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1. 1. ATLAS OF GENETIC DIAGNOSIS AND COUNSELING
2. 2. ATLAS OF GENETIC DIAGNOSIS AND COUNSELING HAROLD CHEN, MD,FAAP, FACMG Professor of Pediatrics, Obstetrics and Gynecology, andPathology, Louisiana State University Health Science Center,Shreveport, LA
3. 3. 2006 Humana Press Inc. 999 Riverview Drive, Suite 208Totowa, New Jersey 07512 humanapress.com For additional copies,pricing for bulk purchases, and/or information about other Humanatitles, contact Humana at the above address or at any of thefollowing numbers: Tel.: 973-256-1699; Fax: 973-256-8341; E-mail:[emailprotected]; Website: humanapress.com All rights reserved.No part of this book may be reproduced, stored in a retrievalsystem, or transmitted in any form or by any means, electronic,mechanical, photocopying, microfilming, recording, or otherwisewithout written permission from the Publisher. All articles,comments, opinions, conclusions, or recommendations are those ofthe author(s), and do not necessarily reflect the views of thepublisher. Due diligence has been taken by the publishers, editors,and author of this book to ensure the accuracy of the informationpublished and to describe generally accepted practices. Thecontributors herein have carefully checked to ensure that the drugselections and dosages set forth in this text are accurate inaccord with the standards accepted at the time of publication.Notwithstanding, as new research, changes in governmentregulations, and knowledge from clinical experience relat- ing todrug therapy and drug reactions constantly occurs, the reader isadvised to check the product information provided by themanufacturer of each drug for any change in dosages or foradditional warnings and contraindications. This is of utmostimportance when the recommended drug herein is a new orinfrequently used drug. It is the responsibility of the health careprovider to ascertain the Food and Drug Administration status ofeach drug or device used in their clinical practice. The publisher,editors, and authors are not responsible for errors or omissions orfor any consequences from the application of the informationpresented in this book and make no warranty, expressed or implied,with respect to the contents in this publication. Coverillustrations: To Come Production Editor: Nicole E. Furia Coverdesign by Patricia F. Cleary This publication is printed onacid-free paper. ANSI Z39.48-1984 (American National StandardsInstitute) Permanence of Paper for Printed Library Materials.Photocopy Authorization Policy: Authorization to photocopy itemsfor internal or personal use, or the internal or personal use ofspecific clients, is granted by Humana Press Inc., provided thatthe base fee of US $30.00 per copy is paid directly to theCopyright Clearance Center at 222 Rosewood Drive, Danvers, MA01923. For those organizations that have been granted a photocopylicense from the CCC, a separate system of payment has beenarranged and is acceptable to Humana Press Inc. The fee code forusers of the Transactional Reporting Service is: [1-58829-681-4/06$30.00]. e-ISBN 1-59259-956-7 Printed in the United States ofAmerica. 10 9 8 7 6 5 4 3 2 1 Library of CongressCataloging-in-Publication Data Atlas of genetic diagnosis andcounseling / authored by Harold Chen. p. cm. Includesbibliographical references. ISBN 1-58829-681-4 (alk. paper) 1.Genetic disorders--Diagnosis--Atlases. 2. Geneticcounseling--Atlases. [DNLM: 1. Genetic Diseases, Inborn--Atlases.2. Genetic Counseling--Atlases. 3. Prenatal Diagnosis--Atlases. QZ17 A880383 2006] I. Chen, Harold. RB155.6.A93 2006 616'.042--dc222005005388
4. 4. 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 familiesand taught innumerable medical students, residents, and prac-ticing 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 mypatients, which are incorporated into this book to illustrateselected genetic disorders, malformations, and malformationsyndromes. A detailed outline of each disorder is provided,describing the genetics, basic defects, clinical features,diagnostic investiga- tions, and genetic counseling, includingrecurrence risk, prenatal diagnosis, and management. Colorphotographs are used to illustrate the clinical fea- tures ofpatients of different ages and ethnicities. Photographs of prenatalultrasounds, imagings, cyto- genetics, and postmortem findings areincluded to help illustrate diagnostic strategies. The cases aresupplemented by case history and diagnostic confir- mation bycytogenetics, biochemical, and molecular studies, if available. Anextensive literature review was done to ensure up-to-dateinformation and to provide a relevant bibliography for eachdisorder. This book was written in the hope that it will helpphysicians improve their recognition and understanding of theseconditions and their care of affected individuals and theirfamilies. It is also my intention to bring the basic science andclinical med- icine together for the readers. Atlas of GeneticDiagnosis and Counseling is designed for physicians involved in theevaluation and counseling of patients with genetic diseases,malformations, and malforma- tion syndromes, including medicalgeneticists, genetic counselors, pediatricians, neonatologists,developmental pediatricians, perinatologists, obste- tricians,neurologists, pathologists, and any physi- cians and health careprofessionals caring for handicapped children such as craniofacialsurgeons, plastic surgeons, otolaryngologists, and orthopedics. Iam grateful to many individuals for their invaluable help inreading and providing cases for illustration. The acknowledgmentsare provided on a separate page. Without the patience and encour-agement of my dear wife, Cheryl, this atlas would not have beenpossible. I would like to dedicate this book to Childrens Hospital,Louisiana State University Health Sciences Center in Shreveport,for its continued excellence in pediatric care and education. Iwould welcome comments, corrections, and crit- icism from readers.Harold Chen, MD, FAAP, FACMG Preface v
5. 5. Preface . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . v Acknowledgments . . . . . . . . . . . . . .. . . . . . . . . . . . . . xi Acardia . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 1 Achondrogenesis . .. . . . . . . . . . . . . . . . . . . . . . . . . . . 7Achondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . 15 Adams-Oliver Syndrome . . . . . . . . . . . . . . . . .. . . . . 23 Agnathia . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . 26 Aicardi Syndrome . . . . . . . . . . . .. . . . . . . . . . . . . . . 29 Alagille Syndrome . . . . . . . .. . . . . . . . . . . . . . . . . . . 32 Albinism . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . 36 AmnioticBand Syndrome . . . . . . . . . . . . . . . . . . . . . 42 AndrogenInsensitivity Syndrome . . . . . . . . . . . . . . . 50 AngelmanSyndrome . . . . . . . . . . . . . . . . . . . . . . . . . 56 ApertSyndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . .61 Aplasia Cutis Congenita . . . . . . . . . . . . . . . . . . . .. . . 70 Arthrogryposis Multiplex Congenita . . . . . . . . . . . .. 74 Asphyxiating Thoracic Dystrophy . . . . . . . . . . . . . . .84 Ataxia Telangiectasia . . . . . . . . . . . . . . . . . . . . .. . . . 92 Atelosteogenesis . . . . . . . . . . . . . . . . . . . .. . . . . . . . . 96 Autism . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . 102 Beckwith-Wiedemann Syndrome . . .. . . . . . . . . . . . 109 Behcet Disease . . . . . . . . . . . .. . . . . . . . . . . . . . . . . 114 Bladder Exstrophy . . . . . .. . . . . . . . . . . . . . . . . . . . 118 Body Stalk Anomaly . .. . . . . . . . . . . . . . . . . . . . . . 122 Branchial CleftAnomalies . . . . . . . . . . . . . . . . . . . . 126 CampomelicDysplasia . . . . . . . . . . . . . . . . . . . . . . . 131 Cat EyeSyndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 136Cerebro-Costo-Mandibular Syndrome . . . . . . . . . . . 139Charcot-Marie-Tooth Disease . . . . . . . . . . . . . . . . . 142CHARGE Association . . . . . . . . . . . . . . . . . . . . . . .149 Cherubism . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . 153 Chiari Malformation . . . . . . . . . . . . . . . . .. . . . . . . . 157 Chondrodysplasia Punctata . . . . . . . . . . .. . . . . . . . 161 Chromosome Abnormalities in Pediatric SolidTumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169Cleft Lip and/or Cleft Palate . . . . . . . . . . . . . . . . . .180 Cleidocranial Dysplasia . . . . . . . . . . . . . . . . . . . .. . 185 Cloacal Exstrophy . . . . . . . . . . . . . . . . . . . . .. . . . . 191 Collodion Baby . . . . . . . . . . . . . . . . . . .. . . . . . . . . 195 Congenital Adrenal Hyperplasia(21-Hydroxylase Deficiency) . . . . . . . . . . . . . . . . 198Congenital Cutis Laxa . . . . . . . . . . . . . . . . . . . . . . .207 Congenital Cytomegalovirus Infection . . . . . . . . . . 212Congenital Generalized Lipodystrophy . . . . . . . . . . 217Congenital Hydrocephalus . . . . . . . . . . . . . . . . . . . .221 Congenital Hypothyroidism . . . . . . . . . . . . . . . . . . .227 Congenital Muscular Dystrophy . . . . . . . . . . . . . . . 231Congenital Toxoplasmosis . . . . . . . . . . . . . . . . . . . .236 Conjoined Twins . . . . . . . . . . . . . . . . . . . . . . . .. . . . 241 Corpus Callosum Agenesis/Dysgenesis . . . . . . . . . .247 Craniometaphyseal Dysplasia . . . . . . . . . . . . . . . . .252 Cri-Du-Chat Syndrome . . . . . . . . . . . . . . . . . . . . .. 256 Crouzon Syndrome . . . . . . . . . . . . . . . . . . . . . .. . . . 261 Cystic Fibrosis . . . . . . . . . . . . . . . . . . . .. . . . . . . . . 265 Dandy-Walker Malformation . . . . . . . . . .. . . . . . . . 273 De Lange Syndrome . . . . . . . . . . . . . . .. . . . . . . . . . 276 Del(22q11.2) Syndromes . . . . . . . . . .. . . . . . . . . . . 282 Diabetic Embryopathy . . . . . . . . . .. . . . . . . . . . . . . 289 Down Syndrome . . . . . . . . . . . .. . . . . . . . . . . . . . . . 295 Dyschondrosteosis (Leri-WeillSyndrome) and Langer Mesomelic Dysplasia . . . . . . . . . . . . .. . . 305 Dysmelia (Limb Deficiency/Reduction) . . . . . . . . .312 Dysplasia Epiphysealis Hemimelica . . . . . . . . . . . . 323Dystonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . 326 Dystrophinopathies . . . . . . . . . . . . . . . . .. . . . . . . . . 331 Ectrodactyly-Ectodermal Dysplasia-Clefting(EEC) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . .339 Ehlers-Danlos Syndrome . . . . . . . . . . . . . . . . . . . .. 342 Ellis-van Creveld Syndrome . . . . . . . . . . . . . . . . .. 350 Enchondromatosis (Maffucci Syndrome; Ollier Syndrome) . . . .. . . . . . . . . . . . . . . . . . . . . 355 Epidermolysis Bullosa. . . . . . . . . . . . . . . . . . . . . . . 360 EpidermolyticPalmoplantar Keratoderma . . . . . . . . 366 Contents vii
