The Developing Human: Clinically Oriented Embryology (10th Edition) PDF

 Any screen. Any time. Anywhere. Activate the eBook version of this title at no additional charge. Student Consult eBooks give you the power to browse and find content, view enhanced images, share notes and highlights—both online and offline. Unlock...

 Any screen. Any time. Anywhere. Activate the eBook version of this title at no additional charge. Student Consult eBooks give you the power to browse and find content, view enhanced images, share notes and highlights—both online and offline. Unlock your eBook today. 1 Visit studentconsult.inkling.com/redeem Scan this QR code to redeem your 2 Scratch off your code eBook through your mobile device: 3 Type code into “Enter Code” box 4 Click “Redeem” 5 Log in or Sign Up 6 Go to “My Library” It’s that easy! For technical assistance: email [email protected] call 1-800-401-9962 (inside the US) call +1-314-447-8200 (outside the US) Use of the current edition of the electronic version of this book (eBook) is subject to the terms of the nontransferable, limited license granted on studentconsult.inkling.com. Access to the eBook is limited to the first individual who redeems the PIN, located on the inside cover of this book, at studentconsult.inkling.com and may not be transferred to another party by resale, lending or other means. THE DEVELOPING HUMAN CLINICALLY ORIENTED EMBRYOLOGY KEITH L. MOORE Recipient of the inaugural Henry Gray/Elsevier Distinguished Educator Award in 2007—the American Association of Anatomists’ highest award for excellence in human anatomy educa- tion at the medical/dental, graduate, and undergraduate levels of teaching; the Honored Member Award of the American Association of Clinical Anatomists (1994) for significant contributions to the field of clinically relevant anatomy; and the J.C.B. Grant Award of the Canadian Association of Anatomists (1984) “in recognition of meritorious service and out- standing scholarly accomplishments in the field of anatomical sciences.” In 2008 Professor Moore was inducted as a Fellow of the American Association of Anatomists. The rank of Fellow honors distinguished AAA members who have demonstrated excellence in science and in their overall contributions to the medical sciences. In 2012 Dr. Moore received an Honorary Doctor of Science degree from The Ohio State University; The Queen Elizabeth II Diamond Jubilee Medal honoring significant contributions and achievements by Canadians; and the Benton Adkins Jr. Distinguished Service Award for an outstanding record of service to the American Association of Clinical Anatomists. T.V.N. (VID) PERSAUD Recipient of the Henry Gray/Elsevier Distinguished Educator Award in 2010—the American Association of Anatomists’ highest award for excellence in human anatomy education at the medical/dental, graduate, and undergraduate levels of teaching; the Honored Member Award of the American Association of Clinical Anatomists (2008) for significant contribu- tions to the field of clinically relevant anatomy; and the J.C.B. Grant Award of the Canadian Association of Anatomists (1991) “in recognition of meritorious service and outstanding scholarly accomplishments in the field of anatomical sciences.” In 2010 Professor Persaud was inducted as a Fellow of the American Association of Anatomists. The rank of Fellow honors distinguished AAA members who have demonstrated excellence in science and in their overall contributions to the medical sciences. In 2003 Dr. Persaud was a recipient of the Queen Elizabeth II Golden Jubilee Medal, presented by the Government of Canada for “significant contribution to the nation, the community, and fellow Canadians.” MARK G. TORCHIA Recipient of the Norman and Marion Bright Memorial Medal and Award and the Silver Medal of the Chemical Institute of Canada in 1990 for outstanding contributions. In 1993 he was awarded the TIMEC Medical Device Champion Award. In 2008 and in 2014 Dr. Torchia was a nominee for the Manning Innovation Awards, for innovation talent. Dr. Torchia’s most cherished award has been the Award for Teaching Excellence in 2011 from the Faculty of Medicine, University of Manitoba, and being asked to address the graduating class of 2014.  THE DEVELOPING HUMAN CLINICALLY ORIENTED EMBRYOLOGY 10th Edition Keith L. Moore, BA, MSc, PhD, DSc, FIAC, FRSM, FAAA Professor Emeritus, Division of Anatomy, Department of Surgery Former Professor and Chair, Department of Anatomy and Associate Dean for Basic Medical Sciences Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Former Professor and Head of Anatomy, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada T.V.N. (Vid) Persaud, MD, PhD, DSc, FRCPath (Lond.), FAAA Professor Emeritus and Former Head, Department of Human Anatomy and Cell Science Professor of Pediatrics and Child Health Associate Professor of Obstetrics, Gynecology, and Reproductive Sciences, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada Professor of Anatomy, St. George’s University, Grenada, West Indies Mark G. Torchia, MSc, PhD Associate Professor and Director of Development, Department of Surgery Associate Professor, Department of Human Anatomy and Cell Sciences Director, Centre for the Advancement of Teaching and Learning, University of Manitoba, Winnipeg, Manitoba, Canada 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 THE DEVELOPING HUMAN, TENTH EDITION  ISBN: 978-0-323-31338-4 INTERNATIONAL EDITION  ISBN: 978-0-323-31347-6 Copyright © 2016 by Elsevier, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2013, 2008, 2003, 1998, 1993, 1988, 1982, 1977, and 1973. Library of Congress Cataloging-in-Publication Data Moore, Keith L., author. The developing human : clinically oriented embryology / Keith L. Moore, T.V.N. (Vid) Persaud, Mark G. Torchia.—10th edition.    p. ; cm. Includes bibliographical references and index. ISBN 978-0-323-31338-4 (pbk. : alk. paper)—ISBN 978-0-323-31347-6 (international edition : alk. paper) I. Persaud, T. V. N., author. II. Torchia, Mark G., author. III. Title. [DNLM: 1. Embryology. QS 604] QM601 612.6′4018—dc23    2015001490 Content Strategist: Meghan Ziegler Senior Content Development Specialist: Jennifer Ehlers Publishing Services Manager: Patricia Tannian Senior Project Manager: Kristine Feeherty Design Direction: Margaret Reid The cover images show a magnetic resonance image of a 27-week-old fetus in the uterus (Courtesy Dr. Deborah Levine, Beth Israel Deaconess Medical Center, Boston, Massachusetts). The photograph of the baby (Kennedy Jackson) was taken 7 days after her birthday. She is wrapped in a knitted cocoon that symbolizes the uterus. Printed in the United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 1  In Loving Memory of Marion My best friend, wife, colleague, mother of our five children and grandmother of our nine grandchildren, for her love, unconditional support, and understanding. Wonderful memories keep you ever near our hearts. —KLM and family For Pam and Ron I should like to thank my eldest daughter, Pam, who assumed the office duties previously