Atlas of genetic diagnosis and counseling

ATLAS OF GENETIC DIAGNOSIS AND COUNSELING


ATLAS

OF

GENETIC

DIAGNOSIS
AND

COUNSELING

HAROLD CHEN,

MD, FAAP, FACMG

Professor of Pediatrics, Obstetrics and Gynecology, and Pathology,
Louisiana State University Health Science Center, Shreveport, LA


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e-ISBN 1-59259-956-7
Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1

Library of Congress Cataloging-in-Publication Data
Atlas of genetic diagnosis and counseling / authored by Harold Chen.
p. cm.
Includes bibliographical references.
ISBN 1-58829-681-4 (alk. paper)
1. Genetic disorders--Diagnosis--Atlases. 2. Genetic counseling--Atlases.
[DNLM: 1. Genetic Diseases, Inborn--Atlases. 2. Genetic Counseling--Atlases. 3. Prenatal Diagnosis--Atlases. QZ 17 A880383 2006] I. Chen, Harold.
RB155.6.A93 2006

616'.042--dc22
2005005388


Preface
This book, Atlas of Genetic Diagnosis and
Counseling, reflects my experience in 38 years of
clinical genetics practice. During this time, I have
cared for many patients and their families and taught
innumerable medical students, residents, and practicing physicians. As an academic physician, I have
found that a picture is truly “worth a thousand
words,” especially in the field of dysmorphology.
Over the years, I have compiled photographs of my
patients, which are incorporated into this book to
illustrate selected genetic disorders, malformations,
and malformation syndromes. A detailed outline of
each disorder is provided, describing the genetics,
basic defects, clinical features, diagnostic investigations, and genetic counseling, including recurrence
risk, prenatal diagnosis, and management. Color
photographs are used to illustrate the clinical features of patients of different ages and ethnicities.
Photographs of prenatal ultrasounds, imagings, cytogenetics, and postmortem findings are included to
help illustrate diagnostic strategies. The cases are
supplemented by case history and diagnostic confirmation by cytogenetics, biochemical, and molecular
studies, if available. An extensive literature review
was done to ensure up-to-date information and to
provide a relevant bibliography for each disorder.
This book was written in the hope that it will
help physicians improve their recognition and

understanding of these conditions and their care of

affected individuals and their families. It is also my
intention to bring the basic science and clinical medicine together for the readers. Atlas of Genetic
Diagnosis and Counseling is designed for physicians
involved in the evaluation and counseling of patients
with genetic diseases, malformations, and malformation syndromes, including medical geneticists,
genetic counselors, pediatricians, neonatologists,
developmental pediatricians, perinatologists, obstetricians, neurologists, pathologists, and any physicians and health care professionals caring for
handicapped children such as craniofacial surgeons,
plastic surgeons, otolaryngologists, and orthopedics.
I am grateful to many individuals for their
invaluable help in reading and providing cases for
illustration. The acknowledgments are provided on
a separate page. Without the patience and encouragement of my dear wife, Cheryl, this atlas would
not have been possible. I would like to dedicate
this book to Children’s Hospital, Louisiana State
University Health Sciences Center in Shreveport,
for its continued excellence in pediatric care and
education.
I would welcome comments, corrections, and criticism from readers.
Harold Chen, MD, FAAP, FACMG

v


Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
Acardia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Achondrogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Achondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Adams-Oliver Syndrome . . . . . . . . . . . . . . . . . . . . . . 23
Agnathia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Aicardi Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Alagille Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Albinism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Amniotic Band Syndrome . . . . . . . . . . . . . . . . . . . . . 42
Androgen Insensitivity Syndrome . . . . . . . . . . . . . . . 50
Angelman Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 56
Apert Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Aplasia Cutis Congenita . . . . . . . . . . . . . . . . . . . . . . . 70
Arthrogryposis Multiplex Congenita . . . . . . . . . . . . . 74
Asphyxiating Thoracic Dystrophy . . . . . . . . . . . . . . . 84
Ataxia Telangiectasia . . . . . . . . . . . . . . . . . . . . . . . . . 92
Atelosteogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Autism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Beckwith-Wiedemann Syndrome . . . . . . . . . . . . . . .
Behcet Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Bladder Exstrophy . . . . . . . . . . . . . . . . . . . . . . . . . .
Body Stalk Anomaly . . . . . . . . . . . . . . . . . . . . . . . .
Branchial Cleft Anomalies . . . . . . . . . . . . . . . . . . . .

109
114
118
122
126

Campomelic Dysplasia . . . . . . . . . . . . . . . . . . . . . . .
Cat Eye Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . .
Cerebro-Costo-Mandibular Syndrome . . . . . . . . . . .

Charcot-Marie-Tooth Disease . . . . . . . . . . . . . . . . .
CHARGE Association . . . . . . . . . . . . . . . . . . . . . . .
Cherubism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chiari Malformation . . . . . . . . . . . . . . . . . . . . . . . . .
Chondrodysplasia Punctata . . . . . . . . . . . . . . . . . . .
Chromosome Abnormalities in Pediatric
Solid Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cleft Lip and/or Cleft Palate . . . . . . . . . . . . . . . . . .

131
136
139
142
149
153
157
161

Cleidocranial Dysplasia . . . . . . . . . . . . . . . . . . . . . .
Cloacal Exstrophy . . . . . . . . . . . . . . . . . . . . . . . . . .
Collodion Baby . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Congenital Adrenal Hyperplasia
(21-Hydroxylase Deficiency) . . . . . . . . . . . . . . . .
Congenital Cutis Laxa . . . . . . . . . . . . . . . . . . . . . . .
Congenital Cytomegalovirus Infection . . . . . . . . . .
Congenital Generalized Lipodystrophy . . . . . . . . . .
Congenital Hydrocephalus . . . . . . . . . . . . . . . . . . . .
Congenital Hypothyroidism . . . . . . . . . . . . . . . . . . .
Congenital Muscular Dystrophy . . . . . . . . . . . . . . .
Congenital Toxoplasmosis . . . . . . . . . . . . . . . . . . . .

Conjoined Twins . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Corpus Callosum Agenesis/Dysgenesis . . . . . . . . . .
Craniometaphyseal Dysplasia . . . . . . . . . . . . . . . . .
Cri-Du-Chat Syndrome . . . . . . . . . . . . . . . . . . . . . .
Crouzon Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . .
Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

185
191
195

Dandy-Walker Malformation . . . . . . . . . . . . . . . . . .
De Lange Syndrome . . . . . . . . . . . . . . . . . . . . . . . . .
Del(22q11.2) Syndromes . . . . . . . . . . . . . . . . . . . . .
Diabetic Embryopathy . . . . . . . . . . . . . . . . . . . . . . .
Down Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Dyschondrosteosis (Leri-Weill Syndrome) and
Langer Mesomelic Dysplasia . . . . . . . . . . . . . . . .
Dysmelia (Limb Deficiency/Reduction) . . . . . . . . .
Dysplasia Epiphysealis Hemimelica . . . . . . . . . . . .
Dystonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Dystrophinopathies . . . . . . . . . . . . . . . . . . . . . . . . . .

273
276
282
289
295

Ectrodactyly-Ectodermal Dysplasia-Clefting

(EEC) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . .
Ehlers-Danlos Syndrome . . . . . . . . . . . . . . . . . . . . .
Ellis-van Creveld Syndrome . . . . . . . . . . . . . . . . . .
Enchondromatosis (Maffucci Syndrome;
Ollier Syndrome) . . . . . . . . . . . . . . . . . . . . . . . . .
Epidermolysis Bullosa . . . . . . . . . . . . . . . . . . . . . . .
Epidermolytic Palmoplantar Keratoderma . . . . . . . .

