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Sixth Edition
Fetal and Neonatal

Physiology
Richard A. Polin, MD David H. Rowitch, MD ScD
William T. Speck Professor of FMedSci FRS
Pediatrics Professor and Head
College of Physicians and Surgeons Department of Paediatrics
Columbia University Wellcome Trust—Medical Research
Executive Vice-Chair Council Stem Cell Institute
Department of Pediatrics University of Cambridge
Morgan Stanley Children’s Hospital Cambridge, United Kingdom
of New York–Presbyterian Adjunct Professor
Columbia University Irving Medical Department of Pediatrics
Center University of California, San Francisco
New York, New York San Francisco, California
Steven H. Abman, MD William E. Benitz, MD
Professor, Department of Pediatrics Philip Sunshine Professor in
Director, Pediatric Heart Lung Center Neonatology Emeritus
University of Colorado School of Division of Neonatal and
Medicine and Children’s Hospital Developmental Medicine
Colorado Stanford University School of Medicine
Aurora, Colorado Stanford, California
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2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.
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FETAL AND NEONATAL PHYSIOLOGY: SIXTH EDITION ISBN-13: 978-0-323-71284-2

Vol 1: 978-0-323-82555-9
Vol 2: 978-0-323-82556-6
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Last digit is the print number: 9 8 7 6 5 4 3 2 1
DEDICATED TO
Our spouses –
Helene Polin, Carolyn Abman, Risa Sorkin, and Andrea Benitz
Our children –
Allison Polin Steinbrenner, Mitchell Polin, Jessica Moseley, and Gregory Polin
Ryan Abman, Lauren Abman, Mark Abman, and Megan Abman
Sophie Rowitch
Lindsey Benitz, Maija Benitz, and Annika Benitz Chaloff
And our grandchildren –

Lindsey Steinbrenner, Eli Steinbrenner, Willa Polin, Jasper Polin, Elliot Polin, Lily Polin, Casey Moseley, Smith Moseley,
Calla Moseley, Winslow Broderick, Mieke Broderick, Isla Abman, and Alina Abman
Contributors
Soraya Abbasi, MD Gabriel Altit, MDCM, MSc

Professor Assistant Professor
Department of Pediatrics Department of Pediatrics
Perelman School of Medicine McGill University
University of Pennsylvania Neonatologist
Philadelphia, Pennsylvania Division of Neonatology
Evaluation of Pulmonary Function in the Neonate Montreal Children’s Hospital
Montreal, Quebec, Canada
Yalda Afshar, MD, PhD Basic Pharmacologic Principles
Assistant Professor
Department of Obstetrics and Gynecology Ruben E. Alvaro, MD
Division of Maternal Fetal Medicine Medical Director of Neonatology
David Geffen School of Medicine St Boniface Hospital
University of California, Los Angeles Associate Professor
Los Angeles, California Department of Pediatrics
Angiogenesis University of Manitoba
Winnipeg, Manitoba, Canada
Sun-Young Ahn, MD Control of Breathing in Fetal Life and Onset and Control of
Associate Professor Breathing in the Neonate
Pediatric Nephrology
Children’s National Hospital Cristina M. Alvira, MD
The George Washington University Associate Professor of Pediatrics
Washington, District of Columbia Division of Critical Care Medicine
Organic Anion Transport in the Developing Kidney Stanford University School of Medicine
Stanford, California
Kurt H. Albertine, PhD Developmental Biology of the Pulmonary Vasculature
Professor
Edward B. Clark Endowed Chair IV in Pediatrics Natália Carlos Maia Amorim, MS
Department of Pediatrics Master in Nutrition
University of Utah Health Postgraduate Program in Nutrition
Editor-in-Chief, The Anatomical Record Nutritionist of University Hospital Ana Bezerra–Federal
Salt Lake City, Utah University of Rio Grande do Norte
Impaired Lung Growth After Injury in Preterm Lung Santa Cruz, Brazil
Vitamin E Nutrition in Pregnancy and the Newborn Infant
Karel Allegaert, MD, PhD
Professor Kelsey L. Anbuhl, PhD
Department of Development and Regeneration Postdoctoral Fellow
Department of Pharmaceutical and Pharmacological Sciences Center for Neural Science
KU Leuven New York University
Leuven, Belgium New York, New York
Department of Clinical Pharmacy Early Development of the Human Auditory System
Erasmus Medical Center
Rotterdam,The Netherlands Claus Yding Andersen, MSc, DMSc
The Physiology of Placental Drug Disposition Professor
Laboratory of Reproductive Biology
Seth L. Alper, MD, PhD University Hospital of Copenhagen
Professor of Medicine Copenhagen, Denmark
Harvard Medical School Differentiation of the Ovary
Division of Nephrology and Vascular Biology Research Center
Beth Israel Deaconess Medical Center Richard A. Anderson, MD, PhD
Boston, Massachusetts Professor
Urinary Acidification MRC Centre for Reproductive Health
University of Edinburgh
Edinburgh, United Kingdom
Differentiation of the Ovary
vi
Contributors vii
Katrina A. Andrews, MB BChir Peter Russell Baker II, MD

Department of Clinical Genetics Associate Professor
Cambridge University Hospitals NHS Foundation Trust Department of Pediatrics
Department of Medical Genetics Section of Clinical Genetics and Metabolism
University of Cambridge and NIHR Cambridge Biomedical University of Colorado School of Medicine
Research Centre Aurora, Colorado
Cancer Research UK Cambridge Centre Fetal Origins of Adult Disease: A Classic Hypothesis With
Cambridge Biomedical Campus New Relevance
Cambridge, United Kingdom
Pathophysiology of Genetic Neonatal Disease Eduardo H. Bancalari, MD
Professor
David J. Askenazi, MD, MSPH Department of Pediatrics—Neonatology
Professor University of Miami Miller School of Medicine
Director, Pediatric and Infant Center for Acute Nephrology Miami, Florida
Department of Pediatrics Pathophysiology of Bronchopulmonary Dysplasia
Division of Nephrology
University of Alabama Birmingham Tatiana Barichello, PhD
Birmingham, Alabama Assistant Professor
Pathophysiology of Neonatal Acute Kidney Injury Department of Psychiatric and Behavioral Sciences
The University of Texas Health Science Center at Houston
Débora Gabriela Fernandes Assunção, MD McGovern Medical School
Nutritionist Houston,Texas
Specialist in Neonate Intensive Care Professor
Postgraduate Program in Nutrition Laboratory of Experimental Pathophysiology
Federal University of Rio Grande do Norte Graduate Program in Health Sciences
Natal, Brazil University of Southern Santa Catarina
Vitamin E Nutrition in Pregnancy and the Newborn Infant Criciúma, Brazil
Pathophysiology of Neonatal Acute Bacterial Meningitis
Richard Lambert Auten Jr., MD
Professor Frederick C. Battaglia, MD
Department of Pediatrics (Neonatology) Professor Emeritus
Cone Health System Department of Pediatrics
Greensboro, North Carolina University of Colorado School of Medicine
Mechanisms of Neonatal Lung Injury Aurora, Colorado
Placental and Fetal Circulatory and Metabolic Changes
Julie Autmizguine, MD, MHS Accompanying Fetal Growth Restriction
Associate Professor
Departments of Pharmacology and Pediatrics Andrew J. Bauer, MD
University of Montreal Director, The Thyroid Center
Infectious Disease Pediatrician Division of Endocrinology and Diabetes
Department of Pediatrics Children’s Hospital of Philadelphia
CHU Sainte-Justine Professor
Montreal, Quebec, Canada Department of Pediatrics
Basic Pharmacologic Principles Perelman School of Medicine
University of Pennsylvania
Timur Azhibekov, MD, MS CBTI Philadelphia, Pennsylvania
Assistant Professor Fetal and Neonatal Thyroid Physiology
Department of Pediatrics
Case Western Reserve University School of Medicine Michel Baum, MD
Department of Pediatrics Professor of Pediatrics and Internal Medicine
MetroHealth Medical Center Sarah M. and Charles E. Seay Chair in Pediatric Research
Cleveland, Ohio UT Southwestern Medical Center
Regulation of Acid-Base Balance in the Fetus and Neonate Dallas,Texas
Renal Transport of Sodium During Development
Stephen A. Back, MD, PhD
Clyde and Elda Munson Professor of Pediatric Research Ryan W. Bavis, PhD
Department of Pediatrics Helen A. Papaioanou Professor of Biological Sciences
Oregon Health & Science University Department of Biology
Portland, Oregon Bates College
Pathophysiology of Neonatal White Matter Injury Lewiston, Maine
Pathophysiology of Apnea of Prematurity
Timothy M. Bahr, MD
Department of Pediatrics-Neonatology
University of Utah Health
Salt Lake City, Utah
Developmental Erythropoiesis
viii Contributors
Kathryn Beardsall, BSc, MBBS, MD John F. Bertram, BSc, PhD, DSc

Lecturer Head, Anatomy and Developmental Biology
Department of Paediatrics Professor
University of Cambridge Biomedicine Discovery Institute
Physician Monash University
Department of Neonatology Melbourne, Victoria, Australia
Cambridge University Hospitals NHS Trust Development of the Kidney: Morphology and Mechanisms
Role of Glucoregulatory Hormones in Hepatic Glucose Shazia Bhombal, MD
Metabolism During the Perinatal Period Clinical Associate Professor of Pediatrics
Division of Neonatal and Developmental Medicine
Simon Beggs, PhD Stanford University School of Medicine
Associate Professor Stanford, California
UCL Great Ormond Street Institute of Child Health Developmental Biology of the Pulmonary Vasculature
London, United Kingdom
Developmental Aspects of Pain Vinod K. Bhutani, MD
Professor
Corinne Benchimol, DO Department of Pediatrics
Assistant Professor Lucile Packard Children’s Hospital at Stanford
Department of Pediatrics Stanford, California
Mount Sinai Hospital Mechanistic Aspects of Phototherapy for Neonatal
New York, New York Hyperbilirubinemia
Potassium Homeostasis in the Fetus and Neonate
Mary Jane Black, BSc (Hons), PhD
Manon J.N.L. Benders, MD, PhD Associate Professor
Professor Deputy Head
Department of Neonatology Department of Anatomy and Developmental Biology
University Medical Center Utrecht Biomedicine Discovery Institute
Utrecht,The Netherlands Monash University
Cerebellar Development—The Impact of Preterm Birth and Melbourne, Victoria, Australia
Comorbidities Development of the Kidney: Morphology and Mechanisms
Laura Bennet, PhD Joseph M. Bliss, MD, PhD

Professor Associate Professor
Department of Physiology Department of Pediatrics
The University of Auckland Women & Infants Hospital of Rhode Island
Auckland, New Zealand Warren Alpert Medical School of Brown University
Neuroprotective Therapeutic Hypothermia Providence, Rhode Island
Normal and Abnormal Neutrophil Physiology in the Newborn
Phillip R. Bennett, MD, PhD David L. Bolender, PhD
Clinical Professor
Professor
Faculty of Medicine
Cell Biology, Neurobiology, and Anatomy
Department of Metabolism, Digestion, and Reproduction
Medical College of Wisconsin
Institute of Reproductive and Developmental Biology
Milwaukee, Wisconsin
Imperial College Parturition Research Group
Basic Embryology
Researcher
March of Dimes Prematurity Research Centre
Imperial College London Sarah C. Bowdin, MD
London, United Kingdom Department of Clinical Genetics
Pathophysiology of Preterm Birth Cambridge University Hospitals NHS Foundation Trust
Pathophysiology of Genetic Neonatal Disease
Melvin Berger, MD, PhD
Adjunct Professor
Scott D. Boyd, MD, PhD
Pediatrics and Pathology
Associate Professor
Case Western Reserve University School of Medicine
Department of Pathology
Cleveland, Ohio
Stanford University School of Medicine
The Complement System of the Fetus and Newborn
Stanford, California
B-Cell Development
Wolfgang Bernhard, MD
Professor Joline E. Brandenburg, MD
Department of Neonatology Assistant Professor
Children’s Hospital Physical Medicine and Rehabilitation
Eberhard-Karls-University Pediatrics and Adolescent Medicine
Tübingen, Germany Mayo Clinic
Regulation of Surfactant-Associated Phospholipid Synthesis Rochester, Minnesota
and Secretion Functional Development of Respiratory Muscles
Contributors ix
Laura D. Brown, MD Jill Chang, MD