carried out by her mother, Marion. She has also been helpful in so many other ways (e.g., reviewing the text). I am also grateful to my son-in-law, Ron Crowe, whose technical skills have helped me utilize the new technology when I was improving this book. —KLM For Gisela My lovely wife and best friend, for her endless support and patience; our three children—Indrani, Sunita, and Rainer (Ren)—and grandchildren (Brian, Amy, and Lucas). —TVNP For Barbara, Muriel, and Erik Nothing could ever mean more to me than each of you. Thank you for your support and your love. —MGT For Our Students and Their Teachers To our students: We hope you will enjoy reading this book, increase your understanding of human embryology, pass all of your exams, and be excited and well prepared for your careers in patient care, research, and teaching. You will remember some of what you hear, much of what you read, more of what you see, and almost all of what you experience. To their teachers: May this book be a helpful resource to you and your students. We appreciate the numerous constructive comments we have received over the years from both students and teachers. Your remarks have been invaluable to us in improving this book.  Contributors CONTRIBUTORS FIGURES AND IMAGES (SOURCES) David D. Eisenstat, MD, MA, FRCPC We are grateful to the following colleagues for the clinical Professor, Departments of Pediatrics, Medical Genetics images they have given us for this book and also for granting us permission to use figures from their published and Oncology, Faculty of Medicine and Dentistry, works: University of Alberta; Director, Division of Pediatric Immunology, Hematology, Oncology, Palliative Care, Steve Ahing, DDS and Environmental Health, Department of Pediatrics, Faculty of Dentistry, University of Manitoba, Winnipeg, Stollery Children’s Hospital and the University of Manitoba, Canada Alberta; Inaugural Chair, Muriel and Ada Hole Kids Figure 19-20F with Cancer Society Chair in Pediatric Oncology, Edmonton, Alberta, Canada Franco Antoniazzi, MD Department of Pediatrics, University of Verona, Jeffrey T. Wigle, PhD Verona, Italy Principal Investigator, Institute of Cardiovascular Figure 20-4 Sciences, St. Boniface Hospital Research Centre; Associate Professor, Department of Biochemistry and Dean Barringer and Marnie Danzinger Medical Genetics, University of Manitoba, Winnipeg, Figure 6-7 Manitoba, Canada †Volker Becker, MD CLINICAL REVIEWERS Pathologisches Institut der Universität, Erlangen, Germany Albert E. Chudley, MD, FRCPC, FCCMG Figures 7-18 and 7-21 Professor, Department of Pediatrics and Child Health; Professor, Department of Biochemistry and Medical J.V. Been, MD Genetics, University of Manitoba, Winnipeg, Department of Pediatrics, Maastricht University Manitoba, Canada Medical Centre, Maastricht, The Netherlands Figure 10-7C Michael Narvey, MD, FRCPC, FAAP Section Head, Neonatal Medicine, Health Sciences Beryl Benacerraf, MD Centre and St. Boniface Hospital; Associate Professor Diagnostic Ultrasound Associates, P.C., Boston, of Pediatrics and Child Health, University of Massachusetts, USA Manitoba, Winnipeg, Manitoba, Canada Figures 13-29A, 13-35A, and 13-37A Kunwar Bhatnagar, MD Department of Anatomical Sciences and Neurobiology, School of Medicine University of Louisville, Louisville, Kentucky, USA Figures 9-33, 9-34, and 19-10 †Deceased. vii viii CONTRIBUT O R S David Bolender, MD João Carlos Fernandes Rodrigues, MD Department of Cell Biology, Neurobiology, and Servico de Dermatologia, Hospital de Desterro, Lisbon, Anatomy, Medical College of Wisconsin, Milwaukee, Portugal Wisconsin, USA Figure 19-5B Figure 14-14BC Frank Gaillard, MB, BS, MMed Dr. Mario João Branco Ferreira Department of Radiology, Royal Melbourne Hospital, Servico de Dermatologia, Hospital de Desterro, Lisbon, Australia Portugal Figures 4-15 and 9-19B Figure 19-5A Gary Geddes, MD Albert E. Chudley, MD, FRCPC, FCCMG Lake Oswego, Oregon, USA Department of Pediatrics and Child Health, Section of Figure 14-14A Genetics and Metabolism, Children’s Hospital, University of Manitoba, Winnipeg, Manitoba, Barry H. Grayson, MD, and Bruno L. Vendittelli, MD Canada New York University Medical Center, Institute of Figures 4-6, 9-38, 11-19AB, 11-28A, 12-24, 12-42, 12-43, Reconstructive Plastic Surgery, New York, 14-11, 15-6, 16-13DE, 16-14, 16-15, 17-14, 17-33, 17-36, New York, USA 18-20, 18-21, 18-23, 19-9, 20-3, 20-5, 20-6CD, 20-7, 20-8, Figure 9-40 20-13, 20-14, 20-17, and 20-19A Christopher R. Harman, MD, FRCSC, FACOG Blaine M. Cleghorn, DMD, MSc Department of Obstetrics, Gynecology, and Faculty of Dentistry, Dalhousie University, Halifax, Reproductive Sciences, Women’s Hospital and Nova Scotia, Canada University of Maryland, Baltimore, Maryland, USA Figures 19-19 and 19-20A-E Figures 7-17 and 12-23 Dr. M.N. Golarz De Bourne †Jean Hay, MSc St. George’s University Medical School, True Blue, Department of Anatomy, University of Manitoba, Grenada Winnipeg, Manitoba, Canada Figure 11-21 Figure 17-25 Heather Dean, MD, FRCPC Blair Henderson, MD Department of Pediatrics and Child Health, University Department of Radiology, Health Sciences Centre, of Manitoba, Winnipeg, Manitoba, Canada University of Manitoba, Winnipeg, Manitoba, Figures 12-28 and 20-18 Canada Figure 13-6 Marc Del Bigio, MD, PhD, FRCPC Department of Pathology (Neuropathology), University Lyndon M. Hill, MD of Manitoba, Winnipeg, Manitoba, Canada Magee-Women’s Hospital, Pittsburgh, Pennsylvania, USA Figures 17-13, 17-29 (inset), 17-30BC, 17-32B, 17-37B, Figures 11-7 and 12-14 17-38, 17-40, and 17-42A †Klaus V. Hinrichsen, MD David D. Eisenstat, MD, MA, FRCPC Medizinische Fakultät, Institut für Anatomie, Manitoba Institute of Cell Biology, Department of Ruhr-Universität Bochum, Bochum, Germany Human Anatomy and Cell Science, University of Figures 5-12A, 9-2, and 9-26 Manitoba, Winnipeg, Manitoba, Canada Figure 17-2 Dr. Jon and Mrs. Margaret Jackson Figure 6-9B Vassilios Fanos, MD Department of Pediatrics, University of Verona, Verona, Italy Figure 20-4 †Deceased.  