6. 6. viii CONTENTS Faciogenital (Aarskog) Dysplasia . . . . . . .. . . . . . . 371 Facioscapulohumeral Muscular Dystrophy . . . . .. . 375 Familial Adenomatous Polyposis . . . . . . . . . . . . . .. 380 Familial Hyperlysinemia . . . . . . . . . . . . . . . . . . .. . 386 Fanconi Anemia . . . . . . . . . . . . . . . . . . . . . .. . . . . . 389 Femoral Hypoplasia-Unusual Facies Syndrome . . .395 Fetal Akinesia Syndrome . . . . . . . . . . . . . . . . . . . .. 398 Fetal Alcohol Syndrome . . . . . . . . . . . . . . . . . . .. . . 403 Fetal Hydantoin Syndrome . . . . . . . . . . . . . . . .. . . 407 Fibrodysplasia Ossificans Progressiva . . . . . . . . . .. 410 Finlay-Marks Syndrome . . . . . . . . . . . . . . . . . . . .. . 415 Fragile X Syndrome . . . . . . . . . . . . . . . . . . . .. . . . . 417 Fraser Syndrome . . . . . . . . . . . . . . . . . . .. . . . . . . . 423 Freeman-Sheldon Syndrome . . . . . . . . . . .. . . . . . . 427 Frontonasal Dysplasia . . . . . . . . . . . . . .. . . . . . . . . 431 Galactosemia . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . 437 Gastroschisis . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . 442 Gaucher Disease . . . .. . . . . . . . . . . . . . . . . . . . . . . . 446 GeneralizedArterial Calcification of Infancy . . . . . 452 Glucose-6-PhosphateDehydrogenase Deficiency . . . 457 Glycogen Storage Disease, TypeII . . . . . . . . . . . . . 461 Goldenhar Syndrome . . . . . . . .. . . . . . . . . . . . . . . . 465 Hallermann-Streiff Syndrome . .. . . . . . . . . . . . . . . 469 Harlequin Ichthyosis (HarlequinFetus) . . . . . . . . . . 473 Hemophilia A . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . 476 Hereditary Hemochromatosis. . . . . . . . . . . . . . . . . . 482 Hereditary MultipleExostoses . . . . . . . . . . . . . . . . . 487 Holoprosencephaly .. . . . . . . . . . . . . . . . . . . . . . . . . 493 Holt-OramSyndrome . . . . . . . . . . . . . . . . . . . . . . . . 502Hydrops Fetalis . . . . . . . . . . . . . . . . . . . . . . . . . .. . 506 Hyper-IgE Syndrome . . . . . . . . . . . . . . . . . . . .. . . . 513 Hypochondroplasia . . . . . . . . . . . . . . . . . . .. . . . . . . 517 Hypoglossia-Hypodactylia Syndrome . . . . . . . .. . . 521 Hypohidrotic Ectodermal Dysplasia . . . . . . . . . . . .524 Hypomelanosis of Ito . . . . . . . . . . . . . . . . . . . . .. . . 528 Hypophosphatasia . . . . . . . . . . . . . . . . . . . .. . . . . . 532 Incontinentia Pigmenti . . . . . . . . . . . . . .. . . . . . . . . 539 Infantile Myofibromatosis . . . . . . . . . .. . . . . . . . . . 545 Ivemark Syndrome . . . . . . . . . . . . .. . . . . . . . . . . . . 549 Jarcho-Levin Syndrome . . . . . . . .. . . . . . . . . . . . . . 553 Kabuki Syndrome . . . . . . . . . .. . . . . . . . . . . . . . . . . 559 Kasabach-Merritt Syndrome . .. . . . . . . . . . . . . . . . 563 KID Syndrome . . . . . . . . .. . . . . . . . . . . . . . . . . . . . 567 Klinefelter Syndrome .. . . . . . . . . . . . . . . . . . . . . . . 570 Klippel-FeilSyndrome . . . . . . . . . . . . . . . . . . . . . . . 575Klippel-Trenaunay Syndrome . . . . . . . . . . . . . . . . . 580Kniest Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . .. . . 585 Larsen Syndrome . . . . . . . . . . . . . . . . . . . . .. . . . . . 589 LEOPARD Syndrome . . . . . . . . . . . . . . . . .. . . . . . 597 Lesch-Nyhan Syndrome . . . . . . . . . . . . . . .. . . . . . . 600 Lethal Multiple Pterygium Syndrome . . . . . . .. . . . 604 Lowe Syndrome . . . . . . . . . . . . . . . . . . . . .. . . . . . . 613 Marfan Syndrome . . . . . . . . . . . . . . . . .. . . . . . . . . . 619 McCune-Albright Syndrome . . . . . . . . .. . . . . . . . . 630 Meckel-Gruber Syndrome . . . . . . . . . . .. . . . . . . . . 636 Menkes Disease (Kinky-Hair Syndrome) . . . .. . . . 639 Metachromatic Leukodystrophy . . . . . . . . . . . . .. . 646 Miller-Dieker Syndrome . . . . . . . . . . . . . . . . . .. . . 650 Mbius Syndrome . . . . . . . . . . . . . . . . . . . . .. . . . . 655 Mucolipidosis II (I-Cell Disease) . . . . . . . . . .. . . . . 660 Mucolipidosis III (Pseudo-Hurler Polydystrophy) . 664Mucopolysaccharidosis I (MPS I) (-L-Iduronidase Deficiency): Hurler(MPS I-H), Hurler-Scheie (MPS I-H/S), and Scheie (MPS I-S)Syndromes . . . . . . . . . . . . 669 Mucopolysaccharidosis II(Hunter Syndrome) . . . . 678 Mucopolysaccharidosis III (SanfilippoSyndrome) . 682 Mucopolysaccharidosis IV (Morquio Syndrome) . . 687Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome) . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . 692 Multiple EpiphysealDysplasia . . . . . . . . . . . . . . . . 697 Multiple PterygiumSyndrome . . . . . . . . . . . . . . . . . 702 Myotonic DystrophyType 1 . . . . . . . . . . . . . . . . . . 708 Netherton Syndrome .. . . . . . . . . . . . . . . . . . . . . . . 715 Neu-LaxovaSyndrome . . . . . . . . . . . . . . . . . . . . . . . 718 NeuralTube Defects . . . . . . . . . . . . . . . . . . . . . . . . . 721Neurofibromatosis I . . . . . . . . . . . . . . . . . . . . . . . .. 731 Noonan Syndrome . . . . . . . . . . . . . . . . . . . . . . .. . . 744 Oblique Facial Cleft Syndrome . . . . . . . . . . . . . .. . 751 Oligohydramnios Sequence . . . . . . . . . . . . . . . . .. . 755 Omphalocele . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . 758 Osteogenesis Imperfecta . . . . . . . . . . . . .. . . . . . . . 762 Osteopetrosis . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . 773
7. 7. CONTENTS ix Pachyonychia Congenita . . . . . . . . . . . . .. . . . . . . . 781 Pallister-Killian Syndrome . . . . . . . . . .. . . . . . . . . . 784 Phenylketonuria (PKU) . . . . . . . . . . .. . . . . . . . . . . 788 Pierre Robin Sequence . . . . . . . . . .. . . . . . . . . . . . . 793 Polycystic Kidney Disease, AutosomalDominant Type . . . . . . . . . . . . . . . . . . . . . . . . . .797 Polycystic Kidney Disease, Autosomal Recessive Type . . . . . .. . . . . . . . . . . . . . . . . . . . . 803 Prader-Willi Syndrome. . . . . . . . . . . . . . . . . . . . . . . 809 Progeria . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 815Prune Belly Syndrome . . . . . . . . . . . . . . . . . . . . . . .821 Pseudoachondroplasia . . . . . . . . . . . . . . . . . . . . .. . 826 R(18) Syndrome . . . . . . . . . . . . . . . . . . . . . .. . . . . . 831 Retinoid Embryopathy . . . . . . . . . . . . . . .. . . . . . . . 835 Rett Syndrome . . . . . . . . . . . . . . . . .. . . . . . . . . . . . 839 Rickets . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . 844 Roberts Syndrome . . . .. . . . . . . . . . . . . . . . . . . . . . 852 Robinow Syndrome .. . . . . . . . . . . . . . . . . . . . . . . . 856Rubinstein-Taybi Syndrome . . . . . . . . . . . . . . . . . . . 860Schizencephaly . . . . . . . . . . . . . . . . . . . . . . . . . .. . . 867 Schmid Metaphyseal Chondrodysplasia . . . . . . . . . 870Seckel Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . .. 874 Severe Combined Immune Deficiency . . . . . . . . . . . 878Short Rib Polydactyly Syndromes . . . . . . . . . . . . . . 884Sickle Cell Disease . . . . . . . . . . . . . . . . . . . . . . . .. . 892 Silver-Russell Syndrome . . . . . . . . . . . . . . . . . .. . . 899 Sirenomelia . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . 903 Smith-Lemli-Opitz Syndrome . . . . . . . . .. . . . . . . . 907 Smith-Magenis Syndrome . . . . . . . . . . . .. . . . . . . . 912 Sotos Syndrome . . . . . . . . . . . . . . . .. . . . . . . . . . . . 916 Spinal Muscular Atrophy . . . . . . . .. . . . . . . . . . . . . 921 Spondyloepiphyseal Dysplasia . . . .. . . . . . . . . . . . . 927 Stickler Syndrome . . . . . . . . . .. . . . . . . . . . . . . . . . 934 Sturge-Weber Syndrome . . . . .. . . . . . . . . . . . . . . . 939 Tay-Sachs Disease . . . . . . .. . . . . . . . . . . . . . . . . . . 943 Tetrasomy 9p Syndrome . .. . . . . . . . . . . . . . . . . . . 947 Thalassemia . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . 950 ThanatophoricDysplasia . . . . . . . . . . . . . . . . . . . . . 955Thrombocytopenia-Absent Radius Syndrome . . . . . 962Treacher-Collins Syndrome . . . . . . . . . . . . . . . . . . . 967Trimethylaminuria . . . . . . . . . . . . . . . . . . . . . . . . .. 972 Triploidy . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . 976 Trismus Pseudocamptodactyly Syndrome . . . . .. . . 982 Trisomy 13 Syndrome . . . . . . . . . . . . . . . . . . .. . . . 985 Trisomy 18 Syndrome . . . . . . . . . . . . . . . . . .. . . . . 990 Tuberous Sclerosis . . . . . . . . . . . . . . . . .. . . . . . . . . 997 Turner Syndrome . . . . . . . . . . . . . . .. . . . . . . . . . . 1007 TwinTwin 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 . . . . . . . . . . . . . . . . . . .. . . . . 1057 XXX Syndrome . . . . . . . . . . . . . . . . . . . .. . . . . . . 1061 XXXXX Syndrome . . . . . . . . . . . . . . . . .. . . . . . . 1064 XXXXY Syndrome . . . . . . . . . . . . . . . . .. . . . . . . 1068 XY Female . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . 1071 XYY Syndrome . . . . . . . . . . . . .. . . . . . . . . . . . . . 1075
