Atlas of Genetic Diagnosis andCounseling

Harold Chen

Atlas of GeneticDiagnosis andCounseling

Third Edition

With 1242 Figures and 1 Table

Harold ChenMedical Genetics, Shriners Hospitals for ChildrenPerinatal and Clinical GeneticsDepartment of PediatricsLSU Health Sciences CenterShreveport, LA, USA

ISBN 978-1-4939-2400-4 ISBN 978-1-4939-2401-1 (eBook)ISBN 978-1-4939-2402-8 (print and electronic bundle)DOI 10.1007/978-1-4939-2401-1

Library of Congress Control Number: 2017934650

1st edition: # Humana Press Inc. 20062nd edition: # Springer Science+Business Media, LLC 20123rd edition: # Springer Science+Business Media LLC 2017This work is subject to copyright. All rights are reserved by the Publisher, whether the whole orpart of the material is concerned, specifically the rights of translation, reprinting, reuse ofillustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way,and transmission or information storage and retrieval, electronic adaptation, computer software, orby similar or dissimilar methodology now known or hereafter developed.The use of general descriptive names, registered names, trademarks, service marks, etc. in thispublication does not imply, even in the absence of a specific statement, that such names are exemptfrom the relevant protective laws and regulations and therefore free for general use.The publisher, the authors and the editors are safe to assume that the advice and information in thisbook are believed to be true and accurate at the date of publication. Neither the publisher nor theauthors or the editors give a warranty, express or implied, with respect to the material containedherein or for any errors or omissions that may have been made. The publisher remains neutral withregard to jurisdictional claims in published maps and institutional affiliations.

Cover illustration: Courtesy of Harold Chen

Printed on acid-free paper

This Springer imprint is published by Springer NatureThe registered company is Springer Science+Business Media LLCThe registered company address is: 233 Spring Street, New York, NY 10013, U.S.A.

I would like to dedicate this atlas to Children’s Hospital,Louisiana State University School of Medicine in Shreveport andShriners Hospitals for Children, Shreveport, Louisiana, USA

Preface to the Third Edition

It has been 5 years since the publication of the second edition of this atlas in2012. Since then, significant progress has been made in the field of geneticdiagnosis and counseling, especially in genomic medicine. The third editioncovers 284 chapters with the addition of the following 30 new chapters: Con-genital Infiltrating Lipomatosis of the Face, Congenital Radioulnar Synostosis,Cutaneous Vasculitis, Emanuel Syndrome, Feingold Syndrome, FibularHemimelia, Gilbert Syndrome, Hemangiomas of Infancy, Hereditary Sensoryand Autonomic Neuropathies, Hereditary Spastic Paraplegia, Hydranencephaly,Hypertrophic Cardiomyopathy, Isolated Growth Hormone Deficiency in Chil-dren, Lymphangiomas and Lymphangiomatosis, Macrodactyly, MitochondrialMyopathies, Mőbius Syndrome, Nager Acrofacial Dysostosis, Nasal Obstruc-tion in Neonates and Children, Niemann-Pick Disease, Opitz TrigonocephalySyndrome, Osteogenesis Imperfecta/Ehlers-Danlos Syndrome Overlap Syn-drome, Patellar Instability, Peutz-Jeghers Syndrome, Primary Microcephaly,Schwartz-Jampel Syndrome, Symphalangism, Tibial Hemimelia, Tyrosinemias,and Winchester Syndrome.

As with the previous edition, a detailed outline of each chapter is provided,describing the genetics/basic defects, clinical features, diagnostic investiga-tions, and genetic counseling including recurrence risk, prenatal diagnosis, andmanagement. The illustrative cases are supplemented by case history anddiagnostic confirmations through imaging, cytogenetic, biochemical, and/ormolecular genetic studies. In this edition, it was a formidable task trying to citethe relevant references in the text, which was not done in the previous editions.

In addition to the individual contributions mentioned in the acknowledg-ments in previous editions, I thank the following individuals for their contri-bution and support to this edition: Richard A. Hruska, Springer PublishingEditor, for inviting me to write this third edition of the atlas and Neha Thapa,Springer Editor, and K. Arun Kumar, Springer Project Manager, for editingand production of this atlas. Individual contributors have been acknowledgedin the case illustrations. I am especially thankful to the staff at the ShreveportShriners Hospitals for Children (Kim Green, administrator; Dee Chambers,Medical Staff Coordinator; Kim Blankenship, Director of Outpatient Clinic;Dr. John Fox, Chief of Staff; Dr. Anne Hollister, hand surgeon; Dr. DonHolton, radiologist; Sheila Barritt, Director of Radiology) and staff at LSUSchool of Medicine (Dr. Susonne Ursin, clinical geneticist; Mary Moore,BBA, Administrative Assistant; Dr. Joseph Bocchini, Chairman of the

