Handbook of Pediatric Autopsy Pathology

Enid Gilbert-Barness • Diane E. Spicer Thora S. Steffensen

Second Edition

Foreword by John M. Opitz Enid Gilbert-Barness, AO, MD, MBBS, FRCPA, Thora S. Steffensen, MD FRCPath, DSci(hc), MD(hc), DSci(hc) Department of Pathology Professor of Pathology and Cell Tampa General Hospital Biology, Laboratory Medicine, Pediatrics and Tampa , Florida Obstetrics and Gynecology USA Tampa General Hospital Morsani College of Medicine University of South Florida Tampa , Florida USA

Diane E. Spicer, BS, PA(ASCP) Department of Pediatrics-Cardiology University of Florida Valrico , Florida USA

ISBN 978-1-4614-6710-6 ISBN 978-1-4614-6711-3 (eBook) DOI 10.1007/978-1-4614-6711-3 Springer New York Heidelberg Dordrecht London

Library of Congress Control Number: 2013941138

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Springer is part of Springer Science+Business Media (www.springer.com) Dr. John Opitz and Dr. Lewis Barness My two heros! —Enid Gilbert-Barness To my husband, Gary Myers; my parents, Agnes and Bjorn Steffensen; and in memory of my father-in-law, Dr. Ivan Myers. —Thora S. Steffensen To my husband, Scott, and son, Andrew, for all of their support and to my parents, Charles and Patricia Debich. —Diane E. Spicer

Foreword

All workers in pediatric and fetal pathology must acknowledge with deep gratitude the massive effort required to revise this book, ﬁ rst published in 2005. It immediately became the standard text for daily use; no autopsy protocol goes out from our service without citation of the Handbook; at times it seems that the residents and fellows must know most of it by heart. It is so far more than a dry recital of facts and data and useful in so many ways concerning growth, development, and developmental pathology, expertly written and beautifully illustrated. Since 2005, a veritable revolution has occurred in our specialty. Huge advances in developmental biology in many species make it now extensively possible to infer pathogenesis, if not cause, from phenotype and known animal “models” involving deﬁ ned signal transduction pathways. This work has also enabled a profound insight into the relationship between evolu- tion and development and, not incidentally, an appreciation of Meckel’s prescient understanding (1812) that primary malformations are not contrary to nature, particularly if they represent the normal anatomical state in other species—think: absent corpus callosum, cleft palate, penoscrotal inversion, tail, cloaca, webbed digits, polymastia, etc. Thus, there is great useful- ness after all in the concept of atavisms (Darwin’s reversions), Ruppert A Willis (1958) not- withstanding. In a nutshell: Everything that develops, whether normal or abnormal, has evolved. And the antiquity of these morphogenetic mechanisms is truly astonishing, even more so the fact that many of these mechanisms are present, in potentiam, in organisms without the corresponding organ or body part—think only of Amphioxus with all the genes for it but no neural crest. As more and more basal organisms are “sequenced,” this will become a common insight. As important are the recent technical advances such as microarray analyses which allow detection of additional causal deletions and/or duplications not detectable by standard karyo- type analysis. Or the gas chromatography/mass spectrometry methods do detect previously biochemically intractable abnormalities of sterol metabolism that may result in fetal/infant death. And not least, the newer radiological methods which improve detection e.g. of cervical ribs as a “litmus test” for lethal developmental disorders such as aneuploidy or childhood cancer. Thus, the completion of this revision of the Gilbert-Barness and Debich-Spicer Handbook with the addition of Dr. Thora Steffensen comes at an extraordinarily propitious time in the history of pathology promising to help us advance even more rapidly our understanding of developmental pathology.

Salt Lake City, UT, USA John M. Opitz, MD, DSci(hc), MD(hc), MD(hc), MD(hc), DSci(hc)

vii

Foreword from the 1st Edition

It is a profoundly gratifying and joyous occasion to welcome and recommend Gilbert-Barness and Debich-Spicer’s Handbook of Pediatric Autopsy Pathology, the distillation of a profes- sional lifetime of experience, practice, and discovery by one of the world’s most distinguished pediatric pathologists (ably assisted by her coworker D. Debich-Spicer). For over a third of a century I have been privileged to collaborate closely, at ﬁ rst as fellow faculty member in Madison, subsequently in a long-distance consultative relationship (Helena to Madison, and ﬁ nally Salt Lake City to Tampa) with one of the most tireless and devoted experts in constitutional, pediatric, developmental, and genetic pathology. Initially it was for me, as apprentice, to learn from this peerless teacher, the practical aspects of studying dead fetuses and infants for inferences of pathogenesis and cause, with the aim to attain diagnosis and a deeper understanding of the underlying biology of the condition. This was an apprenticeship which arose, long ago, out of a combined NIH Medical Genetics Research Center Grant at the University of Wisconsin in which we studied together, whenever possible, the infants and children before death, and after death with all of our trainees, involving coworkers in anatomy, genetics, embryology, and pathology. An apprenticeship moreover that motivated me to continue the vitally (meant literally) important study of dead embryos, fetuses, and infants in Montana, part of a region (including Idaho, Montana, Wyoming, North and South Dakota, and Nevada) without a single pediatric pathologist. This regional fetal genetic pathology program could not have functioned without the almost daily advice and input of Dr. Gilbert-Barness and her coworkers. In recognition of her role as one of the most highly regarded pathology teachers in the world, the University of Wisconsin created the distinguished Enid Gilbert-Barness Lectureship before her departure to the University of South Florida. She has been President of the Society of Pediatric Pathology, the International Pediatric Pathology Association and of several related organizations, has taught on every continent (except Antarctica), was a founder of the International Workshops of Fetal Genetic Pathology, is the editor of the two volume Potter’s Pathology of the Fetus and Infant (under revision) with its companion Atlas, and the author (with D. Debich-Spicer) of Embryo and Fetal Pathology (2004), and with her husband, Lewis A. Barness, author of Metabolic Diseases: Foundations of Clinical Management, Genetics, and Pathology , vol. 2 (2000), and Clinical Use of Pediatric Diagnostic Tests (2003). Recently, Dr. Gilbert-Barness (with a group of enthusiastic editorial coworkers) undertook the editorship of the journal Fetal and Pediatric Pathology , a journal which recognizes the important contributions to the study and biology of fetal and pediatric death by many other specialists, including embryologists, developmental biologists, and geneticists, experts in maternal-fetal medicine, metabolic diseases, peri- and neonatology, and clinical geneticists. The present book is an intensely practical, profusely illustrated, and most useful treatise, published at a propitious time in history, e.g., the formation of the International College of Fetal Genetic Pathology and the initiation of the NICHHD-sponsored and NICHHD-supported multicenter study of the causes of stillbirth for both of which this book can serve as a guide for minimal standards in the practice of the causal analysis of fetal and infant death. In reading this book, I had the vivid experience of having revisited the grove of Akademe with my mentor in recognizing so many of the patients Dr. Gilbert-Barness and I have studied together.

ix x Foreword from the 1st Edition

Medicine arose out of the study of pathology, one of the most important foundations of biomedicine. And western pathology arose out of observations of malformations preserved in folklore and the notes of early surgeons (e.g., Pare, John Hunter) and physician/naturalists (e.g., Aldrovandi), but was not established as a legitimate medical specialty per se until Giovanni Battista Morgagni (1682–1771), a student of Valsalva and Professor of Pathological Anatomy at Padova for 56 years. His three-volume treatise De sedibus et causis morborum per anatomen indagatis (1779) is no less erudite than the present book, but in over 1,500 pages has not a single illustration in it. François Xavier Bichat (1771–1802), a gifted observer, founded histological pathology through his careful study of tissues or “membranes” in disease. Matthew Baillie (1761–1823), nephew of John Hunter and physician of George III, published his won- derful Morbid Anatomy with many excellent engravings, that of pulmonary emphysema illus- trating the lungs of Dr. Samuel Johnson. Carl (von) Rokitansky (1804–1878), a Czech, was Professor of Pathology at Vienna for 30 years, and, like our present authors, performed thou- sands of autopsies, and from this experience published a much-admired, clear, multivolume compendium on pathology that remained the standard for decades. Of his four sons, he said that the two who were physicians healed (heilen), the two who were musicians howled (heu- len). Rudolf (von) Virchow (1821–1902) initially Professor of Pathology in Würzburg, then in Berlin, was the founder of Cellular Pathology, founder and for decades editor of the Archiv für pathologische Anatomie (“Virchows Archiv…”), who is additionally renowned as an anthro- pologist and an advocate for democracy and social justice with the courage to stand up against Bismarck in Parliament. Subsequent developments in infections, genetics, and molecular biology have transformed the face of pathology, but never the guiding sentiment of this book: Mantui vivas docueran : Let the dead teach the living. Handbook of Pediatric Autopsy Pathology stands as a worthy succes- sor to those of the immortal giants mentioned above, who began, while they continue, to enrich our knowledge of life and death and have set highest standards for its study. This is one of those dozen or so books on the ﬁ rst shelf right over my head at my desk where I can reach it at all times without looking, altogether indispensible for the study and practice of developmental pathology.