169
180
vii

198
207
212
217
221
227
231
236
241
247
252
256
261
265

305
312
323

326
331

339
342
350
355
360
366


viii

CONTENTS

Faciogenital (Aarskog) Dysplasia . . . . . . . . . . . . . .
Facioscapulohumeral Muscular Dystrophy . . . . . . .
Familial Adenomatous Polyposis . . . . . . . . . . . . . . .
Familial Hyperlysinemia . . . . . . . . . . . . . . . . . . . . .
Fanconi Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Femoral Hypoplasia-Unusual Facies Syndrome . . .
Fetal Akinesia Syndrome . . . . . . . . . . . . . . . . . . . . .
Fetal Alcohol Syndrome . . . . . . . . . . . . . . . . . . . . . .
Fetal Hydantoin Syndrome . . . . . . . . . . . . . . . . . . .
Fibrodysplasia Ossificans Progressiva . . . . . . . . . . .
Finlay-Marks Syndrome . . . . . . . . . . . . . . . . . . . . . .
Fragile X Syndrome . . . . . . . . . . . . . . . . . . . . . . . . .
Fraser Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . .
Freeman-Sheldon Syndrome . . . . . . . . . . . . . . . . . .
Frontonasal Dysplasia . . . . . . . . . . . . . . . . . . . . . . .

371
375
380
386
389
395
398
403
407
410
415
417
423
427
431

Galactosemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Gastroschisis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Gaucher Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Generalized Arterial Calcification of Infancy . . . . .
Glucose-6-Phosphate Dehydrogenase Deficiency . . .
Glycogen Storage Disease, Type II . . . . . . . . . . . . .
Goldenhar Syndrome . . . . . . . . . . . . . . . . . . . . . . . .

437
442
446
452
457

461
465

Hallermann-Streiff Syndrome . . . . . . . . . . . . . . . . .
Harlequin Ichthyosis (Harlequin Fetus) . . . . . . . . . .
Hemophilia A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hereditary Hemochromatosis . . . . . . . . . . . . . . . . . .
Hereditary Multiple Exostoses . . . . . . . . . . . . . . . . .
Holoprosencephaly . . . . . . . . . . . . . . . . . . . . . . . . . .
Holt-Oram Syndrome . . . . . . . . . . . . . . . . . . . . . . . .
Hydrops Fetalis . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hyper-IgE Syndrome . . . . . . . . . . . . . . . . . . . . . . . .
Hypochondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . .
Hypoglossia-Hypodactylia Syndrome . . . . . . . . . . .
Hypohidrotic Ectodermal Dysplasia . . . . . . . . . . . .
Hypomelanosis of Ito . . . . . . . . . . . . . . . . . . . . . . . .
Hypophosphatasia . . . . . . . . . . . . . . . . . . . . . . . . . .

469
473
476
482
487
493
502
506
513
517
521
524

528
532

Incontinentia Pigmenti . . . . . . . . . . . . . . . . . . . . . . . 539
Infantile Myofibromatosis . . . . . . . . . . . . . . . . . . . . 545
Ivemark Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 549
Jarcho-Levin Syndrome . . . . . . . . . . . . . . . . . . . . . . 553
Kabuki Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 559

Kasabach-Merritt Syndrome . . . . . . . . . . . . . . . . . .
KID Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Klinefelter Syndrome . . . . . . . . . . . . . . . . . . . . . . . .
Klippel-Feil Syndrome . . . . . . . . . . . . . . . . . . . . . . .
Klippel-Trenaunay Syndrome . . . . . . . . . . . . . . . . .
Kniest Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . .

563
567
570
575
580
585

Larsen Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . .
LEOPARD Syndrome . . . . . . . . . . . . . . . . . . . . . . .
Lesch-Nyhan Syndrome . . . . . . . . . . . . . . . . . . . . . .
Lethal Multiple Pterygium Syndrome . . . . . . . . . . .
Lowe Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . .

589

597
600
604
613

Marfan Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . .
McCune-Albright Syndrome . . . . . . . . . . . . . . . . . .
Meckel-Gruber Syndrome . . . . . . . . . . . . . . . . . . . .
Menkes Disease (Kinky-Hair Syndrome) . . . . . . . .
Metachromatic Leukodystrophy . . . . . . . . . . . . . . .
Miller-Dieker Syndrome . . . . . . . . . . . . . . . . . . . . .
Möbius Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . .
Mucolipidosis II (I-Cell Disease) . . . . . . . . . . . . . . .
Mucolipidosis III (Pseudo-Hurler Polydystrophy) .
Mucopolysaccharidosis I (MPS I)
(α-L-Iduronidase Deficiency): Hurler
(MPS I-H), Hurler-Scheie (MPS I-H/S),
and Scheie (MPS I-S) Syndromes . . . . . . . . . . . .
Mucopolysaccharidosis II (Hunter Syndrome) . . . .
Mucopolysaccharidosis III (Sanfilippo Syndrome) .
Mucopolysaccharidosis IV (Morquio Syndrome) . .
Mucopolysaccharidosis VI (Maroteaux-Lamy
Syndrome) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Multiple Epiphyseal Dysplasia . . . . . . . . . . . . . . . .
Multiple Pterygium Syndrome . . . . . . . . . . . . . . . . .
Myotonic Dystrophy Type 1 . . . . . . . . . . . . . . . . . .

619
630
636

639
646
650
655
660
664

Netherton Syndrome . . . . . . . . . . . . . . . . . . . . . . . .
Neu-Laxova Syndrome . . . . . . . . . . . . . . . . . . . . . . .
Neural Tube Defects . . . . . . . . . . . . . . . . . . . . . . . . .
Neurofibromatosis I . . . . . . . . . . . . . . . . . . . . . . . . .
Noonan Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . .

715
718
721
731
744

Oblique Facial Cleft Syndrome . . . . . . . . . . . . . . . .
Oligohydramnios Sequence . . . . . . . . . . . . . . . . . . .
Omphalocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Osteogenesis Imperfecta . . . . . . . . . . . . . . . . . . . . .
Osteopetrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

751
755
758
762
773

669
678
682
687
692
697
702
708


CONTENTS

Pachyonychia Congenita . . . . . . . . . . . . . . . . . . . . .
Pallister-Killian Syndrome . . . . . . . . . . . . . . . . . . . .
Phenylketonuria (PKU) . . . . . . . . . . . . . . . . . . . . . .
Pierre Robin Sequence . . . . . . . . . . . . . . . . . . . . . . .
Polycystic Kidney Disease, Autosomal
Dominant Type . . . . . . . . . . . . . . . . . . . . . . . . . .
Polycystic Kidney Disease, Autosomal
Recessive Type . . . . . . . . . . . . . . . . . . . . . . . . . . .
Prader-Willi Syndrome . . . . . . . . . . . . . . . . . . . . . . .
Progeria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Prune Belly Syndrome . . . . . . . . . . . . . . . . . . . . . . .
Pseudoachondroplasia . . . . . . . . . . . . . . . . . . . . . . .

781
784
788
793

797
803
809
815
821
826

R(18) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Retinoid Embryopathy . . . . . . . . . . . . . . . . . . . . . . .
Rett Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Rickets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Roberts Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . .
Robinow Syndrome . . . . . . . . . . . . . . . . . . . . . . . . .
Rubinstein-Taybi Syndrome . . . . . . . . . . . . . . . . . . .

831
835
839
844
852
856
860

Schizencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Schmid Metaphyseal Chondrodysplasia . . . . . . . . .
Seckel Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . .
Severe Combined Immune Deficiency . . . . . . . . . . .
Short Rib Polydactyly Syndromes . . . . . . . . . . . . . .
Sickle Cell Disease . . . . . . . . . . . . . . . . . . . . . . . . . .
Silver-Russell Syndrome . . . . . . . . . . . . . . . . . . . . .

Sirenomelia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Smith-Lemli-Opitz Syndrome . . . . . . . . . . . . . . . . .
Smith-Magenis Syndrome . . . . . . . . . . . . . . . . . . . .
Sotos Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Spinal Muscular Atrophy . . . . . . . . . . . . . . . . . . . . .

