1, the only gene known to account for the majority of features in SMS: available on a clinical basis 3. Blood chemistry a. Hypercholesterolemia b. Hypertriglyceridemia c. Qualitative immunoglobulins d. Thyroid function tests 4. Renal ultrasound for possible renal and urologic anomalies 5. Echocardiogram for possible cardiac defects 6. Radiography of the spine for scoliosis and other vertebral anomalies 7. EEG for clinical seizures 8. MRI and PET imaging a. A significant decrease of grey matter concentration in the insula and lenticular nuclei b. A significant hypoperfusion in the same regions
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. <1% if parental chromosome analysis is normal, taking account of possible presence of parental germline mosaicism ii. An increased risk, provided a parent carries a chromosome rearrangement and dependent upon the specific chromosome rearrangement b. Patient’s offspring i. Unlikely to have offspring due to severe phenotype ii. Theoretically, a 50% risk of having offspring with SMS 2. Prenatal diagnosis: available for pregnancies at risk using a combination of routine cytogenetic studies and FISH a. Amniocentesis b. CVS
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3. Management a. Early childhood intervention programs b. Special education i. Speech and language ii. Physical and occupational iii. Sensory integration c. Vocational training in later years d. Psychotropic medications to increase attention and decrease hyperactivity e. Behavioral modification f. Administration of β1-adrenergic antagonist and melatonin helps to manage hyperactivity, enhances cognitive performance, and reduces sleep disorders g. Psychosocial support for the family
REFERENCES Allanson JE, Greenberg F, Smith AC: The face of Smith-Magenis syndrome: a subjective and objective study. J Med Genet 36:394–397, 1999. Boddaert N, De Leersnyder H, Bourgeois M, et al.: Anatomical and functional brain imaging evidence of lenticulo-insular anomalies in Smith Magenis syndrome. Neuroimage 21:1021–1025, 2004. Chen K-S, Potocki L, Lupski JR: The Smith-Magenis syndrome (del[17][p11.2]): clinical review and molecular advances. Ment Retard Dev Disabil Res Rev 49:1207–1218, 1996. De Leersnyder H, De Blois MC, Claustrat B, et al.: Inversion of the circadian rhythm of melatonin in the Smith-Magenis syndrome. J Pediatr 139:111–116, 2001. De Leersnyder H, De Blois MC, Vekemans M, et al.: β1-adrenergic antagonists improve sleep and behavioural disturbances in a circadian disorder, Smith-Magenis syndrome. J Med Genet 38:586–590, 2001. Dykens EM, Smith AC: Distictiveness and correlates of maladaptive behaviour in children and adolescents with Smith-Magenis syndrome. J Intellect Disabil Res 42:481–489, 1998. Dykens EM Finucane BM, Gayley C: Brief report: cognitive and behavioral profiles in persons with Smith-Magenis syndrome. J Autism Dev Disord 27:203–211, 1997. Elsea SH, Purandare SM, Adell RA, et al.: Definition of the critical interval for Smith-Magenis syndrome. Cytogenet Cell Genet 79:276–281, 1997. (Published erratum appears in Cytogenet Cell Genet 81:67, 1998.) Greenberg F, Guzzetta V, Montes de Oca-Luna R, et al.: Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with (del[17][p11.2]). Am J Hum Genet 49:1207–1218, 1991. Greenberg F, Lewis RA, Potocki L, et al.: Multidiscip0linary clinical study of Smith-Magenis syndrome (del [17q]11.2). Am J Med Genet 62:274–254, 1996. Juyal RC, Figuera LE, Hauge X, et al.: Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients. Am J Hum Genet 58:998–1007, 1996. Liburd N, Ghosh M, Riazuddin S, et al.: Novel mutations of MYO15A associated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith-Magenis syndrome. Hum Genet 109:535–541, 2001. Potocki L, Glaze D, Tan DX, et al.: Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome. J Med Genet 37:428–433, 2000. Potocki L, Shaw CJ, Stankiewicz P, et al.: Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome (del[17][p11.2p11.2]). Genet Med 5:430–434, 2003. Seranski P, Hoff C, Radelof U, et al.: RAI1 is a novel polyglutamine encoding gene that is deleted in Smith-Magenis syndrome patients. Gene 270:69–76, 2001. Slager RE, Newton TL, Vlangos CN, et al.: Mutations in RAI1 associated with Smith-Magenis syndrome. Nat Genet 33:466–468, 2003. Smith AC, Dykens E, Greenberg F: Behavioral phenotype of Smith-Magenis syndrome (del[17p11.2]). Am J Med Genet 81:179–185, 1998. Smith AC, Dykens E, Greenberg F: Sleep disturbance in Smith-Magenis syndrome (del[17p11.2]). Am J Med Genet 81:186–191, 1998. Smith ACM, MacGavran L, Waldstein G, et al.: Deletion of the 17 short arm in two patients with facial cleft. Am J Hum Genet 34:410A, 1982.
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Smith ACM, MacGravran L, Robinson J, et al.: Interstitial de (17[p11.2p11.2]) in nine patients. Am J Med Genet 24:393–414, 1986. Smith ACM, Gropman AL, Bailey-Wilson JE, et al.: hypercholesterolemia in children with Smith-Magenis syndrome: del (17[p11.2p11.2]). Genet Med 4:118–125, 2002. Smith ACM, Allanson JE, Allen AJ, et al.: Smith-Magenis syndrome. Gene Reviews, 2004. http://genetests.org Spilsbury J, Mohanty K: The orthopaedic manifestations of Smith-Magenis syndrome. J Pediatr Orthop B 12:22–26, 2003.
Straton RF, Dobyns WB, Greenberg F, et al.: Interstitial del (17[p11.2p11.2]): report of six additional patients with a new chromosome deletions syndrome. Am J Med Genet 24:421–432, 1986. Willekens D, De Cock P, Fryns JP: Three young children with Smith-Magenis syndrome: their distinct, recognisable behavioural phenotype as the most important clinical symptoms. Genet Couns 11:103–110, 2000. Zori RT, Lupski JR, Heju Z, et al.: Clinical, cytogenetic, and molecular evidence for an infant with Smith-Magenis syndrome born from a mother having a mosaic 17p11.2p12 deletion. Am J Med Genet 47:504–511, 1993.
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Fig. 1. An infant with Smith-Magenis syndrome showing prominent forehead, broad square-shaped face, synophrys, short full-tipped nose, and fleshy everted upper lip with a “tented” appearance. Chromosome analysis showed an interstitial deletion of 17p11.2.
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Sotos Syndrome Sotos syndrome was described by Sotos in 1964 and is relatively common among overgrowth syndromes. It is also known as cerebral gigantism.
GENETICS/BASIC DEFECTS 1. Inheritance: genetically heterogeneous a. Sporadic in majority of cases (>98%) b. Autosomal dominant inheritance reported in a few families c. Autosomal recessive inheritances postulated in some families 2. Discovery of human NSD1 gene a. Report of a patient with Sotos syndrome who had t(5;8)(q35;q24.1) b. Discovery of a partial genomic sequence homologous to mouse Nsd1 near the breakpoint by constructing a BAC/PAC/cosmid contig covering the breakpoint c. Human NSD1 gene was subsequently isolated and characterized. 3. Molecular defect a. The major cause of Sotos syndrome: haploinsufficiency of the NSD1 gene at 5q35, because the majority of patients had either a common microdeletion including NSD1 or a truncated type of point mutation in NSD1 b. NSD1 gene mutations and deletions i. Japanese patients (66%) a) Point mutations (48.5%) b) Deletions (18.2%) ii. British patients (78%) a) Point mutations (70%) b) Large deletions (8%) c. Size of the deletion correlates with severity of the phenotype. 4. No satisfactory explanation for the overgrowth
CLINICAL FEATURES 1. Prenatal and postnatal overgrowth (major clinical features) a. Large for gestational age at birth b. Excessive growth velocity particularly in the first 3 to 4 years c. Advanced bone age by 2 to 4 years over chronological age during childhood d. Large hands and feet e. Excessive heights in some adult patients 2. Performance a. Developmental retardation b. Mental deficiency of varying degree c. Lack of fine motor control d. Difficulties in neonatal adaptation and/or feeding 916
3. Characteristic craniofacial appearance a. Dolichocephalic large head b. Prominent forehead c. Ocular hypertelorism d. Down slanting of the palpebral fissures e. High-arched palate f. Premature teeth eruptions g. Pointed chin (prominent mandible) 4. CNS manifestations a. Hypotonia b. Seizures c. Clumsy gait d. Mildly enlarged ventricles e. Increased subarachnoid spaces f. Agenesis/hypoplasia of the corpus callosum g. Agenesis of the septal pellucidum h. Hypoplasia/atrophy of the cerebellar vermis i. Large cisternal magna j. Abnormal Sylvian fissure 5. Neoplasms (3.9%) a. Benign tumors i. Multiple hemangiomas ii. Osteochondroma iii. Large hairy nevus iv. Giant cell granulomas of the mandible b. Malignant tumors i. Wilms tumor ii. Neuroblastoma iii. Hepatocellular carcinoma iv. Epidermoid carcinoma of the vagina v. Small-cell carcinoma of the lung 6. Other features a. Strabismus b. Lax joints c. Pes planus d. Kyphoscoliosis e. Asymmetric leg length f. Syndactyly g. Congenital heart defects i. Septal defects ii. Persistent ductus arteriosus iii. Ebstein malformation h. Functional megacolon i. Urinary anomalies i. Hypoplastic kidney ii. Hydronephrosis iii. Vesicoureteric reflux j. Recurrent hernias k. Abnormal dermatoglyphics 7. Social and behavioral difficulties a. Emotional immaturity b. Poor motor control
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c. Temper tantrums d. Good social skills in some patients 8. Weaver syndrome: the major differential diagnosis a. Seen less commonly than Sotos syndrome b. Caused by NSD1 mutations in a significant number of patients c. Cardinal features i. Accelerated growth ii. Distinctive facies with micrognathia and a deep horizontal chin crease iii. Advanced bone age iv. Developmental delay d. Additional features i. A hoarse low-pitched cry ii. Metaphyseal flaring of the femurs iii. Deep-set nails iv. Prominent finger pads v. Camptodactyly
DIAGNOSTIC INVESTIGATIONS 1. Glucose intolerance (14%) 2. Radiography: advanced bone age 3. CNS lesions by CAT scan and/or MRI of the brain a. Ventricles i. Ventriculomegaly ii. Prominent trigone of the lateral ventricles iii. Prominent occipital horn b. Extracerebral fluid i. Increased supratentorial space ii. Increased posterior fossa space c. Midline anomalies i. Persistent cavum septum pellucidum ii. Persistent cavum vergae iii. Cavum velum interpositum iv. Macrocisterna magna v. Agenesis of corpus callosum vi. Hypoplasia (thinning) of corpus callosum d. Periventricular leukomalacia e. Macrocerebellum f. Open operculum 4. DNA analysis a. Deletion of NSD1 gene by FISH analysis b. Mutations of NSD1 gene i. Sequencing of entire coding region ii. Sequencing of select exons iii. Mutation analysis
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected b. Patient’s offspring: 50% 2. Prenatal diagnosis of fetuses at risk for Sotos syndrome a. Ultrasonography in the third trimester i. Macrocephaly ii. Ventriculomegaly iii. Hypoplasia of the corpus callosum iv. An enlarged cisterna magna
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v. Overgrowth vi. Unilateral hydronephrosis vii. Polyhydramnios b. Prenatal diagnosis possible by molecular mutation analysis of fetal DNA obtained from amniocytes or CVS of previously identified disease-causing NSD1 gene: available on a clinical basis 3. Management: No specific therapy exists
REFERENCES Abraham JM, Snodgrass GJ: Sotos’ syndrome of cerebral gigantism. Arch Dis Child 44:203–210, 1969. Allanson JE, Cole TRP: Sotos syndrome: evolution of facial phenotype. Subjective and objective assessment. Am J Med Genet 65:13–20, 1996. Bale AE, Drum MA, Parry DM, et al.: Familial Sotos syndrome (cerebral gigantism): craniofacial and psychological characteristics. Am J Med Genet 20:613–624, 1985. Boman H, Nilsson D: Sotos syndrome in two brothers. Clin Genet 18:421–427, 1980. Butler MG, Dijkstra PF, Meaney FJ, et al.: Metacarpophalangeal pattern profile analysis in Sotos syndrome: a follow-up report on 34 subjects. Am J Med Genet 29:143–147, 1988. Chen CP, Lin SP, Chang TY, et al.: Perinatal imaging findings of inherited Sotos syndrome. Prenat Diagn 22:887–892, 2002. Cohen MM Jr: A comprehensive and critical assessment of overgrowth and overgrowth syndromes. Adv Hum Genet 18:181–303, 373–376, 1989. Cohen MM Jr (ed): The Gorlin Symposium on Overgrowth. Am J Med Genet 79:233–305, 1998. Cohen MM Jr: Overgrowth syndromes: An update. Adv Pediatr 40:441–491, 1999. Cohen MM Jr: Tumors and nontumors in Sotos syndrome. Am J Med Genet 84:173–175, 1999. Cole TR, Hughes HE: Sotos syndrome. J Med Genet 27:571–576, 1990. Cole TR, Hughes HE: Sotos syndrome: a study of the diagnostic criteria and natural history. J Med Genet 31:20–32, 1994. Douglas J, Hanks S, Temple IK, et al.: NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes. Am J Hum Genet 72:132–143, 2003. Gusmao Melo D, Pina-Neto JM, Acosta AX, et al.: Neuroimaging and echocardiographic findings in Sotos syndrome. Am J Med Genet 90:432–434, 2000. Hansen FJ, Friis B: Familial occurrence of cerebral gigantism, Sotos’ syndrome. Acta Paediatr Scand 65:387–389, 1976. Ho˝glund P, Kurotaki N, Kytola S, et al.: Familial Sotos syndrome is caused by a novel 1 bp deletion of the NSD1 gene. J Med Genet 40:51–54, 2003. Imaizumi K, Kimura J, Matsuo M, et al.: Sotos syndrome associated with a de novo balanced reciprocal translocation t(5;8)(q35;q24.1). Am J Med Genet 107:58–60, 2002. Kamimura J, Endo Y, Kurotaki N, et al.: Identification of eight novel NSD1 mutations in Sotos syndrome. J Med Genet 40:e126, 2003. Kurotaki N, Harada N, Shimokawa O, et al.: Fifty microdeletions among 112 cases of Sotos syndrome: low copy repeats possibly mediate the common deletion. Hum Mutat 22:378–387, 2003. Kurotaki N, Imaizumi K, Harada N, et al.: Haploinsufficiency of NSD1 causes Sotos syndrome. Nat Genet 30:365–366, 2002. Maroun C, Schmerler S, Hutcheon RG: Child with Sotos phenotype and a 5:15 translocation. Am J Med Genet 50:291–293, 1994. Miyake N, Kurotaki N, Sugawara H, et al.: Preferential paternal origin of microdeletions caused by prezygotic chromosome or chromatid rearrangements in Sotos syndrome. Am J Hum Genet 72:1331–1337, 2003. Mouridsen SE, Hansen MB: Neuropsychiatric aspects of Sotos syndrome. A review and two case illustrations. Eur Child Adolesc Psychiatry 11:43–48, 2002. Noreau DR, Al-Ata J, Jutras L, et al.: Congenital heart defects in Sotos syndrome. Am J Med Genet 79:327–328, 1998. Opitz JM, Weaver DW, Reynolds JF: The syndrome of Sotos and Weaver: Reports and review. Am J Med Genet 29:294–304, 1998. Rio M, Clech L, Amiel J, et al.: Spectrum of NSD1 mutations in Sotos and Weaver syndromes. J Med Genet 40:436–440, 2003.
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Sarimski K: Behavioural and emotional characteristics in children with Sotos syndrome and learning disabilities. Dev Med Child Neurol 45:172–178, 2003. Scarpa P, Faggioli R, Voghenzi A: Familial Sotos syndrome: longitudinal study of two additional cases. Genet Couns 5:155–159, 1994. Schaefer GB, Bodensteiner JB, Buehler BA, et al.: The neuroimaging findings in Sotos syndrome. Am J Med Genet 68:462–465, 1997. Sotos JF: Overgrowth. Section V. Syndromes and other disorders associated with overgrowth. Clin Pediatr 36:89–103, 1997.
Türkmen S, Gillessen-Kaesbach G, Meinecke P, et al.: Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes. Eur J Hum Genet 11:858–865, 2003. Winship IM: Sotos syndrome-autosomal dominant inheritance substantiated. Clin Genet 28:243–246, 1985. Wit JM, Beemer FA, Barth PG, et al.: Cerebral gigantism (Sotos syndrome). Compiled data of 22 cases. Analysis of clinical features, growth and plasma somatomedin. Eur J Pediatr 144:131–140, 1985.
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Fig. 1. A child with Sotos syndrome showing excessive growth, a large dolichocephalic head, prominent forehead, down slanting palpebral fissures, and a pointed chin.
Fig. 3. A 5-year-old girl with Sotos syndrome showing gigantism, large head, prominent forehead, large hands and feet, and MRI findings of enlarged subarachnoid spaces, mild ventriculomegaly, thinning of the corpus callosum, and mild polymicrogyria.
Fig. 2. The radiograph of the hand from a 20-month-old showing advanced bone age (3 years).
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Fig. 4. An adult with Sotos-like syndrome showing excessive height (compared with other family members), prominent forehead, hypertelorism, a pointed chin, and large hands and feet (compared to normal adult). Chromosome analysis by FISH showed duplication of 4p15.2 and 4q32. Both parents have normal chromosomes.
Spinal Muscular Atrophy Spinal muscular atrophy (SMA) is a disorder characterized by degeneration of lower motor neurons and occasionally bulbar motor neurons leading to progressive limb and trunk paralysis as well as muscular atrophy. It is a clinically and genetically heterogeneous group of neuromuscular diseases. It is the second most common lethal autosomal recessive disorder after cystic fibrosis in Caucasian populations with an overall incidence of 1 in 10,000 live births and a carrier frequency of approximately 1 in 50.
iii. Autosomal dominant form of SMA iv. Amyotrophic lateral sclerosis v. Post-polio syndrome 5. Molecular-phenotype correlation: Phenotype of SMA associated with disease-causing mutations of the SMN gene spans a continuum without a clear delineation of subtypes
CLINICAL FEATURES
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal recessive in most cases (SMA1, SMA2, SMA3) b. Autosomal dominant in both juvenile and adult form, representing 2% of infantile and about 30% of adult SMA 2. Three candidate genes a. Survival motor neuron (SMN) gene, an SMA determining gene i. SMN1 (SMNT, the telomeric copy): Up to 95% of patients suffering from different forms of SMA are homozygously deleted for both telomeric copies of the SMN gene ii. SMN2 (SMNC, the centromeric copy) b. Neuronal apoptosis inhibitory protein gene (NAIP): more frequently deleted in type I than in the milder forms (types II and III) c. P44 (subunit of basal transcription factor TIIH) gene found to be associated with SMA1 3. Mutation in all three forms (SMA1, SMA2, and SMA3) mapped to chromosome 5q13 (SMA critical region) 4. SMN deletions a. High frequency of SMN deletions in SMA patients (92.8%) provides a direct and accurate genetic test for: i. Diagnostic confirmation of SMA ii. Prenatal prediction of SMA b. Homozygous deletion of SMN observed in: i. Atypical forms of SMA associated with congenital heart defects ii. Arthrogryposis iii. Some cases of congenital axonal neuropathy iv. Some patients affected with adult form of SMA c. Rare cases of homozygous SMN exon 7 deletion or conversion reported in asymptomatic relatives of haploidentical type II or III SMA patients d. Absence of deletion of the SMN gene or linkage to chromosome 5q in: i. SMA associated with diaphragmatic involvement ii. SMA with olivopontocerebellar atrophy 921
1. Existing classification system based on age of onset of symptoms: useful for prognosis and management a. Congenital axonal neuropathy i. Prenatal onset of SMA ii. Decreased fetal movement iii. Maternal polyhydramnios iv. Severe muscle weakness (hypotonia) v. Absence of movement vi. Joint contractures vii. Facial diplegia viii. Ophthalmoplegia ix. Respiratory failure requiring immediate endotracheal intubation and ventilation x. Death from respiratory failure within days b. Arthrogryposis multiplex congenita-SMA i. Prenatal onset of SMA ii. Decreased fetal movement iii. Maternal polyhydramnios iv. Breech presentation v. Severe muscular weakness (hypotonia) vi. Arthrogryposis multiplex congenita vii. Absence of movement except for extraocular and facial movement viii. Death from respiratory failure before one month of age c. SMA1 (acute infantile spinal muscular atrophy, Werdnig-Hoffman disease) i. Represents about 30% of all SMA cases ii. Onset before six months of age iii. The most severe form with fatal outcome iv. Severe generalized muscular weakness (hypotonia) v. Lack of motor development vi. Mild joint contractures at the knees and rarely at the elbows vii. Most severely affected neonates a) Difficulty in sucking and swallowing b) Abdominal breathing viii. Facial muscles spared completely with a bright, normal expression ix. Ocular muscles and the diaphragm not involved until late in the course of the disease x. Fasciculation of the tongue seen in most but not all cases
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xi. Intercostal paralysis with severe collapse of the chest: the rule xii. Affected children unable to sit without support xiii. Absence of tendon reflexes (areflexia) xiv. Normal intelligence xv. Usually die within two years due to the following: a) Feeding difficulty b) Breathing difficulty d. SMA2 (chronic infantile spinal muscular atrophy, Dubowitz disease) i. Represent about 45% of SMA cases ii. Onset between six and 12 months iii. The intermediate form (a more slowly progressive generalized disease with a variable prognosis) iv. Poor muscle tone at birth or within first 2 months of life v. Slow attainment of motor milestones a) Not sitting independently by age 9–12 months b) Not standing by age one year vi. Frequent tongue fasciculations and atrophy vii. Common finger trembling and general flaccidity viii. Diminished or absent deep tendon reflexes ix. Intact sensation x. Loss of the ability to sit independently by the mid-teens xi. Slow or arrest of clinical progression xii. Severe scoliosis if untreated xiii. Defect in respiratory ventilation xiv. Highly variable life expectancy, ranging up to adult life in some cases e. SMA3 (juvenile spinal muscular atrophy, KugelbergWelander disease) i. Represents about 8% of all SMA cases ii. Childhood onset after 12 months (usually after 18 months to 30 years of life) iii. The mild chronic form iv. Motor milestones a) Ability to walk but frequent fall on walking b) Trouble walking upstairs and downstairs at age 2–3 years v. Muscle weakness a) Proximal muscle weakness associated with muscle atrophy b) Legs more severely affected than the arms vi. Normal sensation vii. No evidence of upper motor neuron involvement viii. Hypertrophy of the calves in about 25% of cases ix. Prognosis generally correlates with the maximum motor function attained f. SMA4 (adult SMA) i. Adult onset (after 20 or 30 years of age) ii. Muscle weakness (after age 30 years) iii. Clinical features similar to those described for SMA3 with evidence of lower motor neuron involvement a) Tongue fasciculations b) Muscle atrophy c) Depressed deep tendon reflexes d) Normal sensation
2. Consider diagnosis of SMA in infants presenting with the following clinical features: a. During neonatal period i. Severe hypotonia ii. Absent movement iii. Contractures, usually of a mild degree iv. Evidence of anterior horn cell (i.e., lower motor neuron) involvement a) Tongue fasciculations b) Absence of deep tendon reflexes v. Respiratory failure vi. Variable cranial nerve involvement usually apparent late in the course a) Ophthalmoplegia b) Facial diplegia b. After neonatal period i. Poor muscle tone ii. Symmetric muscle weakness a) Sparing the ocular muscles b) Involving the facial muscles and diaphragm late in the course of the disease iii. Delayed acquisition of motor skills iv. Evidence of anterior horn (i.e., lower motor neuron) involvement a) Tongue fasciculations (seen in only 65% of patients) b) Absence of deep tendon reflexes v. Normal reaction to sensory stimuli vi. Normal intelligence
DIAGNOSTIC INVESTIGATIONS 1. Increased serum creatine phosphokinase (CK) activity in about half of the patients with type III SMA 2. Electromyography (EMG) a. During voluntary effort i. Spontaneous discharge activity in resting muscle ii. Increased amplitude iii. Prolonged duration of motor unit potentials b. Severe denervation commonly found in older patients c. Nerve conduction velocity i. Generally considered normal ii. Some decrease in velocity in severe case 3. Muscle histology a. Denervation changes with small groups of atrophic muscle fibers associated with markedly hypertrophied fibers b. Small angular fibers randomly intermixed with normalsized fibers c. Atrophic fibers arranged in groups i. Usually of uniform fiber type based on the myosin ATPase reaction ii. Considered as an extensive collateral reinnervation of previously denervated muscle fibers by sprouts from surviving motor neurons d. In SMA type III, but not in infantile SMA (type I or II) i. Markedly hypertrophic fibers ii. Excessive variation in fiber size iii. Internal nuclei
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iv. Observation of degenerative changes with necrosis and regenerative fibers associated with proliferative interstitial connective tissue a) Interpreted as “pseudomyopathic” changes b) Usually found in patients with high serum levels of CK activity suggesting the presence of a myopathic process secondary to neurogenic process c) These pseudomyopathic changes not observed in other human neurogenic diseases, suggesting that they can be specific to the molecular mechanism resulting in or associated with juvenile SMA 4. Neuropathologic features found at autopsy of SMA patients a. Loss of the large anterior horn cells of the spinal cord (most striking feature) b. Severe degree of central chromatolysis in the remaining surviving motor neurons, appearing as large ballooned cells without stored substances c. Other anterior horn cells i. Pyknotic ii. Presence of occasional figures of neuronophagia associated with astrogliosis iii. Small anterior roots 5. Molecular diagnosis of SMA a. The following relatively simple DNA tests enable confirmation of a suspected clinical diagnosis of SMA or prediction of the outcome of a pregnancy in families with a history of SMA. i. SSCP analysis ii. PCR followed by restriction enzyme digestion b. Mutation analysis of SMN1 available on clinical basis i. Used to detect deletion of exons 7 and 8 of SMN1 ii. Homologous deletions of exon 7 of SMN1 in 95% of cases with clinical diagnosis of SMA iii. Compound heterozygotes for deletion of SMN1 exon 7 and an intragenic mutation of SMN1 in 2–5% of patients with a clinical diagnosis of SMA c. Sequence analysis of all SMN1 exons and intron/exon borders available on clinical basis i. Used to identify the intragenic SMN1 mutations present in the 2–5% of patients who are compound heterozygotes ii. Limitations a) Cannot determine whether the point mutation is in the SMN1 gene or the SMN2 gene, unless one of these genes is absent b) Does not detect exonic duplications c) Cannot detect deletions of whole exons if more than one SMN gene copy is present d. SMA carrier testing (gene dosage analysis) available clinically i. Mutation analysis not reliable for carrier detection since it does not quantitate the number of SMN1 gene copies ii. A PCR-based dosage assay (called SMA carrier testing or SMN gene dosage analysis) allows for the determination of the number of SMN1 gene copies, thus permitting highly accurate carrier detection
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iii. Dosage analysis to differentiate carriers from noncarriers e. Linkage analysis available on clinical basis i. Available to families in which direct DNA testing is not informative ii. May be used for confirmation of carrier testing results and prenatal testing results
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal recessive inheritance: 25% ii. Autosomal dominant inheritance: not increased unless a parent is affected b. Patient’s offspring: only milder forms of SMA likely to reproduce i. Autosomal recessive inheritance a) All offspring: carriers b) Recurrence risk not increased unless the spouse is affected or a carrier ii. Autosomal dominant inheritance: 50% 2. Prenatal diagnosis a. Possible to detect fetuses at 25% risk when the diseasecausing SMN mutations in both parents are known b. Mutation analysis on fetal DNA obtained from CVS or amniocentesis c. Linkage analysis i. Many diagnostic laboratories still perform linkage analysis in addition to direct SMNT mutation analysis in families where the previously affected child lacks both copies of SMNT, since there are people in the normal population who lack both copies of SMNT but not clinically affected ii. The only option available to the families where no deletion has been observed but the clinical findings are consistent with 5q SMA 3. Management a. Feeding gastrostomy for children with difficult in sucking and swallowing b. Management of respiratory function i. Noninvasive ventilation support for patients with sufficient orofacial muscle strength ii. Long-term ventilatory support not usually considered c. Management of scoliosis in patients with SMA2 and SMA3 i. Orthosis to allow to sit upright rather than bedridden ii. Option of surgical repair for the severe scoliosis
REFERENCES Benady SG: Spinal muscular atrophy in childhood. Review of 50 cases. Develop Med Child Neurol 20:746–757, 1978. Bingham PM, Shen N, Rennert H, et al.: Arthrogryposis due to infantile neuronal degeneration associated with deletion of the SMNT gene. Neurology 49:848–851, 1997. Biros I, Forrest S: Spinal muscular atrophy: untangling the knot? J Med Genet 36:1–8, 1999. Brahe C, Bertini E: Spinal muscular atrophies: recent insights and impact on molecular diagnosis. J Mol Med 74:555–562, 1996.
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Burglen L, Amiel J, Viollet L, et al.: Survival motor neuron gene deletion in the arthrogryposis multiplex congenita-spinal muscular atrophy association. J Clin Invest 98:1130–1132, 1996. Burglen L, Seroz T, Miniou P, et al.: The gene encoding p44, a subunit of the transcription factor TFIIH, is involved in large-scale deletions associated with Werdnig-Hoffmann disease. Am J Hum Genet 60:72–77, 1997. Byers RK, Banker BQ: Infantile muscular atrophy. Arch Neurol 5:140–164, 1961. Caire ML, Kishner S: Kugelberg Welander spinal muscular atrophy. Emedicien, 2002. http://www.emedicine.com Carter TA, Bonnemann CG, Wang CH, et al.: A multicopy transcription-repair gene, BTF2p44, maps to the SMA region and demonstrates SMA associated deletions. Hum Mol Genet 6:229–223, 1997. Crawford TO, Pardo CA: The neurobiology of childhood spinal muscular atrophy. Neurobiol Dis 3:97–110, 1996. Dubowitz V: Chaos in the classification of SMA: a possible resolution. Neuromuscul Disord 5:3–5, 1995. Herrera JA, Mehlman CT: Spinal muscle atrophy. Emedicien, 2003. http:// www.emedicine.com Iannaccone ST, Browne RH, Samaha FJ, et al.: Prospective study of spinal muscular atrophy before age 6 years. DCN/SMA Group. Pediatr Neurol 9:187–193, 1993. Ignatius J: The natural history of severe spinal muscular atrophy—further evidence for clinical subtypes [letter]. Neuromuscul Disord 4:527–528, 1994. Korinthenberg R, Sauer M, Ketelsen UP, et al.: Congenital axonal neuropathy caused by deletions in the spinal muscular atrophy region. Ann Neurol 42:364–368, 1997. Kugelberg E, Welander L: Heredofamilial juvenile muscular atrophy simulating muscular dystrophy. Acta Neurol Psychiatr 75:500, 1956. Emery AEH: The nosology of the spinal muscular atrophies. J Med Genet 8:481–495, 1971. Lefebvre S, Burglen L, Reboullet S, et al.: Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80:155–165, 1995. Matthijs G, Devriendt K, Fryns J-P: The prenatal diagnosis of spinal muscular atrophy. Prenat Diagn 18:607–610, 1998. Melki J: Spinal muscular atrophy. Curr Opin Neurol 10:381–385, 1997.
Munsat TL, Davies KE: Meeting report: international SMA consortium meeting. Neuromuscul Disord 2:423–428, 1992. Nicole S, Diaz CC, Frugier T, et al.: Spinal muscular atrophy: recent advances and future prospects. Muscle Nerve 26:4–13, 2002. Ogino S, Leonard DG, Rennert H, et al.: Genetic risk assessment in carrier testing for spinal muscular atrophy. Am J Med Genet 110:301–307, 2002. Pearn J: Autosomal dominant spinal muscular atrophy. A clinical and genetic study. J Neurol Sci 38:263–275, 1978. Pearn J: Classification of spinal muscular atrophies. Lancet 1:919–922, 1980. Pearn JH, Gardner-Medwin D, Wilson J: A clinical study of chronic childhood spinal muscular atrophy. A review of 141 cases. J Neurol Sci 38:23– 37, 1978. Panozzo C, Frugier T, Cifuentes-Diaz C, et al.: Spinal muscular atrophy. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001. Prior TW, Russman B: Spinal muscular atrophy. Gene Reviews, 2003. http://www.genetests.org Roy N, McLean MD, Besner-Johnston A, et al.: Refined physical map of the spinal muscular atrophy gene (SMA) region at 5q13 based on YAC and cosmid contiguous arrays. Genomics 26:451–460, 1995. Rudnik-Schoneborn S, Forkert R, Hahnen E, et al.: Clinical spectrum and diagnostic criteria of infantile spinal muscular atrophy: further delineation on the basis of SMN gene deletion findings. Neuropediatrics 27:8–15, 1996. Russman BS, Buncher CR, White M, et al.: Function changes in spinal muscular atrophy II and III. The DCN/SMA Group. Neurology 47:973–976, 1996. Stewart H, Wallace A, McGaughran J, et al.: Molecular diagnosis of spinal muscular atrophy. Arch Dis Child 78:531–535, 1998. Thomas NH, Dubowitz V: The natural history of type I (severe) spinal muscular atrophy. Neuromuscul Disord 4:497–502, 1994. Tsao B, Armon C: Spinal muscular atrophy. Emedicien, 2003. http://www. emed icine.com Zeesman S, Whelan DT, Carson N, et al.: Parents of children with spinal muscular atrophy are not obligate carriers: carrier testing is important for reproductive decision-making. Am J Med Genet 107:247–249, 2002. Zerres K, Wirth B, Rudnik-Schoneborn S: Spinal muscular atrophy-clinical and genetic correlations. Neuromusc Disord 7:202–207, 1997.
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Fig. 3. Residual muscle seen in a 14 year old female showed chronic denervative change with presence of scattered target fibers (arrows) (H & E ×400).
Fig. 1. A 2 1/2 week-old white male died of respiratory failure associated with congenital spinal muscular atrophy (Werdnig-Hoffman disease). There was generalized muscle atrophy including respiratory muscle.
Fig. 4. Biopsy of quadriceps muscle from a 10 month old girl shows a group atrophy involving several entire fascicles (arrow). Both type I (light-stained) and type II (dark-stained) fibers are affected. This is accompanied by a enervative phenomenon (the large muscle fibers all stain pale) (Myosin ATPase, at 9.4, ×50).
Fig. 2. Quadriceps muscle shows many exceedingly atrophic muscle fibers which tend to be in groups (arrow). No degenerative muscle fibers are present (H & E, ×100).
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Fig. 7. A 5-year-old girl with SMA showing tongue fasciculation.
Fig. 5. A 3-month-old infant boy with Werdnig-Hoffman disease showing generalized hypotonia. He had a small chest with diaphragmatic breathing, fasciculation of the tongue, and absence of deep tendon reflexes. Molecular genetic analysis revealed homozygous exon 7 deletion and homozygous exon 8 deletion for the survival motor neuron genes (SMN).
Fig. 8. A 30-year-old man with Kugelberg-Welander disease showing muscle weakness and had been confined to wheelchair for some time. He had trouble standing and began to walk at 6 years of age. Molecular genetic diagnosis revealed homozygous exon 7 deletion and homozygous exon 8 deletion. Fig. 6. A 27-month-old girl with SMA1. She could not stand holding or independently and had foot drops, absence of deep tendon reflexes, muscle weakness. She was confined to a wheel chair. Molecular genetic analysis revealed homozygous exon 7 deletion and homozygous exon 8 deletion for the SMN gene.
Spondyloepiphyseal Dysplasia Spondyloepiphyseal dysplasia (SED) refers to a group of disorders with primary involvement of the vertebrae and epiphyseal centers resulting in a short-trunk disproportionate dwarfism. Two major types (congenita and tarda) will be discussed here.
GENETICS/BASIC DEFECTS 1. Genetic basis of SED a. SED congenita i. Autosomal dominant inheritance ii. Spondyloepiphyseal dysplasia congenita gene mapped to chromosome 12q13 iii. Gonadal mosaicism reported iv. Advanced paternal age recognized as a risk factor b. SED tarda i. X-linked recessive inheritance a) Most common b) The gene mapped to Xp22.12-p22.31 ii. Autosomal recessive inheritance iii. Autosomal dominant inheritance 2. Molecular basis of SED a. SED congenita i. Caused by mutations in COL2A1 gene, which encodes the α1(II) chain of type II collagen. The gene was mapped on chromosome 12. ii. The mutations result in abnormal type II collagen, which is the major collagen of nucleus pulposus of the spine, hyaline cartilages, fibrocartilages, and vitreous humor of the eyes iii. Other skeletal dysplasias affected by collagen II abnormalities a) Autosomal forms of SED tarda b) Achondrogenesis type II c) Hypochondrogenesis d) Kniest dysplasia e) Stickler dysplasia f) Spondylometaepiphyseal (Strudwick) dysplasia b. SED tarda, X-linked form i. Caused by mutations in SEDL (SED late) gene (designated “sedlin”), mapped on Xp22.2-p22.1 ii. SEDL gene encodes a protein of 140 amino acids with a role in vesicular transport. iii. Over thirty novel mutations affecting the SEDL gene recognized: the most common type of SEDL-gene disruption being deletion, representing 50% of identified mutations
CLINICAL FEATURES 1. SED congenita a. Clinical features present at birth b. Short newborn with disproportionately shortened trunk c. Delayed motor development 927
d. Short neck e. Cervical myelopathy resulting from atlantoaxial instability, odontoid hypoplasia, and spinal cord compression, often presenting at age 5–10 years i. Delayed motor development ii. Decreased endurance iii. Progressive motor weakness iv. Hypotonia v. Sleep apnea vi. Alterations in respiration vii. Pyramidal tract signs (spasticity, hyperreflexia, Babinski sign, and clonus) f. Respiratory insufficiency may develop secondary to thoracic dysplasia g. Barrel-shaped chest with pectus carinatum deformity h. Protuberant abdomen i. Spine abnormalities i. Lumbar lordosis ii. Thoracic kyphoscoliosis evident in adolescence j. Hip abnormalities i. Hip flexion contractures ii. Coxa vara a) An almost universal finding b) Varying severity c) Progressive d) Associated progressive hip dislocation if ligamentous laxity present iii. The delayed ossification of the capital femoral epiphysis predisposing the hip to deformation with flattening, lateral extrusion, hinge abduction, and premature osteoarthritis k. Knee abnormalities i. Valgus alignment of the knees often associated with overgrowth of the medial femoral condyle ii. Rare genu varum l. Other clinical features i. Gait problems often attributed to hip and knee deformities ii. Clubfeet (talipes equinovarus) present in some patients iii. Ocular anomalies a) Myopia and retinal detachment (>50%): important clinical findings in many patients b) Cataracts c) Buphthalmos secondary glaucoma, and strabismus d) Clear corneas iv. Deafness v. Cleft palate vi. Abdominal or inguinal hernias 2. SED tarda a. X-linked recessive form i. Normal appearance at birth
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ii. Variable age of onset a) Hip and trunk features appearing around 4 years of age b) Diagnosis not recognized until the adolescent years in some patients iii. Only males are affected iv. Mild disproportionate trunk shortening v. Barrel-shaped chest vi. Atlantoaxial instability secondary to odontoid hypoplasia vii. Progressive joint and back pain with osteoarthritis commonly involving hip, knee, elbows, and shoulder joints viii. Hip involvement a) Hip pain or stiffness presenting around the first or second decade of life b) Changes mimic bilateral Legg-Calve-Perthes disease c) Varying degrees of coxa magna, flattening, extrusion, and subluxation d) Osteoarthritis of the hip, a common sequelae ix. Kyphoscoliosis x. Lumbar lordosis xi. Epiphyseal involvement a) Primarily in the shoulders, hips, and knees b) Symmetrical and bilateral xii. Rare association with nephrotic syndrome xiii. Craniofacial appearance, vision, and hearing not affected in X-linked SED tarda xiv. Normal intelligence xv. Normal life span b. Autosomal recessive form i. Onset between the age of 4 and 10 years ii. Hip pain becomes worse with increasing age iii. Waddling gait iv. Short stature v. Disproportionately short trunk vi. Accentuated spinal curvatures vii. Restricted mobility of the hip joints c. Autosomal dominant form i. Clinical features identical to those in the recessive form of SED tarda ii. Hip pain and waddling gait noted after the 4th year of life iii. Mild shortness of the trunk iv. Progressive hip changes causing considerable discomfort
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. SED congenita i. A generalized delay in the development of ossification centers a) Absent epiphyseal centers of the distal femur and proximal tibia, os pubis, calcaneus, and talus, which are usually present at birth b) Femoral heads usually not visible on radiographs until patients are aged 5 years c) Femoral capital epiphyses: flattened and irregular in shape when they appear on radiographs
ii. Vertebral abnormalities a) Varying degrees of platyspondyly b) Oval, trapezoid, or pear-shaped vertebrae resulting from posterior wedging of vertebral bodies c) Incompletely fused ossification centers of the vertebral bodies d) End plate irregularities and intervertebral disk spaces narrowing become obvious with an increased anteroposterior diameter of the vertebral bodies in adolescents and young adults e) Exaggerated lumbar lordosis f) Progressive kyphoscoliosis developing in late childhood g) Odontoid hypoplasia or os odontoideum leading to atlantoaxial instability: common iii. Pelvic abnormalities a) Short and small iliac crests with horizontal acetabular roofs and delayed ossification of the pubis b) Small iliac bones with lack of normal flaring of the iliac wings c) Deep acetabular fossae appearing empty due to the severely retarded ossification of femoral heads d) Varying severity of coxa vara e) Delayed ossification of the femoral head predisposing hip to deformation with flattening, lateral extrusion, hinge abduction, and premature osteoarthritis iv. Tubular bone abnormalities a) Delayed ossification centers of the distal femur and proximal tibia leading to flattening and irregularity b) Genu valgum usually present with overgrowth of the medial femoral condyle c) Relatively short and broad long tubular bones d) Presence of some metaphyseal flaring especially in the region of the distal femur and proximal and distal humerus e) Delayed or disorganized ossification of carpal and tarsal centers with occasional extra epiphyses b. SED tarda, X-linked recessive form i. Radiographic changes usually apparent in children older than 4–6 years (not evident at birth) ii. Changes suggestive of atlantoaxial instability, platyspondyly, kyphoscoliosis, and epiphyseal involvement similar to those seen in patients with SED congenita iii. Predominantly affecting the spinal vertebral bodies and epiphyses during skeletal growth iv. A mound of bone (“donkey hump”) typically present in the central and posterior portions of the superior and inferior end plates on lateral radiographs in patients with X-linked recessive type of SED tarda (not features of the autosomal dominant or recessive types of SED tarda).
SPONDYLOEPIPHYSEAL DYSPLASIA
However, absence of ossification at the upper and lower anterior margins of the vertebral bodies is considered to be the distinctive radiographic feature v. Symmetric epiphyseal involvement primarily in the shoulders, hips, and knees vi. Delayed ossification predisposing the weight bearing joints of the lower extremities to deformation and premature osteoarthritis vii. Changes in the hip (dysplastic changes of femoral heads and neck), mimic bilateral LeggCalve-Perthes disease viii. Presence of varying degrees of coxa magna, flattening, extrusion, and subluxation ix. Minor skeletal changes in carrier women with X-linked recessive SED tarda in a 6-generation kindred from Arkansas a) Subtle abnormal shape of the pelvis and knees b) Premature occurrence of degenerative changes in the spine leading to frequent complaint of arthralgia in the middle age c. SED tarda, autosomal recessive form i. Irregular upper and lower plates of the vertebral bodies ii. Anteriosuperior ossification defects of some vertebras iii. Less frequent findings a) Additional ossification defects of the anterioinferior edges of the vertebral bodies b) Anterior protrusion f central portions of the vertebral bodies iv. Femoral heads a) Well developed capital femoral epiphyses in the younger child b) Progressive flattening and destruction of the femoral heads with advancing age c) Milder abnormalities in the knee joints d) Small and irregular carpal bones e) Slightly short and irregular metacarpals and phalanges in some patients d. SED tarda, autosomal dominant form i. Accentuated dorsal flattening of the vertebral bodies in the younger patient ii. Platyspondyly with a rectangular shape of the vertebral bodies in the older patient iii. Mild and slowly progressive deformities of capital femoral epiphyses and knee epiphyses iv. Slightly short phalanges and metacarpals with narrowing of the joint spaces 2. MRI a. To delineate cord compression due to C1–C2 instability b. To evaluate severe spinal deformities prior to surgical intervention c. To evaluate the condition of the epiphyseal centers prior to reconstructive procedures 3. CT scan a. To assess the configuration of bones and joints prior to surgical intervention b. To reconstruct three-dimensional images for help in surgical planning of severe cases
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4. Hip arthrography a. To document congruity of the femoral head or hinged abduction b. To evaluate severe varus deformity of the femoral neck 5. Laboratory features of SED congenita a. Fine metachromatic inclusions in the peripheral lymphocytes b. Normal urinary excretion of acid mucopolysaccharides including keratosulfate c. Histopathology i. Mildly disorganized physis (epiphyseal growth plate) ii. Chondrocytes containing PAS-positive cytoplasmic inclusions iii. Ultrastructurally the inclusions correspond to the accumulations of finely granular material in dilated cisterns of rough endoplasmic reticulum. 6. Molecular genetic analysis a. Mutations in COL2A1 gene in SED congenita b. Mutation in SEDL gene in X-linked recessive SED tarda i. Mutation types a) Deletions b) Splice mutations c) Missense mutations d) Nonsense mutations ii. Detected in >80% of affected males with Xlinked spondyloepiphyseal dysplasia tarda iii. Molecular genetic testing in new patients relied largely on mutation screening by sequencing the entire coding region iv. Carrier testing of at-risk female relatives available once the mutation has been identified in the proband
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Spondyloepiphyseal dysplasia congenita (autosomal dominant): recurrence risk low unless presence of parental gonadal mosaicism ii. Spondyloepiphyseal dysplasia tarda, X-linked a) The risk to sibs depends on the carrier status of the mother b) When the mother is a carrier: a 25% risk of having an affected brother; a 25% risk of having an unaffected brother; a 25% risk of having a carrier sister; a 25% risk of having a noncarrier sister c) When the mother is not a carrier: the risk to sibs is low (the risk of gonadal mosaicism in mothers not yet known) iii. Spondyloepiphyseal dysplasia tarda, autosomal recessive: 25% iv. Spondyloepiphyseal dysplasia tarda, autosomal dominant: low unless a parent is affected b. Patient’s offspring i. Spondyloepiphyseal dysplasia congenita, autosomal dominant a) When the spouse is not affected: 50% of offspring will be affected
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b) When the spouse is also affected with spondyloepiphyseal dysplasia congenita: 50% of offspring are heterozygous and affected; 25% are homozygous, which is ordinarily fatal in the first few months of life; and 25% are unaffected. ii. Spondyloepiphyseal dysplasia tarda a) Autosomal recessive form: recurrence risk to offspring low unless the spouse is a carrier b) Autosomal dominant form: 50% iii. Spondyloepiphyseal dysplasia tarda, X-linked recessive a) None of the sons of an affected male will be affected. b) All daughters of an affected male are carriers. 2. Prenatal diagnosis a. Molecular genetic diagnosis on fetal DNA from amniocytes or CVS available in families at risk for SED congenita, provided the disease-causing mutation (COL2A1) is identified in the proband b. Molecular genetic diagnosis on fetal DNA from amniocytes or CVS possible in families at risk for Xlinked SED tarda, provided the disease-causing mutation (SEDL) is identified in the proband 3. Management a. SED congenita i. Supportive care including psychosocial support ii. Tracheostomy for severe respiratory difficulties to maintain adequate ventilation iii. Posterior atlantoaxial fusion for patients with signs and symptoms of atlantoaxial instability measuring 8 mm or more or myelopathy iv. Brace for scoliosis initially v. Posterior spinal fusion for severe scoliosis or for patients resistant to bracing vi. Surgical correction for hip and knee abnormalities vii. Surgical correction of equinovarus deformities unmanageable by physical therapy or serial casting b. SED tarda, X-linked type i. Supportive care a) Avoid activities and occupations that place undue stress on the spine and weight bearing joints to prevent premature arthritis b) Chronic pain management c) Psychosocial support for the patient and family ii. Bracing for scoliosis iii. Posterior spinal fusion for severe scoliosis iv. Posterior stabilization for atlantoaxial instability v. Valgus or valgus-extension intertrochanteric osteotomy to improve hip congruity vi. Total joint arthroplasty for osteoarthritis in adulthood vii. Management of hip dysplasia a) Acetabular augmentation if the acetabulum is insufficient to contain the enlarged femoral head (coxa magna) b) May require hip replacement
REFERENCES Augenstein KB, Ward MJ, Nelson VS: Spondyloepiphyseal dysplasia congenita with ventilator dependence: two case reports. Arch Phys Med Rehabil 77:1201–1204, 1996. Bannerman RM, Ingall GB, Mohn JF: X-linked spondyloepiphyseal dysplasia tarda: clinical and linkage data. J Med Genet 8:291–301, 1971. Chan D, Rogers JF, Bateman JF, et al.: Recurrent substitutions of arginine 789 by cysteine in pro-alpha 1 (II) collagen chains produce spondyloepiphyseal dysplasia congenita. J Rheumatol Suppl 43:37–38, 1995. Christie PT, Curley A, Nesbit MA, et al.: Mutational analysis in X-linked spondyloepiphyseal dysplasia tarda. J Clin Endocrinol Metab 86:3233–3236, 2001. Cole WG, Hall RK, Rogers JG: The clinical features of spondyloepiphyseal dysplasia congenita resulting from the substitution of glycine 997 by serine in the alpha 1(II) chain of type II collagen. J Med Genet 30:27–35, 1993. Dahiya R, Cleveland S, Megerian CA: Spondyloepiphyseal dysplasia congenita associated with conductive hearing loss. Ear Nose Throat J 79:178–182, 2000. Diamond LS: A family study of spondyloepiphyseal dysplasia. J Bone Joint Surg Am 52:1587–1594, 1970. Gedeon AK, Colley A, Jamieson R, et al.: Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda. Nat Genet 22:400–404, 1999. Gedeon AK, Tiller GE, Le Merrer M, et al.: The molecular basis of X-linked spondyloepiphyseal dysplasia tarda. Am J Hum Genet 68:1386–1397, 2001. Grunebaum E, Arpaia E, MacKenzie JJ, et al.: A missense mutation in the SEDL gene results in delayed onset of X linked spondyloepiphyseal dysplasia in a large pedigree. J Med Genet 38:409–411, 2001. Harding CO, Green CG, Perloff WH, et al.: Respiratory complications in children with spondyloepiphyseal dysplasia congenita. Pediatr Pulmonol 9:49–54, 1990. Harrod MJ, Friedman JM, Currarino G, et al.: Genetic heterogeneity in spondyloepiphyseal dysplasia congenita. Am J Med Genet 18:311–320, 1984. Heuertz S, Smahi A, Wilkie AO, et al.: Genetic mapping of Xp22.12-p22.31, with a refined localization for spondyloepiphyseal dysplasia (SEDL). Hum Genet 96:407–410, 1995. James PA, Shaw J, du Sart D, et al.: Molecular diagnosis in a pregnancy at risk for both spondyloepiphyseal dysplasia congenita and achondroplasia. Prenat Diagn 23:861–863, 2003. Kozlowski K, Masel J, Nolte K: Dysplasia spondylo-epiphysealis congenita Springer-Wiedemann. A critical analysis. Aust Radiol 2:260–280, 1977. Langer LO Jr: Spondyloepiphyseal dysplasia tarda: Hereditary chondrodysplasia with characteristic vertebral configuration in the adult. Radiology 82:833–839, 1964. Lee B, Vissing H, Ramirez F, et al.: Identification of the molecular defect in a family with spondyloepiphyseal dysplasia. Science 244:978–980, 1989. MacKenzie JJ, Fitzpatrick J, Babyn P, et al.: X linked spondyloepiphyseal dysplasia: a clinical, radiological, and molecular study of a large kindred. J Med Genet 33:823–828, 1996. Macpherson RI, Wood BP: Spondyloepiphyseal dysplasia congenita. A cause of lethal neonatal dwarfism. Pediatr Radiol 9:217–224, 1980. Massa G, Vanderschueren-Lodeweyckx M: Spondyloepiphyseal dysplasia tarda in Turner syndrome. Acta Paediatr Scand 78:971–974, 1989. Naumoff P: Thoracic dysplasia in spondyloepiphyseal dysplasia congenita. Am J Dis Child 131:653–654, 1977. Parikh SN, Crawford AH: Spondyloepiphyseal dysplasia. eMedicine 2003. http://www.emedicine.com Reardon W, Hall CM, Shaw DG, et al.: New autosomal dominant form of spondyloepiphyseal dysplasia presenting with atlanto-axial instability. Am J Med Genet 52:432–437, 1994. Savarirayan R, Thompson E, Gecz J: Spondyloepiphyseal dysplasia tarda (SEDL, MIM #313400). Eur J Hum Genet 11:639–642, 2003. Spranger JW, Langer LO Jr: Spondyloepiphyseal dysplasia congenita. Radiology 94:313–322, 1970. Spranger JW, Langer LO Jr: Spondyloepiphyseal dysplasias. Birth Defects Original Article Series X(9):19–61, 1974. Spranger JW, Maroteaux P: Genetic heterogeneity of spondyloepiphyseal dysplasia congenita? Am J Med Genet 13:241–242, 1982.
SPONDYLOEPIPHYSEAL DYSPLASIA Spranger JW, Wiedemann HR: Dysplasia spondyloepiphysaria congenita. Helv Paediatr Acta 21:598–611, 1966. Tiller GE: X-linked Spondyloepiphyseal dysplasia tarda. Gene Reviews, 2001. http://www.genetests.org Tiller GE, Weis MA, Polumbo PA, et al.: An RNA-splicing mutation (G+5IVS20) in the type II collagen gene (COL2A1) in a family with spondyloepiphyseal dysplasia congenita. Am J Hum Genet 56:388–395, 1995. Unger S, Korkko J, Krakow D, et al.: Double heterozygosity for pseudoachondroplasia and spondyloepiphyseal dysplasia congenita. Am J Med Genet 104:140–146, 2001.
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Williams BR, Cranley RE: Morphologic observations on four cases of SED congenita. Birth Defects Original Article Series X(9):75–87, 1974. Whyte MP, Gottesman GS, Eddy MC, et al.: X-linked recessive spondyloepiphyseal dysplasia tarda. Clinical and radiographic evolution in a 6-generation kindred and review of the literature. Medicine (Baltimore) 78:9–25, 1999. Yang SS, Chen H, Williams P, et al.: Spondyloepiphyseal dysplasia congenita. A comparative study of chondrocytic inclusions. Arch Pathol Lab Med 104:208–211, 1980.
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Fig. 2. Photomicrograph of a neonate with SED congenita shows frequent presence of cytoplasmic inclusions in the chondrocytes of resting cartilage and the zone of proliferation. The cytoplasmic inclusion is a dilated rough endoplasmic reticulum containing finely granular material.