Salt Lake City, UT, USA John M. Opitz, MD, MD(hc), DSci(hc), MD(hc) Preface

The fi rst edition of this text was published in 2005, and at that time was written with the explicit aim to fi ll a void in pediatric autopsy pathology. The autopsy still remains of paramount importance for accurate diagnoses, genetic counseling, and for the de fi nitive diagnosis in many malformations and complex genetic conditions and, in particular, in fetal and perinatal pathology. Pediatric pathology includes examination of the embryo, fetus, and child. Of particular importance is the study of the aborted embryo that is so frequently totally neglected. We have, therefore, included speci fi cally a chapter on the examination of the embryo. In this volume, we have attempted to expand on the application of molecular and special recently described procedures such as DNA determination, enzyme analysis, and microarrays. The general format of the book has been maintained, but each chapter has been revised and expanded. In addition, black and white pictures have been replaced by color illustrations, and many new pictures and tables have been added. The additions of several chapters include skin, infectious diseases, hematopoietic diseases, tumors of childhood, and transplantation rejection. We are pleased to have been able to add Dr. Thora S. Steffensen as an additional author. It is our hope that this second edition will provide meaningful information and will assist in making the pediatric autopsy not only of paramount importance but an essential part of understanding the manner and cause of death in its broadest and comprehensive sense.

Tampa, FL, USA Enid Gilbert-Barness, AO, MD, MBBS, FRCPA, FRCPath, DSci(hc), MD(hc), DSci(hc) Valrico, FL, USA Diane E. Spicer, BS, PA(ASCP) Tampa, FL, USA Thora S. Steffensen, MD

Preface from the 1st Edition

The Handbook of Pediatric Autopsy Pathology has been compiled to fi ll a current void in the armamentarium for the pathologist performing the pediatric autopsy. The pediatric autopsy must be approached with great care in technique and dissection; malformations may be easily overlooked by the uninitiated. Of major importance in pediatric autopsy pathology is the need for accurate diagnosis in order to provide genetic counseling and the implication of possible recurrence in future pregnancies. Although adult autopsies have declined in recent years, the importance and demand for pediatric autopsies has accelerated. There have been extensive developments in the pediatric fi eld that enhance the importance of the autopsy, so that at the present time, the autopsy has probably greater importance within the fi eld of the fetal and perinatal pathologist than at any other age. These features largely relate to congenital malformations and genetic counseling. The detailed description of all abnormalities in both fetuses, stillborn, and older children is of paramount importance supplemented by cytogenetic studies, metabolic evaluation, and DNA and other analyses. The effect of any environmental or nutritional hazard is most obvious when related to periods of growth, and the fetus and the newborn are such periods in human development. Thus, any new environmental hazard and the effects of environmental agents and drugs including chemicals such as lead or radioactive materials, alcohol, or intrauterine infection, can and are best assessed by sampling specifi c tissues and organs from fetuses, stillborns, and newborn infants at autopsy examination. The careful performance of perinatal autopsies followed by dissemination of the fi ndings to parents, clinicians, and public health organizations is important in the reduction of perinatal mortality and morbidity. Every pathologist should have a working knowledge of the pediatric autopsy. The careful performance of neonatal autopsies both adds to our basic understanding of neonatal diseases and is an excellent monitor of the results of treatment. The development of perinatology, prenatal diagnosis of birth defects, and genetic counseling requires accuracy of prenatal diagnostic techniques, including ultrasonography and corre- lation of clinical data with the results of carefully performed fetal autopsies. Parents and clinicians depend on accurate autopsy diagnoses for intelligent family planning. The autopsy examination is the foundation upon which a complete perinatal autopsy is built. In addition to the performance of a skilled autopsy biopsy, other ancillary studies and techniques are necessary to address the vital issues of accurate diagnosis. The Handbook of Pediatric Autopsy Pathology thoroughly addresses these issues including microbiologic, cytogenic, X-ray, and special studies such as enzyme and DNA analysis in metabolic diseases. This handbook also addresses the examination of the embryo in spontaneous abortions. The approach outlined is simple enough to be used routinely by the general pathologist with con- ventional facilities. Parts I and II provide principles and a general description of the techniques used in the pediatric autopsy as well as general aspects of the autopsy including the death certifi cate, cause and manner of death, obtaining permissions from the family, and examination of the placenta. Part III includes hydrops, chromosomal defects, and congenital abnormalities, with

xiii xiv Preface from the 1st Edition a discussion of major malformations. Disorders of each of the organ systems and metabolic diseases are discussed in Part I V , including the autopsy on metabolic disorders. Part V includes sudden infant death, the medicolegal and forensic autopsies, special procedures, infection control, and biological hazards at the autopsy. At the end of each chapter is an appendix that includes standard reference tables. This book is not intended to be an exhaustive treatise on pediatric pathology, but rather a guide to the actual performance of the pediatric autopsy as well as to the recognition and interpretation of pathologic ﬁ ndings. The Handbook of Pediatric Autopsy Pathology provides the prosector with a valuable source of information for conducting a meaningful and comprehensive autopsy. Thus, it should also be useful for general pathologists, as well as for specialist pediatric pathologists. The Handbook of Pediatric Autopsy Pathology is dedicated with great pride to Professor John L. Emery who was the master of pediatric pathology and whose techniques in performing an autopsy have been acclaimed worldwide. He, in fact, recognized the need for a pediatric pathology autopsy manual and initiated the writing of this book before his untimely death and before it could become a reality. Not only was he a pediatric pathologist par excellence, but a poet and an accomplished artist. Some of his sketches have been included in this volume.

Tampa, FL, USA Enid Gilbert-Barness, AO, MD, MBBS, FRCPA, FRCPath, DSci(hc), MD(hc), DSci(hc) Valrico, FL, USA Diane E. Spicer, BS, PA(ASCP) Acknowledgments

The authors wish to express thanks to their colleagues, to the chairman of Pathology and Cell Biology at University of South Florida, Dr. Santo Nicosia, the pathology facility at University of South Florida, and Dr. Robert Anderson, all who have been supportive in this effort. We wish to thank Dr. John Opitz for his unfailing support and encouragement and his always willing consultation in dif ﬁ cult cases. This book, however, would not have been possible without the untiring dedication and time- less and meticulous work of Kathleen Lonkey who prepared the entire manuscript.

Contents

Part I General Principles

1 Introduction and General Principles of Autopsy ...... 3 The Death Certiﬁcate ...... 3 Deaths That Must Be Referred to a Medical Examiner ...... 3 Jurisdiction of the Medical Examiner ...... 3 Manners of Death ...... 3 Beneﬁts of the Autopsy ...... 3 Medical Research ...... 3 Legal ...... 4 Family ...... 4 Persons Who May Make an Anatomical Gift of the Body or Organs of the Deceased Person in the United States ...... 4