867
870
874
878
884
892
899
903
907
912
916
921

ix

Spondyloepiphyseal Dysplasia . . . . . . . . . . . . . . . . . 927
Stickler Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 934
Sturge-Weber Syndrome . . . . . . . . . . . . . . . . . . . . . 939
Tay-Sachs Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 943
Tetrasomy 9p Syndrome . . . . . . . . . . . . . . . . . . . . . 947
Thalassemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950
Thanatophoric Dysplasia . . . . . . . . . . . . . . . . . . . . . 955
Thrombocytopenia-Absent Radius Syndrome . . . . . 962
Treacher-Collins Syndrome . . . . . . . . . . . . . . . . . . . 967

Trimethylaminuria . . . . . . . . . . . . . . . . . . . . . . . . . . 972
Triploidy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976
Trismus Pseudocamptodactyly Syndrome . . . . . . . . 982
Trisomy 13 Syndrome . . . . . . . . . . . . . . . . . . . . . . . 985
Trisomy 18 Syndrome . . . . . . . . . . . . . . . . . . . . . . . 990
Tuberous Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . 997
Turner Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 1007
Twin–Twin Transfusion Syndrome . . . . . . . . . . . . 1015
Ulnar-Mammary Syndrome . . . . . . . . . . . . . . . . . . 1021
VATER (VACTERL) Association . . . . . . . . . . . . . 1025
Von Hippel-Lindau Disease . . . . . . . . . . . . . . . . . . 1029
Waardenburg Syndrome . . . . . . . . . . . . . . . . . . . . . 1035
Williams Syndrome . . . . . . . . . . . . . . . . . . . . . . . . 1040
Wolf-Hirschhorn Syndrome . . . . . . . . . . . . . . . . . . 1047
X-Linked Ichthyosis . . . . . . . . . . . . . . . . . . . . . . . .
XXX Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . .
XXXXX Syndrome . . . . . . . . . . . . . . . . . . . . . . . .
XXXXY Syndrome . . . . . . . . . . . . . . . . . . . . . . . .
XY Female . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
XYY Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . .

1057
1061
1064
1068
1071
1075


Acknowledgments

HIROKO TANIAI, MD • A case of Finlay-Marks syndrome
and help in searching of references for the Atlas.
THEODORE THURMON, MD • Comments on the Atlas
and cases on achondrogenesis, arthrogryposis,
cleidocranial dysplasia, chondrodysplasia punctata,
de Lange syndrome, Crouzon syndrome, cutis laxa,
Freeman-Sheldon syndrome, hypophosphatasia,
multiple epiphyseal dysplasia, omphalocele,
prune belly syndrome, Sturge-Weber syndrome,
and Treacher-Collins syndrome.
CATHY TUCK-MULLER, PhD • A karyotype on Roberts
syndrome.
SUSONNE URSIN, MD • Cases of galactosemia
and Gaucher disease and helps covering patient care
for me during the last stage of preparing the Atlas.
WLADIMIR WERTELECKI, MD • Enjoy working together
on birth defects and congenital malformations
and appreciate friendship and encouragement.
SAMUEL YANG, MD • Meticulous reading and editing
of the whole manuscript from the start to the end
during his retirement and encouragement throughout
the preparation of the Atlas. Special thanks to
contribution of his life-time collection of cases
on skeletal dysplasias and malformation syndromes
(acardius, achondrogenesis, achondroplasia, amniotic
band syndrome, anencephaly, asphyxiating thoracic
dystrophy, body stalk anomaly, cebocephaly,
campomelic dysplasia, Chiari malformation, colon
polyposis, congenital cytomegalovirus infection,
congenital toxoplasmosis, cyclopia, cystic fibrosis,

Duchenne muscular dystrophy, Ellis van Creveld
syndrome, gastroschisis, hypophosphatasia, I-cell
disease, Kniest syndrome, polycystic kidney diseases,
premaxillary agenesis, prune belly syndrome, SED
congenita, sirenomelia, short rib polydactyly
syndromes, Tay-Sachs disease, thanatophoric
dysplasia, twin-twin transfusion placentas, VATER
association, and Werdnig-Hoffman syndrome).
CHENG W. YU, PhD • Karyotypes/FISH on pediatric
tumors (meningioma, Wilms tumor), Cri-du-chat
syndrome, and Wolf-Hirschhorn syndrome.

Individuals
DIANA BIENVENU, MD • A case of Marfan syndrome
with apical bleb rupture.
SAMI BAHNA, MD • Comments on del(22q11.2), hyper
IgE syndrome, Netherton syndrome, and severe
combined immunodeficiency.
JOSEPH BOCCHINI, JR. MD • Comments on congenital
cytomegalovirus infection and congenital
toxoplasmosis and encouragement and support
throughout preparation of the Atlas.
CHUNG-HO CHANG, MD • Cases on Duchenne muscular
dystrophy and congenital toxoplasmosis.
SAU CHEUNG, PhD • FISH on a case of STS deficiency.
JAMES GANLEY, MD • Cases on ophthalmology
(Behcet disease, Lisch nodule in NF1, cherry spot
in Tay-Sachs disease, and retinal changes in
congenital toxoplasmosis, von-Hippel Lindal disease,
and Waardenburg syndrome).

ENRIQUE GONZALEZ, MD • Valuable comments
on pathological aspects of clinical entities and cases
on acardius, agnathia, cloacal exstrophy, congenital
cytomegalovirus infection, omphalocele, pediatric
solid tumors (meningioma, neuroblastoma,
retinoblastoma, and Wilms tumor), phocomelia, sickle
cell anemia, thalassemia, and Gaucher disease.
WILLIAM HOFFMAN, MD • Comments on topics
of endocrinological interest and cases on androgen
insensitivity and hypophosphatemic rickets.
RACHEL FLAMHOLZ, MD • Peripheral blood smears on
sickle cell anemia and thalassemia.
MAJED JEROUDI, MD • A case of sickle cell anemia
dactylitis.
DANIEL LACEY, MD • Comments on dystrophinopathy,
spinal muscular atrophy, neural tube defects,
and holoprosencephaly.
MARY LOWERY, MD • Comments on the Atlas and cases
on molecular cytogenetics/pathology (FISH on trisomy
21, trisomy 13, trisomy 18, X/XXX, Williams syndrome,
and neuroblastoma; mutation analysis on cystic
fibrosis and hereditary hemochromatosis).
LYNN MARTIN, LPN • Help in caring for the patients
including obtaining the photographs of patients
and searching for clinical information of the old
files.
LEONARD PROUTY, PhD • Reading of several topics in the
Atlas.
DAN SANUSI, MD • A case of X-linked ichthyosis.
TOHRU SONODA, MD • Cases on chondrodysplasia

punctata, del(22q11.2), Kabuki syndrome, KlippelTrenaunay syndrome, and tuberous sclerosis.

Institutions
Louisiana State University Health Sciences Center
in Shreveport, Louisiana (Drs. Joseph Bocchini, Jr.,
David Lewis, Rose Brouillette, Rodney Wise)
Pinecrest Developmental Center in Pineville, Louisiana
(Drs. Gaylon Bates, Tony Hanna, Renata Pilat)
Shreveport Shriner’s Hospital for Children (Dr. Richard
McCall)
xi


Acardia
b) Presence of rudimentary nerve tissue in
addition to anatomical features in acardius
amorphous
iii. Acardius acephalus
a) The most common type
b) Missing head, part of the thorax, and upper
extremities
c) May have additional malformations in the
remaining organs
iv. Acardius anceps
a) Presence of a partially developed fetal head,
a thorax, abdominal organs, and extremities
b) Lacks even a rudimentary heart
v. Acardius acormus
a) The rarest type
b) Lacks thorax

c) Presence of a rudimentary head only
d) The umbilical cord inserts in the head and
connects directly to the placenta
4. The acardia
a. Characterized by the absence of a normally functioning heart
b. Acardia as a recipient of twin transfusion sequence
i. Reversal of blood flow in various types of acardia, hence the term “twin reversed arterial perfusion (TRAP) sequence” has been proposed
ii. Receiving the deoxygenated blood from an
umbilical artery of its co-twin through the single umbilical artery of the acardiac twin and
returning to its umbilical vein. Therefore, the
circulation is entirely opposite to the normal
direction
c. Usually the severe reduction anomalies occur in the
upper part of the body
d. May develop various structural malformations
i. Growth retardation
ii. Anencephaly
iii. Holoprosencephaly
iv. Facial defects
v. Absent or malformed limbs
vi. Gastrointestinal atresias
vii. Other abnormalities of abdominal organs
5. The co-twin
a. Also known as the “pump twin or donor twin”
b. The donor “pump” twin perfuses itself and its recipient acardiac twin through abnormal arterial anastomosis in the fused placenta
c. Increased cardiac workload often leads to cardiac failure and causes further poor perfusion and oxygenation of the acardiac co-twin
d. May develop various malformations (about 10%)

Acardia is a bizarre fetal malformation occurring only in
twins or triplets. It is also called acardius acephalus, acardiac

twinning, or twin reversed arterial perfusion (TRAP) syndrome
or sequence. This condition is very rare and occurs 1 in 35,000
deliveries, 1 in 100 monozygotic twins, rarely in triplet pregnancy, and even in quintuplet gestations.