8. 8. Individuals DIANA BIENVENU, MD A case of Marfan syndromewith apical bleb rupture. SAMI BAHNA, MD Comments on del(22q11.2),hyper IgE syndrome, Netherton syndrome, and severe combinedimmunodeficiency. JOSEPH BOCCHINI, JR. MD Comments on congenitalcytomegalovirus infection and congenital toxoplasmosis andencouragement and support throughout preparation of the Atlas.CHUNG-HO CHANG, MD Cases on duch*enne muscular dystrophy andcongenital toxoplasmosis. SAU CHEUNG, PhD FISH on a case of STSdeficiency. JAMES GANLEY, MD Cases on ophthalmology (Behcetdisease, Lisch nodule in NF1, cherry spot in Tay-Sachs disease, andretinal changes in congenital toxoplasmosis, von-Hippel Lindaldisease, and Waardenburg syndrome). ENRIQUE GONZALEZ, MD Valuablecomments on pathological aspects of clinical entities and cases onacardius, agnathia, cloacal exstrophy, congenital cytomegalovirusinfection, omphalocele, pediatric solid tumors (meningioma,neuroblastoma, retinoblastoma, and Wilms tumor), phocomelia, sicklecell anemia, thalassemia, and Gaucher disease. WILLIAM HOFFMAN, MDComments on topics of endocrinological interest and cases onandrogen insensitivity and hypophosphatemic rickets. RACHELFLAMHOLZ, MD Peripheral blood smears on sickle cell anemia andthalassemia. MAJED JEROUDI, MD A case of sickle cell anemiadactylitis. DANIEL LACEY, MD Comments on dystrophinopathy, spinalmuscular atrophy, neural tube defects, and holoprosencephaly. MARYLOWERY, MD Comments on the Atlas and cases on molecularcytogenetics/pathology (FISH on trisomy 21, trisomy 13, trisomy 18,X/XXX, Williams syndrome, and neuroblastoma; mutation analysis oncystic fibrosis and hereditary hemochromatosis). LYNN MARTIN, LPNHelp in caring for the patients including obtaining the photographsof patients and searching for clinical information of the oldfiles. LEONARD PROUTY, PhD Reading of several topics in the Atlas.DAN SANUSI, MD A case of X-linked ichthyosis. TOHRU SONODA, MDCases on chondrodysplasia punctata, del(22q11.2), Kabuki syndrome,Klippel- Trenaunay syndrome, and tuberous sclerosis. HIROKO TANIAI,MD A case of Finlay-Marks syndrome and help in searching ofreferences for the Atlas. THEODORE THURMON, MD Comments on theAtlas and cases on achondrogenesis, arthrogryposis, cleidocranialdysplasia, chondrodysplasia punctata, de Lange syndrome, Crouzonsyndrome, cutis laxa, Freeman-Sheldon syndrome, hypophosphatasia,multiple epiphyseal dysplasia, omphalocele, prune belly syndrome,Sturge-Weber syndrome, and Treacher-Collins syndrome. CATHYTUCK-MULLER, PhD A karyotype on Roberts syndrome. SUSONNE URSIN, MDCases of galactosemia and Gaucher disease and helps coveringpatient care for me during the last stage of preparing the Atlas.WLADIMIR WERTELECKI, MD Enjoy working together on birth defects andcongenital malformations and appreciate friendship andencouragement. SAMUEL YANG, MD Meticulous reading and editing ofthe whole manuscript from the start to the end during hisretirement and encouragement throughout the preparation of theAtlas. Special thanks to contribution of his life-time collectionof 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, colonpolyposis, congenital cytomegalovirus infection, congenitaltoxoplasmosis, cyclopia, cystic fibrosis, duch*enne musculardystrophy, Ellis van Creveld syndrome, gastroschisis,hypophosphatasia, I-cell disease, Kniest syndrome, polycystickidney diseases, premaxillary agenesis, prune belly syndrome, SEDcongenita, sirenomelia, short rib polydactyly syndromes, Tay-Sachsdisease, thanatophoric dysplasia, twin-twin transfusion placentas,VATER association, and Werdnig-Hoffman syndrome). CHENG W. YU, PhDKaryotypes/FISH on pediatric tumors (meningioma, Wilms tumor),Cri-du-chat syndrome, and Wolf-Hirschhorn syndrome. InstitutionsLouisiana State University Health Sciences Center in Shreveport,Louisiana (Drs. Joseph Bocchini, Jr., David Lewis, RoseBrouillette, Rodney Wise) Pinecrest Developmental Center inPineville, Louisiana (Drs. Gaylon Bates, Tony Hanna, Renata Pilat)Shreveport Shriners Hospital for Children (Dr. Richard McCall)Acknowledgments xi
9. 9. Acardia is a bizarre fetal malformation occurring only intwins or triplets. It is also called acardius acephalus, acardiactwinning, or twin reversed arterial perfusion (TRAP) syndrome orsequence. This condition is very rare and occurs 1 in 35,000deliveries, 1 in 100 monozygotic twins, rarely in triplet preg-nancy, and even in quintuplet gestations. GENETICS/BASIC DEFECTS 1.Etiology a. Rare complication of monochorionic twinning, pre-sumably resulting from the fused placentation of monochorionictwins b. Represents manifestation of abnormal embryonic and fetalblood flow rather than a primary defect of car- diac formation c.Heterogeneous chromosomal abnormalities are present in nearly 50%of the cases, although chromosome errors are not underlyingpathogenesis 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 offetal arterial perfusion a. First hypothesis i. A primary defect inthe development of the heart ii. Survival of the acardiac twin as aresult of the compensatory anastomoses that develop b. Secondhypothesis i. The acardiac twin beginning life as a normal fetusii. The reversal of the arterial blood flow resulting in atrophy ofthe heart and the tributary organs 3. Classification of TRAPsequence (syndrome) a. Classification according to the status ofthe heart of the acardiac twin i. Hemiacardius (with incompletelyformed heart) ii. Holoacardius (with completely absent heart) b.Morphologic classification of the acardiac twin i. Acardiusamorphous a) The least differentiated form; no resem- blance toclassical human form b) Anatomical features: presence of onlybones, cartilage, muscles, fat, blood vessels, and stroma ii.Acardius myelacephalus a) Resembles the amorphous type, except forthe presence of rudimentary limb formation b) Presence ofrudimentary nerve tissue in addition to anatomical features inacardius amorphous iii. Acardius acephalus a) The most common typeb) Missing head, part of the thorax, and upper extremities c) Mayhave additional malformations in the remaining organs iv. Acardiusanceps a) Presence of a partially developed fetal head, a thorax,abdominal organs, and extremities b) Lacks even a rudimentary heartv. Acardius acormus a) The rarest type b) Lacks thorax c) Presenceof a rudimentary head only d) The umbilical cord inserts in thehead and connects directly to the placenta 4. The acardia a.Characterized by the absence of a normally function- ing heart b.Acardia as a recipient of twin transfusion sequence i. Reversal ofblood flow in various types of acar- dia, hence the term twinreversed arterial perfu- sion (TRAP) sequence has been proposed ii.Receiving the deoxygenated blood from an umbilical artery of itsco-twin through the sin- gle umbilical artery of the acardiac twinand returning to its umbilical vein. Therefore, the circulation isentirely opposite to the normal direction c. Usually the severereduction anomalies occur in the upper part of the body d. Maydevelop various structural malformations i. Growth retardation ii.Anencephaly iii. Holoprosencephaly iv. Facial defects v. Absent ormalformed limbs vi. Gastrointestinal atresias vii. Otherabnormalities of abdominal organs 5. The co-twin a. Also known asthe pump twin or donor twin b. The donor pump twin perfuses itselfand its recipi- ent acardiac twin through abnormal arterial anasto-mosis in the fused placenta c. Increased cardiac workload oftenleads to cardiac fail- ure and causes further poor perfusion andoxygena- tion of the acardiac co-twin d. May develop variousmalformations (about 10%) 1 Acardia
10. 10. 2 ACARDIA CLINICAL FEATURES 1. Perinatal problemsassociated with acardiac twinning a. Pump-twin congestive heartfailure b. In utero fetal death of the pump fetus c. Maternalpolyhydramnios d. Premature rupture of membrane e. Preterm deliveryf. Spontaneous abortions g. Soft tissue dystocia h. Uterine rupturei. Postpartum hemorrhage j. Increased rate of cesarean section, upto 50% 2. Majority of acardiac twins and their normal twin counter-parts are females 3. Nonviable 4. Gross features a. Severereduction anomalies, particularly of the upper body b.Characteristic subcutaneous edema c. Internal organs: invariablymissing d. Absent or rudimentary cardiac development: the keydiagnostic 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. Facialfeatures a. Absent facial features b. Rudimentary facial featuresc. Present with defects d. Anophthalmia/microphthalmia e. Cleftlip/palate 9. Upper limbs a. Absent b. Rudimentary c. Radialaplasia d. Syndactyly/oligodactyly 10. Lower limbs a. Absent b.Rudimentary/reduced c. Syndactyly/oligodactyly d. Talipesequinovarus 11. Thorax a. Absent b. Reduced c. Diaphragmatic defect12. Lungs a. Absent b. Necrotic or rudimentary c. Single midlinelobe 13. Cardiac a. Absent heart tissue b. Unfolded heart tube c.Folded heart with common chamber 14. Gastrointestinal a. Esophagealatresia b. Short intestine c. Interrupted intestine d. Omphalocelee. Incomplete rotation of the gut f. Imperforated anus g. Ascites15. Liver a. Absent b. Reduced 16. Kidney a. Absent (bilateral) b.Hypoplastic and/or lobulated 17. Other viscera a. Absentgallbladder b. Absent spleen c. Absent-to-reduced pancreas d.Absent adrenal e. Absent-to-hypoplastic gonads f. Exstrophy of thecloaca g. Skin with myxedematous thickening 18. Umbilical cordvessels a. Two vessels b. Three vessels 19. Severe obstetricalcomplications a. Maternal polyhydramnios b. Preterm labor c. Cordaccidents d. Dystocia e. Uterine rupture 20. Severe neonatalcomplications 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 growthretardation b) Hydrops c) Ascites d) Pleural effusion e)Hypertrophy of the right ventricle f) Hepatosplenomegaly g) Severeheart failure resulting in pericardial effusion and/or tricuspidinsufficiency ii. Stillbirth iii. Prematurity iv. Neonatal death b.Mortality for the normal twin reported as high as 50% withoutintervention