Fig. 1. A neonate with SED congenita showing moderately shortened limbs, short trunk and large head. Radiograph shows small oval vertebral bodies, reniform ilia and moderately shortened limb bones.
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Fig. 3. A boy with SED congenita showing short trunk, short, broad chest with pectus excavatum, globoid abdomen, and hyperlordosis. Radiographs showed lack of ossification of the femoral epiphysis, short femoral neck, generalized platyspondyly, and thoracolumbar scoliosis.
Fig. 4. An adult with SED showing short-trunk dwarfism. Radiographs showed flat vertebral bodies, severe scoliosis, and retarded ossification of femoral head and neck.
Stickler Syndrome In 1965, Stickler et al. described a family with progressive myopia, retinal detachment and blindness, and premature degenerative changes in various joints. The disorder was subsequently termed ‘hereditary progressive arthroophthalmopathy.’ The incidence is estimated to be about 1 in 10,000.
CLINICAL FEATURES
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal dominant with wide variation in expression 2. Association of the Stickler syndrome with following collagen gene mutations: a. COL2A1 gene mutations i. Observed in the majority of families with type I ocular Stickler syndrome, which shows characteristic type I vitreous phenotype ii. Linkage between the ocular Stickler syndrome and type II procollagen gene on chromosome 12q13.11-q13.2 iii. Almost all COL2A1 gene mutations cause premature termination codons, leading to reduced amounts of collagen II. b. COL11A1 gene mutations (especially those removing 54-bp exons) i. Observed in type II vitreous phenotype ii. Stickler syndrome type II (Marshall syndrome) a) More severe facial features (short nose, midfacial flattening) b) High myopia c) Less risk of retinal detachment d) Moderate hearing impairment c. COL11A2 gene mutations i. Cause nonocular Stickler syndrome type III a) Stickler-like facial features b) Mild to moderate deafness c) Normal eyes ii. Also found in patients with a recessively inherited variant denoted as otospondylomegaepiphyseal dysplasia (OSMED) iii. Also cause autosomal dominant non-syndromic deafness (DFNA13) 3. Genotype-phenotype correlations a. Type I Stickler syndrome: ocular Stickler syndrome with mutations in COL2A1 (chromosome locus: 12q13.11-q13.2) b. Type II Stickler syndrome: ocular Stickler syndrome with mutations in COL11A1 (chromosome locus: 1p21) c. Type III Stickler syndrome: nonocular Stickler syndrome with mutations in COL11A2 (chromosome locus: 6p21.3)
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1. Considerable clinical variability within families and between families, explainable in part by locus and allelic heterogeneity 2. Ocular features a. Myopia i. Congenital ii. Nonprogressive iii. Of high degree b. Abnormalities of vitreous formation and gel architecture i. Pathognomonic of Stickler syndrome ii. A prerequisite for diagnosis iii. Vitreous anomalies a) Characteristic congenital ‘membranous’ vitreous anomaly (type I phenotype) in type I Stickler syndromes b) Sparse and irregularly thickened bundles of fibers throughout the vitreous cavity (type II phenotype) in type II Stickler syndrome c. Retinal detachment: the most serious ophthalmologic complication d. Cataracts e. Strabismus f. Open-angle glaucoma g. No ocular abnormalities in Stickler syndrome type III 3. Hearing impairment a. Considerable variability b. Conductive hearing impairment i. Resulting from recurrent otitis media ii. Secondary to cleft palate c. Sensorineural hearing impairment i. Type I Stickler syndrome with mutations in the COL2A1 gene a) Occurring in 50–60% b) Typically mild to moderate degrees c) Predominantly affecting higher frequencies d) No tangible progression beyond presbycusis ii. Type II Stickler syndrome (Marshall syndrome) with the mutations in the COL11A1 gene a) Occurring in 80–100% b) More severely affected c) Starting at a younger age or congenital in origin d) Showing progression iii. Type III Stickler syndrome with mutations in the COL11A2 gene a) A typical feature b) 100% penetrance c) Mild to moderate impairment
STICKLER SYNDROME
d) Nonprogressive when accounted for presbycusis e) Showing different audiometric configurations 4. Associated anomalies a. Orofacial anomalies i. Facial bone hypoplasia a) Flat midface b) Depressed nasal bridge c) Maxillary hypoplasia d) Mandibular hypoplasia (Pierre-Robin anomaly) ii. High arched/cleft palate iii. Bifid uvula iv. Abnormal teeth v. Malocclusion b. Generalized musculoskeletal abnormalities i. Joint hyperextensibility ii. Enlarged joints iii. Premature osteoarthritis iv. Slender extremities v. Long fingers vi. Hypotonia vii. Relative muscle hypoplasia viii. Kyphosis ix. Scoliosis x. Pectus carinatum xi. Accessory carpal ossicles xii. Hip dislocation xiii. Coxa valga xiv. Genu valga xv. Talipes equinovarus c. Mitral valve prolapse i. 50% of patients in one series ii. 0% in another series 5. Normal intelligence 6. Differential diagnosis a. Wagner hereditary vitreo-retinal degeneration i. Consisting solely of ocular abnormalities a) Myopia b) Vitreous degeneration c) Preretinal avascular membranes d) Retinal degeneration and thinning ii. No increased risk of retinal detachment or systemic abnormalities b. Weissenbacher-Zweymüller syndrome and otospondylomegaephiphyseal dysplasia (OSMED) i. Pierre-Robin sequence ii. Snub nose iii. Proximal limb shortening resolved by adulthood iv. Dumbbell shaped femora and humeri v. Coronal vertebral clefts vi. Sensorineural hearing loss vii. No eye abnormalities viii. COL11A2 mutations ix. Appears to represent the same entity as nonocular Stickler syndrome c. Erosive vitroretinopathy i. Autosomal dominant eye disorder ii. Phenotype resembling Wagner syndrome but lacking any systemic abnormalities
d.
e.
f. g. h.
i.
j.
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iii. Condition mapped to 5q13-q14 suggesting it may be an allelic variant of Wagner syndrome Marshall syndrome i. Autosomal dominant disorder ii. Clinical phenotype a) Cataracts b) Myopia c) Abnormal vitreous d) Midfacial hypoplasia e) Congenital deafness iii. Associated with COL11A1 mutation in a family affected with Marshall syndrome Kniest dysplasia i. Ocular abnormalities a) Severe myopia b) Vitreous veils c) Perivascular lattice d) Retinal detachment e) Cataracts ii. Systemic findings a) Short trunk dwarfism b) Kyphoscoliosis c) Deafness d) Depressed nasal bridge e) Cleft palate Spondyloepiphyseal dysplasia Marfan syndrome Goldmann-Farve syndrome i. A rare recessively inherited condition ii. Ocular abnormalities a) Night blindness b) Retinal detachment c) Pigmentary choroidoretinal degeneration d) Vascular sheathing in the fundus Jansen syndrome i. Ocular abnormalities similar to Wagner syndrome ii. Absent systemic abnormalities Congenital retinoschisis i. A sex-linked recessive trait ii. Usually occurring in emmetropic or hyperopic patients iii. Membrane-like structures in mid-vitreous
DIAGNOSTIC INVESTIGATIONS 1. Audiological testing for hearing loss 2. Radiographic features a. Generalized spondyloepiphyseal dysplasia b. Flattening of the epiphyses c. Narrowing of the diaphyses d. Flaring or widening of the metaphyses e. Wedging of the tubular bones f. Coxa valga g. Widening of femoral neck h. Acetabular protrusio i. Chondrolysis j. Avascular necrosis k. Premature arthritic changes l. Anterior maxillary and mandibular underdevelopment
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3. Clinically available molecular genetic testing for mutations affecting three different genes (COL2A1, COL11A1, COL11A2)
GENETIC COUNSELING 1. Recurrence risk a. Variable clinical expression of Stickler syndrome may complicate the genetic counseling. i. Exercise caution on assuming a de novo mutation: radiographic studies and clinical examination of the parents including formal testing of hearing and vision ii. Mutation search whenever possible iii. Uncertainty in predicting clinical consequences of inheriting a mutation b. Patient’s sib: not increased unless a parent has Stickler syndrome c. Patient’s offspring: 50% 2. Prenatal diagnosis a. Ultrasonographic demonstration of Pierre-Robin sequence as a part of Stickler syndrome b. Mutation analysis on amniocytes or CVS cells in at-risk families with known mutations c. Linkage analysis of the 3’VNTR polymorphism on the involved gene (COL2A1) using amniocytic DNA 3. Management a. Early evaluation of at-risk patients for the development of the following complications i. Retinal tears ii. Retinal detachment iii. Cataracts iv. Glaucoma b. Long-term monitoring c. Cleft palate repair with appropriate feeding techniques d. Corrective lenses for myopia e. Avoid contact sports which may lead to retinal detachment f. Laser photocoagulation of vitreoretinopathy as preventive treatment for retinal detachment g. Surgical repair of retinal detachments and remove cataracts with possible lens implantation h. Glaucoma management i. Corrective treatment for strabismus j. Hearing aids for hearing loss k. Speech therapy l. Symptomatic treatment for arthropathy i. Joint pain management ii. Appropriate splints for strengthening and stabilizing lax joints iii. Braces or aids to assist daily activities iv. Hydrotherapy or other physical therapy modalities to increase range of motion, endurance, and strength m. Management for mitral valve prolapse i. Antibiotics prophylaxis ii. Beta-blocker for symptomatic patients
REFERENCES Admiraal RJ, Szymko YM, Griffith AJ, et al.: Hearing impairment in Stickler syndrome. Adv Otorhinolaryngol 61:216–223, 2002. Bennett JT, McMurray SW: Stickler syndrome. J Pediatr Orthop 10:760–763, 1990. Blair NP, Albert DM, Liberfarb RM, et al.: Hereditary progressive arthroophthalmopathy of Stickler. Am J Ophthalmol 88:876–888, 1979. Bowling EL, Brown MD, Trundle TV: The Stickler syndrome: case reports and literature review. Optometry 71:177–182, 2000. Brown DM, Kimura AE, Weingeist TA, et al.: Erosive vitreoretinopathy. A new clinical entity. Ophthalmology 101:694–704, 1994. Brown DM, Graemiger RA, Hergersberg M, et al.: Genetic linkage of Wagner disease and erosive vitreoretinopathy to chromosome 5q113–14. Arch Ophthalmol 113:671–675, 1995. Brunner HG, van Beersum SE, Warman ML, et al.: A Stickler syndrome gene is linked to chromosome 6 near the COL11A2 gene. Hum Mol Genet 3:1561–1564, 1994. Faber J, Winterpacht A, Zabel B, et al.: Clinical variability of Stickler syndrome with a COL2A1 haploinsufficiency mutation: implications for genetic counselling. J Med Genet 37:318–320, 2000. Freddi S, Savarirayan R, Bateman JF: Molecular diagnosis of Stickler syndrome: a COL2A1 stop codon mutation screening strategy that is not compromised by mutant mRNA instability. Am J Med Genet 90: 398–406, 2000. Griffith AJ, Sprunger KL, Siko-Osadsa DA, et al.: Marshall syndrome associated with a splicing defect at the COL11A1 locus. Am J Hum Genet 62:816–823, 1998. Hall J: Stickler syndrome. Presenting as a syndrome of cleft palate, myopia and blindness inherited as a dominant trait. Birth Defects Orig Artic Ser 10:157–171, 1974. Herrmann J, France TD, Opitz JM: The Stickler syndrome. Birth Defects Orig Artic Ser 11:203–204, 1975. Herrmann J, France TD, Spranger JW, et al.: The Stickler syndrome (hereditary arthroophthalmopathy). Birth Defects Orig Artic Ser 11(2):76–103, 1975. Jacobson J, Jacobson C, Gibson W: Hearing loss in Stickler’s syndrome: a family case study. J Am Acad Audiol 1:37–40, 1990. Leiba H, Oliver M, Pollack A: Prophylactic laser photocoagulation in Stickler syndrome. Eye 10 (Pt 6):701–708, 1996. Lewkonia RM: The arthropathy of hereditary arthroophthalmopathy (Stickler syndrome). J Rheumatol 19:1271–1275, 1992. Liberfarb RM, Goldblatt A: Prevalence of mitral-valve prolapse in the Stickler syndrome. Am J Med Genet 24:387–392, 1986. Liberfarb RM, Hirose T, Holmes LB: The Wagner-Stickler syndrome: a study of 22 families. J Pediatr 99:394–399, 1981. Liberfarb RM, Levy HP, Rose PS, et al.: The Stickler syndrome: Genotype/phenotype correlation in 10 families with Stickler syndrome resulting from seven mutations in the type II collagen gene locus COL2A1. Genet Med 5:21–27, 2003. Lisi V, Guala A, Lopez A, et al.: Linkage analysis for prenatal diagnosis in a familial case of Stickler syndrome. Genet Couns 13:163–170, 2002. Marshall D: Ectodermal dysplasia. Report of a kindred with ocular deformities and hearing defect. Am J Ophthalmol 45:143–156, 1958. McGuirt WT, Prasad SD, Griffith AJ, et al.: Mutations in COL11A2 cause nonsyndromic hearing loss (DFNA13). Nat Genet 23:413–419, 1999. Nowak CB: Genetics and hearing loss: a review of Stickler syndrome. J Commun Disord 31:437–453; 453–434, 1998. Popkin JS, Polomeno RC: Stickler’s syndrome (hereditary progressive arthroophthalmopathy). Can Med Assoc J 111:1071–1076, 1974. Richards AJ, Yates JR, Williams R, et al.: A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in alpha 1 (XI) collagen. Hum Mol Genet 5:1339– 1343, 1996. Richards AJ, Baguley DM, Yates JR, et al.: Variation in the vitreous phenotype of Stickler syndrome can be caused by different amino acid substitutions in the X position of the type II collagen Gly-X-Y triple helix. Am J Hum Genet 67:1083–1094, 2000. Robin NH, Warman M: Stickler syndrome. Gene Reviews, 2003. http://genetests.org
STICKLER SYNDROME Sirko-Osadsa DA, Murray MA, Scott JA, et al.: Stickler syndrome without eye involvement is caused by mutations in COL11A2, the gene encoding the alpha2(XI) chain of type XI collagen. J Pediatr 132:368–371, 1998. Snead MP: Hereditary vitreopathy. Eye 10:653–663, 1996. Snead MP, Yates JR: Clinical and molecular genetics of Stickler syndrome. J Med Genet 36:353–359, 1999. Soulier M, Sigaudy S, Chau C, et al.: Prenatal diagnosis of Pierre-Robin sequence as part of Stickler syndrome. Prenat Diagn 22:567–568, 2002. Spallone A: Stickler’s syndrome: a study of 12 families. Br J Ophthalmol 71:504–509, 1987. Spranger J: The type XI collagenopathies. Pediatr Radiol 28:745–750, 1998. Stickler GB, Belau PG, Farrell FJ, et al.: Hereditary progressive arthro-ophthalmopathy. Mayo Clin Proc 40:433–455, 1965. Stickler GB, Pugh DG: Hereditary progressive arthro-ophthalmopathy. II. Additional observations on vertebral abnormalities, a hearing defect, and a report of a similar case. Mayo Clin Proc 42:495–500, 1967, Stickler GB, Hughes W, Houchin P: Clinical features of hereditary progressive arthro-ophthalmopathy (Stickler syndrome): a survey. Genet Med 3:192–196, 2001.
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Van Steensel MAM, Buma P, de Waal Malefijt MC, et al.: Oto-spondylomegaepiphyseal dysplasia (OSMED): Clinical description of three patients homozygous for a missense mutation in the COL11A2 gene. Am J Med Genet 70:315–323, 1997. Vikkula M, Mariman ECM, Lui VCH, et al.: Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. Cell 80:431–437, 1995. Wilkin DJ, Mortier GR, Johnson CL, et al.: Correlation of linkage data with phenotype in eight families with Stickler syndrome. Am J Med Genet 80:121–127, 1998. Wilkin DJ, Liberfarb R, Davis J, et al.: Rapid determination of COL2A1 mutations in individuals with Stickler syndrome: analysis of potential premature termination codons. Am J Med Genet 94:141–148, 2000. Wilkin DJ, Liberfarb RM, Francomano CA: Stickler syndrome. In Cassidy SB, Allanson JE (eds): management of Genetic Syndromes. Chapter 24, 2001, pp 405–416. Zlotogora J, Sagi M, Schuper A, et al.: Variability of Stickler syndrome. Am J Med Genet 42:337–339, 1992.
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Fig. 1. A 32-year-old female with Stickler syndrome having severe myopia, retinal detachment, cleft palate, sensorineural hearing loss, mitral valve prolapse, hyperextensible joints, and severe degenerative joint disease.
Sturge-Weber Syndrome 4. CNS manifestations a. Seizures b. Mental retardation present in approximately 50% of cases c. Contralateral hemiplegia or hemisensory deficits d. Contralateral homonymous hemianopsia (impaired vision in half of the visual field) e. Headaches f. Developmental delay g. Learning disorders h. Attention deficit hyperactivity disorder 5. Ocular manifestations a. Ipsilateral to the port-wine stain b. Can be seen with V1 or V2 involvement c. Glaucoma (60%) d. Buphthalmos e. Vascular malformations of the conjunctiva, epi-sclera, choroids, and retina 6. Long-term outcome a. Distribution of port-wine stain i. Cranial: 98% ii. Extracranial: 52% b. Glaucoma (60%) c. Seizures (83%) d. Developmental delay usually associated with seizures i. With seizures: 43% ii. Without seizures: 0% e. Presence of behavior and emotional problems i. With seizures: 85% ii. Without seizures: 58% f. Require special education i. With seizures: 71% ii. Without seizures: 0% g. Employability i. With seizures: 46% ii. Without seizures: 78% h. Normal fertility i. Indications of progressive nature i. Increasing duration of seizures and postictal deficits ii. Increase in atrophy or of calcified lesions or both
Sturge-Weber syndrome comprises of vascular malformations of the central nervous system and the port-wine stain or nevus flammeus of the face in a trigeminal nerve distribution. The syndrome is also known as encephalotrigeminal angiomatosis. The incidence is estimated to be approximately 1 in 50,000.
GENETICS/BASIC DEFECTS 1. Genetics a. A sporadic, non-familial disease b. Uncertain inheritance: Only a few familial clusters of the syndrome reported; most of these have not exhibited the clear-cut autosomal dominant inheritance pattern c. Proposed to represent a genetically mosaic condition. Lesions in the Sturge-Weber syndrome result from somatic mutations in affected areas, such as the portwine stain or leptomeningeal angioma, but not in blood or normal skin. d. A potential role of fibronectin in the pathogenesis of Sturge-Weber syndrome. The gene expression findings in fibroblast supported the hypothesis of a somatic mutation underlying the disorder. 2. Basic defect: caused by residual embryonal blood vessels and their secondary effects on surrounding brain tissue 3. Pathophysiology: Neurologic dysfunction of the syndrome results from secondary effects of residual embryonal blood vessels on surrounding brain tissue. a. Hypoxia b. Ischemia c. Venous occlusion d. Thrombosis e. Infarction f. Vasomotor phenomenon g. Seizures
CLINICAL FEATURES 1. Variable natural history of the disease 2. Capillary malformation (port-wine stain, cutaneous angioma) a. Involves the ophthalmic branch of the trigeminal nerve, in particular the upper eyelid and supraorbital region b. May extend into the maxillary and mandibular regions c. May be associated with soft tissue and bony overgrowth d. May be hidden in scalp or mouth e. May be absent in the forme fruste of Sturge-Weber syndrome 3. Leptomeningeal malformation (angioma) a. May be unilateral (more common) or bilateral b. Usually ipsilateral to port-wine stain c. Capillary and venous anomalies of leptomeninges d. No correlation between the size of facial and CNS malformations
DIAGNOSTIC INVESTIGATIONS
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1. Radiography a. Asymmetric skull b. Double contour “gyriform” patterns of intracranial calcifications i. Classic “tram-line”, “tram-track”, or “trolley-track” intracranial calcifications a) Considered pathognomonic prior to modern neuroimaging b) Often a late finding c) May not be present initially
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ii. Distribution a) In the subcortical region, primarily in the parietal and occipital regions b) Unilateral (80%) or bilateral (20%) EEG to evaluate seizure activities Angiographic findings a. Lack of superficial cortical veins b. Nonfilling dural sinuses c. Abnormal, tortuous vessels CT scan findings a. “Tram-track” calcifications b. Cortical atrophy c. Abnormal draining veins d. Enlarged ipsilateral choroid plexus e. Blood-brain barrier breakdown during seizures MRI findings a. Enlarged choroid plexus b. Sinovenous occlusion c. Cortical atrophy d. Accelerated myelination Single-photon emission computed tomography to measure cerebral blood flow a. Hyperperfusion early (before 1 year) b. Hypoperfusion late (after 1 year) Positron emission tomography (PET) for hypometabolism Histology a. Thickened and discolored leptomeninges b. Abnormal venous structures c. Calcifications i. Cerebral vessel walls ii. Perivascular tissue iii. Rarely within neurons
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: low b. Patient’s offspring: low 2. Prenatal diagnosis: not been reported 3. Management a. Medical care i. Medications for recurrent headaches ii. Management of glaucoma to control the intraocular pressure and prevent progressive visual loss and blindness iii. Anticonvulsants for seizure control iv. Dermatologic laser therapy for port-wine stain b. Surgical care i. Surgery for glaucoma if medications fail to lower intraocular pressure ii. Option of early surgery for patients with SturgeWeber syndrome with drug-resistant epilepsy a) Focal cortical resection b) Hemispherectomy c) Corpus callosotomy d) Vagal nerve stimulation iii. Lesionectomy provided that the pial angioma is unilateral and the resection can be complete
REFERENCES Alonso A, Taboada D, Ceres L, et al.: Intracranial calcification in a neonate with the Sturge Weber syndrome and additional problems. Pediatr Radiol 8:39–41, 1979. Arzimanoglou AA, Aicardi J: The epilepsy of Sturge-Weber syndrome: clinical features and treatment in 23 patients. Acta Neurol Scand Suppl 140:18– 22, 1992. Arzimanoglou AA, Andermann F, Aicardi J, et al.: Sturge-Weber syndrome: indications and results of surgery in 20 patients. Neurology 55: 1472–1479, 2000. Boltshauser E, Wilson J, Hoare RD: Sturge-Weber syndrome with bilateral intracranial calcification. J Neurol Neurosurg Psychiatry 39:429– 435, 1976. Brenner RP, Sharbrough FW: Electroencephalographic evaluation in SturgeWeber syndrome. Neurology 26:629–632, 1976. Celebi S, Alagoz G, Aykan U: Ocular findings in Sturge-Weber syndrome. Eur J Ophthalmol 10:239–243, 2000. Chamberlain MC, Press GA, Hesselink JR: MR imaging and CT in three cases of Sturge-Weber syndrome: prospective comparison. AJNR Am J Neuroradiol 10:491–496, 1989. Chao DH: Congenital neurocutaneous syndromes of childhood. III. SturgeWeber disease. J Pediatr 55:635–649, 1959. Chapieski L, Friedman A, Lachar D: Psychological functioning in children and adolescents with Sturge-Weber syndrome. J Child Neurol 15:660–665, 2000. Cibis GW, Tripathi RC, Tripathi BJ: Glaucoma in Sturge-Weber syndrome. Ophthalmology 91:1061–1071, 1984. Comi AM: Pathophysiology of Sturge-Weber syndrome. J Child Neurol 18: 509–516, 2003. Comi AM, Hunt P, Vawter MP, et al.: Increased fibronectin expression in Sturge-Weber syndrome fibroblasts and brain tissue. Pediatr Res 53: 762–769, 2003. Di Trapani G, Di Rocco C, Abbamondi AL, et al.: Light microscopy and ultrastructural studies of Sturge-Weber disease. Childs Brain 9:23–36, 1982. Dolkart LA, Bhat M: Sturge-Weber syndrome in pregnancy. Am J Obstet Gynecol 173:969–971, 1995. Falconer MA, Rushworth RG: Treatment of encephalotrigeminal angiomatosis (Sturge-Weber disease) by hemispherectomy. Arch Dis Child 35:433– 447, 1960. Griffiths PD: Sturge-Weber syndrome revisited: the role of neuroradiology. Neuropediatrics 27:284–294, 1996. Happle R: Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J Am Acad Dermatol 16:899–906, 1987. Huq AH, Chugani DC, Hukku B, et al.: Evidence of somatic mosaicism in Sturge-Weber syndrome. Neurology 59:780–782, 2002. Ito M, Sato K, Ohnuki A, et al.: Sturge-Weber disease: operative indications and surgical results. Brain Dev 12:473–477, 1990. Jay V: Sturge-Weber syndrome. Pediatr Dev Pathol 3:301–305, 2000. King G, Schwarz GA: Sturge-Weber syndrome (encephalotrigeminal angiomatosis). AMA Arch Intern Med 94:743–758, 1954. Kossoff EH, Buck C, Freeman JM: Outcomes of 32 hemispherectomies for Sturge-Weber syndrome worldwide. Neurology 59:1735–1738, 2002. Mirowski GW, Liu AA-T, Stone ML, et al.: Sturge-Weber syndrome. J Am Acad Dermatol 41:772–773, 1999. Oakes WJ: The natural history of patients with the Sturge-Weber syndrome. Pediatr Neurosurg 18:287–290, 1992. Pascual-Castroviejo I, Diaz-Gonzalez C, Garcia-Mclian RM, et al.: SturgeWeber syndrome: study of 40 patients. Pediatr Neurol 9:283–288, 1993. Riviello JJ: Sturge-Weber syndrome. Emedicine, 2001. http://www.emedicine. com Sujansky E, Conradi S: Outcome of Sturge-Weber syndrome in 52 adults. Am J Med Genet 57:35–45, 1995. Sujansky E, Conradi S: Sturge-Weber syndrome: age of onset of seizures and glaucoma and the prognosis for affected children. J Child Neurol 10:49–58, 1995.
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Fig. 1. An infant with Sturge-Weber syndrome showing port-wine stain primarily affecting right side of the face.
Fig. 2. A girl with typical Sturge-Weber syndrome showing port-wine stain affecting left side of the face.
Fig. 3. Radiographs of the skull in another patient demonstrate the typical gyriform pattern of cortical calcification.
Tay-Sachs Disease b. Normal motor development in the first few months of life c. Progressive weakness and loss of motor skills beginning around 2–6 months of life d. Followed by decreased social interaction, increased sensitivity to noise (hyperacusis), and an increased startle response to noise e. Progressive neurodegeneration f. Uniformly fatal: death from pneumonia usually occurring between 2–5 years of age 2. Clinical features a. Delayed development b. Poor feeding c. Lethargy d. Hypotonia e. Hyperreflexia f. Opisthotonos g. Hyperacusis h. A cherry red spot on the fovea centralis of the macula, representing loss of ganglion cells in the foveal area with the remaining ones filled with the ganglioside i. Progressive neurodegeneration i. Developmental regression ii. Macrocephaly secondary to accumulation of storage material within the brain after about 15 months of age. There is no evidence of hepatosplenomegaly or other peripheral evidence of storage disease iii. Myoclonic seizures, most during the first year of life iv. Progressive macular degeneration leading to blindness, usually by 1 year of age v. Deafness vi. Spasticity vii. Complete disability
Tay-Sachs disease is a hereditary neurodegenerative disorder resulting from excess storage of GM2 ganglioside within the lysosomes of cells. The incidence of the disease is estimated to be 1 in 3600 in Ashkenazi Jews with carrier frequency of 1 in 30 and 1 in 360,000 in other population with carrier frequency of 1 in 300. Tay-Sachs disease is the most frequently occurring sphingolipidoses.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Biochemical defect: deficiency of the isoenzyme βhexosaminidase A (Hex A) 3. Genetic basis a. Mutations in the HEXA gene (on chromosome 15q23-q24) that codes for the subunit of the β-hexosaminidases results in the deficiency of Hex A (αβ) that results in Tay-Sachs disease b. Over 100 different mutations have been identified in the HEXA gene to date c. Presence of a small number of common mutations in populations where the carrier frequency is high i. Ashkenazi Jews a) Two common mutations associated with TaySachs disease [a four base-pair insertion into exon 11 of the HEXA gene (1278insTATC) accounting for 75–80% of all mutations in this population; a splice site mutation in intron 12 (1421+1G→C) accounting for 15% of mutations] b) One mutation associated with a late onset form of the disease (G269S in 3% of carriers) c) Pseudodeficiency polymorphism (R247W in 2% of carriers) ii. Pennsylvania Dutch a) An intron 9 splice site mutation (1073+1G →A) b) Pseudodeficiency allele (R247W) iii. Cajuns in Southern Louisiana a) An intron 9 splice site mutations (1073+1G →A) b) 4 base-pair insertion in exon 11 (1278ins TATC) iv. French Canadians in Eastern Quebec a) A large (7.6 kb) deletion at the 5′ end of the gene b) A splice site mutation in intron 7 (805+1G →A) c) Common 4 base-pair insertion in exon 11 seen in Ashkenazi Jews (1278insTATC)
DIAGNOSTIC INVESTIGATIONS
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1. Diagnosis and carrier testing a. Indications for carrier testing i. Fully or partially Jewish ii. Pennsylvania Dutch iii. Cajuns of Southern Louisiana iv. French Canadians of Eastern Quebec b. Preconceptional counseling for at-risk couples c. Enzyme assay i. Using fluorimetric study measuring activity of both Hex A and Hex B in either serum or leukocytes ii. Decreased activity of Hex A with normal or increased activity of Hex B in carriers iii. Limitations of serum assay a) Overlapping of the values between carriers and noncarriers b) Unreliable in pregnant women and in women taking oral contraceptives
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c) Inability to distinguish carriers of pseudodeficiency alleles from carriers of diseasecausing mutations iv. Clarification of abnormal or inconclusive results of enzyme assay by: a) Enzyme assay on leukocytes b) DNA mutation analysis for common mutations and pseudodeficiency alleles 2. CT scan of the brain: areas of low density in the basal ganglia and cerebral white matter 3. MRI of the brain: an increased signal in the basal ganglia and cerebral white matter on T2-weighted images 4. Characteristic neuropathological findings a. Pathologic changes are restricted to the nervous system b. Ballooning of neurons with massive intralysosomal accumulation of lipophilic membranous bodies c. Nature and structure of the stored intraneuronal material: GM2 ganglioside d. Abnormal cytoplasmic inclusion bodies identified in fetal spinal cord at 12 weeks and retina and spinal ganglia during 19th–22nd week of gestation e. Cisternae of the endoplasmic reticulum: the primary site of lipid accumulation in neurons during the fetal stage of Tay-Sachs disease
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not surviving to reproductive age 2. Prenatal diagnosis a. Enzyme analysis (absence of hexosaminidase A) on cultured amniocytes or chorionic villus cells b. DNA analysis when one of the common mutations had been identified in the family i. Preferred method of prenatal diagnosis ii. Less prone to error 3. Management a. No effective treatment to alter the natural history b. Primarily supportive i. Provide adequate nutrition and hydration ii. Manage infections iii. Protect airway iv. Control seizures v. Bowel management c. Enzyme replacement therapy and bone marrow transplantation: not yet successful d. Options to modify 25% risk of having an affected child with each pregnancy if both partners are found to be carriers i. Prenatal diagnosis by amniocentesis or chorionic villus sampling ii. Egg or sperm donation iii. Preimplantation genetic diagnosis iv. Adoption
REFERENCES Adachi M, Schneck L, Volk BW: Ultrastructural studies of eight cases of fetal Tay-Sachs disease. Lab Invest 30:102–112, 1974. Adachi M, Torii J, Schneck L, et al.: The fine structure of fetal Tay-Sachs disease. Arch Pathol 91:48–54, 1971.
Akerman BR, Natowicz MR, Kaback MM, et al.: Novel mutations and DNAbased screening in non-Jewish carriers of Tay-Sachs disease. Am J Hum Genet 60:1099–1106, 1997. Akli S, Boue J, Sandhoff K, et al.: Collaborative study of the molecular epidemiology of Tay-Sachs disease in Europe. Eur J Hum Genet 1:229–238, 1993. Ambani LM, Bhatia RS, Shah SB, et al.: Prenatal diagnosis of Tay-Sachs disease. Indian Pediatr 26:1052–1053, 1989. Argov Z, Navon R: Clinical and genetic variations in the syndrome of adult GM2 gangliosidosis resulting from hexosaminidase A deficiency. Ann Neurol 16:14–20, 1984. Brett EM, Ellis RB, Haas L, et al.: Late onset GM2-gangliosidosis. Clinical, pathological, and biochemical studies on 8 patients. Arch Dis Child 48:775–785, 1973. Brady RO: Tay-Sachs disease: the search for the enzymatic defect. Adv Genet 44:51–60, 2001. Callahan JW, Archibald A, Skomorowski MA, et al.: First trimester prenatal diagnosis of Tay-Sachs disease using the sulfated synthetic substrate for hexosaminidase A. Clin Biochem 23:533–536, 1990. Chamoles NA, Blanco M, Gaggioli D, et al.: Tay-Sachs and Sandhoff diseases: enzymatic diagnosis in dried blood spots on filter paper: retrospective diagnoses in newborn-screening cards. Clin Chim Acta 318:133–137, 2002. Childs B, Gordis L, Kaback MM, et al.: Tay-Sachs screening: social and psychological impact. Am J Hum Genet 28:550–558, 1976. Cotlier E: Tay-Sachs’ disease and Fabry’s disease: clinical and chemical diagnosis of two metabolic eye diseases. Bull N Y Acad Med 50:777–787, 1974. Cutz E, Lowden JA, Conen PE: Ultrastructural demonstration of neuronal storage in fetal Tay-Sachs disease. J Neurol Sci 21:197–202, 1974. Desnick RJ, Goldberg JD: Tay-Sachs disease: prospects for therapeutic intervention. Prog Clin Biol Res 18:129–141, 1977. Desnick RJ, Kaback MM: Future perspectives for Tay-Sachs disease. Adv Genet 44:349–356, 2001. Eeg-Olofsson L, Kristensson K, Sourander P, et al.: Tay-Sachs disease. A generalized metabolic disorder. Acta Paediatr Scand 55:546–562, 1966. Grabowski GA, Kruse JR, Goldberg JD, et al.: First-trimester prenatal diagnosis of Tay-Sachs disease. Am J Hum Genet 36:1369–1378, 1984. Gravel RA, Triggs-Raine BL, Mahuran DJ: Biochemistry and genetics of TaySachs disease. Can J Neurol Sci 18:419–423, 1991. Grebner EE, Jackson LG: Prenatal diagnosis for Tay-Sachs disease using chorionic villus sampling. Prenat Diagn 5:313–320, 1985. Hansis C, Grifo J: Tay-Sachs disease and preimplantation genetic diagnosis. Adv Genet 44:311–315, 2001. Kaback M, Lim-Steele J, Dabholkar D, et al.: Tay-Sachs disease—carrier screening, prenatal diagnosis, and the molecular era. An international perspective, 1970 to 1993. The International TSD Data Collection Network. JAMA 270:2307–2315, 1993. Kaback MM: Tay-Sachs disease: from clinical description to prospective control. Prog Clin Biol Res 18:1–7, 1977. Kaback MM: Screening for reproductive counseling: social, ethical, and medicolegal issues in the Tay-Sachs disease experience. Prog Clin Biol Res 103 Pt B:447–459, 1982. Kaback MM: Population-based genetic screening for reproductive counseling: the Tay-Sachs disease model. Eur J Pediatr 159 Suppl 3:S192–S195, 2000. Kaback MM: Screening and prevention in Tay-Sachs disease: origins, update, and impact. Adv Genet 44:253–265, 2001. Kaback MM, Desnick RJ: Tay-Sachs disease: from clinical description to molecular defect. Adv Genet 44:1–9, 2001. Kaback MM, Nathan TJ, Greenwald S: Tay-Sachs disease: heterozygote screening and prenatal diagnosis—U.S. experience and world perspective. Prog Clin Biol Res 18:13–36, 1977. Kaback MM, Zeiger RS, Reynolds LW, et al.: Approaches to the control and prevention of Tay-Sachs disease. Prog Med Genet 10:103–134, 1974. Kivlin JD, Sanborn GE, Myers GG: The cherry-red spot in Tay-Sachs and other storage diseases. Ann Neurol 17:356–360, 1985. MacQueen GM, Rosebush PI, Mazurek MF: Neuropsychiatric aspects of the adult variant of Tay-Sachs disease. J Neuropsychiatry Clin Neurosci 10:10–19, 1998. Mahuran DJ, Triggs-Raine BL, Feigenbaum AJ, et al.: The molecular basis of Tay-Sachs disease: mutation identification and diagnosis. Clin Biochem 23:409–415, 1990. O’Brien JS, Okada S, Fillerup DL, et al.: Tay-Sachs disease: prenatal diagnosis. Science 172:61–64, 1971.
TAY-SACHS DISEASE Rattazzi MC, Dobrenis K: Treatment of GM2 gangliosidosis: past experiences, implications, and future prospects. Adv Genet 44:317–339, 2001. Risch N: Molecular epidemiology of Tay-Sachs disease. Adv Genet 44:233–252, 2001. Rodriguez-Torres R, Schneck L, Kleinberg W: Electrocardiographic and biochemical abnormalities in Tay-Sachs disease. Bull N Y Acad Med 47:717–730, 1971. Schneck L, Adachi M, Volk BW: The fetal aspects of Tay-Sachs disease. Pediatrics 49:342–351, 1972. Schweitzer-Miller L: Tay-Sachs disease: psychologic care of carriers and affected families. Adv Genet 44:341–347, 2001. Streifler J, Golomb M, Gadoth N: Psychiatric features of adult GM2 gangliosidosis. Br J Psychiatry 155:410–413, 1989.
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Streifler JY, Gornish M, Hadar H, et al.: Brain imaging in late-onset GM2 gangliosidosis. Neurology 43:2055–2058, 1993. Sutton VR: Tay-Sachs disease screening and counseling families at risk for metabolic disease. Obstet Gynecol Clin North Am 29:287–296, 2002. Suzuki K: Saul R. Korey Lecture. Molecular genetics of Tay-Sachs and related disorders: a personal account. J Neuropathol Exp Neurol 53:344–350, 1994. Thurmon TF: Tay-Sachs genes in Acadians. Am J Hum Genet 53:781– 783, 1993. Volk BW: Understanding Tay-Sachs disease. Recent advances. Clin Pediatr (Phila) 5:653–654, 1966. Wilkins RH, Brody IA: Tay-Sachs’ disease. Arch Neurol 20:103–111, 1969.
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Fig. 1. A cherry red spot on the fovea centralis of the macula from the fundus of an infant with Tay-Sachs disease.
Fig. 2. Myenteric plexus of the rectum (H & E, ×400) showing many enlarged ganglion cells with abundant foamy cytoplasm due to ganglioside storage. Rectal biopsy can be a good source of neurons in confirming neuronal storage disease. In this patient, Tay-Sachs disease was confirmed by electron microscopic examination of ganglion cells.
Fig. 3. A section of medulla showing a group of neurons with markedly distended foamy cytoplasm (arrows) due to accumulation of GM2 ganglioside (H & E, ×1000).
Tetrasomy 9p Syndrome Tetrasomy 9p syndrome, a clinically diagnosable condition, is a rare cytogenetic disorder characterized by tetrasomy 9p associated with a distinctive patterns of multiple congenital anomalies. In 1973, Ghymers et al. first described the syndrome.
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GENETICS/BASIC DEFECTS 1. Caused by de novo supernumerary isochromosome 9p (presence of four copies of the short arm of the chromosome 9) a. Pure tetrasomy 9p b. Tetrasomy involving the varying segment of the short arm of chromosome 9 2. Cytogenetic types of tetrasomy 9p a. Presence of an extra dicentric chromosome 9 consisting entirely of 9p b. Presence of an extra dicentric chromosome 9 consisting of 9p and the proximal part of 9q c. Mosaicism involving tetrasomy 9p: mosaic of i(9p) cells 3. Hypotheses proposed to explain tetrasomy 9p a. A meiosis I disturbance with nondisjunction and rearrangement in two of the four chromatids of a bivalent 9, resulting in the formation of an isochromosome 9p b. Meiosis II nondisjunction followed by rearrangements (isochromosome formation) with duplication of the short arm and loss of the acentric long arm at the subsequent mitosis c. Dicentric vs monocentric i. Using conventional cytogenetics and banding techniques revealed an additional dicentric 9p chromosome in most cases. ii. Using molecular studies using a chromosome 9 classic satellite probe shows an error in the division of centromere 9 by a double-break event resulting in the formation of a monocentric isochromosome 9p.
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CLINICAL FEATURES 1. Craniofacial abnormalities a. Delayed closure of the anterior fontanel b. Ocular hypertelorism c. Telecanthus d. Strabismus e. Enophthalmos/microphthalmia f. Epicanthal folds g. Prominent beaked or bulbous nose h. Down-turned corners of the mouth i. Microretrognathia j. Low-set, malformed ears
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k. Cleft lip/palate l. High-arched palate Cardiac anomalies a. Ventricular septal defect b. Atrial septal defect c. Patent ductus arteriosus d. Persistent left superior vena cava e. Double outlet of the right ventricle f. Hypoplastic right ventricle g. Hypoplastic left heart ventricle Lung anomalies a. Lung hypoplasia b. Abnormal lobulation of the lung Renal anomalies a. Renal hypoplasia b. Multicystic dysplasia c. Hydroureter d. Hydronephrosis Genital anomalies a. Cryptorchidism b. Genital hypoplasia c. Micropenis d. Hypoplastic shawl-like scrotum e. Ambiguous genitalia Gastrointestinal anomalies: a. Intestinal malrotation b. Hirschsprung disease CNS anomalies a. Psychomotor retardation b. Hypotonia c. Microcephaly d. Brachycephaly e. Hydrocephalus f. Cerebral hypoplasia g. Dandy-Walker cyst h. Absence of olfactory bulbs i. Hypoplastic cerebellum Skeletal anomalies a. Growth retardation b. Short stature c. Short neck d. Dysplastic fingernails e. Limb anomalies f. Clinodactyly of the 5th fingers g. Club feet h. Articular dislocations i. Shortened hands and feet Other features a. Single umbilical artery b. Failure to thrive c. Redundant skin d. Widely spaced nipples
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e. Single palmar crease f. Sacral dimple 10. The severity of the phenotype correlates with size of the tetrasomic region and the degree of tissue mosaicism for the 9p tetrasomy.
DIAGNOSTIC INVESTIGATIONS 1. Cytogenetic studies a. Conventional and high-resolution analyses b. A whole-chromosome paint probe for chromosome 9 to identify the supernumerary chromosome, using the fluorescence in situ hybridization (FISH) technique 2. Echocardiography for cardiovascular malformations 3. Radiography a. Microcephaly b. Hypertelorism c. Hypoplastic first and 12th ribs d. Kyphoscoliosis e. Clinodactyly and brachymesophalangy of the fifth fingers f. Delayed ossification of pubic bones and ischiopubic synchondrosis g. Delayed ossification of femoral heads h. Spina bifida occulta i. Generalized osteoporosis 4. Ultrasonography of renal abnormalities
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: patient not surviving to reproductive age 2. Prenatal diagnosis: chromosome analysis of amniocytes, CVS, or fetal blood 3. Management a. Early intervention programs for mild developmental delay with minor anomalies b. Supporting care for severe cases with early death
REFERENCES Abe T, Morita M, Kawai K, et al.: Partial tetrasomy 9 (9qter 9q2101) due to extra iso-dicentric chromosome. Ann Genet 20:111–114, 1977.
Cuoco C, Gimelli G, Pasquali F, et al.: Duplication of the short arm of chromosome 9. Analysis of five cases. Hum Genet 61:3–7, 1982. de Azevedo Moreira LM, Freitas LM, Gusmao FA, et al.: New case of nonmosaic tetrasomy 9p in a severely polymalformed newborn girl. Birth Defects Res Part A Clin Mol Teratol 67:985–988, 2003. Dhandha S, Hogge WA, Surti U, et al.: Three cases of tetrasomy 9p. Am J Med Genet 113:375–380, 2002. Dutly F, Balmer D, Baumer A, et al.: Isochromosomes 12p and 9p: parental origin and possible mechanisms of formation. Eur J Hum Genet 6:140–144, 1998. Eggermann T, Rossier E, Theurer-Mainka U, et al.: New case of mosaic tetrasomy 9p with additional neurometabolic findings. Am J Med Genet 75:530–533, 1998. Fryns JP: Trisomy 9p and tetrasomy 9p: a unique, clinically recognisable syndrome. Genet Couns 9:229–230, 1998. Grass Fertil Steril, Parke JC, Kirkman HN, et al.: Tetrasomy 9p: Tissue-limited idic(9p) in a child with mild manifestations and a normal CVS result. Report and review. Am J Med Genet 47:812–816, 1993. Jalad SM, Kukolich MK, Garcia M, et al.: Tetrasomy 9p: an emerging syndrome. Clin Genet 39:60–64, 1991. Kukolich M, Jalal S, Garcia M, et al.: Occurrence of 9p tetrasomy. Am J Hum Genet Suppl 47:360, 1990. Lloveras E, Perez C, Sole F, et al.: Two cases of tetrasomy 9p syndrome with tissue limited mosaicism. Am J Med Genet 124A:402–406, 2004. McDowall AA, Blunt S, Berry AC, et al.: Prenatal diagnosis of a case of tetrasomy 9p. Prenat Diagn 9:809–811, 1989. Melaragno MI, Brunoni D, da Silva Patricio FR, et al.: A patient with tetrasomy 9p, Dandy-Walker cyst and Hirschsprung disease. Ann Genet 35:79–84, 1992. Orye E, Verhaaren H, Van Egmond E, et al.: A new case of trisomy 9p syndrome. Clin Genet 7:134–143, 1975. Park J Pediatr, Rawnsley BE, Marin-Padilla M: Tetrasomy 9p syndrome. Ann Genet 38:54–56, 1995. Penhausen P, Riscile G, Miller K, et al.: Tissue limited mosaicism in a patient with tetrasomy 9p. Am J Med Genet 37:388–391, 1990. Peters J, Pehl C, Miller K, et al.: Case report of mosaic partial tetrasomy 9p mimicking Klinefelter syndrome Birth Defects 18:287–293, 1982. Petit P, Devriendt K, Vermeesch JR, et al.: Localization by FISH of centric fission breakpoints in de novo trisomy 9p patient with i(9p) and t(9p;11p). Genet Couns 9:215–221, 1998. Rutten FJ, Scheres JMC, Hustinx TWJ, et al.: A presumptive tetrasomy of the short arm of chromosome 9. Humangenetik 25:163–170, 1974. Schaefer GB, Domek DB, Morgan MA, et al.: Tetrasomy of the short arm of chromosome 9: Prenatal diagnosis and further delineation of the phenotype. Am J Med Genet 38:612–615, 1991. Shapiro S, Hansen K, Littlefield C: Non-mosaic partial tetrasomy and partial trisomy 9. Am J Med Genet 20:271–276, 1985. Tonk VS: Moving towards a syndrome: a review of 20 cases and a new case of non-mosaic tetrasomy 9p with long-term survival. Clin Genet 52:23–29, 1997. Wilson GN, Faj A, Baker D: The phenotypic and cytogenetic spectrum of partial trisomy 9. Am J Med Genet 20:277–282, 1985. Wisniewski L, Politis G, Higgins J: Partial tetrasomy 9 in a liveborn infant. Clin Genet 14:14153, 1978.
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Fig. 1. An infant with tetrasomy 9p syndrome presenting with widened anterior fontanel, microbrachycephaly, a broad nasal root, telecanthus, bilateral cleft lip and palate, retromicrognathia, small eyes, low-set lop ears, and a skin tag on the antihelix of the right ears. In addition, the infant had short neck with excess nuchal fold, bilateral webbing of the anterior axillary folds, pectus excavatum, congenital heart defects, right hydronephrosis, diastasis recti with an umbilical hernia, a right inguinal hernia, sacral dimple with a tag, micropenis, bilateral metatarsus adductus, bilateral transverse palmar creases, clinodactyly of the fifth fingers, short thumbs, and hypoplastic nails. Chest X-ray showed hemivertebrae in the thoracic spine and fractured right clavicle with callus formation. A rectal biopsy confirmed the diagnosis of Hirschsprung disease.
Thalassemia 3. Pathogenesis a. Basic defect in all types of thalassemia: imbalanced globin chain synthesis b. A decrease in the rate of production of a certain globin chain (α, β, γ, δ) impedes hemoglobin (Hb) synthesis and creates an imbalance with the other globin chain that normally produce globin chains. c. Consequences of impaired production of globin chains i. Result in less Hb deposit in each RBC, leading to hypochomasia ii. Deficiency in Hb causes RBCs to be smaller, leading to the classic hypochromic microcytic features of thalassemia.
The term thalassemia was first applied to the anemias encountered frequently in people of the Italian and Greek coasts and nearby islands. The term now refers to a group of inherited disorders of globin chain synthesis. Thalassemia comprises of a group of hemoglobinopathies, which are classified according to the specific globin chain (α or β) whose synthesis is impaired. Thus, α- and β-thalassemia are depression of synthesis of the respective chain.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Molecular defects a. α-thalassemia i. Synthesis of α-chains: directed by four α-genes, two on each chromosome 16 ii. α-thalassemia: resulting from a loss of α-gene(s) (one or more α-genes deleted) a) α-thalassemia-2 (α–/αα): resulting from deletion of one of the two α-globin genes b) α-thalassemia-1 (–/αα): resulting from deletion of both α-globin genes c) Hb H disease (–/–α ): resulting from deletion of three α-globin genes d) Hb Bart’s/hydrops fetalis (–/–): resulting from deletion of all four α-globin genes b. β-thalassemia i. Synthesis of β-chains: directed by a single β-gene on each chromosome 11 ii. Mutations in β-thalassemia a) In contrast to the α-thalassemias, most of the common β-thalassemia mutants are caused by point mutations rather than by gene deletion. b) Single base-pair mutations in the DNA alter processing of messenger RNA: most common c) Chain terminator defects d) Frame shift mutations e) Poly-adenylation mutations f) Promoter mutations iii. β°-thalassemia a) The mutations prevent β-globin chain synthesis entirely. b) Absent β-globin synthesis in β°-thalassemia homozygotes c) Accounts for about one-third of thalassemia patients iv. β+-thalassemia a) The mutations prevent β-chain synthesis partially. b) β-globin synthesis reduces to 5–30% of normal levels in β+-thalassemia homozygotes. v. β+/β°-thalassemia compound heterozygotes
CLINICAL FEATURES
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1. α-thalassemia a. Found in people of African descent, Indochina, Malaysia, and China b. Severity of resulting anemia depends on the number of functioning α-genes. i. α-thalassemia-2 or silent carrier α-thalassemia (α-/αα) (deficiency of only one globin-gene) a) 25% of African Americans b) 3.4% of Greek-Americans c) Slight microcytic red blood cells d) Borderline or minimal anemia ii. α-thalassemia-1 or α-thalassemia trait (–/αα) (deficiency of two globin-genes) a) 15–20% of Thai b) Mildly anemic c) Microcytic red blood cells d) Slight variation in red blood cell size e) Mild Splenomegaly f) Work capacity not impaired g) Same phenotypic effect in the individual homozygous for α-thalassemia-2 (α-/α-): This form is much more common in black populations iii. Hb H disease or α-thalassemia intermedia (–/-α) (deficiency of three globin-genes) a) 1% of Thai b) Significant hypochromic anemia in the neonatal period c) Microcytic anemia d) Reticulocytosis e) Jaundice f) Splenomegaly g) Hemolysis precipitated by infections or oxidant drugs (e.g., iron, sulfonamides) h) Needs occasional transfusions, splenectomy, or avoidance of precipitating drugs
THALASSEMIA
iv. Hb Bart’s/hydrops fetalis or α-thalassemia major (–/–) (deficiency of all four globin-genes) a) Most severe form of α-thalassemia b) Incompatible with life unless intrauterine blood transfusion is given because not enough functional hemoglobin is produced to sustain tissue oxygenation c) Profound oxygen deprivation in utero with resulting heart failure (hydrops fetalis) d) Stillborn or die soon after birth e) Edema with ascites due to heart failure f) Massive hepatosplenomegaly g) Severe erythroblastic anemia 2. β-thalassemia a. Found largely in people of African and Mediterranean descent, Far East, Middle East, and the Asian subcontinent b. Clinical features dependent on reduced (β+) or absent (β°) synthesis of β-globin i. β-thalassemia major (also known as Cooley’s anemia or homozygous β-thalassemia) a) Due to inheritance of two β-thalassemia alleles, one on each copy of chromosome 11 b) Generally recognized to be a homozygous state for whichever thalassemia gene is involved c) Clinically a severe disorder d) Infants born free of significant anemia, protected by prenatal Hb F production e) Onset: 6–12 months f) Diagnosis: evident by 2 years of age g) Manifestations in early childhood: anemia, pallor, growth retardation, tiredness, abdominal swelling due to hepatosplenomegaly, infection, and jaundice h) Manifestations in childhood and adult: severe anemia, infection, tiredness, growth retardation, distinctive facies, hepatosplenomegaly, cardiomegaly, abdominal pain, leg ulcers, osteoporosis, and iron overload i) At significant risk for developing overwhelming, often fatal infection after splenectomy (post-splenectomy syndrome) j) Severe anemia usually necessitating chronic blood transfusions k) Prognosis: average survival of children with untreated thalassemia major (<4 years) ii. β-thalassemia intermedia (compound heterozygotes) a) Due to inheritance of two β-thalassemia mutations (one mild and one severe or two mild mutations) or occasionally due to inheritance of complex combinations such as αβ-thalassemia b) Affected individuals: either compound heterozygotes for two different thalassemia genes or heterozygotes for a structural variant plus a thalassemia gene. Homozygotes for the milder β+-thalassemia also have thalassemia intermedia.