vii

Department of Pediatrics; Dr. Jennifer Woerner, Program Director ofCraniofacial Fellowship and Oralmaxillofacial Residency Program; DianeDunkiJacobsNolten, RN, Clinical Coordinator; and Dr. Ghali Ghali, Chancel-lor and Dean of School of Medicine and Chairman of the Department of Oraland Maxillofacial Surgery). Special thanks are due to Dr. Grace Guo, apediatric radiologist at Nemours/Alfred I. duPont Hospital for Children, forher contributions to cases with excellent imagings provided throughout thisatlas.

As previously, I would welcome comments, corrections, and criticism fromreaders.

Shreveport, LA, USA Harold ChenFebruary 2017

viii Preface to the Third Edition

Preface to the Second Edition

It has been 5 years since the publication of the first edition of this atlas in 2006.Since then, significant progress has been made in the field of geneticdiagnosis and counseling. The first edition of the atlas covered 203 chapterswhich were revised with current literature and addition of many illustrations,mostly in color. Fifty-two new chapters have been added to this edition.Selected references have also been added to the text for the sources of theinformation.

As with the previous edition, a detailed outline of each disorder is provided,describing the genetics, basic defects, clinical features, diagnostic investiga-tions, and genetic counseling, including recurrence risk, prenatal diagnosis,and management. Relevant references are added in the second edition. Thecases are supplemented by case history and diagnostic confirmations byimaging, cytogenetic, biochemical, and/or molecular studies.

I am grateful to the following individuals for their contribution and supportof this edition: Dr. Susonne Ursin, my genetic colleague and Chief of PerinatalGenetics, for case studies (Joubert syndrome, Mowatt-Wilson syndrome,otopalatodigital syndrome, rigid spine syndrome, Saethre-Chotzen syndrome,Silver-Russell syndrome); Dr. RMS Riel-Romero for megalencephalicleukoencephalopathy with subcortical cysts; Dr. Amal Anga for Duncansyndrome; Drs. RichardMcCall, Phillip Gates, and Anne Hollister, ShreveportShriners Hospital for Children; Dr. Ghali Ghali, Chairman of Oral and Max-illofacial Surgery; and Dr. Renata Pilatova, Pinecrest Development Center, forproviding patients for studies and inclusion into this edition; Dr. LeonardProuty, Ms. Rhonda Lee Young, and Mr. Jozo Ivancic, LSU CytogeneticsLaboratory for part of the karyotypes used in this edition; Mrs. Lynn Martin,Beverely Gildon, and Diane DunkiJacobsNolten for nursing care; andMs. Ashli Daigle and Mrs. Barbara McHenry for their excellent clerical andsecretarial help. My apologies in the event that I failed to mention others whohave contributed to this edition. Without the patience and encouragement ofmy dear wife, Cheryl, this edition of the atlas would not have been possible.I would like to express my sincere appreciation to Dr. Joseph Bocchini,Chairman of the Department of Pediatrics, for his encouragement and support.I would like to dedicate this edition of the atlas to the Children’s Hospital,

ix

Louisiana State University Health Sciences Center in Shreveport, for itsexcellence in pediatric care and education.

As previously, I would welcome comments, corrections, and criticism fromreaders.

Shreveport, LA, USA Harold ChenOctober 2011

x Preface to the Second Edition

Preface to the First Edition

This book, Atlas of Genetic Diagnosis and Counseling, reflects my experiencein 38 years of clinical genetics practice. During this time, I have cared for manypatients and their families and taught innumerable medical students, residents,and practicing physicians. As an academic physician, I have found that apicture is truly “worth a thousand words,” especially in the field ofdysmorphology. 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 eachdisorder 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 illustratethe clinical features of patients of different ages and ethnicities. Photographs ofprenatal ultrasounds, imaging, cytogenetics, and postmortem findings areincluded to help illustrate diagnostic strategies. The cases are supplementedby case history and diagnostic confirmation by cytogenetic, biochemical, andmolecular studies, if available. An extensive literature review was done toensure up-to-date information and to provide a relevant bibliography for eachdisorder.