C O N T R I B U TORS ix Evelyn Jain, MD, FCFP Margaret Morris, MD, FRCSC, MEd Breastfeeding Clinic, Calgary, Alberta, Canada Professor of Obstetrics, Gynaecology, and Reproductive Figure 9-24 Sciences, Women’s Hospital and University of Manitoba, Winnipeg, Manitoba, Canada John A. Jane, Sr., MD Figure 12-46 David D. Weaver Professor of Neurosurgery, Department of Neurological Surgery, University of Stuart C. Morrison, MD Virginia Health System, Charlottesville, Virginia, USA Section of Pediatric Radiology, The Children’s Hospital, Figure 14-12 Cleveland Clinic, Cleveland, Ohio, USA Figures 7-13, 11-20, 17-29E, and 17-41 Robert Jordan, MD St. George’s University Medical School, True Blue, John B. Mulliken, MD Grenada Children’s Hospital Boston, Harvard Medical School, Figures 6-6B and 7-25 Boston, Massachusetts, USA Figure 9-42 Linda J. Juretschke, MD Ronald McDonald Children’s Hospital, Loyola W. Jerry Oakes, MD University Medical Center, Maywood, Illinois, USA Children’s Hospital Birmingham, Birmingham, Figure 7-31 Alabama, USA Figure 17-42B Dagmar K. Kalousek, MD Department of Pathology, University of British †Dwight Parkinson, MD Columbia, Children’s Hospital, Vancouver, British Departments of Surgery and Human Anatomy & Columbia, Canada Cell Science, University of Manitoba, Winnipeg, Figures 8-11AB, 11-14A, 12-12C, 12-16, and 20-6AB Manitoba, Canada Figure 17-14 E.C. Klatt, MD Department of Biomedical Sciences, Mercer University Maulik S. Patel, MD School of Medicine, Savannah, Georgia, USA Consultant Pathologist, Surat, India Figure 7-16 Figure 4-15 Wesley Lee, MD Dr. Susan Phillips Division of Fetal Imaging, William Beaumont Hospital, Department of Pathology, Health Sciences Centre, Royal Oak, Michigan, USA Winnipeg, Manitoba, Canada Figures 13-20 and 13-30A Figure 18-6 Deborah Levine, MD, FACR Srinivasa Ramachandra, MD Departments of Radiology and Obstetric & Figure 9-13A Gynecologic Ultrasound, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA †Dr. M. Ray Figures 6-8, 6-15, 8-10, 9-43CD, 17-35B, and cover image Department of Human Genetics, University of (magnetic resonance image of 27-week fetus) Manitoba, Winnipeg, Manitoba, Canada Figure 20-12B E.A. (Ted) Lyons, OC, MD, FRCPC, FACR Departments of Radiology, Obstetrics & Gynecology, Martin H. Reed, MD, FRCPC and Human Anatomy & Cell Science, Division of Department of Radiology, University of Manitoba and Ultrasound, Health Sciences Centre, University of Children’s Hospital, Winnipeg, Manitoba, Canada Manitoba, Winnipeg, Manitoba, Canada Figure 11-27 Figures 3-7, 3-9, 4-1, 4-13, 5-19, 6-1, 6-10, 6-12, 7-23, 7-26, 7-29, 11-19CD, 12-45, and 13-3 †Deceased. x CONTRIBUT O R S Gregory J. Reid, MD, FRCSC Pierre Soucy, MD, FRCSC Department of Obstetrics, Gynecology, and Division of Pediatric Surgery, Children’s Hospital of Reproductive Sciences, University of Manitoba, Eastern Ontario, Ottawa, Ontario, Canada Women’s Hospital, Winnipeg, Manitoba, Canada Figures 9-10, 9-11, and 18-22 Figures 9-43AB, 11-18, 12-39, 13-12, and 14-9 Dr. Y. Suzuki Michael and Michele Rice Achi, Japan Figure 6-9A Figure 16-13A Dr. S.G. Robben R. Shane Tubbs, PhD Department of Radiology, Maastricht University Children’s Hospital Birmingham, Birmingham, Medical Centre, Maastricht, The Netherlands Alabama, USA Figure 10-7C Figure 17-42B Prem S. Sahni, MD Edward O. Uthman, MD Formerly of the Department of Radiology, Children’s Consultant Pathologist, Houston/Richmond, Hospital, Winnipeg, Manitoba, Canada Texas, USA Figures 8-11C, 10-7B, 10-13, 11-4C, 11-28B, 12-16, Figure 3-11 12-17, 12-19, 14-10, 14-15, and 16-13C Jeffrey T. Wigle, PhD Dr. M.J. Schuurman Department of Biochemistry and Medical Genetics, Department of Pediatrics, Maastricht University University of Manitoba, Winnipeg, Manitoba, Medical Centre, Maastricht, The Netherlands Canada Figure 10-7C Figure 17-2 P. Schwartz and H.M. Michelmann Nathan E. Wiseman, MD, FRCSC University of Goettingen, Goettingen, Germany Pediatric Surgeon, Children’s Hospital, Winnipeg, Figure 2-13 Manitoba, Canada Figure 11-17A Joseph R. Siebert, MD Children’s Hospital and Regional Center, Seattle, M.T. Zenzes Washington, USA In Vitro Fertilization Program, Toronto Hospital, Figures 7-32, 13-36, 16-13B, and 17-16 Toronto, Ontario, Canada Figure 2-17A Bradley R. Smith, MD University of Michigan, Ann Arbor, Michigan, USA Figures 5-16C, 5-17C, 5-20C, 8-6B, 9-3A (inset), 14-13, and 18-18B Gerald S. Smyser, MD Formerly of the Altru Health System, Grand Forks, North Dakota, USA Figures 9-20, 13-45, 17-24, 17-32A, 17-34, 17-37A, and 18-24  Preface W e have entered an era of achievement in the fields of molecular biology, genetics, and clinical embryology, perhaps like no other. The sequencing of the human genome has been achieved and several mammalian species, as well as the human embryo, have been cloned. Scientists have created and isolated human embryonic stem cells, and their use in treating certain intractable diseases continues to generate widespread debate. These remarkable scientific developments have already provided promising directions for research in human embryology, which will have an impact on medical practice in the future. The 10th edition of The Developing Human has been thoroughly revised to reflect current understanding of some of the molecular events that guide development of the embryo. This book also contains more clinically oriented material than previous editions; these sections are set as blue boxes to differentiate them from the rest of the text. In addition to focusing on clinically relevant aspects of embryology, we have revised the Clinically Oriented Prob- lems with brief answers and added more case studies online that emphasize the importance of embryology in modern medical practice. This edition follows the official international list of embryologic terms (Terminologia Embryologica, Georg Thieme Verlag, 2013). It is important that physicians and scientists throughout the world use the same name for each structure. This edition includes numerous new color photographs of embryos (normal and abnor- mal). Many of the illustrations have been improved using three-dimensional renderings and more effective use of colors. There are also many new diagnostic images (ultrasound and magnetic resonance image) of embryos and fetuses to illustrate their three-dimensional aspects. An innovative set of 18 animations that will help students understand the complexi- ties of embryologic development now comes with this book. When one of the animations is especially relevant to a passage in the text, the icon has been added in the margin. Maximized animations are available to teachers who have adopted The Developing Human for their lectures (consult your Elsevier representative). The coverage of teratology (studies concerned with birth defects) has been increased because the study of abnormal development of embryos and fetuses is helpful in understand- ing risk estimation, the causes of birth defects, and how malformations may be prevented. Recent advances in the molecular aspects of developmental biology have been highlighted (in italics) throughout the book, especially in those areas that appear promising for clinical medicine or have the potential for making a significant impact on the direction of future research. We have continued our attempts to provide an easy-to-read account of human develop- ment before birth and during the neonatal period (1 to 28 days). Every chapter has been thoroughly reviewed and revised to reflect new findings in research and their clinical significance. The chapters are organized to present a systematic and logical approach to embryo devel- opment. The first chapter introduces readers to the scope and importance of embryology, xi xii PREFACE the historical background of the discipline, and the terms used to describe the stages of development. The next four chapters cover embryonic development, beginning with the formation of gametes and ending with the formation of basic organs and systems. The development of specific organs and systems is then described in a systematic manner, fol- lowed