GENETICS/BASIC DEFECTS
1. Etiology
a. Rare complication of monochorionic twinning, presumably resulting from the fused placentation of
monochorionic twins
b. Represents manifestation of abnormal embryonic and
fetal blood flow rather than a primary defect of cardiac formation
c. Heterogeneous chromosomal abnormalities are present
in nearly 50% of the cases, although chromosome errors
are not underlying pathogenesis of the acardiac anomaly.
i. 45,XX,t(4;21)del(4p)
ii. 46,X,i(Xp)
iii. 47,XX,+2
iv. 47,XX,+11
v. 47,XY,+G
vi. 47,XXY
vii. 69,XXX
viii. 70,XXX,+15
ix. 94,XXXXYY
2. Pathogenesis: reversal of fetal arterial perfusion
a. First hypothesis
i. A primary defect in the development of the heart
ii. Survival of the acardiac twin as a result of the
compensatory anastomoses that develop
b. Second hypothesis
i. The acardiac twin beginning life as a normal fetus
ii. The reversal of the arterial blood flow resulting

in atrophy of the heart and the tributary organs
3. Classification of TRAP sequence (syndrome)
a. Classification according to the status of the heart of
the acardiac twin
i. Hemiacardius (with incompletely formed heart)
ii. Holoacardius (with completely absent heart)
b. Morphologic classification of the acardiac twin
i. Acardius amorphous
a) The least differentiated form; no resemblance to classical human form
b) Anatomical features: presence of only
bones, cartilage, muscles, fat, blood vessels,
and stroma
ii. Acardius myelacephalus
a) Resembles the amorphous type, except for
the presence of rudimentary limb formation

1


2

ACARDIA

CLINICAL FEATURES
1. Perinatal problems associated with acardiac twinning
a. Pump-twin congestive heart failure
b. In utero fetal death of the pump fetus
c. Maternal polyhydramnios
d. Premature rupture of membrane
e. Preterm delivery

f. Spontaneous abortions
g. Soft tissue dystocia
h. Uterine rupture
i. Postpartum hemorrhage
j. Increased rate of cesarean section, up to 50%
2. Majority of acardiac twins and their normal twin counterparts are females
3. Nonviable
4. Gross features
a. Severe reduction anomalies, particularly of the upper
body
b. Characteristic subcutaneous edema
c. Internal organs: invariably missing
d. Absent or rudimentary cardiac development: the key
diagnostic feature
i. Pseudoacardia (rudimentary heart tissue)
ii. Holoacardia (completely lacking a heart)
5. Growth abnormality
6. Cranial vault
a. Absent
b. Partial
c. Intact
7. Brain
a. Absent
b. Necrotic
c. Open cranial vault
d. Holoprosencephaly
8. Facial features
a. Absent facial features
b. Rudimentary facial features
c. Present with defects

d. Anophthalmia/microphthalmia
e. Cleft lip/palate
9. Upper limbs
a. Absent
b. Rudimentary
c. Radial aplasia
d. Syndactyly/oligodactyly
10. Lower limbs
a. Absent
b. Rudimentary/reduced
c. Syndactyly/oligodactyly
d. Talipes equinovarus
11. Thorax
a. Absent
b. Reduced
c. Diaphragmatic defect
12. Lungs
a. Absent
b. Necrotic or rudimentary
c. Single midline lobe

13. Cardiac
a. Absent heart tissue
b. Unfolded heart tube
c. Folded heart with common chamber
14. Gastrointestinal
a. Esophageal atresia
b. Short intestine
c. Interrupted intestine
d. Omphalocele

e. Incomplete rotation of the gut
f. Imperforated anus
g. Ascites
15. Liver
a. Absent
b. Reduced
16. Kidney
a. Absent (bilateral)
b. Hypoplastic and/or lobulated
17. Other viscera
a. Absent gallbladder
b. Absent spleen
c. Absent-to-reduced pancreas
d. Absent adrenal
e. Absent-to-hypoplastic gonads
f. Exstrophy of the cloaca
g. Skin with myxedematous thickening
18. Umbilical cord vessels
a. Two vessels
b. Three vessels
19. Severe obstetrical complications
a. Maternal polyhydramnios
b. Preterm labor
c. Cord accidents
d. Dystocia
e. Uterine rupture
20. Severe neonatal complications
a. Hydrops
b. Intrauterine demise
c. Prematurity

d. Heart failure
e. Anemia
f. Twin-to-twin transfusion syndrome
21. Outcome for the normal sib in an acardiac twin pregnancy
a. Unsatisfactory
i. Adapting to the increasing circulatory load,
resulting in the following situations:
a) Intrauterine growth retardation
b) Hydrops
c) Ascites
d) Pleural effusion
e) Hypertrophy of the right ventricle
f) Hepatosplenomegaly
g) Severe heart failure resulting in pericardial
effusion and/or tricuspid insufficiency
ii. Stillbirth
iii. Prematurity
iv. Neonatal death
b. Mortality for the normal twin reported as high as 50%
without intervention


ACARDIA

DIAGNOSTIC INVESTIGATIONS
1. Radiography
a. Absent or rudimentary skull
b. Absent or rudimentary thorax
c. Absent or rudimentary heart
d. Vertebral anomalies

e. Rib anomalies
f. Limb defects, especially upper limbs
2. Pathology
a. Microcephaly
b. Severely rudimentary brain
c. Developmental arrest of brain at the prosencephalic
stage (holoprosencephaly)
d. Hypoxic damage to the holospheric brain mantle with
cystic change (hydranencephaly)

GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: overall recurrence risk of about 1 in
10,000 (The recurrence risk is for monoamniotic
twinning [1% for couples who have had one set of
monozygotic twins] times the frequency of the occurrence of TRAP sequence with near-term survival
[about 1% of monozygotic twin sets])
b. Patient’s offspring: not applicable (a lethal condition)
2. Prenatal ultrasonography
a. Monochorionic placenta with a single umbilical
artery in 2/3 of cases
b. Acardiac fetus
i. Unrecognizable head or upper trunk
ii. Without a recognizable heart or a partially
formed heart
iii. A variety of other malformations
iv. Reversal of blood flow in the umbilical artery
with flow going from the placenta toward the
acardiac fetus (reversed arterial perfusion). Such
a reversal of the blood flow in the recipient twin

can be demonstrated in utero by transvaginal
Doppler ultrasound as early as 12 weeks of
gestation
v. Early diagnosis by transvaginal sonography on
the following signs:
a) Monozygotic twin gestation (absence of the
lambda sign)
b) Biometric discordance between the twins
c) Diffuse subcutaneous edema or morphologic anomalies of one of the twins, or
both
d) Detection of reversed umbilical cord flow;
cardiac activity likely to disappear as the
pregnancy progresses
e) Absence of cardiac activity, although hemicardia or pseudocardia may be present
c. The donor fetus
i. Hydrops
ii. Cardiac failure (cardiomegaly, pericardial effusion, and tricuspid regurgitation)