This book was written in the hope that it will help physicians improve theirrecognition and understanding of these conditions and their care of affectedindividuals and their families. It is also my intention to bring the basic scienceand clinical medicine together for the readers. Atlas of Genetic Diagnosis andCounseling is designed for physicians involved in the evaluation and counsel-ing of patients with genetic diseases, malformations, and malformation syn-dromes, including medical geneticists, genetic counselors, pediatricians,neonatologists, developmental pediatricians, perinatologists, obstetricians,neurologists, pathologists, and any physicians and health care professionalscaring for handicapped children such as craniofacial surgeons, plastic sur-geons, otolaryngologists, and orthopedics.

I am grateful to many individuals for their invaluable help in reading andproviding cases for illustration. The acknowledgments are provided on aseparate page. Without the patience and encouragement of my dear wife,Cheryl, this atlas would not have been possible. I would like to dedicate thisbook to the Children’s Hospital, Louisiana State University Health Sciences

xi

Center in Shreveport, for its continued excellence in pediatric care andeducation.

I would welcome comments, corrections, and criticism from readers.

Harold Chen, M.D., FAAP, FACMG

xii Preface to the First Edition

Contents

Volume 1

Acardia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Achondrogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Achondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Adams-Oliver Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Agnathia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Aicardi Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Alagille Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Albinism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Alpha-Thalassemia X-Linked Mental Retardation Syndrome . . . . 87

Ambiguous Genitalia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Amniotic Deformity, Adhesions, Mutilations (ADAM)Complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

Androgen Insensitivity Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 127

Angelman Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

Apert Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

Aplasia Cutis Congenita . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

Arthrogryposis Multiplex Congenita . . . . . . . . . . . . . . . . . . . . . . . . 179

Asphyxiating Thoracic Dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . 199

Ataxia-Telangiectasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

Atelosteogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

Autism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

Bannayan-Riley-Ruvalcaba Syndrome . . . . . . . . . . . . . . . . . . . . . . 249

Beckwith-Wiedemann Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 257

xiii

Behçet Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271

Biotinidase Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283

Bladder Exstrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome . . . 295

Body Stalk Anomaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303

Brachydactyly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311

Branchial Cleft Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323

Calcinosis Cutis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329

Campomelic Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337

Carpenter Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349

Cat Eye Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353

Celiac Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359

Cerebral Palsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

Cerebrocostomandibular Syndrome . . . . . . . . . . . . . . . . . . . . . . . . 385

Charcot-Marie-Tooth Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

CHARGE Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407

Cherubism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417

Chiari Malformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425

Chondrodysplasia Punctata . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435

Chromosome Abnormalities in Pediatric Solid Tumors . . . . . . . . . 451

Cleft Lip and/or Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475

Cleidocranial Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485

Cloacal Exstrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497

Clubfoot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505

Collodion Baby . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515

Congenital Adrenal Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . 521

Congenital Cutis Laxa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541

Congenital Cytomegalovirus Infection . . . . . . . . . . . . . . . . . . . . . . . 553

Congenital Generalized Lipodystrophy . . . . . . . . . . . . . . . . . . . . . . 565

Congenital Hemihyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575

Congenital Hydrocephalus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585

Congenital Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599

xiv Contents

Congenital Infiltrating Lipomatosis of the Face . . . . . . . . . . . . . . . 609

Congenital Muscular Dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . 617

Congenital Radioulnar Synostosis . . . . . . . . . . . . . . . . . . . . . . . . . . 627

Congenital Toxoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635

Conjoined Twins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 645

Corpus Callosum Agenesis/Dysgenesis . . . . . . . . . . . . . . . . . . . . . . 659

Craniometaphyseal Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667

Cri-Du-Chat Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675

Crouzon Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685

Cutaneous Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695

Cutis Marmorata Telangiectatica Congenita . . . . . . . . . . . . . . . . . . 705

Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715

Dandy–Walker Malformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731

De Lange Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737

Del(18p) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753

Del(22q11.2) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761

Del(Yq) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773

Diabetic Embryopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787

Down Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 797

Duncan Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 817

Dyschondrosteosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827

Dysmelia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843

Dysplasia Epiphysealis Hemimelica . . . . . . . . . . . . . . . . . . . . . . . . . 865

Dystonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 873

Dystrophinopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 885

Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) Syndrome . . . 899

Ehlers-Danlos Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907

Ellis-van Creveld Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 925

Emanuel Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937

Enchondromatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943

Epidermolysis Bullosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 957

Epidermolytic Palmoplantar Keratoderma . . . . . . . . . . . . . . . . . . . 973

Contents xv

Faciogenital (Faciodigitogenital) Dysplasia . . . . . . . . . . . . . . . . . . . 983

Facioscapulohumeral Muscular Dystrophy . . . . . . . . . . . . . . . . . . . 993

Familial Adenomatous Polyposis . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005