by chapters dealing with the highlights of the fetal period, the placenta and fetal membranes, the causes of human birth defects, and common signaling pathways used during development. At the end of each chapter there are summaries of key features, which provide a convenient means of ongoing review. There are also references that contain both classic works and recent research publications. Keith L. Moore T.V.N. (Vid) Persaud Mark G. Torchia  Acknowledgments T he Developing Human is widely used by medical, and Reproductive Sciences, University of Manitoba, dental, and many other students in the health sciences. Winnipeg; Dr. L. Ross, Department of Neurobiology and The suggestions, constructive criticisms, and comments Anatomy, University of Texas Medical School, Houston, we received from instructors and students around the Texas; Dr. J. Elliott Scott, Departments of Oral Biology world have helped us improve this 10th edition. and Human Anatomy & Cell Science, University of When learning embryology, the illustrations are an Manitoba, Winnipeg; Dr. Brad Smith, University of essential feature to facilitate both understanding of the Michigan, Ann Arbor, Michigan; Dr. Gerald S. Smyser, subject and retention of the material. Many figures formerly of the Altru Health System, Grand Forks, North have been improved, and newer clinical images replace Dakota; Dr. Richard Shane Tubbs, Children’s Hospital, older ones. Birmingham, Alabama; Dr. Ed Uthman, Clinical Patholo- We are indebted to the following colleagues (listed gist, Houston/Richmond, Texas; and Dr. Michael Wiley, alphabetically) for either critical reviewing of chapters, Division of Anatomy, Department of Surgery, Faculty of making suggestions for improvement of this book, or Medicine, University of Toronto, Toronto, Ontario. The providing some of the new figures: Dr. Steve Ahing, new illustrations were prepared by Hans Neuhart, Presi- Faculty of Dentistry, University of Manitoba, Winnipeg; dent of the Electronic Illustrators Group in Fountain Dr. Albert Chudley, Departments of Pediatrics & Child Hills, Arizona. Health and Biochemistry & Medical Genetics, University The stunning collection of animations of developing of Manitoba, Winnipeg; Dr. Blaine M. Cleghorn, Faculty embryos was produced in collaboration with Dr. David of Dentistry, Dalhousie University, Halifax, Nova Scotia; L. Bolender, Associate Professor, Department of Cell Dr. Frank Gaillard, Radiopaedia.org, Toronto, Ontario; Biology, Neurobiology, and Anatomy, Medical College of Dr. Ray Gasser, Faculty of Medicine, Louisiana State Wisconsin. We would like to thank him for his efforts in University Medical Center, New Orleans; Dr. Boris design and in-depth review, as well as his invaluable Kablar, Department of Anatomy and Neurobiology, advice. Our special thanks go to Ms. Carol Emery for Dalhousie University, Halifax, Nova Scotia; Dr. Sylvia skillfully coordinating the project. Kogan, Department of Ophthalmology, University of At Elsevier, we are indebted to Ms. Meghan K. Ziegler, Manitoba, Winnipeg, Manitoba; Dr. Peeyush Lala, Content Strategist, for her continued interest and encour- Faculty of Medicine, Western University, Ontario, agement, and we are especially thankful to Ms. Kelly London, Ontario; Dr. Deborah Levine, Beth Israel McGowan, Content Development Specialist, for her Deaconess Medical Center, Boston, Massachusetts; Dr. invaluable insights and many helpful suggestions. Their Marios Loukas, St. George’s University, Grenada; Dr. unstinting support during the preparation of this new Stuart Morrison, Department of Radiology, Cleveland edition was greatly appreciated. Finally, we should also Clinic, Cleveland, Ohio; Professor Bernard J. Moxham, like to thank Ms. Kristine Feeherty, Project Manager; Ms. Cardiff School of Biosciences, Cardiff University, Cardiff, Maggie Reid, Designer; Ms. Amy Naylor, Art Buyer; and Wales; Dr. Michael Narvey, Department of Pediatrics Ms. Thapasya Ramkumar, Multimedia Producer, at and Child Health, University of Manitoba, Winnipeg, Elsevier for nurturing this book to completion. This new Manitoba; Dr. Drew Noden, Department of Biomedical edition of The Developing Human is the result of their Sciences, Cornell University, College of Veterinary Medi- dedication and technical expertise. cine, Ithaca, New York; Dr. Shannon Perry, School of Keith L. Moore Nursing, San Francisco State University, California; Dr. T.V.N. (Vid) Persaud Gregory Reid, Department of Obstetrics, Gynecology, Mark G. Torchia xiii  Contents 1 Introduction to Human Menstrual Cycle 23 Phases of Menstrual Cycle 24 Development 1 Developmental Periods 1 Transportation of Gametes 25 Stages of Embryonic Development 2 Oocyte Transport 25 Postnatal Period 2 Sperm Transport 25 Infancy 2 Maturation of Sperms 26 Childhood 2 Viability of Gametes 26 Puberty 2 Sequence of Fertilization 27 Adulthood 4 Phases of Fertilization 29 Significance of Embryology 4 Fertilization 29 Historical Gleanings 4 Cleavage of Zygote 30 Ancient Views of Human Embryology 4 Formation of Blastocyst 33 Embryology in the Middle Ages 5 Summary of First Week 35 The Renaissance 5 Clinically Oriented Problems 36 Genetics and Human Development 7 Molecular Biology of Human 3 Second Week of Human Development 7 Development 39 Human Biokinetic Embryology 8 Completion of Implantation of Descriptive Terms in Embryology 8 Blastocyst 39 Clinically Oriented Problems 8 Formation of Amniotic Cavity, Embryonic Disc, and Umbilical Vesicle 41 2 First Week of Human Development of Chorionic Sac 42 Implantation Sites of Blastocysts 46 Development 11 Gametogenesis 11 Summary of Implantation 46 Meiosis 12 Summary of Second Week 48 Spermatogenesis 12 Clinically Oriented Problems 49 Oogenesis 17 Prenatal Maturation of Oocytes 17 4 Third Week of Human Postnatal Maturation of Oocytes 17 Development 51 Comparison of Gametes 17 Gastrulation: Formation of Germ Uterus, Uterine Tubes, and Ovaries 18 Layers 51 Uterus 18 Primitive Streak 52 Uterine Tubes 18 Fate of Primitive Streak 54 Ovaries 18 Notochordal Process and Notochord 54 Female Reproductive Cycles 20 Allantois 58 Ovarian Cycle 20 Neurulation: Formation of Neural Follicular Development 21 Tube 58 Ovulation 22 Neural Plate and Neural Tube 59 Corpus Luteum 22 Neural Crest Formation 59 xv xvi CONTENTS Development of Somites 61 Factors Influencing Fetal Growth 99 Development of Intraembryonic Cigarette Smoking 99 Coelom 62 Multiple Pregnancy 99 Early Development of Cardiovascular Alcohol and Illicit Drugs 99 System 62 Impaired Uteroplacental and Vasculogenesis and Angiogenesis 62 Fetoplacental Blood Flow 99 Primordial Cardiovascular System 62 Genetic Factors and Growth Development of Chorionic Villi 63 Retardation 100 Summary of Third Week 64 Procedures for Assessing Fetal Clinically Oriented Problems 67 Status 100 Ultrasonography 100 Diagnostic Amniocentesis 100 5 Fourth to Eighth Weeks of Human Alpha-Fetoprotein Assay 101 Development 69 Spectrophotometric Studies 101 Phases of Embryonic Development 69 Chorionic Villus Sampling 101 Folding of Embryo 70 Cell Cultures