3

2. Amniocentesis to diagnose associated chromosome
abnormalities (about 10% of pump twins)
3. Management of pregnancies complicated by an acardiac
fetus
a. Conservative treatment
i. Monitor pregnancy by serial ultrasonography
ii. Conservative approach as long as there is no evidence of cardiac circulatory decompensation in
the donor twin
b. Termination of pregnancies
c. Treatment and prevention of preterm labor by tocolytics

i. Magnesium sulphate
ii. Beta-Sympathomimetics
iii. Indomethacin
d. Treatment of pump fetus heart failure involving
maternal digitalization
e. Treatment of polyhydramnios by therapeutic repeated
amniocentesis
f. Selective termination of the acardiac twin
i. To occlude the umbilical artery of the acardiac
twin in order to stop umbilical flow through the
anastomosis
a) Intrafunicular injection and mechanical
occlusion of the umbilical artery
b) Embolization by steel or platinum coil, alcohol-soaked suture material, or ethanol
c) Hysterotomy and delivery of acardiac twin
d) Ligation of the umbilical cord
e) Hysterotomy and umbilical cord ligation
ii. Fetal surgery: best available treatment for acardiac twinning
a) Endoscopic laser coagulation of the umbilical vessels at or before 24 weeks of gestation
b) Endoscopic or sonographic guided umbilical
cord ligation after 24 weeks of gestation
iii. Summary of acardiac twins treated with invasive
procedures reported in the literature
a) Mortality of the pump twin (13.6%)
b) Preterm delivery (50.3%)
c) Delivery before 30-weeks gestation (27.2%)
d) Perinatal mortality, if untreated, is at least 50%

REFERENCES
Aggarwal N, Suri V, Saxena SV, et al.: Acardiac acephalus twins: a case report

and review of literature. Acta Obstet Gynecol Scand 81:983–984, 2002.
Alderman B: Foetus acardius amorphous. Postgrad Med J 49:102–105, 1973.
Arias F, Sunderji S, Gimpelson R, et al.: Treatment of acardiac twinning.
Obstet Gynecol 91:818–821, 1998.
Benirschke K, des Roches Harper V: The acardiac anomaly. Teratology
15:311–316, 1977.
Blaicher W, Repa C, Schaller A: Acardiac twin pregnancy: associated with trisomy 2. Hum Reprod 15:474–475, 2000.
Blenc AM, Gömez JA, Collins D, et al.: Pathologic quiz case. Pathologic diagnosis: acardiac fetus, acardius acephalus type. Arch Pathol Lab Med
123:974–976, 1999.
Bonilla-Musoles F, Machado LE, Raga F, et al.: Fetus acardius. Two- and threedimensional ultrasonographic diagnoses. J Ultrasound Med 20:1117–1127,
2001.
Chen H, Gonzalez E, Hand AM, Cuestas R: The acardius acephalus and
monozygotic twinning. Schumpert Med Quart 1:195–199, 1983.


4

ACARDIA

Donnenfeld AE, Van de Woestijne J, Craparo F, et al.: The normal fetus of an
acardiac twin pregnancy: perinatal management based on echocardiographic and sonographic evaluation. Prenat Diagn 11:235–244, 1991.
French CA, Bieber FR, Bing DH, et al.: Twins, placentas, and genetics: acardiac twinning in a dichorionic, diamniotic, monozygotic twin gestation.
Hum Pathol 29:1028–1031, 1998.
Hanafy A, Peterson CM: Twin-reversed arterial perfusion (TRAP) sequence:
case reports and review of literature. Aust N Z J Obstet Gynaecol
37:187–191, 1997.
Healey MG: Acardia: predictive risk factors for the co-twin’s survival.
Teratology 50:205–213, 1994.

Sanjaghsaz H, Bayram MO, Qureshi F: Twin reversed arterial perfusion

sequence in conjoined, acardiac, acephalic twins associated with a normal
triplet. A case report. J Reprod Med 43:1046–1050, 1998.
Søgaard K, Skibsted L, Brocks V: Acardiac twins: Pathophysiology, diagnosis,
outcome and treatment. Six cases and review of the literature. Fetal Diagn
Ther 14:53–59, 1999.
Van Allen MI, Smith DW, Shepard TH: Twin reversed arterial perfusion
(TRAP) sequence: a study of 14 twin pregnancies with acardius. Semin
Perinatol 7:285–293, 1983.


ACARDIA

5

Fig. 2. Radiographs of the above acardiac fetus showing a missing
head, cervical vertebrae and part of upper thoracic vertebrae, rudimental lower ribs, malformed lower thoracic and lumbar vertebrae, and
relatively well-formed lower limbs.

Fig. 1. Ventral view of an acardiac acephalus fetus (upper photo)
shows a large abdominal defect, gastroschisis (arrow), through which
small rudiments of gastrointestinal tract are seen. Dorsal view (lower
photo) shows a very underdeveloped cephalic end and relatively welldeveloped lower limbs. The co-twin had major malformations consisting of a large omphalocele, ectopia cordis, and absent pericardium,
incompatible with life.
Fig. 3. The head and part of the thorax of this acardiac fetus are completely missing with relatively well-formed lower limbs.


6

ACARDIA

Fig. 4. Another acardiac fetus with a missing head and part of the
upper thorax. Radiograph shows missing head, and cervical and part
of thoracic vertebrae and ribs. Pelvis and lower limbs are well formed.

Fig. 5. Acardius (second twin, 36-weeks gestation) showing spherical
body with a small amorphous mass of leptomeningeal and glial tissue
at the cephalic end. There were one deformed lower extremity and a
small arm appendage. Small intestinal loops, nodules of adrenal
glands, and testicles were present in the body. There was no heart or
lungs. The placenta was nonoamniotic monochorionic with velamentous insertion of the umbilical cord. The other identical twin was free
of birth defects. Radiograph of acardius twin shows a short segment of
the spine, a femur, a tibia, and a fibula.


Achondrogenesis
e. Heart
i. Patent ductus arteriosus
ii. Atrial septal defect
iii. Ventricular septal defect
f. Protuberant abdomen
g. Limbs
i. Extremely short (micromelia), shorter than type II
ii. Flipper-like appendages
3. Achondrogenesis type II
a. Growth
i. Lethal neonatal dwarfism
ii. Mean birth weight of 2100 g
b. Craniofacial features
i. Disproportionately large head
ii. Large and prominent forehead

iii. Midfacial hypoplasia
a) Flat facial plane
b) Flat nasal bridge
c) Small nose with severely anteverted nostrils
iv. Normal philtrum
v. Micrognathia
vi. Cleft palate
c. Extremely short neck
d. Thorax
i. Short and flared thorax
ii. Bell-shaped cage
iii. Lung hypoplasia
e. Protuberant abdomen
f. Extremely short limbs (micromelia)

Achondrogenesis is a heterogeneous group of lethal chondrodysplasias. Achondrogenesis type I (Fraccaro-Houston-Harris
type) and type II (Langer-Saldino type) were distinguished on the
basis of radiological and histological criteria. Achondrogenesis
type I was further subdivided, on the basis of convincing histological criteria, into type IA, which has apparently normal cartilage matrix but inclusions in chondrocytes, and type IB,
which has an abnormal cartilage matrix. Classification of type
IB as a separate group has been confirmed recently by the discovery of its association with mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene, making it allelic with
diastrophic dysplasia.