11. 11. ACARDIA 3 DIAGNOSTIC INVESTIGATIONS 1. Radiography a.Absent or rudimentary skull b. Absent or rudimentary thorax c.Absent or rudimentary heart d. Vertebral anomalies e. Rib anomaliesf. Limb defects, especially upper limbs 2. Pathology a.Microcephaly b. Severely rudimentary brain c. Developmental arrestof brain at the prosencephalic stage (holoprosencephaly) d. Hypoxicdamage to the holospheric brain mantle with cystic change(hydranencephaly) GENETIC COUNSELING 1. Recurrence risk a. Patientssib: overall recurrence risk of about 1 in 10,000 (The recurrencerisk is for monoamniotic twinning [1% for couples who have had oneset of monozygotic twins] times the frequency of the occur- renceof TRAP sequence with near-term survival [about 1% of monozygotictwin sets]) b. Patients offspring: not applicable (a lethalcondition) 2. Prenatal ultrasonography a. Monochorionic placentawith a single umbilical artery in 2/3 of cases b. Acardiac fetus i.Unrecognizable head or upper trunk ii. Without a recognizable heartor a partially formed heart iii. A variety of other malformationsiv. Reversal of blood flow in the umbilical artery with flow goingfrom the placenta toward the acardiac fetus (reversed arterialperfusion). Such a reversal of the blood flow in the recipient twincan be demonstrated in utero by transvagin*l Doppler ultrasound asearly as 12 weeks of gestation v. Early diagnosis by transvagin*lsonography on the following signs: a) Monozygotic twin gestation(absence of the lambda sign) b) Biometric discordance between thetwins c) Diffuse subcutaneous edema or morpho- logic anomalies ofone of the twins, or both d) Detection of reversed umbilical cordflow; cardiac activity likely to disappear as the pregnancyprogresses e) Absence of cardiac activity, although hemi- cardia orpseudocardia may be present c. The donor fetus i. Hydrops ii.Cardiac failure (cardiomegaly, pericardial effu- sion, andtricuspid regurgitation) 2. Amniocentesis to diagnose associatedchromosome abnormalities (about 10% of pump twins) 3. Management ofpregnancies complicated by an acardiac fetus a. Conservativetreatment i. Monitor pregnancy by serial ultrasonography ii.Conservative approach as long as there is no evi- dence of cardiaccirculatory decompensation in the donor twin b. Termination ofpregnancies c. Treatment and prevention of preterm labor bytocolytics i. Magnesium sulphate ii. Beta-Sympathomimetics iii.Indomethacin d. Treatment of pump fetus heart failure involvingmaternal digitalization e. Treatment of polyhydramnios bytherapeutic repeated amniocentesis f. Selective termination of theacardiac twin i. To occlude the umbilical artery of the acardiactwin in order to stop umbilical flow through the anastomosis a)Intrafunicular injection and mechanical occlusion of the umbilicalartery b) Embolization by steel or platinum coil, alco- hol-soakedsuture material, or ethanol c) Hysterotomy and delivery of acardiactwin d) Ligation of the umbilical cord e) Hysterotomy and umbilicalcord ligation ii. Fetal surgery: best available treatment for acar-diac twinning a) Endoscopic laser coagulation of the umbili- calvessels at or before 24 weeks of gestation b) Endoscopic orsonographic guided umbilical cord ligation after 24 weeks ofgestation iii. Summary of acardiac twins treated with invasiveprocedures reported in the literature a) Mortality of the pump twin(13.6%) b) Preterm delivery (50.3%) c) Delivery before 30-weeksgestation (27.2%) d) Perinatal mortality, if untreated, is at least50% REFERENCES Aggarwal N, Suri V, Saxena SV, et al.: Acardiacacephalus twins: a case report and review of literature. ActaObstet Gynecol Scand 81:983984, 2002. Alderman B: Foetus acardiusamorphous. Postgrad Med J 49:102105, 1973. Arias F, Sunderji S,Gimpelson R, et al.: Treatment of acardiac twinning. Obstet Gynecol91:818821, 1998. Benirschke K, des Roches Harper V: The acardiacanomaly. Teratology 15:311316, 1977. Blaicher W, Repa C, SchallerA: Acardiac twin pregnancy: associated with tri- somy 2. Hum Reprod15:474475, 2000. Blenc AM, Gmez JA, Collins D, et al.: Pathologicquiz case. Pathologic diag- nosis: acardiac fetus, acardiusacephalus type. Arch Pathol Lab Med 123:974976, 1999.Bonilla-Musoles F, Machado LE, Raga F, et al.: Fetus acardius. Two-and three- dimensional ultrasonographic diagnoses. J Ultrasound Med20:11171127, 2001. Chen H, Gonzalez E, Hand AM, Cuestas R: Theacardius acephalus and monozygotic twinning. Schumpert Med Quart1:195199, 1983.
12. 12. 4 ACARDIA Donnenfeld AE, Van de Woestijne J, Craparo F, etal.: The normal fetus of an acardiac twin pregnancy: perinatalmanagement based on echocardio- graphic and sonographic evaluation.Prenat Diagn 11:235244, 1991. French CA, Bieber FR, Bing DH, etal.: Twins, placentas, and genetics: acar- diac twinning in adichorionic, diamniotic, monozygotic twin gestation. Hum Pathol29:10281031, 1998. Hanafy A, Peterson CM: Twin-reversed arterialperfusion (TRAP) sequence: case reports and review of literature.Aust N Z J Obstet Gynaecol 37:187191, 1997. Healey MG: Acardia:predictive risk factors for the co-twins survival. Teratology50:205213, 1994. Sanjaghsaz H, Bayram MO, Qureshi F: Twin reversedarterial perfusion sequence in conjoined, acardiac, acephalic twinsassociated with a normal triplet. A case report. J Reprod Med43:10461050, 1998. Sgaard K, Skibsted L, Brocks V: Acardiac twins:Pathophysiology, diagnosis, outcome and treatment. Six cases andreview of the literature. Fetal Diagn Ther 14:5359, 1999. Van AllenMI, Smith DW, Shepard TH: Twin reversed arterial perfusion (TRAP)sequence: a study of 14 twin pregnancies with acardius. SeminPerinatol 7:285293, 1983.
13. 13. Fig. 1. Ventral view of an acardiac acephalus fetus (upperphoto) 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 endand relatively well- developed lower limbs. The co-twin had majormalformations consist- ing of a large omphalocele, ectopia cordis,and absent pericardium, incompatible with life. Fig. 2. Radiographsof the above acardiac fetus showing a missing head, cervicalvertebrae and part of upper thoracic vertebrae, rudimen- tal lowerribs, malformed lower thoracic and lumbar vertebrae, and relativelywell-formed lower limbs. ACARDIA 5 Fig. 3. The head and part of thethorax of this acardiac fetus are com- pletely missing withrelatively well-formed lower limbs.
14. 14. Fig. 4. Another acardiac fetus with a missing head and partof the upper thorax. Radiograph shows missing head, and cervicaland part of thoracic vertebrae and ribs. Pelvis and lower limbs arewell formed. Fig. 5. Acardius (second twin, 36-weeks gestation)showing spherical body with a small amorphous mass ofleptomeningeal and glial tissue at the cephalic end. There were onedeformed lower extremity and a small arm appendage. Smallintestinal loops, nodules of adrenal glands, and testicl*s werepresent in the body. There was no heart or lungs. The placenta wasnonoamniotic monochorionic with velamen- tous insertion of theumbilical cord. The other identical twin was free of birth defects.Radiograph of acardius twin shows a short segment of the spine, afemur, a tibia, and a fibula. 6 ACARDIA
15. 15. Achondrogenesis is a heterogeneous group of lethal chon-drodysplasias. Achondrogenesis type I (Fraccaro-Houston-Harristype) and type II (Langer-Saldino type) were distinguished on thebasis of radiological and histological criteria. Achondrogenesistype I was further subdivided, on the basis of convincing histo-logical criteria, into type IA, which has apparently normal car-tilage matrix but inclusions in chondrocytes, and type IB, whichhas an abnormal cartilage matrix. Classification of type IB as aseparate group has been confirmed recently by the dis- covery ofits association with mutations in the diastrophic dys- plasiasulfate transporter (DTDST) gene, making it allelic withdiastrophic dysplasia. GENETICS/BASIC DEFECTS 1. Type IA: anautosomal recessive disorder with an unknown chromosomal locus 2.Type IB a. An autosomal recessive disorder b. Resulting frommutations of the DTDST gene, which is located at 5q32-q33 3. TypeII a. Autosomal dominant type II collagenopathy b. Resulting frommutations in the COL2A1 gene, which is located at 12q13.1-q13.3CLINICAL FEATURES 1. Prenatal/perinatal history a. Polyhydramniosb. 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 foreheadiv. Convex facial plane v. Flat nasal bridge, occasionallyassociated with a deep horizontal groove vi. Small nose, often withanteverted 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. Shortand barrel-shaped thorax ii. Lung hypoplasia e. Heart i. Patentductus arteriosus ii. Atrial septal defect iii. Ventricular septaldefect 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 hypoplasiae. Protuberant abdomen f. Extremely short limbs (micromelia)DIAGNOSTIC INVESTIGATIONS 1. Radiological features a. Variablefeatures b. No single obligatory feature c. Distinction betweentype IA and type IB on radi- ographs not always possible d. Degreeof ossification: age dependent, and caution is needed whencomparing radiographs at different ges- tational ages e.Achondrogenesis type I i. Skull: Varying degree of deficientcranial ossifi- cation consisting of small islands of bone inmembranous calvaria ii. Thorax and ribs a) Short and barrel-shapedthorax b) Thin ribs with marked expansion at costo- chondraljunction, frequently with multiple fractures iii. Spine and pelvisa) Poorly ossified spine, ischium, and pubis b) Poorly ossifiediliac bones with short medial margins 7 Achondrogenesis
16. 16. 8 ACHONDROGENESIS iv. Limbs and tubular bones a) Extrememicromelia, with limbs much shorter than in type II b) Prominentspike-like metaphyseal spurs c) Femur and tibia frequentlypresenting as short bone segments v. Subtype IA (Houston-Harristype) a) Poorly ossified skull b) Thin ribs with multiple fracturesc) Unossified vertebral pedicles d) Arched ilium e) Hypoplastic butossified ischium f) Wedged femur with metaphyseal spikes g) Shorttibia and fibula with metaphyseal flare vi. Subtype IB (Fraccarotype) a) Adequately ossified skull b) Absence of rib fractures c)Total lack of ossification or only rudimentary calcification of thecenter of the vertebral bodies d) Ossified vertebral pedicles e)Iliac bones with ossification only in their upper part, giving acrescent-shaped, paraglider- like appearance on X-ray f) Unossifiedischium g) Shortened tubular bones without recognized axis h)Metaphyseal spurring giving the appearance of a thorn apple oracanthocyte (a descrip- tive term in hematology) i) Trapezoid femurj) Stellate tibia k) Unossified fibula l) Poorly ossified phalangesf. Achondrogenesis type II i. Skull a) Normal cranial ossificationb) Relatively large calvaria ii. Thorax and ribs a) Short andflared thorax b) Bell-shaped cage c) Shorter ribs without fracturesiii. Spine and pelvis: relatively well-ossified iliac bones withlong, crescent-shaped medial and inferior margins iv. Limbs andtubular bones a) Short, broad bones, usually with some dia- physealconstriction and flared, cupped metaphyseal ends b) Metaphysealspurs, usually smaller than type I 2. Histologic features a.Achondrogenesis type IA i. Normal cartilage matrix ii. Absentcollagen rings around the chondrocytes