and Chromosomal Folding of Embryo in the Median Analysis 102 Plane 70 Noninvasive Prenatal Diagnosis 102 Folding of Embryo in the Horizontal Fetal Transfusion 103 Plane 70 Fetoscopy 103 Germ Layer Derivatives 70 Percutaneous Umbilical Cord Blood Control of Embryonic Development 72 Sampling 103 Highlights of Fourth to Eighth Magnetic Resonance Imaging 103 Weeks 74 Fetal Monitoring 103 Fourth Week 74 Summary of Fetal Period 103 Fifth Week 75 Clinically Oriented Problems 104 Sixth Week 78 Seventh Week 78 Eighth Week 84 Estimation of Embryonic Age 85 7 Placenta and Fetal Membranes 107 Placenta 107 Summary of Fourth to Eighth Decidua 109 Weeks 87 Development of Placenta 109 Clinically Oriented Problems 88 Placental Circulation 111 Placental Membrane 113 6 Fetal Period: Ninth Week Functions of Placenta 114 to Birth 91 Placental Endocrine Synthesis and Estimation of Fetal Age 93 Secretion 117 Trimesters of Pregnancy 93 The Placenta as an Allograft 117 Measurements and Characteristics of The Placenta as an Invasive Tumor-like Fetuses 93 Structure 118 Highlights of Fetal Period 94 Uterine Growth during Pregnancy 118 Nine to Twelve Weeks 94 Parturition 119 Thirteen to Sixteen Weeks 95 Stages of Labor 119 Seventeen to Twenty Weeks 95 Placenta and Fetal Membranes after Twenty-One to Twenty-Five Weeks 96 Birth 121 Twenty-Six to Twenty-Nine Weeks 97 Maternal Surface of Placenta 121 Thirty to Thirty-Four Weeks 97 Fetal Surface of Placenta 121 Thirty-Five to Thirty-Eight Weeks 97 Umbilical Cord 124 Expected Date of Delivery 99 Amnion and Amniotic Fluid 126  C O N T ENTS xvii Umbilical Vesicle 129 Development of Nasal Cavities 181 Significance of Umbilical Vesicle 130 Paranasal Sinuses 181 Fate of Umbilical Vesicle 130 Development of Palate 182 Allantois 130 Primary Palate 182 Multiple Pregnancies 130 Secondary Palate 182 Twins and Fetal Membranes 130 Summary of Pharyngeal Apparatus, Face, Dizygotic Twins 131 and Neck 191 Monozygotic Twins 132 Clinically Oriented Problems 191 Other Types of Multiple Births 133 Summary of Placenta and Fetal 10 Respiratory System 195 Membranes 135 Respiratory Primordium 195 Neonatal Period 138 Development of Larynx 196 Clinically Oriented Problems 138 Development of Trachea 198 Development of Bronchi and Lungs 200 Maturation of Lungs 201 8 Body Cavities, Mesenteries, Summary of Respiratory System 206 and Diaphragm 141 Clinically Oriented Problems 207 Embryonic Body Cavity 141 Mesenteries 144 Division of Embryonic Body Cavity 144 11 Alimentary System 209 Foregut 210 Development of Diaphragm 146 Development of Esophagus 210 Septum Transversum 147 Development of Stomach 211 Pleuroperitoneal Membranes 147 Omental Bursa 211 Dorsal Mesentery of Esophagus 147 Development of Duodenum 214 Muscular Ingrowth from Lateral Body Development of Liver and Biliary Walls 148 Apparatus 217 Positional Changes and Innervation of Development of Pancreas 219 Diaphragm 148 Development of Spleen 221 Summary of Development of Body Midgut 221 Cavities, Mesenteries, and Herniation of Midgut Loop 223 Diaphragm 151 Rotation of Midgut Loop 224 Clinically Oriented Problems 153 Retraction of Intestinal Loops 224 Cecum and Appendix 225 9 Pharyngeal Apparatus, Face, Hindgut 233 and Neck 155 Cloaca 233 Pharyngeal Arches 155 Anal Canal 233 Pharyngeal Arch Components 157 Summary of Alimentary System 234 Pharyngeal Pouches 161 Clinically Oriented Problems 239 Derivatives of Pharyngeal Pouches 161 12 Urogenital System 241 Pharyngeal Grooves 164 Development of Urinary System 243 Pharyngeal Membranes 164 Development of Kidneys and Development of Thyroid Gland 168 Ureters 243 Histogenesis of Thyroid Gland 169 Development of Urinary Bladder 255 Development of Tongue 172 Development of Urethra 258 Lingual Papillae and Taste Buds 172 Development of Suprarenal Glands 259 Nerve Supply of Tongue 173 Development of Genital System 260 Development of Salivary Glands 174 Development of Gonads 260 Development of Face 174 Development of Genital Ducts 262 xviii CONTENTS Development of Male Genital Ducts Fetal and Neonatal Circulation 325 and Glands 264 Fetal Circulation 325 Development of Female Genital Ducts Transitional Neonatal Circulation 325 and Glands 264 Derivatives of Fetal Vessels and Development of Vagina 266 Structures 329 Development of External Development of Lymphatic System 331 Genitalia 267 Development of Lymph Sacs and Development of Male External Lymphatic Ducts 331 Genitalia 267 Development of Thoracic Duct 331 Development of Female External Development of Lymph Nodes 331 Genitalia 268 Development of Lymphocytes 331 Development of Inguinal Canals 276 Development of Spleen and Relocation of Testes and Ovaries 278 Tonsils 332 Testicular Descent 278 Summary of Cardiovascular Ovarian Descent 278 System 332 Summary of Urogenital System 278 Clinically Oriented Problems 334 Clinically Oriented Problems 280 13 Cardiovascular System 283 14 Skeletal System 337 Development of Bone and Early Development of Heart and Blood Cartilage 337 Vessels 284 Histogenesis of Cartilage 339 Development of Veins Associated with Histogenesis of Bone 339 Embryonic Heart 285 Intramembranous Ossification 339 Fate of Vitelline and Umbilical Endochondral Ossification 340 Arteries 288 Development of Joints 341 Later Development of Heart 289 Fibrous Joints 342 Circulation through Primordial Cartilaginous Joints 342 Heart 291 Synovial Joints 342 Partitioning of Primordial Heart 293 Development of Axial Skeleton 342 Changes in Sinus Venosus 294 Development of Vertebral Conducting System of Heart 301 Column 342 Birth Defects of Heart and Great Development of Ribs 344 Vessels 301 Development of Sternum 344 Derivatives of Pharyngeal Arch Development of Cranium 344 Arteries 317 Cranium of Neonate 346 Derivatives of First Pair of Pharyngeal Postnatal Growth of Cranium 347 Arch Arteries 317 Development of Appendicular Derivatives of Second Pair of Pharyngeal Skeleton 349 Arch Arteries 317 Summary of Skeletal System 353 Derivatives of Third Pair of Pharyngeal Clinically Oriented Problems 353 Arch Arteries 318 Derivatives of Fourth Pair of Pharyngeal Arch Arteries 318 15 Muscular System 355 Fate of Fifth Pair of Pharyngeal Arch Development of Skeletal Muscle 355 Arteries 320 Myotomes 357 Derivatives of Sixth Pair of Pharyngeal Pharyngeal Arch Muscles 358 Arch Arteries 320 Ocular Muscles 358 Pharyngeal Arch Arterial Birth Tongue Muscles 358 Defects 320 Limb Muscles 358  C O N T ENTS xix Development of Smooth Muscle 358 Aqueous Chambers 426 Development of Cardiac Muscle 359 Cornea 427 Summary of Muscular System 361 Choroid and Sclera 427 Clinically Oriented Problems 361 Eyelids 427 Lacrimal Glands 428 16 Development of Limbs 363 Development of Ears 428 Internal Ears 428 Early Stages of Limb Development 363 Final Stages of Limb Development 367 Middle Ears 430 Cutaneous Innervation of Limbs 367 External Ears 431 Blood Supply of Limbs 371 Summary of Eye Development 434 Birth Defects of Limbs 372 Summary of Ear Development 435 Summary of Limb Development 377 Clinically Oriented Problems 435 Clinically Oriented Problems 377 19 Integumentary