Part II Techniques

2 Pediatric Autopsy: Fetus, Newborn, and Child ...... 7 Roentgenographic Examination ...... 7 Photographs ...... 7 Equipment ...... 8 Clinical Information ...... 8 Preautopsy Considerations ...... 10 External Examination ...... 10 Cytogenetics ...... 12 Initial Incision ...... 13 In Situ Examination of the Abdomen ...... 13 In Situ Examination of the Thorax ...... 15 Opening the Heart In Situ ...... 19 Evisceration ...... 21 Cerebrospinal Fluid Culture ...... 23 Removal of the Brain ...... 24 The Pituitary ...... 28 Removal of the Spinal Cord: Anterior Approach ...... 28 Bone Marrow Preparations ...... 29 Smears ...... 29 Reconstruction of the Body ...... 30 Dissecting the Organ Block ...... 32 Microscopic Examination ...... 34 Sectioning the Brain After Fixation ...... 35 Artifacts ...... 37 The Stillborn Autopsy ...... 37 Provisional Anatomic Diagnosis (PAD) ...... 38

xvii xviii Contents

Special Dissections ...... 38 Thoracic Duct ...... 38 Removal of the External Genitalia ...... 40 Examination of the Cardiac Conduction System ...... 40 Removing the Brain and Spinal Cord Intact: Posterior Approach ...... 42 Removal of the Eyes ...... 46 Techniques of Brain Removal for Examination in Suspected Malformations ...... 46 Removing the Temporal Bone ...... 47 Inﬂation of the Lungs with Formalin ...... 47 Hepatic Angiography ...... 47 Preparation of Corrosion Casts of Hepatic Vessels and Bile Ducts ...... 47 Gross Staining for Iron in the Liver ...... 48 Pancreas: Special Techniques ...... 48 Gastrointestinal Tract: Special Techniques ...... 48 Esophagus ...... 48 Angiography ...... 48 Perfusion ...... 48 Preparation of Specimens for Study Under the Dissecting Microscope ...... 49 Appendix 1: Clinical Information and Autopsy Checklist ...... 50 Appendix 2: Autopsy Protocol ...... 51 Appendix 3: List of Blocks ...... 54 Appendix 4: List of Blocks—Neuropathology ...... 54 Appendix 5: Criteria Estimating Fertilization Age During Fetal Period ...... 54 Appendix 6: Growth Characteristics of Placenta and Fetus ...... 55 Appendix 7: Body Surface Area in Children ...... 55 Appendix 8: Development and Growth of the External Dimensions of the Human Body ...... 56 Appendix 9a, b: Development and Growth of the External Dimensions of the Human Body ...... 56 Appendix 10: Intrauterine Growth of Live-Born Caucasian Infants at Sea Level . . 57 Appendix 11: Intrauterine Growth of Live-Born Caucasian Infants at Sea Level . . 58 Appendix 12: Intrauterine Growth of Live-Born Caucasian Infants at Sea Level . . 59 Appendix 13: Intrauterine Growth of Live-Born Caucasian Infants at Sea Level . . 59 Appendix 14: Hand Measurements by Age ...... 60 Appendix 15: Hand Middle Finger and Palm Length ...... 62 Appendix 16: Palpebral Fissure Length From 29 Week Gestation to 14 Years . . . 62 Appendix 17: Palpebral Fissure Length From 29 Week Gestation to 14 Years . . . 63 Appendix 18: Postnatal Growth in Infants Born After 30 Week Gestation ...... 64 Appendix 19: Fetal Organ Weights as a Function of Body Weight ...... 65 Appendix 20: Means and Standard Deviations of Organ Weights and Measurements of Live-Born Infants ...... 66 Appendix 21: Means and Standard Deviations of Organ Weights and Measurements of Stillborn Infants ...... 67 Appendix 22: Percentiles of Weights from Age 1–12 Month ...... 68 Appendix 23: Percentiles of Body Length from 1 to 12 Month of Age ...... 69 Appendix 24: Organ Weights in Children ...... 70 Appendix 25: Weights of All Four Parathyroid Glands Combined (mg) ...... 71 Appendix 26: Protocol for Gross Examination of the Brain ...... 71 Appendix 27: Brain Weight as a Function of Age in Children and Adolescents . . 72 Appendix 28: Gestational Development of the Cerebral Hemispheres ...... 73 Appendix 29: Regional Development of the Cerebral Hemispheres ...... 74 Appendix 30: Gyral Pattern of the Fetal Brain ...... 75 Contents xix

Appendix 31: Gyral Pattern of the Perinatal Brain ...... 76 Appendix 32: Surfaces of Cerebral Hemispheres for Use in Indicating Lesions . . . . . 77 Appendix 33: Gestational Age and Mean Organ Weights and Measurements with 1 Standard Deviation (SD) ...... 78 Appendix 34: Reference Values for Transverse Cerebellar Diameter Throughout Gestation ...... 79 Appendix 35: Reference Values for Second Trimester Fetal and Neonatal Organ Weights and Measurements ...... 80 Appendix 36: Reference Values for Second Trimester Fetal and Neonatal Organ Weights and Measurements ...... 81 Appendix 37: Reference Values for Second Trimester Fetal and Neonatal Organ Weights and Measurements ...... 82 Bibliography ...... 83 3 Examination of the Human Embryo ...... 85 Development of the Chorionic Sac ...... 88 Stages of Embryonic Development ...... 88 Examination of the Early Abortus ...... 91 Artifacts ...... 95 Growth Disorganization ...... 98 Growth Disorganization Type I (GD I) ...... 98 Growth Disorganization Type II (GD II) ...... 98 Growth Disorganization Type III (GD III) ...... 98 Growth Disorganization Type IV (GD IV) ...... 100 Examination of Fetuses from 9 to 20 Weeks of Gestation ...... 100 Equipment ...... 100 External Examination ...... 100 Initial Incision ...... 103 In Situ Examination of the Abdomen and Thorax ...... 103 Examination of the Brain ...... 105 Artifacts ...... 107 Examination of Dilatation and Evacuation Specimens ...... 107 Appendix 1: Specimen Evaluation and Collection ...... 116 Appendix 2: Instructions for Mailing Aborted Tissue ...... 117 Appendix 3: Timetable of Human Prenatal Development 1–6 Weeks/7–10 Weeks ...... 118 Appendix 4: Criteria for Estimating Fertilization Age During the Fetal Period ...... 120 Appendix 5: Crown-Rump Length and Developmental Age in Previable Fetuses ...... 121 Appendix 6: Weights and Measurements of Fetuses of 8–26-Week Gestation (Mean Values) ...... 122 Appendix 7: Hand and Foot Lengths Correlated with Developmental Age in Previable Fetuses ...... 122 Appendix 8: Body Measurements with Relationship to Fetal Age ...... 123 Appendix 9: Organ Weights with Relationship to Fetal Age ...... 123 Bibliography ...... 124 4 The Placenta ...... 125 Maturation of the Placenta ...... 125 Selection of Placentas to Be Examined ...... 125 Handling of the Placenta ...... 126 Immediate Examination of the Fresh Placenta ...... 127 Sectioning for Histology ...... 127 xx Contents

Gross and Microscopic Evaluation of the Placenta ...... 129 Umbilical Cord ...... 129 Membranes and Fetal Surface of the Placenta ...... 134 Placental Disk ...... 141 Microscopic Placental Pathology ...... 151 Fetal Vascular Obstruction ...... 154 Maternal Vascular Underperfusion ...... 156 Placenta from Multiple Pregnancies ...... 157 Placental Changes Related to Fetal Demise In Utero ...... 158 Molar Pregnancy ...... 158 Appendix 1: Placenta Gross Dictation ...... 163 Appendix 2: Placental Weights for Normal Fetuses at Developmental Ages 8–18 Weeks ...... 163 Appendix 3: Percentiles, Means, and Standard Deviations for Placental Weights by Gestational Age ...... 164 Appendix 4: Mean Weights and Percentiles for Twin Placentas ...... 165 Appendix 5: Mean Weights and Percentiles for Triplet Placentas ...... 165 Appendix 6: A Checklist for Umbilical Cords ...... 165 Appendix 7: Conditions Associated with Short Cords ...... 165 Appendix 8: Conditions Associated with Long Cords (>70 cm) ...... 166 Bibliography ...... 166

Part III Developmental Disorders

5 Hydrops, Cystic Hygroma, Fetal Hydrothorax, and Fetal Ascites ...... 171 Fetal Hydrops ...... 171 Pathogenesis and Cause ...... 171 Pathology ...... 172 Posterior Cervical Cystic Hygroma ...... 174 Embryology and Pathogenesis ...... 175 Cause ...... 176 Pathology ...... 177 Fetal Hydrothorax ...... 178 Cause ...... 178 Fetal Pericardial Effusions ...... 178 Fetal Ascites ...... 179 Cause ...... 179 Urinary Ascites ...... 179 Bibliography ...... 180 6 Chromosomal Defects ...... 181 Cytogenic Terminology ...... 181 Pathologic Abnormalities in Chromosomal Defects ...... 182 Conﬁned Placental Mosaicism ...... 182 Trisomy 21 ...... 183 Trisomy 13 ...... 183 Trisomy 18 ...... 183 Cri du Chat Syndrome (del 11p) ...... 186 Trisomy 8 ...... 186 Triploidy ...... 188 Monosomy X (Turner Syndrome) ...... 192 Bibliography ...... 195 Contents xxi