iii. Vacuolated chondrocytesiv. Presence of intrachondrocytic inclusion bodies (periodicacid-Schiff [PAS] stain positive, dia- stase resistant) v.Extraskeletal cartilage involvement vi. Enlarged lacunas vii. Wovenbone b. Achondrogenesis type IB i. Abnormal cartilage matrix:presence of demasked coarsened collagen fibers, particu- larlydense around the chondrocytes, forming collagen rings ii. Abnormalstaining properties of cartilage a) Reduced staining with cationicdyes, such as toluidine blue or Alcian blue, probably because of adeficiency in sulfated proteo- glycans b) This distinguishes typeIB from type IA, in which the matrix is close to normal andinclusions can be seen in chondrocytes, and from achondrogenesistype II, in which cationic dyes give a normal staining pattern c.Achondrogenesis type II i. Cartilage a) Slightly larger than normalb) Grossly distorted (lobulated and mush- roomed) ii. Markedlydeficient cartilaginous matrix iii. Severe disturbance inendochondral ossification iv. Hypercellular and hypervascularreserve cartilage with large, primitive mesenchymal (ballooned)chondrocytes with abundant clear cytoplasm (vacuoles) (Swisscheese-like) v. Overgrowth of membranous bones resulting in cuppingof the epiphyseal cartilages vi. Decreased amount and alteredstructure of pro- teoglycans vii. Relatively lower content ofchondroitin 4-sulfate viii. Lower molecular weight and decreasedtotal chondroitin sulfation ix. Absence of type II collagen x.Increased amounts of type I and type III collagen 3. Biochemicaltesting a. Lack of sulfate incorporation: cumbersome and not usedfor diagnostic purposes b. Sulfate incorporation assay in culturedskin fibrob- lasts or chondrocytes: recommended in the rareinstances in which the diagnosis of achondrogenesis type IB isstrongly suspected but molecular genetic testing fails to detectSLC26A2 (DTDST) mutations 4. Molecular genetic studies a. Mutationanalysis of the DTDST gene, reported in: i. Achondrogenesis type IB(the most severe form) ii. Atelosteogenesis type II (anintermediate form) iii. Diastophic dysplasia (the mildest form) iv.Recessive multiple epiphyseal dysplasia b. Achondrogenesis type IBi. Mutation analysis: testing of the following four most commonSLC26A2 (DTDST) gene muta- tions (mutation detection rate about60%) a) R279W b) IVS1+2T>C (Finnish mutation) c) delV340 d)R178X
17. 17. ACHONDROGENESIS 9 ii. Sequence analysis of the SLC26A2(DTDST) coding region (mutation detection rate over 90%) a) Privatemutations b) Common mutations c. Achondrogenesis type II: mutationanalysis of the COL2A1 gene GENETIC COUNSELING 1. Recurrence riska. Patients sib i. Achondrogenesis type IA and type IB (autoso- malrecessive disorders) a) Recurrence risk: 25% b) Unaffected sibs ofa proband: 2/3 chance of being heterozygotes ii. Achondrogenesistype II a) Usually caused by a new dominant muta- tion, in whichcase recurrence risk is not sig- nificantly increased b)Asymptomatic carrier parent (germline mutation for a dominantmutation) may be present in the families of affected patients, inwhich case recurrence risk is 50% b. Patients offspring: lethalentities 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. Anarrow thorax vii. Short limbs viii. Poor ossification of vertebralbodies and limb tubular bones (leading to difficulties in determin-ing their length) ix. Suspect achondrogenesis type I a) Anextremely echo-poor appearance of the skeleton b) A poorlymineralized skull c) Short limbs d) Rib fractures b. Moleculargenetic studies i. Prenatal diagnosis of achondrogenesis type IBand type II by mutation analysis of chorionic vil- lus DNA oramniocyte DNA in the first or sec- ond trimester ii.Achondrogenesis type IB a) Characterize both alleles of DTDSTbefore- hand b) Identify the source parent of each allele c)Theoretically, analysis of sulfate incorpora- tion in chorionicvilli might be used for pre- natal diagnosis, but experience islacking iii. Achondrogenesis type II a) The affected fetus usuallywith a new domi- nant mutation of the COL2A1 gene b) Possiblepresence of asymptomatic carriers in families of an affectedpatient c) Prenatal diagnosis possible if the mutation has beencharacterized in the affected family 3. Management a. Supportivecare b. No treatment available for the underlying lethal disorderREFERENCES Balakumar K: Antenatal diagnosis of Parenti-Fraccarotype achondrogenesis. Indian Pediatr 27:496499, 1990. Bonaf L,Ballhausen D, Superti-Furga A: Achondrogenesis type 1B. Genereviews, 2004. http://www.genetests.org Borochowitz Z, Lachman R,Adomian GE, et al.: Achondrogenesis type I: delineation of furtherheterogeneity and identification of two distinct sub- groups. JPediatr 112:2331, 1988. Borochowitz Z, Ornoy A, Lachman R, et al.:Achondrogenesis II-hypochondro- genesis: variability versusheterogeneity. Am J Med Genet 24:273288, 1986. Benacerraf B,Osathanondh R, Bieber FR: Achondrogenesis type I: ultrasounddiagnosis in utero. J Clin Ultrasound 12:357359, 1984. Chen H:Achondrogenesis. Emedicine, 2001. http://www.emedicine.com Chen H:Skeletal dysplasia. Emedicine, 2002. http://www.emedicine.com ChenH, Liu CT, Yang SS: Achondrogenesis: a review with specialconsidera- tion of achondrogenesis type II (Langer-Saldino). Am JMed Genet 10:379394, 1981. Faivre L, Le Merrer M, Douvier S, etal.: Recurrence of achondrogenesis type II within the same family:Evidence for germline mosaicism. Am J Med Genet 126A:308312, 2004.Godfrey M, Hollister DW: Type IIachondrogenesis-hypochondrogenesis: identi- fication of abnormaltype II collagen. Am J Hum Genet 43:904913, 1988. Horton WA,Machado MA, Chou JW, et al.: Achondrogenesis type II, abnor-malities of extracellular matrix. Pediatr Res 22:324329, 1987. KrkkJ, Cohn DH, Ala-Kokko L, et al.: Widely distributed mutations inthe COL2A1 gene produce achondrogenesis type II/hypochondrogenesis.Am J Med Genet 92:95100, 2000. Langer LO, Jr, Spranger JW,Greinacher I, et al.: Thanatophoric dwarfism. A condition confusedwith achondroplasia in the neonate, with brief com- ments onachondrogenesis and hom*ozygous achondroplasia. Radiology 92:285294passim, 1969. Meizner I, BarnhardY: Achondrogenesis type Idiagnosed by transvagin*l ultra- sonography at 13 weeks gestation.Am J Obstet Gynecol 173:16201622, 1995. Molz G, Spycher MA:Achondrogenesis type I: light and electron-microscopic studies. EurJ Pediatr 134:6974, 1980. Mortier GR, Wilkin DJ, Wilcox WR, et al.:A radiographic, morphologic, bio- chemical and molecular analysisof a case of achondrogenesis type II resulting from substitutionfor a glycine residue (Gly691>Arg) in the type II collagentrimer. Hum Mol Genet 4:285288, 1995. Ornoy A, Sekeles E, Smith P,et al.: Achondrogenesis type I in three sibling fetuses. Scanningand transmission electron microscopic studies. Am J Pathol 82:7184,1976. Smith WL, Breitweiser TD, Dinno N: In utero diagnosis ofachondrogenesis, type I. Clin Genet 19:5154, 1981. Soothill PW,Vuthiwong C, Rees H: Achondrogenesis type 2 diagnosed by trans-vagin*l ultrasound at 12 weeks gestation. Prenat Diagn 13:523528,1993. Spranger J: International classification ofosteochondrodysplasias. Eur J Pediatr 151:407415, 1992. Spranger J,Winterpacht A, Zabel B: The type II collagenopathies: a spectrum ofchondrodysplasias. Eur J Pediatr 153:5665, 1994. Superti-Furga A:Achondrogenesis type 1B. J Med Genet 33:957961, 1996. Superti-FurgaA, Hstbacka J, Wilcox WR, et al.: Achondrogenesis type IB is causedby mutations in the diastrophic dysplasia sulphate transportergene. Nat Genet 12:100102, 1996. Superti-Furga A, Rossi A,Steinmann B, et al.: A chondrodysplasia family pro- duced bymutations in the diastrophic dysplasia sulfate transporter gene:genotype/phenotype correlations. Am J Med Genet 63:144147,1996.
18. 18. 10 ACHONDROGENESIS Tongsong T, Srisomboon J, Sudasna J:Prenatal diagnosis of Langer-Saldino achondrogenesis. J ClinUltrasound 23:5658, 1995. van der Harten HJ, Brons JT, Dijkstra PF,et al.: Achondrogenesis-hypochon- drogenesis: the spectrum ofchondrogenesis imperfecta. A radiological, ultrasonographic, andhistopathologic study of 23 cases. Pediatr Pathol 8:571597, 1988.Yang SS, Bernstein J: Letter: Proposed readjustment of eponyms forachondro- genesis. J Pediatr 87:333334, 1975. Yang S-S,Heidelberger KP, Brough AJ, et al.: Lethal short-limbed chondrodys-plasia in early infancy. Persp Pediatr Pathol 3:140, 1976. Yang SS,Bernstein J: Achondrogenesis type I. Arch Dis Child 52:253254,1977. Yang SS, Gilbert-Barnes E: Skeletal system. In:Gilbert-Barness E (ed): Potters Pathology of the Fetus and Infant.St Louis: Mosby, 1997, pp 14231478. Yang SS, Brough AJ, Garewal GS,et al.: Two types of heritable lethal achon- drogenesis. J Pediatr85:796801, 1974. Yang SS, Heidelberger KP, Bernstein J:Intracytoplasmic inclusion bodies in the chondrocytes of type Ilethal achondrogenesis. Hum Pathol 7:667673, 1976.
19. 19. ACHONDROGENESIS 11 Fig. 1. A neonate with achondrogenesistype I showing large head, short trunk, and extreme micromelia.Radiograph shows unossified calvarium, vertebral bodies and somepelvic bones. The remaining bones are extremely small. There aremultiple rib fractures. The sagit- tal section of the femora andthe humeri are similar. An extremely small ossified shaft is cappedby a relatively large epiphyseal cartilage at both ends.Photomicrographs of resting cartilage with high magni- ficationshow many chondrocytes that contain large cytoplasmic inclusionswhich are within clear vacuoles (Diastase PAS stain). Electronmicrograph shows inclusion as a globular mass of electron densematerial. It is within a distended cistern of rough endoplasmicreticulum.
20. 20. 12 ACHONDROGENESIS Fig. 2. Achondrogenesis type II. As intype I, this neonate shows large head, short trunk, and micromelia.Sagittal section of the femur shows much better ossification of theshaft than type I. The cartilage lacks glis- tering appearance dueto cartilage matrix deficiency. Photomicrograph of the entirecartilage shows severe deficiency of cartilage matrix. Thecartilage canals are large, fibrotic, and stellate in shape.Physeal growth zone is severely retarded.
21. 21. ACHONDROGENESIS 13 Fig. 3. Two infants with achondrogenesistype II showing milder spec- trum of manifestations, bordering thetype II and spondyloepiphyseal congenita.