System 437 17 Nervous System 379 Development of Skin and Development of Nervous System 379 Appendages 437 Development of Spinal Cord 382 Epidermis 437 Development of Spinal Ganglia 384 Dermis 439 Development of Spinal Meninges 385 Glands 440 Positional Changes of Spinal Hairs 445 Cord 387 Nails 446 Myelination of Nerve Fibers 387 Teeth 446 Development of Brain 392 Summary of Integumentary Brain Flexures 392 System 454 Hindbrain 392 Clinically Oriented Problems 454 Choroid Plexuses and Cerebrospinal Fluid 396 Midbrain 396 20 Human Birth Defects 457 Classification of Birth Defects 457 Forebrain 396 Teratology: Study of Abnormal Birth Defects of Brain 403 Development 458 Development of Peripheral Nervous Birth Defects Caused by Genetic System 412 Factors 458 Spinal Nerves 412 Numeric Chromosomal Cranial Nerves 412 Abnormalities 459 Development of Autonomic Nervous Structural Chromosomal System 414 Abnormalities 466 Sympathetic Nervous System 414 Birth Defects Caused by Mutant Parasympathetic Nervous System 414 Genes 469 Summary of Nervous System 414 Developmental Signaling Clinically Oriented Problems 415 Pathways 471 Birth Defects Caused by Environmental 18 Development of Eyes and Ears 417 Factors 472 Development of Eyes and Related Principles of Teratogenesis 472 Structures 417 Critical Periods of Human Retina 419 Development 472 Ciliary Body 423 Human Teratogens 475 Iris 423 Birth Defects Caused by Multifactorial Lens 425 Inheritance 484 xx CONTENTS Summary of Birth Defects 484 Transcription Factors 496 Clinically Oriented Problems 485 HOX Proteins 496 PAX Genes 496 21 Common Signaling Pathways Used Basic Helix-Loop-Helix Transcription Factors 497 During Development 487 Intercellular Communication 488 Epigenetics 497 Gap Junctions 488 Histones 498 Cell Adhesion Molecules 489 Histone Methylation 498 Morphogens 490 DNA Methylation 498 Retinoic Acid 490 MicroRNAs 499 Transforming Growth Factor-β and Bone Stem Cells: Differentiation versus Morphogenetic Proteins 490 Pluripotency 499 Hedgehog 491 Summary of Common Signaling Pathways WNT/β-Catenin Pathway 492 Used During Development 500 Protein Kinases 493 Receptor Tyrosine Kinases 493 Appendix 503 Hippo Signaling Pathway 494 Notch-Delta Pathway 494 Index 513  C H A P T E R 1 Introduction to Human Development Developmental Periods 1 Embryology in the Middle Ages 5 Stages of Embryonic Development 2 The Renaissance 5 Postnatal Period 2 Genetics and Human Development 7 Infancy 2 Molecular Biology of Human Childhood 2 Development 7 Puberty 2 Adulthood 4 Human Biokinetic Embryology 8 Significance of Embryology 4 Descriptive Terms in Embryology 8 Historical Gleanings 4 Clinically Oriented Problems 8 Ancient Views of Human Embryology 4 H uman development is a continuous process that begins when an oocyte (ovum) from a female is fertilized by a sperm (spermatozoon) from a male (Fig. 1-1). Cell division, cell migration, programmed cell death (apoptosis), differentiation, growth, and cell rearrange- ment transform the fertilized oocyte, a highly specialized, totipotent cell, a zygote, into a multicellular human being. Most changes occur during the embryonic and fetal periods; however, important changes occur during later periods of development: neonatal period (first 4 weeks), infancy (first year), childhood (2 years to puberty), and adolescence (11 to 19 years). Development does not stop at birth; other changes, in addition to growth, occur after birth (e.g., development of teeth and female breasts). DEVELOPMENTAL PERIODS It is customary to divide human development into prenatal (before birth) and postnatal (after birth) periods. The development of a human from fertilization of an oocyte to birth is divided into two main periods, embryonic and fetal. The main changes that occur prenatally are illustrated in the Timetable of Human Prenatal Development (see Fig. 1-1). Examination of the timetable reveals that the most visible advances occur during the third to eighth weeks— the embryonic period. During the fetal period, differentiation and growth of tissues and organs occur and the rate of body growth increases. 1 2 THE DEVEL O P I N G H U M A N extrauterine existence requires many critical changes, Stages of Embryonic Development especially in the cardiovascular and respiratory systems. Early development is described in stages because of the If neonates survive the first crucial hours after birth, their variable period it takes for embryos to develop certain chances of living are usually good. The body grows morphologic characteristics. Stage 1 begins at fertiliza- rapidly during infancy; total length increases by approxi- tion and embryonic development ends at stage 23, which mately one half and weight is usually tripled. By 1 year occurs on day 56 (see Fig. 1-1). A trimester is a period of age, most infants have six to eight teeth. of 3 months, one third of the 9-month period of gesta- tion. The most critical stages of development occur during the first trimester (13 weeks), when embryonic and early Childhood fetal development is occurring. This is the period between infancy and puberty. The primary (deciduous) teeth continue to appear and are later replaced by the secondary (permanent) teeth. During Postnatal Period early childhood, there is active ossification (formation of This is the period occurring after birth. Explanations of bone), but as the child becomes older, the rate of body frequently used developmental terms and periods follow. growth slows down. Just before puberty, however, growth accelerates—the prepubertal growth spurt. Infancy This is the period of extrauterine life, roughly the first Puberty year after birth. An infant age 1 month or younger This is the period when humans become functionally is called a neonate. Transition from intrauterine to capable of procreation (reproduction). Reproduction is TIMETABLE OF HUMAN PRENATAL DEVELOPMENT 1 TO 10 WEEKS Primary follicles Oocyte EARLY DEVELOPMENT OF OVARIAN FOLLICLE MENSTRUAL PHASE PROLIFERATIVE PHASE Day 1 of last normal menstrual cycle Antrum Mature Oocyte follicle Ovulation COMPLETION OF DEVELOPMENT OF FOLLICLE Oocyte Oocyte Ovary CONTINUATION OF PROLIFERATIVE PHASE OF MENSTRUAL CYCLE AGE (weeks) 1 Stage 1 2 Stage 2 begins 3 4 Stage 3 begins 5 6 Stage 4 7 Stage 5 begins Trophoblast Zona pellucida Implantation begins 1 Fertilization Zygote divides Morula Early blastocyst Late blastocyst Embryoblast SECRETORY PHASE OF MENSTRUAL CYCLE 8 9 10 Cytotrophoblast 11 Maternal blood 12 Extraembryonic 13 Stage 6 begins 14 Lacunar Connecting stalk Lacunae appear in Amnion Eroded mesoderm syncytiotrophoblast gland network Primary villi Amnion Amniotic cavity 2 Primary Embryonic disc Bilaminar embryonic Primary umbilical umbilical Coelom disc vesicle Closing plug vesicle Embryonic disc Prechordal plate F I G U R E 1 – 1 Early stages of development. Development of an ovarian follicle containing an oocyte, ovulation, and the phases of the menstrual cycle are illustrated. Human development begins at fertilization, approximately 14 days after the onset of the last normal menstrual period. Cleavage of the zygote in the uterine tube, implantation of the blastocyst in the endometrium (lining) of the uterus, and early development of the embryo are also shown. The alternative term for the umbilical vesicle is the yolk sac; this is an inappropriate term because the human vesicle does not contain yolk.  