Associate Professor Assistant Professor
University of Colorado School of Medicine Division of Neonatology
Aurora, Colorado Northwestern University Feinberg School of Medicine
Placental Transfer and Fetal Requirements of Chicago, Illinois
Amino Acids Placental Function in Intrauterine Growth Restriction
Douglas G. Burrin, PhD Jennifer R. Charlton, MD

Research Physiologist and Professor Associate Professor
USDA-ARS Children’s Nutrition Research Center Department of Pediatrics
Department of Pediatrics Division of Nephrology
Baylor College of Medicine University of Virginia Children’s Hospital
Houston,Texas Charlottesville, Virginia
Trophic Factors and Regulation of Gastrointestinal Tract Response to Nephron Loss in Early Development
and Liver Development Pathophysiology of Neonatal Acute Kidney Injury
Barbara Cannon, BSc, PhD Sylvain Chemtob, MD, PhD

Professor Professor
Department of Molecular Biosciences Departments of Pediatrics and Pharmacology
The Wenner-Gren Institute CHU Ste-Justine and University of Montreal
Stockholm University Professor
Stockholm, Sweden Department of Ophthalmology
Brown Adipose Tissue: Development and Function Hospital Maisonneuve Rosemont and University of Montreal
Montreal, Quebec, Canada
Michael Caplan, MD Basic Pharmacologic Principles
Chairman
Department of Pediatrics Sadhana Chheda, MBBS, DTMH
NorthShore University HealthSystem Assistant Professor
Evanston, Illinois Department of Pediatrics
Clinical Professor Texas Tech University Health Sciences Center–El Paso
Department of Pediatrics El Paso,Texas
University of Chicago Pritzker School of Medicine Immunology of Human Milk
Chicago, Illinois
Pathophysiology and Prevention of Neonatal Necrotizing Andrew J. Childs, BSc (Hons), MSc, PhD
Enterocolitis Lecturer
Susan E. Carlson, PhD Imperial College London
A. J. Rice Professor of Nutrition and University Distinguished London, United Kingdom
Professor Differentiation of the Ovary
Department of Dietetics and Nutrition
University of Kansas David H. Chu, MD, PhD
Kansas City, Kansas Staff Physician
Long-Chain Polyunsaturated Fatty Acids in Division of Dermatology and Cutaneous Surgery
Neurodevelopment Scripps Clinic Medical Group
La Jolla, California
David P. Carlton, MD Structure and Development of the Skin and Cutaneous
Marcus Professor and Chief Appendages
Division of Neonatology
Emory University Wendy K. Chung, MD, PhD
Atlanta, Georgia Kennedy Family Professor of Pediatrics and Medicine
Regulation of Liquid Secretion and Absorption by the Fetal Department of Pediatrics
and Neonatal Lung Division of Molecular Genetics
Pathophysiology of Edema Columbia University Irving Medical Center
New York, New York
Piya Chaemsaithong, MD, PhD Basic Genetic Principles
Division of Maternal Fetal Medicine
Department of Obstetrics and Gynecology Maria Roberta Cilio, MD, PhD
Faculty of Medicine Professor
Ramathibodi Hospital Department of Pediatrics
Mahidol University Saint-Luc University Hospital
Bangkok,Thailand Université Catholique de Louvain
Intra-Amniotic Infection/Inflammation and the Fetal Brussels, Belgium
Inflammatory Response Syndrome Electroencephalography in the Preterm and Term Infant
x Contributors
David A. Clark, MD Amélie Collins, MD, PhD

Chairman and Professor Assistant Professor
Albany Medical College Columbia University Irving Medical Center
Albany, New York New York, New York
Development of the Gastrointestinal Circulation in the Developmental Biology of Hematopoietic Stem Cells
Fetus and Newborn
Allan Collodel, PhD
Paul Clarke, MD, DCH DCCH Laboratory of Experimental Pathophysiology
Professor Graduate Program in Health Sciences
Neonatal Intensive Care Unit University of Southern Santa Catarina
Norfolk and Norwich University Hospitals NHS Foundation Criciúma, Brazil
Trust Pathophysiology of Neonatal Acute Bacterial Meningitis
Professor
Norwich Medical School John Colombo, PhD
University of East Anglia Professor
Norwich, United Kingdom Department of Psychology
Vitamin K Metabolism in the Fetus and Neonate University of Kansas
Lawrence, Kansas
Jane K. Cleal, PhD Long-Chain Polyunsaturated Fatty Acids in
Lecturer in Epigenetics Neurodevelopment
School of Human Development and Health
Faculty of Medicine Alexander N. Combes, PhD
University of Southampton Senior Research Fellow
Southampton, United Kingdom Monash Biomedicine Discovery Institute
Mechanisms of Transfer Across the Human Placenta Department of Anatomy and Developmental Biology
Biomedicine Discovery Institute
Ethel G. Clemente, MD Monash University
Assistant Professor Melbourne, Victoria, Australia
Department of Pediatrics Development of the Kidney: Morphology and Mechanisms
Western Michigan University Homer Stryker MD School of
Medicine Andrew J. Copp, MBBS, DPhil
Kalamazoo, Michigan Professor
Luteinizing Hormone and Follicle-Stimulating Hormone GOS Institute of Child Health
Secretion in the Fetus and Newborn Infant University College London
London, United Kingdom
John A. Clements, MD Pathophysiology of Neural Tube Defects
Professor Emeritus
Department of Pediatrics C. Michael Cotten, MD
University of California, San Francisco Professor
San Francisco, California Chief, Division of Pediatric Neonatology
Historical Perspective Department of Pediatrics
Duke University School of Medicine
Ronald I. Clyman, MD Durham, North Carolina
Professor Emeritus Genetic Variants and Neonatal Disease
University of California, San Francisco Peter A. Crawford, MD, PhD
San Francisco, California Professor
Mechanisms Regulating Closure of the Ductus Arteriosus Vice Chair for Research
Department of Medicine
Jennifer L. Cohen, MD Director, Division of Molecular Medicine
Assistant Professor University of Minnesota Medical School
Department of Pediatrics Minneapolis, Minnesota
Division of Medical Genetics Pediatrics Ketone Body Metabolism in the Neonate
Duke University School of Medicine
Durham, North Carolina James E. Crowe, Jr., MD
Genetic Variants and Neonatal Disease Director
Vanderbilt Vaccine Center
Susan S. Cohen, MD Ann Scott Carell Chair
Associate Professor Pediatrics and Pathology, Microbiology and Immunology
Department of Pediatrics Vanderbilt University Medical Center
Medical College of Wisconsin Nashville,Tennessee
Milwaukee, Wisconsin Host Defense Mechanisms Against Viruses
Development of the Blood-Brain Barrier
Contributors xi
C.A. Crowther, MBChB, DCH, MD, CMFM Diomel de la Cruz, MD

Professor Assistant Professor
Liggins Institute Department of Pediatrics
University of Auckland Division of Neonatology
Auckland, New Zealand University of Florida College of Medicine
Antenatal Hormonal Therapy for Prevention of Respiratory Gainesville, Florida
Distress Syndrome Digestive-Absorptive Functions in Fetuses, Infants, and
Children
Luise A. Cullen-McEwen, BSc, PhD
Research Fellow Priscila Gomes de Oliveira, MD
Department of Anatomy and Developmental Biology Nutritionist
Biomedicine Discovery Institute Specialist in Neonate Intensive Care
Monash University Postgraduate Program in Nutrition
Melbourne, Victoria, Australia Federal University of Rio Grande do Norte
Development of the Kidney: Morphology and Mechanisms Natal, Brazil
Wayne S. Cutfield, MD
Professor Barbra de Vrijer, MD
Liggins Institute Associate Professor
University of Auckland Department of Obstetrics and Gynaecology
Auckland, New Zealand Western University
Epigenetics London, Ontario, Canada
Chanèle Cyr-Depauw, MSc Accompanying Fetal Growth Restriction
PhD Candidate
Sinclair Centre for Regenerative Medicine Andrew Del Colle, MS
Ottawa Hospital Research Institute Research Assistant
Department of Cellular and Molecular Medicine Department of Pediatrics
University of Ottawa Columbia University Vagelos College of Physicians and Surgeons
Ottawa, Ontario, Canada New York, New York
Developmental Biology of Lung Stem Cells Development of the Enteric Nervous System and
Gastrointestinal Motility
Karla Danielly da S. Ribeiro, PhD
Nutritionist Christophe Delacourt, MD, PhD
Professor Adjunct Physician
Department of Nutrition Department of Paediatric Pulmonology and Allergology
Researcher University Hospital Necker-Enfants Malades
Postgraduate Program in Nutrition Assistance Publique-Hôpitaux de Paris
Federal University of Rio Grande do Norte Paris, France
Natal, Brazil Regulation of Alveolarization
Thomas G. Diacovo, MD
Nicolas Dauby, MD, PhD Professor
Deputy Head of Clinic Department of Pediatrics
Infectious Diseases University of Pittsburgh School of Medicine
CHU Saint-Pierre Chief, UMPC Division of Newborn Medicine
Post-Doctoral Researcher University of Pittsburgh Medical Center
Institute for Medical Immunology Pittsburgh, Pennsylvania
Université Libre de Bruxelles Platelet–Vessel Wall Interactions
Brussels, Belgium
Host Defense Mechanisms Against Bacteria Clémence Disdier, PhD, PharmD
Postdoctoral Fellow
Patricia Davenport, MD Department of Pediatrics
Instructor of Pediatrics The Warren Alpert Medical School of Brown University
Division of Newborn Medicine Providence, Rhode Island
Children’s Hospital Boston and Harvard Medical School Development of the Blood-Brain Barrier
Boston, Massachusetts
Developmental Megakaryopoiesis John P. Dormans, MD
Chief, Pediatric Orthopedic Surgery
Joanne O. Davidson, PhD Riley Hospital for Children
Senior Research Fellow Garceau Professor of Orthopedic Surgery
Department of Physiology Indiana University School of Medicine
University of Auckland Indianapolis, Indiana
Auckland, New Zealand The Growth Plate: Embryologic Origin, Structure, and
Neuroprotective Therapeutic Hypothermia Function
xii Contributors
François Duhamel, BPharm, MSc Melinda Erdős, MD, PhD