22. 22. 14 ACHONDROGENESIS Fig. 4. A newborn girl withachondrogenesis type II showing large head, midfacial hypoplasia,short neck, small chest, and short limbs. The radi- ographs showsgeneralized shortening of the long bones of the upper and lowerextremities with marked cupping (metaphyseal spurs) at the meta-physeal ends of the bones. This is most evident at the distal endsof the tibia, fibular, radius and ulna, and distal ends of thedigits. Radiographs also shows short ribs without fractures andhemivertebrae involving thoracic vertebrae as well as the sacrum.Conformation-sensitive gel electrophoresis analysis indicated asequence variation in the fragment containing exon 19 and theflanking sequences of the COL2A1 gene (Gly244Asp). Similarmutations in this area have been seen in patients diagnosed withhypochondroplasia and achondrogenesis type II.
23. 23. Achondroplasia is the most common form of short-limbeddwarfism. 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 10,000births. The mutation rate is high and is estimated to be between1.72105 and 5.57105 per gamete per generation. Most infants withachondroplasia are born unexpectedly to parents of average stature.GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominantdisorder with complete pene- trance b. Sporadic in about 80% of thecases, the result of a de novo mutation c. Presence of paternal ageeffect (advanced paternal age in sporadic cases) d. Gonadalmosaicism (two or more children with clas- sic achondroplasia bornto normal parents) 2. Caused by mutations in the gene of thefibroblast 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 inthe substitution of an argi- nine residue for a glycine at position380 (G380A) of the mature protein in the transmembrane domain ofFGFR3 b. A rare mutation causing substitution of a nearby glycine375 with a cysteine (G375C) c. Another rare mutation causingsubstitution of glycine346 with glutamic acid (G346E) d. Thespecific mechanisms by which FGFR3 mutations disrupt skeletaldevelopment in achondroplasia remain elusive 3. Basic defect: zoneof chondroblast proliferation in the physeal growth plates a.Abnormally retarded endochondral ossification with resultantshortening of tubular bones and flat verte- bral bodies, whilemembranous ossification (skull, facial bones) is not affected b.Physeal growth zones show normal columnization, hypertrophy,degeneration, calcification, and ossifica- tion. However, thegrowth is quantitatively reduced significantly c. Achondroplasia asthe result of a quantitative loss of endochondral ossificationrather than the formation of abnormal tissue d. Normal diameter ofthe bones secondary to normal subperiosteal membranous ossificationof tubular bones; the results being production of short, thicktubular bones, leading to short stature with dispropor- tionatelyshortened limbs CLINICAL FEATURES 1. Major clinical symptoms a.Delayed motor milestones during infancy and early childhood b.Sleep disturbances secondary to both neurological and respiratorycomplications c. Breathing disorders i. A high prevalence (75%) ofbreathing disorders during sleep ii. Obstructive apnea caused byupper airway obstruction iii. The majority of respiratorycomplaints due to restrictive lung disease secondary to diminishedchest size or upper airway obstruction and rarely due to spinalcord compression d. Symptomatic spinal stenosis in more than 50% ofpatients 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 30seconds e. Neurologic symptoms classified based on neurologicseverity and presentation of spinal stenosis (Lutter and Langer,1977) i. Type I (back pain with sensory and motor change of aninsidious nature) ii. Type II (intermittent claudication limitingambu- lation) iii. Type III (nerve root compression) iv. Type IV(acute onset paraplegia) f. Symptoms secondary to foramen magnumstenosis i. Respiratory difficulty ii. Feeding problems iii.Cyanosis, quadriparesis iv. Poor head control g. Symptoms secondaryto cervicomedullary compression i. Pain ii. Ataxia iii.Incontinence iv. Apnea v. Progressive quadriparesis vi. Respiratoryarrest 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, documentedby CT d. Foramen magnum stenosis considered as the cause ofincreased incidence of: 15 Achondroplasia
24. 24. 16 ACHONDROPLASIA i. Hypotonia ii. Sleep apnea iii. Suddeninfant death syndrome e. Symptomatic hydrocephalus in infancy andearly child- hood rarely due to narrowing of the foramen magnum f.Characteristic craniofacial appearance i. Disproportionately largehead ii. Frontal bossing iii. Depressed nasal bridge iv. Midfacialhypoplasia v. Narrow nasal passages vi. Prognathism vii. Dentalmalocclusion g. A normal trunk length h. A thoracolumbar kyphosisor gibbus usually present at birth or early infancy i. Exaggeratedlumbar lordosis when the child begins to ambulate j. Prominentbuttocks and protuberant abdomen sec- ondary to increased pelvictilt in children and adults k. Generalized joint hypermobility,especially the knees l. Rhizomelic micromelia (relatively shorterproximal segment of the limbs compared to the middle and the distalsegments) m. Limited elbow and hip extension n. Trident hands(inability to approximate the third and fourth fingers in extensionproduces a trident con- figuration of the hand) o. Short fingers(brachydactyly) p. Bowing of the legs (genu varum) due to lax kneelig- aments q. Excess skin folds around thighs 3.Complications/risks a. Recurrent otitis media during infancy andchildhood i. Conductive hearing loss ii. Delayed languagedevelopment b. Thoraco-lumbar gibbus c. Osteoarthropathy of theknee joints d. Neurological complications i. Small foramen magnumii. Cervicomedullary junction compression causing sudden unexpecteddeath in infants with achon- droplasia iii. Apnea iv. Communicatinghydrocephalus v. Spinal stenosis vi. Paraparesis vii. Quadriparesisviii. Infantile hypotonia e. Obesity i. Aggravating the morbidityassociated with lum- bar stenosis ii. Contributing to thenonspecific joint problems and to the possible early cardiovascularmortal- ity in this condition f. Obstetric complications i. Largehead of the affected infant ii. An increased risk of intracranialbleeding during delivery iii. Marked obstetrical difficultiessecondary to very narrow pelvis of achondroplastic women 4.Prognosis a. Normal intelligence and healthy, independent, andproductive lives in vast majority of patients. Rarely, intelligencemay be affected because of hydro- cephalus or other CNScomplications b. Mean adult height i. Approximately 131 5.6 cm formales ii. Approximately 124 5.9 cm for females c. Psychosocialproblems related to body image because of severe disproportionateshort stature d. Life- span for heterozygous achondroplasia i.Usually normal unless there are serious compli- cations ii. Meanlife expectancy approximately 10 years less than the generalpopulation e. hom*ozygous achondroplasia i. A lethal condition withsevere respiratory dis- tress caused by rib-cage deformity andupper cervical cord damage caused by small foramen magnum. Thepatients die soon after birth ii. Radiographic changes much moresevere than the heterozygous achondroplasia f. Normal fertility inachondroplasia i. Pregnancy at high risk for achondroplastic womenii. Respiratory compromise common during the third trimester iii.Advise baseline pulmonary function studies before pregnancy to aidin evaluation and man- agement iv. A small pelvic outlet usuallyrequiring cesarean section under general anesthesia since thespinal or epidural approach is contraindicated because of spinalstenosis g. Anticipatory guidance: patients and their families canbenefit greatly from anticipatory guidance published by AmericanAcademy of Pediatrics Committee on Genetics (1995) h. Adaptationsof patients to the environment to foster independence i. Loweringfaucets and light switches ii. Using a step stool to keep feet fromdangling when sitting iii. An extended wand for toileting iv.Adaptations of toys for short limbs i. Support groups: Manyfamilies find it beneficial to interact with other families andchildren with achon- droplasia through local and national supportgroups DIAGNOSTIC INVESTIGATIONS 1. Diagnosis of achondroplasiamade by clinical findings, radiographic features, and/or FGFR3mutation analysis 2. Radiologic features a. Skull i. Relativelylarge calvarium ii. Prominent forehead iii. Depressed nasal bridgeiv. Small skull base v. Small foramen magnum vi. Dentalmalocclusion
25. 25. ACHONDROPLASIA 17 b. Spine i. Caudal narrowing ofinterpedicular distances in the lower lumbar spine ii. Shortvertebral pedicles iii. Wide disc spaces iv. Dorsal scalloping ofthe vertebral bodies in the newborn v. Concave posterior aspect ofthe vertebral bodies in childhood and adulthood vi. Differentdegree of anterior wedging of the ver- tebral bodies causing gibbusc. 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 theproximal humerus and femur during infancy iii. Tubular bones withwidened diaphyses and flared metaphyses during childhood andadulthood 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. Effacementof the subarachnoid spaces at the cervi- comedullary junction c.Abnormal intrinsic cord signal intensity d. Mild-to-moderateventriculomegaly 4. Histology a. Normal histologic appearance ofepiphyseal and growth plate cartilages b. Shorter than normalgrowth plate: the shortening is greater in hom*ozygous than inheterozygous achon- droplasia, suggesting a gene dosage effect 5.Mutation analysis a. G1138A substitution in FGFR3 (about 98% ofcases) b. G1138C substitution in FGFR3 (about 1% of cases) GENETICCOUNSELING 1. Recurrence risk a. Patients sib i. Recurrence risk ofachondroplasia in the sibs of achondroplastic children withunaffected par- ents: presumably higher than twice the mutationrate because of gonadal mosaicism. Currently, the risk is estimatedas 1 in 443 (0.2%) ii. 50% affected if one of the parents isaffected iii. 25% affected with hom*ozygous achondroplasia(resulting in a much more severe phenotype that is usually lethalearly in infancy) and 50% affected with heterozygous achondroplasiaif both parents are affected with achondroplasia b. Patientsoffspring i. 50% affected (with heterozygous achondropla- sia) ifthe spouse is normal ii. 25% affected with hom*ozygousachondroplasia and 50% affected with heterozygous achondropla- siaif the spouse is also affected with achondropla- sia. There isstill a 25% chance that the offspring will be normal 2. Prenataldiagnosis a. Prenatal ultrasonography i. Suspect achondroplasia onroutine ultrasound findings of a fall-off in limb growth, usuallydur- ing the third trimester of pregnancy, in case of parents withnormal heights. About one-third of cases are suspected this way.However, one must be cautious because disproportionately