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c) Less severe clinical phenotype: cardiomegaly, osteoporosis, fractures, arthritis, and splenomegaly in some patients d) Significant anemia but usually do not require chronic blood transfusions iii. β-thalassemia minor (also known as β-thalassemia trait or heterozygous β-thalassemia) a) Due to presence of a single β-thalassemia mutation and a normal β-globin gene on the other chromosome b) Clinically asymptomatic but may have mild or minimal anemia iv. Silent carrier β-thalassemia a) No symptoms except for possible low RBC indices b) Mutation causing thalassemia is very mild and represents β+-thalassemia
DIAGNOSTIC INVESTIGATIONS 1. Screening tests for thalassemias a. Low MCV i. Increased Hb A2 and/or Hb F: indicate βthalassemia syndrome ii. Normal Hb A2 and Hb F, and ferritin >20 ng/ml: suggest possible α-thalassemia syndrome b. Normal MCV, normal electrophoresis: thalassemia syndrome unlikely 2. α-thalassemia: More difficult to diagnose because characteristic elevations in Hb A2 (α2δ2) or Hb F (α2γ2), seen in β-thalassemia, do not occur a. α-thalassemia-2 i. Laboratory notation: FA + Bart’s ii. Small amount of Hb Bart’s (1–2%) in affected infants at birth iii. Remainder of the hemoglobin: Hb F and Hb A (α2β2) iv. Hb F and Hb Bart’s: disappear after a few months of age v. Minimal microcytosis: remains b. α-thalassemia-1 i. Laboratory notation: FA + Bart’s (impossible to differentiate the two forms of α-thalassemia from the electrophoretic pattern) ii. Slightly larger amount of Hb Bart’s in cord blood (3–5%) iii. Hb F and Hb Bart’s: disappear after birth iv. Unequivocal microcytosis: Mean red cell volume of 65–70 fL/cell remains v. Abnormally low Hb A2 proportion c. Hb H disease i. Reduction in α-chain does not affect the production of β-chain which are produced in excess and tend to form tetramers (β4 or Hb H) ii. Hb A + Hb H (β4) + Hb Bart’s (γ4) iii. Presence of Heinz bodies: inclusions representing β-chain tetramers (Hb H), which are unstable and precipitate in the RBC, giving the appearance of a golf ball
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c. Hb Bart’s/hydrops fetalis i. Hypochromic macrocytes with nucleated red blood cells ii. γ4 (Bart hemoglobin): nonfunctional as an oxygen transporter 3. β-thalassemia a. β-thalassemia major i. Small, thin, and distorted red blood cells containing markedly reduced amounts of hemoglobin ii. Peripheral blood smear a) Severe microcytic hypochromic anemia (no anemia at birth) b) Anisocytosis c) Poikilocytosis (speculated tear-drop and elongated cells) d) Abundant nucleated red cells (i.e., erythroblasts) e) Occasional immature leukocytes iii. Hemolytic anemia iv. Hemoglobin profile: predominant Hb F v. In patient with homozygous βo-thalassemia: absent Hb A with normal amounts of Hb A2 vi. In newborn with β+-thalassemia: Hb F (about 90%) decreases with advancing age but always considerably higher than normal (10–90%) b. β-thalassemia intermedia i. Intermediate Hb concentration (8–10 gm/dL) ii. Microcytic hypochromic anemia iii. Hb F (5–99%) c. β-thalassemia minor i. Mild hypochromic microcytosis ii. Target cells iii. Mild to minimal anemia (hemoglobin concentration average 1–2 gm/dL below normal) iv. Elevation of Hb A2 and Hb F (70–99%) during early years of life v. Anemia worsen during pregnancy 4. Imaging studies a. Chest X-ray to evaluate cardiac size and shape b. Skeletal survey i. Skeletal response to marrow proliferation a) Expanding marrow space b) Thinning of cortical bone c) Resorption of cancellous bone d) Resulting in generalized loss of bone density e) Frequent small lucencies resulting from focal proliferation of marrow f) “Periosteal response” caused by perforation of the cortex by hypertrophic and hyperplastic marrow subperiosteally ii. Classic facies observed in thalassemia major a) Classic “hair on end” appearance of the skull b) Maxilla overgrowth resulting in maxillary overbite c) Prominent upper incisors d) Separation of the orbits iii. Various bone deformities seen in ribs, long bones, and flat bones iv. Premature fusion of the epiphyses c. MRI/CT scans to evaluate the amount of iron in the liver in patients on chelation therapy
GENETIC COUNSELING 1. Recurrence risk a. α-thalassemia i. Patterns of inheritance of the α-thalassemia when both parents are α-thalassemia-1 (–/αα) a) 25% normal b) 50% α-thalassemia-1 c) 25% Hb Bart’s (hydrops) ii. Patterns of inheritance of the α-thalassemia syndrome when one parent is α-thalassemia-1 (–/αα) and the other parent is α-thalassemia-2 (α-/αα) a) 25% normal b) 25% α-thalassemia-1 c) 25% α-thalassemia-2 d) 25% Hb H disease iii. Patient’s offspring: not increased unless the spouse is a carrier iv. 25% of African Americans have heterozygous αthalassemia-2 (α-/αα). Thus, 1.5 per cent are homozygotes for α-thalassemia-2 (α-/α-). But since the more severe α-thalassemia-1 is not present, subsequent children are not at risk of having Hb H or Bart’s/hydrops b. β-thalassemia i. Patient’s sib: 25% ii. Patient’s offspring: not increased unless the spouse is a carrier 2. Prenatal diagnosis: available to all families at risk of either severe α-thalassemia or β-thalassemia a. α-thalassemia i. Ultrasonography a) Hepatosplenomegaly (>90%) b) Cardiomegaly (>90%) c) Edematous placenta (90%) d) Ascites (>90%) e) Oligohydramnios (82%) f) Subcutaneous edema (75%) g) Decreased fetal movement (74%) h) Cord edema (63%) i) Enlarged umbilical vessel (62%) j) Pericardial or pleural effusion (15%) ii. Molecular hydridization technique to detect complete absence of α-genes in fetal amniocytes in a pregnancy at risk for homozygous α-thalassemia-1 and the hydrops fetalis syndrome iii. Quantitative polymerase chain reaction for the rapid prenatal diagnosis of homozygous αthalassemia (Hb Barts hydrops fetalis) b. β-thalassemia i. Available to couples who are carriers of βthalassemia and their hemoglobin gene mutations have been identified by DNA analysis ii. Direct DNA analysis by molecular hybridization methods for the presence of the thalassemia mutation from fetal cells obtained by amniocentesis and chorionic villus biopsy iii. DNA analysis of fetal nucleated RBCs from maternal peripheral blood iv. Approach to prenatal diagnosis complicated by presence of the heterogeneity of thalassemia mutations
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3. Management a. α-thalassemia i. No therapy necessary for patients with αthalassemia trait ii. Avoid exposure to oxidant medications (e.g., iron, sulfonamides) which accelerate precipitation of Hb H and exacerbate hemolysis iii. Prompt treatment of infection especially in postsplenectomy iv. Hb H disease a) Folate supplementation b) Chronic transfusion therapy (consider iron chelation therapy to avoid iron overloading) c) Splenectomy in rare instances of hypersplenism d) Allogeneic bone marrow transplantation limited to the most severely affected patients v. Bart hemoglobinopathy a) Usually result in neonatal death b) Patients rarely salvaged by intrauterine transfusions and subsequent stem cell transplantation b. β-thalassemia i. No specific therapy required for β-thalassemia trait ii. Regular blood transfusions iii. Iron chelation with Desferrioxamine to eliminate the iron overload secondary to multiple blood cell transfusions and to increase iron absorption iv. Bone marrow transplantation a) From an HLA-identical sib b) Outcome dependent on pretransplantation clinical conditions, specifically the presence of hepatomegaly, extent of liver fibrosis and magnitude of iron accumulation c) Risk of chronic graft-vs-host disease of variable severity: 5–8% v. Cord blood transplantation a) Human umbilical cord blood contains hematopoietic stem cells capable of reconstituting bone marrow. b) Possibility of using cord blood obtained from unrelated donors with a decrease in the incidence of graft-vs-host disease vi. Attempts to increase Hb F production by following agents: variable without substantial effects a) 5-azacytidine b) Erythropoietin c) Butyrate compounds d) Hydroxyurea
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vii. Hematopoietic stem cells to correct the molecular defect by transfer of a normal gene via a suitable vector or by homologous recombination: currently under investigation
REFERENCES Abramson SD: ‘Common’ uncommon anemias. Am Fam Physician 59:851– 858, 1999. Cao A, Galanello R: Beta-thalassemia. Gene Reviews. 2003. http://www. genetests.org Cao A, Rosatelli MC, Monni G, et al.: Screening for thalassemia: a model of success. Obstet Gynecol Clin 29:305–328, 2003. Carr S, Rubin L et al.: Intrauterine therapy for homozygous alpha-thalassemia. Obstet Gynecol 85:876, 1995. Chen H: Genetic testing & counseling for hemoglobinopathies. In Chen H (ed): Ohio Department of Health. The Resource Manual for hemoglobinopathies. An Essential Guide for Health Professionals. 1992, pp 97–107. Cheung M-C, Goldberg J, Kan Y: Prenatal diagnosis of sickle cell anaemia and thalassemia by analysis of fetal cells in maternal blood. Nature Genet 14:264, 1996. Dozy AM, Kan YW, Forman EN et al.: Antenatal diagnosis of homozygous & alpha thalassemia. JAMA 241:1610, 1979. Dumars KW, Boehm G, Eckman JR, et al.: Practical guide to the diagnosis of thalassemia. Am J Med Genet 62:29–37, 1996. Giardini C, Lucarelli G: Bone marrow transplantation for beta-thalassemia. Hematol Oncol Clin North Am 13:1059–1064, 1999. Irwin JJ: Anemia in children. Am Fam Physician 64:1379–1386, 2001. Kan YW, Schwartz E, Nathan DG: Globin chain synthesis in the alpha thalassemia syndrome. J Clin Invest 45:2515, 1968. Kan YW, Golbus MS, Klein P, et al.: Successful application of prenatal diagnosis in a pregnancy at risk for homozygous β-thalassemia. N Engl J Med 292:1096–1099, 1975. Kan YW, Lee KY, Furbetta M, et al.: Polymorphism of DNA sequence in the β-globin gene region: application to prenatal diagnosis of b-thalassemia in Sardinia. N Engl J Med 302:185–188, 1980. Kelly P, Kurtzberg J, Vichinsky E, et al.: Umbilical cord blood stem cells: application for the treatment of patients with hemoglobinopathies. J Pediatr 130:695–703, 1997. Lawson JP: Thalassemia. eMedicine. 2001. http://www.emedicine.com Locatelli F, Rocha V, Reed W, et al.: Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Blood 101:2137–2143, 2003. Lucarelli G, Giardini C, Baronciani D: Bone marrow transplantation in thalassemia. Semin Hematol 32:297–303, 1995. Rucknagel DL: Microcytosis and the thalassemias. In Chen H (ed): Ohio Department of Health. The Resource Manual for hemoglobinopathies. An Essential Guide for Health Professionals. 1992, pp 15–18. Sackey K: Hemolytic anemia: Part 2. Pediatr Rev 20:204–208, 1999. Schwartz E, Benz EJ Jr: The thalassemia syndromes. In Hoffman R, Benz EJ Jr, Shattil SJ, et al. (eds): Hematology. Basic Principles and Practice. New York: Churchill Livingstone, pp 368–392. Segel GB, Hirsh MG, Feig SA: Managing anemia in pediatric office practice: Part 1. Pediatr Rev 23:75–84, 2002. Tongson T, Wanapirak C, Srisomboon J, et al.: Antenatal sonographic features of 100 alpha-thalassemia hydrops fetalis fetuses. J Clin Ultrasound 24:73–77, 1998. Yaish HM: Thalassemia. eMedicine. 2001. http://www.emedicine.com
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Fig. 1. Peripheral blood smear from a 58-year-old woman with microcytic anemia and frequent target cells (codocytes). Hemoglobin electrophoresis showed an AA pattern with an increased hemoglobin A2 (5.8% by HPLC) consistent with β+-thalassemia trait.
Fig. 2. Peripheral blood smear from a patient with alpha thalassemia minor shows hypochromia, target cells (arrows), and anisopoikilocytosis (Wright Giemsa stain, ×1000).
Thanatophoric Dysplasia Thanatophoric dysplasia was originally described by Maroteaux et al. in 1967. The term “thanatophoric” was coined to mean “death bearing” in Greek. Thanatophoric dysplasia is probably the most common lethal neonatal dwarfism with an estimated incidence of 0.2–0.5 per 10,000 births.
GENETICS/BASIC DEFECTS 1. Genetic heterogeneity a. Sporadic in most cases b. A new autosomal dominant mutation c. Caused by mutations in the transmembrane domains of the fibroblast growth factor receptor 3 (FGFR3) 2. Having the most extreme micromelia and the most extensive craniofacial involvement, compared to two other short limb skeletal dysplasias (achondroplasia and hypochondroplasia) which are also caused by mutations of FGFR3 3. Pathogenesis for the phenotypic features of thanatophoric dysplasia a. Normal function of FGFR3: to regulate endochondral ossification by “putting the brakes on growth” b. “Gain-of-function” type of known mutations on FGFR3 i. Primarily affect the cranial base and nasal capsule (endochondral bones) ii. With secondary effect on membrane bones which articulates with endochondral bones 4. Two major forms (TD1, TD2) of thanatophoric dysplasia, postulated based on subtle differences in skeletal radiographs and the underlying genetic mutation a. TD1 i. Curved femora ii. Very flat vertebral bodies iii. Very few TD1 patients with cloverleaf skull iv. Molecular defect consisting of a stop codon mutation or missense mutation in the extracellular domain of the FGFR3 protein, resulting in a newly created cysteine residue (Arg248Cys, most common) b. TD2 i. Straight femora ii. Taller vertebral bodies iii. Most TD2 patients with cloverleaf skull (severe craniosynostosis) iv. Molecular defect consisting of a single nucleotide substitution resulting in replacement of lysine with glutamine at position 650 (Lys650Glu) in the tyrosine kinase 2 domain of the receptor
CLINICAL FEATURES 1. Unique and homogeneous clinical features observed in patients with TD1 955
2. General features a. Virtually lethal neonatally b. A few reports with survival up to 4–5 years of age with aggressive neonatal intervention i. Markedly limited growth potential ii. Markedly delayed cognitive development iii. Respiratory insufficiency iv. Neurologic abnormalities v. Long-term medical care and chronic ventilator dependence 3. Craniofacial features a. Head i. Disproportionally large (macrocephaly) ii. Frontal bossing iii. With or without cloverleaf (Kleeblattschdel) anomaly of the skull resulting from premature closure of cranial sutures b. Facial features i. Bulging eyes ii. Hypertelorism iii. Severely depressed or indented nasal bridge 4. Short neck 5. Chest a. Extremely narrow b. Constricted thoracic cage c. Reduced size of the thoracic cavity d. Short ribs e. Hypoplastic lungs 6. Protuberant abdomen 7. Limbs a. Extremely short b. Thickened skin c. Excessive skin folds d. Usually outstretched arms e. Externally rotated legs with abducted thighs f. Syndactyly 8. Early death in most children secondary to: a. Chest constriction and consequent respiratory insufficiency b. Foramen magnum stenosis resulting in failure of respiratory control 9. A few children with longer survival (up to 9–10 years) a. Respiratory insufficiency i. Reduced chest circumference ii. Upper cervical cord compression resulting from a diminutive foramen magnum b. Markedly limited growth potential c. Markedly delayed cognitive development d. Seizures e. Hearing loss f. Additional CNS anomalies i. Hydrocephalus ii. Polymicrogyria
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iii. Neuronal heterotopia iv. Megalencephaly v. Cerebral Gyral disorganization vi. Hippocampal malformation vii. Temporal lobe malformations viii. Nuclear dysplasia ix. Abnormal axonal bundles x. Cerebellar hypoplasia in the small posterior fossa xi. Partial agenesis of the corpus callosum xii. Spinal stenosis xiii. Hyperreflexia xiv. Clonus g. Acanthosis nigricans, an associated rare skin disorder 10. Differential diagnosis a. Achondroplasia i. Autosomal dominant disorder ii. Rhizomelic shortening of the bones, less prominent than thanatophoric dysplasia iii. Macrocrania iv. Heterozygous achondroplasia a) Compatible with normal life span b) Normal intelligence v. Homozygous achondroplasia with two affected parents b. Campomelic dysplasia i. Autosomal recessive disorder ii. Typical anterior bowing of the lower limbs iii. Hypoplastic fibula iv. Hypoplastic scapulae v. A sex reversal phenomenon (phenotypical female with male karyotype) c. Osteogenesis imperfecta type II and type III i. Varying degree of bone demineralization ii. Shortened long bones with multiple fractures iii. Blue sclerae iv. Polyhydramnios frequently associated with type II d. Hypophosphatasia i. Demineralization of bone tissue ii. Lack of calcification of the fetal skull iii. Mild to moderate shortening of limb bones iv. Difficult to differentiate from osteogenesis imperfecta if fractures are present e. Achondrogenesis i. Severe Micromelia ii. Poor ossification of the vertebral bodies, cranium, pelvis and sacrum iii. Narrow and shortened thorax iv. Frequent complications with fetal hydrops and hydramnios f. Short rib-polydactyly and other rare skeletal dysplasia syndromes
DIAGNOSTIC INVESTIGATIONS 1. Radiographic features a. Skull i. Relatively large calvarium ii. A small foramen magnum iii. Trilobed skull with a towering calvarium and bitemporal bulging in the cloverleaf skull type (type 2)
b. Ribs i. Very short ribs with cupped anterior ends ii. Short ribs (type 2) c. Vertebrae i. Flat vertebral bodies (platyspondyly) ii. Increasing interverteral disc space iii. “Inverted U-shaped or H-shaped” vertebral bodies iv. Narrow interpedunculate distance at the lumbar level v. Taller vertebral bodies (type 2) d. Pelvis i. Short ii. Small sacrosciatic notches e. Tubular bones i. Extremely shortened long bones of the limbs ii. Rhizomelic shortening of the limbs iii. Flared metaphyses iv. “Telephone-receiver”-like curved femora in the noncloverleaf type v. Relatively straight femora (type 2) 2. Histologic features a. Generalized disruption of endochondral ossification i. Hallmark of the histologic findings ii. Physeal growth zone shows minimal proliferation and hypertrophy of chondrocytes with absence of column formation. iii. Lateral overgrowth of metaphyseal bone around the physis iv. Mesenchymal cells extending inward from the perichondrium as a narrow band at the periphery of the physeal zone (the so-called fibrous band) v. Increased vascularity of the resting cartilage b. Brain i. Neuronal migration abnormalities of the temporal lobe ii. Hydrocephalus iii. Partial agenesis of the corpus callosum iv. Upper cord compression v. Spinal stenosis 3. DNA mutation analysis of FGFR3 a. TD1 i. 742C→T (Arg248Cys): most common ii. Tyr373Cys iii. Ser249Cys iv. Other missense mutations v. Stop-codon mutations b. TD2: missense mutation of 1948A→G (Lys650Glu) in TD2
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: about 2% b. Patient’s offspring: not surviving to reproduction 2. Prenatal diagnosis a. Ultrasonography i. Hydramnios in most cases ii. Megacephaly with or without cloverleaf-shaped skull iii. Progressive hydrocephaly
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iv. Hypoplastic thorax disproportionately small in relation to the abdomen v. Small chest and lung measurement to predict severe pulmonary hypoplasia vi. Short ribs vii. Short limbs with curved “telephone handleshaped” or straight femurs viii. Excessive skin giving fetus a “boxer’s face” appearance ix. Flattened vertebrae with increased intervertebral spaces, giving the vertebral bodies the form of an “H” b. Prenatal radiography for documenting characteristic skeletal anomalies c. DNA mutation analysis of FGFR3 in fetal cells from amniocentesis or CVS 3. Management a. Limited intervention i. Appropriate because of the inevitable lethal outcome ii. Aggressive neonatal management, at times, not even resulting in short-term survival b. Debatable issues about the level of intensity of medical care for unanticipated long-term survival i. Long-term medical care ii. Chronic ventilator support iii. Requiring extensive health maintenance measures iv. Anticipate frequent medical exacerbations requiring recurrent hospitalizations v. Possibility of lethal complication, an ever present concern vi. Special education programs for the longer survivals
REFERENCES Baker KM, Olson DS, Harding CO, et al.: Long-term survival in typical thanatophoric dysplasia type 1. Am J Med Genet 70:427–436, 1997. Bonaventure J, Rousseau F, Legeai-Mallet L, et al.: Common mutations in the gene encoding fibroblast growth factor receptor 3 account for achondroplasia, hypochondroplasia and thanatophoric dysplasia. Acta Paediatr Suppl 417:33–38, 1996. Bonaventure J, Rousseau F, Legeai-Mallet L, et al.: Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism. Am J Med Genet 63:148–154, 1996. Chen CP, Chern SR, Shih JC, et al.: Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia. Prenat Diagn 21:89–95, 2001. Chen CP, Chern SR, Chang TY, et al.: Second trimester molecular diagnosis of a stop codon FGFR3 mutation in a type I thanatophoric dysplasia fetus following abnormal ultrasound findings. Prenat Diagn 22:736–737, 2002. Cohen MM, Jr: Achondroplasia, hypochondroplasia and thanatophoric dysplasia: clinically related skeletal dysplasias that are also related at the molecular level. Int J Oral Maxillofac Surg 27:451–455, 1998. Coulter CL, Leech RW, Brumback RA, et al.: Cerebral abnormalities in thanatophoric dysplasia. Childs Nerv Syst 7:21–26, 1991. De Biasio P, Prefumo F, Baffico M, et al.: Sonographic and molecular diagnosis of thanatophoric dysplasia type I at 18 weeks of gestation. Prenat Diagn 20:835–837, 2000.
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Horton WA, Hood OJ, Machado MA, et al.: Abnormal ossification in thanatophoric dysplasia. Bone 9:53–61, 1988. International Working Group on Constitutional Diseases of Bone. International nomenclature and classification of the osteochondrodysplasias (1997). Am J Med Genet 79:376–382, 1998. Isaacson G, Blakemore KJ, Chervenak FA: Thanatophoric dysplasia with cloverleaf skull. Am J Dis Child 137:896–898, 1983. Langer LO, Jr, Yang SS, Hall JG, et al.: Thanatophoric dysplasia and cloverleaf skull. Am J Med Genet Suppl 3:167–179, 1987. Lemyre E, Azouz EM, Teebi AS, et al.: Bone dysplasia series. Achondroplasia, hypochondroplasia and thanatophoric dysplasia: review and update. Can Assoc Radiol J 50:185–197, 1999. Machado LE, Bonilla-Musoles F, Osborne Nat Genet: Thanatophoric dysplasia. Ultrasound Obstet Gynecol 18:85–86, 2001. MacDonald IM, Hunter AG, MacLeod PM, et al.: Growth and development in thanatophoric dysplasia. Am J Med Genet 33:508–512, 1989. Maroteaux P, Lamy M, Robert J-M: Le nanisme thanatophore. Presse Med 49:2519–2524, 1967. Martinez-Frias ML, Ramos-Arroyo MA, Salvador J: Thanatophoric dysplasia: an autosomal dominant condition? Am J Med Genet 31:815– 820, 1988. Nerlich AG, Freisinger P, Bonaventure J: Radiological and histological variants of thanatophoric dysplasia are associated with common mutations in FGFR-3. Am J Med Genet 63:155–160, 1996. Norman AM, Rimmer S, Landy S, et al.: Thanatophoric dysplasia of the straight-bone type (type 2). Clin Dysmorphol 1:115–120, 1992. Orioli IM, Castilla EE, Barbosa Neto JG: The birth prevalence rates for the skeletal dysplasias. J Med Genet 23:328–332, 1986. Partington MW, Gonzales-Crussi F, Khakee SG, et al.: Cloverleaf skull and thanatophoric dwarfism. Report of four cases, two in the same sibship. Arch Dis Child 46:656–664, 1971. Passos-Bueno MR, Wilcox WR, Jabs EW, et al.: Clinical spectrum of fibroblast growth factor receptor mutations. Hum Mutat 14:115–125, 1999. Rousseau F, Saugier P, Le Merrer M, et al.: Stop codon FGFR3 mutations in thanatophoric dwarfism type 1. Nature Genet 10:11–12, 1995. Rousseau F, el Ghouzzi V, Delezoide AL, et al.: Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type 1 (TD1). Hum Mol Genet 5:59–512, 1996. Schild RL, Hunt GH, Moore J, et al.: Antenatal sonographic diagnosis of thanatophoric dysplasia: a report of three cases and a review of the literature with special emphasis on the differential diagnosis. Ultrasound Obstet Gynecol 8:62–67, 1996. Spranger J, Maroteaux P: The lethal osteochondrodysplasias. Adv Hum Genet 19:1–103, 1990. Stensvold K, Ek J, Hovland AR: An infant with thanatophoric dysplasia surviving 169 days. Clin Genet 29:157–159, 1986. Tavormina PL, Shiang R, Thompson LM, et al.: Thanatophoric dysplasia (types 1 and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet 9:321–328, 1995. Tonoki H: A boy with thanatophoric dysplasia surviving 212 days. Clin Genet 32:415–416, 1987. Vajo Z, Francomano CA, Wilkin DJ: The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocrine Rev 21:23–29, 2000. Weber M, Johannisson T, Thomsen M, et al.: Thanatophoric dysplasia type I: new radiologic, morphologic, and histologic aspects toward the exact definition of the disorder. J Pediatr Orthop B 7:1–9, 1998. Wilcox WR, Tavormina PL, Krakow D, et al.: Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasia. Am J Med Genet 78:274–281, 1998. Wongmongkolrit T, Bush M, Roessmann U: Neuropathological findings in thanatophoric dysplasia. Arch Pathol Lab Med 107:132–135, 1983. Yang SS, Heidelberger KP, Brough AJ, et al.: Lethal short-limbed chondrodysplasia in early infancy. Perspect Pediatr Pathol 3:1–40, 1976.
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Fig. 1. Front views of 3 infants showing frontal bossing, flat facies, short neck, micromelia, and small chest.
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Fig. 3. Lateral radiographic views of the spines in two infants with typical TD1 showing extreme platyspondyly and short ribs.
Fig. 2. AP radiographic views of three infants with typical findings of TD1 showing profound platyspondyly, decreased thoracic volume, characteristic pelvic configuration, micromelia, and so-called “telephone receiver” femoral bowing.
Fig. 4. Gross appearance of a femur resembling “telephone-receiver”.
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Fig. 5. Prenatal radiographs of two fetuses affected with thanatophoric dysplasia showing platyspondyly, short ribs, and micromelia.
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Fig. 6. Thanatophoric dysplasia in identical twin fetuses. The pregnancy was terminated following ultrasonographic diagnosis at 22 weeks gestation. The placenta was diamniotic monochorionic, consistent with monozygotic pregnancy. Fig. 8. Photomicrograph of the cartilage-bone junction, cloverleaf skull type of thanatophoric dysplasia. The physeal growth zone is markedly retarded and disorganized. Similar changes are seen in the classic type thanatophoric dysplasia. A partially ossified cartilage canal is present at the center of physis. It is more prominent in size and number in cloverleaf type than in classic type.
Fig. 7. Thanatophoric dysplasia with cloverleaf skull in a neonate. The head is large and trilobed. The narrow chest and rhizomelic shortening of limbs are similar to those of classic thanatophoric dysplasia. Radiograph revealed platyspondyly and small ilium that are similar to those of classic thanatophoric dysplasia (not shown). However, the femur is straight and not as curved as seen in the classic type.
Thrombocytopenia-Absent Radius Syndrome Thrombocytopenia-absent radius (TAR) syndrome is a congenital malformation syndrome characterized by bilateral absence of the radii and congenital thrombocytopenia.
GENETICS/BASIC DEFECTS 1. Genetic inheritance: autosomal recessive inheritance, based on the following observations a. Families with at least two affected children born to unaffected parents b. Rare instances of association with consanguinity 2. Etiology of thrombocytopenia: unknown but is considered to be the result of a decreased production of platelets from the bone marrow 3.
CLINICAL FEATURES 1. Thrombocytopenia (100%) a. May be transient b. Symptomatic in over 90% of cases within the first four months of life i. Purpura ii. Petechiae iii. Epistaxis iv. Gastrointestinal bleeding a) Hematemesis b) Melena v. Hemoptysis vi. Hematuria vii. Intracerebral bleeding c. More severe thrombocytopenia can be precipitated by stress, infection, gastrointestinal disturbances, or surgery d. Platelet count tends to rise as the child gets older and may approach normal levels in adulthood (spontaneous improvement of platelet counts after one year) 2. Upper extremity anomalies (100%) a. Bilateral absence of the radius (100%): the most striking skeletal manifestation b. Hand anomalies i. Presence of the thumbs (100%) a) An important clinical feature distinguishing TAR syndrome from other disorders featuring radial aplasia, which are usually associated with absent thumbs b) Relatively functional thumbs c) Thumbs often adducted d) Thumbs often hypoplastic ii. Radially deviated iii. Limited extension of the fingers iv. Hypoplasia of the carpal and phalangeal bones c. Associated ulnar anomalies i. Usually short ii. Usually malformed 962
4.
5.
6.
7.
iii. Absent ulna a) Absent bilaterally in about 20% of cases b) Absent unilaterally in about 10% of cases d. Associated humeral anomalies i. Often abnormal in about 50% of cases ii. Absent humeri in about 5–10% of cases (rare phocomelia) e. Associated shoulder and arm anomalies i. One arm shorter than the other in about 15% of cases ii. Hypoplasia of muscles and soft tissue in the arm and shoulder iii. Abnormal shoulder joint secondary to abnormal humeral head Lower limb anomalies (47%) a. Correlation exists between the severity of skeletal changes in the lower limbs and the severity of abnormalities of the upper limbs b. Variable involvement but usually milder than the upper limbs i. Dislocation of the patella and/or of the hips ii. Knee involvement a) Dysplasia: rare severe knee dysplasia due to agenesis of cruciate ligaments and menisci b) Ankylosis c) Subluxation iii. Hip dislocation iv. Coxa valga v. Absent tibiofibular joint vi. Femoral or tibial torsion vii. Lower limb phocomelia viii. Valgus and varus foot deformities ix. Abnormal toe placement x. Severe cases with lower limb phocomelia Cow’s milk intolerance (62%) a. Presentation symptoms i. Persistent diarrhea ii. Failure to thrive b. Thrombocytopenia episodes i. Precipitated by introduction of cow’s milk ii. Relieved by its exclusion from the diet Urogenital anomalies (23%) a. Horseshoe kidney b. Absent uterus Cardiac anomalies (22–33%) a. Tetralogy of Fallot b. Atrial septal defect c. Ventricular septal defect Other associated congenital anomalies a. Facial capillary haemangiomata in the glabella region b. Micrognathia c. Cleft palate d. Intracranial vascular malformation
THROMBOCYTOPENIA-ABSENT RADIUS SYNDROME
e. Sensorineural hearing loss f. Epilepsy g. Other skeletal anomalies i. Scoliosis ii. Cervical rib iii. Fused cervical spine iv. Short stature h. Neural tube defect 8. Prognosis a. Variable clinical course among patients b. Survival related to the severity and duration of thrombocytopenia c. Good prognosis after surviving the first year of life d. Early diagnosis and treatment with platelet therapy minimize mortality risks e. Mental retardation secondary to intracranial bleed (7%) f. Good hand and upper extremity functions, especially if bilateral radial aplasia is the only skeletal abnormality 9. Differential diagnosis a. Holt-Oram syndrome i. An autosomal dominant condition caused by mutations in the TBX5 gene ii. Often with a family history of heart and limb defects iii. Absence of the thumb associated with radial aplasia iv. Absence of thrombocytopenia b. Roberts syndrome i. An autosomal recessive trait ii. Pre- and postnatal growth retardation iii. Facial clefting iv. Genitourinary abnormalities v. Limb defects involving upper or lower limbs or both vi. Characteristic chromosome abnormality in the majority (79%) of cases a) Premature centromeric separation (PCS) b) “Puffing” of the chromosomes caused by repulsion of the heterochromatic regions near the centromeres of chromosomes 1, 9, and 16 with splaying of the short arms of the acrocentric chromosomes and of distal Yp.33 c) Evidence of abnormal mitosis vii. Postulated that TAR syndrome and Roberts syndrome might be part of the same condition with TAR syndrome being the milder and Roberts the severer variants c. Fanconi anemia i. An autosomal recessive disorder ii. Bone marrow failure iii. Skeletal defects iv. Cutaneous pigmentation v. Microcephaly vi. Short stature vii. May present with thrombocytopenia viii. Upper limb abnormalities also involve the radial ray ix. Hypoplastic thumbs may be accompanied by radial hypoplasia but absence of the radius is associated with absence of the thumbs
d.
e.
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g.
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x. Spontaneous chromosome breakage, a consistent feature of Fanconi anemia and is a reliable diagnostic test Aase syndrome i. Radial hypoplasia ii. Triphalangeal thumbs iii. Hypoplastic anemia, similar to Blackfan-Diamond syndrome iv. Thrombocytopenia not a feature Thalidomide embryopathy i. May present with radial anomalies of the upper limb ii. Malformations of the lower limbs showing a less consistent pattern iii. Diagnosed based on: a) Phenotype b) History of exposure to thalidomide during pregnancy c) Increasing use of thalidomide as a therapeutic agent for the treatment of conditions such as Beçhet’s disease, graft vs host disease, multiple myeloma, and Kaposi’s sarcoma Rapadilino syndrome i. Absent thumbs and radial aplasia/hypoplasia ii. Patellar aplasia/hypoplasia iii. Cleft palate Other syndromes with limb reduction abnormalities predominantly involving the upper extremities i. Adams-Oliver syndrome a) Transverse limb defects b) Aplasia cutis congenita c) Growth deficiency ii. Aglossia-adactylia a) Absence/hypoplasia of digits b) Absence/hypoplasia of the tongue iii. Amniotic band sequence a) Limb constriction or amputation b) Asymmetric facial clefts c) Cranial defects d) Compression deformities iv. CHILD syndrome a) Unilateral hypomelia b) Ichthyosiform erythroderma c) Cardiac septal defect v. Cornelia de Lange syndrome a) Micromelia b) Growth deficiency c) Facial dysmorphism vi. Femur-fibula-ulnar syndrome a) Femoral/fibular defects associated with malformations of the arms b) Amelia c) Peromelia at the lower end of the humerus d) Humeroradial synostosis e) Defects of the ulna and ulnar rays vii. Poland anomaly a) Unilateral defect of pectoralis major muscle b) Ipsilateral limb abnormalities viii. VATER association (vertebral, anal, tracheoesophageal, renal and radial anomalies)
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ix. Weyers ulnar ray/oligodactyly syndrome a) Deficient ulnar and fibular rays b) Oligodactyly c) Hydronephrosis h. Megakaryocytic aplasia i. Amegakaryocytic thrombocytopenia ii. Congenital hypoplastic thrombocytopenia with microcephaly iii. Thrombocytopenia associated with trisomy 13 and trisomy 18
DIAGNOSTIC INVESTIGATIONS 1. Hematological studies a. Blood platelet counts: thrombocytopenia b. Anemia secondary to bleeding c. Eosinophilia d. Leukemoid reaction i. Reported in about 60–70% of patients during the first year of life ii. White blood counts >35,000 per mm3 with a shift to the left, particularly with the stress and infections iii. Usually associated with worse thrombocytopenia and often with hepatosplenomegaly e. Bone marrow aspirates i. Normal or hypercellular bone marrow ii. Hypomegakaryocytic thromobocytopenia (<100,000 platelets per mm3) a) Absence of megakaryocytes in two thirds of cases b) Decreased in number of megakaryocytes, which are small, immature, basophilic, and vacuolated, in the rest of cases 2. Chromosome analysis: normal to differentiate from chromosome abnormality syndrome 3. Radiography a. Upper extremities i. Bilateral radial aplasia ii. Radial club hand iii. Hypoplastic carpals and phalanges iv. Thumb and fingers always present v. Hypoplastic ulnae, humeri, and shoulder girdles vi. Syndactyly and clinodactyly of fingers and toes b. Lower extremities i. Hip dislocation ii. Femoral torsion iii. Tibial torsion iv. Knee dysplasia v. Absent patella vi. Valgus and varus foot deformities vii. Abnormal toe placement viii. Overriding toes
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased unless the spouse is a carrier
2. Prenatal diagnosis: reported mostly in pregnancies with a prior affected sibling a. Ultrasonography i. Bilateral radial aplasia ii. Club hands with normal thumbs and metacarpals b. Cordocentesis to evaluate fetal platelet count (thrombocytopenia) and anemia 3. Management a. Platelet infusions i. Remains the only real option for treatment of thrombocytopenia ii. To prevent the intracerebral hemorrhage, which was previously the main cause of mortality iii. Potential risks of platelet transfusion a) Infection (hepatitis viruses, HIV) b) Anaphylaxis c) Hemolytic reaction b. Injury prevention strategies i. Avoid contact sports ii. Use appropriate protective gear (helmet, padding) c. Splenectomy usually effective for the treatment of thrombocytopenia in adults d. Bone marrow transplantation as an option for patients who continue to remain thrombocytopenic with bleeding despite platelet transfusions e. Physical and occupational therapies to improve function and quality of life f. Management of the upper extremity i. Postpone surgery till later as thrombocytopenic related bleeding problems are less frequent in older individuals ii. Prosthetic fitting is generally rejected by patients as most patients are able to perform tasks by approximating themselves closely enough to an object to use their own hands. iii. Adaptive devices for feeding, dressing, and toileting are generally well tolerated. g. Management of the lower extremity i. Rejection of any lower extremity intervention by most patients ii. Use of power wheelchair or motorized cart for ambulation
REFERENCES Christensen CP, Ferguson RL: Lower extremity deformities associated with thrombocytopenia and absent radius syndrome. Clin Orthop 202–206, 2000. Dell PC, Sheppard JE: Thrombocytopenia, absent radius syndrome: report of two siblings and a review of the hematologic and genetic features. Clin Orthop 129–134, 1982. Donnenfeld AE: Prenatal diagnosis of thrombocytopenia in TAR syndrome. Prenat Diagn 14:73–74, 1994. Donnenfeld AE, Wiseman B, Lavi E, et al.: Prenatal diagnosis of thrombocytopenia absent radius syndrome by ultrasound and cordocentesis. Prenat Diagn 10:29–35, 1990. Dreyfus M, Tchernia G: Thrombocytopenia with absent radii (TAR syndrome): new advances in the mechanism of thrombocytopenia. Pediatr Hematol Oncol 17:521–522, 2000. Fayen WT, Harris JW: Thrombocytopenia with absent radii (the TAR syndrome). Am J Med Sci 280:95–99, 1980.
THROMBOCYTOPENIA-ABSENT RADIUS SYNDROME Freeman MH: Congenital failure of hematopoiesis in the newborn period. Clin Perinatol 11:417–431, 1984. Greenhalgh KL, Howell RT, Bottani A, et al.: Thrombocytopenia-absent radius syndrome: a clinical genetic study. J Med Genet 39:876–881, 2002. Hall JG: Thrombocytopenia with absent radius. Arch Dis Child 52:83, 1977. Hall JG: Thrombocytopenia and absent radius (TAR) syndrome. J Med Genet 24:79–83, 1987. Hall JG, Levin J, Kuhn JP, et al.: Thrombocytopenia with absent radius (TAR). Medicine (Baltimore) 48:411–439, 1969. Hedberg VA, Lipton JM: Thrombocytopenia absent radii. A review of 100 cases. Am J Pediatr Hematol/Oncol 10:51–64, 1988.
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McLaurin TM, Bukrey CD, Lovett RJ, et al.: Management of thrombocytopenia-absent radius (TAR) syndrome. J Pediatr Orthop 19:289–296, 1999. Ray R, Zorn E, Kelly T, et al.: Lower limb anomalies in the thrombocytopenia absent-radius (TAR) syndrome. Am J Med Genet 7:523–528, 1980. Tongsong T, Sirichotiyakul S, Chanprapaph P: Prenatal diagnosis of thrombocytopenia-absent-radius (TAR) syndrome. Ultrasound Obstet Gynecol 15:256–258, 2000. Whitfield MF, Barr DG: Cows’ milk allergy in the syndrome of thrombocytopenia with absent radius. Arch Dis Child 51:337–343, 1976. Wu JK, Williams S: Thrombocytopenia-absent radius syndrome. E medicine J. www.emedicine.com
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1
Fig. 1. A 2 ⁄2 year-old girl with TAR syndrome showing club hands with finger-like thumbs and radial aplasia, illustrated by radiographs. The patient had thrombocytopenia early in life.
Fig. 2. A 14-year-old boy with TAR syndrome showing similar clinical and radiographic features.
Treacher-Collins Syndrome Treacher-Collins syndrome (TCS), also called Treacher Collins-Franceschetti Syndrome or mandibulofacial dysostosis, is an autosomal dominant disorder affecting the development of structures derived from the first and second branchial arches during early embryonic development. The incidence is estimated to be 1 in 50,000 live births.
GENETICS/BASIC DEFECTS 1. Inheritance a. An autosomal dominant disorder i. Rare incomplete penetrance ii. Wide variability b. 40% of cases have a previous family history c. 60% of cases possibly arise from de novo mutations of TCOF1 2. The TCS gene (TCOF1) a. The only gene currently known to be associated with TCS b. Mapped to chromosome 5q31.3-q33.3 c. Encoding a serine/alanine-rich protein, called “treacle” d. A complete coding sequence of the Treacher CollinsFranceschetti Syndrome 1 gene (TCOF1) has been identified. e. Mutations in the TCOF1 gene i. Type of mutations a) Deletions b) Insertions c) Missense mutations ii. Two mutations affecting splicing of the primary transcript are located in: a) Introns 3 (304+5 G→C) b) Introns 22 (3550+1 G→A) iii. Most mutations result in a premature termination codon, producing a truncated protein devoid of the nuclear localization signals (NLSs). 3. Basic defect a. Probably caused by adverse effects of truncated treacle occurring exclusively during development in the affected structures b. The observation that these mutations are spread throughout the gene indicates that the mechanism underlying the disorder is haploinsufficiency.
CLINICAL FEATURES 1. Interfamilial and intrafamilial variability 2. Eyes a. Antimongoloid slant of the palpebral fissures b. Colobomata and hypoplasia of the lower lids and lateral canthi c. Partial absence of eyelid cilia d. Hypertelorism 967
3. Ears a. External ear anomalies i. Symmetric ii. Normal iii. Absent iv. Malformed v. Malposed b. External auditory canal abnormalities i. Symmetric (88%) ii. Atretic (54%) iii. Stenotic (31%) iv. Normal (15%) c. Middle ear cavity ossicular deformities i. Symmetric (96%) ii. Hypoplastic (85%) d. Conductive hearing loss results from variable degrees of hypoplasia of the external auditory canals and ossicles of the middle ears 4. Nose/mouth a. Respiratory compromise in severely affected patients as a result of the following two factors: i. Presence of maxillary hypoplasia, which tends to constrict the nasal passages and results in a degree of choanal stenosis or atresia ii. Presence of mandibular micrognathia and a retropositioned tongue obstructing the oropharyngeal and hypopharyngeal spaces b. Nasal deformity c. Macrostomia d. Cleft palate with or without cleft lip e. High-arched palate f. Malocclusion g. Open bite 5. Facial bone malformations: the most characteristic findings a. Hypoplasia of the malar bones i. Often with clefting through the arches ii. Limited formation of the residual zygomatic complex b. Orbits i. Hypoplastic lateral aspects of the orbits ii. Dysplastic inferior-lateral orbits c. Maxilla and mandible i. Characteristically hypoplastic (malar hypoplasia) ii. Variable effects on the temporomandibular joints and the muscles of mastication iii. Anterior open bite malocclusion iv. A steep (clockwise-rotated) occlusal plane 6. Sleep apnea and sudden infant death syndrome 7. Differential diagnosis a. Nager acrofacial dysostosis i. Features similar to those of TCS a) Zygomatic hypoplasia b) Downward slanting of the palpebral fissures
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c) Micrognathia d) Anomalies of the external ears e) Cleft palate ii. Limb defects (not observed in TCS) a) Often asymmetrical b) Preaxial limb defects c) Hypoplastic or absent thumbs d) Radial hypoplasia or aplasia e) Radioulnar synostosis b. Miller acrofacial dysostosis i. Facial features similar to TCS and Nager syndrome ii. Limb defects a) Postaxial limb defects b) Most commonly with absence or incomplete development of the 5th digital ray of all four limbs c. Oculoauriculovertebral (OAV) spectrum i. OAV spectrum a) Sporadic occurrence in vast majority of cases b) 1–2% of cases with a previous family history c) Includes hemifacial microsomia and Goldenhar syndrome ii. Hemifacial microsomia a) Primarily affecting development of the ear, mouth, and mandible b) Wide variable expression c) Affecting primarily only one side of the face iii. Goldenhar syndrome a) Facial involvement b) Vertebral anomalies c) Epibulbar dermoids
DIAGNOSTIC INVESTIGATIONS 1. Radiography and CT for evaluation of craniofacial abnormalities 2. Audiological evaluation for hearing impairment 3. DNA diagnosis: Direct sequencing of the coding and flanking intronic regions of TCOF1 detects mutations in about 90–95% of patients.
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: low unless a parent is affected b. Patient’s offspring: 50% 2. Prenatal diagnosis available for pregnancies at increased risk for TCS a. 2-dimensional and preferably 3-dimensional sonography i. Polyhydramnios ii. Demonstration of characteristic facies of TCS a) Downward slanting palpebral fissures b) Micrognathia c) Abnormal appearance of the nose with narrow nostrils d) Cleft lip/palate e) Low-set dysplastic ears f) Abnormal fetal swallowing b. Amniocentesis or CVS i. To detect TCOF1 mutation
ii. The disease-causing allele of an affected individual must be identified before prenatal testing can be performed. iii. The presence of a TCOF1 mutation detected by prenatal diagnosis does not predict the specific malformations or severity of the disease. 3. Management a. Severe case i. Secure airway by tracheostomy if necessary ii. A gastrostomy for feeding b. To promote normal language development i. Cleft palate repair ii. Evaluation by an otolaryngologist, audiologist, and speech pathologist c. Orthodontic alignment of the teeth d. Craniofacial reconstruction i. Zygomatic and orbital reconstruction ii. Maxillomandibular reconstruction iii. Nasal reconstruction iv. Soft tissue reconstruction v. External ear reconstruction vi. External auditory canal and middle ear reconstruction
REFERENCES Arndt EM, Travis F, Lefebvre A, et al.: Psychosocial adjustment of 20 patients with Treacher Collins syndrome before and after reconstructive surgery. Br J Plast Surg 40:605–609, 1987. Behrents RG, McNamara JA, Avery JK: Prenatal mandibulofacial dysostosis (Treacher Collins syndrome). Cleft Palate J 14:13–34, 1977. Cohen J, Ghezzi F, Goncalves L, et al.: Prenatal sonographic diagnosis of Treacher Collins syndrome: a case and review of the literature. Am J Perinatol 12:416–419, 1995. Crane JP, Beaver HA: Midtrimester sonographic diagnosis of mandibulofacial dysostosis. Am J Med Genet 25:251–255, 1986. Dixon MJ: Treacher Collins syndrome. J Med Genet 32:806–808, 1995. Dixon MJ: Treacher Collins syndrome. Hum Mol Genet 5 Spec No:1391–1396, 1996. Dixon J, Edwards SJ, Anderson I, et al.: Identification of the complete coding sequence and genomic organization of the Treacher Collins syndrome gene. Genome Res 7:223–234, 1997. Edwards SJ, Fowlie A, Cust MP, et al.: Prenatal diagnosis in Treacher Collins syndrome using combined linkage analysis and ultrasound imaging. J Med Genet 33:603–606, 1996. Ellis PE, Dawson M, Dixon MJ: Mutation testing in Treacher Collins Syndrome. J Orthod 29:293–297; discussion 278, 2002. Franceschetti A, Klein DP Mandibulo-facial dysostosis, new hereditary syndrome. Acta Ophthal 27:143–224, 1949. Gorlin RJ, Cohen MM, Hennekam RCM: Syndromes of the Head and Neck. 4th ed, New York: Oxford University Press, 2001. Hsu TY, Hsu JJ, Chang SY, et al.: Prenatal three-dimensional sonographic images associated with Treacher Collins syndrome. Ultrasound Obstet Gynecol 19:413–422, 2002. Isaac C, Marsh KL, Paznekas WA, et al.: Characterization of the nucleolar gene product, treacle, in Treacher Collins syndrome. Mol Biol Cell 11: 3061–3071, 2000. Katsanis SH, Cutting GR: Treacher Collins syndrome. Gene Reviews, 2004. http://genetests.org Marres HA: Hearing loss in the Treacher-Collins syndrome. Adv Otorhinolaryngol 61:209–215, 2002. Marszalek B, Wojcicki P, Kobus K, et al.: Clinical features, treatment and genetic background of Treacher Collins syndrome. J Appl Genet 43:223–233, 2002. Meizner I, Carmi R, Katz M: Prenatal ultrasonic diagnosis of mandibulofacial dysostosis (Treacher Collins syndrome). J Clin Ultrasound 19:124–127, 1991.
TREACHER-COLLINS SYNDROME Murty PS, Hazarika P, Rajshekhar B, et al.: Familial Treacher-Collins syndrome. J Laryngol Otol 102:620–622, 1988. Nicolaides KH, Johansson D, Donnai D, et al.: Prenatal diagnosis of mandibulofacial dysostosis. Prenat Diagn 4:201–205, 1984. Ochi H, Matsubara K, Ito M, et al.: Prenatal sonographic diagnosis of Treacher Collins syndrome. Obstet Gynecol 91:862, 1998. Posnick JC: Treacher Collins syndrome: perspectives in evaluation and treatment. J Oral Maxillofac Surg 55:1120–1133, 1997. Posnick JC, Ruiz RL: Treacher Collins syndrome: current evaluation, treatment, and future directions. Cleft Palate Craniofac J 37:434, 2000. Poswillo D: The pathogenesis of the Treacher Collins syndrome (mandibulofacial dysostosis). Br J Oral Surg 13:1–26, 1975.
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Rogers BO: Berry-Treacher Collins Syndrome: A Review of 200 Cases (Mandibulo-Facial Dysostosis; Franceschetti-Zwahlen-Klein Syndromes). Br J Plast Surg 17:109–137, 1964. The Treacher Collins Syndrome Collaborative Group: Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome. Nat Genet 12:130–136, 1996. Wise CA, Chiang LC, Paznekas WA, et al.: TCOF1 gene encodes a putative nucleolar phosphoprotein that exhibits mutations in Treacher Collins Syndrome throughout its coding region. Proc Natl Acad Sci U S A 94:3110–3115, 1997.
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Fig. 1. A child and the father with Treacher-Collins syndrome. The faces are characterized by an antimongoloid slant of the palpebral fissure, colobomata and hypoplasia of the lower lids, and small and receding chins.
Fig. 2. An infant and his mother with Treacher-Collins syndrome showing similar features. The infant is mildly affected.
TREACHER-COLLINS SYNDROME
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Fig. 3. A newborn and a child with Treacher-Collins syndrome showing antimongoloid slant of the palpebral fissures, coloboma and hypoplasia of the lower lids, and microtia.
Fig. 4. Another infant with typical Treacher-Collins syndrome.
Trimethylaminuria Trimethylaminuria, also called fish odor syndrome, is a metabolic disorder characterized by a distinctive fish odor of sweat, urine, breath, and other body secretions due to presence of abnormal amounts of the dietary-derived tertiary amine, trimethylamine (TMA).
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal recessive b. The incidence of heterozygous carriers of the allele for impaired N-oxidation is estimated to be of the order of 1%. 2. Basic defect a. Caused by deficiency of the flavin-containing mono-oxygenase isoform 3 (FMO3). A defect in hepatic N-oxidation of dietary derived TMA causes excess excretion of TMA, leading to affected individuals to have a body odor resembling rotten fish. b. Caused by loss-of-function mutations in the FMO3 gene encoding an isoform of flavin-containing monooxygenase have been shown to underlie trimethylaminuria/fish odor syndrome. c. Common variants in the FMO3 gene lead to greatly reduced enzyme activity in vivo, shown to cause mild to transient trimethylaminuria. d. Also can be caused by liver, kidney, and/or gastrointestinal dysfunction, including dietary carnitine overloading secondary to the gut-generated substrate overwhelming the hepatic enzymes’ oxidizing capacity e. Trimethylaminuria reflects how genetic constitution can adversely influence interactions with one’s diet. 3. TMA a. Derived from the intestinal bacterial degradation of foods rich in choline and carnitine, such as egg yolk, liver, kidney, soybeans, peas and salt-water fish b. Readily absorbed from the gut and is normally oxidized by the liver FMO3 to odorless trimethylamine N-oxide which is then excreted in the urine c. Impaired oxidation of TMA, thought to be the cause of the fish odor syndrome, is responsible for the smell of rotting fish. 4. FMO3 a. One of the major enzyme systems protecting humans from the potentially toxic properties of drugs and chemicals b. Converts nucleophilic heteroatom-containing chemicals and endogenous materials to polar metabolites, which facilitate their elimination c. N-oxygenates trimethylamine to trimethylamine N-oxide which is excreted in a detoxication and deoderation process 972
d. Prevalent polymorphisms of the human FMO3 may contribute to low penetrance and predispositions to diseases associated with adverse environmental exposures to heteroatom-containing chemicals, drugs (e.g., tricyclic antidepressants, ranitidine, amphetamine, methamphetamine, clozapine, chlorpromazine, methimazole), and endogenous amines. 5. Classification of the disorder a. Primary genetic form i. The best understood of the various forms of the disorder ii. Accounts for a large proportion of the known cases iii. Human FMO3 a) Highly polymorphic b) Some mutations, either alone or in combination, are associated with dysfunctional enzyme activity and the metabolic disorder. c) Two relatively common polymorphisms (P153L and E305X) appear to account for the majority of severe cases of trimethylaminuria. d) Some other mutations are associated with inactivation of FMO3. e) Combinations of intragenic polymorphisms within FMO3 appear to determine a modified and less severe form of the condition. f) Some mutations appear to be benign. b. Acquired form i. Several cases of clinical and biochemically diagnosed trimethylaminuria have been reported to emerge in adult life. ii. No previous history in childhood iii. No familial background iv. Possible mechanism: Viral hepatitis may have been responsible for precipitation of the condition possibly by insertion of viral DNA into the genome thereby affecting normal expression of the human FMO3 gene. c. Transient childhood forms i. A transient or mild form of trimethylaminuria may occur during early childhood. ii. Compound heterozygosity for several mutations has been detected by molecular analysis in some cases. d. Transient form associated with menstruation i. Fish odor intensifies with onset of menstruation. ii. Trimethylaminuric condition deepens just prior to the onset of menstruation. e. Precursor overload i. Overload of precursors, such as choline, lecithin, and carnitine, saturates the existing levels of flavin monooxygenase.