PhD Candidate Associate Professor
Department of Pharmacology Primary Immunodeficiency Clinical Unit and Laboratory
University of Montreal Department of Dermatology, Venereology, and
Montreal, Quebec, Canada Dermatooncology
Basic Pharmacologic Principles Faculty of Medicine
Semmelweis University
Minh Dien Duong, MD Budapest, Hungary
Department of Pediatrics Host Defense Mechanisms Against Fungi
Division of Nephrology T-Cell Development
The Children’s Hospital at Montefiore
Albert Einstein College of Medicine Mariella Errede, MD, PhD
Bronx, New York Department of Basic Medical Sciences, Neurosciences, and
Role of the Kidney in Calcium and Phosphorus Sensory Organs
Homeostasis Human Anatomy and Histology Unit
University of Bari School of Medicine
Kevin Dysart, MD Bari, Italy
Associate Medical Director Development of the Blood-Brain Barrier
Children’s Hospital of Philadelphia Brian J. Feldman, MD, PhD
Philadelphia, Pennsylvania Walter L. Miller Distinguished Professorship
Evaluation of Pulmonary Function in the Neonate Department of Pediatrics
University of California San Francisco
Eric C. Eichenwald, MD San Francisco, California
Professor of Pediatrics Development of the Hypothalamus-Pituitary-Adrenal Axis
Department of Pediatrics/Neonatology in the Fetus
Perelman School of Medicine
University of Pennsylvania Mario Fidanza, PhD
Chief, Division of Neonatology Postdoctoral Scientist
Children’s Hospital of Philadelphia Systems Vaccinology
Philadelphia, Pennsylvania Telethon Kids Institute
Evaluation of Pulmonary Function in the Neonate Perth, Western Australia, Australia
Host Defense Mechanisms Against Bacteria
Afif F. El-Khuffash, MB, BCh, BAO, BA(Sci), MD, DCE
Consultant Neonatologist and Pediatrician Matthew J. Fogarty, BVSc, PhD
Department of Neonatology Assistant Professor
The Rotunda Hospital Physiology and Biomedical Engineering
Clinical Professor Mayo Clinic
Department of Paediatrics Rochester, Minnesota
Royal College of Physicians in Ireland Functional Development of Respiratory Muscles
Dublin, Ireland
Oxygen Transport and Delivery Philippe S. Friedlich, MD, MS Epi, MBA
Teresa and Byron Pollitt Family Chair in Fetal & Neonatal
Peter James Ivor Ellis, PhD Medicine
Senior Lecturer Professor
School of Biosciences Departments of Pediatrics and Surgery
University of Kent Keck School of Medicine
Canterbury, United Kingdom University of Southern California
Genetics of Sex Determination and Differentiation Co-Director, Fetal and Neonatal Institute
Children’s Hospital Los Angeles
Kerry M. Empey, PharmD, PhD Chief, Division of Neonatology
Associate Professor Department of Pediatrics
Department of Pharmacy and Therapeutics Children’s Hospital Los Angeles
Associate Professor (secondary appointment) Los Angeles, California
Clinical Translational Science Institute Regulation of Acid-Base Balance in the Fetus and
Associate Professor (secondary appointment) Neonate
Department of Immunology Pathophysiology of Shock in the Fetus and Neonate
University of Pittsburgh
Pittsburgh, Pennsylvania Ryoichi Fujiwara, PhD
Neonatal Pulmonary Host Defense Assistant Professor
Department of Pharmaceutical Sciences
Baris Ercal, MD, PhD College of Pharmacy
Instructor University of Arkansas for Medical Sciences
Department of Psychiatry Little Rock, Arkansas
Washington University School of Medicine Fetal and Neonatal Bilirubin Metabolism
St. Louis, Missouri
Ketone Body Metabolism in the Neonate
Contributors xiii
Vittorio Gallo, PhD Armond S. Goldman, MD

Chief Research Officer Emeritus Professor
Center for Neuroscience Research Department of Pediatrics
Children’s National Research Institute and George Washington University of Texas Medical Branch
University School of Medicine and Health Sciences Galveston,Texas
Washington, District of Columbia Immunology of Human Milk
Cellular and Molecular Mechanisms of Neonatal Brain
Injury and Neuroprotection Nardhy Gomez-Lopez, PhD
Associate Professor
Abhrajit Ganguly, MD Division of Maternal-Fetal Medicine
Assistant Professor of Pediatrics Department of Obstetrics and Gynecology
Section of Neonatal-Perinatal Medicine Wayne State University School of Medicine
Center for Pregnancy & Newborn Research Detroit, Michigan
University of Oklahoma Health Science Center Intra-Amniotic Infection/Inflammation and the Fetal
Oklahoma City, Oklahoma Inflammatory Response Syndrome
Regulation of Lower Airway Function
Misty Good, MD
Yuansheng Gao, PhD Assistant Professor
Professor Division of Newborn Medicine
Department of Physiology and Pathophysiology Departments of Pediatrics, Pathology, and Immunology
Peking University Health Science Center Washington University School of Medicine
Beijing, China St. Louis, Missouri
Regulation of Pulmonary Circulation Neonatal Pulmonary Host Defense
Pathophysiology and Prevention of Neonatal Necrotizing
Marianne Garland, MB ChB Enterocolitis
Associate Professor
Department of Pediatrics Pamela I. Good, MD
Columbia University Vagelos College of Physicians and Instructor
Surgeons Division of Neonatology-Perinatology
Attending Neonatologist Department of Pediatrics
Department of Pediatrics Columbia University Vagelos College of Physicians and Surgeons
Children’s Hospital of New York New York, New York
New York, New York Response to Nephron Loss in Early Development
Drug Distribution in Fetal Life
Scott M. Gordon, MD, PhD
Donna Geddes, Post Grad Dip (Sci), PhD Attending Physician
Professor Division of Neonatology
School of Molecular Sciences Children’s Hospital of Philadelphia
The University of Western Australia, Perth Instructor
Perth, Western Australia, Australia Perelman School of Medicine
Human Milk Composition and Function in the Infant University of Pennsylvania
Philadelphia, Pennsylvania
Michael K. Georgieff, MD Cytokines and Inflammatory Response in the Fetus and
Professor Neonate
University of Minnesota Medical School Lucy R. Green, BSc, PhD
Minneapolis, Minnesota Physician
Fetal and Neonatal Iron Metabolism Institute of Developmental Sciences
University of Southampton
Jason Gien, MD Southampton, United Kingdom
Associate Professor Nutritional and Environmental Effects on the Fetal
Department of Pediatrics Circulation
Section of Neonatology
University of Colorado School of Medicine Nicholas D.E. Greene, PhD
Aurora, Colorado Professor
Pathophysiology of Meconium Aspiration Syndrome Great Ormond Street Institute of Child Health
University College London
Dino A. Giussani, PhD, ScD London, United Kingdom
Professor Pathophysiology of Neural Tube Defects
Department of Physiology Development and Neuroscience
Professorial Fellow Zoya Gridneva, BSc, PhD
Gonville & Caius College Research Associate
Cambridge, United Kingdom School of Molecular Sciences
Regulation of Cardiovascular Function During Fetal and The University of Western Australia, Crawley
Newborn Life Crawley, Western Australia, Australia
Human Milk Composition and Function in the Infant
xiv Contributors
Emmanouil Grigoriou, MD Gabriel G. Haddad, MD

Pediatric Orthopaedic Surgery Professor
Texas Scottish Rite Hospital for Children Department of Pediatrics
Dallas,Texas University of California, San Diego
The Growth Plate: Embryologic Origin, Structure, and La Jolla, California
Function Basic Mechanisms of Oxygen Sensing and Adaptation to
Hypoxia
Adda Grimberg, MD
Professor Thomas W. Hale, RPh, PhD
Department of Pediatrics Professor
Perelman School of Medicine Associate Dean of Research
University of Pennsylvania Texas Tech University Health Science Center
Scientific Director Department of Pediatrics
Diagnostic and Research Growth Center School of Medicine
Children’s Hospital of Philadelphia Amarillo,Texas
Philadelphia, Pennsylvania Drug Transfer During Breastfeeding
Hypothalamus: Neuroendometabolic Center
K. Michael Hambidge, MD, ScD
Ruth E. Grunau, PhD Professor Emeritus
Professor Department of Pediatrics
Department of Pediatrics Section of Nutrition
University of British Columbia University of Colorado School of Medicine
Vancouver, Canada Aurora, Colorado
Developmental Aspects of Pain Zinc in the Fetus and Neonate
Jean-Pierre Guignard, MD Cathy Hammerman, MD

Honorary Professor of Pediatric Nephrology Professor of Pediatrics
Lausanne University Medical School Faculty of Medicine
Lausanne, Switzerland Hebrew University
Postnatal Development of Glomerular Filtration Rate in Director, Newborn Nurseries Division
Neonates Neonatology
Concentration and Dilution of Urine Shaare Zedek Medical Center
Jerusalem, Israel
Alistair J. Gunn, MBChB, PhD Hereditary Contributions to Neonatal
Professor Hyperbilirubinemia
Department of Physiology
University of Auckland Thor Willy Ruud Hansen, MD, PhD, MHA
Auckland, New Zealand Professor Emeritus
Neuroprotective Therapeutic Hypothermia Division of Pediatric and Adolescent Medicine
Oslo University Hospital and Institute of Clinical
Nursen Gurtunca, MD Medicine
Assistant Professor Oslo, Norway
Department of Pediatrics Pathophysiology of Kernicterus
Division of Endocrinology and Diabetes
Children’s Hospital of Pittsburgh Mark A. Hanson, MA, DPhil
Pittsburgh, Pennsylvania Director
Growth Hormone, Prolactin, and Placental Lactogen in the Institute of Developmental Sciences
Fetus and Newborn University of Southampton
Southampton, United Kingdom
Kathleen M. Gustafson, PhD Nutritional and Environmental Effects on the Fetal
Associate Professor Circulation
Department of Neurology
Hoglund Biomedical Imaging Center Danny Harbeson, PhD
University of Kansas Medical Center Experimental Medicine
Kansas City, Kansas University of British Columbia
Long-Chain Polyunsaturated Fatty Acids in Vancouver, British Columbia, Canada
Neurodevelopment Host Defense Mechanisms Against Bacteria
Alice Hadchouel, MD, PhD J.E. Harding, MBChB, DPhil

Physician Professor
Department of Paediatric Pulmonology and Allergology Liggins Institute
University Hospital Necker-Enfants Malades University of Auckland
Assistance Publique-Hôpitaux de Paris Auckland, New Zealand
Paris, France Antenatal Hormonal Therapy for Prevention of Respiratory
Regulation of Alveolarization Distress Syndrome
Contributors xv
Richard Harding, PhD, DSc William W. Hay, Jr., MD

Emeritus Professor Professor (Retired)
Department of Anatomy and Developmental Biology Department of Pediatrics
Monash University University of Colorado School of Medicine
Melbourne, Victoria, Australia Aurora, Colorado
Physiologic Mechanisms of Normal and Altered Lung Placental and Fetal Circulatory and Metabolic Changes
Growth Before and After Birth Accompanying Fetal Growth Restriction
Placental Transfer and Fetal Requirements of Amino Acids
Mary Catherine Harris, MD
Professor Vivi M. Heine, PhD
Division of Neonatology Assistant Professor
Department of Pediatrics Pediatrics/Child Neurology
Children’s Hospital of Philadelphia Vrije University Medical Center
Philadelphia, Pennsylvania Amsterdam,The Netherlands
Cytokines and Inflammatory Response in the Fetus and Cerebellar Development—The Impact of Preterm Birth and
Neonate Comorbidities
Peter Hartmann, BSc, PhD Michael A. Helmrath, MD

Emeritus Professor Professor
School of Molecular Sciences Division of Pediatric General and Thoracic Surgery
The University of Western Australia, Perth Cincinnati Children’s Hospital Medical Center
Perth, Western Australia, Australia Cincinnati, Ohio
Human Milk Composition and Function in the Infant Organogenesis of the Gastrointestinal Tract
M. Elizabeth Hartnett, MD Karen D. Hendricks-Muñoz, MD, MPH

Distinguished Professor in Ophthalmology and Visual Sciences William Tate Graham Professor
Department of Ophthalmology Chair, Neonatal Medicine
John A. Moran Eye Center Department of Pediatrics
University of Utah Health Virginia Commonwealth University School of Medicine
Salt Lake City, Utah Richmond, Virginia
Pathophysiology of Retinopathy of Prematurity Structure and Development of Alveolar Epithelial Cells
Rodrigo Hasbun, MD, MPH Emilio Herrera, PhD