7 Congenital Abnormalities ...... 197 Concepts and Terms of Morphogenesis ...... 197 Mild Malformations Versus Minor Anomalies ...... 199 Examples of Defects of Blastogenesis: Developmental Field Defects ...... 199 Robinson Defect ...... 199 Otocephaly ...... 199 Holoprosencephaly ...... 199 Acrocephalosyndactyly Syndromes ...... 200 Malformation Syndrome ...... 200 Seckel Syndrome ...... 200 Roberts Syndrome ...... 200 Opitz Syndrome ...... 201 Brachmann–de Lange Syndrome (BDLS) ...... 202 Meckel Syndrome ...... 204 Craniosynostosis Syndromes ...... 204 Disruptions: Secondary Malformation ...... 204 Teratogenic Disruptions ...... 204 Fetal Alcohol Syndrome ...... 206 Radiation Disruption ...... 207 Metabolic Disruptions ...... 207 Infectious Disruptions ...... 208 Early and Late Amnion Rupture ...... 208 The ADAM Complex ...... 208 Ischemic and Vascular Disruptions ...... 209 Twinning Disruption ...... 209 Hyperthermia ...... 209 Dysplasias ...... 210 Nonmetabolic Dysplasia ...... 211 Beckwith–Wiedemann Syndrome (BWS) ...... 211 Hamartosis Syndromes ...... 212 Neuroﬁbromatosis (NF) ...... 212 Tuberous Sclerosis ...... 213 von Hippel–Lindau Syndrome (VHL) ...... 213 Marfan Syndrome ...... 215 Metabolic Dysplasias ...... 217 Zellweger Syndrome ...... 217 Smith–Lemli–Opitz Syndrome ...... 219 Associations ...... 220 VATER Association ...... 220 MURCS Association ...... 220 CHARGE Association ...... 220 SCHISIS Association and Its Variants ...... 220 Deformations ...... 220 Pena–Shokeir Phenotype ...... 220 Sequences ...... 222 Potter Sequence ...... 222 Pierre Robin Sequence ...... 222 Prune-Belly Sequence and Related Defects ...... 222 Chromosome Microdeletion Syndromes ...... 224 Appendix 1: Congenital Abnormalities in Embryos and Fetuses by Age ...... 225 Appendix 2: Dysmorphology Examination ...... 226 Bibliography ...... 227 xxii Contents

Part IV Organ Systems and Metabolic Disorders

8 Cardiovascular System ...... 231 The Morphologic Method and Sequential Segmental Analysis ...... 231 Atrial Morphology ...... 234 Bronchial Morphology ...... 234 Ventricular Morphology ...... 236 Ventricular Topology ...... 238 Arterial Trunks ...... 238 Atrioventricular Connections ...... 240 Ventricular Relationships ...... 241 Arterial Relationships ...... 241 Ventriculoarterial Connections ...... 241 Examination of the Coronary Arteries ...... 242 Coronary Arterial Anatomy ...... 243 Coronary Veins ...... 245 Congenital Malformations ...... 245 Isomerism of the Atrial Appendages ...... 245 Isomerism of the Right Atrial Appendages ...... 245 Isomerism of the Left Atrial Appendages ...... 249 Persistent Left Superior Caval Vein ...... 249 Anomalous Pulmonary Venous Connections ...... 249 Atrial Septal Defects ...... 255 Interatrial Communications ...... 259 Atrioventricular Septal Defect ...... 259 Ventricular Septal Defect ...... 262 Hypoplasia of the Left Heart ...... 264 Hypoplasia of the Right Heart ...... 267 Pulmonary Atresia with Intact Ventricular Septum ...... 267 Tricuspid Atresia ...... 270 Double-Inlet Ventricle (Functionally Univentricular Heart) ...... 270 Ebstein Malformation ...... 274 Mitral Valve Defects ...... 275 Tetralogy of Fallot ...... 275 Tetralogy of Fallot with Pulmonary Atresia ...... 276 Transposition ...... 281 Congenitally Corrected Transposition ...... 283 Double-Outlet Right Ventricle ...... 284 Common Arterial Trunk ...... 288 Patent Arterial Duct ...... 289 Premature Closure of the Arterial Duct ...... 289 Aortic and Pulmonary Stenosis ...... 289 Coronary Arterial Anomalies ...... 290 Coarctation of the Aorta ...... 296 Interrupted Aortic Arch ...... 297 Vascular Rings and Slings ...... 298 Methods of Dissection ...... 303 Following the Flow of Blood ...... 303 Tomographic Methods of Dissection ...... 303 Windowing the Heart ...... 306 Repairing Mistakes ...... 308 Dissection of the Conduction System ...... 308 Ectopia Cordis ...... 312 Contents xxiii

Endocardial Fibroelastosis ...... 312 Mitral Valve Prolapse...... 313 Conduction Defects with Pathologic Changes...... 313 Arrhythmogenic Right Ventricular Dysplasia ...... 313 Histiocytoid (Oncocytic) Cardiomyopathy ...... 314 Noncompaction of the Left Ventricle ...... 315 Cardiomyopathy ...... 315 Idiopathic Dilated Cardiomyopathy ...... 315 Hypertrophic Cardiomyopathy ...... 315 Metabolic Cardiomyopathies ...... 317 Myocarditis ...... 317 Infective Endocarditis ...... 319 Ischemic Myocardial Necrosis ...... 320 Appendix 1: Autopsy Checklist for Evaluation of Congenital Heart Disease . . . . . 322 Appendix 2: Female Infant Heart Weights and Measurements ...... 325 Appendix 3: Male Fetus and Newborn Heart Weights and Measurements ...... 325 Appendix 4: Male Infant Heart Weights and Measurements ...... 326 Appendix 5: Perfusion Fixation of the Heart ...... 327 Appendix 6: Parafﬁn Preservation of Heart Specimens ...... 327 Bibliography ...... 328 9 Respiratory System ...... 329 Development of the Human Respiratory Tract ...... 329 Respiration Before Birth ...... 329 Respiration After Birth ...... 330 Evidence of Live Birth ...... 330 Developmental Abnormalities of the Mouth, Nose, and Larynx ...... 331 Cleft Palate ...... 331 Choanal Atresia ...... 331 Anterior Nasal Obstruction ...... 331 Laryngomalacia ...... 331 Congenital Paralysis of Vocal Cord ...... 331 Laryngeal Stenosis ...... 331 Laryngeal Atresia ...... 331 Laryngotracheoesophageal Cleft ...... 332 Laryngotracheal Papillomatosis ...... 332 Developmental Abnormalities of the Trachea ...... 332 Tracheal Agenesis ...... 333 Tracheomalacia ...... 333 Tracheal Stenosis ...... 333 Tracheobronchomegaly (Mounier-Kuhn Syndrome) ...... 333 Tracheoesophageal Fistula (TEF) ...... 334 VATER/VACTERL Association ...... 334 Short Right Main Bronchus ...... 334 Bronchial (Pulmonary) Isomerism Syndromes ...... 334 Bronchomalacia ...... 336 Bronchial Atresia ...... 336 Bronchiectasis ...... 336 Immotile Cilia Syndrome and Kartagener Syndrome ...... 337 Congenital Lobar Emphysema ...... 337 Developmental Abnormalities of the Lungs ...... 337 Herniation of Lungs ...... 337 Horseshoe Lung ...... 337 xxiv Contents

Absence (Agenesis, Aplasia) of Lung(s) ...... 338 Hypoplasia of Lungs ...... 338 Hyaline Membrane Disease (HMD) and Bronchopulmonary Dysplasia (BPD) ...... 338 Interstitial Pulmonary Emphysema (IPE) ...... 339 Bronchogenic Cysts ...... 339 Congenital Pulmonary Airway Malformation (CPAM) or Congenital Cystic Adenomatoid Malformation ...... 342 Peripheral Cysts ...... 342 Congenital Pulmonary Lymphangiectasis (CPL) ...... 342 Vascular Abnormalities ...... 343 Pulmonary Arteriovenous Fistula ...... 343 Scimitar Syndrome ...... 344 Capillary Alveolar Dysplasia (Misalignment of Pulmonary Veins) ...... 344 Intralobar and Extralobar Sequestration ...... 344 Primary Pulmonary Hypertension ...... 345 Pulmonary Hemorrhage ...... 347 Amniotic Fluid and Meconium Aspiration Syndrome ...... 347 Perinatal Pneumonia ...... 347 Gastric Aspiration ...... 348 Lipid Pneumonia ...... 348 Pulmonary Emboli ...... 349 Cystic Fibrosis ...... 349 Surfactant Deﬁciency (Pulmonary Alveolar Proteinosis) ...... 350 Idiopathic Pulmonary Hemosiderosis ...... 350 Abnormalities of the Diaphragm ...... 350 Diaphragmatic Hernia ...... 350 Eventration of Diaphragm ...... 352 Accessory Diaphragm ...... 352 Appendix 1: Lung Weights, Left and Right, Male and Female, from 1 Day to 19 Years of Age ...... 353 Bibliography ...... 354 10 Gastrointestinal (GI) System ...... 355 Esophagus ...... 355 Malformations and Deformations ...... 355 Diseases of the Esophagus ...... 355 Stomach ...... 355 Malformations and Deformations ...... 355 Diseases of the Stomach ...... 356 Gastritis ...... 356 Small and Large Intestine ...... 356 Malformations and Deformations ...... 356 Diseases of the Small and Large Intestine ...... 362 Gastrointestinal Infections ...... 366 Malabsorption and Related Disorders with Abnormalities of the Intestine ...... 367 Polyps ...... 370 Diseases ...... 371 Appendicitis ...... 371 GI Bleeding ...... 372 Bibliography ...... 375 Contents xxv