TRIMETHYLAMINURIA
ii. Exposure to unusually high levels of such precursors may hasten a fish odor syndrome, especially if the individual is a haplotype for certain mutations. f. Disease states that impair trimethylamine metabolism i. Advanced liver disease ii. Advanced renal disease iii. Association with temporal lobe epilepsy and behavioral disturbances iv. Bacterial vaginosis with fish odor in vaginal secretions g. Exacerbating factors i. Pyrexic states ii. Stress iii. Puberty iv. Sweating v. Exercise vi. Emotional upsets vii. Menstruation viii. Oral contraceptives ix. Foods rich in choline
CLINICAL FEATURES 1. Unmistakable, strong fishy body odor from excess unmetabolized trimethylamine in the urine, sweat and other body secretions (breath, saliva, vaginal secretions) 2. Skin sores induced by choline-rich foods 3. Serious social/behavioral problems resulting from strong body odor a. Subject to ridicule, loss of confidence, and school disruption b. Destructive to personal, working, and career lives of the affected individuals c. Clinical depression d. Attempted suicide 4. Highly variable severity of the syndrome
DIAGNOSTIC INVESTIGATIONS 1. Demonstration of elevated TMA after a choline-rich diet by gas chromatography-mass spectrometry measurement. TMA challenge test (with a 600 mg TMA oral challenge dose and analysis of 0–8 hour’s urine samples) is useful in confirming unequivocally the trimethylaminuric patients as well as indicating the status of the parents as carriers 2. Increase in urinary excretion of trimethylamine with decreased trimethylamine oxide 3. Sequence analysis of FMO3 gene to detect mutations 4. Combination of the proton nuclear magnetic resonance (NMR) spectroscopy to assess activity of the mutant enzyme with gene sequence and expression technology provides a powerful means of determining genotype-phenotype relationships in trimethylaminuria
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased unless the spouse is a carrier
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2. Prenatal diagnosis: possible by demonstrating the previously characterized mutation in the fetal DNA obtained by amniocentesis or CVS 3. Management a. Restriction of dietary sources of trimethylamine i. Avoid choline-rich food a) Egg yolk b) Liver c) Kidney d) Legumes e) Soybeans f) Peas g) Fish h) TMA-oxide sources such as some saltwater fish (cod, skate) and shellfish (lobster) ii. Dietary restriction appears to be successful in the management of the majority of patients. iii. Appears to be most effective in mild to moderate forms of fish odor syndrome arising from particular mutations or haplotypes b. Avoid exacerbation factors such as pyrexia and stress c. Vitamin supplementation with riboflavin, a precursor of the FAD cofactor for flavin monooxygenase function, in an attempt to maximize any residual activity d. Drug treatment: Occasionally a short course of metronidazole, neomycin and lactulose may suppress production of TMA by reducing the activity of gut microflora in some patients. e. Use of “malodor suppressants” in hygiene products to disguise the offensive smell of trimethylamine f. Counseling of the social/behavioral problems g. Gene therapy and enzyme induction with drugs provide hope for the future.
REFERENCES Akerman BR: Two novel mutations of the FMO3 gene in a proband with Trimethylaminuria. Hum Mutat 13:376–379, 1999. Akerman BR: Trimethylaminuria is caused by mutations of the FMO3 gene in a North American cohort. Mol Genet Metab 68:24–31, 1999. Al-Waiz M, Ayesh R, Mitchell SC, et al.: Trimethylaminuria (fish-odour syndrome): an inborn error of oxidative metabolism. Lancet 1:634–635, 1987. Al-Waiz M, Ayesh R, Mitchell SC, et al.: A genetic polymorphism of the Noxidation of trimethylamine in humans. Clin Pharmacol Ther 42:588–594, 1987. Al-Waiz M, Ayesh R, Mitchell SC, et al.: Trimethylaminuria (‘fish-odour syndrome’): a study of an affected family. Clin Sci 74:231–236, 1988. Al-Waiz M, Ayesh R, Mitchell SC, et al.: Trimethylaminuria: the detection of carriers using a trimethylamine load test. J Inherited Metab Dis 12:80–85, 1989. Ayesh R, Mitchell SC, Zhang A, et al.: The fish odour syndrome: biochemical, familial, and clinical aspects. Brit Med J 307:655–657, 1993. Basarab T: Sequence variations in the flavin-containing mono-oxygenase 3 gene (FMO3) in fish odour syndrome. Br J Dermatol 140:164–167, 1999. Blumenthal I, Lealman GT, Franklyn PP: Fracture of the femur, fish odour, and copper deficiency in a preterm infant. Arch Dis Child 55:229–231, 1980. Cashman JR: Population-specific polymorphisms of the human FMO3 gene: significance for detoxication. Drug Metab Dispos 28:169–173, 2000. Cashman JR, Camp K, Fakharzadeh SS, et al.: Biochemical and clinical aspects of the human flavin-containing monooxygenase form 3 (FMO3) related to trimethylaminuria. Curr Drug Metab 4:151–170, 2003. Chen H, Aiello F: Trimethylaminuria in a girl with Prader-Willi syndrome and del(15)(q11q13). Am J Med Genet 45:335–339, 1993. Dolphin CT, Janmohamed A, Smith RL, et al.: Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nat Genet 17:491–494, 1997.
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Forrest SM: A novel deletion in the flavin-containing monooxygenase gene (FMO3) in a Greek patient with trimethylaminuria. Pharmacogenetics 11:169–174, 2001. Hollinger MA, Sheikholislam B: Effects of dietary alteration on Trimethylaminuria as measured by mass spectrometry. J Int Med Res 19:63–66, 1991. Kashyap AS, Kashyap S: Fish odour syndrome. Postgrad Med J 76:318–319, 2000. Lambert DM: In vivo variability of TMA oxidation is partially mediated by polymorphisms of the FMO3 gene. Mol Genet Metab 73:224–229, 2001. Marks R, Greaves MW, Danks D, et al.: Trimethylaminuria or fish odour syndrome in a child. Br J Dermatol 95:11–12, 1976. Marks R, Greaves MW, Prottey C, et al.: Trimethylaminuria: the use of choline as an aid to diagnosis. Br J Dermatol 96:399–402, 1977. Mayatepek E, Kohlmuller D: Transient trimethylaminuria in childhood. Acta Paediatr 87:1205–1207, 1998. Mills GA: Quantitative determination of trimethylamine in urine by solidphase microextraction and gas chromatography-mass spectrometry. J Chromatogr B Biomed Sci Appl 723:281–285, 1999. Mitchell SC: The fish-odor syndrome. Perspect Biol Med 39:514–526, 1996.
Mitchell SC: Trimethylaminuria: susceptibility of heterozygotes. Lancet 354: 2164–2165, 1999. Mitchell SC: Trimethylaminuria: the fish malodor syndrome. Drug Metab Dispos 29:517–521, 2001. Mitchell SC, Smith RL: Trimethylaminuria: the fish malodor syndrome. Drug Metab Dispos 29:517–521, 2001. Murphy HC:L A novel mutation in the flavin-containing monooxygenase 3 gene, FMO3, that causes fish-odour syndrome: activity of the mutant enzyme assessed by proton NMR spectroscopy. Pharmacogenetics 10:439–451, 2000. Rehman HU: Fish odor syndrome. Postgrad Med J 75:451–452, 1999. Ruocco V, Florio M, Filioli FG, et al.: An unusual case of Trimethylaminuria. Br J Dermatol 120:459–461, 1989. Shelley ED, Shelley WB: The fish odor syndrome. Trimethylaminuria. J Am Med Assoc 251:253–255, 1984. Tjoa S, Fennessey P: The identification of trimethylamine excess in man: Quantitative analysis and biochemical origins. Anal Biochem 197:77–82, 1991. Zschocke J: Mild trimethylaminuria caused by common variants in FMO3 gene. Lancet 354:834–835, 1999.
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Fig. 1. A 12-year-old girl with trimethylaminuria showing multiple sores on the hands and legs. At age 4, she developed unpleasant fish odor and constant scratching of her skin. Trimethylaminuria was diagnosed based on markedly increased urinary TMA by gas chromatography after loading with choline. The patient started with a baseline level of 0.28 mg TMA mg/mg creatine that is 4 times of control. After 8, 16, and 24 hours of loading with choline, the values went up to 2.8 mg (41x), 3.99 mg (57x), and 9.93 mg (95x) respectively. In addition, the diagnosis of Prader-Willi syndrome was made at age 9 because of relative obesity, hypotonia, delayed psychomotor development, almond-shaped eyes, small hands and feet and presence of chromosome abnormality of del(15)(q11q13).
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Triploidy iv. Fertilization of the first polar body and ovum by individual spermatozoa with suppression of one second polar body v. Dispermy or diploid sperm fertilization with incorporation of an independently fertilized second polar body vi. Chimera formation by union of diploid and triploid embryos vii. Vanishing twin and chimerism b. Characteristics of diploid/triploid fetuses: rarer and less severe phenotype than true triploidy
Triploidy is defined as the presence of three sets of haploid (69) chromosomes. Triploid fetuses occur in about 1% of recognized pregnancies, 1 in 100,000 liveborns, and constitute about 15 percent of all fetuses with chromosome abnormalities. There is a slight excess of males (M1.5:F1). Most triploid fetuses often result in spontaneous abortions between 7 and 17 weeks of gestation. However, rare instances of a live triploid infant have been reported.
GENETICS/BASIC DEFECTS 1. Origin of triploidy a. Diandric origin of the triploid fetuses (type I) i. Mechanisms of paternal origin of the supernummary haploid set a) Dispermy: fertilization of a haploid egg by two haploid sperms (dispermy) accounting for 66% (most common mechanism leading to triploidy) b) Faulty meiotic division in the male: fertilization of a normal ovum by a diploid sperm (diandry) (about 24%) ii. Characteristics of diandric fetuses a) Relatively normal fetal growth b) Slight macrocephaly c) Marked syncytiotrophoblastic hyperplasia d) Hydatidiform changes of the placental villi (partial mole) (large cystic placenta) b. Digynic origin of triploid fetuses (type II) i. Mechanisms of maternal origin of the supernummary haploid set a) Mitotic errors in female germ cell precursors: fertilization of a diploid ovum by a normal sperm (digyny) (about 10%) b) Errors in maternal meiosis: an error at meiosis I or II or incorporation of the second polar body postulated ii. Characteristics of digynic fetuses a) Generally marked fetal (asymmetric) growth retardation b) Relative macrocephaly c) Small, noncystic placenta d) Maternally derived triploidy was often found in those fetuses that survived until late pregnancy. 2. Diploidy/triploid mosaicism a. Mechanisms i. Postzygotic maldivision of a triploid or diploid zygote ii. Incorporation of the second polar body into a daughter nucleus of the developing embryo iii. Fertilization of a diploid ovum with incorporation of the second diploid polar body
CLINICAL FEATURES
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1. Prenatal history a. IUGR i. Asymmetrical (digynic) ii. Symmetrical (diandric) b. Prematurity c. Hydrops d. Polyhydramnios e. Oligohydramnios f. Partial hydatidiform mole (placenta) 2. Craniofacial features a. Dysplastic calvarium b. Microcephaly c. Large posterior fontanelle d. Ocular hypertelorism or hypotelorism e. Epicanthal folds f. Exomphalos g. Microphthalmia h. Iris and choroid colobomas i. Midfacial hypoplasia j. Arhinia k. Small upturned nose l. Choanal atresia m. Single nostril (in holoprosencephaly) n. Micrognathia o. Cleft lip/palate p. Low-set ears q. Short neck r. Thick nuchal fold s. Cystic hygroma 3. CNS a. Hypotonia b. Arnold-Chiari malformation c. Posterior fossa cyst (Dandy-Walker malformation) d. Holoprosencephaly e. Hydranencephaly f. Hydrocephalus (20%) g. Absent corpus callosum (15%) h. Absent gyri of the brain i. Hypoplastic cerebellum
TRIPLOIDY
4.
5.
6.
7.
8.
9.
10.
j. Absent 1st cranial nerve k. Encephalocele l. Lumbosacral meningomyelocele (20%) Gastrointestinal malformations a. Omphalocele b. Ventral wall defects c. Incomplete rotation of colon d. Agenesis of gallbladder e. Meckel diverticulum f. Duodenal atresia g. Malfixation of caecum h. Inguinal hernia Endocrine abnormalities a. Adrenal hypoplasia b. Thyroid hypoplasia c. Lingual thyroid d. Thymic hypoplasia e. Leydig cell hyperplasia f. Gonadal dysgenesis Genitourinary abnormalities a. 69,XXY triploid fetus i. Varying degree of ambiguous genitalia (40%) ii. Hypospadias (40%) iii. Cryptorchidism (85%) iv. Micropenis (75%) v. Scrotal abnormalities (60%) including bifidity, scrotal hypoplasia, or agenesis vi. Leydig cell hyperplasia (20%) b. 69,XXX triploid fetus i. Gonadal dysgenesis ii. Renal abnormalities a) Multicystic kidneys b) Hydronephrosis c) Glomerulosclerosis Gastrointestinal abnormalities a. Omphalocele b. Diaphragmatic hernia c. Gastroschisis d. Malrotation e. Gallbladder hypoplasia f. Pancreas hypoplasia Cardiovascular anomalies a. VSD b. ASD c. PDA d. PA e. Tetralogy of Fallot f. Truncus arteriosus g. Aberrant right subclavian artery h. Cardiomegaly Respiratory tract abnormalities a. Small chest b. Pulmonary hypoplasia c. Absent lung lobation d. Congenital cystic adenomatoid malformation of the lung Prognosis a. Majority die early in gestation b. Very few surviving into the third trimester c. The fetuses rarely survive to delivery i. Profoundly malformed
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ii. Growth-restricted iii. Survival measured in hours to days d. Fetuses with extra maternal-haploid set of chromosomes appear to survive longer in utero than those with extra paternal-haploid set of chromosomes e. Some cases of diploid/triploid mixoploidy survive after the neonatal period, which is exceptional 11. Diploid/triploid mosaicism a. A well known malformation syndrome b. Common features i. Mental retardation ii. Growth retardation iii. Body and/or facial asymmetry iv. Hypotonia v. Truncal obesity vi. Prominent forehead vii. Depressed nasal bridge viii. Micrognathia ix. Malformed low-set ears x. Syndactyly xi. Clinodactyly xii. Transverse palmar creases xiii. A small phallus xiv. Cryptorchidism xv. Precocious puberty c. Additional features i. Sandal gap ii. Short halluces iii. Seizures iv. Respiratory distress v. Microstomia vi. Irregular skin vii. Feeding difficulties viii. Muscular atrophy of the limbs d. Rarer and less severe than true triploidy in which infants can survive beyond neonatal period till over 20 years e. Presence of a normal diploid cell line and a second triploid cell line in varying degrees and with varying tissue distribution
DIAGNOSTIC INVESTIGATIONS 1. Karyotype of fetus and newborn a. 69,XXX (one third of cases) b. 69,XXY (Two thirds of cases) c. Diploid/triploid mosaicism i. Less severe phenotype ii. More compatible with life iii. Harder to diagnose clinically iv. Peripheral lymphocyte cultures showing a normal karyotype only v. Need fibroblast culture to show the cell line with triploid complement d. Molecular determination of the origin of the extra haploid set of chromosomes i. Fluorescent-polymerase chain reaction (F-PCR) analysis of short tandem repeats (STRs) located on chromosomes such as 21, 18, and 13 ii. Assessment of numerous polymorphic DNA markers
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TRIPLOIDY
2. Radiography a. Poor ossification of calvarium b. Craniolacunae c. Chondrodysplasia punctata-like calcification d. Vertebral fusions e. Harlequin orbits f. Gracile ribs g. Upswept clavicles h. Diaphyseal overtubulation of long bones i. Vertical ilia j. Proximal radioulnar synostosis k. Asymmetry of occipitoparietal calvaria (50%) 3. CT and MRI of the brain a. Cortical hypoplasia b. Agenesis of corpus callosum (15%) c. Hypoplasia of basal ganglia/occipital lobe d. Dandy-Walker anomaly e. Arnold-Chiari malformation 4. Histopathology of the placenta a. Partial hydatidiform mole change of villi on gross and microscopic examination b. The villi with molar change show hydropic swelling of the stroma and trophoblastic proliferation (hyperplasia) is also present in scattered areas c. Irregular cystic cavitation may be seen in larger hydropic villi
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: the true recurrence risk for cytogenetic abnormalities in subsequent offspring is uncertain, but may be slightly increased and higher than expected b. Patient’s offspring: a lethal condition not surviving to reproduce 2. Prenatal diagnosis a. First-trimester markers screening i. Low serum marker pregnancy-associated plasma protein A (PAPP-A) ii. Low serum marker free β-chain of chorionic gonadotrophin (free β-hCG) b. Second trimester maternal serum screening i. High maternal serum hCG associated with triploidy a) Nearly always indicating placenta with partial mole (93%) b) A high frequency of open neural tube defects or ventral wall defects (29%) c) With either XXX or XXY karyotype ii. Low hCG associated with triploidy a) Infrequently associated with a molar placenta (9%) b) Not appear to be associated with open neural tube defects or ventral wall defects c) An excess of XXX over XXY karyotypes iii. Large placentas with molar changes (diandry) generally associated with increased maternal serum AFP (MSAFP) and high hCG levels iv. Those with digyny and small monocystic placentas generally associated with normal MSAFP and low hCG
c. Isolation of nucleated red blood cells from the maternal peripheral circulation at the first-trimester (12 weeks gestation): FISH analysis using X and Y and other chromosome specific probes d. Amniocentesis/CVS i. Triploidy ii. Diploidy/triploidy mosaicism e. Ultrasonography of structural anomalies compatible with triploidy i. Severe, early-onset asymmetrical growth restriction in the late first and early second trimester (the head size remains almost normal whereas the remainder of the fetal body and skeleton is severely growth-restricted) ii. Oligohydramnios, asymmetric growth restriction, and a small placenta when the third set of chromosomes is maternal iii. Large, hydropic-appearing placenta consistent with partial moles (60–80%) when the third set of chromosomes is paternal iv. Most common sonographic abnormalities a) Large thickened placenta containing multiple sonolucent areas b) Characteristic sharply defined, large and small cystic spaces within the placenta c) Hydrops d) Ventriculomegaly e) Dandy-Walker malformation f) Holoprosencephaly g) Agenesis of the corpus callosum h) Micrognathia i) Echogenic bowel j) Omphalocele k) Renal malformations l) Thickened nuchal folds m) Neural tube defects n) Club feet o) Syndactyly of the 3rd and 4th fingers f. Preimplantation genetic diagnosis in conjunction with in vitro fertilization by a single sperm injection: a viable approach when there are clinical or genetic indications of repeated dispermy, unreduced (diploid) spermatozoa or unreduced (diploid) oocytes 3. Management a. No treatment available for true triploidy, a lethal condition b. Supportive therapy for diploid/triploid mosaicism who may survive beyond neonatal period
REFERENCES Al Saadi A, Juliar JF, Harm J, et al.: Triploidy syndrome: A report of two liveborn (69,XXY) and one still-born (69,XXX) infant. Clin Genet 9:43–50, 1976. Allen RW, Pritchard JK: DNA analysis in a paternity case involving a triploid fetus. Transfusion 40:240–244, 2000. Bán Z, Nagy B, Papp C, et al.: Rapid diagnosis of triploidy of maternal origin using fluorescent PCR and DNA fragment analysis in the third trimester of pregnancy. Prenat Diagn 22:984–987, 2002. Baumer A, Balmer D, Binkert F, et al.: Parental origin and mechanisms of formation of triploidy: a study of 25 cases. Eur J Hum Genet 8:911–917, 2000. Bendon RW, Siddiqi T, Soukup S, et al.: Prenatal detection of triploidy. J Pediatr 112:149–153, 1988.
TRIPLOIDY Benn PA, Gainey A, Ingardia CJ, et al.: Second trimester maternal serum analytes in triploid pregnancies: correlation with phenotype and sex chromosome complement. Prenat Diagn 21:680–686, 2001. Blackburn WR, Miller WP, Superneau DW, et al.: Comparative studies of infants with mosaic and complete triploidy: an analysis of 55 cases. Birth Defects Orig Artic Ser 18(3B):251–274, 1982. Book JA, Santession B: Malformation syndrome in man associated with triploid (69) chromosomes. Lancet 1:858–859, 1960. Carakushansky G, Teich E, Ribeiro MG, et al.: Diploid/triploid mosaicism: further delineation of the phenotype. Am J Med Genet 52:399–401, 1994. Craig K, Pinette M, Blackstone J, et al.: Highly abnormal maternal serum inhibin and (beta)-human chorionic gonadotropin levels along with severe HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome at 17 weeks’ gestation with triploidy. Am J Obstet Gynecol 182:737–739, 2000. Daniel A, Wu Z, Bennetts B, et al.: Karyotype, phenotype and parental origin in 19 cases of triploidy. Prenat Diagn 21:1034–1048, 2001. De Graaf IM, van Bezouw SMCA, Jakobs ME, et al.: First-trimester noninvasive prenatal diagnosis of triploidy. Prenat Diagn 19:175–177, 1999. Dean J, Cohen G, Kemp J, et al.: Karyotype 69,XXX/47,XX,+15 in a 11/2-yearold child. J Med Genet 34:246–249, 1997. Delatycki MB, Pertile MD, Garner RJM: Trisomy 13 mosaicism at prenatal diagnosis: dilemmas in interpretation. Prenat Diagn 18:45–49, 1998. Deshi N, Surti U, Szulman NE: Morphologic anomalies in triploid liveborn fetuses. Hum Pathol 14:716, 1983. Dewald G, Alvarez MN, Clouthier MD, et al.: A diploid-triploid human mosaic with cytogenetic evidence of double fertilization. Clin Genet 8:149–160, 1975. Dietzsch E, Ramsay M, Christianson AL, et al.: Maternal origin of extra haploid set of chromosomes in third trimester triploid fetuses. Am J Med Genet 58:360–364, 1995. Egozcue S, Blanco J, Vidal E, et al.: Diploid sperm and the origin of triploidy. Hum Reprod 17:5–7, 2002. Fejgin M, Amiel A, Goldberger S, et al.: Placental insufficiency as a possible cause of low maternal serum human chorionic gonadotropin and low maternal serum unconjugated estriol levels in triploidy. Am J Obstet Gynecol 167:766–767, 1992. Fernández-Moya JM, Sanz R, Rodríguez de Alba M, et al.: Sonographic, cytogenetic and DNA analysis in four 69,XXX fetuses diagnosed in the second trimester. Fetal Diagn Ther 15:97–101, 2000. Fryns JP, van de Kerckhove A, Goddeeris P, et al.: Unusually long survival in a case of full triploidy of maternal origin. Hum Genet 38:147–155, 1977. Fryns JP, Vinken L, Geutjens J, et al.: Triploid-diploid mosaicism in a deeply mentally retarded adult. Ann Genet 23:232–234, 1980. Graham JM, Rawnsley E, Simmons GM, et al.: Triploidy: pregnancy complications and clinical findings in seven cases. Prenat Diagn 9:409–419, 1989. Harris MJ, Poland BJ, Dill FJ: Triploidy in 40 human spontaneous abortuses. Assessment of phenotype in embryos. Obstet Gynecol 151:600–606, 1981. Hasegawa T, Harada N, Ikeda K, et al.: Digynic triploid infant surviving for 46 days. Am J Med Genet 87:306–310, 1999. Hsu LYF, Kaffe S, Jenkins EC, et al.: Proposed guidelines for diagnosis of chromosome mosaicism in amniocytes based on data derived from chromosome mosaicism and pseudomosaicism studies. Prenat Diagn 12:555–573, 1992. Jacobs PA, Szulman AE, Funkhouser J, et al.: Human triploidy: relationship between parental origin of the additional haploid complement and development of partial hydatidiform mole. Ann Hum Genet 46:223–231, 1982. Jauniaux E: Partial moles: from postnatal to prenatal diagnosis. Placenta 20:–388, 1999. Jauniaux E, Campbell S: Ultrasound assessment of placental abnormalities. Am J Obstet Gynecol 163:1650–1658, 1990. Jauniaux E, Hustin J: Chromosomally abnormal early ongoing pregnancies: correlation of ultrasound and placental histological findings. Hum Pathol 29:1195–1199, 1998. Jauniaux E, Brown R, Rodeck C, et al.: Prenatal diagnosis of triploidy during the second trimester of pregnancy. Obstet Gynecol 88:983–989, 1996. Jauniaux E, Brown R, Snijders RJM, et al.: Early prenatal diagnosis of triploidy. Am J Obstet Gynecol 176:550–554, 1997. Jonasson J, Therkelsen AJ, Lauritsen JG, Linsten J: Origin of triploidy in human abortuses. Hereditas 71:168–171, 1972. Kalousek DK: Adrenal hypoplasia in triploidy. Pediatr Pathol 2:359, 1984. Kennerknecht I, Just W, Vogel W: A triploid fetus with a diploid placenta: proposal of a mechanism. Prenat Diagn 13:885–886, 1993.
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Kjaer I et al.: Pattern of malformations in the axial .skeleton in human triploid fetuses. Am J Med Genet 72:216–221, 1999 Lawler SD, Fisher RA, Pickthall VJ, et al.: Genetic studies on hydatidiform moles. I. The origin of partial moles. Cancer Genet Cytogenet 5:309–320, 1982. Lockwood C, Scioscia A, Stiller R, et al.: Sonographic features of the triploid fetus. Am J Obstet Gynecol 157:285–287, 1987. McFadden DE, Kalousek DK: Two different phenotypes of fetuses with chromosomal triploidy: correlation with parental origin of the extra haploid set. Am J Med Genet 38: 535–538, 1991. MacFadden DE, Pantzar JT: Placental pathology of triploidy. J Pediatr 27:1018–1020, 1996. McFadden DE, Langlois S: Parental and meiotic origin of triploidy in the embryonic and fetal periods. Clin Genet 58:192–200, 2000. Merlob P et al.: Phenotypic expression of the first liveborn 68,XX triploid newborn. J Med Genet 28:886–887, 1991 Miny P et al. Parental origin of the extra haploid chromosome set in triploidies diagnosed prenatally. Am J Med Genet 57 (1): 102–106, 1995 Mittal TK, Vujanic GM, Morrissey BM, et al.: Triploidy: antenatal sonographic features with post-mortem correlation. Prenat Diagn 18:153–162, 1998. Muller U, Weber JL, Berry P, et al.: Second polar body incorporation into a blastomere results in 46,XX/69,XXX mixoploidy. J Med Genet 30:597–600, 1993. Niebuhr E: Triploidy in man. Cytogenetical and clinical aspects. Humangenetik 21:103–125, 1974. Nolting D, Hansen BF, Keeling JW, et al.: Histological examinations of bone and cartilage in the axial skeleton of human triploidy fetuses. APMIS 110:186–192, 2002. Pergament E, Confino E, Zhang JX, et al.: Recurrent triploidy of maternal origin. Prenat Diagn 20:561–563, 2000. Petit P, et al.: Full 69,XXY triploidy and sex-reversal: A further example of true hermaphroditism associated with multiple malformations. Clin Genet 41:175–177, 1992 Pircon RA, Towers CV, Porto M, et al.: Maternal serum alpha-fetoprotein and fetal triploidy. Prenat Diagn 9:701–707, 1989. Phelan MC, Rogers RC, Michaelis RC, et al.: Prenatal diagnosis of mosaicism for triploidy and trisomy 13. Prenat Diagn 21:457–460, 2001. Priest JH, Adams WR, Sanford-Hanna J, et al.: The nature of recurrent triploidy in humans. Am J Hum Genet 57 (Suppl):A123, 1995. Redline RW, Hassold T, Zaragoza MV: Prevalence of the partial molar phenotype in triploidy of maternal and paternal origin. Hp; 28:505–511, 1998. Rijhsinghani A, Yankowitz J, Strauss RA, et al.: Risk of preeclampsia in second-trimester triploid pregnancies. Obstet Gynecol 90:884–888, 1997. Silverthorn KG, et al.: Radiographic findings in liveborn triploidy. Pediatr Radiol 19:237–241, 1989 Spencer K, Liao AWJ, Skentou H, et al.: Screening for triploidy by fetal nuchal translucency and maternal serum free b-hCG and PAPP-A at 10–14 weeks of gestation. Prenat Diagn 20:495–499, 2000. Szulman AE, Surti U: The syndromes of hydatidiform mole II: morphologic evolution of the complete and partial mole. Am J Obstet Gynecol 132:20–27, 1978. Szulman AE, Philippe E, Boue JG, et al.: Human triploidy: association with partial hydatidiform moles and nonmolar conceptuses. Hum Pathol 12:1016–1021, 1981. Tharapel AT, Wilroy RS, Martens PR, et al.: Diploid/triploid mosaicism: delineation of the syndrome. Ann Genet 26:229–233, 1983. Tuerlings JHAM, Breed ASPM, Vosters R, et al.: Evidence of a second gamete fusion after the first cleavage of the zygote in a 47,XX,+18/70,XXX,+18 mosaic. A remarkable diploid-triploid discrepancy after CVS. Prenat Diagn 13:301–306, 1993. Van De Laar I, Rabelink G, Hochstenbach R, et al.: Diploid/triploid mosaicism in dysmorphic patients. Clin Genet 62:376–382, 2002. Wertelecki V, Graham JM, Sergovich FR: The clinical syndrome of triploidy. Obstet Gynecol 47:69–76, 1976. Wulfsberg EA, Wassel W C, Polo CA: Monozygotic twin girls with diploid/ triploid chromosome mosaicism and cutaneous pigmentary dysplasia. Clin Genet 39:370–375, 1991. Yu CW, Chen H, Fowler M: Specific terminal DNA replication sequence of X chromosomes in different tissues of a live-born triploid infant. Am J Med Genet 14:501–511, 1983. Zaragoza MV, Surti U, Redline RW, et al.: Parental origin and phenotype of triploidy in spontaneous abortions: Predominance of diandry and association with the partial hydatidiform mole. Am J Hum Genet 66:1807– 1820, 2000.
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Fig. 1. A newborn with triploidy (69,XXY) showing woolly hair, distinctive facial appearance (epicanthal folds, microphthalmia, beaked nose, small mouth, receding jaw, low-set and malformed ears), partial syndactyly between 3rd–4th fingers and toes, and ambiguous genitalia. The infant also had bilateral coloboma and cataracts, short neck, loud continuous heart murmur along the left sternal border, and bilateral transverse palmar creases. The infant died at 25 hours.
Fig. 2. An infant with triploidy showing abnormal craniofacial features, omphalocele, thick nuchal fold, and lumbosacral meningomyelocele.
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Fig. 4. Partial mole of triploidy placenta. Many villi are enlarged, hydropic and hypovascular. Prominent infolding and nests of trophoblastic cells in the villous stroma are seen in other areas.
Fig. 5. A G-banded karyotype showing 69,XXX.
Fig. 3. An infant with triploidy (69,XXX) showing low-set/malformed ears, syndactyly of 2–3–4 fingers, spina bifida, and pulmonary hypoplasia at autopsy. The infant also had a large ventricular septal defect.
Fig. 6. Triploidy for all chromosomes shown by multicolor FISH on interphase cells. Three copies of chromosome 13 (green) and chromosome 21 (orange) are shown here.
Trismus Pseudocamptodactyly Syndrome The trismus pseudocamptodactyly syndrome, a relatively rare hereditary disorder, is characterized by inability to open the mouth fully, pseudocamptodactyly, mild foot deformities, and mild short stature. This malformation syndrome was first reported by Hecht and Beals and Wilson et al. in 1969. The term Dutch-Kentucky syndrome was coined for trismus pseudocamptodactyly by Mabry et al. because the earliest affected member was a young Dutch girl who emigrated to the southern United States soon after the American Revolution.
GENETICS/BASIC DEFECTS 1.
Inheritance a. Autosomal dominant b. Variable expression 2. Pathogenesis a. Possible mechanisms of trismus i. The shortened lengths of certain mastication muscles presumed to be responsible for the clinical manifestations a) Temporalis muscle b) Internal pterygoid muscle c) Masseter muscle ii. Enlarged coronoid processes a) Resulted from tension exerted by short temporal muscle tendon units b) Impinging on the body of the zygomatic bone and inner margin of the arch, thereby limiting mandibular excursion iii. Secondary to an abnormal ligament between the maxilla and that of the mandible anterior to the masseter muscles iv. Fibrotic abnormality of the masseter muscle mass in the vicinity of the ascending ramus b. Pseudocamptodactyly of fingers i. More appropriate term than camptodactyly because of: a) Not associated with progressive deformities b) Not associated with fixed joint contractures ii. Caused by a shortening of the flexor digitorum profundus muscle tendon units, involving all fingers c. Foot deformities explainable by a shortening of the various muscle tendon groups in the leg and foot
CLINICAL FEATURES 1. Highly variable expression 2. Two main clinical features a. Limited excursion of the mandible i. Trismus (restricted opening of the mouth) a) Present at birth and persisting throughout life b) Greatly variable degree of restricted opening of the mouth 982
c) The mouth opening is measured between the incisal edges of the central upper and lower incisors (in millimeter) d) Children: less than the value for normal children (36.6 ± 5.7 for age 7 years to 47.2 ± 6.4 for age 18 years) e) Adults: less than the value for normal adults (53.8 ± 6.5 for males; 50.4 ± 5.9 for females) ii. Mastication problems iii. Feeding problems with inadequate caloric intake iv. Swallowing difficulty (dysphagia) v. Difficulty with dental care vi. Delayed in speech development vii. Difficulty in endotracheal intubation for general anesthesia b. A flexion deformity of the fingers i. Clenched fists may be present at birth ii. Typically crawling on the knuckles later in infancy iii. Occurring with wrist extension (pseudocamptodactyly) which is reversed by wrist flexion iv. Flexion of the fingers when the hand is dorsiflexed in minimally affected patients v. Pronounced flexion with ulnar deviation of the fingers in severely affected patients 3. Other clinical features a. Lower extremity and foot deformities (5% of cases) i. Mild calcaneovalgus ii. Equinovarus iii. Metatarsus varus iv. Camptodactyly v. Vertical talus vi. Hammertoe deformities vii. Shortening of both the gastrocnemiae and hamstring muscles b. Soft tissue syndactyly occasionally present c. Mild short stature 4. Differential diagnosis of restricted mouth opening and/or (pseudo)camptodactyly a. Restricted mandibular opening caused by: i. Intraarticular processes a) Trauma b) Infection c) Ankylosis ii. Extraarticular processes a) Soft tissue and bony obstructions b) Neurologic disorders such as tetanus b. Trismus in temporomandibular joint dysfunction c. Trismus caused by hypoplasia and fibrosis of the muscles around the mouth in Freeman-Sheldon syndrome d. Trismus and camptodactyly in patients with distal arthrogryposis who may have hyperextension of the
TRISMUS PSEUDOCAMPTODACTYLY SYNDROME
metacarpophalangeal joints, but also have contractures of the hips and feet, and short stature e. Trismus with a fixed facies secondary to hypoplasia or atrophy of small muscle fibers in Schwartz-Jampel syndrome f. A new arthrogryposis syndrome with facial and limb anomalies i. An autosomal dominant disorder ii. Small mouth and jaw with limited jaw movement in infancy iii. Associated with short stature and severe flexion contractures of the hands and feet g. Digitotalar syndrome i. An autosomal dominant disorder ii. Flexion deformities iii. Ulnar deviation and narrowing of the fingers iv. Soft tissue webbing causing abnormal positions of the thumbs v. A vertical talus
DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Enlargement of the coronoid processes b. Normal hands and forearms 2. Manometry for demonstrating abnormal swallowing 3. Histology of the affected muscles showing presence of fibrous tissue along with some muscle atrophy
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected (A mildly affected parent may be missed) b. Patient’s offspring: 50% 2. Prenatal diagnosis: not been reported 3. Management a. Use a flattened nipple to assist feeding in infancy b. Anesthetic implications i. Limited excursion of the mandible ii. Potentially difficult or impossible to apply artificial ventilation and endotracheal intubation iii. Inhalational anesthesia with spontaneous breathing recommended for minor surgery iv. Bullard laryngoscope, an excellent device for intubating patients with limited mouth opening v. Fiberoptic nasotracheal intubation vi. Needs for emergency tracheostomy and cricothyrotomy c. Surgical release in the severe cases of trismus i. Bilateral coronoidotomies with excision of accessory fibrous tissue ii. Bilateral excision of hypertrophic coronoid processes
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iii. Surgical release of the shortened muscle-tendon units iv. Ongoing physical therapy with postsurgical stretching of the jaw opening on a daily basis to avoid relapse d. Surgical flexor slide-through procedure on the flexion tendons of the forearms
REFERENCES Browder FH, Lew D, Shahbazian TS: Anesthetic management of a patient with Dutch-Kentucky syndrome. Anesthesiology 65:218–219, 1986. Chen H, Fowler M, Hogan Genome Res, et al.: Trismus-pseudocamptodactyly syndrome: Report of a family and review of literature with special consideration of morphologic features of the muscles. Dysmorph Clin Genet 6:165–174, 1992. Chen H, Hogan Genome Res, Fowler M, et al.: Trismus-pseudocamptodactyly syndrome: Morphologic studies of muscle. Am J Med Genet 25:736– 737, 1986. DeJong JGY: A family showing strongly reduced ability to open the mouth and limitation of some movements of the extremities. Humangenetik 13:210–217, 1971. Hall JG, Reed SD, Green A: The distal arthrogryposis: Delineation of new entities. Review and nosologic discussion. Am J Med Genet 11:185– 239, 1982. Hecht F, Beals RK: Inability to open the mouth fully: An autosomal dominant phenotype with facultative camptodactyly and short stature. Preliminary note. Birth Defects 5(3):96–98, 1969. Hertrich K, Schuch H: Restricted mouth opening as a leading symptom of: trismus-pseudocamptodactyly syndrome. Dtsch Zahnarztl Z 46:416– 419, 1991. Horowitz SL, McNutty EC, Chabora AJ: Limited intermaxillary opening, an inherited trait. Oral Surg 36:490–492, 1973. Lano CF, Werkhaven J: Airway management in a patient with Hecht’s syndrome. South Med J 90:1241–1243, 1997. Lefaivre J-F, Aitchison MJ: Surgical correction of trismus in a child with Hecht syndrome. Ann Plast Surg 50:310–314, 2003. Mabry CC, Barnett IS, Hutcheson MW, et al.: Trismus pseudocamptodactyly syndrome. Dutch-Kentucky syndrome. J Pediatr 85:503–508, 1974. Markus AF: Limited mouth opening and shortened flexor muscle-tendon units: Trismus-pseudocamptodactyly syndrome> Br J Oral Maxillofacial Surg 24:137–142, 1986. Mercuri LG: The Hecht, Beals and Wilson syndrome. J Oral Maxillofac Surg 39:53–56, 1981. O’Brien PJ, Gropper PT, Tredwell SJ, et al.: Orthopaedic aspects of the trismus pseudocamptodactyly syndrome. J Pediatr Orthop 4:469–471, 1984. Robertson RD, Spence MA, Sparkes RS, et al.: Linkage analysis with the trismus-pseudocamptodactyly syndrome. Am J Med Genet 12:115–120, 1982. Seavello J, Hammer GB: Tracheal intubation in a child with trismus pseudocamptodactyly (Hecht) syndrome. J Clinic Anesth 11:254–256, 1999. Ter Haar BGA, Van Hoof RF: The trismus-pseudocamptodactyly syndrome. J Med Genet 11:41–49, 1974. Tsukahara M, Shinozaki F, Kajii T: Trismus-pseudocamptodactyly syndrome in a Japanese family. Clin Genet 28:247–250, 1985. Wilson RV, Gaines DL, Brooks A, et al.: Autosomal dominant inheritance of shortening of the flexor profundus muscle-tendon unit with limitation of jaw excursion. Birth Defects 5(3):99–102, 1969. Yamashita D-DR, Amet GF: trismus-pseudocamptodactyly syndrome. J Oral Surg 38:625–630, 1980. Vaghadia H, Blackstock D: Anaesthetic implications of the trismus pseudocamptodactyly syndrome (Dutch-Kentucky or Hecht-Beals) syndrome. Can J Anaesth 35:80–85, 1988.
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Fig. 1. Facial appearance of a child and his mother.
Fig. 3. Hands of the child and his mother demonstrating no contractures of fingers on neutral positions but flexion contractures of fingers on dorsiflexion. Interphalangeal webbings are also seen.
Fig. 2. Front and lateral views of the child and his mother illustrating maximal abilities to open their mouth.
Fig. 4. Marked flexion contractures of fingers on dorsiflexion in other relatives.
Trisomy 13 Syndrome In 1960, Patau et al. first recognized the relation of trisomy 13 to a clinical syndrome. Incidence is estimated to be 1/4000–1/10,000 live births.
GENETICS/BASIC DEFECTS 1. Trisomy 13 a. Mechanism: due to meiotic nondisjunction i. Maternal origin of the extra chromosome (90%) ii. Stage of nondisjunction: mostly maternal meiosis I (vs. meiosis II in trisomy 18) iii. Paternal origin of the extra chromosome (10%): The majority are primarily postzygotic mitotic errors. b. Frequency: 75% of cases 2. Translocation trisomy 13 a. Mechanism: de novo (75%) or familial transmission (25%) b. Frequency: 20% of cases c. Trisomy 13 due to t(13;13): The structural abnormalities are usually isochromosomes originating in mitosis. 3. Mosaic trisomy 13 a. Mechanism: due to postzygotic (postfertilization) mitotic nondisjunction b. Frequency: 5% of cases c. Variable phenotype from full trisomy to near normal d. Variable mental retardation with longer survival e. Trisomy 13/triploidy mosaicism: a rare event 4. Partial trisomy 13 a. Partial trisomy of proximal segment with nonspecific clinical features and little similarity to full trisomy 13 b. Partial trisomy of distal segment with specific clinical features
4.
5.
6.
7.
CLINICAL FEATURES 1. General a. Low birth weight b. Thrombocytopenia 2. CNS a. Severe mental retardation b. Holoprosencephaly c. Seizures d. Central apnea 3. Craniofacial abnormalities a. Microcephaly b. Wide sagittal sutures c. Wide fontanels d. Scalp defect (aplasia cutis congenita, 50%) e. Capillary hemangioma of the forehead f. Ocular abnormalities i. Microphthalmia/anophthalmia ii. Colobomas iii. Retinal dysplasia
8.
9.
10.
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g. Cleft lip/palate h. Abnormal auricles i. Low-set ears j. Sensorineural and conductive deafness k. Recurrent otitis media l. Abundant nuchal skin folds Cardiovascular abnormalities a. Ventricular septal defect b. Atrial septal defect c. Patent ductus d. Coarctation of the aorta e. Dextrocardia Gastrointestinal abnormalities a. Omphalocele b. Malrotation c. Umbilical hernia d. Inguinal hernia e. Accessory spleen f. Heterotopic pancreatic tissue g. Meckel’s diverticulum h. Diaphragmatic defects i. Large gallbladder Genitourinary abnormalities a. Polycystic kidneys b. Cryptorchidism c. Hypospadias d. Bicornuate uteri e. Abnormal fallopian tubes f. Hypoplastic ovaries Skeletal abnormalities a. Polydactyly b. Posterior prominence of heel c. Flexed fingers d. Hypoplasia of pelvis e. Shallow acetabulum f. Thin posterior ribs g. Flexion deformity of large joints h. Limb deficiency (5.3%) i. Radial aplasia j. Hyperconvex narrow fingernails Dermatoglyphics a. Transverse palmar crease b. t’ c. Hallucal arch fibular or loop tibial Others a. Thymic cyst b. Persistence of fetal hemoglobin Prognosis a. Majority of trisomy 13 conceptuses i. Abort during pregnancy ii. Stillborn b. 25% die by 24 hours of life
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c. 45% die by 1 month of life d. 60% die by 6 months of life e. 72% die by 1 year of age f. Usual mode of death: primary apnea g. Survivals up to 11 and 19 years old reported 11. Mosaic trisomy 13 a. The phenotype ranges i. Typical features of trisomy 13 ii. More mild mental retardation or even normal intellectual function (rare), milder physical features, and longer survival b. The range in clinical severity is likely due to the varying proportion of trisomy 13 cells and their distribution within the body 12. Partial trisomy 13 of the proximal segment a. Severe mental retardation b. Large nose c. Short upper lip d. Receding mandible e. Clinodactyly of the 5th fingers 13. Partial trisomy 13 of the distal segment a. Severe mental retardation b. Bushy eyebrows (synophrys) with long incurved lashed c. Frontal capillary hemangioma d. Long philtrum e. Prominent antihelix
DIAGNOSTIC INVESTIGATIONS 1. Cytogenetic studies a. Conventional technique b. FISH of interphase cells for rapid diagnosis c. Parental karyotyping in case of translocation trisomy 13 d. Trisomy 13 mosaicism 2. Echocardiography for cardiovascular anomalies 3. EEG: hypsarrhythmia 4. CT/MRI for central nervous system anomalies 5. Radiography a. Wide anterior fontanelle b. Presence of a cervical rib c. Absence of the 12th rib d. Anomalies of rib morphology e. Low acetabular angle f. Long distal phalanges g. Cranial bone abnormalities in case of holoprosencephaly h. Clefting of the vertebral bodies i. Abnormal postsphenoid component of the sphenoid bone j. Agenesis of the nasal bones 6. Placenta: Partial molar change of the placenta may rarely occur in Trisomy 13.
GENETIC COUNSELING 1. Recurrence risk a. Patient’s, sib i. Trisomy 13: about 1 in 4000 ii. De novo translocation: about 1 in 4000
iii. Familial translocation: 5–15% iv. Mosaicism: 1 in 4000 b. Patient’s offspring: not surviving to reproductive age 2. Prenatal diagnosis a. Prenatal ultrasonography: prevalence of ultrasound abnormalities (91%) i. General a) IUGR (48%) b) Single umbilical artery c) Polyhydramnios (15%) d) Oligohydramnios (12%) ii. Cranium and CNS abnormalities (58%) a) Holoprosencephaly (39%) b) Neural tube defects c) Lateral ventricular dilatation without holoprosencephaly (9%) d) Enlarged cisterna magna or Dandy-Walker variant (15%) e) Microcephaly (12%) f) Linear branching echogenicity of the thalamus or basal ganglia (representing vasculopathy) g) Choroid plexus cyst iii. Facial anomalies a) Cyclopia b) Proboscis c) Hypotelorism d) Hypoplastic midface e) Cleft lip/palate (36%) f) Micrognathia iv. Neck anomalies a) Nuchal thickening b) Cystic hygroma c) Hydrops d) Lymphangiectasia v. Chest/cardiac abnormalities a) Diaphragmatic hernia b) Ventricular septal defect c) Hypoplastic left heart d) Echogenic chorda tendineae (30%) vi. Renal abnormalities (33%) a) Echogenic kidneys b) Pyelectasis c) Enlarged kidneys d) Hydronephrosis vii. Abdominal abnormalities a) Omphalocele b) Echogenic bowel (6%) c) Bladder exstrophy viii. Limb abnormalities (33%) a) Clenched and overlapping digits b) Polydactyly c) Radial aplasia d) Short femur length e) Talipes equinovarus f) Rocker bottom feet b. Chromosome analyses i. Amniocentesis ii. CVS, followed by amniocentesis
TRISOMY 13 SYNDROME
iii. Fetal cells isolated from maternal blood using either flow sorting or magnetic sorting c. Dilemma for genetic counseling with trisomy 13 mosaicism i. Infrequent occurrence ii. Single cell pseudomosaicism (3.3%) iii. Multiple-cell pseudomosaicism (4%) iv. Often represents pseudomosaicism or confined placental mosaicism v. True fetal mosaicism (in the context of low-level single-digit percentage mosaicism): not necessarily associated with congenital defects and/or mental abnormalities vi. An optimistic approach in case of normal ultrasonography and absence of trisomy 13 cells in the fetal blood vii. Possibility of adverse phenotype and intellectual function in case of true low-level fetal mosaicism 3. Management a. Feedings i. Nasal tube feeding ii. Oral gastric tube feeding iii. Gastrostomy feeding b. Nissan fundoplication for gastroesophageal reflux c. Risk for anesthesia d. Early intervention programs e. Seizure control f. Monitor apneic spells g. Treat infections h. Symptomatic treatment for heart failure i. Cardiac operation rarely performed
REFERENCES Alizad A, Seward JB: Echocardiographic features of genetic diseases: part 7. Complex genetic disorders. J Am Soc Echocardiogr 13:707–714, 2000. Baty BJ, Blackburn BL, Carey JC: Natural history of trisomy 18 and trisomy 13: I. Growth physical assessment, medical histories, survival, and recurrence risk. Am J Med Genet 49:175–188, 1994. Baty BJ, Jorde LB, Blackburn BL: Natural history of trisomy 18 and trisomy 13: II. Psychomotor development. Am J Med Genet 49:189–194, 1994. Benacerraf BR, Miller WA, Frigoletto FD Jr: Sonographic detection of fetuses with trisomies 13 and 18: accuracy and limitations. Am J Obstet Gynecol 158:404–409, 1988. Brewer CM, Holloway SH, Stone DH, et al.: Survival in trisomy 13 and trisomy 18 cases ascertained from population based registers. J Med Genet 39:e54, 2002. Chabra S, Kriss VM, Pauly TH, et al.: Neurosonographic diagnosis of thalamic/basal ganglia vasculopathy in trisomy 13—An important diagnostic aid. Am J Med Genet 72:291–293, 1997. Colacino SC, Pettersen JC: Analysis of the gross anatomical variations found in four cases of trisomy 13. Am J Med Genet 2:31–50, 1978. Curtin WM, Marcotte MP, Myers LL, et al.: Trisomy 13 appearing as a mimic of a triploid partial mole. J Ultrasound Med 20:1137–1139, 2001. Delatycki M, Gardner RJ: Three cases of trisomy 13 mosaicism and a review of the literature. Clin Genet 51:403–407, 1997. Delatycki MB, Pertile MD, Gardner RJ: Trisomy 13 mosaicism at prenatal diagnosis: dilemmas in interpretation. Prenat Diagn 18:45–50, 1998. Eubanks SR, Kuller JA, Amjadi D, et al.: Prenatal diagnosis of mosaic trisomy 13: a case report. Prenat Diagn 18:971–974, 1998. Goldstein H, Nielsen KG: Rates and survival of individuals with trisomy 13 and 18. Data from a 10-year period in Denmark. Clin Genet 34:366–372, 1988.
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Hahnemann JM, Vejerslev LO: European collaborative research on mosaicism in CVS (EUCROMIC)—fetal and extrafetal cell lineages in 192 gestations with CVS mosaicism involving single autosomal trisomy. Am J Med Genet 70:179–187, 1997. Hansen CB, Fergestad JM, Barnes A, et al.: An analysis of heart surgery in children with trisomy 18, 13. J Med Invest 48:47A, 2000. Has R, Ibrahimogˇlu L, Ergene H, et al.: partial molar appearance of the placenta in trisomy 13. Fetal Diagn Ther 17:205–208, 2002. Hodes ME et al.: Clinical experience with trisomies 18 and 13. J Med Genet 15:48–60, 1978. Janiaux E, Halder A, Partington C: A case of partial mole associated with trisomy 13. Ultrasound Obstet Gynecol 11:62–64, 1998. Kjaer I, Keeling JW, Hansen BF: Pattern of malformations in the axial skeleton in human trisomy 13 fetuses. Am J Med Genet 70:421–426, 1997. Lehman CD, Nyberg DA, Winter TC III, et al.: Trisomy 13 syndrome: prenatal US findings in a review of 33 cases. Radiology 194:217–222, 1995. Martínez-Frías ML, Villa A, de Pablo RA, et al.: Limb deficiencies in infants with trisomy 13. Am J Med Genet 93:339–341, 2000. Moerman P, Fryns JP, van der Steen K, et al.: The pathology of trisomy 13 syndrome: a study of 12 cases. Hum Genet 80:349–356, 1988. Nyberg DA, Souter VL: Sonographic markers of fetal trisomies. J Ultrasound Med 20:655–674, 2001. Oosterwijk JC, Mesker WE, Ouwerkerk-van Velzen MCM, et al.: Prenatal diagnosis of trisomy 13 on fetal cells obtained from maternal blood after minor enrichment. Prenat Diagn 18:1082–1085, 1998. Patau K, Therman DG, Cameron AH, et al.: A new trisomic syndrome. Lancet 1:787–789, 1960. Pettersen JC et al.: An examination of the spectrum of anatomic defects and variations found in eight cases of trisomy 13. Am J Med Genet 3:183–210, 1979. Phelan MC, Rogers RC, Michaelis RC, et al.: Prenatal diagnosis of mosaicism for triploidy and trisomy 13. Prenat Diagn 21:457–460, 2001. Redheendran R, Neu RL, Bannerman RM: Long survival in trisomy 13 syndrome: 21 cases including prolonged survival in two patients 11 and 19 years old. Am J Med Genet 8:167–172, 1981. Robinson WP, Bernasconi F, Dutly F, et al.: Molecular studies of translocations and trisomy involving chromosome 13. Am J Med Genet 61:158–163, 1996. Rogers JF: Clinical delineation of proximal and distal partial 13q trisomy. Clin Genet 25:221–229, 1984. Schinzel A et al.: Further delineation of the clinical picture of trisomy for the distal segment of chromosome 13. Hum Genet 32:1–12, 1976. Smith K, Lowther G, Maher E, et al.: The predictive value of findings of the common aneuploidies, trisomies 13, 18 and 21, and numerical sex chromosome abnormalities at CVS: experience from the ACC U.K. Collaborative Study. Association of Clinical Cytogeneticists Prenatal Diagnosis Working Party. Prenat Diagn 19:817–826, 1999. Snijders RJ, Sebire NJ, Nayar R, et al.: Increased nuchal translucency in trisomy 13 fetuses at 10–14 weeks of gestation. Am J Med Genet 86:205–207, 1999. Taylor AI: Autosomal trisomy syndromes: A detailed study of 27 cases of Edwards’ syndrome and 27 cases of Patau’s syndrome. J Med Genet 5:227–241, 1968. Tharapel SA, Lewadowski RC, Tharapel AT, et al.: Phenotype–karyotype correlation in patients trisomic for various segments of chromosome 13. J Med Genet 23:310–315, 1986. Tongson T, Sirichotiyakul S, Wanapirak C, et al.: Sonographic features of trisomy 13 at midpregnancy. Int J Gynecol Obstet 76:143–148, 2002. Tuohy JF, James DK: Pre-eclampsia and trisomy 13. Br J Obstet Gynaecol 99:891–894, 1994. Warkany J et al.: Congenital malformations in autosomal trisomy syndromes. Am J Dis Child 112:502–517, 1966. Wallerstein R, Yu M-T, Neu RL, et al.: Common trisomy mosaicism diagnosed in amniocytes involving chromosomes 13, 18, 20 and 21: karyotype–phenotype correlations. Prenat Diagn 20:103–122, 2000. Wyllie JP, Wright MJ, Burn J, et al.: Natural history of trisomy 13. Arch Dis Child 71:343–345, 1994. Zoll B, Wolf J, Lensing-Hebben D, et al.: Trisomy 13 (Patau syndrome) with an 11-year survival. Clin Genet 43:46–50, 1993.
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Fig. 4. An infant with trisomy 13 showing microcephaly, forehead hemangioma, upslanted palpebral fissures, cleft lip/palate, and short neck. Fig. 1. An infant with trisomy 13 showing microcephaly, microphthalmia, forehead hemangioma, cleft lip/palate, and post-axial polydactyly.
Fig. 5. An infant with trisomy 13 showing scalp defect on the vertex.
Fig. 2. An infant with trisomy 13 showing microcephaly, microphthalmia, cleft lip/palate, and Omphalocele.
Fig. 6. A child with trisomy 13 associated with premaxillary dysgenesis, hypotelorism, cleft nose, and smooth philtrum. Fig. 3. Postaxial polydactyly of the hand and the feet in an infant with trisomy 13.
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Fig. 7. An infant with trisomy 13-Klinefelter syndrome showing hypotelorism and a single nostril (holoprosencephaly).
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Fig. 9. Trisomy 13 karyotype (G-banded)
Fig. 10. Translocation trisomy 13 [t(13q;14q)].
Fig. 11. Trisomy 13 shown by FISH analysis of interphase cells with three copies of the green signal (LSI 13/SpectrumGreen) representing three chromosome 13s and two copies of the red signal representing two chromosome 21s (LSI 21/ SpectrumOrange). Fig. 8. A neonate with trisomy 13 showing similar facial features. In addition, the infant has polydactyly.