Professor Emeritus Professor of Biochemistry and Molecular Biology
Division of Infectious Diseases Department of Chemistry and Biochemistry
The University of Texas Health Science Center at Houston Faculties of Pharmacy and Medicine
McGovern Medical School University San Pablo-CEU
Houston,Texas Madrid, Spain
Pathophysiology of Neonatal Acute Bacterial Meningitis Maternal-Fetal Transfer of Lipid Metabolites
Lipids as an Energy Source for the Premature and Term
Guttorm Haugen, MD Neonate
Consultant
Department of Fetal Medicine Michael J. Hiatt, PhD
Division of Obstetrics and Gynaecology Senior Scientist Research and Development
Oslo University Hospital Stemcell Technologies
Professor Vancouver, British Columbia, Canada
Institute of Clinical Medicine Functional Development of the Kidney in Utero
Faculty of Medicine
University of Oslo Stuart B. Hooper, BSc (Hons), PhD
Oslo, Norway Professor
Umbilical Circulation The Ritchie Centre
Hudson Institute for Medical Research
Colin P. Hawkes, MD, PhD Professor
Physician Department of Obstetrics and Gynaecology
Division of Endocrinology and Diabetes Monash University
Children’s Hospital of Philadelphia Melbourne, Victoria, Australia
Adjunct Professor Physiologic Mechanisms of Normal and Altered Lung
Department of Pediatrics Growth Before and After Birth
Perelman School of Medicine Physiology of Neonatal Resuscitation
University of Pennsylvania
Philadelphia, Pennsylvania Thomas A. Hooven, MD
Consultant Paediatric Endocrinologist Assistant Professor
Department of Paediatrics and Child Health Department of Pediatrics
University College Cork University of Pittsburgh School of Medicine
Cork, Ireland Pittsburgh, Pennsylvania
Growth Factor Regulation of Fetal Growth Pathophysiology of Chorioamnionitis: Host Immunity and
Pathophysiology of Neonatal Hypoglycemia Microbial Virulence
xvi Contributors
Silvia Iacobelli, MD, PhD Alan H. Jobe, MD, PhD

Professor of Pediatrics Professor
Réanimation Néonatale et Pédiatrique, Neonatologie Department of Pediatrics
Centre Hospitalier Universitaire La Réunion Director, Division of Perinatal Biology
Saint Pierre, France Cincinnati Children’s Hospital Medical Center
Centre d’Etudes Périnatales de l’Océan Indien Cincinnati, Ohio
Université de la Réunion Antenatal Factors That Influence Postnatal Lung
Réunion, France Development and Injury
Postnatal Development of Glomerular Filtration Rate in Surfactant Treatment
Neonates Pathophysiology of Respiratory Distress Syndrome
Concentration and Dilution of Urine
Helen Jones, PhD
Terrie E. Inder, MBChB, MD Associate Professor
Chair Department of Physiology and Functional Genomics
Pediatric Newborn Medicine Department of Obstetrics and Gynecology
Brigham and Women’s Hospital University of Florida College of Medicine
Professor Gainesville, Florida
Department of Pediatrics Placental Development
Harvard Medical School
Boston, Massachusetts Pedro A. Jose, MD, PhD
Intraventricular Hemorrhage in the Neonate Professor
Departments of Medicine and Pharmacology-Physiology
M. Luisa Iruela-Arispe, PhD The George Washington University School of Medicine & Health
Stephen Walter Ranson Professor and Chair Sciences
Department of Cell and Developmental Biology Washington, District of Columbia
Feinberg School of Medicine Development and Regulation of Renal Blood Flow in the
Northwestern University Neonate
Chicago, Illinois
Angiogenesis Eunjung Jung, MD
Assistant Professor
Sudarshan Rao Jadcherla, MD, DCH, AGAF Division of Maternal-Fetal Medicine
Professor Department of Obstetrics and Gynecology
Department of Pediatrics Wayne State University School of Medicine
Sections of Neonatology and Pediatric Gastroenterology & Detroit, Michigan
Nutrition Intra-Amniotic Infection/Inflammation and the Fetal
The Ohio State University College of Medicine Inflammatory Response Syndrome
Attending Neonatologist
Section of Neonatology Suhas G. Kallapur, MD
Director Professor
Neonatal and Infant Feeding Disorders Program Department of Pediatrics
Nationwide Children’s Hospital Division of Neonatology
Principal Investigator UCLA David Geffen School of Medicine
Center for Perinatal Research UCLA Mattel Children’s Hospital
Abigail Wexner Research Institute at Nationwide Children’s Los Angeles, California
Hospital Antenatal Factors That Influence Postnatal Lung
Columbus, Ohio Development and Injury
Pathophysiology of Gastroesophageal Reflux Surfactant Treatment
Deepak Jain, MD Michael Kaplan, MB ChB

Associate Professor Emeritus Director
Department of Pediatrics Department of Neonatology
Division of Neonatology Shaare Zedek Medical Center
Rutgers Robert Wood Johnson Medical School Professor of Pediatrics
New Brunswick, New Jersey Faculty of Medicine
Pathophysiology of Bronchopulmonary Hebrew University
Dysplasia Jerusalem, Israel
Hereditary Contributions to Neonatal Hyperbilirubinemia
Jennifer G. Jetton, MD S. Ananth Karumanchi, MD
Medical Director, Pediatric Dialysis Unit
Professor
Clinical Associate Professor
Department of Medicine
Division of Nephrology
Harvard Medical School
Stead Family Department of Pediatrics
University of Iowa Health Care
Staff Physician
Iowa City, Iowa
Medallion Chair in Vascular Biology
Pathophysiology of Neonatal Acute Kidney
Director, Nephrology
Injury
Cedars-Sinai Medical Center
Los Angeles, California
Pathophysiology of Preeclampsia
Contributors xvii
Frederick J. Kaskel, MD, PhD Chang-Ryul Kim, MD, PhD

Professor Professor
Division of Nephrology Hanyang University College of Medicine
The Children’s Hospital at Montefiore Seoul, South Korea
Albert Einstein College of Medicine Director in NICU
Bronx, New York Hanyang University Guri Hospital
Role of the Kidney in Calcium and Phosphorus Guri-si, South Korea
Homeostasis Fluid Distribution in the Fetus and Neonate
Lorraine E. Levitt Katz, MD Paul S. Kingma, MD, PhD

Physician Associate Professor of Pediatrics
Division of Endocrinology and Diabetes Division of Neonatology
Children’s Hospital of Philadelphia University of Cincinnati
Professor Cincinnati Children’s Hospital Medical Center
Perelman School of Medicine Cincinnati, Ohio
University of Pennsylvania Surfactant Homeostasis: Composition and Function of
Philadelphia, Pennsylvania Pulmonary Surfactant Lipids and Proteins
Growth Factor Regulation of Fetal Growth
John P. Kinsella, MD
Haluk Kavus, MD Professor
Medical Geneticist, Postdoctoral Research Scientist Department of Pediatrics
Pediatrics, Division of Molecular Genetics Section of Neonatology
Columbia University Vagelos College of Physicians and University of Colorado School of Medicine
Surgeons Aurora, Colorado
New York, New York Pulmonary Gas Exchange in the Developing Lung
Basic Genetic Principles Pathophysiology of Meconium Aspiration Syndrome
Susan E. Keeney, MD Torvid Kiserud, MD, PhD

Associate Professor Professor
Department of Pediatrics Department of Clinical Science
University of Texas Medical Branch University of Bergen
Galveston,Texas Consultant
Immunology of Human Milk Fetal Medicine Unit
Department of Obstetrics and Gynecology
Steven E. Kern, PhD Haukeland University Hospital
Deputy Director, Quantitative Sciences Bergen, Norway
Global Health-Integrated Development Umbilical Circulation
Bill & Melinda Gates Foundation
Seattle, Washington Joyce M. Koenig, MD
Principles of Pharmacokinetics Professor
Division of Neonatal/Perinatal Medicine
Shirin Khanjani, MD, PhD Department of Pediatrics
University College London Hospitals Saint Louis University School of Medicine
London, United Kingdom St. Louis, Missouri
Pathophysiology of Preterm Birth Normal and Abnormal Neutrophil Physiology in the
Newborn
Julie Khlevner, MD
Associate Professor Rohit Kohli, MBBS, MS
Department of Pediatrics Chief, Division of Gastroenterology
Columbia University Vagelos College of Physicians and Surgeons Children’s Hospital Los Angeles
New York, New York Professor of Pediatrics
Development of the Enteric Nervous System and Keck School of Medicine
Gastrointestinal Motility University of Southern California
Los Angeles, California
Laurie E. Kilpatrick, PhD Bile Acid Metabolism During Development
Professor
Department of Thoracic Medicine and Surgery Tobias R. Kollmann, MD, PhD
Lewis Katz School of Medicine Professor
Temple University Systems Biology and Pediatric Infectious Diseases
Philadelphia, Pennsylvania Telethon Kids Institute
Cytokines and Inflammatory Response in the Fetus and Perth, Western Australia, Australia
Neonate Host Defense Mechanisms Against Bacteria
xviii Contributors
Jay K. Kolls, MD T. Rajendra Kumar, PhD

Professor of Pediatrics Professor and Edgar L. Patricia M. Makowski and Family
Medicine and Pediatrics Endowed Chair
Tulane University School of Medicine Department of Obstetrics and Gynecology
New Orleans, Louisiana University of Colorado School of Medicine
Neonatal Pulmonary Host Defense Aurora, Colorado
Luteinizing Hormone and Follicle-Stimulating Hormone
Christina M. Konecny, MD Secretion in the Fetus and Newborn Infant
Postdoctoral Scholar
Department of Pediatrics Jessica Katz Kutikov, MD
Stanford University School of Medicine Pediatrics Specialist
Stanford, California Voorhees, New Jersey
Mechanistic Aspects of Phototherapy for Neonatal Hypothalamus: Neuroendometabolic Center
Hyperbilirubinemia
Satyan Lakshminrusimha, MBBS, MD
Panagiotis Kratimenos, MD, PhD Professor
Assistant Professor Dennis and Nancy Marks Chair of Pediatrics
Center for Neuroscience Research Pediatrician-in-Chief
Children’s National Research Institute and George Washington UC Davis Children’s Hospital
University School of Medicine and Health Sciences Sacramento, California
Department of Pediatrics Pathophysiology of Persistent Pulmonary Hypertension of
Division of Neonatology the Newborn
Children’s National Hospital
Washington, District of Columbia Miguel Angel Lasunción, PhD
Cellular and Molecular Mechanisms of Neonatal Brain Head, Servicio de Bioquímica-Investigación
Injury and Neuroprotection Hospital Universitario Ramón y Cajal, IRyCIS, and CIBEROBN
Madrid, Spain
Nancy F. Krebs, MD Maternal-Fetal Transfer of Lipid Metabolites
Professor
Department of Pediatrics Pascal M. Lavoie, MDCM, PhD
Section of Nutrition Associate Professor
University of Colorado School of Medicine Department of Pediatrics
Aurora, Colorado University of British Columbia
Zinc in the Fetus and Neonate Clinician-Scientist
BC Children’s Hospital Research Institute
Kaytlin Krutsch, PharmD, MBA Canada Staff Neonatologist
Assistant Professor Children’s & Women’s Health Centre of British Columbia
Texas Tech University Health Sciences Center Vancouver, British Columbia, Canada
Department of Obstetrics and Gynecology Mononuclear Phagocyte System
School of Medicine
Amarillo,Texas Shelley M. Lawrence, MD
Drug Transfer During Breastfeeding Associate Professor
Kara Kuhn-Riordon, MD Divisions of Neonatal-Perinatal Medicine and Host-Microbe
Assistant Clinical Professor Systems and Therapeutics
Department of Pediatrics University of California, San Diego
Division of Neonatology La Jolla, California
University of California Davis School of Medicine Neutrophil Granulopoiesis and Homeostasis
Sacramento, California
Endocrine Factors Affecting Neonatal Growth Mark K. Lee, MD
Professor and Chief Physician
†Thomas J. Kulik, MD Nemours Children’s Hospital
Senior Associate in Cardiology Wilmington, Delaware
Department of Cardiology Regulation of Embryogenesis
Boston Children’s Hospital
Associate Professor of Pediatrics Mary M. Lee, MD
Harvard Medical School Professor
Boston, Massachusetts Department of Pediatrics
Physiology of Congenital Heart Disease in the Neonate Sidney Kimmel Medical College
Jefferson University
Philadelphia, Pennsylvania
Physician-in-Chief
Nemours, AI duPont Hospital for Children
Chief Scientific Officer
Nemours Health Care System
Wilmington, Delaware
†Deceased. Testicular Development and Descent
Contributors xix
Yvonne K. Lee, MD Steven Lobritto, MD