GENETICS/BASIC DEFECTS
1. Type IA: an autosomal recessive disorder with an
unknown chromosomal locus
2. Type IB
a. An autosomal recessive disorder
b. Resulting from mutations of the DTDST gene, which
is located at 5q32-q33

3. Type II
a. Autosomal dominant type II collagenopathy
b. Resulting from mutations in the COL2A1 gene, which
is located at 12q13.1-q13.3

CLINICAL FEATURES
1. Prenatal/perinatal history
a. Polyhydramnios
b. Hydrops
c. Breech presentation
d. Perinatal death
2. Achondrogenesis type I
a. Growth
i. Lethal neonatal dwarfism
ii. Mean birth weight of 1200 g
b. Craniofacial features
i. Disproportionately large head
ii. Soft skull
iii. Sloping forehead
iv. Convex facial plane
v. Flat nasal bridge, occasionally associated with a
deep horizontal groove
vi. Small nose, often with anteverted nostrils
vii. Long philtrum
viii. Retrognathia
ix. Increased distance between lower lip and lower
edge of chin
x. Double chin appearance
c. Extremely short neck
d. Thorax

i. Short and barrel-shaped thorax
ii. Lung hypoplasia

DIAGNOSTIC INVESTIGATIONS
1. Radiological features
a. Variable features
b. No single obligatory feature
c. Distinction between type IA and type IB on radiographs not always possible
d. Degree of ossification: age dependent, and caution is
needed when comparing radiographs at different gestational ages
e. Achondrogenesis type I
i. Skull: Varying degree of deficient cranial ossification consisting of small islands of bone in
membranous calvaria
ii. Thorax and ribs
a) Short and barrel-shaped thorax
b) Thin ribs with marked expansion at costochondral junction, frequently with multiple
fractures
iii. Spine and pelvis
a) Poorly ossified spine, ischium, and pubis
b) Poorly ossified iliac bones with short medial
margins
7


8

ACHONDROGENESIS

iv. Limbs and tubular bones
a) Extreme micromelia, with limbs much shorter

than in type II
b) Prominent spike-like metaphyseal spurs
c) Femur and tibia frequently presenting as
short bone segments
v. Subtype IA (Houston-Harris type)
a) Poorly ossified skull
b) Thin ribs with multiple fractures
c) Unossified vertebral pedicles
d) Arched ilium
e) Hypoplastic but ossified ischium
f) Wedged femur with metaphyseal spikes
g) Short tibia and fibula with metaphyseal flare
vi. Subtype IB (Fraccaro type)
a) Adequately ossified skull
b) Absence of rib fractures
c) Total lack of ossification or only rudimentary
calcification of the center of the vertebral
bodies
d) Ossified vertebral pedicles
e) Iliac bones with ossification only in their upper
part, giving a crescent-shaped, “paragliderlike” appearance on X-ray
f) Unossified ischium
g) Shortened tubular bones without recognized
axis
h) Metaphyseal spurring giving the appearance
of a “thorn apple” or “acanthocyte” (a descriptive term in hematology)
i) Trapezoid femur
j) Stellate tibia
k) Unossified fibula
l) Poorly ossified phalanges

f. Achondrogenesis type II
i. Skull
a) Normal cranial ossification
b) Relatively large calvaria
ii. Thorax and ribs
a) Short and flared thorax
b) Bell-shaped cage
c) Shorter ribs without fractures
iii. Spine and pelvis: relatively well-ossified iliac
bones with long, crescent-shaped medial and
inferior margins
iv. Limbs and tubular bones
a) Short, broad bones, usually with some diaphyseal constriction and flared, cupped
metaphyseal ends
b) Metaphyseal spurs, usually smaller than type I
2. Histologic features
a. Achondrogenesis type IA
i. Normal cartilage matrix
ii. Absent collagen rings around the chondrocytes
iii. Vacuolated chondrocytes
iv. Presence of intrachondrocytic inclusion bodies
(periodic acid-Schiff [PAS] stain positive, diastase resistant)
v. Extraskeletal cartilage involvement

vi. Enlarged lacunas
vii. Woven bone
b. Achondrogenesis type IB
i. Abnormal cartilage matrix: presence of
“demasked” coarsened collagen fibers, particularly dense around the chondrocytes, forming
collagen rings

ii. Abnormal staining properties of cartilage
a) Reduced staining with cationic dyes, such as
toluidine blue or Alcian blue, probably
because of a deficiency in sulfated proteoglycans
b) This distinguishes type IB from type IA, in
which the matrix is close to normal and
inclusions can be seen in chondrocytes, and
from achondrogenesis type II, in which
cationic dyes give a normal staining pattern
c. Achondrogenesis type II
i. Cartilage
a) Slightly larger than normal
b) Grossly distorted (lobulated and mushroomed)
ii. Markedly deficient cartilaginous matrix
iii. Severe disturbance in endochondral ossification
iv. Hypercellular and hypervascular reserve cartilage
with large, primitive mesenchymal (ballooned)
chondrocytes with abundant clear cytoplasm
(vacuoles) (“Swiss cheese-like”)
v. Overgrowth of membranous bones resulting in
cupping of the epiphyseal cartilages
vi. Decreased amount and altered structure of proteoglycans
vii. Relatively lower content of chondroitin 4-sulfate
viii. Lower molecular weight and decreased total
chondroitin sulfation
ix. Absence of type II collagen
x. Increased amounts of type I and type III collagen
3. Biochemical testing
a. Lack of sulfate incorporation: cumbersome and not
used for diagnostic purposes

b. Sulfate incorporation assay in cultured skin fibroblasts or chondrocytes: recommended in the rare
instances in which the diagnosis of achondrogenesis
type IB is strongly suspected but molecular genetic
testing fails to detect SLC26A2 (DTDST) mutations
4. Molecular genetic studies
a. Mutation analysis of the DTDST gene, reported in:
i. Achondrogenesis type IB (the most severe form)
ii. Atelosteogenesis type II (an intermediate form)
iii. Diastophic dysplasia (the mildest form)
iv. Recessive multiple epiphyseal dysplasia
b. Achondrogenesis type IB
i. Mutation analysis: testing of the following four
most common SLC26A2 (DTDST) gene mutations (mutation detection rate about 60%)
a) R279W
b) IVS1+2T>C (“Finnish” mutation)
c) delV340
d) R178X


ACHONDROGENESIS

ii. Sequence analysis of the SLC26A2 (DTDST)
coding region (mutation detection rate over 90%)
a) Private mutations
b) Common mutations
c. Achondrogenesis type II: mutation analysis of the
COL2A1 gene

GENETIC COUNSELING
1. Recurrence risk

a. Patient’s sib
i. Achondrogenesis type IA and type IB (autosomal recessive disorders)
a) Recurrence risk: 25%
b) Unaffected sibs of a proband: 2/3 chance of
being heterozygotes
ii. Achondrogenesis type II
a) Usually caused by a new dominant mutation, in which case recurrence risk is not significantly increased
b) Asymptomatic carrier parent (germline
mutation for a dominant mutation) may be
present in the families of affected patients, in
which case recurrence risk is 50%
b. Patient’s offspring: lethal entities not surviving to
reproduction
2. Prenatal diagnosis
a. Ultrasonography
i. Polyhydramnios
ii. Fetal hydrops
iii. Disproportionally big head
iv. Nuchal edema
v. Cystic hygroma
vi. A narrow thorax
vii. Short limbs
viii. Poor ossification of vertebral bodies and limb
tubular bones (leading to difficulties in determining their length)
ix. Suspect achondrogenesis type I
a) An extremely echo-poor appearance of the
skeleton
b) A poorly mineralized skull
c) Short limbs
d) Rib fractures

b. Molecular genetic studies
i. Prenatal diagnosis of achondrogenesis type IB
and type II by mutation analysis of chorionic villus DNA or amniocyte DNA in the first or second trimester
ii. Achondrogenesis type IB
a) Characterize both alleles of DTDST beforehand
b) Identify the source parent of each allele
c) Theoretically, analysis of sulfate incorporation in chorionic villi might be used for prenatal diagnosis, but experience is lacking
iii. Achondrogenesis type II
a) The affected fetus usually with a new dominant mutation of the COL2A1 gene

9

b) Possible presence of asymptomatic carriers
in families of an affected patient
c) Prenatal diagnosis possible if the mutation
has been characterized in the affected family
3. Management
a. Supportive care
b. No treatment available for the underlying lethal
disorder

REFERENCES
Balakumar K: Antenatal diagnosis of Parenti-Fraccaro type achondrogenesis.
Indian Pediatr 27:496–499, 1990.
Bonafé L, Ballhausen D, Superti-Furga A: Achondrogenesis type 1B. Gene
reviews, 2004.
Borochowitz Z, Lachman R, Adomian GE, et al.: Achondrogenesis type I:
delineation of further heterogeneity and identification of two distinct subgroups. J Pediatr 112:23–31, 1988.
Borochowitz Z, Ornoy A, Lachman R, et al.: Achondrogenesis II-hypochondrogenesis: variability versus heterogeneity. Am J Med Genet 24:273–288,
1986.