Trisomy 18 Syndrome Edwards et al. and Smith et al. independently described trisomy 18 syndrome in 1960. It is the second most common autosomal trisomy after trisomy 21. Prevalence is approximately 1 in 6000–8000 live births.
GENETICS/BASIC DEFECTS 1. Caused by an extra chromosome 18 resulting from nondisjunction in meiosis a. Maternal origin of an extra chromosome 18 in 90% of cases b. An error in maternal meiosis II is the most frequent cause of nondisjunction for chromosome 18, unlike all other human trisomies that have been studied, which show a higher frequency in maternal meiosis I. c. Increased incidence with advanced maternal age 2. Types of trisomy 18 a. Full trisomy 18 in 95% of cases b. Rare mosaicism and translocation cases: translocation trisomy giving rise to partial trisomy 18 syndrome 3. Preponderance of females with trisomy 18 in liveborns (sex ratio 0.63) (sex ratio defined as the number of males divided by the number of females) compared to fetuses diagnosed prenatally (sex ratio 0.90) indicating a prenatal selection against trisomy 18 males after the time of amniocentesis 4. The smallest extra region necessary for expression of serious anomalies of trisomy 18: Two critical regions, one proximal (18q12-q21.2) and one distal (18q22.3-qter), which work jointly to produce the typical trisomy 18 phenotype
CLINICAL FEATURES 1. Prenatal history a. Maternal polyhydramnios possibly related to defective fetal sucking and swallowing reflexes in utero b. Oligohydramnios secondary to renal defects c. Disproportionately small placenta d. Single umbilical artery e. Intrauterine growth retardation f. Weak fetal activity g. Fetal distress 2. Clinical history a. Apneic episodes b. Poor feeding c. Marked failure to thrive 3. Physical growth: profound growth retardation 4. Central nervous system (CNS) a. Inevitable profound delay in psychomotor development and mental retardation (100%) b. Neonatal hypotonia followed by hypertonia c. Jitteriness 990
d. Apnea e. Seizures f. Malformations i. Microcephaly ii. Cerebellar hypoplasia iii. Meningoencephalocele iv. Meningomyelocele v. Anencephaly vi. Hydrocephaly vii. Holoprosencephaly viii. Arnold-Chiari malformation ix. Hypoplasia or aplasia of the corpus callosum x. Defective falx cerebri xi. Frontal lobe defect xii. Abnormal gyri xiii. Migration defect xiv. Arachnoid cyst 5. Cranial a. Microcephaly b. Elongated skull c. Narrow bifrontal diameter d. Wide fontanels and cranial sutures e. Prominent occiput 6. Facial a. Microphthalmia b. Ocular hypertelorism c. Epicanthal folds d. Short palpebral fissures e. Iris coloboma f. Cataracts g. Corneal clouding h. Abnormal retinal pigmentation i. Short nose with upturned nares j. Choanal atresia k. Micrognathia/retrognathia l. Microstomia m. Narrow palatal arch n. Infrequent cleft lip and cleft palate o. Preauricular tags p. Low-set, malformed ears (faun-like with flat pinnae and a pointed upper helix) 7. Skeletal a. Severe growth retardation b. Characteristic hand posture, with clenched hands with the index finger overriding the middle finger and the fifth finger overriding the fourth finger c. Camptodactyly d. Radial hypoplasia or aplasia e. Thumb aplasia f. Syndactyly of the second and third digits g. Arthrogryposis h. Rocker-bottom feet with prominent calcanei i. Talipes equinovarus
TRISOMY 18 SYNDROME
j. k. l. m. n. o. p.
8.
9.
10.
11.
Hypoplastic nails Dorsiflexed great toes Short neck with excessive skin folds Short sternum Narrow pelvis Limited hip abduction Severe kyphoscoliosis and tendency to spontaneous fracture of long bones emerging later Cardiac malformations in more than 90% of infants with trisomy 18 a. Ventricular septal defects i. Present in about two-thirds of cases ii. Large defect unlikely to undergo spontaneous closure b. Polyvalvular heart disease (pulmonary and aortic valve defects) c. Double outlet right ventricle d. Atrial septal defects e. Patent ductus arteriosus f. Overriding aorta g. Coarctation of aorta h. Hypoplastic left heart syndrome i. Tetralogy of Fallot j. Transposition of great arteries k. Endocardial fibroelastosis l. Persistent left superior vena cava m. Absent right superior vena cava n. Dextrocardia Pulmonary a. Pulmonary hypoplasia b. Abnormal lobation of the lung Gastrointestinal a. Omphalocele b. Malrotation of the intestine c. Ileal atresia d. Common mesentery e. Meckel diverticulum f. Esophageal atresia with or without tracheoesophageal fistula g. Diaphragmatic eventration h. Prune belly anomaly i. Diastasis recti j. Abnormal lobulation of the liver k. Absent or hypoplasia of gallbladder l. Absent appendix m. Accessory spleens n. Exstrophy of cloaca o. Pyloric stenosis p. Common mesentery q. Megacolon r. Imperforate or malpositioned anus s. Pilonidal sinus t. Umbilical, inguinal or diaphragmatic hernias Genitourinary a. Micromulticystic kidneys b. Double ureters c. Megaloureters d. Hydroureters e. Hydronephrosis f. Horseshoe kidneys
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g. h. i. j.
Ectopic kidney Unilateral renal agenesis Cryptorchidism, hypospadias and micropenis in males Hypoplasia of labia and ovaries, bifid uterus, hypoplastic ovaries and clitoral hypertrophy in females 12. Endocrine a. Thymic hypoplasia b. Thyroid hypoplasia c. Adrenal hypoplasia 13. Dermatoglyphics a. Increased number of simple arches (six or more) on the finger tips b. Transverse palmar crease c. Increased atd angle d. Clinodactyly of the fifth fingers with a single flexion crease 14. Prognosis a. Approximately 95–97.5% of conceptuses with trisomy 18 die in embryonic or fetal life b. Only 30% of live fetuses at mid-trimester amniocentesis surviving to term c. 5–10% of affected children survive beyond the first year d. Rare reports of long survival into 20’s e. High mortality rate secondary to cardiac and renal malformations, feeding difficulties, sepsis, and central apnea caused by CNS defects f. Severe psychomotor and growth retardation invariably present for those who survive beyond infancy g. Milder nonspecific phenotype in mosaic trisomy 18 correlates with the proportion of normal cells in the body
DIAGNOSTIC INVESTIGATIONS 1. Conventional cytogenetic study to detect full trisomy, mosaic trisomy, or rare translocation type trisomy 18 2. Echocardiography for cardiac anomalies 3. Barium swallow for gastrointestinal anomalies 4. Ultrasound for genitourinary anomalies 5. Skeletal radiography a. Phocomelia b. Absent radius c. Tight flexion of the fingers with second over the third and the fifth over the fourth d. Talipes equinovarus e. Short sternum f. Hemivertebrae g. Fused vertebrae h. Short neck i. Scoliosis j. Rib anomaly k. Dislocated hips 6. Histopathological study of temporal bone (auditory organ) a. External ear: arctation or atresia of external acoustic meatus (38%) b. Middle ear i. Anomalies of auditory ossicles (61%) a) Incus or malleus b) Stapes
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ii. Absence or aberration of tensor tympani muscle or its tendon (31%) iii. Complete absence or hypoplasia of stapedial muscle or its tendon (28%) c. Inner ear i. Hypoplasia of the ductus semicirculares (37%) ii. Shortened cochlea (22%) iii. Anomalies of stria vascularis (22%) iv. Absence or hypoplasia of lymphatic valve in utricle (21%) v. Enlargement of canaliculus cochleae (11%) d. Facial nerve: geniculate ganglion cells displaced into the internal auditory meatus (53%)
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. De novo full trisomy 18: 1% or less ii. Low grade parental mosaicism has been reported in two occasions in sporadic cases of trisomy 18 iii. A parent being a balanced carrier of a structural rearrangement: increased recurrence risk pending on the type of structural rearrangement and the pattern of segregation b. Patient’s offspring: unlikely to survive to reproduction 2. Prenatal diagnosis a. Prenatal screening in families without history of trisomy 18 using maternal serum markers i. Low human chorionic gonadotrophin (hCG) and low unconjugated estriol (uE3) in maternal serum during mid-trimester: useful predictors for an increased risk for trisomy 18. ii. Possible future first-trimester biochemical screening for trisomy 18: reduced levels of pregnancyassociated plasma protein A (PAPP-A) and free beta-human chorionic gonadotropin (beta-hCG) at 8–13 weeks gestation. The mean MOM in affected pregnancies was 0.25 for PAPP-A and 0.34 for free beta-hCG. iii. Screening for trisomy 18 using a combination of maternal age, PAPP-A and beta-hCG: reported to achieve a detection rate of 76.6% with a falsepositive rate of 0.5% b. Prenatal ultrasonography: the majority of fetuses with trisomy 18 have detectable structural abnormalities i. Oligohydramnios/polyhydramnios (12%) ii. Intrauterine growth retardation (29%) iii. Two-vessel umbilical cord (40%) iv. CNS a) Abnormally shaped fetal head (strawberry or lemon) (43%) b) Microcephaly c) Dandy-Walker malformation (posterior fossa enlargement associated with cerebellar hypoplasia) d) Enlarged cysterna magna e) Choroid plexus cysts (43%) f) Neural tube defects (9%) v. Micrognathia
vi. vii. viii. ix. x.
Thickened nuchal skin fold Cystic hygroma or lymphangiectasia (14%) Omphalocele (20%) Esophageal atresia Cardiac defects (37%): septal defects with polyvalvular disease xi. Renal anomalies (9%) a) Polycystic kidneys b) Horseshoe and ectopic kidneys. xii. Limb abnormalities a) Clenched hands with overlapping index finger (89%) b) Forehand and hand abnormalities such as a short radial ray c) Rocker-bottom feet d) Club feet c. Amniocentesis or CVS by conventional cytogenetic or FISH techniques i. Straight trisomy 18 ii. Trisomy 18 mosaicism: 54% risk for an abnormal outcome, including phenotypically abnormal offspring, IUGR, or fetal demise. The risk is increased with increasing percentage of amniotic fluid trisomic cell line d. Culturing fetal hematopoietic stem-progenitor cells from maternal blood during pregnancy: a new strategy holding great promise for noninvasive prenatal genetic diagnosis 3. Management a. Genetic counseling in prenatally diagnosed trisomy 18 i. Traumatic experience in the lives of all couples having a fetus with trisomy 18 ii. Emotional upheaval persisting for variable time periods after the diagnoses and the decisions concerning the pregnancy outcomes b. Medical care of trisomy 18 infants i. Supportive ii. Treat infections a) Otitis media b) Upper respiratory infections (bronchitis, pneumonia) c) Urinary tract infections iii. Nasogastric and gastrostomy supplementation for feeding problems iv. Orthopedic management of scoliosis secondary to hemivertebrae v. Primarily medical management of congenital heart disease vi. Diuretic and digoxin for congestive heart failure vii. Referral for early intervention including physical and occupational therapy viii. Psychosocial management: discuss implications, possible outcomes, and available supportive services in the community ix. Severe developmental delay exhibited by longterm survivors presenting the greatest challenge to parental coping during the childhood years x. Informed and empathetic care to families undergoing a complex grieving process that combines both the reactive grief predominant in chronic
TRISOMY 18 SYNDROME
illness and the preparatory grief associated with impending death c. Surgical care of trisomy 18 infants: Because of the extremely poor prognosis, surgical repair of severe congenital anomalies such as esophageal atresia or congenital heart defects is not likely to improve the survival rate of infants and should be discussed with families.
REFERENCES Adler B, Kushnick T: Genetic counseling in prenatally diagnosed trisomy 18 and 21: psychosocial aspects. Pediatrics 69:94–99, 1982. Alizad A, Seward JB: Echocardiographic features of genetic diseases: part 7. Complex genetic disorders. J Am Soc Echocardiogr 13:707–714, 2000. Bass HN, Fox M, Wulfsberg E, et al.: Trisomy 18 mosaicism: clues to the diagnosis. Clin Genet 22:327–330, 1982. Baty BJ, Blackburn BL, Carey JC: Natural history of trisomy 18 and trisomy 13: I. Growth, physical assessment, medical histories, survival, and recurrence risk. Am J Med Genet 49:175–188, 1994. Baty BJ, Jorde LB, Blackburn BL: Natural history of trisomy 18 and trisomy 13: II. Psychomotor development. Am J Med Genet 49:189–194, 1994. Benacerraf BR, Miller WA, Frigoletto FD Jr: Sonographic detection of fetuses with trisomies 13 and 18: accuracy and limitations. Am J Obstet Gynecol 158:404–409, 1988. Bersu ET, Ramirez-Castro JL: Anatomical analysis of the developmental effects of aneuploidy in man—the 18-trisomy syndrome: I. Anomalies of the head and neck. Am J Med Genet 1:173–193, 1977. Biagiotti R, Cariati E, Brizzi L: Maternal serum screening for trisomy 18 in the first trimester of pregnancy. Prenat Diagn 18: 907–913, 1998. Bugge M, Collins A, Petersen MB, et al.: Non-disjunction of chromosome 18. Hum Molec Genet 7:661–669, 1998. Carey J: Health supervision and anticipatory guidance for children with genetic disorders (including specific recommendations for trisomy 21, trisomy 18, and neurofibromatosis I). Pediatr Clin North Am 39:25–53, 1992. Carey JC: The trisomy 18 and 13 syndromes. In: Cassidy S, Allanson J: Management of Genetic Syndromes, Wiley, 2000. Chen H: Trisomy 18. Emedicine, 2001. http://emedicine.com Collins AL, Fisher J, Crolla JA: Further case of trisomy 18 mosaicism with a mild phenotype [letter]. Am J Med Genet 56:121–122, 1995. Edwards JH, Harnden DG, Cameron AH: A new trisomic syndrome. Lancet 1: 787–789, 1960. Embleton ND, Wyllie JP, Wright MJ: Natural history of trisomy 18. Arch Dis Child Fetal Neonatal Ed 75:F38–F41, 1996. Findlay I, Toth T, Matthews P: Rapid trisomy diagnosis (21, 18, and 13) using fluorescent PCR and short tandem repeats: applications for prenatal diagnosis and preimplantation genetic diagnosis. J Assist Reprod Genet 15: 266–275, 1998. Gardner RJM, Sutherland GR: Chromosome Abnormalities and Genetic Counselling. 2nd ed. Oxford University Press, Oxford, 1996. Gilbert-Barnes E: Chromosome Abnormalities. In Gilbert-Barnes E (ed): Potter’s Pathology of the Fetus and Infant. St Louis: Mosby 1997; Vol I:402–404. Gross SJ, Bombard AT: Screening for the aneuploid fetus. Obstet Gynecol Clin North Am 25:573–595, 1998. Hansen CB, Fergestad JM, Barnes A, et al.: An analysis of heart surgery in children with trisomy 18, 13. J Med Invest 48:47A, 2000. Hecht F, Bryant JS, Motulusky AG: The No. 17-18 (E) trisomy syndrome. J Pediatr 63:605–621, 1963.
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Hook EB, Lehrke R, Roesner A, et al.: Trisomy-18 in a 15-year-old female. Lancet 2:910–911, 1965. Huether CA, Martin RL, Stoppelman SM: Sex ratios in fetuses and liveborn infants with autosomal aneuploidy. Am J Med Genet 63:492–500, 1996. Kinoshita M, Nakamura Y, Nakano R: Thirty-one autopsy cases of trisomy 18: clinical features and pathological findings. Pediatr Pathol 9: 445– 457, 1989. Kjaer I, Keeling JW, Hansen BF: Pattern of malformations in the axial skeleton in human trisomy 18 fetuses. Am J Med Genet 65:332–336, 1996. Lam YH, Tang MH: Sonographic features of fetal trisomy 18 at 13 and 14 weeks: four case reports. Ultrasound Obstet Gynecol 13:366–369, 1999. Leporrier N, Herrou M, Herlicoviez M: The usefulness of hCG and unconjugated oestriol in prenatal diagnosis of trisomy 18. Br J Obstet Gynaecol 103:335–338, 1996. Mehta L, Shannon RS, Duckett DP, et al.: Trisomy 18 in a 13-year-old girl. J Med Genet 23:256–278, 1986. Nicolaidis P, Petersen MB: Origin and mechanisms of nondisjunction in human autosomal trisomies. Hum Reprod 13:313–319, 1998. Nicolaides KH, Azar G, Byrne D: Fetal nuchal translucency: Ultrasound screening for chromosome defects in the first trimester of pregnancy. Br Med J 304:704–707, 1992. Nyberg DA, Kramer D, Resta RG: Prenatal sonographic findings of trisomy 18: review of 47 cases. J Ultrasound Med 2:103–113, 1993. Nyberg DA, Souter VL: Sonographic markers of fetal trisomies. J Ultrasound Med 20:655–674, 2001. Ramirez-Castro JL, Bersu ET: Anatomical analysis of the developmental effects of aneuploidy in man—the 18-trisomy syndrome: II. Anomalies of the upper and lower limbs. Am J Med Genet 2:285–306, 1978. Ries MD, Ray S, Winter RB, et al.: Scoliosis in trisomy 18. Spine 15:1281–1284, 1990. Root S, Carey JC: Survival in trisomy 18. Am J Med Genet 1994 49:170–174, 1994. Shields LE, Carpenter LA, Smith KM: Ultrasonographic diagnosis of trisomy 18: is it practical in the early second trimester? J Ultrasound Med 17: 327–331, 1998. Smith A, Silink M, Ruxton T, et al.: Trisomy 18 in an 11-year-old child. J Ment Defic Res 22:277–286, 1978. Smith A, Field B, Learoyd BM: Trisomy 18 at 21 years. Am J Med Genet 34:338–339, 1989. Smith DW, Patau K, Therman E: A new autosomal trisomy syndrome: multiple congenital anomalies caused by an extra chromosome. J Pediatr 57: 338–345, 1960. Sumi SM: Brain malformations in the trisomy 18 syndrome. Brain 93:821–830, 1970. Surana RB, Bain HW, Conen PE: 18 trisomy in a 15-year-old girl. Am J Dis Child 123:75–77, 1972. Tadaki T, Kamiyama R, Okamura HO, et al.: Anomalies of the auditory organ in trisomy 18 syndrome: human temporal bone histopathological study. J Laryngol Otol 117:580–583, 2003. Taylor AI: Autosomal trisomy syndromes: a detailed study of 27 cases of Edwards’ syndrome and 27 cases of Patau’s syndrome. J Med Genet 5: 227–252, 1968. Van Dyke DC, Allen M: Clinical management considerations in long-term survivors with trisomy 18. Pediatrics 85:753–759, 1990. Wallerstein R, Yu M-T, Neu RL, et al.: Common trisomy mosaicism diagnosed in amniocytes involving chromosomes 13, 18, 20 and 21: karyotype-phenotype correlations. Prenat Diagn 20:103–122, 2000. Weber WW, Mamues P, Day R, et al.: Trisomy 17-18(E): studies in longterm survival with reports of two autopsied cases. Pediatrics 34:533– 541, 1964.
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Fig. 2. An infant with trisomy 18 showing small eyes, microstomia, low-set/malformed ears, and short neck.
Fig. 3. An infant with trisomy 18 showing micro/retrognathia, short neck, and characteristic finger grasping pattern.
Fig. 1. A fetus with trisomy 18 showing malformed and low-set ears, characteristic finger clenching pattern, spina bifida, hyperextended knee, and talipes equinovarus.
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Fig. 4. Three infants with trisomy 18 showing reduction malformations of the upper extremities.
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Fig. 5. Two infants with trisomy 18 showing small eyes, micro/retrognathia, and low-set/malformed ears.
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Fig. 8. Translocation trisomy 18 karyotype [46,XX,+18,der(13)t(13;18) (q10;q10)].
Fig. 6. Typical hand grasping pattern (left) and rocker-bottom feet with prominent calcaneus (right) observed in trisomy 18.
Fig. 9. Trisomy 18 shown by FISH (CEP X/SpectrumGreen, CEP 18/SpectrumAqua, Vysis/Abbott) on an uncultured amniocyte. Three copies of the aqua signal are present in the cells (CEP 18). Two copies of the green signal (CEP X) confirm a female fetus.
Fig. 7. Trisomy 18 karyotype (47,XY,+18).
Tuberous Sclerosis ii. Observed in 41% of all hamartomas including renal angiomyolipomas, cardiac rhabdomyomas and subependymal giant cell astrocytomas 4. Hamartin and tuberin a. Widely expressed in the brain b. May interact as part of a cascade pathway that modulates cellular differentiation, tumor suppression, and intracellular signaling 5. Mosaicism in tuberous sclerosis reported a. Somatic mosaicism: The mutation is not found in all cell lines b. Gonadal mosaicism: The mutation found only in gonadal cells and is therefore transmitted to offspring while parents are spared from any disease manifestation 6. Genotype-phenotype correlations a. Overlap of many clinical features exists among the patients with TSC1 and TSC2 mutations. b. Sporadic patients with TSC1 mutations i. On average, milder phenotypic manifestations compared with patients with TSC2 mutations ii. Lower frequencies of seizures iii. Lower frequencies of moderate-to-severe mental retardation iv. Fewer subependymal nodules and cortical tubers v. Less severe kidney involvement vi. No retinal hamartomas vii. Less severe facial angiofibroma c. Some features are rare or not seen at all in TSC1 patients i. Grade 2–4 kidney cysts or angiomyolipomas ii. Forehead plaques iii. Retinal hamartomas iv. Liver angiomyolipomas d. Both germline and somatic mutations are less common in TSC1 than TSC2 e. Patients without mutation i. Milder than patients with TSC2 mutations ii. Somewhat distinct from patients with TSC1 mutations
Tuberous sclerosis is the second most common neurocutaneous syndrome after neurofibromatosis. The term “tuberous sclerosis” derived from the “tubers” (swellings or protuberances) and areas of “sclerosis” (hardening) of the cerebral gyri that calcifies with age. The classic description of the syndrome includes Bogt’s triad: mental retardation, seizures, and adenoma sebaceum (a misnomer) or facial angiofibromas. Tuberous sclerosis affects about one in 6000 newborns.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant i. Almost complete penetrance ii. Extremely variable in its manifestations and severity b. Sporadic (new mutations) in two third of cases 2. Caused by mutations in either of the following two tuberous sclerosis complex (TSC) genes a. TSC1 i. Located on chromosome 9q34 ii. Encodes protein, hamartin (TSC1), a protein implicated in regulating cell adhesion via interactions with cortical actin filaments and a plasma membrane binding protein ezrin-radixin-moesin, part of a Rho-mediated signaling pathway iii. Approximately 50% of tuberous sclerosis families show linkage to TSC1. iv. Most described mutations in the TSC1 gene result in a truncated protein. b. TSC2 i. Located on chromosome 16p13.3 ii. Encodes protein, tuberin (TSC2), a protein implicated in regulating cytoplasmic vesicle transport to the cell membrane iii. Approximately 50% of families show linkage to TSC2. iv. Many mutations in the TSC2 gene are large (contiguous) deletions, which may involve the PKD1 gene, resulting in a severe phenotype called very early onset polycystic kidney disease. 3. Both TSC1 and TSC2 a. Have properties consistent with tumor suppressor genes functioning according to Knudson’s “two hit” hypothesis b. The clinical variability occurs secondary to the random nature of the second “hit” in individuals carrying a germline mutation. c. Loss of heterozygosity for TSC1 or TSC2 gene i. Suggests that one mutation is acquired embryonically and another is acquired later on somatically (2-hit hypothesis)
CLINICAL FEATURES
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1. Characteristic cutaneous features (virtually 100% of cases) a. Hypomelanotic macules (“ash-leaf spots”) (87–100% of cases) i. One of the earliest skin lesions (often present at birth) ii. Commonly on trunk and buttocks, rarely on the face, and best appreciated by the Wood’s fluorescence lamp iii. Not specific to tuberous sclerosis because they are seen in unaffected children
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iv. Smaller depigmented spots over the anterior shins: characteristically distributed in a “confetti” fashion (clustered skin lesions with a reticulated appearance) b. Shagreen patches (a form of collagenomas) (20–80%) i. Elevated discolored skin lesions commonly over lumbosacral region, observed in about 21% of patients ii. Age at presentation: birth to adulthood c. Facial angiofibromas (47–90%) i. One of the most common and specific cutaneous manifestations ii. Causing the most disfigurement among the skin lesions iii. Red to brown nodules, observed over the nose and cheeks in bilaterally symmetrical butterfly distribution. Rarely segmental tuberous sclerosis may present as unilateral facial angiofibromas iv. Age of presentation a) Usually appear after two years of age b) Increase in size and number of facial angiofibromas with time c) Observed in about 80% of adults with tuberous sclerosis v. Chance of small and discrete papules of facial angiofibromas to become confluent and fungating lesions vi. Presence of large fibromas without angiomatous appearance on the scalp or the forehead areas (forehead fibrous plaques) d. Periungual fibromas (17–87%): characteristically appear during puberty and persist through life e. Café au lait spots: seen in 15–30% of patients with tuberous sclerosis f. Molluscum fibrosum pendulum (skin tags) (23%) 2. CNS abnormalities (the most common manifestations of the disorder) a. Epilepsy i. The major neurologic manifestation, affecting 85% of patients ii. Onset usually at few months of age iii. Typically with initial classic hypsarrhythmia and infantile spasms, which transform into adulttype partial complex or tonic-clonic seizures iv. Carries a poor prognosis with congnitive impairment v. Intractable seizures b. Presence of cortical “tubers” i. A pathognomonic sign ii. Subependymal nodules (abnormal neuronal and glial elements): the most common cerebral lesion iii. Cortical or subcortical white matter tubers (70% of cases) a) Composed of abnormal giant astrocytes b) Found in 90% of patients with tuberous sclerosis c) Large cortical tubers may occasionally block the foramen of Monro resulting in hydrocephalus
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c. Subependymal giant cell astrocytomas i. The most common CNS tumors (6–14%) ii. Subependymal nodules lining the ventricles may calcify iii. A radiologically confirmed cortical tuber or calcified subependymal nodule are highly suggestive of tuberous sclerosis iv. Rare malignant transformation of these astrocytomas, accounting for 25% of deaths in tuberous sclerosis d. Other abnormalities i. Cerebral atrophy ii. Cerebral infarct iii. Cerebral aneurysm iv. Arachnoid cyst Developmental disorders (>50%) a. Childhood i. Learning disabilities ii. Behavioral problems iii. Pervasive developmental disorder iv. Autism more common in childhood v. Hyperactivity or attention deficit hyperactivity disorder (ADHD) vi. Aggression b. Adulthood: Mental retardation present in less than 50% of the affected individuals Ocular involvement (at least 50% of the patients) a. Retinal and optic nerve astrocytic hamartomas (the most frequent manifestations) b. Retinal phakoma i. Astrocytomas of the retina ii. Often called “mulberry lesions” iii. Absence of the normal “red reflex” in the newborn suggests the presence of retinal phakoma. c. Visual loss resulting from: i. Macular hamartoma ii. Vitreous hemorrhage iii. Papilledema or optic atrophy secondary to intracranial tumors d. Rare sector hypopigmentation of the iris, vitiligo, or poliosis of the eyelid and eyelashes Dental involvement a. Pitting of the dental enamel i. Invariably present in the permanent teeth ii. Seen in the primary (deciduous) teeth (30%) iii. Rarely produce symptoms b. Gingival fibromas (50% of children; 70% of adults) Neoplasms affecting heart, kidneys, lungs, and other organ systems a. Cardiac rhabdomyomas i. The earliest diagnostic finding in some patients detected on prenatal sonography ii. Detected by echocardiography, rarely causing problems iii. Observed in two-thirds of affected children. However, more than 80% of children with cardiac rhabdomyomas have tuberous sclerosis. iv. Usually resolve spontaneously or regress with age
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v. A rare cause of prenatal and neonatal cardiac failure, mostly from dysrhythmias vi. Rare tumor obstruction to cardiac valves or chambers b. Renal cysts or angiomyolipomas (70–80% of patients) i. Bilateral multiple renal angiomyolipomas (70%) a) Diagnostic of tuberous sclerosis b) Renal angiomyolipomas are benign tumors but contain vascular tissue, which may cause bleeding, hypovolemic shock, and renal failure ii. Epithelial cysts (20%) iii. Polycystic kidney disease (2–3%) iv. Rare occurrence of renal cell carcinoma (<1%) v. Malignant angiomyolipoma (<1%) vi. Benign adenomatous hamartoma (oncocytoma) (<1%) vii. Lymphangioleiomyomatosis of the renal sinus: rare c. Pulmonary manifestations i. Lymphangio(leio)myomatosis (1–6% of patients) a) Observed almost exclusively in young female patients, suggesting that a hormonal component is involved in the development of pulmonary sequelae b) Progressive, diffuse interstitial disease, detected by chest radiographs which show diffuse reticular pattern and multiple cyst lesions in the lungs c) Often complicated by pneumothorax from rupture of subpleural pulmonary cysts d) The end-stage disease shows “honeycomb” lungs. ii. Multifocal micronodular pneumocyte hyperplasia a) Affects men and women b) May accompany lymphangioleiomyomatosis d. Hamartomas and polyposis of the stomach, intestine, and colon i. Almost never cause significant symptoms ii. Occasional GI bleeding leading to positive tests for fecal occult blood e. Hepatic cysts and angiomyolipomas (up to 24%) i. Asymptomatic and nonprogressive ii. Marked female predominance f. Arterial aneurysms reported in the brain, aorta, and axillary arteries g. Musculoskeletal manifestations i. Sclerotic and hypertrophic lesions of bone a) Mostly an incidental finding b) Occasionally palpable and associated with pains c) Common locations including calvarium, pelvis, vertebrae, and long bones ii. Bone lucencies a) Nonspecific hamartomas b) Found in the phalanges of the hands and feet c) Usually asymptomatic d) Involvement in two-thirds of patients 7. Pregnancy does not increase the risk of developing renal and pulmonary complications in women with tuberous sclerosis.
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8. Diagnostic criteria of tuberous sclerosis complex (first proposed in 1992). The presence of one of the primary diagnostic criteria is considered sufficient to diagnose tuberous sclerosis complex a. Primary features i. Facial angiofibromas ii. Multiple ungula fibromas (or periungual fibromas in the absence of trauma) iii. Cortical tuber (histologically confirmed) iv. Subependymal nodule or giant cell astrocytomas (histologically confirmed) v. Multiple calcified subependymal nodules protruding into the ventricle (radiographic evidence) vi. Multiple retinal astrocytomas (retinal hamartomas) b. Secondary features i. Affected first-degree relative ii. Cardiac rhabdomyoma (histologic or radiographic confirmation) iii. Other retinal hamartomas or achromic patch iv. Cerebral tubers (radiographic confirmation) v. Noncalcified subependymal nodules (radiographic confirmation) vi. Shagreen patch vii. Forehead plaque viii. Pulmonary lymphangiomyomatosis (histologic confirmation) (lymphangioleiomyomatosis) ix. Renal angiomyolipoma (radiographic or histologic confirmation) x. Renal cysts (histologic confirmation) c. Tertiary features i. Hypomelanotic macules (three or more ash-leaf spots) ii. “Confetti” skin lesions iii. Renal cysts (radiographic evidence) iv. Randomly distributed enamel pits in deciduous or permanent teeth v. Hamartomatous rectal polyps (histologic confirmation) vi. Bone cysts (radiographic evidence) vii. Pulmonary lymphangiomyomatosis (radiographic evidence) viii. Cerebral white-matter “migration tracts” or heterotropias (radiographic evidence) ix. Gingival fibromas x. Hamartoma of other organs (histologic confirmation) xi. Infantile spasms d. Diagnostic criteria i. Definitive: either one primary, two secondary or one primary plus two tertiary features ii. Probable: either one secondary plus one tertiary or three tertiary features iii. Suspect: either one secondary or two tertiary features 7. The Tuberous Sclerosis Consensus Conference: devised the above clinical diagnostic criteria in 1998 (Roach et al., 1998) a. Major features i. Facial angiofibromas or forehead plaque ii. Nontraumatic ungual or periungual fibroma iii. Hypomelanotic macules (three or more)
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iv. Shagreen patch (connective tissue nevus) v. Multiple retinal nodular hamartomas vi. Cortical tuber vii. Subependymal nodule viii. Subependymal giant cell astrocytoma ix. Cardiac rhabdomyoma, single or multiple x. Lymphangiomyomatosis xi. Renal angiomyolipoma b. Minor features i. Multiple, randomly distributed pits in dental enamel ii. Hamartomatous rectal polyps iii. Bone cysts iv. Cerebral white matter radial migration lines v. Gingival fibromas vi. Nonrenal hamartoma vii. Retinal achromic patch viii. “Confetti” skin lesions ix. Multiple renal cysts c. Diagnostic criteria i. Definitive diagnosis: Presence of two major features or one major feature plus two minor features ii. Probable diagnosis: Presence of one major feature plus one minor feature iii. Possible diagnosis: Presence of one major feature or two or more minor features 8. Prognosis a. The mild form of tuberous sclerosis: live full life without loss of function b. The severe form: significant morbidity and mortality from seizures, mental retardation, and associated cardiac, retinal, renal and pulmonary pathology c. Causes of deaths i. Epilepsy ii. Cardiac arrhythmias iii. Complications of a giant cell astrocytomas or pulmonary lymphangiomyomatosis
DIAGNOSTIC INVESTIGATIONS 1. 2. 3. 4. 5. 6.
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Cutaneous evaluation including Wood’s lamp Ophthalmologic evaluation for harmatomas Echocardiography to identify rhabdomyomas ECG for cardiac arrhythmias EEG for seizures Radiography of the skull a. Calcification frequently seen in subependymal nodules and giant cell astrocytomas b. Les commonly seen in cortical and white matter tubers c. Calcification increases with the age of the patient Plain chest radiographic films: diffuse reticular pattern in lymphangiomyomatosis of the lung Pulmonary CT scan a. Diffuse interstitial changes with infiltrates b. Cystic changes Renal ultrasound/CT/MRI a. Assess angiomyolipomas b. Assess renal cysts Neuroimagings by MRI or CT of the brain a. Calcification best detected on computed tomography
b. Magnetic resonance imaging more sensitive for detecting small subependymal nodules and cortical and white matter tubers, especially when not calcified i. Extent and number of cortical tubers ii. Subependymal gliomas iii. Dilated lateral ventricles iv. Hamartomatous foci v. Vascular dysplastic lesions such as aneurysms vi. Identify subependymal giant cell astrocytomas before occurrence of obstructive hydrocephalus 11. Histologic findings a. Angiofibromas i. Atrophic sebaceous glands with dermal fibrosis and dilation of some capillaries ii. “Glial” appearance of fibrosis due to the large size and stellate shape of the fibroblasts iii. Absence of elastic tissue in the angiofibromas b. Ungual fibromas i. Fibrosis ii. Rare capillary dilation c. Shagreen patches i. Increased dense sclerotic mass of broad collagenous bundles ii. Normal collagen bundles sometimes arranged in an interwoven pattern iii. Reduced elastic tissue d. Hypopigmented ash-leaf macule i. Normal melanocytes numbers with decreased pigmentation ii. Smaller melanosomes with defective melanization by electron microscopy 12. DNA mutation analysis a. Mutation of TSC1 gene i. 50% of familial cases ii. About 10% of sporadic cases b. Mutation of TSC2 gene i. 50% of familial cases ii. About 60–70% of sporadic cases c. Linkage analysis using closely flanking/intragenic polymorphic markers for the two tuberous sclerosis genes to determine which of the two genes is likely to be responsible for the disorder if multiple individuals in different generations of a family are affected with tuberous sclerosis d. A deletion of the two contiguous genes (TSC2 and APKD1) likely responsible if a child with tuberous sclerosis is found to have polycystic kidney disease
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. 1–4% recurrence risk (in case of unaffected parents) due to germline mosaicism and nonpenetrance of the disorder ii. 50% if one of the parent is affected b. Patient’s offspring: 50% 2. Prenatal diagnosis a. Prenatal ultrasonographic detection of cardiac lesions consistent with rhabdomyoma
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i. 50% risk for tuberous sclerosis in the fetus ii. Cardiac rhabdomyomas a) The most common cardiac tumor diagnosed in utero and in children b) Favorable natural history of tumors detected prenatally: Most tumors regress after the third trimester c) In rare cases, there is progression in utero with a fetal demise risk of 4–6% b. Molecular genetic analysis from amniocytes or CVS for the known familial disease-causing mutation 3. Management a. Multidisciplinary team approach b. Early intervention programs c. Assess intellectual function and educational needs d. Pharmacologic management of behavioral problems e. Treat cardiac failure or cardiac arrhythmias f. Anticonvulsants for seizure control: Treatment for infantile spasm is difficult because it is often intractable to conventional antieplileptic drugs i. ACTH among other anticonvulsant therapies with variable benefits ii. Vigabatrin g. Surgical care i. Laser treatment of facial angiofibromas ii. Removal of ungual fibromas by laser, diathermy, liquid nitrogen, or dermabrasion iii. CSF shunting to relief raised intracranial pressure iv. Epilepsy surgery: Unifocal onset seizures and mild to no developmental delay at the time of surgery are predictive of excellent long-term outcome a) Focal cortical resection (tuberectomy) b) Lobar or multilobar resection c) Corpus callosotomy v. Vagus nerve stimulation vi. A partial nephrectomy or selective embolization preferable to total nephrectomy for treating angiomyolipomata vii. Cystic renal lesions rarely required surgery viii. Renal transplantation for end-stage renal insufficiency resulting from replacement of renal parenchyma by angiomyolipomas and growing cysts or from the removal of the kidneys for intractable hemorrhage a) Offers prolonged survival b) Appears to be the treatment of choice in such patients
REFERENCES Al-Saleem T, Wessner LL, Scheithauer BW, et al.: Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer 83:2208–2216, 1998. Alcorn DM: Phacomatoses for the general ophthalmologist. Ophthalmol Clin N Am 12:243–253, 1999. Ali JB, Sepp T, Ward S, et al.: Mutations in the TSC1 gene account for a minority of patients with tuberous sclerosis. J Med Genet 35:969–972, 1998. Altman NR, Purser RK, Post MJ: Tuberous sclerosis: characteristics at CT and MR imaging. Radiology 167:527–532, 1988. Au K-S, Pollom GJ, Roach ES, et al.: TSC1 and TSC2 gene mutations: detection and genotype/phenotype correlation. Am J Hum Genet 63(S):350, 1998.
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Au KS, Rodriguez JA, Finch JL, et al.: Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis patients. Am J Hum Genet 62:286–294, 1998. Avellino AM, Berger MS, Rostomily RC, et al.: Surgical management and seizure outcome in patients with tuberous sclerosis. J Neurosurg 87:391–396, 1997. Bader RS, Chitayat D, Kelly E, et al.: Fetal rhabdomyoma: prenatal diagnosis, clinical outcome, and incidence of associated tuberous sclerosis complex. J Pediatr 143:620–624, 2003. Baker P, Piven J, Sato Y: Autism and tuberous sclerosis complex: prevalence and clinical features. J Autism Dev Disord 28:279–285, 1998. Baron Y, Barkovich AJ: MR imaging of tuberous sclerosis in neonates and young infants. AJNR Am J Neuroradiol 20:907–916, 1999. Barron RP, Kainulainen VT, Forrest CR, et al.: Tuberous sclerosis: clinicopathologic features and review of the literature. J Craniomaxillofac Surg 30:361–366, 2002. Baumgartner JE, Wheless JW, Kulkarni S, et al.: On the surgical treatment of refractory epilepsy in tuberous sclerosis complex. Pediatr Neurosurg 27:311–318, 1997. Benvenuto G, Li S, Brown SJ, et al.: The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination. Oncogene 19:6306–6316, 2000. Bernauer TA, Mirowski GW, Caldemeyer KS: Tuberous sclerosis. Part II. Musculoskeletal and visceral findings. J Am Acad Dermatol 45:450–452, 2001. Brook-Carter PT, Peral B, Ward CJ, et al.: Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease—a contiguous gene syndrome. Nat Genet 8:328–332, 1994. Caldemeyer KS, Mirowski GW: Tuberous sclerosis. Part I. Clinical and central nervous system findings. J Am Acad Dermatol 45:448–449, 2001. Carbonara C, Longa L, Grosso E, et al.: Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas. Genes Chromosomes Cancer 15:18–25, 1996. Cassidy SB, Pagon RA, Pepin M, et al.: Family studies in tuberous sclerosis. Evaluation of apparently unaffected parents. J Am Med Assoc 249:1302–1304, 1983. Crino PB, Henske EP: New developments in the neurobiology of the tuberous sclerosis complex. Am Acad Neurol 53:1384–1390, 1999. Curatolo P, Cusmai R, Cortesi F, et al.: Neuropsychiatric aspects of tuberous sclerosis. Ann N Y Acad Sci 615:8–16, 1991. Dabora SL, Jozwiak S, Franz DN, et al.: Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 68:64–80, 2001. Ewalt DH, Sheffield E, Sparagana SP, et al.: Renal lesion growth in children with tuberous sclerosis complex. J Urol 160:141–145, 1998. Fitzpatrick TB: History and significance of white macules, earliest visible sign of tuberous sclerosis. Ann N Y Acad Sci 615:26–35, 1991. Franz DN: Diagnosis and management of tuberous sclerosis complex. Semin Pediatr Neurol 5:253–268, 1998. Franz DN, Glauser TA: Tuberous sclerosis. eMedicine, 2002. Fryer AE, Chalmers A, Connor JM, et al.: Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet 1:659–661, 1987. Gibbs JL: The heart and tuberous sclerosis. An echocardiographic and electrocardiographic study. Br Heart J 54:596–599, 1985. Gillberg IC, Gillberg C, Ahlsen G: Autistic behaviour and attention deficits in tuberous sclerosis: a population-based study. Dev Med Child Neurol 36:50–56, 1994. Gomez MR: Tuberous Sclerosis, 2 ed. Raven Press, New York, 1988. Gomez MR: Phenotypes of the tuberous sclerosis complex with a revision of diagnostic criteria. Ann N Y Acad Sci 615:1–7, 1991. Goodman M, Lamm SH, Engel A, et al.: Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex. J Child Neurol 12:85–90, 1997. Green AJ, Smith M, Yates JR: Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. Nat Genet 6:193–196, 1994. Gutierrez GC, Smalley SL, Tanguay PE: Autism in tuberous sclerosis complex. J Autism Dev Disord 28:97–103, 1998. Haines JL, Short MP, Kwiatkowski DJ, et al.: Localization of one gene for tuberous sclerosis within 9q32-9q34, and further evidence for heterogeneity. Am J Hum Genet 49:764–772, 1991.
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Hancock E, Osborne JP: Vigabatrin in the treatment of infantile spasms in tuberous sclerosis. Literature review. J Child Neurol 14:71–74, 1999. Henske EP, Neumann HP, Scheithauer BW, et al.: Loss of heterozygosity in the tuberous sclerosis (TSC2) region of chromosome band 16p13 occurs in sporadic as well as TSC-associated renal angiomyolipomas. Genes Chromosomes Cancer 13:295–298, 1995. Houser OW, Shepherd CW, Gomez MR: Imaging of intracranial tuberous sclerosis. Ann N Y Acad Sci 615:81–93, 1991. Hunt A, Dennis J: Psychiatric disorder among children with tuberous sclerosis. Dev Med Child Neurol 29:190–198, 1987. Hurst JS, Wilcoski S: Recognizing an index case of tuberous sclerosis. Am Fam Physician 61:703–708, 2000. Jarrar RG, Buchhalter JR, Raffel C: Long-term outcome of epilepsy surgery in patients with tuberous sclerosis. Neurology 62:479–481, 2004. Johnson CL, Pedersen R: Tuberous sclerosis. eMedicine 2002. Jones AC, Daniells CE, Snell RG, et al.: Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Hum Mol Genet 6:2155– 2161, 1997. Jones AC, Shyamsundar MM, Thomas MW, et al.: Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am J Hum Genet 64:1305–1315, 1999. Jozwiak S, Kawalec W, Dluzewska J, et al.: Cardiac tumours in tuberous sclerosis: their incidence and course. Eur J Pediatr 153:155–157, 1994. Kandt RS, Haines JL, Smith M, et al.: Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. Nat Genet 2:37–41, 1992. Lendvay TS, Marshall FF: The tuberous sclerosis complex and its highly variable manifestations. J Urol 169:1635–1642, 2003. Levine D, Barnes P, Korf B, et al.: Tuberous sclerosis in the fetus. Secondtrimester diagnosis of subependymal tubers with ultrafast MR imaging. Am J Roentgenol 175:1067–1069, 2000. Martignoni G, Pea M, Rocca PC, et al.: Renal pathology in the tuberous sclerosis complex. Pathology 35:505–512, 2003. Mitchell AL, Parisi MA, Sybert VP: Effects of pregnancy on the renal and pulmonary manifestations in women with tuberous sclerosis complex. Genet Med 5:154–160, 2003. Muller RF: Tuberous sclerosis. In: Cassidy SB, Allanson JE (eds): Management of Genetic Syndromes. New York: Wiley-Liss, 2001. Nambi R: Tuberous sclerosis. eMedicine 2001. Nevin NC, Pearce WG: Diagnostic and genetical aspects of tuberous sclerosis. J Med Genet 5:273–280, 1968. Northrup H: Tuberous sclerosis complex. Gene Reviews, 2002. Northrup H, Wheless JW, Bertin TK, et al.: Variability of expression in tuberous sclerosis. J Med Genet 30:41–43, 1993. O’Callaghan FJ, Osborne JP: Advances in the understanding of tuberous sclerosis. Arch Dis Child 83:140–142, 2000. Osborne JP, Fryer A, Webb D: Epidemiology of tuberous sclerosis. Ann NY Acad Sci 615:125–127, 1991. Papaioannou EG, Staikou CV, Lambadarioui A, et al.: Anesthetic management of a patient with tuberous sclerosis presenting for renal transplantation. J Anesth 17:193–195, 2003.
Roach ES, Smith M, Huttenlocher P, Bhat M, Alcorn D, Hawley L: Report of the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association. J Child Neurol 7:221–224, 1992. Roach ES, Gomez MR, Northrup H: Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 13:624–628, 1998. Roach ES, DiMario FJ, Kandt RS, et al.: Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation. National Tuberous Sclerosis Association. J Child Neurol 14:401–407, 1999. Rose VM, Au KS, Pollom G, et al.: Germ-line mosaicism in tuberous sclerosis: how common? Am J Hum Genet 64:986–992, 1999. Sampson JR, Maheshwar MM, Aspinwall R, et al.: Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene. Am J Hum Genet 61:843–851, 1997. Shepherd CW, Gomez MR, Lie JT, et al.: Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 66:792–796, 1991. Smith HC, Watson GH, Patel RG, et al.: Cardiac rhabdomyomata in tuberous sclerosis: their course and diagnostic value. Arch Dis Child 64:196–200, 1989. Stillwell TJ, Gomez MR, Kelalis PP: Renal lesions in tuberous sclerosis. J Urol 138:477–481, 1987. Strizheva GD, Carsillo T, Kruger WD, et al.: The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis. Am J Respir Crit Care Med 163:253–258, 2001. Tekin M, Bodurtha JN, Riccardi VM: Café au lait spots: The pediatrician’s perspective. Pediatr Rev 22:82–90, 2001. The European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75:1305–1315, 1993. Trauner MA, Ruben BS, Lynch PJ: Segmental tuberous sclerosis presenting as unilateral facial angiofibromas. J Am Acad Dermatol 49:S164–166, 2003. Tworetzky W, McElhinney DB, Margossian R, et al.: Association between cardiac tumors and tuberous sclerosis in the fetus and neonate. Am J Cardiol 92:487–489, 2003. van Slegtenhorst M, de Hoogt R, Hermans C, et al.: Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805–808, 1997. van Slegtenhorst M, Nellist M, Nagelkerken B, et al.: Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet 7:1053–1057, 1998. Verhoef S, Bakker L, Tempelaars AM, et al.: High rate of mosaicism in tuberous sclerosis complex. Am J Hum Genet 64:1632–1637, 1999. Vicente MP, Pons M, Medina M: Pulmonary involvement in tuberous sclerosis. Pediatr Pulmonol 37:178–180, 2004. Weiner DM, Ewalt DH, Roach ES, et al.: The tuberous sclerosis complex: a comprehensive review. J Am Coll Surg 187:548–561, 1998. Yeung RS: Tuberous sclerosis as an underlying basis for infantile spasm. Int Rev Neurobiol 49:315–332, 2002. Yeung RS: Multiple roles of the tuberous sclerosis complex genes. Genes Chromosomes Cancer 38:368–375, 2003. Young JM, Burley MW, Jeremiah SJ, et al.: A mutation screen of the TSC1 gene reveals 26 protein truncating mutations and 1 splice site mutation in a panel of 79 tuberous sclerosis patients. Ann Hum Genet 62 (Pt 3):203–213, 1998.
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Fig. 1. An ash-leaf spot is observed in a child affected with tuberous sclerosis, inherited from his mother who has characteristic facial angiofibromas with symmetrical “butterfly” distribution on the nasolabial folds and cheeks.
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TUBEROUS SCLEROSIS by high or low signals. Some lesions can be seen in the periventricular region. Abbreviations: AO (aorta), IAS (interatrial septum), IVS (interventricular septum), LA (left atrium), LV (left ventricle), MV (mitral valve), RA (right atrium), RV (right ventricle), TV (tricuspid valve).
Fig. 3. Severe facial angiofibromas in symmetrical butterfly distribution over nose and cheek with a large forehead plaque. Some angiofibromas have become confluent and fungating lesions. Fig. 2. A 3-month-old infant was found to have small angiofibromatous skin lesions on the cheek, two depigmented spots on the back, and a white round lesion in the left fundus. Echocardiography showed a tumor (measured 2 cm × 1 cm) in the left ventricular cavity (A, four chamber view; B, short axis view; C, long axis view). MRI with T1enhanced images (D,E) showed the same rhabdomyoma (arrow) in the left ventricular cavity. T1-enhanced (F) and T2-enhanced (G) images of the brain showed many lesions at subcortical white matter indicated
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Fig. 4. An adult with tuberous sclerosis showing typical facial angiofibromas and a scalp plaque. A plain skull X-ray film demonstrated intracranial calcifications. CT of the brain showed presence of calcified subependymal nodules. CT scan of the abdomen demonstrates an enlarged left kidney. Histologic examination of the tumor showed renal cell carcinoma.
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Fig. 6. Shagreen patches are seen in upper back and lower back in two different patients with tuberous sclerosis. Periungual (4th finger) and ungual (thumb) fibromas were present in one of the patient.
Fig. 5. Four adults with tuberous sclerosis showing typical facial features.
Turner Syndrome vi. Short 4th metacarpals vii. Hypoplastic nails viii. Multiple pigmented nevi ix. Coarctation of the aorta b. Absence or deletion of the long arm of the X chromosome correlates with infertility and gonadal dysgenesis. c. The degree of mosaicism correlates with the presence of clinical features of Turner syndrome. d. Severe phenotype associates with a small or tiny ring X chromosome which lacks the XIST (X-inactivespecific transcript) at Xq13: i. Loss of XIST results in functional X disomy for the sequences contained in the ring. ii. Some r(X), ascertained because of severe phenotypes, undergo X inactivation.
In 1938, Turner reported a syndrome of sexual infantilism, short stature, webbed neck, cubitus valgus, and primary amenorrhea in seven female patients. Later in 1954, it was observed that the ovaries were usually replaced by streaks of stroma without follicles; hence the name gonadal agenesis. Negative sex chromatin was discovered in 1954; only one X chromosome was demonstrated cytogenetically in these patients in 1959. About 99% of 45,X fetuses abort spontaneously and only 1% of these fetuses survive to term. Despite this, Turner syndrome is a relatively common chromosome disorder affecting 1 in 2500 female live births. About 10% of all spontaneous abortuses have a 45,X karyotype.
GENETICS/BASIC DEFECTS 1. Caused by complete or partial X chromosome monosomy in all or some of the body cells 2. Short stature and skeletal manifestations (short 4th metacarpals, cubitus valgus, Madelung deformity, higharched palate, and short neck) are attributed to haploinsufficiency of the SHOX, the short-stature homeoboxcontaining gene on the pseudoautosomal region of the sex chromosomes (Xp22 and Yp11.3). SHOX gene is also known as PHOG gene for pseudoautosomal homeoboxcontaining osteogenic gene, lying on the very tip of the short arm of both sex chromosomes 3. Pathogenesis a. Gonadal dysgenesis: Oocytes undergoing accelerated degeneration during the first meiosis, resulting in loss of nearly all oocytes by late childhood b. Somatic stigmata i. Lymph fluid stasis caused by lymphatic hypoplasia results in distension of the main and tributary lymphatic ducts and generalized lymphedema ii. Distended lymphatics and lymphedema cause mechanical extension of surrounding tissues, giving rise to deformations recognized as lymphatic obstruction stigmata: a) Webbed neck b) Low posterior hairline c) Rotated auricles d) Puffy hands and feet e) Redundant skin f) Nail hypoplasia g) Whorl dominant finger tip pattern 4. Phenotype–karyotype correlation a. Absence or deletion of the short arm of the X chromosome correlates with Turner stigmata: i. Short stature ii. Broad chest iii. Widespread nipples iv. Webbing of the neck v. Peripheral lymphedema at birth
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1. Skeletal manifestations a. Short stature (100%): an invariant feature in the 45,X Turner syndrome b. Characteristic growth pattern i. Intrauterine growth retardation ii. Progressive decline in growth velocity in childhood iii. Lack of pubertal growth spurt iv. Delayed growth cessation c. Cubitus valgus d. Madelung deformity of the wrist (a bayonet-like deformity of the wrist) with decreased extension and supination e. Hypoplastic nails f. Short 4th metacarpals 2. Characteristic craniofacial features a. Down slanting of the palpebral fissures b. Epicanthal folds c. Occasional ptosis and strabismus d. Midfacial hypoplasia e. Broad nasal bridge f. High arched palate g. Micrognathia h. Rotated auricles 3. Teeth a. Crowding b. Malocclusion 4. Neck a. Short and broad neck b. Webbed neck (pterygium coli) with low posterior hairline from the resolution of the cystic hygroma that was present in fetal life 5. Chest a. Shield chest b. Increased internipple distance
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6. Congenital heart defects (30%) a. Coarctation of the aorta b. Bicuspid aortic valve c. Aortic stenosis d. Aneurysm (aortic root dilatation) e. Cystic medial necrosis of the aorta 7. Vascular anomalies a. Multiple intestinal telangiectasia b. Hemangiomas c. Lymphangiectasia d. Venous ectasias e. Intermittent and recurrent gastrointestinal bleeding f. Protein-losing enteropathy secondary to gastrointestinal lymphangiomas g. Chylous fluid accumulation in the abdomen and chest 8. Peripheral lymphedema in the newborn infant involving dorsum of the hands and feet 9. Nail dysplasia a. Concave fingernails b. Upturned toenails 10. Skin a. Redundant skin b. Multiple pigmented nevi c. Tendency of hypertrophic scarring or keloid formation 11. Gonadal dysgenesis a. Sexual infantilism: one of the most common clinical findings b. Primary amenorrhea (the rule) c. Spontaneous menstruation occurring in about 5% of patients. Some of these women even give birth (3–5%). d. Delayed pubertal development in most patients e. Up to 30% of patients with at least some pubertal development indicating the presence of follicles in their ovaries in adolescence f. A high frequency of miscarriage reported among the spontaneous pregnancies of women with Turner syndrome g. Progressive ovarian failure h. Infertility/sterility 12. Genitourinary lesions a. Horseshoe and ectopic kidneys b. Ureteropelvic obstruction c. A double collecting system d. A bifid renal pelvis e. Hydronephrosis f. Vaginal agenesis: rare 13. Hypertension (common even without cardiac or renal malformations) 14. Conductive and sensorineural hearing losses 15. Autoimmune disease a. A markedly increased incidence of thyroid antibodies b. Autoimmune hypothyroidism c. Impaired serum glucose tolerance in 25–60% of patients d. Diabetes mellitus in 5% of patients e. An increased incidence of inflammatory bowel disease i. Regional enteritis ii. Ulcerative colitis f. Rheumatoid arthritis g. Acute hyperthyroidism: rare
16. Abnormal dermatoglyphics a. Predominant digital whorls b. Distal triradii 17. Psychosocial aspects a. Significantly higher verbal level than performance level attributed to a specific space form-perception deficit b. Arithmetic subtests: most difficult among verbal subtests c. Difficulty in performance i. Reading ii. Figure drawing iii. Geometry iv. Arithmetic 18. Presence of Y chromosome material in some cases of Turner syndrome a. A high risk of developing gonadoblastoma and dysgerminoma b. Requiring preventive removal of the dysgenetic gonads 19. Mosaic patients with a structurally abnormal X chromosome a. Classic Turner phenotype i. X-derived marker in majority of cases ii. Usually a large ring X chromosome that includes XIST not associated with a severe phenotype, although a low IQ or even mental retardation has been observed in some cases b. Severe phenotype i. Mental retardation ii. Dysmorphic features uncharacteristic of Turner syndrome iii. Observed in patients associated with a small or tiny ring X chromosome lacking the XIST gene at Xq13
DIAGNOSTIC INVESTIGATIONS 1. Endocrine study a. Very low estrogen levels b. Elevated pituitary gonadotrophins after puberty 2. Karyotype analyses a. 45,X i. Observed in 50% of cases ii. Maternal origin of the X chromosome in twothirds of cases b. Structurally abnormal sex chromosome, such as i(Xq) c. Mosaicism with a second cell line containing a normal or abnormal X or Y i. Most common forms of mosaicism a) 45,X/46,XX b) 45,X/46,X,i(Xq) ii. Containing a sex marker chromosome in about 20% of cases a) Sex marker chromosome: usually an X chromosome b) Second cell line containing a structurally abnormal Y chromosome in 6% of cases d. Determination of the chromosomal origin of sex marker chromosomes i. Fluorescence in situ hydridization (FISH)
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3.