CHAPTER 1 | I n tr o d u cti on t o H u man Devel op me nt 3 15 16 Stage 7 begins 17 Trilaminar embryo 18 Stage 8 begins 19 20 Stage 9 begins 21 Neural First missed groove menstrual period Amnion Neural plate Neural plate Brain First pairs Neural of somites Primitive groove Neural groove 3 streak Primitive Somite Somite streak Arrows indicate Primitive node migration of Migration of cells from Thyroid gland begins Primitive streak primitive streak Length: 1.5 mm Primitive streak to develop mesenchymal cells 22 Stage 10 begins 23 Rostral neuropore 24 Stage 11 begins 25 26 Stage 12 begins 27 Site of otic pit 28 Stage 13 begins Otic (ear) pit Heart bulge Fore- brain Heart Primordia Upper begins of eye Rostral limb bud Pharyngeal 4 to beat and ear neuropore closes arches present Caudal 2 pairs of 3 pairs of Indicates CRL = crown− neuropore Neural folds fusing pharyngeal arches pharyngeal arches actual size rump length CRL: 5.0 mm 29 30 31 32 Stage 14 begins 33 Stage 15 begins 34 Cerebral vesicles 35 Eye Developing eye distinct Eye Upper limb bud 5 Nasal Hand pit Heart plate Cord Lower Foot Lens pits, optic cups, limb plate CRL: 5.5 mm nasal pits forming Primordial mouth bud CRL: 7.0 mm present CRL: 8.5 mm 36 37 Stage 16 begins 38 39 40 External acoustic 41 Stage 17 begins 42 Large head meatus Ear Eye Digital Ear rays 6 Eye Eye Digital rays Foot- Oral and nasal plate Upper lip and Foot plate cavities confluent CRL: 9.5 mm nose formed CRL: 12.5 mm CRL: 10.5 mm Ventral view AGE (weeks) 43 Actual size 44 Stage 18 begins 45 46 47 Genital tubercle 48 Stage 19 begins 49 Actual size Amniotic sac Wall of uterus Head large but chin Eyelid Uterine Urogenital poorly formed. cavity membrane Grooves between 7 digital rays External ear Anal indicate fingers. membrane Wrist, Eyelids fingers CRL: 13.0 mm forming Smooth or fused CRL: 18 mm chorion 50 Stage 20 begins 51 52 Stage 21 begins 53 54 Stage 22 begins 55 56 Stage 23 Genital Eye Ear Upper limbs tubercle Eye Ear longer and bent External genitalia Urethral at elbows. have begun groove Wrist 8 Nose to differentiate. Fingers distinct Fingers Knee but webbed. Anus Elbow Toes or Large forehead Toes CRL: 30 mm 57 58 59 Placenta 60 Genitalia 61 62 Genitalia 63 Phallus Phallus Eye Ear Urogenital Urogenital Beginning fold fold of Wrist 9 fetal Labioscrotal Knee Labioscrotal fold period fold Perineum Perineum Toes Elbow CRL: 45 mm CRL: 50 mm 64 65 66 67 68 69 70 Clitoris Labium Glans of penis Face has minus Genitalia have more developed or Urethral profile. Urogenital 10 characteristics groove groove but still not Note growth fully formed. Scrotum of chin Labium compared majus to day 44. Ears still lower than normal. CRL: 61 mm FIGURE 1–1, cont’d 4 THE DEVEL O P I N G H U M A N the process by which organisms produce children. In now possible in some situations. The understanding and females, the first signs of puberty may be after age 8; in correction of most defects depend on knowledge of males, puberty commonly begins at age 9. normal development and the deviations that may occur. An understanding of common congenital birth defects and their causes also enables physicians, nurses, and other Adulthood health-care providers to explain the developmental basis Attainment of full growth and maturity is generally of birth defects, often dispelling parental guilt feelings. reached between the ages of 18 and 21 years. Ossification Health-care professionals who are aware of common and growth are virtually completed during early adult- birth defects and their embryologic basis approach hood (21 to 25 years). unusual situations with confidence rather than surprise. For example, when it is realized that the renal artery represents only one of several vessels originally supplying SIGNIFICANCE OF EMBRYOLOGY the embryonic kidney, the frequent variations in the number and arrangement of renal vessels are understand- Clinically oriented embryology refers to the study of able and not unexpected. embryos; the term generally means prenatal development of embryos, fetuses, and neonates (infants aged 1 month and younger). Developmental anatomy refers to the HISTORICAL GLEANINGS structural changes of a human from fertilization to adult- If I have seen further, it is by standing on the shoulders hood; it includes embryology, fetology, and postnatal of giants. development. Teratology is the division of embryology – Sir Isaac Newton, English mathematician, 1643–1727 and pathology that deals with abnormal development (birth defects). This branch of embryology is concerned This statement, made more than 300 years ago, empha- with various genetic and/or environmental factors that sizes that each new study of a problem rests on a base of disturb normal development and produce birth defects knowledge established by earlier investigators. The theo- (see Chapter 20). ries of every age offer explanations based on the knowl- Clinically oriented embryology: edge and experience of investigators of the period. Although we should not consider them final, we should Bridges the gap between prenatal development and appreciate rather than scorn their ideas. People have obstetrics, perinatal medicine, pediatrics, and clinical always been interested in knowing how they developed anatomy and were born and why some embryos and fetuses Develops knowledge concerning the beginnings of life develop abnormally. Ancient people developed many and the changes occurring during prenatal development answers to the reasons for these birth defects. Builds an understanding of the causes of variations in human structure Illuminates clinically oriented anatomy and explains Ancient Views of Human Embryology how normal and abnormal relations develop Egyptians of the Old Kingdom, approximately 3000 BC, Supports the research and application of stem cells for knew of methods for incubating birds’ eggs, but they left treatment of certain chronic diseases no records. Akhnaton (Amenophis IV) praised the sun Knowledge that physicians have of normal develop- god Aton as the creator of the germ in a woman, maker ment and the causes of birth defects is necessary for of the seed in man, and giver of life to the son in the body giving the embryo and fetus the best possible chance of of his mother. The ancient Egyptians believed that the developing normally. Much of the modern practice soul entered the infant at birth through the placenta. of obstetrics involves applied embryology. Embryologic A brief Sanskrit treatise on ancient Indian embryology topics of special interest to obstetricians are oocyte and is thought to have been written in 1416 BC. This scrip- sperm transport, ovulation, fertilization, implantation, ture of the Hindus, called Garbha Upanishad, describes fetal-maternal relations, fetal