Pediatric Endocrinology Professor
Kaiser Permanente NY Presbyterian–Columbia
Oakland, California New York, New York
Endocrine Factors Affecting Neonatal Growth Organogenesis and Histologic Development of the Liver
Sandra L. Leibel, MD Cynthia A. Loomis, MD

Assistant Professor Assistant Professor
Department of Pediatrics Ronald O. Perelman Department of Dermatology
University of California, San Diego NYU Grossman School of Medicine
La Jolla, California New York, New York
The Extracellular Matrix in Development Structure and Development of the Skin and Cutaneous
Molecular Mechanisms of Lung Development and Lung Appendages
Branching Morphogenesis
Peter M. MacFarlane, PhD
Ofer Levy, MD, PhD Associate Professor
Director, Precision Vaccines Program Department of Pediatrics
Division of Infectious Diseases Division of Neonatology
Boston Children’s Hospital Case Western Reserve University School of Medicine
Professor Cleveland, Ohio
Department of Pediatrics Regulation of Lower Airway Function
Harvard Medical School Pathophysiology of Apnea of Prematurity
Associate Member David A. MacIntyre, PhD
Broad Institute of MIT and Harvard Senior Lecturer
Cambridge, Massachusetts Faculty of Medicine
Mononuclear Phagocyte System Department of Metabolism, Digestion, and Reproduction
Philip T. Levy, MD Imperial College Parturition Research Group
Physician Researcher
Department of Neonatology March of Dimes Prematurity Research Centre
Division of Newborn Medicine Imperial College London
Boston Children’s Hospital London, United Kingdom
Harvard Medical School Pathophysiology of Preterm Birth
Physiology of Congenital Heart Disease in the Neonate Maxime M. Mahe, PhD
Assistant Professor
Rohan M. Lewis, PhD TENS,The Enteric Nervous System in Gut and Brain Diseases
Professor INSERM
School of Human Development and Health Université de Nantes
Faculty of Medicine Nantes, France
University of Southampton Adjunct Assistant Professor
Southampton, United Kingdom Department of Pediatric General and Thoracic Surgery
Mechanisms of Transfer Across the Human Placenta Cincinnati Children’s Hospital Medical Center
Placental Transfer and Fetal Requirements of Amino Acids Department of Pediatrics
University of Cincinnati
Changgong Li, PhD Cincinnati, Ohio
Associate Professor Organogenesis of the Gastrointestinal Tract
Keck School of Medicine Linn Salto Mamsen, MSc, PhD
University of Southern California Researcher
Los Angeles County–University of Southern California Medical Laboratory of Reproductive Biology
Center University Hospital of Copenhagen, Rigshospitalet
Los Angeles, California Copenhagen, Denmark
Regulation of Embryogenesis Differentiation of the Ovary
Fangming Lin, MD, PhD Anastasiya Mankouski, MD

Director, Pediatric Nephrology Assistant Professor
Columbia University Vagelos College of Physicians and Surgeons Division of Neonatology
New York, New York University of Utah Health
Response to Nephron Loss in Early Development Salt Lake City, Utah
Mechanisms of Neonatal Lung Injury
xx Contributors
Carlos B. Mantilla, MD, PhD Hugo R. Martinez, MD

Professor and Chair Assistant Professor
Anesthesiology and Perioperative Medicine Department of Pediatrics
Professor University of Tennessee Health Science Center
Physiology and Biomedical Engineering Cardiomyopathy and Transplant Cardiology
Mayo Clinic Cardio-Vascular Genetics Service
Rochester, Minnesota Le Bonheur Hospital
Functional Development of Respiratory Muscles Cardio-Oncology Service
St. Jude Children’s Research Hospital
Arnaud Marchant, MD, PhD Memphis,Tennessee
Director Pathophysiology of Cardiomyopathies
Institute for Medical Immunology
Université Libre de Bruxelles Douglas G. Matsell, MDCM
Brussels, Belgium Head, Division of Nephrology
Host Defense Mechanisms Against Bacteria British Columbia Children’s Hospital
Host Defense Mechanisms Against Viruses University of British Columbia
Vancouver, British Columbia, Canada
Kara Gross Margolis, MD Functional Development of the Kidney in Utero
Associate Professor
Department of Pediatrics Dwight E. Matthews, PhD
Columbia University Vagelos College of Physicians and Surgeons Professor Emeritus
New York, New York Chemistry and Medicine
Development of the Enteric Nervous System and University of Vermont
Gastrointestinal Motility Burlington, Vermont
General Concepts of Protein Metabolism
László Maródi, MD, PhD
Professor Harry J. McArdle, BSc (Hons), PhD
Primary Immunodeficiency Clinical Unit and Laboratory Professor
Department of Dermatology, Venereology, and Dermatooncology Rowett Institute of Nutrition and Health
Faculty of Medicine University of Aberdeen
Semmelweis University Aberdeen, United Kingdom
Budapest, Hungary Fetal and Neonatal Iron Metabolism
Host Defense Mechanisms Against Fungi
T-Cell Development C.J.D. McKinlay, MBChB, PhD
Senior Lecturer
Karel Maršál, MD, PhD Liggins Institute
Professor Emeritus University of Auckland
Department of Obstetrics and Gynecology Auckland, New Zealand
Lund University Antenatal Hormonal Therapy for Prevention of Respiratory
Lund, Sweden Distress Syndrome
Fetal and Placental Circulation During Labor
James L. McManaman, PhD
Richard J. Martin, MBBS Professor
Professor of Pediatrics, Reproductive Biology, and Physiology & Department of Obstetrics and Gynecology
Biophysics University of Colorado School of Medicine
Division of Neonatology Aurora, Colorado
Case Western Reserve University School of Medicine Physiology of Lactation
Drusinsky-Fanaroff Professor
Director, Neonatal Research Patrick J. McNamara, MD, MRCPCH, MSc
Department of Pediatrics/Neonatology Professor
Rainbow Babies and Children’s Hospital Department of Pediatrics
Cleveland, Ohio Director, Division of Neonatology
Regulation of Lower Airway Function University of Iowa Health Care
Iowa City, Iowa
Jayne F. Martin Carli, PhD Oxygen Transport and Delivery
Fellow
Department of Pediatrics Giacomo Meschia, MD
University of Colorado School of Medicine Emeritus Professor
Aurora, Colorado Department of Physiology
Physiology of Lactation University of Colorado School of Medicine
Pathophysiology of Apnea of Prematurity Aurora, Colorado
Accompanying Fetal Growth Restriction
Contributors xxi
Karen Mestan, MD Jeremiah D. Momper, PharmD, PhD

Associate Professor Associate Professor
Department of Pediatrics Skaggs School of Pharmacy and Pharmaceutical Sciences
Northwestern University Feinberg School of Medicine University of California, San Diego
Chicago, Illinois La Jolla, California
Placental Function in Intrauterine Growth Restriction Organic Anion Transport in the Developing Kidney
Steven P. Miller, MDCM, MAS Paul Monagle, MBBS, MD, MSC

Division Head, Neurology Professor
Bloorview Children’s Hospital Department Paediatrics
Chair, Paediatric Neuroscience University of Melbourne
The Hospital for Sick Children Haematologist
Professor Department of Haematology
Department of Pediatrics Royal Children’s Hospital
University of Toronto Group Leader
Senior Scientist, Chair Haematology Research
Neuroscience and Mental Health Murdoch Childrens Research Institute
SickKids Research Institute Melbourne, Victoria, Australia
Toronto, Ontario, Canada Staff Specialist
Pathophysiology of Neonatal White Matter Injury Kids Cancer Centre
Sydney Children’s Hospital
Parviz Minoo, PhD Sydney, New South Wales, Australia
Professor Developmental Hemostasis
Keck School of Medicine Jenifer Monks, PhD
University of Southern California Assistant Professor
Los Angeles County—University of Southern California Medical Department of Obstetrics and Gynecology
Center University of Colorado School of Medicine
Los Angeles, California Aurora, Colorado
Regulation of Embryogenesis Physiology of Lactation
Imran N. Mir, MD Jacopo P. Mortola, MD

Assistant Professor Professor
Department of Pediatrics Department of Physiology
University of Texas Southwestern Medical Center McGill University
Dallas,Texas Montreal, Quebec, Canada
Regulation of the Placental Circulation Mechanics of Breathing
Lisa J. Mitchell, DO Louis J. Muglia, MD, PhD

Assistant Professor Adjunct Professor
F. Edward Hébert School of Medicine Cincinnati Children’s Hospital Medical Center
Uniformed Services University of the Health Sciences Cincinnati, Ohio
Bethesda, Maryland President and CEO
Medical Director Burroughs Wellcome Fund
Neonatal Intensive Care Unit Research Triangle Park, North Carolina
Carl R. Darnall Army Medical Center Fetal and Neonatal Adrenocortical Physiology
Fort Hood,Texas
Pathophysiology of Apnea of Prematurity Upender K. Munshi, MBBS, MD
Associate Professor
Ivana Mižíková, PhD Department of Pediatrics
Postdoctoral Fellow Albany Medical Center
Sinclair Centre for Regenerative Medicine Albany, New York
Ottawa Hospital Research Institute Development of the Gastrointestinal Circulation in the
Department of Cellular and Molecular Medicine Fetus and Newborn
University of Ottawa
Ottawa, Ontario, Canada Sumana Narasimhan, MD
Developmental Biology of Lung Stem Cells Assistant Professor
Pediatric Endocrinology
Tomoyuki Mizuno, PhD Case Western Reserve University
Assistant Professor Cleveland, Ohio
Division of Clinical Pharmacology Luteinizing Hormone and Follicle-Stimulating
Cincinnati Children’s Hospital Medical Center Hormone Secretion in the Fetus and Newborn
Assistant Professor Infant
University of Cincinnati College of Medicine
Cincinnati, Ohio
Pharmacogenomics
xxii Contributors
Vivek Narendran, MD, MRCP (UK), MBA Lawrence M. Nogee, MD

Professor of Pediatrics Professor
Perinatal Institute Eudowood Neonatal Pulmonary Division
Cincinnati Children’s Hospital and Medical Center Department of Pediatrics
Director UCMC-NICU Johns Hopkins University School of Medicine
University of Cincinnati Medical Center Baltimore, Maryland
Cincinnati Children’s Hospital Medical Center Genetics and Physiology of Surfactant Protein Deficiencies
Cincinnati, Ohio
Physiologic Development of the Skin Shahab Noori, MD, MS CBTI
Professor
Jan Nedergaard, PhD Department of Pediatrics
Professor Keck School of Medicine
Department of Molecular Biosciences University of Southern California
The Wenner-Gren Institute Administrative Director of Clinical Research
Stockholm University Division of Neonatology
Stockholm, Sweden Children’s Hospital Los Angeles
Brown Adipose Tissue: Development and Function Los Angeles, California
Pathophysiology of Shock in the Fetus and Neonate
Leif D. Nelin, MD
Dean W. Jeffers Chair in Neonatology Andrew W. Norris, MD, PhD
Nationwide Children’s Hospital Professor
Professor and Chief Department of Pediatrics
Division of Neonatology University of Iowa Health Care
The Ohio State University Iowa City, Iowa
Columbus, Ohio Glucose Metabolism in the Fetus and Newborn, and
Pulmonary Gas Exchange in the Developing Lung Methods for Its Investigation
Josef Neu, MD Barbara M. O’Brien, MD