Benacerraf B, Osathanondh R, Bieber FR: Achondrogenesis type I: ultrasound
diagnosis in utero. J Clin Ultrasound 12:357–359, 1984.
Chen H: Achondrogenesis. Emedicine, 2001.
Chen H: Skeletal dysplasia. Emedicine, 2002.
Chen H, Liu CT, Yang SS: Achondrogenesis: a review with special consideration of achondrogenesis type II (Langer-Saldino). Am J Med Genet
10:379–394, 1981.
Faivre L, Le Merrer M, Douvier S, et al.: Recurrence of achondrogenesis type
II within the same family: Evidence for germline mosaicism. Am J Med
Genet 126A:308–312, 2004.
Godfrey M, Hollister DW: Type II achondrogenesis-hypochondrogenesis: identification of abnormal type II collagen. Am J Hum Genet 43:904–913, 1988.
Horton WA, Machado MA, Chou JW, et al.: Achondrogenesis type II, abnormalities of extracellular matrix. Pediatr Res 22:324–329, 1987.
Körkkö J, Cohn DH, Ala-Kokko L, et al.: Widely distributed mutations in the
COL2A1 gene produce achondrogenesis type II/hypochondrogenesis.
Am J Med Genet 92:95–100, 2000.
Langer LO, Jr, Spranger JW, Greinacher I, et al.: Thanatophoric dwarfism. A
condition confused with achondroplasia in the neonate, with brief comments on achondrogenesis and homozygous achondroplasia. Radiology
92:285–294 passim, 1969.
Meizner I, Barnhard Y: Achondrogenesis type I diagnosed by transvaginal ultrasonography at 13 weeks’ gestation. Am J Obstet Gynecol 173:1620–1622,
1995.
Molz G, Spycher MA: Achondrogenesis type I: light and electron-microscopic
studies. Eur J Pediatr 134:69–74, 1980.
Mortier GR, Wilkin DJ, Wilcox WR, et al.: A radiographic, morphologic, biochemical and molecular analysis of a case of achondrogenesis type II
resulting from substitution for a glycine residue (Gly691>Arg) in the type
II collagen trimer. Hum Mol Genet 4:285–288, 1995.
Ornoy A, Sekeles E, Smith P, et al.: Achondrogenesis type I in three sibling
fetuses. Scanning and transmission electron microscopic studies. Am J
Pathol 82:71–84, 1976.
Smith WL, Breitweiser TD, Dinno N: In utero diagnosis of achondrogenesis,
type I. Clin Genet 19:51–54, 1981.
Soothill PW, Vuthiwong C, Rees H: Achondrogenesis type 2 diagnosed by transvaginal ultrasound at 12 weeks’ gestation. Prenat Diagn 13:523–528, 1993.

Spranger J: International classification of osteochondrodysplasias. Eur J
Pediatr 151:407–415, 1992.
Spranger J, Winterpacht A, Zabel B: The type II collagenopathies: a spectrum
of chondrodysplasias. Eur J Pediatr 153:56–65, 1994.
Superti-Furga A: Achondrogenesis type 1B. J Med Genet 33:957–961, 1996.
Superti-Furga A, Hästbacka J, Wilcox WR, et al.: Achondrogenesis type IB is
caused by mutations in the diastrophic dysplasia sulphate transporter
gene. Nat Genet 12:100–102, 1996.
Superti-Furga A, Rossi A, Steinmann B, et al.: A chondrodysplasia family produced by mutations in the diastrophic dysplasia sulfate transporter gene:
genotype/phenotype correlations. Am J Med Genet 63:144–147, 1996.


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ACHONDROGENESIS

Tongsong T, Srisomboon J, Sudasna J: Prenatal diagnosis of Langer-Saldino
achondrogenesis. J Clin Ultrasound 23:56–58, 1995.
van der Harten HJ, Brons JT, Dijkstra PF, et al.: Achondrogenesis-hypochondrogenesis: the spectrum of chondrogenesis imperfecta. A radiological,
ultrasonographic, and histopathologic study of 23 cases. Pediatr Pathol
8:571–597, 1988.
Yang SS, Bernstein J: Letter: Proposed readjustment of eponyms for achondrogenesis. J Pediatr 87:333–334, 1975.
Yang S-S, Heidelberger KP, Brough AJ, et al.: Lethal short-limbed chondrodysplasia in early infancy. Persp Pediatr Pathol 3:1–40, 1976.

Yang SS, Bernstein J: Achondrogenesis type I. Arch Dis Child 52:253–254,
1977.
Yang SS, Gilbert-Barnes E: Skeletal system. In: Gilbert-Barness E (ed):
Potter’s Pathology of the Fetus and Infant. St Louis: Mosby, 1997, pp
1423–1478.
Yang SS, Brough AJ, Garewal GS, et al.: Two types of heritable lethal achondrogenesis. J Pediatr 85:796–801, 1974.

Yang SS, Heidelberger KP, Bernstein J: Intracytoplasmic inclusion bodies in
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7:667–673, 1976.


ACHONDROGENESIS

11

Fig. 1. A neonate with achondrogenesis type I showing large head,
short trunk, and extreme micromelia. Radiograph shows unossified
calvarium, vertebral bodies and some pelvic bones. The remaining
bones are extremely small. There are multiple rib fractures. The sagittal section of the femora and the humeri are similar. An extremely
small ossified shaft is capped by a relatively large epiphyseal cartilage
at both ends. Photomicrographs of resting cartilage with high magnification show many chondrocytes that contain large cytoplasmic
inclusions which are within clear vacuoles (Diastase PAS stain).
Electron micrograph shows inclusion as a globular mass of electron
dense material. It is within a distended cistern of rough endoplasmic
reticulum.


12

ACHONDROGENESIS

Fig. 2. Achondrogenesis type II. As in type I, this neonate shows large
head, short trunk, and micromelia. Sagittal section of the femur shows
much better ossification of the shaft than type I. The cartilage lacks glistering appearance due to cartilage matrix deficiency. Photomicrograph
of the entire cartilage shows severe deficiency of cartilage matrix. The
cartilage canals are large, fibrotic, and stellate in shape. Physeal growth

zone is severely retarded.


ACHONDROGENESIS

Fig. 3. Two infants with achondrogenesis type II showing milder spectrum of manifestations, bordering the type II and spondyloepiphyseal
congenita.

13


14

ACHONDROGENESIS

Fig. 4. A newborn girl with achondrogenesis type II showing large head,
midfacial hypoplasia, short neck, small chest, and short limbs. The radiographs shows generalized shortening of the long bones of the upper and
lower extremities with marked cupping (metaphyseal spurs) at the metaphyseal ends of the bones. This is most evident at the distal ends of the
tibia, fibular, radius and ulna, and distal ends of the digits. Radiographs
also shows short ribs without fractures and hemivertebrae involving
thoracic vertebrae as well as the sacrum. Conformation-sensitive gel
electrophoresis analysis indicated a sequence variation in the fragment
containing exon 19 and the flanking sequences of the COL2A1 gene
(Gly244Asp). Similar mutations in this area have been seen in patients
diagnosed with hypochondroplasia and achondrogenesis type II.