11 Liver, Gallbladder, Biliary Tract, and Pancreas ...... 377 Developmental Defects of the Liver ...... 377 Absence of the Liver ...... 377 Hypoplasia or Absence of the Left Lobe of the Liver ...... 377 Hypoplasia or Absence of the Right Lobe of the Liver ...... 377 Anomalous Lobation ...... 377 Cysts ...... 378 Physiologic Jaundice ...... 378 Hereditary Hyperbilirubinemias ...... 378 Idiopathic Neonatal Hepatitis (INH) ...... 379 Intrahepatic Biliary Duct Atresia and Hypoplasia ...... 379 Alagille Syndrome (Paucity of Interlobular Bile Ducts, Arteriohepatic Dysplasia) ...... 379 Progressive Familial Intrahepatic Cholestasis (PFIC [Byler Disease and Byler Syndrome]) ...... 380 Nonsyndromic Paucity of Intrahepatic Ducts ...... 381 Neonatal Iron Storage Disease ...... 381

Alpha-1-Antitrypsin (a1AT) Deﬁciency ...... 381 Hemosiderosis ...... 382 Acute Hepatitis ...... 382 Chronic Hepatitis ...... 382 The Liver in Sickle Cell Disease ...... 382 Diffuse Toxic Necrosis ...... 383 Congenital Syphilis ...... 383 Benign Tumors of the Liver ...... 383 Hemangioma ...... 383 Peliosis Hepatis ...... 383 Mesenchymal Hamartoma ...... 383 Liver Cell Adenoma ...... 383 Focal Nodular Hyperplasia ...... 384 Gallbladder ...... 384 Developmental Abnormalities of the Gallbladder ...... 384 Extrahepatic Biliary Ducts ...... 384 Disorders of Biliary and Hepatic Ducts ...... 384 Extrahepatic Biliary Atresia ...... 385 Congenital Dilatation of the Bile Ducts (Choledochal Cyst) ...... 385 Congenital Hepatic Fibrosis (CHF) ...... 385 Cystic Fibrosis ...... 386 Pancreas ...... 386 Congenital Anomalies of the Pancreas ...... 386 Annular Pancreas ...... 386 Pancreas Divisum ...... 387 Cysts ...... 387 Pseudocysts ...... 387 Dermoid Cysts ...... 387 Echinococcus Cysts ...... 387 Diseases ...... 387 Acute Pancreatitis ...... 387 Relapsing and Chronic Pancreatitis ...... 387 Shwachman–Diamond Syndrome ...... 387 Pancreas in Infant of Diabetic Mother ...... 388 xxvi Contents

Diffuse Calciﬁcation ...... 388 Hemochromatosis ...... 388 Cystic Fibrosis ...... 388 Johanson–Blizzard Syndrome ...... 388 Hyperinsulinemic Hypoglycemia: Nesidioblastosis ...... 388 Bibliography ...... 388 12 Renal System ...... 391 Malformation of the Kidney and Upper Urinary Tract ...... 391 Renal Agenesis ...... 391 Bilateral Renal Agenesis ...... 391 Unilateral Renal Agenesis ...... 392 Renal Hypoplasia ...... 392 Renal Findings in Oligohydramnios Sequence ...... 392 Supernumerary Kidney ...... 392 Ectopic Kidney ...... 392 Duplication ...... 392 Cystic Kidney Diseases ...... 393 Autosomal Recessive Polycystic Kidney Disease ...... 393 ARPKD Associated with Congenital Hepatic Fibrosis ...... 394 Autosomal Dominant Polycystic Kidney Disease (ADPKD) ...... 396 Glomerulocystic Disease (GCKD) ...... 397 Localized Cystic Disease ...... 398 Renal Dysplasia ...... 398 Renal Cysts Associated with Syndromes of Multiple Malformations ...... 400 Tuberous Sclerosis (TSC) ...... 401 Von Hippel–Lindau Disease ...... 401 Meckel Syndrome ...... 403 Medullary Cystic Disease ...... 403 Medullary Sponge Kidney (MSK) ...... 403 Familial Nephronophthisis–Medullary Cystic Disease ...... 403 Multilocular Renal Cysts ...... 403 Transient and Minor Renal Abnormalities ...... 404 Neonatal and Infantile Glomerular Sclerosis ...... 404 Diffuse Mesangial Sclerosis ...... 404 Congenital Hydronephrosis ...... 405 Congenital Nephrotic Syndrome ...... 406 Lupus Nephritis ...... 407 Renal Enlargement ...... 407 Renal Segmental Atrophy (Segmental Hypoplasia, Ask-Upmark Kidney) ...... 407 Renal Circulatory Disturbances ...... 407 Glomerulonephritis ...... 407 Postinfectious Glomerulonephritis ...... 407 Membranoproliferative Glomerulonephritis (MPGN) ...... 408 Renal Cortical and Medullary Necrosis ...... 408 Renal Thrombosis ...... 408 Abnormalities of the Bladder ...... 408 Duplication ...... 408 Septation ...... 408 Megacystis ...... 409 Urachal Anomalies ...... 409 Bladder Exstrophy ...... 409 Urinary Tract Anomalies Associated with Imperforate Anus ...... 410 Contents xxvii

Congenital Abnormalities of the Urethra ...... 410 Posterior Urethral Valves ...... 410 Epispadias and Hypospadias ...... 411 Prune-Belly Syndrome ...... 411 Appendix 1: Kidney Weights, Left and Right, Male and Female, From 1 Day to 19 Years of Age ...... 413 Appendix 2: Renal and Urinary Tract Abnormalities in Genetic Disorders and Malformation Syndromes ...... 414 Appendix 3: Renal and Urinary Tract Abnormalities in Chromosomal Defects ...... 428 Bibliography ...... 431

13 Male and Female Genitourinary (GU) Systems ...... 433 Male Genitourinary System ...... 433 Urethra ...... 433 Prostate ...... 433 Seminal Vesicles ...... 433 Vasa Deferentia ...... 433 Testes and Epididymis ...... 433 Penis and Scrotum ...... 433 Congenital Anomalies ...... 433 Urethra ...... 433 Prostate ...... 435 Testis ...... 435 Penis ...... 435 Scrotum ...... 436 The Female Urogenital System ...... 436 Congenital Anomalies of the Female Genitourinary Tract ...... 437 Tubes and Ovaries ...... 437 Uterus and Vagina ...... 437 Intersexuality ...... 438 Appendix 1: Penile Length by Conceptual Age ...... 443 Appendix 2: Development of External Genitalia...... 443 Bibliography ...... 444

14 Central Nervous System (CNS) ...... 445 Brain Development ...... 445 Abnormalities of Brain Development ...... 445 Anencephaly ...... 445 Craniorachischisis ...... 445 Myeloschisis ...... 445 Encephalocele ...... 445 Arnold–Chiari Malformation ...... 446 Other Spinal Cord Abnormalities ...... 446 Holoprosencephalies ...... 447 Aprosencephaly (Atelencephaly) ...... 450 Abnormalities of Midline Structures ...... 451 Agenesis of Corpus Callosum (ACC) ...... 451 Agenesis of Septum Pellucidum (SP) ...... 453 Brain Stem Abnormalities ...... 455 Abnormalities of Aqueduct of Sylvius ...... 455 Isolated Stenosis of the Aqueduct of Sylvius ...... 455 Dysplasia of the Aqueduct of Sylvius ...... 455 Occlusion of Aqueduct ...... 455 xxviii Contents