Professor Beth Israel Deaconess Medical Center
Department of Pediatrics Department of Obstetrics and Gynecology
Division of Neonatology Boston, Massachusetts
University of Florida College of Medicine Prenatal Diagnosis
Gainesville, Florida
Digestive-Absorptive Functions in Fetuses, Infants, and Lori L. O’Brien, PhD
Children Assistant Professor
The Developing Microbiome of the Fetus and Neonate: A Department of Cell Biology and Physiology
Multiomic Approach University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Sandra C.A. Nielsen, PhD Development of the Kidney: Morphology and Mechanisms
Scientist
Department of Pathology Karen M. O’Callaghan, PhD
Stanford University School of Medicine Research Fellow
Stanford, California Centre for Global Child Health
B-Cell Development SickKids Research Institute
The Hospital for Sick Children
Sanjay K. Nigam, MD Toronto, Ontario, Canada
Nancy Kaehr Chair in Research Fetal and Neonatal Calcium, Phosphorus, and Magnesium
Pediatrics and Medicine Homeostasis
University of California, San Diego
La Jolla, California Amanda Ogilvy-Stuart, BM, DM
Organic Anion Transport in the Developing Kidney Consultant Neonatologist
Department of Neonatology
Victor Nizet, MD Cambridge University Hospitals NHS Trust
Distinguished Professor Cambridge, United Kingdom
Vice Chair for Basic Research Role of Glucoregulatory Hormones in Hepatic Glucose
Department of Pediatrics Metabolism During the Perinatal Period
Distinguished Professor
Department of Pharmacy and Pharmaceutical Sciences Robin K. Ohls, MD
University of California, San Diego Professor
La Jolla, California Department of Pediatrics-Neonatology
Neutrophil Granulopoiesis and Homeostasis University of Utah Health
Developmental Erythropoiesis
Contributors xxiii
Henar Ortega-Senovilla, PhD Francesco Pisani, MD, PhD

Adjunct Professor Professor
Department of Chemistry and Biochemistry Child Neuropsychiatry Unit
Faculties of Pharmacy and Medicine Department of Medicine and Surgery
Universidad San Pablo-CEU Neuroscience Section
Madrid, Spain University of Parma
Lipids as an Energy Source for the Premature and Term Parma, Italy
Neonate Electroencephalography in the Preterm and Term Infant
Justin M. O’Sullivan, PhD David Pleasure, MD

Professor Distinguished Professor
Deputy Director, Liggins Institute Department of Neurology and Pediatrics
University of Auckland University of California Davis School of Medicine
Auckland, New Zealand Sacramento, California
Epigenetics Trophic Factor, Nutritional, and Hormonal Regulation of
Brain Development
Howard B. Panitch, MD
Medical Director, Technology Dependence Program Scott L. Pomeroy, MD, PhD
Division of Pulmonary and Sleep Medicine Bronson Crothers Professor
Children’s Hospital of Philadelphia Department of Neurology
Professor Harvard Medical School
Department of Pediatrics Neurologist-in-Chief and Chairman
Perelman School of Medicine Department of Neurology
University of Pennsylvania Boston Children’s Hospital
Philadelphia, Pennsylvania Boston, Massachusetts
Pathophysiology of Ventilator-Dependent Infants Development of the Nervous System
Anna A. Penn, MD, PhD Martin Post, PhD

Associate Professor Senior Scientist
Department of Pediatrics Translational Medicine
George Washington University School of Medicine The Hospital for Sick Children
Attending Physician and Director Professor
Translational Research for Hospital-Based Services Department of Physiology
Co-Director, Cerebral Palsy Prevention Program Laboratory Medicine and Pathobiology
Fetal and Transitional Medicine, Neonatology University of Toronto
Investigator Toronto, Ontario, Canada
Children’s Research Institute Center for Neuroscience The Extracellular Matrix in Development
Children’s National Medical Center Molecular Mechanisms of Lung Development and Lung
Washington, District of Columbia Branching Morphogenesis
Endocrine and Paracrine Function of the Human Placenta
Y.S. Prakash, MD, PhD
Raymond B. Penn, PhD Professor
Robley Dunglison Professor of Pulmonary Research Anesthesiology and Physiology
Director, Center for Translational Medicine Mayo Clinic
Director, Pulmonary Research Rochester, Minnesota
Jefferson Jane and Leonard Korman Lung Institute Regulation of Lower Airway Function
Vice Chair, Research
Department of Medicine Joshua D. Prozialeck, MD, MSA
Division of Pulmonary, Allergy, and Critical Care Medicine Assistant Professor
Thomas Jefferson University Department of Pediatrics
Philadelphia, Pennsylvania Northwestern University Feinberg School of Medicine
Upper Airway Structure: Function, Regulation, and Development Ann & Robert H. Lurie Children’s Hospital of Chicago
Chicago, Illinois
Margaret G. Petroff, PhD Development of Gastric Secretory Function
Associate Professor
Pathobiology and Diagnostic Investigation Theodore J. Pysher, MD
Michigan State University Professor
East Lansing, Michigan Chief, Division of Pediatric Pathology
Placental Development Department of Pathology
Anthony F. Philipps, AB, MD Salt Lake City, Utah
Professor Impaired Lung Growth After Injury in Preterm Lung
University of California Davis School of Medicine
Sacramento, California
Oxygen Consumption and General Carbohydrate
Metabolism of the Fetus
xxiv Contributors
Raymond Quigley, MD Timothy R.H. Regnault, PhD

Professor Associate Professor
Department of Pediatrics Departments of Obstetrics/Gynaecology and Physiology/
UT Southwestern Medical Center Pharmacology
Dallas,Texas Western University
Potassium Homeostasis in the Fetus and Neonate London, Ontario, Canada
Transport of Amino Acids in the Fetus and Neonate Placental and Fetal Circulatory and Metabolic Changes
Accompanying Fetal Growth Restriction
Marlene Rabinovitch, MD Placental Transfer and Fetal Requirements of Amino Acids
Professor of Pediatrics
Division of Cardiology Danielle R. Rios, MD
Stanford University School of Medicine Associate Professor
Stanford, California Department of Pediatrics
Developmental Biology of the Pulmonary Vasculature Division of Neonatology
University of Iowa Health Care
Thomas M. Raffay, MD Iowa City, Iowa
Assistant Professor of Pediatrics Oxygen Transport and Delivery
Case Western Reserve University Roberto Romero, MD, DMedSci
Rainbow Babies and Children’s Hospital Chief, Perinatology Research Branch
Cleveland, Ohio Eunice Kennedy Shriver National Institute for Child Health and
Regulation of Lower Airway Function Human Development
National Institutes of Health
J. Usha Raj, MD, MHA U.S. Department of Health and Human Services
Anjuli S. Nayak Professor of Pediatrics Detroit, Michigan
University of Illinois at Chicago Intra-Amniotic Infection/Inflammation and the Fetal
Chicago, Illinois Inflammatory Response Syndrome
Regulation of Pulmonary Circulation
Charles R. Rosenfeld, MD
Laura B. Ramsey, PhD Professor Emeritus
Assistant Professor Departments of Pediatrics, Obstetrics/Gynecology,
Divisions of Clinical Pharmacology and Research in Patient Anesthesiology
Services University of Texas Southwestern Medical Center
Cincinnati Children’s Hospital Medical Center Dallas,Texas
Assistant Professor Regulation of the Placental Circulation
University of Cincinnati College of Medicine A. Catharine Ross, PhD
Co-Director, Genetic Pharmacology Service Professor of Nutrition and Physiology
Cincinnati Children’s Hospital Medical Center Nutritional Sciences
Cincinnati, Ohio Pennsylvania State University
Pharmacogenomics University Park, Pennsylvania
Vitamin A Metabolism in the Fetus and Neonate
Sarosh Rana, MD, MPH
Professor Daniel E. Roth, MD, PhD
Division of Maternal Fetal Medicine Staff Pediatrician
Department of Obstetrics and Gynecology Division of Pediatric Medicine
University of Chicago The Hospital for Sick Children
Chicago, Illinois Associate Professor
Pathophysiology of Preeclampsia Departments of Pediatrics and Nutritional Sciences
University of Toronto
Tara M. Randis, MD Toronto, Ontario, Canada
Associate Professor Fetal and Neonatal Calcium, Phosphorus, and Magnesium
Department of Pediatrics and Molecular Medicine Homeostasis
USF Health Morsani College of Medicine
Tampa, Florida Henry J. Rozycki, MD
Pathophysiology of Chorioamnionitis: Host Immunity and Professor and Vice Chair for Research
Microbial Virulence Department of Pediatrics
Children’s Hospital of Richmond at VCU
Manon Ranger, PhD Director, Children’s Health Research Institute
Assistant Professor Virginia Commonwealth University School of Medicine
School of Nursing Richmond, Virginia
University of British Columbia Structure and Development of Alveolar Epithelial Cells
Vancouver, British Columbia, Canada
Developmental Aspects of Pain
Contributors xxv
Thomas D. Ryan, MD, PhD George J. Schwartz, MD

Associate Professor Professor
University of Cincinnati College of Medicine Division of Nephrology
Director, Clinical Operations, Cardiomyopathy, and University of Rochester Medical Center and Golisano Children’s
Heart Failure Hospital
Co-Director, Cardio-Oncology Program Rochester, New York
The Heart Institute Urinary Acidification
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio Jeffrey L. Segar, MD
Pathophysiology of Cardiomyopathies Physician
Rakesh Sahni, MBBS University of Iowa Children’s Hospital
Professor Iowa City, Iowa
Department of Pediatrics Regulation of Cardiovascular Function During Fetal and
Columbia University Vagelos College of Physicians and Newborn Life
Surgeons
New York, New York David T. Selewski, MD
Temperature Control in Newborn Infants Associate Professor
Harvey B. Sarnat, MD Division of Nephrology
Professor Medical University of South Carolina
Departments of Paediatrics, Pathology (Neuropathology), and Charleston, South Carolina
Clinical Neurosciences Pathophysiology of Neonatal Acute Kidney Injury
University of Calgary Faculty of Medicine and Alberta Children’s
Hospital Research Institute Istvan Seri, MD, PhD, HonD
Calgary, Alberta, Canada Professor
Development of Olfaction and Taste in the Human Fetus Pediatrics (Research)
and Neonate First Department of Pediatrics
Ontogenesis of Striated Muscle Semmelweis University
Budapest, Hungary, Professor of Pediatrics (Adjunct)
Lisa M. Satlin, MD Pediatrics/Neonatology
Professor and System Chair Children’s Hospital Los Angeles
Department of Pediatrics Keck School of Medicine
Icahn School of Medicine at Mount Sinai University of Southern California
Pediatrician-in-Chief Los Angeles, California
Mount Sinai Kravis Children’s Hospital Regulation of Acid-Base Balance in the Fetus and Neonate
New York, New York Pathophysiology of Shock in the Fetus and Neonate
Potassium Homeostasis in the Fetus and Neonate
Thomas H. Shaffer, MSE, PhD
Joseph Scafidi, DO, MS Professor Emeritus
Associate Professor Physiology, Pediatrics, and Medicine
Department of Neurology and Pediatrics Lewis Katz School of Medicine at Temple University
Kennedy Krieger Institute Professor of Pediatrics
Johns Hopkins School of Medicine Sidney Kimmel Medical College
Baltimore, Maryland Thomas Jefferson University
Cellular and Molecular Mechanisms of Neonatal Brain Philadelphia, Pennsylvania
Injury and Neuroprotection Associate Director, Biomedical Research
Alfred I. duPont Hospital for Children
Michael A. Schellpfeffer, MD Wilmington, Delaware
Professor Upper Airway Structure: Function, Regulation, and
Departments of Cell Biology, Neurobiology, and Anatomy Development
Medical College of Wisconsin
Milwaukee, Wisconsin Martin J. Shearer, BSc, PhD, FRCPath
Developmental Electrophysiology in the Fetus and Physician
Neonate Centre for Haemostasis and Thrombosis
St Thomas’ Hospital
William Schierding, PhD London, United Kingdom
Senior Research Fellow Vitamin K Metabolism in the Fetus and Neonate
Liggins Institute
University of Auckland Noah F. Shroyer, PhD
Auckland, New Zealand Associate Professor
Epigenetics Department of Medicine
Section of Gastroenterology and Hepatology
Baylor College of Medicine
Houston,Texas
Organogenesis of the Gastrointestinal Tract
xxvi Contributors
Gary C. Sieck, PhD Markus Sperandio, MD