4. 5. 6.
7.
ii. Primed in situ labeling (PRINS) diagnostic for repetitive sequences in specific human chromosomes e. Painting probes and libraries to detect “hidden” mosaicism i. Classical alpha-satellite probes for the X (CEP-X) chromosome and Y chromosomes (CEP-Y) (Vysis) ii. Whole chromosome painting probes (WCP-X, WCP-Y) (Vysis) iii. XIST-digoxigenin (Oncor) hybridizing specifically to Xq13.2 indicating the X-inactivation center iv. DXZ4-biotin (Oncor) hybridizing specifically to a cluster of 50–100 copies of a 3-kb repeat in the Xq24 region v. Subchromosomal painting libraries (SCPL116 specific for the short arm of the X chromosome, SCPL102 specific for the long arm of the X chromosome) Identification of specific X and Y sequences a. Important for establishing phenotype-karyotype correlations b. Important for adequate genetic counseling c. PCR to identify the presence or absence of specific Y sequences Echocardiography for cardiovascular malformations Renal ultrasound for renal anomalies Radiography a. Madelung deformity i. Prominent and dorsally dislocated but reducible distal ulna ii. Short and bowed radius iii. Carpal articular surface of the radius tilted in a volar and ulnar direction producing a triangular configuration and premature fusion of the ulnar side of the radial growth plate b. Short 4th metacarpals and metatarsals c. Short distal phalanges with tufting d. Carpal bone fusion e. Pes cavus f. Irregular tibial metaphyses with mushroom projections on the medial surface of the proximal tibial metaphyses g. Spine i. Schmorl’s nodes (abnormalities of cartilaginous end plates) ii. Scheurermann’s disease of the vertebrae (osteochondrosis of vertebral epiphyses in juveniles) iii. Scoliosis iv. Lack of lumbar lordosis v. Congenital hip dislocation h. Skull i. Midfacial hypoplasia ii. An obtuse cranial base angle iii. Short cranial base i. Osteoporosis Other investigations a. Blood pressure measurement for hypertension b. Thyroid function
c. d. e. f.
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Audiology for conductive and sensorineural hearing loss Orthodontic evaluation Orthopedic evaluation Glucose intolerance
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: low b. Patient’s offspring: rarely pass to offspring due to infertility 2. Prenatal diagnosis a. Maternal serum screening (α-fetoprotein, hCG, inhibin A, unconjugated estriol) b. Ultrasonographic screening i. Fetal hydrops ii. Increased nuchal translucency iii. Fetal cystic hygroma iv. Coarctation of the aorta v. Left-sided cardiac defects vi. Lymphedema vii. Renal anomalies viii. Intrauterine growth retardation ix. Polyhydramnios x. Oligohydramnios c. Amniocentesis or CVS for chromosome analysis 3. Management a. Psychosocial counseling i. Degree of parental understanding and appropriate attitudes toward the patient with Turner syndrome depends, in general, on good family relationships, socioeconomic level of the family, and appropriate physician’s counseling ii. Short stature: a major concern when entering school iii. Pubertal failure and sterility: major concerns to the parents and patients at pubertal age iv. Webbed neck less frequent concern cosmetically unless that defect is marked and visible v. Occasional parental rejection and over protectiveness vi. Child’s adjustment to the disease influenced by parental personalities and their ability to cope with the implications of the syndrome vii. Development of a high degree of social competency permitting patients to be integrated into a society where they will be self sufficient and self-sustaining b. Estrogen replacement therapy i. To induce near normal pubertal development ii. To prevent osteoporosis iii. To reduce the risk of developing cardiovascular disease c. Growth hormone with or without anabolic steroids for short stature d. Pregnancies among women with Turner syndrome i. A high risk of miscarriages among spontaneous pregnancies ii. A high incidence of cardiac abnormalities, even fatal aortic dissection
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REFERENCES American Academy of Pediatrics. Committee on Genetics. Health supervision for children with Turner syndrome. Pediatrics 96:1166–1173, 1995. Bercu BB, Kramer SS, Bode HH: A useful radiologic sign for the diagnosis of Turner’s syndrome. Pediatrics 58:737–739, 1976. Binder G, Schwarze CP, Ranke MB: Identification of short stature caused by SHOX defects and therapeutic effect of recombinant human growth hormone. J Clin Endocrinol Metab 85:245–249, 2000. Cervantes A, Guevara-Yáñez R, López M, et al.: PCR-PRINS-FISH analysis of structurally abnormal sex chromosomes in eight patients with Turner phenotype. Clin Genet 60:385–392, 2001. Chen H, Espiritu C, Casquejo C, et al.: Internipple distance in normal children from birth to 14 years and in children with Turner’s, Noonan’s, Down’s, and other aneuploidies. Growth 38:421–436, 1974. Chen H, Hoffman W, Chang CH, et al.: Lymphocytic thyroiditis, myasthenia gravis, and Turner syndrome. Birth Defects XIV:137–147, 1978. Chen H, Faigenbaum D, Weiss H: Psychosocial aspects of patients with the Ullrich-Turner syndrome. Am J Med Genet 8:191–203, 1981. Collins AL, Cockwell AE, Jacobs PA, et al.: A comparison of the clinical and cytogenetic findings in nine patients with a ring(X) cell line and 16 45,X patients. J Med Genet 31:528–533, 1994. Ellison JW, Wardak Z, Young MF, et al.: PHOG, a candidate gene for involvement in the short stature of Turner syndrome. Hum Mol Genet 6:1341–1347, 1997. Fernández R, Méndez J, Pásaro E: Turner syndrome: a study of chromosomal mosaicism. Hum Genet 98:29–35, 1996. Fernández-García R, Carcía-Doval S, Costoya S, et al.: Analysis of sex chromosome aneuploidy in 41 patients with Turner syndrome: a study of “hidden” mosaicism. Clin Genet 58:201–208, 2000. Fingby N, Archibald RM: Skeletal abnormalities associated with gonadal dysgenesis. Am J Radiol 9:354–361, 1965. Gicquel C, Cabrol S, Schneid H, et al.: Molecular diagnosis of Turner syndrome. J Med Genet 29:547–551, 1992. Gøtzsche CO, Krag-Olsen B, Nielsen J, et al.: Prevalence of cardiovascular malformations and association with karyotypes in Turner’s syndrome. Arch Dis Child 71:433–436, 1994. Gravholt CH, Huul S, Naeraa RW, et al.: Morbidity in Turner syndrome. J Clin Epidemiol 51:147–158, 1998. Hall JG, Gilchrist DM: Turner syndrome and its variants. Pediatr Clin North Am 37:1421–1440, 1990. Hassold T, Benham F, Leppert M: Cytogenetic and molecular analysis of sexchromosome monosomy. Am J Hum Genet 42:534–541, 1988. Held KR, Kerber S, Kaminsky E, et al.: Mosaicism in 45,X Turner syndrome: does survival in early pregnancy depend on the presence of two sex chromosomes? Hum Genet 88:288–294, 1992. Hook EB, Warburton D: The distribution of chromosomal genotypes associated with Turner’s syndrome: livebirth prevalence rates and evidence for diminished fetal mortality and severity in genotypes associated with structural X abnormalities or mosaicism. Hum Genet 64:24–27, 1983. Hreinsson JG, Otala M, Fridstrom M, et al.: Follicles are found in the ovaries of adolescent girls with Turner’s syndrome. J Clin Endocrinol Metab 87:3618–3623, 2002. Hunter AG, DesLauriers GE, Gillieson MS, et al.: Prenatal diagnosis of Turner’s syndrome by ultrasonography. Can Med Assoc J 127:401, 1982. Jacobs P, Dalton P, James R, et al.: Turner syndrome: a cytogenetic and molecular study. Ann Hum Genet 61:471–483, 1997. Kleczkowska A, Dmoch E, Kubien E, et al.: Cytogenetic findings in a consecutive series of 478 patients with Turner syndrome. The Leuven experience 1965–1989. Genet Couns 1:227–233, 1990. Kosho T, Muroya K, Nagai T, et al.: Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: implications for the development of Turner syndrome. J Clin Endocrinol Metab 84:4613–4621, 1999. Larsen T, Gravhott CH, Tillebeck A, et al.: Parental origin of the X chromosome, X chromosome mosaicism and screening for “hidden” Y chromosome in 45,X Turner syndrome ascertained cytogenetically. Clin Genet 48:6–11, 1995. Lesczynki S, Kosowica J: Radiologic changes in the skeletal system in Turner’s syndrome-Review of 102 cases. Prog Radiol 1:510–517, 1965.
Matsuo M, Muroya K, Nanao K, et al.: Mother and daughter with 45,X/46,X,r(X) (p22.3q28) and mental retardation: analysis of the Xinactivation patterns. Am J Med Genet 91:267–272, 2000. Migeon BR, Luo S, Jani M, et al.: The severe phenotype of females with tiny ring X chromosomes is associated with inability of these chromosomes to undergo X inactivation. Am J Hum Genet 55:497–504, 1994. Migeon BR, Ausems M, Giltay J, et al.: Severe phenotypes associated with inactive ring X chromosomes. Am J Med Genet 93:52–57, 2000. Nietzel A, Rocchi M, Starke H, et al.: A new multicolor-FISH approach for the characterization of marker chromosomes: centromere-specific multicolor-FISH (cenM-FISH). Hum Genet 108:199–204, 2001. Ogata T, Kosho T, Wakui K, et al.: Short stature homeobox-containing gene duplication on the der(X) chromosome in a female with 45,X/46,X, der(X), gonadal dysgenesis, and tall stature. J Clin Endocrinol Metab 85:2927–2930, 2000. Ogata T, Matsuo N: Turner syndrome and female sex chromosome aberrations: deduction of the principal factors involved in the development of clinical features. Hum Genet 95:607–629, 1995. Ogata T, Muroya K, Matsuo N, et al.: Turner syndrome and Xp deletions: clinical and molecular studies in 47 patients. J Clin Endocrinol Metab 86:5498–5508, 2001. Page DC: Y chromosome sequences in Turner’s syndrome and risk of gonadoblastoma or virilisation. Lancet 343:240, 1994. Pavlidis K, McCauley E, Sybert VP: Psychosocial and sexual functioning in women with Turner syndrome. Clin Genet 47:85–89, 1995. Pellestor F, Girardet A, Lefort G, et al.: Use of the primed in situ labeled (PRINS) technique for a rapid detection of chromosomes 13, 16, 18, 21, X and Y. Hum Genet 95:12–17, 1995. Rao E, Weiss B, Fukami M, et al.: Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nature Genet 16:54–63, 1997. Robinson A: Demography and prevalence of Turner syndrome. In Rosenfeld RG, Grumbach MM (eds): Turner syndrome. New York: Marcell Dekker. 1990, pp 93–100. Robinson DO, Dalton P, Jacobs PA, et al.: A molecular and FISH analysis of structural abnormal Y chromosomes in patients with Turner syndrome. J Med Genet 36:279–284, 1999. Saenger P, Wikland KA, Conway GS, et al.: Recommendations for the diagnosis and management of Turner syndrome. J Clin Endocdrinol Metab 86:3061–3069, 2001. Schmid W, Naef E, Murset G, et al.: Cytogenetic findings in 89 cases of Turner’s syndrome with abnormal karyotypes. Humangenetik 24:93–104, 1974. Schwartz RP, Sumner TE: Madelung’s deformity as a presenting sign of Turner’s syndrome. J Pediatr 136:563, 2000. Schwartz S, Depinet TW, Leana-Cox J, et al.: Sex chromosome markers: characterization using fluorescence in situ hybridization and review of the literature. Am J Med Genet 71:1–7, 1997. Subramaniam PN: Turner’s syndrome and cardiovascular anomalies: a case report and review of the literature. Am J Med Sci 297:260–262, 1989. Sybert VP: Turner syndrome. In: Cassidy SB, Allanson JE (eds): Management of Genetic Syndromes. 1st ed. New York: Wiley & Sons, 2001:459–484. Tsezou A, Hadjiathanasiou C, Gourgiotis D, et al.: Molecular genetics of Turner syndrome: correlation with clinical phenotype and response to growth hormone therapy. Clin Genet 56:441–446, 1999. Turner HH: A syndrome of infantilism, congenital webbed neck and cubitus valgus. Endocrinology 23:566–578, 1938. Turner C, Dennis NR, Skuser DH, et al.: Seven ring(X) chromosomes lacking the XIST locus, six with an unexpectedly mild phenotype. Hum Genet 106:93–100, 2000. Van Dyke DL, Wiktor A, palmer Clin Genet, et al.: Ulrich-Turner syndrome with a small ring X chromosome and presence of mental retardation. Am J Med Genet 43:996–1005, 1992. Wolff DJ, Brown CJ, Schwartz S, et al.: Small marker X chromosomes lack the inactivation center: implications for karyotype/phenotype correlations. Am J Hum Genet 55:87–95, 1994. Zinn AR, Page DC, Fisher EMC: Turner syndrome: the case of the missing sex chromosome. Trends Genet 9:90–93, 1993.
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Fig. 1. A multi-septated cystic hygroma is observed in a fetus with Turner syndrome at 18 weeks of gestation.
Fig. 2. A 45,X fetus showing massive cystic hygroma and hydrops fetalis.
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Fig. 4. A 45,X newborn with classic facial features (epicanthal folds, down-slanting palpebral fissures, flat nasal bridge, receding chin, lowset/posteriorly rotated ears) and excessive nuchal skin folds.
Fig. 3. A newborn with 45,X showing classic facial features, webbed neck, shield chest, and wide space between nipples.
Fig. 5. Two 45,X newborns with severe lymphedema of the dorsum of hand and feet and toe nail hypoplasia.
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Fig. 7. A 45,X/46,XX patient showing short stature, characteristic facial features, webbed neck, lymphocytic thyroiditis, and follicular formation of thymus medulla.
Fig. 6. A 45,X girl showing short stature, classic facial features, severe webbed neck, shield-like chest, and widely spaced nipples.
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Fig. 9. A girl with 45,X/46,X,r(X) ring chromosome X Turner mosaicism. The ring chromosome is illustrated by partial karyotype with ideogram and FISH with an X chromosome centromelic probe.
Fig. 8. An adult patient with 45,X/46,XX mosaic Turner syndrome showing webbed neck with low posterior hair line and short metacarpals, illustrated by hand radiograph.
Fig. 10. 45,X karyotype.
Fig.11. FISH showing a mosaic fetus with XXX/X (CEP X/SpectrumOrange). Three copies of the orange signal are in the XXX cells and one copy in the monosomy X cells.
Twin–Twin Transfusion Syndrome Twin–twin transfusion syndrome results from intrauterine blood transfusion from one twin to another twin as a serious complication in 10–20% of monochorionic diamniotic twin pregnancies.
GENETICS/BASIC DEFECTS 1. Cause: a serious complication of monozygotic, monochorionic twin pregnancy through placental vascular anastomoses (unilateral arteriovenous anastomoses), resulting in transfusion of blood from one fetal twin to another twin 2. Pathogenesis a. Imbalance in net blood flow through transplacental fetofetal transfusion, resulting in a discrepancy in blood volume distribution in two twins b. The donor twin i. Becoming hypovolemic, hypotensive, and oliguric ii. Leading to oligo/anhydramnios and growth restriction c. The recipient twin i. Becoming hypervolemic, hypertensive, and polyuric ii. Leading to polyhydramnios and congestive heart failure
CLINICAL FEATURES 1. Donor twin a. Birth weight: small for gestational age b. Pallor and anemic c. Poor peripheral perfusion d. Oligohydramnios in the amniotic sac secondary to hypovolemia and decreased urine output e. Stuck twin phenomenon (the twin appears in a fixed position against the uterine wall) resulting from severe oligohydramnios f. Hydrops fetalis secondary to anemia and high-output heart failure 2. Recipient twin a. Birth weight: larger at birth b. Plethoric and ruddy c. Jaundice d. Polyhydramnios in the amniotic sac secondary to hypervolemia and increased fetal urine output e. Hydrops fetalis secondary to hypervolemia f. Hypertension g. Hypertrophic cardiomegaly h. Right-sided heart failure with tricuspid regurgitation and right ventricular outflow tract obstruction i. Increased risk of cardiac malformations j. Intravascular coagulation
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3. Prognosis a. Premature delivery in case of mild to moderate twin–twin transfusion syndrome b. Guarded with possible serious maternal and fetal complications c. Antenatal death as well as neonatal death secondary to preterm delivery d. Survival rate for those diagnosed before 28 weeks: 20–45% 4. Antenatal factors that predict poor outcome a. Early gestational age at diagnosis with delivery before 28 weeks of gestation b. Fetal polyhydramnios requiring multiple therapeutic amniocenteses c. Fetal hydrops d. Absent or reversed diastolic flow in umbilical artery Doppler studies 5. Neonatal complications a. Neurologic sequelae in 25% of surviving twin in case of fetal demise in other twin b. Divergent intrauterine growth in association with subsequent physical and mental deficiencies in the smaller twins c. Thrombocytopenia suggested as the cause of cataracts, impaired hearing, and growth retardation of the donor twin d. Intrauterine growth deficiency of the brain and profound neonatal hypoglycemia implicated as reasons for cerebral impairment of the donor twin, resulting in subsequent lower intelligence compared with its co-twin e. Circulatory overload with heart failure if severe hypervolemia occurs f. Occlusive thrombosis due to hyperviscosity g. Polycythemia that may lead to severe hyperbilirubinemia and kernicterus h. Brain damage with cerebral palsy, microcephaly, or encephalomalacia 6. Maternal complications a. Secondary to multiple gestations i. Preeclampsia ii. Preterm labor iii. Hemorrhage iv. Diabetes b. Maternal mirror syndrome i. A rare complication associated with fetal hydrops ii. Also known as “Ballantyne syndrome” or “triple edema syndrome” iii. A syndrome of severe water retention that “mirrors” fetal hydropic changes iv. Frequent occurrence in the mid-trimester
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DIAGNOSTIC INVESTIGATIONS 1. Difference in birth weight: inter-twin difference >20% (heavier twin = 100%) 2. CBC to demonstrate inter-twin differences of hemoglobin level (difference ≥5 g/dL) a. Anemia: frequently in donor twin at birth b. Polycythemia frequently in recipient twin at birth 3. Blood chemistry a. Hypoglycemia in either twins b. Hypocalcemia, hypoproteinemia in donor twin c. High creatinine in either twins with renal dysfunction 4. Thrombocytopenia in either twins 5. Hyperbilirubinemia in polycythemic recipient twin 6. Imagings a. Cranial ultrasound: intraventricular hemorrhage and periventricular leukomalacia in premature twins b. Chest radiography; pleural effusions and cardiomegaly in hydrops fetalis c. Echocardiography i. Myocardial dysfunction/hypertrophy ii. Valvular insufficiency iii. Pericardial effusion d. Renal ultrasound: abnormal renal echogenicity indicating hypoxic-ischemic cortical necrosis e. Abdominal ultrasound: Ascites in hydrops fetalis 7. Demonstration of transplacental vascular connections: an important criterion for the diagnosis of the twin–twin transfusion syndrome a. Donor twin i. Placenta a) Pale b) Swollen c) Atrophied ii. Amniotic membrane showing amnion nodosum in the presence of oligohydramnios b. Placenta of the recipient twin i. Red ii. Congested iii. Hypertrophied 8. Surgical pathologic assessment of vascular anastomoses in monochorionic placentas with strong clinical correlation of placental types and occurrence of twin–twin transfusion a. Type A (placenta without vascular anastomoses): 0% b. Type B (placenta with only deep arteriovenous anastomoses): 81% c. Type C (placenta with only superficial anastomoses): 1% d. Type D (placenta with combined deep arteriovenous and superficial anastomoses): 18% 9. Sonographic criteria for determining chorionicity a. Dichorionic i. Separate placentas ii. Well-visualized septum b. Monochorionic diamniotic i. One placenta ii. A paper-thin, reflective hair-like septum (only small parts visible) c. Dichorionic diamniotic: septum readily seen with a thickness similar to one wall of the umbilical cord
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless in another pregnancy with monochorionic twinning (twin–twin transfusion syndrome affects 10–15% of monochorionic twins) b. Patient’s offspring: not increased unless in pregnancy with monochorionic twinning 2. Prenatal diagnosis a. Ultrasonography i. Divergent fetal size: striking differences in the sizes of the twins a) Disparity in size of inter-twin abdominal circumference (difference > 18 mm) b) Disparity in size or in the number of vessels in the umbilical cords: The donor twin may have a single umbilical artery. The size of the umbilical cord of the recipient twin may be much larger than that of its co-twin ii. Divergent size of amniotic sacs a) Presence of polyhydramnios (largest pocket >8 cm) in one sac (the recipient twin persistently has a distended bladder and produces a large amount of urine) b) Presence of oligohydramnios (largest pocket <2 cm or stuck twin) in other sac (the donor twin produces little urine) iii. “Stuck twin” sign: a growth-retarded fetus tightly enwrapped within its membrane and trapped or stuck against the uterine wall due to oligohydramnios iv. Determination of monozygosity a) Like-sex twins b) Monochorionic/diamniotic placentation (absence of twin-peak sign, thin separating membrane, and single placenta showing divergent echogenicity of the cotyledons supplying the two cords) v. Evidence of hydrops in either twin vi. Evidence of congestive cardiac failure in the recipient twin vii. A sonographic staging classification for twin–twin transfusion syndrome allowing for the grading of the severity of the disease by standardized criteria a) Stage I: visible bladder of the donor twin, normal Doppler studies b) Stage II: not visible bladder of the donor twin (during the length of examination, usually 1 hour), not critically abnormal Doppler studies c) Stage III: critically abnormal Doppler studies in either twin, characterized as absent or reverse end-diastolic velocity in the umbilical artery, reverse flow in the ductus venosus, or pulsatile umbilical venous flow d) Stage IV: ascites, pericardial or pleural effusion, scalp edema, or overt hydrops of one or both twins e) Stage V: presence of one or both demised twins
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b. Echocardiography i. Possible advantages a) Assessment of cardiovascular adaptation to inter-twin transfusion b) Early recognition of deterioration c) Evaluation of antenatal management ii. Fetal heart rate monitoring: A silent, sinusoidal pattern in tracings of the fetal heart rate may indicate signs of fetal anemia. iii. Doppler studies a) Detection of arterio–arterial anastomoses in monochorionic twins b) Doppler velocimetry of the umbilical arteries: inter-twin differences in systolic/diastolic ratio > 0.4 predicting growth discordancy of at least 350 g iv. Ultrasound-guided fetal blood sampling a) Establishing the diagnosis of monozygosity when blood group studies are performed on both twins b) Allowing an accurate antenatal assessment of the inter-twin hemoglobin difference and consequently establishing the diagnosis of twin–twin transfusion c) Revealing the degree of fetal anemia in the donor twin c. Fetoscopy i. Plethora donor twin ii. Pale recipient twin 3. Management a. General approach i. Monochorionic twining at high risk for twin–twin transfusion syndrome ii. Requiring close obstetrical monitoring iii. Requiring specialized care in neonatal intensive care unit b. Post-partum therapies i. Directed towards the problems of each twin, such as prematurity, anemia, polycythemia, and hydrops fetalis ii. Severely anemic donor twin: requires packed red blood cell transfusions or partial exchange transfusions iii. Polycythemic recipient twin: requires partial exchange transfusion to lower serum hematocrit c. Prenatal therapies i. Treating the mother with digoxin with favorable results when the recipient twin is showing signs of cardiac failure ii. Serial amniodrainage (amnioreduction): currently the most widely used therapy because it is simple and requires commonly available skills and equipment a) Removing large volumes of amniotic fluid from the recipient twin’s sac b) Reducing the amniotic fluid volume, thereby reducing the risk of preterm labor or ruptured membranes c) Overall perinatal survival with serial aggressive amnioreduction: about 60% in uncontrolled published series
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d) Double survival rate (50%) and single survival rate (20%) in severe twin–twin transfusion syndrome presenting before 28 weeks of gestation e) Fail to address the underlying cause of twin–twin transfusion syndrome f) Complications: uterine contractions, premature rupture of membranes, chorioamnionitis, abruptio placenta, and inadvertent septostomy resulting in iatrogenic monoamniotic twins iii. Amniotic septostomy: intentionally puncturing the intertwine septum a) To create a hole in the intertwine membrane between the anhydramniotic donor’s sac and the hydramniotic recipient’s sac b) Restoring normal amniotic fluid pressure gradient, allowing fluid to move along a hydrostatic gradient from the hydramnios sac into the oligohydramnios sac c) Also an inadvertent occurrence during amnioreduction procedure d) Limited experience iv. Endoscopic laser coagulation of all placental vascular anastomoses a) Reduces and abolishes intertwine transfusion by ablating chorionic plate anastomoses, producing functionally dichorionic pregnancies b) Proponents arguing that the procedure reduces the risk of neurological injury in survivors c) Overall survival rate (58%) with single survival of 32% and double survival of 42% for cases presenting prior to 18 weeks d) Rare fetal complications (relationship to the procedure not established): aplasia cutis, limb necrosis, amniotic bands, and microphthalmia/ anophthalmia v. Selective feticide by cord occlusion (umbilical cord ligation): used as a last resort in cases in which both twins are at risk because of the serious condition of one twin a) Considered in case of monochorionic twin pregnancy in which one twin is a nonviable fetus, especially the condition is compromising the nonaffected fetus b) A typical example in twin reversed arterial perfusion sequence. The relatively normal twin risks high-output cardiac failure, complications of polyhydramnios and death in utero. c) Another example of twin–twin transfusion syndrome, in which one fetus has major congenital anomalies or in utero acquired abnormality, such as demonstrable cerebral lesions, terminal cardiac failure, or other conditions with a poor prognosis d) Benefits of selective termination of the affected twin: arrest the fetofetal transfusion process and protect the survivor
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vi. In general, twin–twin transfusion syndrome diagnosed before 26 weeks of gestation has significantly better survival rates and fewer neurological sequelae after laser ablation therapy than amnioreduction. Twin–twin transfusion syndrome diagnosed after 26 weeks can best be treated by amnioreduction or delivery.
REFERENCES Banek CS, Hecher K, Hackeloer BJ, et al.: Long-term neurodevelopmental outcome after intrauterine laser treatment for severe twin–twin transfusion syndrome. Am J Obstet Gynecol 188:876–880, 2003. Barss VA, Benacerraf BR, Frigoletto FD: Ultrasonographic determination of chorion type in twin gestation. Obstet Gynecol 66:779–783, 1985. Berghella V, Kaufmann M: Natural history of twin–twin transfusion syndrome. J Reprod Med 46:480–484, 2001. Bermúdez C, Becerra CH, Bornick PW, et al.: Placental types and twin–twin transfusion syndrome. Am J Obstet Gynecol 187:489–494, 2002. Blickstein I: The twin–twin transfusion syndrome. Obstet Gynecol 76:714–722, 1990. Chiang MC, Lien R, Chao AS, et al.: Clinical consequences of twin-to-twin transfusion. Eur J Pediatr 162:68–71, 2003. Cincotta RB, Fisk NM: Current thoughts on Twin–twin transfusion syndrome. Clin Obstet Gynecol 40:290–302, 1997. Crombleholme TM: The treatment of twin–twin transfusion syndrome. Semin Pediatr Surg 12:175–181, 2003. De Lia J, Emery MG, Sheafor SA, et al.: Twin transfusion syndrome: successful in utero treatment with digoxin. Int J Gynaecol Obstet 23:197–201, 1985. De Lia J, Fisk N, Hecher K, et al.: Twin-to-twin transfusion syndrome— debates on the etiology, natural history and management. Ultrasound Obstet Gynecol 16:210–213, 2000. Deprest JA, Audibert F, van Schoubroeck D, et al.: Bipolar coagulation of the umbilical cord in complicated monochorionic twin pregnancy. Am J Obstet Gynecol 182:340–345, 2000. Duncombe GJ, Dickinson JE, Evans SF: Perinatal characteristics and outcomes of pregnancies complicated by twin–twin transfusion syndrome. Obstet Gynecol 101:1190–1196, 2003.
Gardiner HM, Taylor MJ, Karatza A, et al.: Twin–twin transfusion syndrome: the influence of intrauterine laser photocoagulation on arterial distensibility in childhood. Circulation 107:1906–1911, 2003. Jauniaux E, Holmes A, Hyett J, et al.: Rapid and radical amniodrainage in the treatment of severe twin–twin transfusion syndrome. Prenat Diagn 21:471–476, 2001. Johnson JR, Rossi KQ, O’Shaughnessy RW: Amnioreduction versus septostomy in twin–twin transfusion syndrome. Am J Obstet Gynecol 185:1044–1047, 2001. Mari G, Detti L, Oz U, et al.: Long-term outcome in twin–twin transfusion syndrome treated with serial aggressive amnioreduction. Am J Obstet Gynecol 183:211–217, 2000. Quintero RA: Twin–twin transfusion syndrome. Clin Perinatol 30:591–600, 2003. Quintero RA, Morales WJ, Allen MH, et al.: Staging of twin–twin transfusion syndrome. J Perinatol 19:550–555, 1999. Quintero RA, Martinez JM, Bermudez C, et al.: Fetoscopic demonstration of perimortem feto-fetal hemorrhage in twin–twin transfusion syndrome. Ultrasound Obstet Gynecol 20:638–639, 2002. Quintero RA, Dickinson JE, Morales WJ, et al.: Stage-based treatment of twin–twin transfusion syndrome. Am J Obstet Gynecol 188:1333–1340, 2003. Ropacka M, Markwitz W, Blickstein I: Treatment options for the twin–twin transfusion syndrome: a review. Twin Res 5:507–514, 2002. Senat MV, Bernard JP, Loizeau S, et al.: Management of single fetal death in twin-to-twin transfusion syndrome: a role for fetal blood sampling. Ultrasound Obstet Gynecol 20:360–363, 2002. Seng YC, Rajadurai VS: Twin–twin transfusion syndrome: a five year review. Arch Dis Child Fetal Neonatal Ed 83:F168–170, 2000. Taylor MJ, Govender L, Jolly M, et al.: Validation of the Quintero staging system for twin–twin transfusion syndrome. Obstet Gynecol 100:1257–1265, 2002. Taylor MJ, Wee L, Fisk NM: Placental types and twin–twin transfusion syndrome. Am J Obstet Gynecol 188:1119; author reply 1119–1120, 2003. van Gemert MJ, Umur A, Tijssen JG, et al.: Twin–twin transfusion syndrome: etiology, severity and rational management. Curr Opin Obstet Gynecol 13:193–206, 2001. Wee LY, Fisk NM: The twin–twin transfusion syndrome. Semin Neonatol 7:187–202, 2002. Weiner CP, Ludomirski A: Diagnosis, pathophysiology, and treatment of chronic twin-to-twin transfusion syndrome. Fetal Diagn Ther 9:283–290, 1994.
TWIN–TWIN TRANSFUSION SYNDROME
Fig. 1. Diamniotic monochorionic twin placenta with features of twin–twin transfusion (the placental discs are not fused in this case): The placenta corresponding to the recipient twin (right) is small but plethoric and dark in color. The placenta of the donor twin (left) is large but anemic, pale and edematous. The amniotic sacs were removed at the margins of the placental discs. The root of the thin monochorionic septum between the two sacs is shown on the fetal surface (first picture). The color difference between the two placentas is better shown on the maternal surface (second picture).
Fig. 2. The donor twin (right) showing smaller and pallor and the recipient twin (left) showing larger and plethoric at birth.
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Ulnar-Mammary Syndrome Ulnar-mammary syndrome was originally described by Gilly in 1882 in a woman with mammary hypoplasia, inability to lactate, absence of the 3rd–5th digits and ulna. Later in 1978, Pallister et al. reported a complex malformation syndrome in a young woman with abnormal development of ulnar rays, forearms, mammary gland tissue, axillary apocrine glands, teeth, palate, vertebral column and urogenital system. Ulnar-mammary syndrome is a pleiotropic disorder affecting limb, apocrinegland, teeth, hair, and genital development.
GENETICS/BASIC DEFECTS 1. Inheritance: autosomal dominant with variable expression 2. A gene for ulnar-mammary syndrome mapped to chromosome 12q23-q24.1 3. Caused by mutations that disrupt the DNA-binding domain of the T-box gene, TBX3 4. Mutations in human TBX3 alter limb, apocrine, and genital development in ulnar-mammary syndrome 5. No obvious phenotypic differences between those who have missense mutations and those who have deletions or frameshifts
CLINICAL FEATURES 1. Posterior limb defects a. Widely variable b. Ulnar ray defects in most patients i. Hypoplasia of the terminal phalanx of the 5th digit ii. Hypoplasia or complete absence of the ulna and 3rd, 4th, 5th digits c. Postaxial digital duplications d. Camptodactyly e. Digital fusion 2. Apocrine gland abnormalities a. Mammary gland abnormalities: variable i. Hypoplasia to aplasia of the mammary glands and hypoplasia of the nipples ii. Accessory nipples iii. Inability to nipple feed iv. Normal breast development and lactation b. Decreased ability to sweat c. Reduced body odor d. Absent axillary perspiration e. Sparse axillary hair 3. Genital abnormalities: hypogenitalism a. Affected males i. Delayed puberty ii. Diminished to absent axillary hair iii. Micropenis iv. Cryptorchidism v. Small testes vi. Shawl scrotum vii. Reduced fertility
b. Affected females i. Diminished to absent axillary hair ii. Imperforate hymen in some affected females 4. Dental abnormalities a. Misplaced teeth b. Absent teeth c. Hypodontia 5. Other abnormalities a. Obesity b. Scanty lateral eyebrows c. Subglottic stenosis d. Pyloric stenosis e. Renal agenesis/malformation f. Pulmonary hypoplasia g. Inguinal hernia h. Anal atresia/stenosis i. Musculoskeletal abnormalities i. Short forearms ii. Hypoplastic humeri, scapulae, and clavicles iii. Hypoplastic pectoralis major muscles iv. Short, stiff, and crooked terminal phalanges of 4th–5th toes 6. Differential diagnosis a. Hand-foot-uterus syndrome i. Autosomal dominant disorder ii. Allelic to ulnar-mammary syndrome speculated iii. Manifestations similar to ulnar-mammary syndrome include the following: a) Digital hypoplasia b) Carpal fusion c) Supernumerary nipples d) Genital anomalies b. Split hand/split foot syndrome: a causal relationship to ulnar-mammary syndrome suggested c. Scalp-ear-nipple syndrome: overlapping manifestations with ulnar-mammary syndrome i. Mammary hypoplasia ii. Diminished axillary perspiration iii. Dental abnormalities iv. Digital syndactyly: characteristic limb anomaly found in this syndrome (vs limb deficiency or duplications in ulnar-mammary syndrome)
DIAGNOSTIC INVESTIGATIONS
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1. Radiography a. Short and stiff 5th finger b. Absent 5th finger ray c. Absent 4th finger ray d. Absent 4th–5th finger rays e. Absent 3rd–5th finger rays f. Camptodactyly g. Hypoplastic/absent/deformed ulna
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h. Hypoplastic/absent/deformed radius i. Hypoplastic humerus, scapula, clavicle, and pectoralis major muscle j. Absent xiphisternum k. Postaxial polydactyly l. Short, stiff 4th and 5th toes 2. Endocrine investigations for hypogenitalism 3. Mutation analysis a. Missense mutations (L143P and Y149S) b. Nonsense mutation (Q360TER, S343TER) c. Splice-site mutations (IVS+1G to IVS2+1G) producing a truncated protein product d. Frameshift mutations of small duplications
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected b. Patient’s offspring: 50% 2. Prenatal diagnosis a. Ultrasonography and fetoscopy: possible to pregnancy at risk with presence of obvious fetal skeletal anomalies b. Mutation analysis of amniocytes and CVS: possible to families with identified mutation causing ulnarmammary syndrome 3. Management a. Orthopedic management of limb defects b. Orchiopexy for cryptorchidism c. Testosterone management for hyogonadism in male patients d. Bottle feeding of infants born to mothers who has hypoplastic or absent nipples
REFERENCES Bamshad M, Krakowiak PA, Watkins WS, et al.: A gene for ulnar-mammary syndrome maps to 12q23-q24.1. Hum Mol Genet 4:1973–1977, 1995. Bamshad M, Le T, Watkins WS, et al.: The spectrum of mutations in TBX3: genotype /phenotype relationship in ulnar-mammary syndrome. Am J Hum Genet 64:1550–1562, 1999. Bamshad M, Lin RC, Law DJ, et al.: Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nat Genet 16:311–315, 1997. Bamshad M, Root S, Carey JC: Clinical analysis of a large kindred with the Pallister ulnar-mammary syndrome. Am J Med Genet 65:325–331, 1996.
Brummelkamp TR, Kortlever RM, Lingbeek M, et al.: TBX-3, the gene mutated in Ulnar-Mammary Syndrome, is a negative regulator of p19ARF and inhibits senescence. J Biol Chem 277:6567–6572, 2002. Carlson H, Ota S, Campbell CE, et al.: A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause ulnar-mammary syndrome. Hum Mol Genet 10:2403–2413, 2001. Coll M, Seidman JG, Muller CW: Structure of the DNA-bound T-box domain of human TBX3, a transcription factor responsible for ulnar-mammary syndrome. Structure (Camb) 10:343–356, 2002. Davenport TG, Jerome-Majewska LA, Papaioannou VE: Mammary gland, limb and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome. Development 130:2263–2273, 2003. Edwards MJ, McDonald D, Moore P, et al.: Scalp-ear-nipple syndrome: additional manifestations. Am J Med Genet 50:247–250, 1994. Franceschini P, Vardeu MP, Dalforno L, et al.: Possible relationship between ulnar-mammary syndrome and split hand with aplasia of the ulna syndrome. Am J Med Genet 44:807–812, 1992. Froster GU, Baird PA: Upper limb deficiencies and associated malformations: a population-based study. Am J Med Genet 44:767–781, 1992. Gilly E: Absence complète des mamelles chez une femme mère: Atrophie du member superieur droit. Courrier Med 32:27–28, 1882. Gonzalez CH, Herrmann J, Opitz JM: Studies of malformation syndromes of man XXXXIIB: mother and son affected with the ulnar-mammary syndrome type Pallister. Eur J Pediatr 123:225–235, 1976. He M, Wen L, Campbell CE, et al.: Transcription repression by Xenopus ET and its human ortholog TBX3, a gene involved in ulnar-mammary syndrome. Proc Natl Acad Sci USA 96:10,212–10,217, 1999. Hecht JT, Scott CI: The Schinzel syndrome in a mother and daughter. Clin Genet 25:63–67, 1984. Pallister PD, Hermann J, Opitz JM: Studies of Malformation Syndromes in Man XXXXII: a pleiotropic dominant mutation affecting skeletal, sexual and apocrine-mammary development. Birth Defects Original Article Series XII(5):247–254, 1976. Rogers C, Anderson G: Hand-foot-uterus syndrome vs. ulnar-mammary syndrome in a patient with overlapping phenotypic features. Proc Greenwood Genet Ctr 14:17–20, 1995. Sasaki G, Ogata T, Ishii T, et al.: Novel mutation of TBX3 in a Japanese family with ulnar-mammary syndrome: implication for impaired sex development. Am J Med Genet 110:365–369, 2002. Schinzel A: Ulnar-mammary syndrome. J Med Genet 24:778–781, 1987. Schinzel A, Illig R, Prader A: The ulnar-mammary syndrome: an autosomal dominant pleiotropic gene. Clin Genet 32:160–168, 1987. Sherman J, Angulo MA, Sharp A: Mother and infant son with ulnar-mammary syndrome of Pallister plus additional findings. Am J Hum Genet 39:A82, 1986. van Bokhoven H, Jung M, Smits AP, et al.: Limb mammary syndrome: a new genetic disorder with mammary hypoplasia, ectrodactyly, and other Hand/Foot anomalies maps to human chromosome 3q27. Am J Hum Genet 64:538–546, 1999. Wollnik B, Kayserili H, Uyguner O, et al.: Haploinsufficiency of TBX3 causes ulnar-mammary syndrome in a large Turkish family. Ann Genet 45:213–217, 2002.
ULNAR-MAMMARY SYNDROME
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Fig. 1. A newborn (A,B) with ulnar mammary syndrome showing ulnar hypoplasia (missing 4th and 5th fingers) (C), ectrodactyly, syndactyly, and hypoplasia of the breast and nipples (D). The infant also had cryptorchidism, anal atresia, pulmonary hypoplasia, pyloric stenosis and bilateral renal hypoplasia.
VATER (VACTERL) Association VATER association is an acronym for the following nonrandom association of defects: Vertebral defects, Anal atresia, Tracheoesophageal fistula with Esophageal atresia, and Renal or Radial defects. VACTERL association is an expanded acronym to include Cardiac defects and Limb defects. Diagnosis of VACTERL association is made if three out of seven above defects are present in an infant. The incidence is estimated to be 1.6 cases in 10,000 live births.
GENETICS/BASIC DEFECTS 1. Etiologic heterogeneity a. Isolated cases in most cases b. Reports of rare familial cases (single gene disorders) c. Reports of chromosome abnormality cases d. Recognized syndromes or phenotypes e. Observed more frequently in infants of diabetic mothers 2. Pathogenesis: suggestion of a defective mesodermal development during embryogenesis due to a variety of causes, leading to overlapping manifestations 3. Molecular basis of VACTERL association a. Report of a family in which a female infant was born and died at age 1 month due to renal failure. The mother and sister later developed classic mitochondrial cytopathy, associated with the A-to-G point mutation at nucleotide position 3243 of mitochondrial DNA. b. Mitochondrial NP 3243 point mutation considered not a common cause of VACTERL association c. Sonic hedgehog in the human: a possible explanation for the VATER association
CLINICAL FEATURES 1. Vertebral anomalies a. Hemivertebrae b. Fused vertebrae c. Hypersegmentation of the vertebrae d. Hypersegmentation of the ribs e. Scoliosis f. Sacral anomalies g. Incomplete pedicle h. Sternal anomalies 2. Anal and urachal anomalies a. Anal atresia with or without fistula b. Persistent urachus 3. Cardiac anomalies a. Ventricular septal defects b. Patent ductus arteriosus c. Tetralogy of Fallot d. Transposition of the great arteries 1025
4. 5. 6.
7.
8.
e. Other cardiovascular anomalies i. Right aortic arch ii. Double aortic arch iii. Coarctation of the aorta iv. Dextrocardia v. Total anomalous pulmonary venous drainage vi. Left superior vena cava vii. Congenital mitral stenosis viii. Right anomalous coronary artery ix. Single umbilical artery Tracheoesophageal fistula Esophageal atresia Renal anomalies a. Renal agenesis/dysgenesis b. Ectopic kidney c. Horseshoe kidney d. Ureteral/urethral anomalies e. Hydronephrosis f. Renal ectopia g. Vesicoureteral reflux h. Posterior urethral valves i. Ureteropelvic junction obstruction Limb defects a. Radial aplasia/dysplasia b. Hypoplastic thumbs c. Triphalangeal thumb d. Preaxial polydactyly e. Syndactyly f. Radioulnar synostosis Other associated abnormalities a. Failure to thrive b. Short stature c. Wide cranial suture d. Large fontanel e. Potter facies f. Ear anomalies g. Cleft palate h. Gastrointestinal anomalies i. Malrotation ii. Meckel diverticulum iii. Duodenal atresia iv. Pyloric atresia v. Ileal atresia vi. Pancreatic heterotopia vii. Vermiform appendix agenesis viii. Omphalocele ix. Inguinal hernia i. Genital anomalies i. Hypospadias ii. Cryptorchidism iii. Bifid scrotum iv. Micropenis
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j. Neurological anomalies i. Tethered cord ii. Spinal dysrhaphia iii. Occipital encephalocele k. Anomalies more commonly associated with CHARGE association
DIAGNOSTIC INVESTIGATIONS 1. 2. 3. 4. 5. 6.
Radiography for vertebral and limb defects Echocardiography for congenital heart defects GI investigation for TE fistula or esophageal atresia Renal ultrasonography for renal dysplasia Urological evaluation of urogenital defects Chromosome analysis
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: low recurrence risk unless in a single gene disorder b. Patient’s offspring: low recurrence risk unless in a single gene disorder 2. Prenatal diagnosis by ultrasonography revealing multiple congenital anomalies compatible to VACTERL association a. Vertebral anomalies b. Anorectal anomalies c. Congenital hart defects d. TE fistula or esophageal atresia e. Renal anomalies f. Limb defects 3. Management a. Medical care b. Surgical care i. TE fistula and/or esophageal atresia ii. Major cardiac defects iii. Urogenital anomalies iv. Skeletal and limb defects
REFERENCES Arsic D, Qi BQ, Beasley SW: Hedgehog in the human: a possible explanation for the VATER association. J Paediatr Child Health 38:117–121, 2002.
Auchterlonie IA, White MP: Recurrence of the VATER association within a sibship. Clin Genet 21:122–124, 1982. Barnes JC, Smith WL: The VATER Association. Radiology 126:445–449, 1978. Botto LD, Khoury MJ, Mastroiacovo P, et al.: The spectrum of congenital anomalies of the VATER association: an international study. Am J Med Genet 71:8–15, 1997. Corsello G, Maresi E, Corrao AM, et al: VATER/VACTERL association: clinical variability and expanding phenotype including laryngeal stenosis. Am J Med Genet 44:813–815, 1992. Czeizel A, Ludanyi I: An aetiological study of the VACTERL-association. Eur J Pediatr 144:331–337, 1985. Damian MS, Seibel P, Schachenmayr W, Reichmann H, et al: VACTERL with the mitochondrial 3243 point mutation. Am J Med Genet 62:398–403, 1996. Fernbach SK, Glass RB: The expanded spectrum of limb anomalies in the VATER association. Pediatr Radiol 18:215–220, 1988. Heifetz SA: Requirements for the VATER association. Am J Dis Child 140:1098–1099, 1986. Iuchtman M, Brereton R, Spitz L, et al.: Morbidity and mortality in 46 patients with the VACTERL association. Isr J Med Sci 28:281–284, 1992. Khoury MJ, Cordero JF, Greenberg F, et al.: A population study of the VACTERL association: evidence for its etiologic heterogeneity. Pediatrics 71:815–820, 1983. Lubinsky MS: Current concepts: VATER and other associations: historical perspectives and modern interpretations. Am J Med Genet Suppl 2:6–16, 1986. Martinez-Frías ML, Frías JL: VACTERL as primary polytopic developmental field defects. Am J Med Genet 83:13–16, 1999. Martinez-Frias ML, Bermejo E, Frias JL: The VACTERL association: lessons from the Sonic hedgehog pathway. Clin Genet 60:397–398, 2001. McGahan JP, Leeba JM, Lindfors KK: Prenatal sonographic diagnosis of VATER association. J Clin Ultrasound 16:588–591, 1988. Miller OF, Kolon TF: Prenatal diagnosis of VACTERL association. J Urol 166:2389–2391, 2001. Quan L, Smith DW: The VATER association. Vertebral defects, Anal atresia, T-E fistula with esophageal atresia, Radial and Renal dysplasia: a spectrum of associated defects. J Pediatr 82:104–107, 1973. Say B, Greenberg D, Harris R, et al.: The radial dysplasia/imperforate anus/ vertebral anomalies syndrome (the VATER association): developmental aspects and eye findings. Acta Paediatr Scand 66:233–235, 1977. Smith DW: The VATER association. Am J Dis Child 128:767, 1974. Stone DL, Biesecker LG: Mitochondrial NP 3243 point mutation is not a common cause of VACTERL association. Am J Med Genet 72:237–238, 1997. Temtamy SA, Miller JD: Extending the scope of the VATER association: definition of the VATER syndrome. J Pediatr 85:345–349, 1974. Tongsong T, Wanapirak C, Piyamongkol W, et al.: Prenatal sonographic diagnosis of VATER association. J Clin Ultrasound 27:378–384, 1999. Weaver DD, Mapstone CL, Yu PL: The VATER association. Analysis of 46 patients. Am J Dis Child 140:225–229, 1986. Weber TR, Smith W, Grosfeld JL: Surgical experience in infants with the VATER association. J Pediatr Surg 15:849–854, 1980.
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Fig. 1. An infant with VATER association showing club hands, abnormally rotated left lower limb, fused/split ribs, hemivertebrae, radial aplasia on the right, and radioulnar fusion on the left elbow.
Fig. 2. A child with VATER association showing club hands and radial aplasia.
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Fig. 3. A male neonate with VATER association showing phocomelia, rudimentary external genitalia and anal atresia. Congenital heart anomalies (type 2 truncus arteriosus, tricuspid valve atresia, ventricular septal defect, large atrial septal defect), type 1 tracheoesophageal fistula, nonlobated lungs, agenesis of kidneys and ureters, malrotation of bowel and vesico-colonic fistula were demonstrated in the necropsy.
Von Hippel-Lindau Disease Von Hippel-Lindau disease (VHL) is a rare hereditary cancer syndrome. The prevalence is estimated as 1 in 85,000 with an incidence of 1 in 45,500 live births. b.
GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant b. Reduced penetrance (95% penetrance at age 60) c. Positive family history in up to 80% of cases d. Sporadic new mutation in about 20% of cases e. Parental mosaicism described 2. Molecular pathogenesis of VHL disease a. VHL disease i. Caused by deletions or mutations in a tumor suppressor gene, the VHL gene ii. Two-hit theory of Knudson in a familial cancer syndrome such as VHL disease a) Prediction of the genotype of each neoplasm which consists of an allele with an inherited germ-line mutation and loss of the second wild-type allele through allelic deletion b) Loss of heterozygosity at chromosome 3p at the VHL gene region has been demonstrated in different VHL disease-associated tumors. iii. A germline mutation in the VHL gene a) Predisposes carriers to tumors in multiple organs b) Consistently detected in 100% of classic families with more than one affected family member or classic sporadic patients with multiple VHL-related tumors c) Missense mutations leading to an amino acid substitution in VHL gene product pVHL, observed in 40% of the families with an identified VHL gene germline mutation d) Microdeletions, insertions, splice site, and nonsense mutations, all predicted to lead to a truncated protein: observed in 30% of the families e) Large deletions including deletions encompassing the entire gene: account for the remaining 30% of the VHL gene germline mutations iv. Somatic mutations a) Independent somatic alteration of both alleles of the VHL tumor suppressor gene leading to tumorigenesis in nonfamilial (VHLrelated) tumors b) Somatic VHL gene mutations and allele loss: frequent events in sporadic clear cell
c.
d.
e.
renal cell carcinomas and sporadic central nervous system hemangioblastoma; uncommon in sporadic (i.e., nontumor syndrome associated) pheochromocytoma VHL gene i. Mapped on chromosome 3p25 ii. Involved in blood vessel formation by regulation of the activity of hypoxia-inducible factor (HIF)-1α Patients with VHL disease i. With a positive family history: have inherited an inactive VHL allele from an affected parent ii. Without a positive family history: have a parent who is mosaic for a VHL mutation, presumably as the result of a de novo mutation during early development Angiogenesis of VHL tumors: critical role of inactivation of VHL gene i. Overexpression of vascular endothelial growth factor (VEGF) resulting in hypervascularization ii. Negative regulation of hypoxia-inducible mRNAs including VEGF mRNA by VHL protein Tumor development in VHL disease i. Linked to inactivation or loss of the remaining wild-type VHL allele in a susceptible cell, leading to loss of the VHL gene product pVHL ii. Inactivation of VHL gene contributing to tumorigenesis of the VHL tumor since VHL protein is required for the down-regulation of transcription activity of certain genes
CLINICAL FEATURES
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1. Great variation in the clinical presentation with variable age of onset 2. Classification of VHL disease a. VHL type 1 i. Without pheochromocytoma ii. Truncating or null mutations in the VHL gene (deletions or frameshift, nonsense, or splice site mutations) observed in approximately 96–97% of patients with type 1 VHL b. VHL type 2 i. With pheochromocytomas ii. Missense mutations observed in 92–98% of patients with type 2 VHL c. Subtypes of type 2 VHL i. VHL type 2A a) VHL without predisposition to renal cell carcinoma and pancreatic neuroendocrine tumor b) Specific mutations (Y98H, Y112H, V116F, L188V) in the VHL gene conferring an increased risk for VHL disease
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ii. VHL type 2B a) VHL with predisposition to renal cell carcinoma and pancreatic neuroendocrine tumor b) Specific mutations (R167Q, R167W) in the VHL gene conferring an increased risk for VHL disease iii. VHL type 2C a) VHL with only pheochromocytoma manifestation b) Specific mutations (V155L, R238W) in the VHL gene conferring an increased risk for VHL disease 3. Tumors/cysts linked to VHL disease, typically develop in the 2nd, 3rd, and 4th decades of life a. Retinal angioma/hemangioblastoma i. Responsible for the first manifestation of VHL in 50% of the patients ii. Retinal lesions a) Formerly called retinal angiomas b) Histologically identical to hemangioblastomas c) Identified in about 70% of the patients d) Bilateral in about 50% of the patients e) Multiple in about 66% of the patients iii. Complications when the condition is unrecognized and untreated at early stage a) Majority of retinal angiomas eventually hemorrhage. b) Resulting in massive exudation and retinal detachment c) Ultimate development of neovascular glaucoma and blindness b. Cerebellar hemangioblastomas (80% of CNS hemangioblastoma) i. The most common initial manifestation (34.9%) ii. Cumulative occurrence: 60.2% iii. The most common cause of death (47.7%) iv. Symptoms and signs a) Headache b) Slurred speech c) Nystagmus d) Positional vertigo e) Labile hypertension (without pheochromocytoma) f) Vomiting g) Wide-based gait h) Dysmetria c. Spinal hemangioblastoma (20% of CNS hemangioblastoma) i. More specific for VHL disease ii. About 80% of cases are caused by VHL. iii. Cumulative occurrence (14.5%) iv. Symptoms and signs a) Pain b) Sensory and motor loss secondary to cord compression d. Renal lesions i. Renal cysts: Precursor lesions to clear cell renal carcinomas (75% of patients with VHL) which is a frequent cause of death
ii. Hemangioblastoma iii. Renal cell adenoma iv. Renal cell carcinoma (20–40%) e. Pheochromocytomas (tumor of adrenal medulla) i. Type 1 families a) Absence of pheochromocytomas b) Most type 1 families are affected by deletions or premature termination mutations. ii. Type 2 families (7–20% of families) a) Presence of pheochromocytomas b) Most type 2 families are affected by missense mutations. iii. Arg238trp and arg238gln mutations: associated with a 62% risk for pheochromocytoma iv. Location of tumors a) Usually located in one or both adrenal glands b) May present anywhere along the sympathetic axis in the abdomen or thorax (paragangliomas) or head and neck (chemodectomas) v. Symptoms and signs a) Sustained or episodic hypertension b) Asymptomatic f. Pancreatic lesions i. Type of lesions a) Simple pancreatic cysts b) Serous cystadenomas c) Pancreatic neuroendocrine tumors ii. Rarely causing endocrine or exocrine insufficiency unless the lesion is extensive iii. Occasionally causing biliary obstruction secondary to cysts in the head of the pancreas g. Liver lesions i. Hemangiomas ii. Cyst iii. Adenoma iv. Carcinoid of the common bile duct h. Splenic lesions i. Hemangiomas ii. Cyst i. Pulmonary lesions i. Hemangiomas ii. Cyst j. Bladder hemangioblastoma k. Endolymphatic sac tumors of the inner ears (labyrinth) i. Tinnitus or vertigo ii. Deafness l. Papillary cystadenomas of the epididymis in males i. Relatively common in males ii. Unilateral: rarely causing problem iii. Bilateral: infertility m. Papillary cystadenomas of the broad ligament in females: much less common n. Skin lesions i. Nevus ii. Café au lait spot o. Bone lesions i. Hemangioma ii. Cyst 4. Diagnosis of VHL disease usually made on clinical grounds
VON HIPPEL-LINDAU DISEASE
a. A positive family history of VHL disease plus one of the following lesion (hemangioblastoma or visceral lesion): i. Retinal hemangioblastoma ii. Cerebellar hemangioblastoma iii. Pheochromocytoma iv. Renal cell carcinoma v. Multiple pancreatic cysts b. A negative family history of VHL disease need one of the following: i. Two or more retinal or cerebellar hemangioblastomas ii. One hemangioblastoma plus one visceral tumor 5. Prognosis a. Life expectancy: <50 years b. Most common causes of death i. Renal cell carcinoma ii. Cerebellar hemangioblastoma c. Improved prognosis in patients with: i. Earlier diagnosis ii. Regular monitoring for predictable complications iii. Followed by early interventions
7.
8.
DIAGNOSTIC INVESTIGATIONS 1. Biochemical test: elevated urinary catecholamines (VMA, metanephrine, and total catecholamine) suggesting pheochromocytoma even in the absence of hypertension 2. Eye examinations a. Ophthalmoscopy b. Fluorescein angiography, a valuable tool useful in detecting subclinical fundus lesions 3. Radiography for rare associated bone cysts and osseous hemangiomas 4. Ultrasound examinations a. Evaluation of the epididymus and broad ligament b. Screening of the kidneys 5. CAT scan a. To document the presence of CNS and visceral tumors i. CNS hemangioblastomas a) Cystic lesions (75%) b) An enhancing lesion with multiple cystic areas (15%) c) An enhancing solid mass (10%) ii. Retinal hemangiomas too small to be depicted on CT scans, the diagnosis mainly dependent on the results of an ophthalmoscopic examination iii. Papillary endolymphatic sac tumors presenting as a thin peripheral rim of calcification, representing the expanded cortex of petrous bone b. Low sensitivity in the detection of renal cell carcinoma associated with VHL i. Not reliable in differentiating cystic renal cell carcinomas, cancers within a cyst, and atypical cysts ii. Impossible to differentiate a renal cell adenoma from a renal cell carcinoma 6. MRI to document the presence of CNS and visceral tumors
9.
10.
11.
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a. MRI appearances of a CNS hemangioblastoma: a well-demarcated cystic lesion with a highly vascular mural nodule that always abuts on the pia mater b. Spinal hemangioblastomas: intramedullary tumors in most patients (75%) but may be radicular (20%) or intradural extramedullary (5%) c. Pheochromocytoma: high signal intensity on T2wighted MRI, differentiating it from adrenal cortical nodules d. Endolymphatic sac tumors: high signal intensity with T1 imaging on MRI as a mass on the posterior wall of the petrous part of the temporal bone Radionuclide studies a. To provide an indication of metabolic activity of CNS tumors by positron emission tomography (PET) with 2-[fluorine 18]-fluoro-2-deoxy-D-glucose (FDG) b. To detect bone metastases resulting from primary malignant tumor of bone of VHL c. To assess renal function prior to resection of renal tumors d. To detect pheochromocytoma using iodine-131 metaiodobenzylguanidine (131I MIBG) Angiography a. Hemangioblastoma: a hypervascular lesion with intense and prolonged early enhancement of the mural nodule associated with dilated feeding vessels b. Endolymphatic sac tumors i. Hypervascular on angiography and the blood supply is derived from the external carotid artery ii. Large tumors with an additional blood supply from the internal carotid artery and posterior circulation Histologic features of VHL tumors a. High degree of vascularization b. Presence of a clear cell component NIH group recommendation for monitoring VHL patients and family members a. Birth to 2 years i. Annual physical examination ii. Annual ophthalmologic examination b. 2–10 years: urinary catecholamines every 1–2 years c. 11–19 years i. Biannual MRI of the brain and spine ii. Annual ultrasound examination of abdomen iii. CT scans of abdomen every 6 months if renal cysts or tumor present d. 20–59 years: annual CT scan of abdomen e. 60 years and above without VHL i. MRI of the brain and spine every 3–5 years ii. CT scan of the abdomen every other year f. Not necessary to monitor the family members identified previously with an empiric risk of 50% of being affected but are found not to have inherited the mutation Molecular genetic analysis a. Considered standard for the evaluation of patients and families with suspected VHL disease b. Identification of VHL gene germline mutations i. Identification of constitutional VHL gene deletions by FISH using probes from the VHL gene critical region in 3p25.3
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a) Offers a comprehensive way to screen for the presence of germline deletions because it enables visualization of individual cells b) May identify mosaicism or cryptic translocation events that cannot be readily detected by other molecular strategies in patients with submicroscopic germline deletions and a normal karyotype c) Enable to identify a de novo mosaic for the VHL gene deletion ii. Molecular diagnosis accomplished in virtually all families with classic VHL disease (families with multiple tumors) and in the majority of isolated patients with multiple VHL-associated tumors a) Qualitative and quantitative Southern blotting to detect partial or complete gene deletions responsible for 28% of all cases b) DNA-sequence analysis of the proteinencoding region (all three exons) to detect point mutations in the remainder (72%) of the cases c. Mosaicism i. A potential cause for failure of molecular diagnosis in VHL ii. Individuals with mosaicism: a) Asymptomatic b) Manifesting as a single-system disease c) Manifesting as a multisystem disease d. Identification of a mutation in a proband allows the identification of mutation carriers among family members who do not yet exhibit any clinical manifestation of VHL
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. A small risk of having a sib with VHL since parental mosaicism accounts for some apparently sporadic or new cases of VHL ii. A 50% risk of having a sib with VHL disease if one of the parent is clinically affected or has a disease-causing VHL gene mutation b. Patient’s offspring i. A 50% risk of inheriting the VHL disease-causing mutation ii. An individual mosaic for a disease mutation is at increased risk for having affected offspring, despite negative testing for the mutation by routine DNA diagnostic tests 2. Prenatal diagnosis available by molecular genetic testing of fetal DNA obtained from amniocentesis or CVS for pregnancies at 50% risk when the disease-causing mutation has been identified in the affected parent 3. Management a. Ocular management i. Laser photocoagulation therapy or cryotherapy of retinal lesions
ii. Several treatment strategies on the horizon that show promise for the ocular management of VHL disease a) Vascular endothelial growth factor (VEGF) inhibitors b) Use of radiotherapy, such as brachytherapy or linear-accelerated based radiosurgery b. Surgery: the mainstay of treatment for the tumors arising in patients with VHL disease i. Renal cell carcinomas a) Partial nephrectomy or radiofrequency ablation to spare renal function if tumor involvement is not extensive b) Total nephrectomy often necessary for extensive tumor involvement ii. CNS hemangioblastomas: radiation therapy in patients with CNS symptoms
REFERENCES Choyke PL, Glenn GM, Walther MM, et al.: von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology 194:629–642, 1995. Clifford SC, Maher ER: Von Hippel-Lindau disease: clinical and molecular perspectives. Adv Cancer Res 82:85–105, 2001. Couch V, Lindor NM, Karnes PS, et al.: von Hippel-Lindau disease. Mayo Clin Proc 75:265–272, 2000. Dannenberg H, De Krijger RR, van der Harst E, et al.: Von Hippel-Lindau gene alterations in sporadic benign and malignant pheochromocytomas. Int J Cancer 105:190–195, 2003. Decker HJ, Klauck SM, Lawrence JB, et al.: Cytogenetic and fluorescence in situ hybridization studies on sporadic and hereditary tumors associated with von Hippel-Lindau syndrome (VHL). Cancer Genet Cytogenet 77:1–13, 1994. Dollfus H, Massin P, Taupin P, et al.: Retinal hemangioblastoma in von HippelLindau disease: a clinical and molecular study. Invest Ophthalmol Vis Sci 43:3067–3074, 2002. Friedrich CA: Genotype-phenotype correlation in von Hippel-Lindau syndrome. Hum Mol Genet 10:763–767, 2001. Glenn GM, Linehan WM, Hosoe S, et al.: Screening for von Hippel-Lindau disease by DNA polymorphism analysis. JAMA 267:1226–1231, 1992. Hes FJ, Hoppener JW, Lips CJ: Clinical review 155: Pheochromocytoma in Von Hippel-Lindau disease. J Clin Endocrinol Metab 88:969–974, 2003. Jordan DK, Patil SR, Divelbiss JE, et al.: Cytogenetic abnormalities in tumors of patients with von Hippel-Lindau disease. Cancer Genet Cytogenet 42:227–241, 1989. Kaelin WG, Jr: The von Hippel-Lindau gene, kidney cancer, and oxygen sensing. J Am Soc Nephrol 14:2703–2711, 2003. Khan AN, Turnbull I: Von Hippel-Lindau syndrome. Emedicine, 2003. http://www.emedicine.com Latif F, Tory K, Gnarra J, et al.: Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317–1320, 1993. Lubensky IA, Pack S, Ault D, et al.: Multiple neuroendocrine tumors of the pancreas in von Hippel-Lindau disease patients. Histopathological and molecular genetic analysis. Am J Pathol 153:223–231, 1998. Maher ER, Yates JR, Harries R, et al.: Clinical features and natural history of von Hippel-Lindau disease. Q J Med 77:1151–1163, 1990. Murgia A, Martella M, Vinanzi C, et al.: Somatic mosaicism in von HippelLindau Disease. Hum Mutat 15:114–119, 2000. Neumann HP, Bender BU: Genotype-phenotype correlations in von HippelLindau disease. J Intern Med 243:541–545, 1998. Neumann HP, Berger DP, Sigmund G, et al.: Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med 329:1531–1538, 1993. Neumann HP, Lips CJ, Hsia YE, et al.: Von Hippel-Lindau syndrome. Brain Pathol 5:181–193, 1995. Pack SD, Zbar B, Pak E, et al.: Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization. Cancer Res 59:5560–5564, 1999. Petersen G: Genetic testing. Hematol Oncol Clin North Am 14:939–952, 2000.
VON HIPPEL-LINDAU DISEASE Richard S: Von Hippel-Lindau disease: recent advances and therapeutic perspectives. Expert Rev Anticancer Ther 3:215–233, 2003. Richards FM, Webster AR, McMahon R, et al.: Molecular genetic analysis of von Hippel-Lindau disease. J Intern Med 243:527–533, 1998. Richard S, David P, Marsot-Dupuch K, et al.: Central nervous system hemangioblastomas, endolymphatic sac tumors, and von Hippel-Lindau disease. Neurosurg Rev 23:1–22; discussion 23–24, 2000. Sanfilippo P, Troutbeck R, Vandeleur K: Retinal angioma associated with von Hippel-Lindau disease. Clin Exp Optom 86:187–191, 2003. Sano T, Horiguchi H: Von Hippel-Lindau disease. Microsc Res Tech 60:159–164, 2003. Schimke RN, Collins DL, Stolle CA: Von Hippel-Lindau syndrome. Gene Reviews, 2002. http:// www.genetests.org
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Sgambati MT, Stolle C, Choyke PL, et al.: Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents. Am J Hum Genet 66:84–91, 2000. Stolle C, Glenn G, Zbar B, et al.: Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat 12:417–423, 1998. Taouli B, Ghouadni M, Correas JM, et al.: Spectrum of abdominal imaging findings in von Hippel-Lindau disease. AJR Am J Roentgenol 181:1049–1054, 2003. Torreggiani WC, Keogh C, Al-Ismail K, et al.: Von Hippel-Lindau disease: a radiological essay. Clin Radiol 57:670–680, 2002. Zbar B, Kaelin W, Maher E, et al.: Third International Meeting on von HippelLindau disease. Cancer Res 59:2251–2253, 1999.
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Fig. 1. Retinal malformation secondary to von Hippel-Lindau disease.
Fig. 2. Retinal exudates from vascular leakage in a patient with von Hippel-Lindau disease.
Fig. 3. A giant macroaneurysm of retinal vessels in a patient with von Hippel-Lindau disease.
Waardenburg Syndrome 3. Congenital sensorineural deafness (deaf-mutism): Waardenburg syndrome is the most common syndromal cause of deafness and is responsible for 2–3% of congenital deafness. 4. Pigmentary abnormalities a. Cutaneous pigmentary abnormalities i. Achromatic spots, with sharply defined irregular borders and containing scattered islands of hyperpigmention, resemble those of piebaldism ii. Hyperpigmented macules on normally pigmented skin that have been described as a “patchy skin” and give the cases a “dappled appearance” b. Hair pigmentary abnormalities i. White forelock (may be evident at birth, soon afterwards, or develop later) ii. Premature graying of the scalp hair and of the eyebrows, cilia, or body hair c. Fundus pigmentary abnormalities i. Albinotic fundi (generalized decrease in retinal pigment) ii. Pigmentary mottling in the periphery d. Partial albinism e. Heterochromia (different color) of the iris f. Bilateral isohypochromia iridis (pale blue eyes) g. Ocular albinism (type II) 5. Musculoskeletal abnormalities (type III, Klein-Waardenburg syndrome) a. Ortho-osteomyo-dysplasia of the upper limbs b. Bilateral upper limb defects c. Flexion contractures d. Fusion of the carpal bones e. Syndactyly 6. Congenital aganglionic megacolon association (type IV, Shah-Waardenburg syndrome) 7. Occasional associated anomalies a. Cleft lip/palate b. Neural tube defects c. Facial asymmetry d. Facial palsy e. Hypokalemic periodic paralysis f. Preauricular pit g. Hypoplasia of the middle ear ossicles h. Blepharoptosis i. Microphthalmia j. Hypertelorism k. Iris coloboma l. Fixed dilated pupil, anterior lenticonus m. High arched palate n. “Cupid bow” configuration of the upper lip o. Prognathism p. Microcephaly q. Mental retardation r. Esophageal atresia with tracheo-esophageal fistula
Waardenburg syndrome is a rare autosomal dominant disorder characterized by patchy depigmentation, sensorineural hearing loss, and other developmental defects. There are four types of this syndrome.
GENETICS/BASIC DEFECTS 1. Inheritance: genetic heterogeneity a. Autosomal dominant i. Type I (Waardenburg syndrome) (presence of dystopia canthorum) ii. Type II (Waardenburg syndrome with ocular albinism; absence of dystopia canthorum) iii. Type III (Klein-Waardenburg syndrome; presence of musculoskeletal abnormalities) b. Autosomal recessive: Type IV (Shah-Waardenburg syndrome or Waardenburg-Hirschsprung disease) 2. Cause a. Type I and Type III: mutations in PAX3 (paired box) gene on chromosome 2q35 b. Type II: mutations in MITF (microphthalmia associated transcription factor) gene on chromosome 3p12p14.1 c. Type IV i. Mutations in the genes for endothelin-3 (EDN3) on chromosome 13q22 or endothelin B receptor (EDNRB) on chromosome 20q13.2–q13.3 ii. Mutations in SOX10 gene on chromosome 22q13 3. Pathogenesis: None of the following theories explains all the features of Waardenburg syndrome. a. Deficient neural crest theory i. Developmental abnormality of the neural crest as a cause of the disease ii. Supported by the association of Waardenburg syndrome with aganglionic megacolon b. As a part of the first arch syndrome theory c. A relationship of Waardenburg syndrome with status dysraphicus theory d. Intrauterine necrosis theory 4. Genotype-phenotype correlations: Specific mutations in the PAX3 gene correlate with the expression of different features of Waardenburg syndrome.
CLINICAL FEATURES 1. Wide clinical spectrum 2. Facial appearance a. Dystopia canthorum (lateral displacement of the medial canthi) b. Bushy eyebrows with synophrys c. A narrow nose with prominent nasal root d. Marked hypoplasia of the nasal bone e. Short philtrum f. Short/retro positioned maxilla 1035
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s. Imperforate anus t. Bifid spine u. Vertebral agenesis v. Absence of vagina and right adnexal uteri w. Syndactyly x. Cardiovascular anomalies y. Polythelia z. Urinary anomalies aa. Hyperkeratosis of palms and soles bb. Black forelock cc. Hyperpigmented skin lesions 8. Diagnostic criteria for Waardenburg type 1 and type 2 as proposed by the Waardenburg Consortium. To be affected with Waardenburg type 1, an individual must have two major or one major plus two minor criteria. To be affected with Waardenburg type 2, an individual should show two major features (with one major feature of an affected firstdegree relative who should show two major features) (more stringent criteria by Liu et al., 1995). a. Major criteria i. Congenital sensorineural hearing loss ii. Pigmentary disturbances of iris a) Complete heterochromia iridum (two eye of different color) b) Partial or segmental heterochromia (segments of blue or brown pigmentation in one or both eyes) c) Hypoplastic blue eyes (characteristically brilliant blue in both eyes) iii. Hair hypopigmentation (white forelock) iv. Dystopia canthorum v. Affected first degree relatives b. Minor criteria i. Congenital leucoderma (several areas of hypopigmented skin) ii. Synophrys or medial eyebrow flare iii. Broad and high nasal root iv. Hypoplasia of alae nasi v. Premature graying of hair (scalp hair predominantly white before age 30)
DIAGNOSTIC INVESTIGATIONS 1. Audiologic evaluation for hearing loss 2. Histochemical studies of achromic skin a. Absent melanocytes b. Presence of only a few dihydroxyphenylalanine (dopa)positive cells 3. Ultrastructural findings of depigmented skin a. Absence or dramatically reduced melanocytes b. Dendritc cells containing poorly melanized melanosomes c. Absence of melanosomes in the keratinocytes 4. Chromosome abnormalities observed in Type I Waardenburg syndrome a. Inversion 2q35-q36.1 b. Deletion 2q35-q36.2 c. Del(2)(q34;q36.2) 5. Molecular studies of mutations for different types of Waardenburg syndrome
a. Waardenburg syndrome type I: PAX3 gene mutation b. Waardenburg syndrome type II: 15–20% of cases have heterozygous mutation in the MITF gene c. Waardenburg syndrome type III: interstitial deletion of chromosome 2 (2q35-q36.2) including the PAX3 gene d. Waardenburg syndrome type IV: i. Mutations in the gene encoding endothelin-3 (Edn 3) or one of its receptors, the endothelin-B receptor (Ednrb) ii. Mutations in SOX10
GENETIC COUNSELING 1. Recurrence risk a. Autosomal dominant inheritance i. Patient’s sibs: not increased unless one of the parent is also affected ii. Patient’s offspring: 50% b. Autosomal recessive inheritance i. Patient’s sibs: 25% ii. Patient’s offspring: not increased unless the spouse is a carrier or affected 2. Prenatal diagnosis a. Possible when a mutation has been defined in the family b. Impossible to predict how severe the fetus will be affected 3. Management a. No effective treatment available b. Photoprotection to protect the amelanotic areas from burning with sun exposure i. Sunscreens ii. Camouflage a) Hair dye b) Dermablend c. Autologous grafts or transplants of autologous cultured melanocytes used to repigment the areas of hypomelanosis (piebaldism) d. Important to diagnose and improve hearing loss e. Folate supplementation during pregnancy advisable for a fetus at risk for Waardenburg type 1, although the risk for neural tube defect is low
REFERENCES Baldwin CT, Hoth CF, Macina RA, et al.: Mutations in PAX3 that cause Waardenburg syndrome type I. Ten new mutations and review of the literature. Am J Med Genet 58:115–122, 1995. Bondurand N, Pingault V, Goerich DE, et al.: Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome. Hum Mol Genet 9:1907–1917, 2000. Bonnet J Pediatr, Till M, Edery P, et al.: Waardenburg-Hirschsprung disease in two sisters: a possible clue to the genetics of this association? Eur J Pediatr Surg 6:245–248, 1996. Da-Silva EO: Waardenburg I syndrome: a clinical and genetic study of two large Brazilian kindreds, and literature review. Am J Med Genet 40:65–74, 1991. Delleman JW, Hagerman MJ: Ophthalmologic findings in 34 patients with Waardenburg syndrome. J Pediatr Ophthalmol Strabism 15:341–345, 1978. DeStefano AL, Cupples LA, Arnos KS, et al.: Correlation between Waardenburg syndrome phenotype and genotype in a population of individuals with identified PAX3 mutations. Hum Genet 102:499–506, 1998.
WAARDENBURG SYNDROME Dourmishev AL, Dourmishev LA, Schwartz RA, et al.: Waardenburg syndrome. Int J Dermatol 38:656–663, 1999. Goodman RM, Lewithal I, Solomon A, et al.: Am J Med Genet 11:425–433, 1982. Hageman MJ, Delleman JW: Heterogeneity in Waardenburg syndrome. Am J Hum Genet 29:468–485, 1977. Hofstra RM, Osinga J, Tan-Sindhunata G, et al.: A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). Nature Genet 12:445–447, 1996. Hoth CF, Milunsky A, Lipsky N, et al.: Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I). Am J Hum Genet 52:455–462, 1993. Hughes AE, Newton VE, Liu XZ, et al.: A gene for Waardenburg syndrome type 2 maps close to the human homologue of the microphthalmia gene at chromosome 3p12-p14.1. Nature Genet 7:509–512, 1994. Klein D: Historical background and evidence for dominant inheritance of the KleinWaardenburg syndrome (Type III). Am J Med Genet 14:231–239, 1983.
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Liu XZ, Newton VE, Read AP: Waardenburg syndrome type II. Phenotypic findings and diagnostic criteria. Am J Med Genet 55:95–100, 1995. Mallory SB, Wiener E, Nordlund JJ: Waardenburg’s syndrome with Hirschsprung’s disease: a neural crest defect. Pediatr Dermatol 3:119–124, 1986. Reed AP, Newton VE: Waardenburg syndrome. J Med Genet 34:656–665, 1997. Tassabehji M, Newton VE, Read AP: Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nature Genet 8:251–255, 1994. Touraine RL: Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain. Am J Hum Genet 66:1496–1503, 2000. Waardenburg PJ: A new syndrome combining developmental anomalies of the eyelids, eyebrows, and nose root with pigmentary defects of the iris and head hair and with congenital deafness. Dystonia canthi medialis et punctorum lacrimalium lateroversa, hyperplasia supercilii medialis et readicis nasi, Heterochromia iridum totalis sive partialis, albinismus circumscriptus (leucismus, poliosis), et surditas congenita (surdimutitas). Am J Hum Genet 3:195–253, 1951.
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Fig. 2. An adult patient with Waardenburg syndrome showing white forelock, white eyelashes, and patchy hyperpigmented macules on the neck.
Fig. 1. A 3-week-old infant with Waardenburg syndrome showing white forelock and vitiligo involving symmetrically anterior lower chest, anterior upper abdomen, lower legs, elbows, and fingers. Fig. 3. A patient with Waardenburg syndrome. Notice grey forelock hair, broad based brow and increased interpalpebral space.
WAARDENBURG SYNDROME
Fig. 4. Two patients with Waardenburg syndrome showing iris heterochromia.
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Williams Syndrome In 1961, Williams et al. described children with a constellation of abnormalities including “unusual” facial features, growth retardation, supravalvular aortic stenosis, and cognitive impairment. In 1962, Beuren described a series of children with similar features, dental anomalies, peripheral pulmonary artery stenosis and friendly personalities. Consequently, Williams syndrome is also known as Williams-Beuren syndrome. These characteristics are observed in virtually every patient with Williams syndrome, now known to be caused by a microdeletion of chromosome 7q11.23. The incidence of the syndrome is estimated to be between 1/20,000 and 1 in 50,000 live births.
GENETICS/BASIC DEFECTS 1. Inheritance a. Sporadic new deletion in most cases b. Rare autosomal dominant transmission of microdeletion involving the Wolf-Hirschhorn syndrome critical region in a few cases 2. Association of the elastin (ELN) gene disruption by chromosome translocation or partial deletion involving chromosome 7q11.23 and the supravalvular aortic stenosis: the first clue to the location of the Williams syndrome microdeletion 3. Caused by the haploinsufficiency of genes within a microdeletion of the long arm of chromosome 7 (7q11.23) 4. Deletions in the ELN gene a. Mechanism: deletions typically caused by unequal recombination during meiosis b. Deletion with equal frequency on the maternally or paternally inherited chromosome 7 c. A total of at least 16 genes mapped within the commonly deleted interval d. ELN gene mapped approximately at the center of the deletion e. Responsible for supravalvular aortic stenosis and other vascular stenoses f. Possibly responsible for some of the connective tissue problems i. Lax joints ii. Premature aging of the skin iii. Joint contractures iv. A hoarse voice v. Bladder and bowel diverticula vi. Hernias g. Majority of patients with Williams syndrome with large deletion spans (approximately 1.5 Mb of DNA), which contain many genes that contribute to the additional clinical symptoms not seen in patients with isolated supravalvular aortic stenosis h. Genetic studies demonstrate that isolated nonsyndromic supravalvular aortic stenosis is associated with intragenic deletions within the ELN gene, while
Williams syndrome involves deletions spanning the entire ELN gene i. Other genes identified in the commonly deleted region: e.g., LIMK1, CYLN2, GTF21, and STX1A
CLINICAL FEATURES 1. Characteristic dysmorphic facies, frequently referred to as elfin facies (100%). Effort must be made to curtail the use of “elfin-facies” to denote a resemblance to a mythological creature since the term is not well received by family members. a. Periorbital fullness b. Stellate lacy iris pattern c. Short nose with bulbous nasal tip d. Flat nasal bridge e. Prominent full cheeks f. Long philtrum g. Wide mouth h. Full lips i. Mild micrognathia j. Long narrow face and long neck in older children and adults 2. Cardiovascular diseases a. Supravalvular aortic stenosis (80%), often a progressive condition that may require surgical repair b. Generalized arteriopathy (narrowing of arteries secondary to abnormal elastin protein, an important component of elastic fibers in the arterial wall) i. Peripheral pulmonary artery stenosis often present in infancy and usually improves over time ii. Possible worsening over time of the coarctation of the aorta, renal artery stenosis, and systemic hypertension iii. Possible narrowing of any arterial wall since elastin protein is an important component of elastic fibers in the arterial wall c. Other congenital cardiac defects i. Mitral valve prolapse (11.6%) ii. Bicuspid aortic valve (15%) iii. Aortic hypoplasia iv. Septal defects v. Left ventricular hypertrophy 3. Variable mental retardation (75%) 4. Characteristic cognitive/behavioral profile (90%) a. Characteristic behavioral pattern i. Relative preservation of linguistic abilities ii. Gross deficiencies in visual-spatial processing and motor skills b. Motor disabilities affecting balance, strength, coordination, and motor planning c. Delayed speech acquisition, followed by excessive talking (“cocktail party” verbal abilities)
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d. Overfriendliness and an empathetic nature e. Uncontrollable loquacity f. Behavioral problems i. Hypersensitivity to sound (hyperacusis) ii. Sleep problems iii. Attention deficit/hyperactivity disorder (ADHD) iv. Anxiety v. Distractability vi. Inflexibility vii. Rituralism 5. Idiopathic infantile hypercalcemia (15%) a. Symptoms and signs of hypercalcemia (usually resolves during childhood) i. Extreme irritability ii. Vomiting iii. Constipation iv. Muscle cramps b. Possible lifelong persistence of abnormal calcium and vitamin D metabolism c. Hypercalcinuria predisposing to nephrocalcinosis 6. Other features a. Growth i. Post-term birth (>41 weeks) ii. Failure to thrive iii. Short stature (50%) iv. Hypothyroidism v. A premature and abbreviated pubertal growth spurt b. CNS i. Muscle hypotonia early ii. Muscle tone increases with age; hypertonia in some cases iii. Poor coordination iv. Awkward gait v. Chiari I malformation vi. Hyperreflexia of the lower extremities c. EENT i. Ocular findings a) Strabismus b) Hyperopia c) Stellate iris d) Retinal vessel tortuosity ii. Chronic otitis media iii. Dental abnormalities a) Hypodontia/Microdontia b) Malocclusion c) Overbite d) Excessive interdental spacing e) Small roots f) High incidence of caries iv. A hoarse or brassy voice d. GI i. Difficulty feeding ii. Gastroesophageal reflux/vomiting iii. Prolong colic iv. Bowel diverticula v. Hernias vi. Rectal prolapse vii. Constipation viii. Peptic ulcers e. Genitourinary (18%) i. Bladder diverticula: the most common defects
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ii. Renal artery stenosis iii. Renal agenesis iv. Duplicated kidneys v. Horseshoe kidney vi. Renal cysts vii. Nephrocalcinosis viii. Vesicouriteral reflux f. Orthopedic problems i. Low/hoarse voice ii. Hernias iii. Joint laxity mostly during infancy iv. Joint contractures may develop by childhood and adolescence (50%) v. Radioulnar synostosis vi. Kyphosis vii. Lordosis viii. Scoliosis ix. Hallux valgus x. Hypoplastic nails xi. Clinodactyly of 5th fingers
DIAGNOSTIC INVESTIGATIONS 1. Echocardiography for cardiac lesions 2. Ultrasonography a. Bladder and kidneys b. Intravascular ultrasound imaging: to detect vascular wall thickening with secondary lumen narrowing 3. Serum creatinine level 4. Blood calcium levels to detect hypercalcemia during early infancy 5. Thyroid function test 6. Ophthalmologic evaluation for strabismus and retinal vessel tortuosity 7. Urinalysis to detect hypercalcinuria 8. Renal ultrasound for possible nephrocalcinosis if hypercalcinuria is noted 9. Radiography: osteosclerosis of the metaphyses of long bones, the skull vault, or lamina dura of the alveolar bone in adolescence and adulthood, if overt hypercalcemia is present 10. Full cytogenetic studies a. Larger deletions detectable by standard cytogenetic techniques, especially by high-resolution chromosome analysis b. To rule out possible chromosomal rearrangements involving the 7q11.23 locus as well as any other cytogenetic abnormalities 11. Fluorescence in situ hybridization (FISH) with a cosmid probe corresponding to ELN for diagnostic testing a. 99% of the patients with a hemizygous submiroscopic deletion of 7q11.23 detectable by FISH b. Cases undetectable by FISH i. Rare cases with a smaller deletion which does not fully encompass the FISH probe ii. Cases with phenocopies of Williams syndrome with same clinical phenotype produced by mutation or deletion of other gene(s) iii. Cases with a Williams syndrome-like phenotype associated with various cytogenetic rearrangements
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GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Recurrence risk low (<1%) (most cases are sporadic and neither parent is affected) ii. Presence of a small theoretical risk of germline mosaicism in an unaffected parent b. Patient’s offspring: 50% recurrence risk of having an affected offspring in individuals who have the deletion of the Williams syndrome critical region (Parent-to-child transmission observed occasionally) 2. Prenatal diagnosis by amniocentesis or CVS a. Rarely utilized because most cases are sporadic and no prenatal indicators exist for low-risk pregnancies b. Utilized for pregnancies at 50% risk of having Williams syndrome c. FISH probe covering approximately 180 kb of the critical region deleted in the Williams syndrome including ELN gene, lim-kinase1 (LIMK1), and the D7S613 locus 3. Management a. Management of hypercalcemia i. Limit high calcium food ii. Avoid preparations containing vitamin D b. Supravalvular aortic stenosis (a life-threatening component of the phenotype): surgically correctable c. Early dental care d. Education and vocational concerns i. Early daily learning activities and strategies a) Auditory cues b) Music activities, singing/rhyming songs, and toys with soft sounds c) Teaching communication skills through daily routines d) Use of language expansions and parallel talk ii. Special education for older children iii. Restrictive levels of care required for most adult patients e. Social and emotional concerns i. At increased risk for exploitation and abuse ii. Teaching of appropriate social skills f. Psychotherapy i. Verbally oriented psychotherapy ii. Group therapy
REFERENCES American Academy of Pediatrics Committee on Genetics: Health care supervision for children with Williams syndrome. Pediatrics 107:1192–1204, 2001. Bellugi U, Bihrle A, Jernigan T, et al.: Neuropsychological, neurological and neuroanatomical profile of Williams syndrome. Am J Med Genet 6:115–125, 1990. Burn J: Williams syndrome. J Med Genet 23:389–395, 1986. Curran ME, Atkinson DL, Ewart AK, et al.: The elastin gene is disrupted by a translocation associated with supravalvular aortic stenosis. Cell 73:159–168, 1993. Donnai D, Karmiloff-Smith A: Williams syndrome: from genotype through to the cognitive phenotype. Am J Med Genet 97:164–171, 2000. Eronen M, Peippo M, Hiippala A, et al.: Cardiovascular manifestations in 75 patients with Williams syndrome. J Med Genet 39:554–558, 2002. Ewart AK, Morris CA, Atkinson D, et al.: Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet 5:11–16, 1993.
Francke U: Williams-Beuren syndrome: genes and mechanisms. Hum Mol Genet 8:1947–1954, 1999. Greenberg F: Williams syndrome professional symposium. Am J Med Genet Suppl 6 (suppl):85–88, 1990. Greenberg F, Lewis RA: The Williams syndrome: spectrum and significance of ocular features. Ophthalmology 95:1608–1612, 1988. Hallidie-Smith KA, Karas S: Cardiac anomalies in Williams-Beuren syndrome. Arch Dis Child 63:809–813, 1988. Hirota H, Matsuoka R, Kimura M, et al.: Molecular cytogenetic diagnosis of Williams syndrome. Am J Med Genet 64:473–477, 1996. Hodapp RM, DesJardin JL, Ricci LA: Genetic syndromes of mental retardation. Should they matter for the early interventionist/Infants & Young Children 16:152–160, 2003. Hoogenraad CC, Akhmanova A, Galjart N, et al.: LIMK1 and CLIP-115: linking cytoskeletal defects to Williams syndrome. Bioessays 26:141–150, 2004. Jurado LAP: Williams-Beuren syndrome: a model of recurrent genomic mutations. Horm Res 59(suppl 1): 106–113, 2003. Kaplan P, Wang PP, Francke U: Williams (Williams Beuren) syndrome: a distinct neurobehavioral disorder. J Child Neurol 16:177–190, 2001. Kara-Mostefa A, Raoul O, Lyonnet S, et al.: Recurrent Williams-Beuren syndrome in a sibship suggestive of maternal germ-line mosaicism. Am J Hum Genet 64:1475–1478, 1999. Lashkari A, Smith AK, Graham JM Jr: Williams-Beuren syndrome: an update and review for the primary physician. Clin Pediatr (Phila) 38:189–208, 1999. Li DY, Toland AE, Boak BB, et al.: Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis. Hum Mol Genet 7:1021–1028, 1997. Lopez-Rangel E, Maurice M, McGillivray B, et al.: Williams syndrome in adults. Am J Med Genet 44:720–729, 1992. Lowery MC, Morris CA, Ewart A, et al.: Strong correlation of elastin deletions, detected by FISH, with Williams syndrome: evaluation of 235 patients. Am J Hum Genet 57:49–53, 1995. Mari A, Amati F, Mingarelli R, et al.: Analysis of the elastin gene in 60 patients with clinical diagnosis of Williams syndrome. Hum Genet 96:444–448, 1995. Metcalfe K: Williams syndrome: an update on clinical and molecular aspects. Arch Dis Child 81:198–200, 1999. Morris CA, Thomas IT, Greenberg F: Williams syndrome: autosomal dominant inheritance. Am J Med Genet 47:478–481, 1993. Morris CA, Demsey SA, Leonard CO, et al.: Natural history of Williams syndrome: physical characteristics. J Pediatr 113:318–326, 1988. Morris CA, Leonard CO, Dilts C, et al.: Adults with Williams syndrome. Am J Med Genet Suppl 6:102–107, 1990. Morris CA: Williams syndrome. Gene Reviews, 2003. http://www.genetests.org. Nickerson E, Greenberg F, Keating MT, et al.: Deletions of the elastin gene at 7q11.23 occur in approximately 90% of patients with Williams syndrome. Am J Hum Genet 56:1156–1161, 1995. Osborne LR: Williams-Beuren syndrome: unraveling the mysteries of a microdeletion disorder. Mol Genet Metab 67:1–10, 1999 Õunap K, Laidre P, Bartsch O, et al.: Familial Williams-Beuren syndrome. Am J Med Genet 80:491–493, 1998. Pankau R, Siebert R, Kautza M, et al.: Familial Williams-Beuren syndrome showing varying clinical expression. Am J Med Genet 98:324–329, 2001. Pober BR, Dykens EM: Williams syndrome: an overview of medical, cognitive, and behavioural features. Child Adolesc Psychiatr Clin N Am 5:929–943, 1996. Pober BR, Lacro RV, Rice C, et al.: Renal findings in 40 individuals with Williams syndrome. Am J Med Genet 46:271–274, 1993. Rein AJ, Preminger TJ, Perry SB, et al.: Generalized arteriopathy in Williams syndrome: an intravascular ultrasound study. J Am Coll Cardiol 21:1727–1730, 1993. Schultz RT, Grelotti DJ, Pober B: Genetics of childhood disorders: XXVI. Williams syndrome and brain-behavior relationships. J Am Acad Child Adolesc Psychiatry 40:606–609, 2001. Tassabehji M, Metcalfe K, Karmiloff-Smith A, et al.: Williams syndrome: use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes. Am J Hum Genet 64:118–125, 1999. Udwin O, Yule W: A cognitive and behavioural phenotype in Williams syndrome. J Clin Exp Neuropsychol 13:232–244, 1991. Urban Z, Helms C, Fekete G, et al.: 7q11.23 deletions in Williams syndrome arise as a consequence of unequal meiotic crossover. Am J Hum Genet 59:958–962, 1996. Williams JC, Barratt-Boyes BG, Lowe JB: Supravalvular aortic stenosis. Circulation 24:1311–1318, 1961.
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Fig. 1. An infant with Williams syndrome showing periorbital fullness, stellate lacy iris pattern, flat nasal bridge, short nose with bulbous tip, wide mouth, and full cheeks and lips.
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Fig. 2. A child with Williams syndrome showing similar features.
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Fig. 3. Two young children with Williams syndrome showing characteristic facial appearance.
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Fig. 6. A G-banded karyotype in a patient with Williams syndrome showing del(17q11) (arrow with D).
Fig. 4. A child with Williams syndrome and severe scoliosis.
Fig. 5. An adult with Williams syndrome confirmed by FISH studies.
Fig. 7. FISH showing the classic microdeletion seen in Williams syndrome (7q11.23) [LSI(r) Williams Syndrome (Elastin Gene) Region Probe, Vysis/Abbott]. The metaphase cell shows only one chromosome 7 homologue with the orange signal (normal chromosome 7). The hemizygous deletion is shown on the chromosome with only the green loci [internal control probes for D7S486 and D7S522 (7q31)].
Wolf-Hirschhorn Syndrome 4. LETM1 a. A gene deleted in WHS, encodes mitochondrial protein b. Current evidence suggests that at least some (neuromuscular) features of WHS may be caused by mitochondrial dysfunction.
Wolf-Hirschhorn syndrome (WHS) is a chromosome 4p deletion syndrome, first described by Cooper and Hirschhorn in 1961, followed by report of Wolf et al. in 1965. The incidence is estimated to be approximately 1 in 50,000 births.
GENETICS/BASIC DEFECTS 1. Caused by the deletion of the distal short arm of chromosome 4 a. Variable size of the deletion b. Deletion of the terminal band (4p16.3): essential for full expression of the phenotype c. Identification of a 165 kb minimal critical region (WHSCR) within 4p16.3 d. Mechanism of deletions i. De novo deletions (75%): interstitial deletion of preferential paternal origin in 85–90% ii. Deletions resulting from unusual cytogenetic abnormality (12%) such as ring chromosome 4 iii. Deletions resulting from unbalanced product of a parental chromosomal rearrangement, usually of a reciprocal translocation (10–15%) 2. Types of chromosome abnormalities a. Detectable by conventional cytogenetic technique: large deletions b. Detectable only by molecular methods i. Terminal microdeletions ii. Interstitial microdeletions iii. Cryptic translocations 3. Genotype-phenotype correlation a. Patients with a large 4p16.3 deletion i. Severe mental and growth retardation ii. Major malformations iii. Seizures iv. Characteristic facial appearance with wide forehead, large and protruding eyes, hypertelorism, prominent glabella, down-turned mouth, and micrognathia b. Patients with a 4p16.3 microdeletion i. Milder phenotype ii. Lack congenital malformations c. Using genotype-phenotype correlation analysis in eight informative patients, Zollino (2003) characterized the following distinctive WHS clinical signs that represent the minimal diagnostic criteria for this condition, and mapped this basic phenotype outside the currently defined WHSCR and designated as a new critical region, WHSCR-2. i. Presence of typical facial appearance ii. Mental retardation iii. Growth delay iv. Congenital hypotonia v. Seizures
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1. Maternal gestational history a. Intrauterine growth retardation b. Decreased fetal movements c. Small placenta 2. Developmental history a. Delayed psychomotor development b. Difficulty in ambulation, often with ataxic gait c. Seizures (50% of cases) 3. Behavior history a. Stereotypes i. Holding the hands in front of the face ii. Hand-washing or flapping iii. Patting self on chest iv. Rocking v. Head shaking vi. Stretching of legs b. Absence of speech c. Babbling or guttural sounds, occasionally modulated in a communicative way d. Comprehension limited to simple orders or to a specific context e. Affect disorder that improves over time f. Walking with or without support g. Self-feeding h. Helps in dressing and undressing self i. Improved abilities and adaptation to new situations j. Communicative abilities and verbal comprehension with extension of the gesture repertoire and decreased occurrence of withdrawal and anxiety behaviors 4. Growth: severe growth retardation (short stature) 5. CNS a. Profound mental retardation b. Microcephaly c. Seizures (50–100%) d. Congenital hypotonia with muscle hypotrophy particularly of the lower limbs e. Malformation (33%) i. Hypoplasia of cerebellum ii. Cavum or absent septum pellucidum iii. Agenesis of corpus callosum iv. Hypoplasia or absence of olfactory bulbs and tracts v. Microgyria vi. Migration defects vii. Hydrocephalus
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6. Skull a. Frontal bossing b. High frontal hairline c. Hemangioma over forehead or glabella d. Scalp defect with or without underlying bony defect 7. Face: characteristic dysmorphic features collectively described as “Greek warrior helmet” facies (prominent glabella, hypertelorism, broad beaked nose, and frontal bossing) 8. Eyes a. Hypertelorism b. Down-slanting palpebral fissures c. Epicanthal folds d. Strabismus e. Coloboma f. Proptosis due to hypoplasia of orbital ridges g. Ectopic pupils h. Esotropia i. Ptosis j. Microphthalmia k. Megalocornea l. Sclerocornea m. Cataracts n. Hypoplastic anterior chamber and ciliary body of iris o. Persistence of lenticular membrane p. Hypoplastic retina with formation of rosettes q. Cup-shaped optic discs r. Congenital nystagmus s. Early onset glaucoma t. Rieger anomaly 9. Nose a. Broad or beaked nose b. Nasolacrimal duct stenosis or atresia 10. Mouth a. Short upper lip b. Short philtrum c. Cleft lip or palate d. Bifid uvula e. Carplike mouth f. Micrognathia g. Retrognathia 11. Ears a. Low-set ears b. Large, floppy, or misshapen ears c. Microtia d. Preauricular dimples e. Chronic otitis media with effusion f. Sensorineural hearing loss 12. Cardiovascular a. Atrial septal defect b. Ventricular septal defect c. Persistent left superior vena cava d. Valve abnormalities e. Complex cardiac defects 13. Pulmonary a. Bilateral bilobed or trilobed lungs b. Lung hypoplasia secondary to diaphragmatic hernia 14. GI anomalies a. Diastasis recti b. Umbilical or inguinal hernias
15.
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17. 18.
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c. Accessory spleens d. Absent gallbladder e. Diaphragmatic hernia f. Intestinal malrotation Genitourinary anomalies (25%) a. Hypoplastic kidneys b. Cystic dysplastic kidneys c. Unilateral renal agenesis d. Hydronephrosis e. Exstrophy of the bladder f. Hypoplastic external genitalia g. Cryptorchidism and hypospadias in males h. Hypoplastic müllerian derivatives (i.e., agenesis of vagina, cervix or uterus; hypoplastic uterus; ovarian streaks) in females Skeletal anomalies (60–70%) a. Long slender fingers with additional flexion creases b. Long narrow chest c. Hypoplastic widely spaced nipples d. Hypoplasia or duplication of thumbs and great toes e. Talipes equinovarus f. Hypoplasia of pubic bones g. Vertebral and rib anomalies h. Defective calvarium ossification i. Scoliosis j. Kyphosis k. Osteoporosis l. Delayed bone maturation m. Sacral dimple Infection-prone, immunodeficiency Malignant hematological disorders a. Myelodysplastic syndrome b. Leukemia Dermatoglyphics a. Hypoplastic dermal ridges b. Transverse palmar creases (25%) c. Excess of digital arches d. t or t’ Pitt-Rogers-Danks syndrome (PRDS) a. Phenotypic overlap with WHS i. Prenatal and postnatal growth retardation ii. Microcephaly iii. Seizures iv. Developmental delay v. Facial features a) A wide mouth b) Short upper lip c) Flat philtrum d) Beaked nose e) Prominent eyes f) Maxillary hypoplasia b. Microdeletion of 4p16.3 detected in most cases c. Current evidence suggests that PRDS is not a separate clinical entity but may represent the milder end of the WHS spectrum. Fetal phenotype a. Major anomalies i. Intrauterine growth retardation ii. Microcephaly iii. Cleft palate
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iv. Corpus callosum agenesis v. Ventricular septal defect vi. Diaphragmatic hernia vii. Renal hypoplasia b. Minor anomalies i. Scalp defect ii. Hypertelorism usually with a prominent glabella iii. Pulmonary isomerism iv. Common mesentery v. Hypospadias vi. Sacral dimple 22. Prognosis a. Crude infant mortality rate: 17% b. Mortality rate in the first two years: 21% c. Cases with large de novo deletions are more likely to die than those with smaller deletions. d. Causes of death i. Birth anoxia ii. Withdrawal of treatment after premature delivery iii. Lower respiratory tract infections iv. Sudden unexplained death v. Congenital anomalies, such as congenital heart disease, dysplastic kidneys, renal hypoplasia, diaphragmatic hernia, and pulmonary hypoplasia
DIAGNOSTIC INVESTIGATIONS 1. Conventional cytogenetic studies: most common method to detect chromosome arm 4p deletions (60–70% of deletions) 2. High resolution cytogenetic studies: to detect smaller deletions of chromosome band 4p16.3 3. Fluorescence in situ hybridization (FISH) using WolfHirschhorn critical region probe: detecting >95% of deletions. Molecular cytogenetic studies using FISH allow the diagnosis to be made in patients with very small deletions or cryptic translocations. FISH uses genetic markers that have been precisely localized to the area of interest. The absence of signal from either the maternal or the paternal allele for the marker is indicative of monosomy for that chromosomal region. 4. Immune workup a. Common variable immunodeficiency b. Immunoglobulin A (IgA) and immunoglobulin G2 (IgG2) subclass deficiency c. IgA deficiency d. Impaired polysaccharide responsiveness e. Normal T-cell immunity 5. Radiography a. Delayed bone maturation b. Microcephaly c. Hypertelorism d. Micrognathia e. Anterior fusion of vertebrae f. Fused ribs g. Dislocated hips h. Proximal radioulnar synostosis i. Clubfeet 6. Echocardiography to detect heart defects 7. Renal ultrasound to detect renal anomalies
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8. MRI and CT scans to demonstrate underlying brain pathology including agenesis of corpus callosum and ventriculomegaly 9. EEG for seizure monitoring 10. Swallowing study for feeding difficulty 11. Comprehensive audiologic and otologic evaluation to rule out possible hearing impairment 12. Ophthalmologic examination 13. Developmental testing a. Speech and motor evaluation b. Appropriate psychometric evaluation
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. De novo deletion cases: no significant increased risk ii. Deletion resulting from a parental chromosomal rearrangement: increased risk for unbalanced product in offspring b. Patient’s offspring: reproduction unlikely due to mental retardation 2. Prenatal diagnosis available to families in which one parent is known to be a carrier of a chromosome rearrangement by amniocentesis, CVS, or PUBS a. Ultrasonography to detect in utero manifestation of distinct phenotype i. Severe intrauterine growth retardation ii. Microcephaly iii. Hypertelorism, usually with prominent glabella iv. Micrognathia v. Cleft lip and palate vi. Diaphragmatic hernia b. Chromosome analysis i. Conventional karyotyping ii. FISH iii. Whole chromosome painting 3. Management a. Multidisciplinary team approach i. Early intervention program to improve motor development, cognition, communication, and social skills ii. Speech, physical, and occupational therapies iii. Appropriate school placement b. Manage feeding difficulties and failure to thrive i. Gavage feeding ii. Gastrostomy iii. Occasional gastroesophageal fundoplication c. Anticonvulsants for seizure control d. Orthopedic care for skeletal abnormalities i. Clubfoot ii. Scoliosis iii. Kyphosis e. Care for possible immunodeficiency
REFERENCES Altherr MR, Wright TJ, Denison K, et al.: Delimiting the Wolf-Hirschhorn syndrome critical region to 750 kilobase pairs. Am J Med Genet 71: 47–53, 1997.
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Battaglia A, Carey JC: Wolf-Hirschhorn syndrome and Pitt-Rogers-Danks syndrome. Am J Med Genet 75:541, 1998. Battaglia A, Carey JC: Health supervision and anticipatory guidance of individuals with Wolf-Hirschhorn syndrome. Am J Med Genet (Semin Med Genet) 89:111–115, 1999. Battaglia A, Carey JC: Update on the clinical features and natural history of Wolf-Hirschhorn syndrome (WHS): experience with 48 cases. Am J Hum Genet 67(Suppl 2):127, 2000. Battaglia A, Carey JC, Cederholm P, et al.: Natural history of Wolf-Hirschhorn syndrome: experience with 15 cases. Pediatrics 103:830–836, 1999. Battaglia A, Carey JC, Wright TJ: Wolf-Hirschhorn (4p-) syndrome. Adv Pediatr 48:75–113, 2001. Chen H: Wolf-Hirschhorn syndrome. EMed J 2(3):March 27, 2003. Clemens M, Martsolf JT, Rogers JG, et al.: Pitt-Rogers-Danks syndrome: the result of a 4p microdeletion. Am J Med Genet 66:95–100, 1996. Dallapiccola B, Mandich P, Bellone E, et al.: Parental origin of chromosome 4p deletion in Wolf-Hirschhorn syndrome. Am J Med Genet 47:921–924, 1993. Dietze I, Fritz B, Huhle D, et al.: Clinical, cytogenetic and molecular investigation in a fetus with Wolf-Hirschhorn syndrome with paternally derived 4p deletion. Case report and review of the literature. Fetal Diagn Ther 19:251–260, 2004. Dufke A, Seidel J, Schoning M, et al.: Microdeletion 4p16.3 in three unrelated patients with Wolf-Hirschhorn syndrome. Cytogenet Cell Genet 91:81–84, 2000. Estabrooks LL, Breg WR, Hayden MR, et al.: Summary of the 1993 ASHG ancillary meeting “recent research on chromosome 4p syndromes and genes.” Am J Med Genet 55:453–458, 1995. Fang YY, Bain S, Haan EA, et al.: High resolution characterization of an interstitial deletion of less than 1.9 Mb at 4p16.3 associated with WolfHirschhorn syndrome. Am J Med Genet 71:453–457, 1997. Fryns J Pediatr, Smeets E, Devriendt K, et al.: Wolf-Hirschhorn syndrome with cryptic 4p16.3 deletion and balanced/unbalanced mosaicism in the mother. Ann Génét 41:73–76, 1998. Hanley-Lopez J, Estabrooks LL, Stiehm R: Antibody deficiency in WolfHirschhorn syndrome. J Pediatr 133:141–143, 1998. Hirschhorn K, Cooper HL, Firschein IL: Deletion of short arms of chromosome 4–5 in a child with defects of midline fusion. Humangenetik 1:479–482, 1965. Johnson VP, Mulder RD, Hosen R: The Wolf-Hirschhorn (4p-) syndrome. Clin Genet 10:104–112, 1976. Lazjuk GI, Lurie IW, Ostrowskaja TI, et al.: The Wolf-Hirschhorn syndrome. II. Pathologic anatomy. Clin Genet 18:6–12, 1980. Lesperance MM, Grundfast KM, Rosenbaum KN: Otologic manifestations of Wolf-Hirschhorn syndrome. Arch Otolaryngol Head Neck Surg 124:193–196, 1998. Lurie IW, Lazjuk GI, Ussova YI, et al.: The Wolf-Hirschhorn syndrome. I. Genetics. Clin Genet 17:375–384, 1980.