Malformations of Cerebellum ...... 455 Agenesis ...... 455 Hypoplasia ...... 456 Anomalies of the Vermis of the Cerebellum ...... 456 Dandy–Walker Malformation ...... 456 Arachnoid Cysts ...... 456 Choroid Plexus Cysts ...... 457 Subependymal Pseudocysts ...... 457 Intracranial Vascular Malformations ...... 457 Telangiectasias ...... 457 Sturge–Weber Disease ...... 458 Von Hippel–Lindau Disease ...... 458 Congenital Hydrocephalus ...... 458 Ventriculomegaly ...... 459 Defects of Neuronal Migration ...... 460 Heterotopia and Ectopia ...... 460 Polymicrogyria ...... 460 Agyria/Pachygyria/Lissencephaly ...... 460 Type I Lissencephaly ...... 461 Type II Lissencephaly ...... 461 Type III Lissencephaly ...... 461 Microcephaly ...... 461 Primary Constitutional Microcephaly ...... 461 Secondary Acquired Microcephaly ...... 462 Isolated Microcephaly ...... 462 Microgyria and Ulegyria ...... 462 Hydranencephaly, Porencephaly, and Multicystic Encephalomalacia ...... 462 Hydrolethalus ...... 462 Schizencephaly ...... 462 Iniencephaly ...... 462 Subarachnoid Hemorrhage ...... 462 Subdural Hemorrhage ...... 462 Periventricular Leukomalacia ...... 463 Germinal Matrix/Intraventricular Hemorrhage ...... 463 Galeal Hemorrhage ...... 463 Cephalhematoma ...... 463 Extradural (Epidural) Hemorrhage ...... 464 Meningitis ...... 464 Bacterial Meningoencephalitis ...... 466 Fungal Meningoencephalitis ...... 466 Toxoplasma ...... 466 Syphilis ...... 467 Viral Infection ...... 469 Craniosynostosis ...... 469 Appendix 1: Defects of Closure of the Neural Tube ...... 470 Bibliography ...... 471 15 Thymus, Spleen, Lymph Nodes, and Immunodeﬁciency ...... 473 Lymph Nodes ...... 473 Accessory Spleen ...... 473 Spleen ...... 473 Asplenia ...... 473 Polysplenia ...... 474 Cysts ...... 474 Contents xxix

Thymus ...... 474 Anatomy and Histology ...... 475 Thymic Lesions ...... 475 Thymus in Acquired Immunodeficiency Syndrome ...... 476 Thymic Hyperplasia ...... 476 Lymphoid Depletion ...... 476 Selected Immunodeficiencies Presenting in Child Hood Predominantly Antibody Immunodeficiencies ...... 476 X-Linked Agammaglobulinemia (XLA) ...... 476 Common Variable Immunodeficiency (CVID) ...... 476 Severe Combined Immunodeficiency (SCID) ...... 476 Wiskott–Aldrich Syndrome (WAS) ...... 478 Ataxia-Telangiectasia (AT) and Nijmegen Breakage Syndrome ...... 478 DiGeorge Syndrome and Chromosome 22q11.2 Deletion Syndrome ...... 478 Chronic Mucocutaneous Candidiasis ...... 478 Appendix 1: Spleen Weights, Male and Female, from 1 Day to 19 Year of Age ...... 484 Bibliography ...... 484

16 Hematopoietic System ...... 485 Leukemia ...... 485 Classiﬁcation of Leukemia ...... 485 Lymphomas in Childhood ...... 488 Hodgkin Lymphomas ...... 489 Nodular Sclerosing Hodgkin Lymphoma ...... 490 Mixed Cellularity Classic Hodgkin Lymphoma (CHL) ...... 490 Lymphocyte-Rich CHL ...... 490 Lymphocyte-Depleted CHD ...... 490 Nodular Lymphocyte-Predominant Hodgkin Lymphoma ...... 490 Diffuse Large-Cell Lymphoma (DLCL) ...... 491 Burkitt Lymphoma ...... 493 Anaplastic Large-Cell Lymphoma (ALCL) ...... 495 Langerhans Cell Histiocytosis (LCH) ...... 496 Post-transplant Lymphoproliferative Disorder ...... 497 Bibliography ...... 497

17 Pediatric Tumors ...... 499 Wilms’ Tumor/Nephroblastoma ...... 499 Immunostaining of Wilms’ Tumor ...... 499 Staging System of Wilms’ Tumor: Children’s Oncology Group (COG) ...... 499 Nephrogenic Rests ...... 500 Clear Cell Sarcoma of the Kidney (CCSK) ...... 500 Rhabdoid Tumor ...... 501 Neuroblastoma ...... 502 Rhabdomyosarcoma ...... 502 Embryonal Rhabdomyosarcoma ...... 502 Alveolar Rhabdomyosarcoma ...... 503 Desmoplastic Small Round Cell Tumor ...... 504 Primitive Neuroectodermal Tumor (PNET)/Ewing Sarcoma ...... 504 Polyphenotypic Tumor ...... 504 Angiosarcoma of the Liver ...... 504 Hepatoblastoma ...... 507 Hepatocellular Carcinoma ...... 508 xxx Contents

Germ Cell Tumors ...... 508 Teratomas ...... 508 Yolk Sac Tumor ...... 508 Embryonal Carcinoma ...... 508 Choriocarcinoma ...... 510 Central Nervous System Tumors ...... 510 Astrocytic Tumors ...... 510 Glioblastoma ...... 512 Giant Cell Glioblastoma (WHO Grade IV) ...... 513 Pleomorphic Xanthoastrocytoma ...... 513 Oligodendroglioma ...... 513 Ependymoma ...... 514 Myxopapillary Ependymoma ...... 514 Dysembryoplastic Neuroepithelial Tumor ...... 515 Atypical Teratoid/Rhabdoid Tumor ...... 516 Medulloblastoma (PNET) ...... 516 Craniopharyngioma ...... 517 Meningeal Tumors ...... 518 Meningioma ...... 518 Bibliography ...... 520 18 Skeletal System ...... 521 Sampling and Handling of Bone in Autopsies of Skeletal Dysplasias ...... 521 Decalcification Procedures ...... 522 Preparation of Undecalcified Sections and Microradiography ...... 522 Reduction Defects ...... 522 Fetal Akinesia-Hypokinesia Sequence and Congenital Arthrogryposis ...... 523 Nomenclature ...... 523 Type II Collagenopathies ...... 524 Short-Rib Dysplasia with or without Polydactyly ...... 525 Short-Trunk Chondrodysplasias ...... 525 Type IB Achondrogenesis (Fraccaro) ...... 525 Achondrogenesis Type II (Langer–Saldino) ...... 525 Hypochondrogenesis (Achondrogenesis Type III) ...... 525 Spondyloepiphyseal Dysplasia Congenita ...... 525 Kniest Dysplasia ...... 526 Dyssegmental Dysplasia ...... 526 Atelosteogenesis ...... 529 Type I Atelosteogenesis ...... 529 Type II Atelosteogenesis ...... 529 Fibrochondrogenesis ...... 529 Short-Rib–Polydactyly Syndromes ...... 531 Type I Asphyxiating Thoracic Dystrophy (ATD) ...... 532 Type II ATD ...... 532 SRPS Type I (Saldino–Noonan) ...... 534 SRPS Type II (Majewski) ...... 534 SRPS Type III (Verma–Naumoff) ...... 534 SRPS Type IV ...... 535 Unclassified Types of SRPS ...... 535 Chondrodysplasias with Significant Platyspondyly ...... 535 Thanatophoric Dysplasia (TD) ...... 535 TD with Cloverleaf Skull ...... 538 Achondroplasia ...... 538 Heterozygous Achondroplasia ...... 538 Contents xxxi