Professor Professor
Physiology and Biomedical Engineering Institute for Cardiovascular Physiology and Pathophysiology
Mayo Clinic Walter Brendel Center for Experimental Medicine
Rochester, Minnesota Ludwig-Maximilians-Universität
Functional Development of Respiratory Muscles Munich, Germany
Normal and Abnormal Neutrophil Physiology in the
Rebecca A. Simmons, MD Newborn
Hallam Hurt Professor Pediatrics
Department of Pediatrics Mark A. Sperling, MBBS
Children’s Hospital of Philadelphia Emeritus Professor and Chair
Philadelphia, Pennsylvania Department of Pediatrics
Cell Glucose Transport and Glucose Handling During Fetal Children’s Hospital University of Pittsburgh
and Neonatal Development Pittsburgh, Pennsylvania
Professorial Lecturer
Neel Kamal Singh, MBBS, MD Pediatric Endocrinology and Diabetes
NICU Fellow Icahn School of Medicine at Mt. Sinai
Department of Pediatrics New York, New York
Division of Neonatology Growth Hormone, Prolactin, and Placental Lactogen in the
University of Florida College of Medicine Fetus and Newborn
Gainesville, Florida
The Developing Microbiome of the Fetus and Neonate: A Lakshmi Srinivasan, MBBS
Multiomic Approach Assistant Professor
Emidio Sivieri, MS, BE Children’s Hospital of Philadelphia
Biomedical Engineer Philadelphia, Pennsylvania
Department of Neonatology Cytokines and Inflammatory Response in the Fetus and
CHOP Newborn Care at Pennsylvania Hospital Neonate
Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania Diana E. Stanescu, MD
Evaluation of Pulmonary Function in the Neonate Assistant Professor
Laura Smith, MD Perelman School of Medicine
Beth Israel Deaconess Medical Center University of Pennsylvania
Department of Obstetrics and Gynecology Philadelphia, Pennsylvania
Boston, Massachusetts Pathophysiology of Neonatal Hypoglycemia
Prenatal Diagnosis
Charles A. Stanley, MD
Ian M. Smyth, PhD Senior Endocrinologist
Group Leader Division of Endocrinology and Diabetes
Department of Anatomy and Developmental Biology Children’s Hospital of Philadelphia
Biomedicine Discovery Institute Professor Emeritus
Associate Professor of Pediatrics Department of Pediatrics
Department of Biochemistry and Molecular Biology Perelman School of Medicine
Biomedicine Discovery Institute University of Pennsylvania
Monash University Philadelphia, Pennsylvania
Melbourne, Victoria, Australia Pathophysiology of Neonatal Hypoglycemia
Development of the Kidney: Morphology and Mechanisms
Robin H. Steinhorn, MD
Martha C. Sola-Visner, MD Senior Vice President and Executive Director
Associate Professor of Pediatrics Rady Children’s Specialists of San Diego
Department of Medicine Vice Dean, Children’s Clinical Services
Division of Newborn Medicine University of California, San Diego
Children’s Hospital Boston and Harvard Medical School La Jolla, California
Boston, Massachusetts Pathophysiology of Persistent Pulmonary Hypertension of
Developmental Megakaryopoiesis the Newborn
Michael J. Solhaug, MD Lisa Stinson, BSc, MMedSci, PhD

Professor of Pediatrics and Physiology Research Fellow
Physiological Sciences School of Molecular Sciences
Eastern Virginia Medical School The University of Western Australia, Perth
Norfolk, Virginia Perth, Western Australia, Australia
Development and Regulation of Renal Blood Flow in the Human Milk Composition and Function in the Infant
Neonate
Contributors xxvii
Barbara S. Stonestreet, MD Vadim S. Ten, MD, PhD

Professor Professor
Women & Infants Hospital of Rhode Island Division of Neonatology
The Warren Alpert Medical School of Brown University Columbia University Irving Medical Center
Providence, Rhode Island New York, New York
Fluid Distribution in the Fetus and Neonate Pathophysiology of Neonatal Hypoxic-Ischemic Brain
Development of the Blood-Brain Barrier Injury
Janette F. Strasburger, MD Bernard Thébaud, MD, PhD

Professor Senior Scientist
Department of Pediatrics Sinclair Centre for Regenerative Medicine
Medical College of Wisconsin Ottawa Hospital Research Institute
Attending Cardiologist Professor
Herma Heart Institute Department of Pediatrics
Children’s Hospital of Wisconsin Neonatologist
Milwaukee, Wisconsin Children’s Hospital of Eastern Ontario
Developmental Electrophysiology in the Fetus and University of Ottawa
Neonate Ottawa, Ontario, Canada
Developmental Biology of Lung Stem Cells
Dennis M. Styne, MD
Yocha Dehe Chair of Pediatric Endocrinology Claire Thornton, PhD
Professor Senior Lecturer
Department of Pediatrics Comparative Biomedical Sciences
University of California Davis School of Medicine Royal Veterinary College
Davis, California London, United Kingdom
Endocrine Factors Affecting Neonatal Growth Mechanisms of Cell Death in the Developing Brain
Xin Sun, PhD Daniel J. Tollin, PhD

Professor Professor
Pediatrics and Biological Sciences Department of Physiology and Biophysics
University of California, San Diego University of Colorado School of Medicine
La Jolla, California Aurora, Colorado
Normal and Abnormal Structural Development of Early Development of the Human Auditory System
the Lung
Jeffrey A. Towbin, MD
Lori Sussel, PhD Executive Co-Director
Professor The Heart Institute
Barbara Davis Center for Diabetes Le Bonheur Children’s Hospital
University of Colorado School of Medicine Professor and Chief
Aurora, Colorado Pediatric Cardiology
Development of the Endocrine and Exocrine Pancreas Medical Director, Cardiomyopathy, Heart Failure, and Transplant
Services
Emily W.Y. Tam, MDCM, MAS University of Tennessee Health Science Center
Associate Professor Memphis,Tennessee
Department of Paediatrics Pathophysiology of Cardiomyopathies
University of Toronto
Toronto, Ontario, Canada William E. Truog III, MD
Cerebellar Development—The Impact of Preterm Birth and Sosland Endowed Chair in Neonatal Research
Comorbidities Center for Infant Pulmonary Disorders
Children’s Mercy Hospital
Libo Tan, PhD Professor
Assistant Professor Department of Pediatrics
Human Nutrition and Hospitality Management University of Missouri Kansas City School of Medicine
University of Alabama Kansas City, Missouri
Tuscaloosa, Alabama Pulmonary Gas Exchange in the Developing Lung
Vitamin A Metabolism in the Fetus and Neonate
Kristin M. Uhler, PhD
Arjan B. te Pas, MD, PhD Audiologist/Associate Professor
Professor Otolaryngology, Physical Medicine & Rehabilitation
Department of Pediatrics University of Colorado School of Medicine
Leiden University Medical Center Chair
Leiden,The Netherlands Audiology, Speech Pathology, and Learning
Physiology of Neonatal Resuscitation Children’s Colorado Hospital
Aurora, Colorado
Early Development of the Human Auditory System
xxviii Contributors
Chris H.P. van den Akker, MD, PhD Marty O. Visscher, PhD
Pediatrician, Neonatologist Professor
Amsterdam UMC—Emma Children’s Hospital James L. Winkle College of Pharmacy
Department of Pediatrics/Neonatology University of Cincinnati College of Medicine
University of Amsterdam and Vrije Universiteit Amsterdam Cincinnati, Ohio
Amsterdam,The Netherlands Physiologic Development of the Skin
General Concepts of Protein Metabolism
Caitlin E. Vonderohe, DVM, PhD
John Nicolaas van den Anker, MD, PhD Postdoctoral Fellow
Chief, Clinical Pharmacology USDA-ARS Children’s Nutrition Research Center
Children’s National Health System Baylor College of Medicine
Washington, District of Columbia Houston,Texas
Chair, Paediatric Pharmacology and Pharmacometrics Trophic Factors and Regulation of Gastrointestinal Tract
Department of Pediatrics and Liver Development
University Children’s Hospital Basel
Basel, Switzerland Neha V. Vyas, MD
Faculty, Intensive Care Pediatric Endocrinology Fellow
Pediatric Surgery Pediatric Endocrinology
Erasmus Medical Center–Sophia Children’s Hospital Rainbow Babies and Children’s Hospital
Rotterdam,The Netherlands Cleveland, Ohio
The Physiology of Placental Drug Disposition Luteinizing Hormone and Follicle-Stimulating Hormone
Secretion in the Fetus and Newborn Infant
Maurice J.B. van den Hoff, PhD
Associate Professor Annette Wacker-Gussmann, MD
Department of Medical Biology Department of Sport and Health Sciences
Amsterdam UMC Institute of Preventive Pediatrics
Amsterdam,The Netherlands Department of Pediatric Cardiology and Congenital Heart Defects
Cardiovascular Development German Heart Center
Munich, Germany
Johannes (Hans) B. van Goudoever, MD, PhD Developmental Electrophysiology in the Fetus and Neonate
Professor
Amsterdam UMC—Emma Children’s Hospital Abby Walch, MD
Department of Pediatrics Clinical Fellow
University of Amsterdam and Vrije Universiteit Amsterdam Pediatric Endocrinology
Amsterdam,The Netherlands University of California, San Francisco
General Concepts of Protein Metabolism San Francisco, California
Development of the Hypothalamus-Pituitary-Adrenal Axis
Mark H. Vickers, PhD in the Fetus
Professor
Liggins Institute Megan J. Wallace, BSc, BSc (Hons), PhD
University of Auckland Associate Professor
Auckland, New Zealand Department of Obstetrics and Gynaecology
Epigenetics Director, Medical Student Research
School of Medicine
Alexander A. Vinks, PhD, PharmD Monash University
Cincinnati Children’s Research Foundation Endowed Chair Head, Lung Development Research Group
Professor of Pediatrics and Pharmacology The Ritchie Centre
University of Cincinnati College of Medicine Hudson Institute of Medical Research
Director, Division of Clinical Pharmacology Clayton, Victoria, Australia
Director, Pediatric Clinical Pharmacology Fellowship Program Physiologic Mechanisms of Normal and Altered Lung
Scientific Director, Pharmacy Research in Patient Services Growth Before and After Birth
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio Brian H. Walsh, MB, BCh, PhD
Pharmacogenomics Physician
Department of Neonatology
Daniela Virgintino, MD Cork University Maternity Hospital
Professor Cork, Ireland
Department of Basic Medical Sciences, Neurosciences, and Intraventricular Hemorrhage in the Neonate
Sensory Organs
University of Bari School of Medicine Jennifer A. Wambach, MD
Bari, Italy Associate Professor
Development of the Blood-Brain Barrier Edward Mallinckrodt Department of Pediatrics
Washington University School of Medicine
St. Louis, Missouri
Genetics and Physiology of Surfactant Protein Deficiencies
Contributors xxix
Linda X. Wang, MD Andy Wessels, PhD