Familial Hyperlysinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1019

Volume 2

Familial Mediterranean Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1023

Fanconi Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1031

Feingold Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1045

Femoral Hypoplasia: Unusual Facies Syndrome . . . . . . . . . . . . . . . 1049

Fetal Akinesia Deformation Sequence . . . . . . . . . . . . . . . . . . . . . . . 1055

Fetal Alcohol Spectrum Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 1071

Fetal Hydantoin Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1079

Fibrodysplasia Ossificans Progressiva . . . . . . . . . . . . . . . . . . . . . . . 1083

Fibular Hemimelia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1095

Finlay-Marks Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103

Floppy Infant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107

Fragile X Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1129

Fraser Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1143

Freeman-Sheldon Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153

Friedreich Ataxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163

Frontonasal Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1173

Galactosemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1183

Gastroschisis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1193

Gaucher Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201

Generalized Arterial Calcification of Infancy . . . . . . . . . . . . . . . . . 1213

Genitopatellar Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1221

Giant Congenital Melanocytic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . 1227

Gilbert Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1237

Glucose-6-Phosphate Dehydrogenase Deficiency . . . . . . . . . . . . . . . 1241

Glycogen Storage Disease, Type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . 1249

Goldenhar Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1261

Gorlin Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1271

xvi Contents

Greig Cephalopolysyndactyly Syndrome . . . . . . . . . . . . . . . . . . . . . 1281

Hallermann-Streiff Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1289

Harlequin Ichthyosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1295

Hemangiomas of Infancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1303

Hemophilia A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1319

Hereditary Hearing Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1331

Hereditary Hemochromatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1345

Hereditary Multiple Exostoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1357

Hereditary Sensory and Autonomic Neuropathies . . . . . . . . . . . . . 1367

Hereditary Spastic Paraplegia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1373

Herlyn-Werner-Wunderlich Syndrome . . . . . . . . . . . . . . . . . . . . . . 1387

Holoprosencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1393

Holt-Oram Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1421

Huntington Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1429

Hydranencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1439

Hydrolethalus Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1447

Hydrops Fetalis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1453

Hyper-IgE Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1469

Hypertrophic Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1477

Hypochondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1485

Hypoglossia-Hypodactylia Syndrome . . . . . . . . . . . . . . . . . . . . . . . 1495

Hypohidrotic Ectodermal Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . 1509

Hypomelanosis of Ito . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1519

Hypophosphatasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1527

Hypopituitarism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1539

I(1p), I(1q) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1555

Idic(Yq) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1561

Incontinentia Pigmenti . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1571

Infantile Myofibromatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1581

Isolated Growth Hormone Deficiency in Children . . . . . . . . . . . . . 1589

Ivemark Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1597

Jarcho-Levin Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1605

Contents xvii

Joubert Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1615

Kabuki Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1625

Kasabach–Merritt Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1635

KID Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1643

Klinefelter Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1649

Klippel-Feil Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1663

Klippel-Trenaunay Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1673

Kniest Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1685

Larsen Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1693

LEOPARD Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1707

Lesch-Nyhan Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1715

Lethal Multiple Pterygium Syndrome . . . . . . . . . . . . . . . . . . . . . . . 1723

Loeys-Dietz Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1733

Lowe Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1743

Lymphangiomas and Lymphangiomatosis . . . . . . . . . . . . . . . . . . . 1753

Macrodactyly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1765

Marfan Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1773

McCune-Albright Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1797

Meckel-Gruber Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1809

Megalencephalic Leukoencephalopathy with SubcorticalCysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1815

Menkes Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1823

Metachromatic Leukodystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . 1835

Miller-Dieker Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1845

Mitochondrial Leber Hereditary Optic Neuropathy . . . . . . . . . . . . 1857

Mitochondrial Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1871

Mowat-Wilson Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1881

Mucolipidosis 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1887

Mucolipidosis 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1897

Mucopolysaccharidosis 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1905

Mucopolysaccharidosis 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1913

Mucopolysaccharidosis 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1923

Mucopolysaccharidosis 6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1935

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Mucopolysaccharidosis I (MPS I) . . . . . . . . . . . . . . . . . . . . . . . . . . . 1943

Multiple Endocrine Neoplasia Syndromes . . . . . . . . . . . . . . . . . . . . 1963

Multiple Epiphyseal Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1975

Multiple Pterygium Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1989

Myotonic Dystrophy Type 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1999

Möbius Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2013

Nager Acrofacial Dysostosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2025

Nail-Patella Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2033

Nasal Obstruction in Neonates and Children . . . . . . . . . . . . . . . . . 2043

Neonatal Herpes Simplex Infection . . . . . . . . . . . . . . . . . . . . . . . . . 2051