Achondroplasia
CLINICAL FEATURES

Achondroplasia is the most common form of short-limbed
dwarfism. Gene frequency is estimated to be 1/16,000 and
1/35,000. There are about 5000 achondroplasts in the USA and
65,000 on Earth. The incidence for achondroplasia is between
0.5 and 1.5 in 10,000 births. The mutation rate is high and is
estimated to be between 1.72×10–5 and 5.57×10–5 per gamete
per generation. Most infants with achondroplasia are born
unexpectedly to parents of average stature.

1. Major clinical symptoms
a. Delayed motor milestones during infancy and early
childhood
b. Sleep disturbances secondary to both neurological
and respiratory complications
c. Breathing disorders
i. A high prevalence (75%) of breathing disorders
during sleep
ii. Obstructive apnea caused by upper airway
obstruction
iii. The majority of respiratory complaints due to
restrictive lung disease secondary to diminished
chest size or upper airway obstruction and rarely
due to spinal cord compression
d. Symptomatic spinal stenosis in more than 50% of
patients as a consequence of a congenitally small
spinal canal
i. Back pain
ii. Lower extremity sensory changes
iii. Incontinence
iv. Paraplegia

v. Onset of symptoms: usually after 20 seconds or
30 seconds
e. Neurologic symptoms classified based on neurologic
severity and presentation of spinal stenosis (Lutter
and Langer, 1977)
i. Type I (back pain with sensory and motor change
of an insidious nature)
ii. Type II (intermittent claudication limiting ambulation)
iii. Type III (nerve root compression)
iv. Type IV (acute onset paraplegia)
f. Symptoms secondary to foramen magnum stenosis
i. Respiratory difficulty
ii. Feeding problems
iii. Cyanosis, quadriparesis
iv. Poor head control
g. Symptoms secondary to cervicomedullary compression
i. Pain
ii. Ataxia
iii. Incontinence
iv. Apnea
v. Progressive quadriparesis
vi. Respiratory arrest
2. Major clinical signs
a. Disproportionate short stature (dwarfism)
b. Hypotonia during infancy and early childhood
c. Relative stenosis of the foramen magnum in all
patients, documented by CT
d. Foramen magnum stenosis considered as the cause of
increased incidence of:

GENETICS/BASIC DEFECTS
1. Inheritance
a. Autosomal dominant disorder with complete penetrance
b. Sporadic in about 80% of the cases, the result of a de
novo mutation
c. Presence of paternal age effect (advanced paternal
age in sporadic cases)
d. Gonadal mosaicism (two or more children with classic achondroplasia born to normal parents)
2. Caused by mutations in the gene of the fibroblast growth
factor receptor 3 (FGFR3) on chromosome 4p16.3
a. About 98% of achondroplasia with G-to-A transition
and about 1% G-to-C transversion at nucleotide 1138.
Both mutations resulted in the substitution of an arginine residue for a glycine at position 380 (G380A) of
the mature protein in the transmembrane domain of
FGFR3
b. A rare mutation causing substitution of a nearby
glycine 375 with a cysteine (G375C)
c. Another rare mutation causing substitution of
glycine346 with glutamic acid (G346E)
d. The specific mechanisms by which FGFR3 mutations
disrupt skeletal development in achondroplasia remain
elusive
3. Basic defect: zone of chondroblast proliferation in the
physeal growth plates
a. Abnormally retarded endochondral ossification with
resultant shortening of tubular bones and flat vertebral bodies, while membranous ossification (skull,
facial bones) is not affected
b. Physeal growth zones show normal columnization,
hypertrophy, degeneration, calcification, and ossification. However, the growth is quantitatively reduced
significantly

c. Achondroplasia as the result of a quantitative loss of
endochondral ossification rather than the formation of
abnormal tissue
d. Normal diameter of the bones secondary to normal
subperiosteal membranous ossification of tubular
bones; the results being production of short, thick
tubular bones, leading to short stature with disproportionately shortened limbs
15


16

ACHONDROPLASIA

i. Hypotonia
ii. Sleep apnea
iii. Sudden infant death syndrome
e. Symptomatic hydrocephalus in infancy and early childhood rarely due to narrowing of the foramen magnum
f. Characteristic craniofacial appearance
i. Disproportionately large head
ii. Frontal bossing
iii. Depressed nasal bridge
iv. Midfacial hypoplasia
v. Narrow nasal passages
vi. Prognathism
vii. Dental malocclusion
g. A normal trunk length
h. A thoracolumbar kyphosis or gibbus usually present
at birth or early infancy
i. Exaggerated lumbar lordosis when the child begins to

ambulate
j. Prominent buttocks and protuberant abdomen secondary to increased pelvic tilt in children and adults
k. Generalized joint hypermobility, especially the knees
l. Rhizomelic micromelia (relatively shorter proximal
segment of the limbs compared to the middle and the
distal segments)
m. Limited elbow and hip extension
n. Trident hands (inability to approximate the third and
fourth fingers in extension produces a “trident” configuration of the hand)
o. Short fingers (brachydactyly)
p. Bowing of the legs (genu varum) due to lax knee ligaments
q. Excess skin folds around thighs
3. Complications/risks
a. Recurrent otitis media during infancy and childhood
i. Conductive hearing loss
ii. Delayed language development
b. Thoraco-lumbar gibbus
c. Osteoarthropathy of the knee joints
d. Neurological complications
i. Small foramen magnum
ii. Cervicomedullary junction compression causing
sudden unexpected death in infants with achondroplasia
iii. Apnea
iv. Communicating hydrocephalus
v. Spinal stenosis
vi. Paraparesis
vii. Quadriparesis
viii. Infantile hypotonia
e. Obesity
i. Aggravating the morbidity associated with lumbar stenosis

ii. Contributing to the nonspecific joint problems
and to the possible early cardiovascular mortality in this condition
f. Obstetric complications
i. Large head of the affected infant
ii. An increased risk of intracranial bleeding during
delivery
iii. Marked obstetrical difficulties secondary to very
narrow pelvis of achondroplastic women

4. Prognosis
a. Normal intelligence and healthy, independent, and
productive lives in vast majority of patients. Rarely,
intelligence may be affected because of hydrocephalus or other CNS complications
b. Mean adult height
i. Approximately 131 ± 5.6 cm for males
ii. Approximately 124 ± 5.9 cm for females
c. Psychosocial problems related to body image because
of severe disproportionate short stature
d. Life- span for heterozygous achondroplasia
i. Usually normal unless there are serious complications
ii. Mean life expectancy approximately 10 years
less than the general population
e. Homozygous achondroplasia
i. A lethal condition with severe respiratory distress caused by rib-cage deformity and upper
cervical cord damage caused by small foramen
magnum. The patients die soon after birth
ii. Radiographic changes much more severe than
the heterozygous achondroplasia
f. Normal fertility in achondroplasia
i. Pregnancy at high risk for achondroplastic

women
ii. Respiratory compromise common during the
third trimester
iii. Advise baseline pulmonary function studies
before pregnancy to aid in evaluation and management
iv. A small pelvic outlet usually requiring cesarean
section under general anesthesia since the spinal
or epidural approach is contraindicated because
of spinal stenosis
g. Anticipatory guidance: patients and their families can
benefit greatly from anticipatory guidance published
by American Academy of Pediatrics Committee on
Genetics (1995)
h. Adaptations of patients to the environment to foster
independence
i. Lowering faucets and light switches
ii. Using a step stool to keep feet from dangling
when sitting
iii. An extended wand for toileting
iv. Adaptations of toys for short limbs
i. Support groups: Many families find it beneficial to
interact with other families and children with achondroplasia through local and national support groups

DIAGNOSTIC INVESTIGATIONS
1. Diagnosis of achondroplasia made by clinical findings,
radiographic features, and/or FGFR3 mutation analysis
2. Radiologic features
a. Skull
i. Relatively large calvarium
ii. Prominent forehead

iii. Depressed nasal bridge
iv. Small skull base
v. Small foramen magnum
vi. Dental malocclusion