Ogle R, Sillence DO, Merrick A, et al.: The Wolf-Hirschhorn syndrome in adulthood: evaluation of a 24-yr-old man with a rec(4) chromosome. Am J Med Genet 65:124–127, 1996. Opitz JM: Twenty-seven-years follow-up in the Wolf-Hirschhorn syndrome [editorial]. Am J Med Genet 55:459–461, 1995. Pitt DB, Rogers JG, Danks DM: Mental retardation, unusual face, and intrauterine growth retardation: a new recessive syndrome? Am J Med Genet 19:307–313, 1984. Rauch A, Schellmoser S, Kraus C, et al.: First known microdeletion within the Wolf-Hirschhorn syndrome critical region refines genotype-phenotype correlation. Am J Med Genet 99:338–342, 2001. Roulston D, Altherr M, Wasmuth JJ, et al.: Confirmation of a suspected deletion 4p16 by fluorescent in situ hybridization (FISH) with a cosmid probe. Am J Hum Genet 49:274, 1991. Schlickum S, Moghekar A, Simpson JC, et al.: LETM1, a gene deleted in Wolf-Hirschhorn syndrome, encodes an evolutionarily conserved mitochondrial protein. Genomics 83:254–261, 2004. Shannon NL, Maltby FL, Rigby AS, et al.: An epidemiological study of Wolf-Hirschhorn syndrome: life expectancy and cause of mortality. J Med Genet 38:674–679, 2001. Sharathkumar A, Kirby M, Freedman M, et al.: Malignant hematological disorders in children with Wolf-Hirschhorn syndrome. Am J Med Genet 119A:194–199, 2003. Tachdjian G, Fondacci C, Tapia S, et al.: The Wolf-Hirschhorn syndrome in fetuses. Clin Genet 42: 281–287, 1992. Thomson P: Wolf-Hirschhorn syndrome. Review of the literature and three case studies. J Am Podiatr Med Assoc 88:192–197, 1998. Wieczorek D, Krause M, Majewski F, et al.: Effect of the size of the deletion and clinical manifestation in Wolf-Hirschhorn syndrome analysis of 13 patients with a de novo deletion. Eur J Hum Genet 8:519–526, 2000. Wilson MG, Towner JW, Coffin GS, et al.: Genetic and clinical studies in 13 patients with the Wolf-Hirschhorn syndrome [del(4p)]. Hum Genet 59:297–307, 1981. Wolf U, Reinwein H, Porsch R, et al.: Deficiency on the short arms of a chromosome No. 4. Humangenetik 1:397–413, 1965. Wright TJ, Ricke DO, Denison K, et al.: A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region. Hum Mol Genet 6:317–324, 1997. Wright TJ, Clemens M, Quarrell O, et al.: Wolf-Hirschhorn and Pitt-RogersDanks syndromes caused by overlapping 4p deletions. Am J Med Genet 75:345–350, 1998. Zollino M, Di Stefano C, Zampino G, et al.: Genotype-phenotype correlations and clinical diagnostic criteria in Wolf-Hirschhorn syndrome . Am J Med Genet 94:254–261, 2000. Zollino M, Lecce R, Fischetto R, et al.: Mapping the Wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am J Hum Genet 72:590–597, 2003.
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Fig. 1. A patient with Wolf-Hirschhorn syndrome at different ages showing characteristic facial features consisting of prominent glabella, hypertelorism, beaked nose, and frontal bossing, collectively described as “Greek warrior helmet” facies.
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Fig. 2. A girl with WHS showing characteristic face and deletion of WHS locus (FISH).
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Fig. 3. Two children with WHS showing characteristic facial features of the syndrome.
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Fig. 5. Karyotype of the sister showing deletion of 4p, derived from the mother with balanced translocation (4p;8p) (partial karyotypes).
Fig. 4. Two siblings with WHS showing characteristic features of the syndrome.
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Fig. 6. Karyotype and FISH of another patient with Wolf-Hirschhorn syndrome.
Fig. 7. A fetus with WHS showing broad triangular-shaped nasal root and the flat facial profile resembling “Greek warrior helmet.” The radiographs show hypoplasia of the cervical vertebral bodies.
X-Linked Ichthyosis X-linked ichthyosis is a relatively common genetic disorder of keratinization. It is the second most common type of ichthyosis after vulgaris. The incidence is estimated to be between 1 in 2000 and 1 in 6000 male live births.
GENETICS/BASIC DEFECTS 1. Inheritance a. X-linked recessive b. Usually affects males only c. Transmitted by carrier females (about 1 in 2000 women are carriers of steroid sulfatase (STS) enzyme deficiency) d. Most apparently sporadic cases appear to be inherited based on biochemical analysis (as their mothers showed low values of STS enzyme activity) e. Reports of a few affected female patients. 2. Etiology a. Caused by a deficiency of STS enzyme b. The STS gene i. Mapped on the distal part of the short arm of the X chromosome (Xp22.3) ii. Close to the pseudoautosomal region iii. Unlike most X-chromosome genes, the STS gene escapes the X-inactivation process. 3. Molecular defects a. Deletion of the entire steroid sulfatase (STS) gene: the most common molecular defect in X-linked ichthyosis (XLI) patients (observed in 90% of patients) b. Partial deletion or point mutation (observed in 10% of patients) c. The deletion of STS gene may occasionally extend to involve neighboring genes (interstitial and terminal deletions of Xp22.3), resulting in a contiguous gene defect and may be associated with the following conditions. Depending on the length of the deletion, these disorders occur independently from each other or in combination as a contiguous gene syndrome. i. Kallmann syndrome (hypogonadotropic hypogonadism and anosmia) ii. X-linked chondrodysplasia punctata iii. Short stature iv. Mental retardation v. Ocular albinism vi. Ichthyosis
CLINICAL FEATURES 1. Cutaneous manifestation a. Generalized scaling of the skin (ichthyosiform hyperkeratosis) i. Early onset: usually at birth or within 4 months of life 1057
ii. Large, dark-brown polygonal scales a) Usually symmetrically distributed b) More prominent on the trunk and the extensor aspects of the limbs c) Usually the flexures less affected iii. Face usually free from scales, except in the preauricular areas, giving the classic “unwashed appearance,” which is considered by many to be pathognomonic iv. Sparing palms and soles in most cases b. Normal nails and hair c. Seasonal influence i. Improve during the summer ii. Worsen during dry, cold weather 2. Extracutaneous manifestations a. Corneal opacities i. The most common extracutaneus features ii. Secondary to deposits of cholesterol sulfate crystals iii. Asymptomatic (not affecting the visual acuity) iv. Occurring in the posterior capsule of Descemet’s membrane or the corneal stroma v. More frequent during the second and third decades of life vi. Observed in 10–50% of affected males and carrier females b. Cryptorchidism i. Occurring in 10–20% of patients (vs the incidence of cryptorchidism in the normal population of 1%) ii. Possible mechanisms a) A deficit in the STS enzyme b) A genetic disturbance located on the short arm of chromosome X close to the STS gene c. Patients at an increased risk of testicular cancer development d. CNS manifestations i. Epileptic seizures ii. Reactive psychological disorders e. Clinical manifestations as a part of the contiguous gene syndrome expression i. Kallmann syndrome ii. Short stature iii. Mental retardation iv. X-linked chondrodysplasia punctata f. Other rare manifestations i. Pyloric hypertrophy ii. Congenital abdominal wall defect iii. Acute lymphoblastic leukemia 3. Steroid sulfatase deficiency during pregnancy in carrier females a. Leads to an overall decrease in the levels of estrogen b. Causes poor cervical dilatation and prolonged labor c. Frequently necessitates a Caesarean section
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DIAGNOSTIC INVESTIGATIONS 1. Direct biochemical demonstration of STS deficiency (undetectable levels of STS activity) from the following tissue: a. Placenta b. Skin fibroblasts c. Leukocytes d. Keratinocytes 2. Demonstration of an increase in substrates of STS a. Dihydroepiandrosterone sulfate (DHEAS) b. Cholesterol sulfate 3. Electrophoresis: rapid migration of serum cholesterol sulfate (negatively charged and carried by low-density lipoprotein [LDL] particles) towards the positive pole during electrophoresis 4. Molecular genetic diagnosis yielding reliable results in most affected patients a. Detection of complete deletion of the STS gene in most patients i. Fluorescence in situ hybridization (FISH) ii. Southern blotting iii. Multiplex polymerase chain reaction (PCR) b. Partial deletion by FISH: may provide a false negative FISH result c. A very small number of cases carrying point mutations instead of deletions at the STS gene: undetectable by Southern blot or PCR d. Carrier detection i. STS enzyme assay ii. FISH technique especially useful in carrier detection since the enzymatic assay often provides inconclusive results
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib (given that the mother is a carrier) i. 50% of male sibs affected ii. 50% of female sibs carriers b. Patient’s offspring i. Affected male patients a) Male offspring normal b) All female offspring carriers ii. Affected female patients (heterozygous) a) 50% of male offspring affected b) 50% of female offspring carriers iii. Affected female patients (homozygous) a) All male offspring affected b) All female offspring carriers 2. Prenatal diagnosis a. Maternal plasma demonstrating low or undetectable estriol levels in routine maternal serum screening, which is associated with the following conditions: i. Placental steroid sulfatase deficiency ii. Fetal death iii. Miscarriages iv. Anencephaly v. Fetal adrenal hypoplasia vi. High-dose corticosteroid therapy
vii. Aneuploidies a) Down syndrome b) Triploidy viii. Smith-Lemli-Opitz syndrome in rare cases b. Maternal urine and plasma profiles of affected fetuses indicating a primary placental sulfatase deficiency (low estriol levels) c. Amniocentesis i. Elevated sulfated steroids in the amniotic fluid ii. FISH to detect deletion in one copy of X chromosome at region Xp22.3 using steroid sulfatase probe d. Skin biopsy through fetoscopy to measure sulfated steroid 3. Management a. Spontaneous improvement in most cases with age and during summer months and hardly require any treatment b. Attempt to diminish the abnormal cohesion of corneocytes by facilitating their separation in the milder forms i. Topical keratolytics ii. Emollients iii. Hydrating agents c. Retinoids for potential treatment in severely affected patients d. Liarozole, a imidazole derivative which inhibit cytochrome P450 to increase the level of endogenous retinoid acid by blocking its P450-dependent catabolism e. Examination of male patients to detect cryptorchidism which has an increased risk of testicular cancer
REFERENCES Ahmed MN, Killam A, Thompson KH, et al.: Unconjugated estriol as an indication for prenatal diagnosis of steroid sulfatase deficiency by in situ hybridization. Obstet Gynecol 92:687–689, 1998. Aviram-Goldring A, Goldman B, Netanelov-Shapira I, et al.: Deletion patterns of the STS gene and flanking sequences in Israeli X-linked ichthyosis patients and carriers: analysis by polymerase chain reaction and fluorescence in situ hybridization techniques. Int J Dermatol 39:182–187, 2000. Ballabio A, Bardoni B, Carrozo R, et al.: Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome. Proc Natl Acad Sci USA 86:10001–10005, 1989. Basler E, Grompe M, Parenti G, et al.: Identification of point mutations in the steroid sulfatase gene of three patients with X-linked ichthyosis. Am J Hum Genet 50:483–491, 1992. Bonifas JM, Epstein EH Jr: Detection of carriers for X-linked ichthyosis by Southern blot analysis and identification of one family with a de novo mutation. J Invest Dermatol 95:16–19, 1990. Bradshaw KD, Carr BR: Placental sulfatase deficiency: maternal and fetal expression of steroid sulfatase deficiency and X-linked ichthyosis. Obstet Gynecol Surv 41:401–413, 1986. Braunstein GD, Zeil FH, Allen A, et al.: Prenatal diagnosis of placental steroid sulfatase deficiency. Am J Obstet Gynecol 126:716–719, 1976. Casaroli Marano RP, Ortiz Stradtmann MA, Uxo M, et al.: Ocular findings associated with congenital X-linked ichthyosis. Ann Ophthalmol 23:167–172, 1991. Crawfurd MA: Review: genetics of steroid sulphatase deficiency and X-linked ichthyosis. J Inherit Metab Dis 5:153–163, 1982. Cuevas-Covarrubias SA, Jimenez-Vaca AL, Gonzalez-Huerta LM, et al.: Somatic and germinal mosaicism for the steroid sulfatase gene deletion in a steroid sulfatase deficiency carrier. J Invest Dermatol 119:972–975, 2002. Cuevas-Covarrubias SA, Kofman-Alfaro S, Orozco E, et al.: The biochemical identification of carrier state in mothers of sporadic cases of X-linked recessive ichthyosis. Genet Couns 6:103–107, 1995.
X-LINKED ICHTHYOSIS Cuevas-Covarrubias SA, Valdes-Flores M, Orozco E, et al.: Most “sporadic” cases of X-linked ichthyosis are not de novo mutations. Acta Derm Venereol 79:143–144, 1999. Glass IA, Lam RC, Chang T, et al.: Steroid sulphatase deficiency is the major cause of extremely low oestriol production at mid-pregnancy: a urinary steroid assay for the discrimination of steroid sulphatase deficiency from other causes. Prenat Diagn 18:789–800, 1998. Gohlke BC, Haug K, Fukami M, et al.: Interstitial deletion in Xp22.3 is associated with X linked ichthyosis, mental retardation, and epilepsy. J Med Genet 37:600–602, 2000. Hernandez-Martin A, Gonzalez-Sarmiento R, De Unamuno P: X-linked ichthyosis: an update. Br J Dermatol 141:617–627, 1999. Janniger CK, Schwartz RA: Ichthyosis, X-linked. Emedicine, 2001. http://www. emedicine.com Jasmi FA, Al-Khenaizan SA: X-linked ichthyosis and undescended tested. Int J Dermatol 41:614, 2002. Kashork CD, Sutton VR, Fonda Allen JS, et al.: Low or absent unconjugated estriol in pregnancy: an indicator for steroid sulfatase deficiency detectable by fluorescence in situ hybridization and biochemical analysis. Prenat Diagn 22:1028–1032, 2002. Keren DF, Canick JA, Johnson MZ, et al.: Low maternal serum unconjugated estriol during prenatal screening as an indication of placental steroid sulfatase deficiency and X-linked ichthyosis. Am J Clin Pathol 103:400–403, 1995. Lebo RV, Lynch ED, Golbus MS, et al.: Prenatal in situ hybridization test for deleted steroid sulfatase gene. Am J Med Genet 46:652–658, 1993. Lykkesfeldt G, Nielsen MD, Lykkesfeldt AE: Placental steroid sulfatase deficiency: biochemical diagnosis and clinical review. Obstet Gynecol 64:49–54, 1984. Mevorah B, Frenk E, Muller CR, et al.: X-linked recessive ichthyosis in three sisters: evidence for homozygosity. Br J Dermatol 105:711–717, 1981.
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Nomura K, Nakano H, Umeki K, et al.: A study of the steroid sulfatase gene in families with X-linked ichthyosis using polymerase chain reaction. Acta Derm Venereol 75:340–342, 1995. Okano M, Kitano Y, Yoshikawa K, et al.: X-linked ichthyosis and ichthyosis vulgaris: comparison of their clinical features based on biochemical analysis. Br J Dermatol 119:777–783, 1988. Paige DG, Emilion GG, Bouloux PM, et al.: A clinical and genetic study of X-linked recessive ichthyosis and contiguous gene defects. Br J Dermatol 131:622–629, 1994. Saeki H, Kuwata S, Nakagawa H, et al.: Deletion pattern of the steroid sulphatase gene in Japanese patients with X-linked ichthyosis. Br J Dermatol 139:96–98, 1998. Shapiro LJ: Steroid sulfatase deficiency and the genetics of the short arm of the human X chromosome. Adv Hum Genet 14:331–381, 388–389, 1985. Shapiro LJ, Yen P, Pomerantz D, et al.: Molecular studies of deletions at the human steroid sulfatase locus. Proc Natl Acad Sci USA 86:8477–8481, 1989. Traupe H, Happle R: Mechanisms in the association of cryptorchidism and X-linked recessive ichthyosis. Dermatologica 172:327–328, 1986. Watanabe T, Fujimori K, Kato K, et al.: Prenatal diagnosis for placental steroid sulfatase deficiency with fluorescence in situ hybridization: a case of X-linked ichthyosis. J Obstet Gynaecol Res 29:427–430, 2003. Wells RS, Kerr CB. Genetic classification of ichthyosis. Arch Dermatol 92:1–6, 1965. Wells RS, Jennings MC: X-linked ichthyosis and ichthyosis vulgaris. Clinical and genetic distinctions in a second series of families. JAMA 202:485–488, 1967. Zalel Y, Kedar I, Tepper R, et al.: Differential diagnosis and management of very low second trimester maternal serum unconjugated estriol levels, with special emphasis on the diagnosis of X-linked ichthyosis. Obstet Gynecol Surv 51:200–203, 1996.
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Fig. 1. A sporadic case of X-linked ichthyosis showing thick, large, polygonal, dark-brown scales involving the extensor.
Fig. 3. Abnormal FISH analysis showed a deletion in the steroid sulfatase critical region on the X chromosome [del(X)(p22.3p22.3)(STS-)] in a male fetus (upper photo). The case was ascertained because of undetectable UE3 from maternal serum screen. The lower photo (FISH) showed a normal XX control.
Fig. 2. X-linked ichthyosis affecting 3 boys in a family.
XXX Syndrome i. ii. iii. iv. v.
Less well adapted With more stress With work, leisure, and relationship problems With a lower IQ With more psychopathology when contrasted with the comparison group c. Most 47,XXX women i. Self sufficient ii. Functioning reasonably well
Females with a 47,XXX karyotype were first described by Jacobs et al. in 1959. The incidence of 47,XXX among female newborns is approximately 1 in 1000 live births.
GENETICS/BASIC DEFECTS 1. Etiology: an extra chromosome X is responsible for 47,XXX 2. Mechanism of the origin for the 47,XXX condition a. Almost all 47,XXX result from maternal nondisjunction b. Typically at meiosis I
DIAGNOSTIC INVESTIGATIONS 1. Chromosome analysis 2. Psychological and psychiatric evaluation when needed
CLINICAL FEATURES 1. No specific phenotype exists in 47,XXX females 2. A higher incidence of minor anomalies a. Epicanthal folds b. Upslanting palpebral fissures c. Ear abnormalities d. Clinodactyly 3. Growth and development a. Birth weights tend to be slightly lower than the general population. b. Taller in older children c. Relative microcephaly d. At risk for mild speech/language and motor delays and learning disabilities e. Intelligence i. Normal range ii. Lower intelligence quotients (10–15 points) in comparison to unaffected sibs 4. Gonadal structures and function a. Heterosexual b. Normal secondary sexual characteristics c. Normal menstruation d. Fertility usually normal e. Late menarche f. Occasional amenorrhea g. Premature ovarian failure h. Sterility with streak gonads 5. Congenital anomalies reported in a very small number of patients a. Urogenital tract abnormalities b. Brain abnormalities c. Skeletal abnormalities d. Congenital heart defects e. Craniofacial abnormalities 6. Adaptation status: variable a. At risk for intellectual and psychological problems b. 47,XXX women during adolescence and young adulthood
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring i. An increased risk of a cytogenetically abnormal child but the extent of the risk cannot yet be determined ii. Majority of offspring normal 2. Prenatal diagnosis by fetal karyotyping from amniocytes or CVS 3. Management a. Infancy/toddler: assess milestones b. Childhood i. Assess school performance ii. Provide intervention if needed a) Speech/language therapy b) Physical/occupational therapy c) Educational remediation c. Adolescence: usually no intervention needed d. Adult adulthood: annual physical examination
REFERENCES Barr ML, Sergovich FR, Carr DH, et al.: The triplo X female. Can Med Assoc J 101:247–258, 1969. Bender BG, Harmon RJ, Linden MG, et al.: Psychosocial competence of unselected young adults with sex chromosome abnormalities. Am J Med Genet 88:200–206, 1999. Chudley AE, Stoeber GP, Greenberg CR: Intrauterine growth retardation and minor anomalies in 47,XXX children. Birth Defects Orig Artic Ser 26:267–272, 1990. Dewhurst J: Fertility in 47,XXX and 45,X patients. J Med Genet 15:132–135, 1978. Evans JA, de von Flindt R, Greenberg C, et al.: A cytogenetic survey of 14,069 newborn infants. IV. Further follow up on the children with sex chromosome anomalies. Birth Defects Orig Artic Ser 18(4):169–184, 1982. Harmon RJ, Bender BG, Linden MG, et al.: Transition from adolescence to early adulthood: adaptation and psychiatric status of women with 47,XXX. J Am Acad Child Adolesc Psychiatry 37:286–291, 1998.
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Hassold T, Arnovitz K, Jacobs PA, et al.: The parental origin of the missing or additional chromosome in 45,X and 47,XXX females. Birth Defects Orig Artic Ser 26:297–304, 1990. Jacobs PA: The incidence and etiology of sex chromosome abnormalities in man. Birth Defects Orig Artic Ser XV(1):3–14, 1979. Linden MG, Bender BG, Harmon RJ, et al.: 47,XXX: what is the prognosis? Pediatrics 82:619–630, 1988. Linden MG, Bender BG, Robinson A: Genetic counseling for sex chromosome abnormalities. Am J Med Genet 110:3–10, 2002.
May KM, Jacobs PA, Lee M, et al.: The parental origin of the extra X chromosome in 47,XXX females. Am J Hum Genet 46:754–761, 1990. Ogata T, Matsuo M, Muroya K, et al.: 47,XXX male: A clinical and molecular study. Am J Med Genet 98:353–356, 2001. Pennington B, Puck M, Robinson A: Language and cognitive development in 47,XXX females followed since birth. Behav Genet 10:31–41, 1980. Robinson A, Lubs HA, Nielsen J, et al.: Summary of clinical findings: profiles of children with 47,XXY, 47,XXX and 47,XYY karyotypes. Birth Defects Orig Artic Ser 15:261–266, 1979.
XXX SYNDROME
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Fig. 2. A girl with 47,XXX showing normal phenotype.
Fig. 3. 47,XXX karyotype.
Fig. 1. A girl with 47,XXX at different ages showing normal phenotype.
XXXXX Syndrome 2. Craniofacial features a. Microcephaly b. Flattened occiput c. Epicanthus d. Upslanting palpebral fissures e. Ocular hypertelorism f. Uncoordinated eye movements g. Flat broad nose h. Cleft palate i. Low-set ears j. Malformed teeth 3. Skeletal abnormalities a. Short neck b. Lax joints c. Multiple dislocations i. Shoulders ii. Elbows iii. Hips d. Radioulnar synostosis e. Spinal abnormalities f. Clinodactyly of the 5th fingers g. Lower leg abnormalities i. Genu valgus ii. Talipes iii. Metatarsus varus h. Delayed bone age 4. Congenital heart defects a. Ventricular septal defect b. Patent ductus arteriosus 5. Abnormal lobulation of the lungs 6. Renal hypoplasia 7. Sexual development a. Delayed puberty b. Incomplete secondary sexual development c. Small uterus d. Hypoplastic/absent ovaries i. Composed mainly of stroma and atrophic follicles ii. Absence of ova iii. Unilateral absence of an ovary reported e. Reduced fertility 8. Normal external genitalia 9. Dermatoglyphics a. Finger-dermal-ridge hypoplasia and a low total ridge count, consistent with the inverse proportion between the number of X chromosomes and the total ridge count (exceptions exist) b. Transverse palmar creases
49,XXXXX (pentasomy X) is a rare sex chromosome aneuploidy. The birth prevalence of pentasomy X is estimated to be 1 in 85,000 females.
GENETICS/BASIC DEFECTS 1. Etiology: Three extra X chromosomes are responsible for the pentasomy X syndrome. 2. Occurrence of a 49,XXXXX complement: secondary to sequential non-disjunctions in meiosis I and meiosis II in the mother a. Involves the survival of both X chromosomes in a single oocytes through both meiotic divisions i. Once between homologous X chromosomes at the first meiosis ii. Twice between sister chromatids in both X chromosomes in the secondary oocytes at the second meiosis b. Followed by the fertilization by a sperm contributing the 5th chromosome X 3. Formation of four Barr bodies a. Lyon hypothesis i. Inactivation of all X chromosomes but one ii. Account for the viability of the X-chromosome aneuploidies b. Inactivation of four X chromosomes resulting in four Barr bodies 4. Effect of supernumerary X chromosomes: a direct relationship between the number of supernumerary X chromosomes and phenotypic abnormalities and mental retardation, with each additional chromosome increasing the severity a. Affects somatic development most significantly i. Skeletal abnormalities ii. Cardiovascular abnormalities b. Delays sexual development c. Affects cognitive development i. Severe mental retardation ii. Language delay (both expressive and receptive language) iii. Behavioral problems
CLINICAL FEATURES 1. Growth and development a. Prenatal growth retardation b. Small birth weight c. Low postnatal weight d. Failure to thrive e. Hypotonia f. Short stature g. Delayed psychomotor retardation h. Mental retardation
DIAGNOSTIC INVESTIGATIONS 1. Chromosome analysis a. 49,XXXXX karyotype b. Fluorescence in situ hybridization (FISH), using DNA probe for α-satellite sequence in chromosome 1064
XXXXX SYNDROME
X (DXZ1), reveals five signals representing the presence of XXXXX 2. Radiography a. Dislocations of the elbows and/or hips b. Radioulnar synostosis c. Clinodactyly
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: not reported due to severe mental retardation 2. Prenatal diagnosis a. Ultrasonography: bilateral radioulnar synostosis b. Amniocentesis and CVS i. Chromosome analysis ii. FISH using DNA probe (DXZ1) applied to uncultured amniocytes 3. Management a. Physical/occupational therapy b. Speech therapy
REFERENCES Archidiacono N, Rocchi M, Valente M, et al.: X pentasomy: A case and review. Hum Genet 52:69–77, 1979. Brody J, Fitzgerald MG, Spiers ASD: A female child with five X chromosomes. J Pediatr 70:105–109, 1967. Deng H-X, Abe K, Kondo I, et al.: Parental origin and mechanism of formation of polysomy X: an XXXXX case and four XXXXY cases determined with RFLPs. Hum Genet 86:541–544, 1991.
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Dryer RF, Patil SR, Zellweger HU, et al.: Pentasomy X with multiple dislocations. Am J Med Genet 4:313–321, 1979. Fryns JP, Kleczkowska A, Petit P, et al.: X-chromosome polysomy in the female: personal experience and review of the literature. Clin Genet 23:341–349, 1983. Funderburk SJ, Valente M, Klisak I: Pentasomy X: report of patient and studies of X-inactivation. Am J Med Genet 8:27–33, 1981. Kassai R, Hamada I, Furuta H, et al.: Penta X syndrome: A case report with review of the literature. Am J Med Genet 40:51–56, 1991. Kesaree N, Woolley PV Jr: A phenotypic female with 49 chromosomes, presumably XXXXX. J Pediatr 63:1099–1103, 1963. Leal CA, Belmont JW, Nachtman R, et al.: parental origin of the extra chromosomes in polysomy X. Hum Genet 94:423–426, 1994. Linden MG, Bender BG, Robinson A: Sex chromosome tetrasomy and pentasomy. Pediatrics 96:672–682, 1995. Martini G, Carillo G, Catizone F, et al.: On the parental origin of the X’s in a prenatally diagnosed 49,XXXXX syndrome. Prenat Diagn 13:763–766, 1993. Monheit A, Francke U, Saunders B, et al.: The penta-X syndrome. J Med Genet 17:392–396, 1980. Myles TD, Burd L, Font G, et al.: Dandy-Walker malformation in a fetus with pentasomy X (49,XXXXX) prenatally diagnosed by fluorescence in situ hybridization technique. Fetal Diagn Ther 10:333–336, 1995. Sepulveda W, Ivankovic M, Be C, et al.: Sex chromosome pentasomy (49,XXXXY) presenting as cystic hygroma at 16 weeks’ gestation. Prenat Diagn 19:257–259, 1999. Sergovich F, Uilenberg C, Pozsony J: The 49,XXXXX chromosome constitution: similarities to the 49,XXXXY condition. J Pediatr 78:285–290, 1971. Silengo MC, Davi GF, Franceschini P: The 49XXXXX syndrome. Report of a case with 48XXXX/49XXXXX mosaicism. Acta Paediatr Scand 68:769–771, 1979. Toussi T, Hala F, Lesage R, et al.: Renal hypodysplasia and unilateral ovarian agenesis in the penta-X syndrome. Am J Med Genet 6:153–162, 1980.
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Fig. 1. The first reported case of 49,XXXXX at infancy (A) and adulthood (B) with 4 Barr bodies (C), two drumsticks in a polymorphonuclear leukocyte (D), and a karyotype of 49,XXXXX (E).
XXXXX SYNDROME
Fig. 2. A girl with 49,XXXXX syndrome at birth (A), 6 month (B), and 2 years 4 months (C).
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XXXXY Syndrome 49,XXXXY syndrome was first described by Fraccaro and Lindsten in 1960. The incidence is estimated to be approximately 1 in 85,000 newborn males.
GENETICS/BASIC DEFECTS 1. Etiology: Three extra X chromosomes are responsible for the 49,XXXXY syndrome. 2. Mechanism a. All four X chromosomes are of maternal in origin b. Resulting from successive nondisjunctions in maternal meiosis I and II c. Inactivation of three out of four X chromosomes results in three Barr bodies (Lyon hypothesis). 3. Effect of supernumerary X chromosomes: a direct relationship between the number of supernumerary X chromosomes and phenotypic abnormalities and mental retardation, with each additional chromosome increasing the severity a. Somatic development most significantly affected i. Skeletal abnormalities ii. Cardiovascular abnormalities b. Gonadal development in males: particularly susceptible to extra genetic material i. Addition of a single X chromosome to a 46,XY karyotype resulting in seminiferous tubal dysgenesis rendering infertile as such males with Klinefelter syndrome ii. Additional extra X chromosomes in polysomy X males such as 48,XXXY and 49,XXXXY can result in not only infertility but hypoplastic and malformed genitalia. c. Affects cognitive development i. Severe mental retardation ii. Language delay (both expressive and receptive language) iii. Behavioral problems
3. 4.
5.
6.
7.
8.
g. Micrognathia h. Prognathism i. High arched or cleft palate j. Irregular teeth implantation k. Malformed ears Webbed and short neck Congenital heart defects a. Patent ductus arteriosus b. Atrial septal defect c. Pulmonic stenosis d. Tetralogy of Fallot Skeletal abnormalities a. Short stature b. Proximal radio-ulnar dysostosis c. Vertebral anomalies d. Clinodactyly of the 5th fingers e. Coxa valga f. Genu valga g. Pes planus Genital abnormalities a. Hypoplastic male genitalia b. Micropenis c. Hypospadias d. Small testes e. Hypogonadism f. Infertility Dermatoglyphics a. Decrease in total finger ridge count b. Transverse palmar creases Psychological profile a. Timid and shy b. Emotional disturbances with low frustration level c. Strong reaction to minor changes d. Adaptive function higher than cognitive function
DIAGNOSTIC INVESTIGATIONS
CLINICAL FEATURES 1. Growth and development a. Growth retardation b. Severe speech impairment c. Varying degree of mental retardation 2. Craniofacial features a. Microcephaly b. A full, round face c. Ocular hypertelorism d. Upslanted palpebral fissures e. Epicanthus f. Broad nasal bridge
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1. Chromosome analysis showing 49,XXXXY 2. Radiography a. Elbows i. Proximal radio-ulnar dysostosis ii. Radio-ulnar dislocation without synostosis iii. Elongated upper radius iv. Wide, club-shaped proximal ulna b. Wrists and hands i. Elongated distal ulna ii. “Pseudoepiphyses” iii. Clinodactyly of the 5th fingers iv. Brachymesophalangia V v. Retarded bone age vi. Corner defect in capitate vii. Poor modeling of the 5th metacarpals
XXXXY SYNDROME
c. Pelvis and hips i. Coxa valga ii. Narrow iliac wings d. Knees i. Shallow intercondylar fossa ii. Genu valgum e. Ankles and feet i. Gap between the 1st and 2nd toes ii. Short wide distal phalanx of the great toes f. Skull i. Sclerotic cranial sutures ii. Thick cranial vault iii. Ocular hypertelorism iv. J-shaped sella v. Prognathism g. Spine i. Scoliosis ii. Thoracic kyphosis iii. Square vertebral bodies h. Sternum i. Thick ii. Abnormal segmentation 3. Echocardiography for congenital heart defects 4. Histology of testicular biopsies: dysgenesis of testicular germ cells and tubules leading to fibrosis
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: no offspring due to infertility of the condition 2. Prenatal diagnosis a. Ultrasonographic markers i. Polyhydramnios ii. Cystic hygroma iii. Clubfoot iv. Micropenis b. Amniocentesis and CVS i. Chromosome analysis ii. FISH using DNA probe (DXZ1) applied to uncultured amniocytes
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3. Management a. Early intervention and stimulation programs i. Speech/language therapy ii. Physical/occupational therapy b. Testosterone replacement therapy
REFERENCES Chen C-P, Chern S-R, Chang C-L, et al.: Prenatal diagnosis and genetic analysis of X chromosome polysomy 49,XXXXY. Prenat Diagn 20:754–757, 2000. Curfs LM, Schreppers-Tijdink G, Wiegers A, et al.: The 49,XXXXY syndrome: clinical and psychological findings in five patients. J Ment Defic Res 34:277–282, 1990. Deng HX, Abe K, Kondo I, et al.: Parental origin and mechanism of formation of polysomy X: an XXXXX case and four XXXXY cases determined with RFLPs. Hum Genet 86:541–544, 1991. Galasso C, Arpino C, Fabbri F, et al.: Neurologic aspects of 49,XXXXY syndrome. J Child Neurol 18:501–504, 2003. Hecht F: Observations on the natural history of 49,XXXXY individuals. Am J Med Genet 13:335–336, 1982. Houston CS: Roentgen findings in the XXXXY chromosome anomaly. J Can Assoc Radiol 18:258–267, 1967. Karsh RB: Congenital heart disease in 49, XXXXY syndrome. Pediatrics 56:462–464, 1975. Kleczkowska A, Fryns J-P, Van den Berghe H: X-chromosome polysomy in the male. The Leuven experience 1966–1967, 1988. Kojima Y, Hayashi Y, Maruyama T, et al.: 49,XXXXY syndrome with hydronephrosis caused by intravesical ureterocele. Urol Int 63:212–214, 1999. Leal CA, Belmont JW, Nachtman R, et al.: parental origin of the extra chromosomes in polysomy X. Hum Genet 94:423–426, 1994. Linden MG, Bender BG ,Robinson A: Sex chromosome tetrasomy and pentasomy. Pediatrics 96:672–682, 1995. Lomelino CA, Reiss AL: 49,XXXXY syndrome: behavioural and developmental profiles. J Med Genet 28:609–612, 1991. Peet J, Weaver DD,Vance GH: 49,XXXXY: a distinct phenotype. Three new cases and review. J Med Genet 35:420–424, 1998. Rehder H, Fraccaro M, Cuoco C, et al.: The fetal pathology of the XXXXYsyndrome. Clin Genet 30:213–218, 1986. Schluth C, Doray B, Girard-Lemaire F, et al.: Prenatal sonographic diagnosis of the 49,XXXXY syndrome. Prenat Diagn 1177–1180, 2002. Sepulveda W, Ivankovic M, Be C, et al.: Sex chromosome pentasomy (49,XXXXY) presenting as cystic hygroma at 16 weeks’ gestation. Prenat Diagn 19:257–259, 1999. Villamar M, Benitez J, Fernandez E, et al.: Parental origin of chromosomal nondisjunction in a 49,XXXXY male using recombinant-DNA techniques. Clin Genet 36:152–155, 1989. Zaleski WA, Houston CS, Pozsonyi J, et al.: The XXXXY chromosome anomaly: report of three new cases and review of 30 cases from the literature. Can Med Assoc J 94:1143–1154, 1966.
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Fig. 2. A younger boy with 49,XXXXY showing a full, round face. He also has incontinentia pigmenti achromians. Fig. 1. An older boy with 49,XXXXY showing bilateral dislocation of the elbows, radio-ulnar synostosis and 3 Barr bodies (buccal smear).
XY Female XY females are completely sex-reversed individuals who are phenotypically females with 46,XY karyotype, failure to develop secondary sex characteristics, amenorrhea, and “streak gonads”.
GENETICS/BASIC DEFECTS
b.
1. SRY gene and its mouse homologue, Sry a. The sex-determining region on the Y chromosome i. Mapped to the short arm of the Y chromosome ii. Encodes for a testis-determining factor (TDF) iii. Candidate gene narrowed down to a 35-kb interval on the Y chromosome adjacent to the pseudoautosomal boundary which contains a Y chromosomal-specific sequence, named SRY (sex-determining region Y gene) iv. Demonstration that mice transgenic for Sry developed into sex-reversed males despite an XX karyotype provided the confirmation of SRY being the TDF that directs the undifferentiated gonad into a testis b. Deletions or mutations occurring in the SRY i. Result in failure of testis development ii. Sex differentiation along the female pathway 2. Mechanism of male to female sex reversal (abnormalities of XY sex determination) a. Mutations in the SRY gene resulting in XY females with gonadal dysgenesis (vs translocation of this gene sequence to X chromosome giving rise to XX males) i. Increasing variety of unique mutations within SRY gene reported in patients with gonadal dysgenesis/XY reversal. These patients are, in general, normal 46,XY females with complete gonadal dysgenesis ii. SRY gene mutations noted in 15–20% of cases with complete gonadal dysgenesis a) Most mutations are located in the High Mobility Group (HMG) box b) De novo mutations affect only one individual in a family in the majority of cases c) Phenotypic variability is associated with different mutations iii. About one third of the SRY mutations reported are inherited. a) No apparent explanation available to explain why an inherited SRY mutation which results in sex reversal in the offspring is associated with a normal male phenotype in the father and sometime in brothers and uncles. b) Paternal mosaicism for the mutant SRY provides an explanation for the other familial cases of XY gonadal dysgenesis.
c.
d.
e.
iv. 80% of patients with sporadic or familial 46,XY gonadal dysgenesis lack a mutation or deletion of the SRY gene, indicating that other autosomal or X-linked genes have a role in sex determination. Sox9 i. Another gene involved in sex determination identified by positional cloning of a chromosomal breakpoint has been identified in the XY female with campomelic dysplasia, a condition in which three-quarters of XY patients show genital and gonadal malformations. ii. Belongs to a family of SRY-box related (SOX) genes which encode proteins with at least 60% amino acid homology to the HMG box of the SRY protein Atrx i. The gene responsible for the ATR-X syndrome causes α-thalassemia, severe mental retardation and multiple congenital anomalies which may include 46,XY gonadal dysgenesis and undermasculinization. ii. The C-terminal region of the protein has been lost in most cases where there has been gonadal dysgenesis associated with ATR-X syndrome. Deletions of variable portions of the short arm of chromosome 9 (DMRT-1 identified as a candidate gene) result in partial or complete gonadal dysgenesis in XY females Sex-reversing Xp duplication (Xp21)
CLINICAL FEATURES 1. 46,XY females (individuals with 46,XY complete gonadal dysgenesis) (Swyer Syndrome) a. Diagnosed usually not made until puberty when the patient presents with delayed pubertal development b. Unambiguous female phenotype with completely female external genitalia c. Gonadal dysgenesis (streak gonads) d. Well developed Mullerian structures e. Absence of testicular development f. Absence of Wolffian structures g. Absence of other somatic abnormalities h. Absence of secondary sexual characteristics i. Amenorrhea j. High risk of developing gonadal tumors i. Gonadoblastoma ii. Dysgerminoma 2. Differential diagnosis a. Individuals with 46,XY partial gonadal dysgenesis (also called 46,XY mixed gonadal dysgenesis or dysgenetic male pseudohermaphroditism)
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i. Majority of patients present in the newborn period for evaluation of ambiguous genitalia ii. Partial testicular determination. The extent of masculinization of the external genitalia depends on the extent of testicular differentiation. iii. Dysgenetic gonads iv. Presence of Mullerian and Wolffian structures v. Regarded as the clinical spectrum of 46,XY gonadal dysgenesis b. Individuals with 46,XY embryonic testicular regression syndrome (also called true agonadism or gonadal agenesis) i. A term used to describe the spectrum of genital anomalies resulting from regression of testis development from 8–14 weeks of gestation ii. Regression of the fetal testes between the 8–10 weeks of gestation a) Complete absence of gonads b) Rudimentary Mullerian and/or Wolffian ductal structure c) Hypoplastic uterus d) Female genitalia with/or without ambiguity iii. Regression of the testes after the critical period of male differentiation (around 12–14 weeks) a) Anorchia b) Partial testicular regression resulting in a male phenotype as in anorchia but with small rudimentary testes
DIAGNOSTIC INVESTIGATIONS 1. Karyotype analysis a. 46,XY in phenotypic females b. To exclude 45,X/46,XY and other forms of mosaicism, served to exclude the more common forms of gonadal dysgenesis 2. Molecular analysis for SRY gene a. Nucleotide substitutions (missense/nonsense) b. Deletions c. Insertions 3. Ultrasonography/laparotomy a. Complete gonadal dysgenesis i. Streak gonads ii. Presence of Mullerian ducts iii. Absence of Wolffian ducts b. Partial gonadal dysgenesis i. Dysgenetic gonads ii. Presence of Mullerian and Wolffian structures 4. Gonadal histology a. Streak gonads i. Absence of primordial follicles ii. Wavy ovarian stroma intermixed with fibrous tissue b. Gonadal tumors observed in about 30% of cases i. Gonadoblastomas: usually benign ii. Dysgerminoma iii. Embryonal carcinoma: more life-threatening 5. Biochemical findings a. Elevated levels of FSH and LH b. Low levels of estradiol c. No elevation of androgen levels
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: recurrence risk depending on whether the inheritance is X-linked recessive, male-limited autosomal dominant, or autosomal recessive b. Patient’s offspring: Patients are nonreproductive c. To rule out the disease in siblings because of the presence of familial aggregation. 2. Prenatal diagnosis: demonstration of the sexual discrepancy between fetal karyotype (XY) and ultrasonographic fetal phenotype a. To exclude sample error and placental mosaicism b. Detailed fetal ultrasound examination to check for syndromic gender discrepancy such as: i. Campomelic dysplasia (skeletal malformation) ii. Denys-Drash syndrome iii. Smith-Lemli-Opitz syndrome a) Microcephaly b) Abnormal cholesterol metabolism iv. Alfi syndrome a) Craniostenosis b) Trigonocephaly c) Multiple congenital anomalies c. Prenatal diagnosis possible by SRY analysis for XY gonadal dysgenesis (SRY-negative XY female and SRY-positive XY female) i. FISH using SRY probe on metaphase chromosomes ii. Sequencing of entire coding region 3. Management a. Removal of gonads to avoid malignancy b. Initiate cyclic hormonal therapy with estrogen and progesterone at puberty c. Psychological counseling i. Raise as a female ii. Increase patient’s knowledge about medical and surgical history and karyotype iii. Counseling for sexual function iv. Achievement of pregnancy in some patients following in vitro fertilization with a donor egg
REFERENCES Ahmed SF, Hughes IA: The genetics of male undermasculinization. Clin Endocr 56:1–18, 2002. Arn P, Chen H, Tuck-Muller CM, et al.: SRVX, a sex reversing locus in Xp21.2-p22.11. Hum Genet 93:389–393, 1994. Bardoni B, Zanaria E, Guioli S, et al.: A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nature Genet 7:497–501, 1994. Barr ML, Carr DH, Plunkett E R, et al.: Male pseudohermaphroditism and pure gonadal dysgenesis in sisters. Am J Obstet Gynec 99:1047–1055, 1967. Berkovitz GD: Abnormalities of gonad determination and differentiation. Semin Perinatol 16:289–298, 1992. Berta P, Hawkins JR, Sinclair AH, et al.: Genetic evidence equating SRY and the testis-determining factor. Nature 348:448–450, 1990. Bretelle F, Salomon L, Senat M-V, et al.: Fetal gender: antenatal discrepancy between phenotype and genotype. Ultrasound Obstet Gynecol 20:286–289, 2002. Calvan V, Bertini V, De Grandi A, et al.: A new submicroscopic deletion that refines the 9p region for sex reversal. Genomics 65:203–212, 2000.
XY FEMALE Cameron F, Sinclair AH: Mutations in SRY and SOX9: testis-determining genes. Hum Mutat 9:388–395, 1997. Davis RM: Localization of male-determining factors in man: A thorough review of structural anomalies of the Y chromosome. J Med Genet 18:161–195, 1981. Goodfellow PN, Lovell-Badge R: SRY and sex determination in mammals. Annu Rev Genet 27:71–92, 1993. Graves PE, Davis D, Erickson RP, et al.: Ascertainment and mutational studies of SRY in nine XY females. Am J Med Genet 83:138–139, 1999. Harley VR, Goodfellow PN: The biochemical role of SRY in sex determination. Mol Reprod Dev 39:184–193, 1994. Hawkins JR: Genetics of XY sex reversal. J Endocrinol 147:183–187, 1995. Hawkins JR, Taylor A, Berta P, et al.: Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal. Hum Genet 88:471–475, 1992. Hawkins JR, Taylor A, Goodfellow PN, et al.: Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis. Am J Hum Genet 51:979–984, 1992. Hines RS, Tho SPT, Zhang YY, et al.: Paternal somatic and germ-line mosaicism for a sex-determining region on Y (SRY) missense mutation leading to recurrent 46,XY sex reversal. Fertil Steril 67:675–679, 1997. Jacob PA, Ross A: Structural abnormalities of the Y chromosome in man. Nature 210:352–354, 1966. Jäger RJ, Anvret M, Hall K, et al.: A human XY female with a frame shift mutation in the candidate testis-determining gene SRY. Nature 348:452–454, 1990. Jordan BK, Jain M, Natarajan S, et al.: Familial mutation in the testis-determining gene SRY shared by an XY female and her normal father. J Clin Endocrinol Metab 87:3428–3432, 2002. Koopman P, Gubay J, Vivian N, et al.: Male development of chromosomally female mice transgenic for Sry. Nature 351:117–121, 1991. Kwok C, Weller PA, Guioli S, et al.: Mutations in SOX9, the gene responsible for campomelic dysplasia and autosomal sex reversal. Am J Hum Genet 57:1028–1036, 1995. Kwok C, Tyler-Smith C, Mendonca BB, et al.: Mutation analysis of the 2 kb 5' to SRY in XY females and XY Intersex subjects. J Med Genet 33:465–468, 1996. McDonald MT, Flejter W, Sheldon S, et al.: XY sex reversal and gonadal dysgenesis due to 9p24 monosomy. Am J Med Genet 73:321–326, 1997. McElreavey K, Fellous M: Sex determination and the Y chromosome. Am J Med Genet (Semin Med Genet) 89:176–185, 1999.
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McElreavey K, Vilain E, Abbas N, et al.: XY sex reversal associated with a deletion 5’ to the SRY “HMG box” in the testis-determining region. Proc Natl Acad Sci USA 89:11016–11020, 1992. McElreavey K, Vilain E, Barbauxz S, et al.: Loss of sequences 3’ to the testisdetermining gene, SRY, including the Y pseudoautosomal boundary associated with partial testicular determination. Proc Natl Acad Sci USA 93:8590–8594, 1996. Morerio C, Calvari V, Rosanda C, et al.: XY female with a dysgerminoma and no mutation in the coding sequence of the SRY gene. Cancer Genet Cytogenet 136:58–61, 2002. Nazareth HRS, Moreira-Filho CA, Cunha AJB, et al. antigens in 46,XY pure testicular dysgenesis. Am J Med Genet 3:149–154, 1979. Portuondo JA, Neyro JL, Barral A, et al.: management of phenotypic female patients with an XY karyotype. J Reprod Med 31:611–615, 1986. Sarafoglou K, Ostrer H: Familial sex reversal: a review. J Clin Endocrinol Metab 85:483–493, 2000. Sauer MV, Lobo RA, Paulson RJ: Successful twin pregnancy after embryo donation to a patient with 46,XY gonadal dysgenesis. Am J Obstet Gynecol 161:380–381, 1989. Schäffler A, Barth N, Winkler K, et al.: Identification of a new missense mutation (Gly95Glu) in a highly conserved codon within the high-mobility group box of the sex-determining region Y gene: report on a 46,XY female with gonadal dysgenesis and yolk-sac tumor. J Clin Endocrinol Metab 85:2287–2292, 2000. Simpson JL, Blgowidow N, Martin AO: XY gonadal dysgenesis: genetic heterogeneity based upon clinical observations, H-Y antigen status, and segregation analysis. Hum Genet 58:91–97, 1981. Sinclair AH, Berta P, Palmer MS, et al.: A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 346:240–245, 1990. Swain A, Zanaria E, Hacker A, et al.: Mouse Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function. Nature Genet 12:404–409, 1996. Veitia R, Ion A, Barbaux S, et al.: Mutations and sequence variants in the testisdetermining region of the Y chromosome in individuals with a 46,XY female phenotype. Hum Genet 99:648–652, 1997. Vilain E, Jaubert F, Fellous M, et al.: Pathology of 46,XY pure gonadal dysgenesis: absence of testis differentiation associated with mutations in the testis-determining factor. Differentiation 52:151–159, 1993.
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Fig. 1. A patient with 46,XY female with gonadal dysgenesis at 42 years of age. Patient has short stature (4’6”), primary amenorrhea, lack of secondary sex characteristics (absent axillary hair, poor breast development), but normal female external genitalia. Laparotomy revealed absent Wolffian structures and presence of uterus and streak gonads which were excised.
XYY Syndrome In 1961, Sandberg described an XYY man. The incidence is estimated to be approximately 1 in 1000 live male newborns.
GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: Patient generally has chromosomally normal children, despite the high theoretical risk of aneuploidy. 2. Prenatal diagnosis: fetal karyotyping from amniocytes or CVS 3. Management a. The extra Y chromosome represents a risk factor for motor and language development, but the environment remains a primary force in shaping child’s development b. The increased frequency of prenatal detection of 47,XYY by amniocentesis necessitates the importance of making accurate information about the developmental prognosis of these individuals. c. Infancy and toddler: assess developmental milestones d. Childhood: assess school performance and provide intervention if needed e. Adolescence: no intervention needed f. Adulthood annual physical examination
GENETICS/BASIC DEFECTS 1. Caused by an additional Y chromosome in a male 2. Mechanisms of the extra Y chromosome in 47,XYY males a. Paternal nondisjunction at meiosis II after a normal chiasmate meiosis I (84%) b. Postzygotic mitotic error or nondisjunction at meiosis II after a nullichiasmate meiosis I (16%) 3. Spermatogenesis a. Normal spermatogenesis in majority of XYY males i. The supernumerary Y chromosome probably lost at the early stage of spermatogenesis ii. A large proportion of primary spermatocytes containing only one Y chromosome b. Altered spermatogenesis in a proportion of XYY males: Persistence of the supernumerary Y chromosome through meiotic prophase increases spermatocyte degeneration. 4. A higher incidence of the XYY complement in the institutions for the retarded, the mentally ill, the criminally insane, and the aggressive offender: controversial and biased
REFERENCES
CLINICAL FEATURES 1. Earlier observation of the association between the additional Y chromosome and aggressive behavior: considered to be due to selection bias and has since been challenged 2. No consistent physical stigmata or medical disorders 3. Growth and development a. Tall stature b. Larger tooth size c. At risk for mild speech/language and motor delays and learning disabilities 4. Intelligence a. Normal range b. IQ: 10–15 points lower than siblings 5. Behavioral profile a. Childhood temper tantrums b. No increased incidence of aggression c. Heterosexual 6. Normal reproduction 7. Normal adult adaptation 8. Low fertility
DIAGNOSTIC INVESTIGATIONS 1. Chromosome analysis to detect 47,XYY 2. Psychological and psychiatric evaluation when needed 3. Studies of sperm karyotypes or FISH analysis of sperm: The majority of sperm are chromosomally normal in 47,XYY men.
Abramsky L, Chapple J: 47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling. Prenat Diagn 17:363–368, 1997. Bender BG, Puck MH, Salbenblatt JA, et al.: The development of four unselected 47,XYY boys. Clin Genet 25:435–445, 1984. Court Brown WM: Males with an XYY sex chromosome complement. J Med Genet 5:341–359, 1968. Daly RF, Chun RW, Ewanowski S, et al.: The XYY condition in childhood: clinical observations. Pediatrics 43:852–857, 1969. Gabriel-Robez O, Delobel B, Croquette MF, et al.: Synaptic behaviour of sex chromosome in two XYY men. Ann Genet 39:129–132, 1996. Hoffman BF: Two new cases of XYY chromosome complement: and a review of the literature. Can Psychiatr Assoc J 22:447–455, 1977. Hsu LY, Shapiro LR, Hirschhorn K: Meiosis in an XYY male. Lancet 1:1173–1174, 1970. Linden MG, Bender BG, Robinson A: Genetic counseling for sex chromosome abnormalities. Am J Med Genet 110:3–10, 2002. Martin RH, Shi Q, Field LL: Recombination in the pseudoautosomal region in a 47,XYY male. Hum Genet 109:143–145, 2001. Money J, Franzke A, Borgaonkar DS: XYY syndrome, stigmatization, social class, and aggression: study of 15 cases. South Med J 68:1536–1542, 1975. Owen DR: The 47,XYY male: a review. Psychol Bull 78:209–233, 1972. Rives N, Simeon N, Milazzo JP, et al.: Meiotic segregation of sex chromosomes in mosaic and non-mosaic XYY males: case reports and review of the literature. Int J Androl 26:242–249, 2003. Robinson DO, Jacobs PA: The origin of the extra Y chromosome in males with a 47,XYY karyotype. Hum Mol Genet 8:2205–2209, 1999. Robinson A, Lubs HA, Nielsen J, et al.: Summary of clinical findings: profiles of children with 47,XXY, 47,XXX and 47,XYY karyotypes. Birth Defects Orig Artic Ser 15:261–266, 1979. Stewart DA, Netley CT, Park E: Summary of clinical findings of children with 47,XXY, 47,XYY, and 47,XXX karyotypes. Birth Defects Orig Artic Ser 18:1–5, 1982.
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Fig. 1. A 7-year-old boy with 47,XYY syndrome showing normal phenotype. Fig. 3. An adult with 47,XYY syndrome showing tall stature.
Fig. 2. A 13-year-old boy with XYY syndrome showing normal phenotype. He also has systemic carnitine deficiency and received Carnitol treatment.