Nephrogenic Diabetes Insipidus . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2061

Netherton Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2069

Volume 3

Neu-Laxova Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2077

Neural Tube Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2085

Neurofibromatosis 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2105

Neurofibromatosis 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2133

Niemann-Pick Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2143

Noonan Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2151

Oblique Facial Cleft Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2163

Oligohydramnios Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2173

Omphalocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2181

Opitz Trigonocephaly Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 2191

Oral-Facial-Digital Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2195

Osteogenesis Imperfecta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2211

Osteogenesis Imperfecta/Ehlers-Danlos Syndrome OverlapSyndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2237

Osteopetrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2241

Osteopoikilosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2259

Otopalatodigital Spectrum Disorders . . . . . . . . . . . . . . . . . . . . . . . . 2267

Pachyonychia Congenita . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2279

Pallister–Killian Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2289

Contents xix

Patellar Instability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2299

Peutz-Jeghers Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2305

Phenylketonuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2311

Pierre Robin Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2327

Polycystic Kidney Disease: Autosomal Dominant Type . . . . . . . . . 2333

Polycystic Kidney Disease: Autosomal Recessive Type . . . . . . . . . . 2347

Popliteal Pterygium Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2357

Prader-Willi Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2365

Primary Microcephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2383

Progeria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2389

Prune Belly Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2399

Pseudoachondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2409

R(18) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2417

Retinoid Embryopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2427

Rett Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2435

Rickets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2449

Rigid Spine Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2471

Roberts Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2481

Robinow Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2491

Rubinstein-Taybi Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2499

Saethre-Chotzen Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2513

Sagittal Craniosynostosis Associated with ChromosomeAbnormalities with a Brief Review on Craniosynostosis . . . . . . . . 2523

Schizencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2537

Schmid Metaphyseal Chondrodysplasia . . . . . . . . . . . . . . . . . . . . . 2547

Schwartz-Jampel Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2553

Seckel Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2565

Severe Combined Immune Deficiency . . . . . . . . . . . . . . . . . . . . . . . 2573

Short-Rib Polydactyly Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . 2585

Sickle Cell Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601

Silver–Russell Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2617

Sirenomelia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2629

Smith–Lemli–Opitz Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2639

xx Contents

Smith-Magenis Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2653

Sotos Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2661

Spinal Muscular Atrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2673

Spondyloepiphyseal Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2687

Stickler Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2699

Sturge-Weber Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2711

Symphalangism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2721

Tay-Sachs Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2725

Tetrasomy 9p Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2733

Thalassemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2739

Thanatophoric Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2753

Thrombocytopenia-Absent Radius Syndrome . . . . . . . . . . . . . . . . . 2767

Tibial Hemimelia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2781

Treacher-Collins Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2789

Trimethylaminuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2799

Triploidy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2807

Trismus-Pseudocamptodactyly Syndrome . . . . . . . . . . . . . . . . . . . . 2821

Trisomy 13 Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2829

Trisomy 18 Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2845

Trisomy 8 Mosaicism Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2861

Tuberous Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2869

Turner Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2891

Twin-Twin Transfusion Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 2913

Tyrosinemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2925

Ulnar-Mammary Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2931

Urofacial Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2937

VATER (VACTERL) Association . . . . . . . . . . . . . . . . . . . . . . . . . . . 2943

Von Hippel-Lindau Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2953

Waardenburg Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2967

Weill-Marchesani Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2975

Williams Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2981

Winchester Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2995

Contents xxi

Wolf–Hirschhorn Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3001

X-Linked Agammaglobulinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . 3017

X-Linked Ichthyosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3027

XX Male . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3035

XXX Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3045

XXXXX Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3051

XXXXY Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3057

XY Female . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3063

XYY Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3075

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Biography

Harold Chen was born in I-Lan, Taiwan, and was a graduate from theNational Taiwan University School of Medicine (M.D. degree) in Taipei,Taiwan. He received M.S. degree in Human Genetics from the University ofMichigan Graduate School in Ann Arbor, Michigan. He finished pediatricresidency and fellowship training from Wayne State University School ofMedicine in Detroit, Michigan. He had been faculty at Wayne State University(Detroit), Wright State University (Dayton, Ohio), and University of SouthAlabama (Mobile, Alabama). Currently, he is Professor of Pediatrics, Obstet-rics and Gynecology, Pathology, and Oral and Maxillofacial Surgery at theLouisiana State University Health Sciences Center. He is also Chief of MedicalGenetics at the Shriners Hospitals for Children, Shreveport, LA. Dr. Chen isboard-certified in American Board of Pediatrics and American Board ofMedical Genetics in Clinical Genetics and Clinical Cytogenetics.

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