Homozygous Achondroplasia ...... 539 Metatropic Dysplasia ...... 539 Opsismodysplasia ...... 541 Schneckenbecken (Snail Pelvis) Dysplasia...... 542 Miscellaneous Osteochondrodysplasias ...... 544 Chondrodysplasia Punctata ...... 544 Conradi–Hunermann Type ...... 544 Rhizomelic Type ...... 544 Campomelic Syndrome ...... 546 Kyphomelic Dysplasia ...... 546 Diastrophic Dysplasia ...... 547 Larsen Syndrome ...... 547 Osteogenesis Imperfecta (OI) ...... 547 Hypophosphatasia (Congenital Lethal Type) ...... 549 Lethal Osteosclerotic Bone Dysplasia (Raine Syndrome) ...... 549 Atelosteogenesis–Omodysplasia and Diastrophic Dysplasia ...... 550 Boomerang Dysplasia ...... 550 Appendix 1: Appearance of Ossiﬁcation Centers from 1 to 40 Weeks ...... 551 Bibliography ...... 552 19 Skin ...... 553 Nail Development ...... 553 Sebaceous Gland ...... 553 Sweat Gland Development ...... 553 Vesicular Lesions in the Fetus and Newborn ...... 553 Epidermolysis Bullosa ...... 553 Chronic Bullous Disease of Childhood (CBDC) (Linear IgA Dermatosis) ...... 554 Staphylococcal Scalded Skin Syndrome (Ritter Disease) ...... 555 Toxic Epidermal Necrolysis (Lyell Type) ...... 555 Incontinentia Pigmenti ...... 555 Acrodermatitis Enteropathica ...... 555 Ichthyosis ...... 557 Trichothiodystrophy ...... 558 Vesiculopustular Eruptions in the Newborn ...... 558 Erythema Toxicum Neonatorum (ETN) ...... 558 Neonatal Pustular Melanosis (NPM) ...... 558 Acropustulosis of Infancy ...... 558 Infectious Eruptions ...... 558 Impetigo ...... 558 Candida Infection ...... 558 Syphilis ...... 559 Herpes Simplex ...... 559 Varicella Zoster ...... 559 Subcutaneous Fat Necrosis (SFN) ...... 559 Sclerema Neonatorum ...... 559 Scleredema ...... 560 Restrictive Dermopathy ...... 562 Malformation of the Skin and Its Appendages ...... 562 Sebaceous Nevus of Jadassohn ...... 562 Linear Sebaceous Nevus Syndrome ...... 562 Congenital Cutaneous Dystrophy (Rothmund–Thomson Syndrome, Poikiloderma Congenitale) ...... 562 Focal Dermal Hypoplasia (Goltz Syndrome) ...... 563 Melanocytic Lesions ...... 563 xxxii Contents

Blue Nevus ...... 563 Leopard (Multiple Lentigines) Syndrome ...... 563 Urticaria Pigmentosa ...... 564 Xeroderma Pigmentosum ...... 564 Ectodermal Dysplasia ...... 564 Multiple Pterygia (Fetal Akinesia) ...... 564 Langerhans Cell Histiocytosis ...... 565 Bibliography ...... 567 20 Infections ...... 569 Bacterial Infections ...... 569 TORCH Infections ...... 570 Toxoplasmosis ...... 571 Viral Infections ...... 571 Rubella Infection ...... 571 Herpes Infection ...... 572 Cytomegalovirus Infection (CMV) ...... 573 Herpes Simplex Virus Type 2 ...... 573 Varicella Zoster ...... 574 Epstein–Barr Virus ...... 575 Influenza Virus ...... 575 Enteroviruses ...... 575 Hepatitis Viruses ...... 576 Parvovirus ...... 577 Adenovirus ...... 577 Human Immunodeficiency Virus ...... 577 Chagas Disease (South American Trypanosomiasis) ...... 577 Malaria ...... 578 Q Fever ...... 579 Borreliosis (Lyme Disease) ...... 579 Campylobacter (Vibrio) Fetus Infection ...... 579 Fungal Infections ...... 579 Bibliography ...... 580 21 Transplantation ...... 581 Hyperacute Allograft Rejection ...... 581 Acute Allograft Rejection ...... 581 Chronic Allograft Rejection ...... 581 Signs of Rejection ...... 581 Transplant Pathology of the Heart ...... 581 Acute Cellular Rejection ...... 581 Antibody-Mediated Rejection (AMR) ...... 582 Chronic Rejection (Cardiac Allograft Vasculopathy) ...... 582 Infection ...... 582 The Quilty Lesion ...... 582 Calcifications ...... 582 Fibrosis ...... 582 Transplant Pathology of the Kidney ...... 582 Hyperacute and Accelerated Acute Rejection ...... 583 Acute Rejection ...... 584 Chronic Allograft Nephropathy (CAN) ...... 586 Vascular Thrombosis ...... 586 Recurrent Disease ...... 587 Immunosuppressive Drug Toxicity ...... 587 Contents xxxiii

Polyomavirus Type BK (BKV) Infection ...... 587 Posttransplant Lymphoproliferative Disorders ...... 587 Transplant Pathology of the Liver ...... 587 Preservation Injury ...... 588 Hepatic Artery Thrombosis (HAT) ...... 588 Biliary Complications ...... 588 Hyperacute (Humoral) Rejection ...... 588 Acute Rejection ...... 588 Chronic Rejection ...... 588 Liver in Bone Marrow Transplantation ...... 589 Transplant Pathology of the Lung ...... 589 Hyperacute Rejection ...... 589 Acute Rejection ...... 589 Chronic Rejection ...... 589 Transplant Pathology of the Intestines ...... 589 Preservation Injury and Hyperacute Rejection ...... 589 Acute Rejection ...... 589 Chronic Rejection ...... 590 Complications of Transplantation ...... 590 The Gastrointestinal Tract in Graft-Versus-Host Disease ...... 590 Transplant Pathology of the Pancreas ...... 590 Histopathology of Acute and Chronic Rejection ...... 590 Bibliography ...... 591 22 Eye and Adnexa ...... 593 Methods for Removal and Sectioning ...... 593 Vitreous Sampling ...... 593 Removal of the Eye and Orbital Contents ...... 593 Eyes for Transplantation ...... 594 Removal of the Lacrimal Gland ...... 594 Processing of the Ocular Specimens ...... 594 Fixation, Orientation, Documentation of Lesions, and Sectioning ...... 594 Major Anomalies of the Eye ...... 595 Microphthalmos ...... 595 Cyclopia and Synophthalmos ...... 595 Structural Abnormalities ...... 595 Epicanthus ...... 596 Ptosis ...... 596 Retinopathy of Prematurity ...... 597 Infections of the Eye ...... 597 Retinoblastoma ...... 597 Metabolic Diseases ...... 597 Bibliography ...... 603 23 Metabolic Diseases ...... 605 Carbohydrate Disorders ...... 605 Galactosemia ...... 605 Disorders of Fructose Metabolism ...... 605 Glycogen Storage Diseases (Glycogenoses) ...... 605 Mucopolysaccharidosis ...... 609 Hurler Syndrome ...... 613 Fucosidosis ...... 614 Mannosidoses ...... 614 Geleophysic Dysplasia ...... 616 xxxiv Contents

Lysosomal Storage Diseases ...... 616 Abnormal Serum Lipids or Lipoproteins ...... 616 Lysosomal Transport Disorders ...... 616 Sialic Acid Disorders (Sialidoses) ...... 616 Lipidosis ...... 617 Cholesterol Esters/Triglyceride Storage ...... 617 Farber Disease ...... 617 Gaucher Disease ...... 617 Krabbe Disease ...... 617 Fabry Disease ...... 618 Sphingomyelin Storage Disease ...... 618 Niemann–Pick Disease ...... 618 Sulfatide Lipidoses ...... 619 Metachromatic Leukodystrophy ...... 619 Multiple Sulfatase Deﬁciency (Austin Disease) ...... 619 The Gangliosidoses ...... 619

GM1-Gangliosidosis ...... 619

GM2-Gangliosidosis, Type 1 (Tay–Sachs Disease) ...... 619

GM2-Gangliosidosis, Type 2 (Sandhoff Disease) ...... 620 Galactosialidosis ...... 620 Other Neural Lipidoses ...... 621 Mucolipidoses ...... 621 Mucolipidosis II (I-Cell Disease) ...... 621 Amino Acid Disorders ...... 622 Phenylketonuria ...... 622 Hereditary Tyrosinemia...... 622 Pathology ...... 622 Alkaptonuria ...... 622 Homocystinuria ...... 623 Lesch–Nyhan Syndrome (L–NS) ...... 624 Organic Acidemias ...... 624 Maple Sugar Urine Disease ...... 624 Methylmalonic Acidemia ...... 625 Propionic Acidemia (Ketotic Hyperglycinemia) ...... 625 Isovaleric Acidemia (IVA) ...... 625 Nonketotic Hyperglycinemia ...... 625 Pyruvate Dehydrogenase Deficiency ...... 625 Fatty Acid b-Oxidation Defects ...... 626 Carnitine Deficiency ...... 626 Smith–Lemli–Opitz Syndrome (SLOS) ...... 626 Urea Cycle Defects ...... 628 Ornithine Transcarbamylase Deficiency ...... 628 Carbamyl Phosphate Synthetase Deficiency ...... 629 Citrullinemia ...... 629 Hyperornithinemia, Hyperammonemia, Homocitrullinuria Syndrome (HHH Syndrome) ...... 629 Argininosuccinicaciduria ...... 630 Argininemia ...... 630 Peroxisomal Disorders ...... 630 X-Linked Adrenoleukodystrophy ...... 630 Zellweger Syndrome ...... 631 Neonatal Adrenoleukodystrophy (NALD) ...... 632 Hyperpipecolic Acidemia ...... 632 Hyperoxaluria Type I ...... 632 Contents xxxv