shortlimbs are observed in a variety of conditions ii. Inability to makespecific diagnosis of achon- droplasia with certainty byultrasonography unless by radiography late in gestation or afterbirth iii. Request of prenatal ultrasonography by an affectedparent, having 50% risk of having a similarly affected child, tooptimize obstetric management iv. Follow pregnancy by a femoralgrowth curve in the second trimester by serial ultrasound scans toenable prenatal distinction between hom*ozy- gous, heterozygous, andunaffected fetuses, in case of both affected parents b. Prenatalmolecular testing i. Molecular technology applied to prenatal diag-nosis of a fetus suspected of or at risk for having achondroplasiaii. Simple methodology requiring only one PCR and one restrictiondigest to detect a very limited number of mutations causingachondroplasia iii. Preimplantation genetic diagnosis a) Availableat present (Montou et al., 2003) b) The initial practice raisingquestions on the feasibility of such a test, especially withaffected female patients 3. Management a. Adaptive environmentalmodifications i. Appropriately placed stools ii. Seatingmodification iii. Other adaptive devices b. Obesity control c.Obstructive apnea i. Adenoidectomy and tonsillectomy ii. Continuouspositive airway pressure (CPAP) and bilevel positive airwaypressure (BiPAP) for clin- ically significant persistentobstruction iii. Extremely rare for requiring temporary tra-cheostomy d. Experimental growth hormone therapy resulting intransient increases in growth velocity e. Hydrocephalus i.Observation for benign ventriculomegaly ii. May need surgicalintervention for clinically sig- nificant hydrocephalus f. Kyphosisi. Adequate support for sitting in early infancy ii. Bracing usinga thoracolumbosacral orthosis for severe kyphosis in young childreniii. Surgical intervention for medically unrespon- sive cases
26. 26. 18 ACHONDROPLASIA g. Surgical decompression for unequivocalevidence for cervical cord compression h. Decompression laminectomyfor severe and progres- sive lumbosacral spinal stenosis i. Limblengthening 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 theirfamilies for the time in the hospital and the number of operationsb) Occurrence of possible severe permanent sequelae j. Potentialanesthetic risks related to: i. Obstructive apnea ii. Cervicalcompression k. Risks associated with pregnancy in women withachondroplasia: relatively infrequent i. Worsening neurologicsymptoms related to increasing hyperlordosis and maternalrespiratory failure ii. Anticipate a scheduled cesarean deliverydue to cephalopelvic disproportion iii. Preeclampsia iv.Polyhydramnios REFERENCES Allanson JE, Hall JG: Obstetrics andgynecologic problems in women with chondrodystrophies. ObstetGynecol 67:7478, 1986. American Academy of Pediatrics Committee onGenetics: Health supervision for children with achondroplasia.Pediatrics 95:443451, 1995. Bellus GA, Hefferon TW, Ortiz de LunaRI, et al.: Achondroplasia is defined by recurrent G380R mutationsof FGFR3.Am J Hum Genet 56:368373, 1995. Chen H, Mu X, Sonoda T, etal.: FGFR3 gene mutation (Gly380Arg) with achondroplasia and i(21q)Down syndrome: phenotype-genotype correla- tion. South Med J93:622624, 2000. Francomano CA:Achondroplasia. Gene Reviews, 2003.http:// www.genetests.org Fryns JP, Kleczkowska A, Verresen H, etal.: Germinal mosaicism in achon- droplasia: a family with 3affected siblings of normal parents. Clin Genet 24:156158, 1983.Hall JG: The natural history of achondroplasia. In: Nicoletti B,Kopits SE, Ascani E, et al. (eds): Human Achondroplasia: AMultidisciplinary Approach. New York: Plenum Press, 1988 pp 310.Hall JG, Dorst J, Taybi H, et al.: Two probable cases ofhom*ozygosity for the achondroplasia gene. Birth Defects Orig ArtSer V(4):2434, 1969. Hecht JT, Butler IJ: Neurologic morbidityassociated with achondroplasia. J Child Neurol 5:8497, 1990. HechtJT, Francomano CA, Horton WA et al.: Mortality in achondroplasia.Am J Hum Genet 41:454464, 1987. Henderson S, Sillence D, LoughlinJ, et al.: Germline and somatic mosaicism in achondroplasia. J MedGenet 37:956958, 2000. Horton WA: Molecular genetic basis of thehuman chondrodysplasias. Endocr Metabol Clin 25:683697, 1996.Horton WA: Fibroblast growth factor receptor 3 and the humanchondrodys- plasias. Curr Opin Pediatr 9:437442, 1997. Horton WA,Rotter JI, Rimoin DL, et al.: Standard growth curves for achon-droplasia. J Pediatr 93:435438, 1978. Horton WA, Hood OJ, MachadoMA, et al.: Growth plate cartilage studies in achondroplasia. In:Nicoletti B, Kopits SE, Ascani E, et al. (eds): HumanAchondroplasia: A Multidisciplinary Approach. New York: PlenumPress 1988, pp 8189. Horton WA, Hecht JT, Hood OJ, et al.: Growthhormone therapy in achon- droplasia. Am J Med Genet 42: 667670,1992. Hunter AGW, Hecht JT, Scott CI: Standard weight for heightcurves in achon- droplasia. Am J Med Genet 62:255261, 1996. HunterAGW, Bankier A, Rogers JG, et al.: Medical complications of achon-droplasia: a multicenter patient review. J Med Genet 35:705712,1998. Kornblum M, Stanitski DF: Spinal manifestations of skeletaldysplasias. Orthop Clin N Amer 30:501520, 1999. Langer LO Jr,Baumann PA, Gorlin RJ: Achondroplasia. Am J Roentgen 100:1226,1967. Lattanzi DR, Harger JH: Achondroplasia and pregnancy. JReprod Med 27:363366, 1982. Mettler G, Fraser FC: Recurrence riskfor sibs of children with sporadic achondroplasia. Am J Med Genet90:250, 251, 2000. Mogayzel PJ Jr, Carroll JL, Loughlin GM, et al.:Sleep-disordered breathing in children with achondroplasia. JPediatr 132:667671, 1998. Moutou C, Rongieres C, Bettahar-LebugleK, et al.: Preimplantation genetic diagnosis for achondroplasia:genetics and gynaecological limits and dif- ficulties. Hum Reprod18:509514, 2003. Overlaid F, Danks DM, Jensen F, et al.:Achondroplasia and hypochondropla- sia. Comments on frequency,mutation rate, and radiological features in skull and spine. J MedGenet 16:140146, 1979. Patel MD, Filly RA: hom*ozygousachondroplasia: US distinction between hom*ozygous, heterozygous,and unaffected fetuses in the second trimester. Radiology196:541545, 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 25:857859,1988. Pierre-Kahn A, Hirsch JF, Renier D, et al.: Hydrocephalus andachondroplasia. A study of 25 observations. Childs Brain 7:205219,1980. Prinos P, Kilpatrick MW, Tsipouras P, et al.: A novel G346Emutation in achon- droplasia. Pediatr Res 37:151, 1994. Rimoin DL:Limb lengthening: past, present, and future. Growth Genet Hormones7:46, 1991. Rousseau F, Bonaventure J, Legeal-Mallet L, et al.:Mutations in the gene encoding fibroblast growth factor receptor-3in achondroplasia. Nature 371:252254, 1994. Shiang R, Thompson LM,Zhu Y-Z, et al.: Mutations in the transmembrane domain of FGFR3cause the most common genetic form of dwarfism, achondroplasia.Cell 78:335342, 1994. Shohat M, Tick D, Barakat S, et al.:Short-term recombinant human growth hormone treatment increasesgrowth rate in achondroplasia. J Clin Endocr Metab 81:40334037,1996. Spranger JW, Langer LO Jr, Wiedemann HR: Bone dysplasias.Anatlas of con- stitutional disorders of skeletal development.Philadelphia: WB Saunders Co., 1974. Todorov AB, Scott CI, WarrenAE, et al.: Developmental screening tests in achondroplasticchildren. Am J Med Genet. 9:1923, 1981. Vajo Z, Francomano CA,Wilkin DJ: The molecular and genetic basis of fibrob- last growthfactor receptor 3 disorders: The achondroplasia family of skeletaldysplasias, Muenke craniosynostosis, and Crouzon syndrome withacanthosis nigricans. Endocr Rev 21:2339, 2000. Velinov M,Slaugenhaupt SA, Stoilov I, et al.: The gene for achondroplasiamaps to the telomeric region of chromosome 4p. Nature Genet6:318321, 1994. Yang SS, Corbett DP, Brough AJ, et al.: Uppercervical myelopathy in achon- droplasia. Am J Clin Path 68:6872,1977. Yang SS, Gilbert-Barnes E: Skeletal system. In:Gilbert-Barness E (ed): Potters Pathology of the Fetus and Infant.St Louis: Mosby, 1997, pp 14231478. Yasui N, Kawahata H, KojimotoH, et al.: Lengthening of the lower limbs in patients withachondroplasia and hypochondroplasia. Clin Orthop 344:298306, 1997.Zucconi M, Weber G, Castronova V, et al.: Sleep and upper airwayobstruction in children with achondroplasia. J Pediatr 129:743749,1996.
27. 27. ACHONDROPLASIA 19 Fig. 1. A newborn with achondroplasiashowing large head, depressed nasal bridge, short neck, normallength of the trunk, narrow chest, rhi- zomelic micromelia, andtrident hands. The radiographs showed nar- row chest,characteristic pelvis, micromelia, and oval radiolucent proximalportion of the femurs. Molecular analysis showed 1138GC mutation.Fig. 2. A 4-month-old boy with achondroplasia showing typicalcranio- facial features and rhizomelic shortening of limbs(confirmed by radi- ograms). Molecular study revealed 1138 G-to-Atransition mutation.
28. 28. 20 ACHONDROPLASIA Fig. 3. Another achondroplastic neonatewith typical clinical features and radiographic findings. Note theabnormal vertebral column with wide intervertebral spaces andabnormal vertebral bodies. Fig. 4. A boy (7 month and 2 year 7month old) with achondroplasia showing a large head, small chest,normal size of the trunk, rhizomelic micromelia, and exaggeratedlumbar lordosis. Fig. 5. Two older children with achondroplasiashowing rhizomelic micromelia, typical craniofacial features,exaggerated lumbar lordosis, and trident hands.
29. 29. ACHONDROPLASIA 21 Fig. 6. A boy with achondroplasia andi(21q) Down syndrome pre- sented with diagnostic dilemma. Besidescraniofacial features typical for Down syndrome, the skeletalfindings of achondroplasia dominate the clinical picture. Thediagnosis of Down syndrome was based on the clinical features andthe cytogenetic finding of i(21q) trisomy 21. The diagnosis ofachondroplasia was based on the presence of clini- cal andradiographic findings, and confirmed by the presence of a commonFGFR3 gene mutation (Gly380Arg) detected by restriction enzymeanalysis and sequencing of the PCR products.
30. 30. 22 ACHONDROPLASIA Fig. 7. Schematic of the FGFR3 gene andDNA sequence of normal allele and mutant FGFR3 achondroplasiaallele (modified from Shiang et al., 1994). Fig. 8. Nucleotidechange in the 1138C allele creates a Msp1 site and nucleotidechange in the 1138A allele creates a Sfc1. The base in the codingsequence that differs in the three alleles is boxed (modified fromShiang et al., 1994). Fig. 9. hom*ozygous achondroplasia. Bothparents are achondroplas- tic. The large head, narrow chest, andsevere rhizomelic shortening of the limbs are similar to those ofthanatophoric dysplasia. Radiograph shows severe platyspondyly,small ilia, and short limb bones. Photomicrograph of the physealgrowth zone shows severe retardation and disorganization, similarto that of thanatophoric dysplasia.