circulation, critical periods ancient views concerning the embryo. It states: of development, and causes of birth defects. From the conjugation of blood and semen (seed), the In addition to caring for the mother, physicians guard embryo comes into existence. During the period the health of the embryo and fetus. The significance of favorable for conception, after the sexual intercourse, embryology is readily apparent to pediatricians because (it) becomes a Kalada (one-day-old embryo). After some of their patients have birth defects resulting from remaining seven nights, it becomes a vesicle. After a maldevelopment, such as diaphragmatic hernia, spina fortnight it becomes a spherical mass. After a month it bifida cystica, and congenital heart disease. becomes a firm mass. After two months the head is Birth defects cause most deaths during infancy. Knowl- formed. After three months the limb regions appear. edge of the development of structure and function is essential for understanding the physiologic changes that Greek scholars made many important contributions to occur during the neonatal period (first 4 weeks) and for the science of embryology. The first recorded embryologic helping fetuses and neonates in distress. Progress in studies are in the books of Hippocrates of Cos, the surgery, especially in the fetal, perinatal, and pediatric age famous Greek physician (circa 460–377 BC), who is groups, has made knowledge of human development even regarded as the father of medicine. In order to understand more clinically significant. Surgical treatment of fetuses is how the human embryo develops, he recommended:  CHAPTER 1 | I n tr o d u cti o n t o H u man De vel op me nt 5 Take twenty or more eggs and let them be incubated by two or more hens. Then each day from the second to that of hatching, remove an egg, break it, and examine it. You will find exactly as I say, for the nature of the bird can be likened to that of man. Aristotle of Stagira (circa 384–322 BC), a Greek phi- losopher and scientist, wrote a treatise on embryology in which he described development of the chick and other A B embryos. Aristotle promoted the idea that the embryo developed from a formless mass, which he described as a “less fully concocted seed with a nutritive soul and all bodily parts.” This embryo, he thought, arose from men- strual blood after activation by male semen. Claudius Galen (circa 130–201 AD), a Greek physi- cian and medical scientist in Rome, wrote a book, On the Formation of the Foetus, in which he described the development and nutrition of fetuses and the C D E structures that we now call the allantois, amnion, and placenta. The Talmud contains references to the formation of the embryo. The Jewish physician Samuel-el-Yehudi, who lived during the second century AD, described six stages in the formation of the embryo from a “formless, rolled-up thing” to a “child whose months have been completed.” Talmud scholars believed that the bones and tendons, the nails, the marrow in the head, and the white of the eyes, were derived from the father, “who sows the white,” but the skin, flesh, blood, and hair were derived from the F G mother, “who sows the red.” These views were according to the teachings of both Aristotle and Galen. F I G U R E 1 – 2 A-G, Illustrations from Jacob Rueff’s De Con- ceptu et Generatione Hominis (1554) showing the fetus develop- ing from a coagulum of blood and semen in the uterus. This Embryology in the Middle Ages theory was based on the teachings of Aristotle, and it survived The growth of science was slow during the medieval until the late 18th century. (From Needham J: A history of embry- period, but a few high points of embryologic investiga- ology, ed 2, Cambridge, United Kingdom, 1934, Cambridge Uni- tion undertaken during this time are known to us. It is versity Press; with permission of Cambridge University Press, cited in the Quran (seventh century AD), the Holy Book England.) of Islam, that human beings are produced from a mixture of secretions from the male and female. Several references (Fig. 1-3). He introduced the quantitative approach to are made to the creation of a human being from a nutfa embryology by making measurements of prenatal growth. (small drop). It also states that the resulting organism It has been stated that the embryologic revolution settles in the womb like a seed, 6 days after its beginning. began with the publication of William Harvey’s book De Reference is made to the leech-like appearance of the Generatione Animalium in 1651. Harvey believed that early embryo. Later the embryo is said to resemble a the male seed or sperm, after entering the womb or “chewed substance.” uterus, became metamorphosed into an egg-like sub- Constantinus Africanus of Salerno (circa 1020–1087 stance from which the embryo developed. Harvey (1578– AD) wrote a concise treatise entitled De Humana Natura. 1657) was greatly influenced by one of his professors at Africanus described the composition and sequential the University of Padua, Fabricius of Acquapendente, an development of the embryo in relation to the planets and Italian anatomist and embryologist who was the first to each month during pregnancy, a concept unknown in study embryos from different species of animals. Harvey antiquity. Medieval scholars hardly deviated from the examined chick embryos with simple lenses and made theory of Aristotle, which stated that the embryo was many new observations. He also studied the development derived from menstrual blood and semen. Because of a of the fallow deer; however, when unable to observe early lack of knowledge, drawings of the fetus in the uterus developmental stages, he concluded that embryos were often showed a fully developed infant frolicking in the secreted by the uterus. Girolamo Fabricius (1537–1619) womb (Fig. 1-2). wrote two major embryologic treatises, including one entitled De Formato Foetu (The Formed Fetus), which contained many illustrations of embryos and fetuses at The Renaissance different stages of development. Leonardo da Vinci (1452–1519) made accurate draw- Early microscopes were simple but they opened an ings of dissections of pregnant uteri containing fetuses exciting new field of observation. In 1672, Regnier de 6 THE DEVEL O P I N G H U M A N F I G U R E 1 – 3 Reproduction of Leonardo da Vinci’s drawing made in the 15th century showing a fetus in a uterus that has F I G U R E 1 – 4 Copy of a 17th-century drawing of a sperm been incised and opened. by Hartsoeker. The miniature human being within it was thought to enlarge after the sperm entered an ovum. Other embryologists at this time thought the oocyte contained a miniature human being that enlarged when it was stimulated by a sperm. Graaf observed small chambers in the rabbit’s uterus and concluded that they could not have been secreted by the uterus. He stated that they must have come from organs The preformation controversy ended in 1775 when that he called ovaries. Undoubtedly, the small chambers Lazzaro Spallanzani showed that both the oocyte and that de Graaf described we