Mitochondrial Disorders ...... 633 Pathology ...... 633 Electron Microscopy ...... 634 Subacute Necrotizing Encephalomyelopathy (SNE) ...... 634 Disorders of Metal Metabolism ...... 635 Neonatal Iron Storage Disease ...... 635 Wilson Disease ...... 635 Pathology ...... 635 Menkes Syndrome ...... 636 Other Metabolic Disorders ...... 636 Neuronal Ceroid Lipofuscinosis (NCL) (Batten Disease) ...... 636 Pathology ...... 636

a1-Antitrypsin (a1-Antiprotease) Deﬁciency ...... 637 Defects in Renal Transport Mechanisms ...... 638 Cystinosis ...... 638 Autopsy on Metabolic Case ...... 638 Appendix 23.1: The Metabolic Disease Autopsy ...... 640 Fluid Samples ...... 640 Tissue Samples ...... 640 Appendix 23.2: Handling Tissues for Molecular Diagnosis ...... 641 Appendix 23.3: Tissues Used for Diagnosis of Metabolic Disorders ...... 641 Appendix 23.4: Biochemical Tests for Metabolic Disorders ...... 642 Appendix 23.5: Metabolic Laboratories ...... 642 Bibliography ...... 649

Part V Special Considerations

24 Sudden Infant Death ...... 653 Deﬁnition ...... 653 Category I SIDS ...... 653 Category II SIDS ...... 653 Category III SIDS ...... 653 Environmental Versus Genetic Disorders ...... 654 The Sudden Infant Death Autopsy...... 654 Routine Autopsy Protocol ...... 654 Metabolic Studies ...... 655 Bed-Related Deaths and the Prone Sleeping Position ...... 656 Risk Factors Versus Prediction ...... 657 Gross and Microscopic Autopsy Findings ...... 657 Central Nervous System in SIDS...... 657 Hypoxemia: The Final Common Pathway ...... 658 Explained Sudden Infant Death ...... 659 Myocarditis ...... 659 Congenital Aortic Stenosis ...... 659 Endocardial Sclerosis ...... 659 Anomalous Origin of the Left Coronary Artery ...... 660 Primary Hypertrophic Cardiomyopathy ...... 660 Tuberous Sclerosis with Cardiac Rhabdomyomas ...... 661 Cardiac Arrhythmias ...... 661 Other Cardiac Arrhythmias That May Result in Sudden Infant Death ...... 662 Respiratory Causes ...... 663 Metabolic Disorders and SIDS: Medium-Chain Acyl-CoA Dehydrogenase Deﬁciency ...... 663 Apnea Monitors ...... 664 xxxvi Contents

Dehydration Secondary to Diarrhea with Fluid and Electrolyte Imbalance ...... 664 Fluid and Electrolyte Imbalance in Cystic Fibrosis ...... 666 Adrenal Insufﬁciency ...... 666 Upper Airway Obstruction ...... 666 Post-autopsy Conference with Parents ...... 666 Appendix 1: International Standardized Autopsy Protocol for Sudden Unexpected Infant Death ...... 667 Bibliography ...... 671

25 Forensic Pathology ...... 675 The Postmortem Examination ...... 675 The Forensic Autopsy Protocol ...... 679 Identiﬁcation of the Body ...... 679 Postmortem Changes ...... 679 Algor Mortis ...... 679 Livor Mortis ...... 679 Rigor Mortis ...... 680 Postmortem Interval ...... 680 Autopsy Toxicology ...... 680 Cerebrospinal Fluid ...... 680 Vitreous Humor ...... 681 Blood ...... 681 Bile ...... 681 Gastrointestinal Tract ...... 681 Hair ...... 681 Skin ...... 681 Urine ...... 681 Postmortem Decomposition ...... 681 Examination of a Decomposed Body ...... 682 X-Ray Examination ...... 682 Degree and Type of Decomposition ...... 682 Animal Damage ...... 682 Scars ...... 683 Tattoos ...... 683 Color ...... 683 Swabs ...... 683 Head ...... 683 Brain ...... 683 Neck ...... 683 Trunk ...... 683 Microscopy ...... 683 Toxicology ...... 683 Dental Examination ...... 684 Postmortem Chemistries ...... 684 Glucose ...... 684 Lactic Acid ...... 684 Nitrogen ...... 684 Electrolytes ...... 684 Protein ...... 684 Enzymes ...... 685 Hormones ...... 685 Contents xxxvii

Poisoning and Toxicology ...... 685 Injuries ...... 685 Motor Vehicle Injuries ...... 685 Falls ...... 685 Examination of the Skin ...... 685 Abrasions ...... 686 Bruises (Contusions) ...... 686 Lacerations ...... 687 Incisions ...... 687 Stab Wounds ...... 687 Other Skin Wounds ...... 687 Vital Reaction and Timing of Injury ...... 687 Skeletal Injuries ...... 687 Asphyxia ...... 688 Deliberate Suffocation ...... 689 Burns ...... 689 Hypothermia ...... 692 Hyperthermia ...... 692 Drowning ...... 692 Alcohol Intoxication ...... 692 Narcotics ...... 693 Child Abuse ...... 693 Deﬁnitions ...... 693 Cutaneous Trauma ...... 693 Facial Injuries ...... 693 Eye Injuries ...... 694 Skeletal Injuries ...... 695 Visceral Trauma ...... 696 Head Injuries ...... 697 Shaken Baby (Whiplash Shaken Infant) ...... 698 Munchausen Syndrome by Proxy ...... 699 Starvation ...... 700 Neglect and Failure to Thrive ...... 700 Dehydration ...... 700 Subtle Forms of Abuse ...... 700 Determination of Live Birth, Stillbirth, and Gestational Age ...... 701 Was Death due to Perinatal Accident or Deliberate? ...... 701 Infanticide ...... 701 Sexual Abuse ...... 701 Reporting Child Abuse ...... 702 Appendix 1: Special Studies ...... 702 Appendix 2: Agents Commonly Used in Non-accidental Poisonings ...... 703 Bibliography ...... 703 26 Special Procedures ...... 707 Electron Microscopy ...... 707 Virus Identiﬁcation ...... 707 Electron Microscopic Fixation ...... 707 Specimen Preparation ...... 708 Molecular Techniques ...... 709 Applications ...... 709 Cytogenetics ...... 709 Applications ...... 709 xxxviii Contents

FISH ...... 711 Limitations of FISH ...... 711 Polymerase Chain Reaction (PCR) ...... 711 Gene Chips or Microarrays (Gene Expression Arrays) ...... 712 Basis of the Methodology ...... 712 Applications ...... 712 Limitations ...... 712 The Human Genome Project ...... 712 Metabolic Inborn Errors That Should Be Examined in Unexpected Infant Death ...... 712 Procedure at Autopsy ...... 713 Fluid Samples ...... 713 Tissue Samples ...... 713 General ...... 714 Microbiology ...... 714 X-Ray Analysis ...... 716 Electron Diffraction ...... 716 Cytochemistry ...... 716 Cytogenetics ...... 716 Chromosome Analysis by Mail ...... 717 Techniques of Postmortem Chromosome Analysis ...... 717 Peripheral Blood Lymphocyte Cultures ...... 717 Lymphocytes from the Thymus and Spleen ...... 718 Fibroblast Cultures ...... 718 Chemistry ...... 719 Interpretation of Postmortem Chemical Data ...... 719 Organ Transplantation ...... 720 Bibliography ...... 721 27 Infection Control and Biological Hazards ...... 723 HIV Infection ...... 723 HIV and Hepatitis B ...... 723 Precautions ...... 724 Disinfection, Decontamination, and Disposal ...... 724 Bibliography ...... 727

Index ...... 729