31. 31. In 1945, Adams and Oliver described congenital transverselimb defects associated with aplasia cutis congenita in a three-generation kindred with typical autosomal dominant inheri- tanceand 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. Vasculardisruption sequence i. Concomitant occurrence of Poland sequenceii. Both Poland sequence and Adams-Oliver syn- drome: secondary tovascular disruption due to thrombosis of subclavian and vertebralarteries e. Massive thrombus from the placenta occluding thebrachial artery f. Abnormalities in small vessel structuresmanifesting during embryogenesis g. A developmental disorder ofmorphogenesis CLINICAL FEATURES 1. Marked intrafamilial andinterfamilial variability 2. Terminal transverse limb defects a.Most common manifestation (84%) b. Usually asymmetrical c. Tendencytoward bilateral lower limb rather than upper limb involvement d.Mild spectrum of defects i. Nail hypoplasia ii. Cutaneoussyndactyly iii. Bony syndactyly iv. Ectrodactyly v. Brachydactylye. Severe spectrum of transverse defects i. Absence of the hand ii.Absence of the foot iii. Absence of the limb 3. Aplasia cutiscongenita a. Second most common defect (almost 75%) b. Associatedwith skull defect (64%) i. Small lesion: 0.5 cm in diameter ii.Intermediate lesion: 810 cm involving the vertex iii. Severelesion: involves most of the scalp with acrania c. Skull defectwithout scalp defect, often mistaken for an enlarged fontanelle d.May involve other areas of the body e. Severe end of the spectrumof scalp defects i. Encephalocele ii. Acrania 4. Congenitalcardiovascular malformations (13.420%) a. Mechanisms proposed toexplain the pathogenesis of congenital cardiovascular malformationsi. Alteration of mesenchymal cell migration result- ing inconotruncal malformations; e.g., tetralogy of Fallot, double outletright ventricle, and trun- cus arteriosus ii. Alteration of fetalcardiac hemodynamics result- ing in different malformations such ascoarctation of the aorta, aortic stenosis, perimembranous VSD, andhypoplastic left heart iii. Persistence of normal fetal vascularchannels resulting in postnatal vascular abnormalities b. Diversevascular and valvular abnormalities i. Bicuspid aortic valve ii.Pulmonary atresia iii. Parachute mitral valve iv. Pulmonaryhypertension 5. Other associated anomalies a. Cutis marmoratatelangiectasia 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 palatef. Cryptorchidism g. Lymphatic abnormalities i. Lymphedema of theleg ii. Chylothorax iii. Dilated pulmonary lymphatics iv.Intestinal lymphangiectasia v. Marmorata telangiectasia congenita(a cutaneous vascular abnormality) h. CNS abnormalities: unusualmanifestation i. Mental retardation ii. Learning disability iii.Epilepsy i. Short stature j. Renal malformations k. Spina bifidaocculta l. Accessory nipples 23 Adams-Oliver Syndrome
32. 32. 24 ADAMS-OLIVER SYNDROME 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. Ventriculomegalyc. Irregular cortical thickening d. Cerebral cortex dysplasia e.Microcephaly f. Arhinencephaly g. Periventricular and parenchymalcalcium deposits GENETIC COUNSELING 1. Recurrence risk a. Patientssib i. Autosomal dominant: not increased unless a par- ent isaffected in which case the risk is 50% ii. Autosomal recessive: 25%b. Patients offspring i. Autosomal dominant: 50% ii. Autosomalrecessive: not increased unless the spouse carries the gene or isaffected 2. Prenatal diagnosis by ultrasonography a. Transverselimb defects b. Concomitant skull defect 3. Management a. Treatminor scalp lesions with daily cleansing of the involved areas withapplications of antibiotic oint- ment b. Surgically close largerlesions and exposed dura with minor or major skin graftingprocedure (split-thick- ness or full-thickness) c. Prevent sepsisand/or meningitis from an open scalp lesion which is highlyvascular and rarely involves the sagittal sinus predisposing toepisodes of spontaneous hemorrhage d. Orthopedic care for variousdegrees of limb defects REFERENCES Adams FH, Oliver CP: Hereditarydeformities in man due to arrested develop- ment. J Hered 36:37,1945. Arand AG, et al.: Congenital scalp defects: Adams-Oliversyndrome. A case report and review of the literature. PediatrNeurosurg 17:203207, 1991. Bamforth JS, Kaurah P, Byrne J, et al.:Adams Oliver syndrome: a family with extreme variability inclinical expression. Am J Med Genet 49: 393396, 1994. Becker R,Kunze J, Horn D, et al.:Autosomal recessive type ofAdams-Oliversyn- drome: prenatal diagnosis. Ultrasound Obstet Gynecol20:506-510, 2002. Bonafede RP, Beighton P: Autosomal dominantinheritance of scalp defects with ectrodactyly. Am J Med Genet3:3541, 1979. Bork K, Pfeifle J: Multifocal aplasia cutiscongenita, distal limb hemimelia, and cutis marmoratatelangiectatica in a patient with Adams-Oliver syn- drome. Br JDermatol 127:160163, 1992. Burton BK, Hauser H, Nadler HL:Congenital scalp defects with distal limb anomalies: report of afamily. J Med Genet 13:466468, 1976. Frieden I: Aplasia cutiscongenita: a clinical review and proposal for classifica- tion. JAm Acad Dermatol 14:646660, 1986. Fryns JP: Congenital scalpdefects with distal limb reduction anomalies. J Med Genet24:493496, 1987. Fryns JP, Leigius E, Demaere P, et al.: Congenitalscalp defects, distal limb reduction anomalies, right spastichemiplegia and hypoplasia of the left arterial cerebri media. ClinGenet 50:505509, 1996. Hoyme HE, Der Kaloustian VM, Entin M, etal.: Possible common patho- genetic mechanisms for Poland sequenceand Adams-Oliver syndrome: an additional clinical observation. Am JMed Genet 42:398399, 1992. Klinger G, Merlob P: Adams-Oliversyndrome: autosomal recessive inheri- tance and newphenotypic-anthropometric findings. Am J Med Genet 79:197199, 1998.Koiffmann CP, Wajntal A, Huyke BJ, et al.: Congenital scalp skulldefects with distal limb anomalies (Adams-Oliver syndromeMcKusick10030): fur- ther suggestion of autosomal recessive inheritance. AmJ Med Genet 29:263268, 1988. Kster W, Lenz W, Kaariainen H, et al.:Congenital scalp defects with distal limb anomalies (Adams-Oliversyndrome): report of ten cases and review of the literature. Am JMed Genet 31:99115, 1988. Lin AE, Wesgate MN, van der Velde ME, etal.: Adams-Oliver syndrome associ- ated with cardiovascularmalformation. Clin Dysmorphol 7:235241, 1998. Mempel M, Abeck D,Lange I, et al.: The wide spectrum of clinical expressioninAdams-Oliver syndrome: a report of two cases. Br J Dermatol140:1157 1160, 1999. Pauli RM, et al.: Familial recurrence ofterminal transverse defects of the arm. Clin Genet 27:555563, 1985.Pereira-da-Silva L, Leal F, Cassiano Santos G, et al.: Clinicalevidence of vas- cular abnormalities at birth in Adams-Oliversyndrome: report of two fur- ther cases. (Letter) Am J Med Genet94:7576, 2000. Pousti TJ, Bartlett RA: Adams-Oliver syndrome:genetics and associated anomalies of cutis aplasia. Plast ReconstrSurg 100:14911496, 1997. Shapiro SD, Escobedo MK: Terminaltransverse defects with aplasia cutis con- genita (Adams-Oliversyndrome). Birth Defects Orig Artic Ser 21(2):135142, 1985.Stevenson RE, Deloache WR: Aplasia cutis congenita of the scalp.Proc Greenwood Genet Center 7:1418, 1988. Sybert VP: Congenitalscalp defects with distal limb anomalies (Adams-OliverSyndromeMcKusick 10030): further suggestion of autosomal recessiveinheritance. Am J Med Genet 32:266-267, 1989. Tekin M, Bodurtha J,ifti E, et al.: Further family with possible autosomal recessiveinheritance of Adams-Oliver syndrome. (Letter) Am J Med Genet86:9091, 1999. Toriello HV, Graff RG, Florentine MF, et al.: Scalpand limb defects with cutis marmorata telangiectatica congenita:Adams-Oliver syndrome?. Am J Med Genet 29:269276, 1988. Verdyck P,Holder-Espinasse M, Hul WV, et al.: Clinical and molecular analy-sis of nine families with Adams-Oliver syndrome. Eur J Hum Genet11:457463, 2003. Whitley CB, Gorlin RJ: Adams-Oliver syndromerevisited. Am J Med Genet 40:319326, 1991. Zapata HH, Sletten LJ,Pierpont MEM: Congenital cardiac malformations in Adams-Oliversyndrome. Clin Genet 47:8084, 1995.
33. 33. ADAMS-OLIVER SYNDROME 25 Fig. 1. A 9-month-old boy withAdams-Oliver syndrome showing alopecia, absent eyebrows andeyelashes, scalp defect, tortuous scalp veins, and limb defects(brachydactyly, syndactyly, broad great toes, and nail hypoplasia).Radiography showed absent middle and distal phalanges of 2nd5thtoes and absent distal phalanges of the great toes.
34. 34. 26 Agnathia is an extremely rare lethal neurocristopathy.The disorder has also been termed agnathia-holoprosencephaly,agnathia-astomia-synotia, or cyclopia-otocephaly association. Theincidence is estimated to be 1/132,000 births in Spain.GENETICS/BASIC DEFECTS 1. Sporadic occurrence in majority of cases2. Rare autosomal recessive inheritance 3. Possible autosomaldominant inheritance a. Supported by an observation of dysgnathiain mother and daughter b. Possibility of a defect in the OTX2 geneas the basis of the disorder 4. A prechordal mesoderm inductivedefect affecting neural crest cells a. A developmental field defectb. Different etiologic agents (etiological heterogeneity) acting onthe same developmental field producing a highly similar complex ofmalformations 5. Possible existence of a mild form of agnathiawithout brain malformation (holoprosencephaly) a. Situsinversus-congenital hypoglossia b. Severe micrognathia, aglossia,and choanal atresia 6. A well-recognized malformation complex inthe mouse, guinea pig, rabbit, sheep, and pig CLINICAL FEATURES 1.Polyhydramnios due to persistence of oropharyngeal membrane orblind-ending mouth 2. Agnathia (absence of the mandible) 3.Microstomia or astomia (absence of the mouth) 4. Aglossia (absenceof the tongue) 5. Blind mouth 6. Ear anomalies a. Otocephaly(variable ear positions) b. Synotia (external ears approaching oneanother in the midline) c. Dysplastic inner ear d. Atretic earcanal 7. Down-slanting palpebral fissures 8. Variable degree ofholoprosencephaly a. Cyclopia b. Synophthalmia c. Arrhinencephaly9. Other brain malformations a. Cerebellar hypoplasia b. Septumpellucidum Cavum c. Absence of cranial nerves (I-IV) d. Absence ofthe corpus callosum e. Meningocele 10. Intrauterine growthretardation 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. Retinaldysplasia g. Microcornea h. Anterior segment dysgenesis i. Uvealcolobomas 13. Nasal anomalies a. Absence of the nasal cavity b.Cleft nose c. Blind nasal pharynx 14. Various visceralmalformations a. Choanal atresia b. Tracheoesophageal fistula c.Absence of the thyroid gland d. Absence of the submandibular andparotid salivary glands e. Abnormal glottis and epiglottis f.Thyroglossal duct cyst g. Carotid artery anomalies h. Situsinversus i. Cardiac anomalies j. Unlobulated lungs k. Renogenitalanomalies i. Unilateral renal agenesis ii. Renal Ectopia iii.Cystic kidneys iv. Horseshoe kidne