Division of Gastroenterology Professor
Children’s Hospital Los Angeles Regenerative Medicine and Cell Biology
Clinical Instructor of Pediatrics Pediatric Cardiology
Keck School of Medicine Medical University of South Carolina
University of Southern California Charleston, South Carolina
Los Angeles, California Cardiovascular Development
Bile Acid Metabolism During Development
Jeffrey A. Whitsett, MD
David Warburton, DSc, MD Professor of Pediatrics
Professor Divisions of Pulmonary Biology and Neonatology
Developmental Biology and Regenerative Medicine Program Perinatal Institute
Saban Research Institute University of Cincinnati
Children’s Hospital Los Angeles Cincinnati Children’s Hospital Medical Center
Los Angeles, California Cincinnati, Ohio
Regulation of Embryogenesis Surfactant Homeostasis: Composition and Function of
Pulmonary Surfactant Lipids and Proteins
Robert M. Ward, MD
Professor Emeritus Fabienne Willems, PhD
Department of Pediatrics Professor
Division of Pediatric Clinical Pharmacology Institute for Medical Immunology
Adjunct Professor Université Libre de Bruxelles
Department of Pharmacology/Toxicology Brussels, Belgium
University of Utah Health Host Defense Mechanisms Against Viruses
Principles of Pharmacokinetics Myat Su Win, MBBS, MRCPCH
Physician
Kevin M. Watt, MD, PhD Department of Paediatrics
Chief, Division of Clinical Pharmacology Cambridge University Hospitals NHS Trust
Associate Professor Cambridge, United Kingdom
Department of Pediatrics Role of Glucoregulatory Hormones in Hepatic Glucose
Division of Pediatric Critical Care Medicine Metabolism During the Perinatal Period
Salt Lake City, Utah Christoph Wohlmuth, MD, PhD
Principles of Pharmacokinetics Department of Obstetrics and Gynecology
Paracelsus Medical University
Kristi L. Watterberg, MD Salzburg, Austria
Professor Emerita The Pathophysiology of Twin-Twin Transfusion Syndrome,
Division of Neonatology Twin-Anemia Polycythemia Sequence, and Twin-Reversed
University of New Mexico Arterial Perfusion
Albuquerque, New Mexico
Fetal and Neonatal Adrenocortical Physiology Matthias T. Wolf, MD
Associate Professor
Lynne A. Werner, PhD Department of Pediatrics
Professor Emeritus UT Southwestern Medical Center
Department of Speech & Hearing Sciences Dallas,Texas
University of Washington Potassium Homeostasis in the Fetus and Neonate
Seattle, Washington
Early Development of the Human Auditory System Marla R. Wolfson, PhD
Professor
Sarah A. Wernimont, MD, PhD Departments of Physiology, Medicine, and Pediatrics
Assistant Professor Center for Inflammation,Translational, and Clinical Lung
Department of Obstetrics, Gynecology, and Women’s Health Research
University of Minnesota Medical School Associate Chair
Minneapolis, Minnesota Department of Physiology
Glucose Metabolism in the Fetus and Newborn, and Lead Researcher
Methods for Its Investigation CENTRe: Collaborative for Environmental and Neonatal
Therapeutics Research
Barry K. Wershil, MD Lewis Katz School of Medicine
Professor Temple University
Department of Pediatrics Philadelphia, Pennsylvania
Feinberg School of Medicine at Northwestern Upper Airway Structure: Function, Regulation, and
Chief, Division of Gastroenterology, Hepatology, and Nutrition Development
Ann & Robert H. Lurie Children’s Hospital of Chicago
Chicago, Illinois
Development of Gastric Secretory Function
xxx Contributors
Ronald J. Wong, MD Christopher J. Yuskaitis, MD, PhD

Senior Research Scientist Assistant
Department of Pediatrics Department of Neurology
Stanford University School of Medicine Boston Children’s Hospital
Stanford, California Instructor in Neurology
Mechanistic Aspects of Phototherapy for Neonatal Harvard Medical School
Hyperbilirubinemia Boston, Massachusetts
Development of the Nervous System
James L. Wynn, MD
Professor Jennifer Zabinsky, MD
Departments of Pediatrics and Pathology, Immunology, and Clinical Fellow
Laboratory Medicine Pediatric Endocrinology
University of Florida College of Medicine University of California, San Francisco
Gainesville, Florida San Francisco, California
Pathophysiology of Neonatal Sepsis Development of the Hypothalamus-Pituitary-Adrenal Axis
in the Fetus
Lami Yeo, MD
Professor Dan Zhou, PhD
Division of Maternal-Fetal Medicine Scientist
Department of Obstetrics and Gynecology Department of Pediatrics
Wayne State University School of Medicine University of California San Diego
Director, Fetal Cardiology La Jolla, California
Perinatology Research Branch, NICHD/NIH/DHHS Basic Mechanisms of Oxygen Sensing and Adaptation to
Detroit, Michigan Hypoxia
Intra-Amniotic Infection/Inflammation and the Fetal
Inflammatory Response Syndrome
Bradley A. Yoder, MD
Professor
Impaired Lung Growth After Injury in Preterm Lung
Preface
The care of critically ill newborn infants has its foundations in physiologic medicine by Can Ince.1 Dr. Ince has suggested
neonatal physiology. Practitioners have traditionally used general four pillars of personalized physiology: fitness and frailty (to
physiologic principles in combination with clinical effectiveness determine physiologic reserve), organ function response to
studies to provide the most appropriate care. The sixth edition therapy, hemodynamic coherence (assessment of the macro- and
of Fetal and Neonatal Physiology marks the beginning of a new micro-circulations to determine appropriate resuscitation), and
era in our specialty in which care providers will use genetic integration and feedback (which provides ongoing assessments
information, biomarkers, and big data to make clinical decisions. and includes predictive models).
We are poised to rapidly diagnose and better understand the Our specialty is poised to apply these four pillars to neonatal
genetic basis of a variety of diseases affecting newborn infants, intensive care, and we believe the sixth edition of Fetal and
including chronic lung disease, necrotizing enterocolitis, Neonatal Physiology will help support this. Most of the 174
retinopathy of prematurity, white matter injury, and sepsis.Whole chapters in the book have been extensively updated by nearly
genome sequencing (WGS) to identify the genetic basis for 400 authors. More than 1500 visual elements—photographs,
complex neonatal diseases (and to identify potentially treatable illustrations, diagrams, charts, tables—are included, and we are
conditions) is becoming a bedside tool and will practically pleased to offer over 100 brand new color illustrations and
support pharmacogenomics to tailor treatments for neonatal diagrams to illuminate the text. The genetics content has been
conditions and limit side effects. Indeed, in the next 2 decades expanded to include new chapters such as “Pathophysiology of
we expect WGS to augment newborn screening, providing Genetic Neonatal Disease” and “Genetic Variants and Neonatal
information not only for NICU care but extending across the Disease.” Each of the chapters on disease pathophysiology has
life span. In a critically ill infant, repeated RNA sequencing may been extensively revised by leading experts in our specialty.
be needed as a new parameter to monitor changes during the We want to thank many individuals who made this edition
course of the illness. Well done randomized clinical trials will possible, including foremost the chapter authors who not
always be necessary to test the hypotheses that a new therapy only wrote superb chapters but who also adhered to the tight
is better or equivalent to a current therapy. However, success of production schedule. We deeply appreciate the editorial help
any clinical trial begins with having a strong physiologic basis from two individuals at Elsevier. Mary Hegeler was our content
for any given intervention, and ensuring the enrollment of well- development specialist, without whom we could never have
phenotyped and endotyped subjects will enhance the precision, done this revision. She was with us every step of the way and
success, and impact of such studies. Unfortunately, most provided invaluable guidance as we moved through the stages of
randomized trials are based upon a best guess or power analysis book development. We also wish to thank Sarah Barth at Elsevier
of sample size and with limited insights into critical differences who supported the decision to undertake the sixth edition.
within the cohort that may affect outcomes. No matter how Finally, we would like to thank the many readers of Fetal
carefully patients are selected for a trial, underlying biases and and Neonatal Physiology, who provided the stimulus and
physiologic differences will still exist and must be considered a encouragement to revise the book.
priori. Data unable to demonstrate differences in two treatment
arms does not mean an individual patient may not benefit. For RAP
precision medicine to be effective, genetic information must SHA
become available on a continuous and real-time basis and linked WEB
with ongoing assessment of organ function. This concept is DHR
not unique to neonatology and has been termed personalized
1Ince C. Personalized physiological medicine. Crit Care 2017;21:308.
xxxi
SECTION I
Genetics and Embryology
Basic Genetic Principles 1

Haluk Kavus | Wendy K. Chung
INTRODUCTION STRUCTURE OF CHROMOSOMES

Humans usually have 46 chromosomes in 23 pairs: 44 are
The human genome refers to the complete set of human autosomes, and 2 are the sex chromosomes (X and Y) involved in
DNA (with the suffix -ome arising from the Greek for “all” or sex determination. The homologous pairs are numbered from 1
“complete”). A copy of our genome comprises approximately 3 to 22 in order of decreasing size, with one member of each pair
billion base pairs (bp) and about 20,000 protein-coding genes. inherited from one parent.
The Human Genome Project was a significant contribution Every chromosome consists of a long, single, and continuous
toward understanding the organization, structure, and sequence DNA molecule located in the nucleus. DNA is packaged as
of the human genome.1,2 With these developments, genomic chromatin complexed with histone proteins to condense the
medicine has emerged as a new discipline to analyze the genome DNA into the nucleus. The five major types of histone proteins
and genetic information as a part of clinical care. play a critical role in packaging of the chromatin. Two copies
Having in-depth knowledge about the genome and the types of the four core histones H2A, H2B, H3, and H4 constitute an
and consequences of genomic variations is important for all octamer, around which a segment of DNA winds. A fifth histone,
medical professionals, especially neonatologists. Recognizing H1, binds to DNA at the tip of each nucleosome. Approximately
the most common chromosomal and monogenic disorders 140 bp of DNA are linked with each histone core, making just
and genetic concepts such as inheritance, genomic imprinting, under two turns around the octamer. After a short (20- to 60-bp)
uniparental disomy (UPD), and X chromosome inactivation can “spacer” segment of DNA, the pattern repeats, giving chromatin
help clinicians understand the origins of genetic conditions and the look of beads on a string. Each complex of DNA with its core
risk of recurrence to patients and their families. Knowing the histones is called a nucleosome, which is the basic structural unit
types of available clinical genomic tests, along with their utility of chromatin.
and limitations, is critical for appropriate clinical use. In this Between cell divisions, the chromatin is unwound where
chapter, we will also review prenatal diagnosis, clinical physical genes are being expressed. With cell division, the chromosomes
examination of the dysmorphic child, the future of newborn condense and become visible as the structures we observe in a
sequencing, and therapeutic approaches for monogenic karyotype. Noncoding RNA molecules play an essential role in
diseases. gene regulation. For example, Xist, a noncoding RNA molecule,
is a central regulator of X chromosome inactivation. It coats the
inactivated X chromosome, which is structurally condensed,
GENOMIC ORGANIZATION with most (but not all) genes being transcriptionally inactive.4
DNA AND RNA MITOCHONDRIAL GENOME
Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) Mitochondria are organelles within cells that transform the
are long polymers of nucleotides. Each nucleotide has three energy from food into a form that cells can use. Each cell contains
elements: (1) a nitrogenous base, (2) a sugar molecule, and thousands of mitochondria, each containing several copies of a
(3) a phosphate molecule. The nitrogenous bases fall into two small circular mitochondrial chromosome. The mitochondrial
types: purines and pyrimidines.The purines include adenine and DNA molecule is 16 kb in length and encodes 37 genes, all of
guanine; the pyrimidines include cytosine, thymine, and uracil. which are fundamental for both normal mitochondrial function
The primary difference between RNA and DNA is related to a and also required for the function of ribosomal and transfer RNA
base composition, such that RNA contains uracil, whereas DNA molecules in the mitochondria. Mitochondrial genes are solely
contains thymine. The other difference between RNA and DNA inherited from the mother.
is in their sugar-phosphate backbones: RNA contains ribose, and
DNA contains 2-deoxyribose. Deoxyribose confers resistance to STRUCTURE OF GENES
hydrolysis, which gives DNA chemical stability, supporting the Genes in humans are composed of protein-coding sequences
fidelity of the information as cells divide. While DNA is packaged called exons and the intervening (noncoding) DNA sequences
in chromosomes in the nucleus, RNA carries that message from called introns (Fig. 1.1). Introns are initially transcribed into
the nucleus to the cytoplasm, where it is made into proteins. RNA in the nucleus and are spliced out to make the mature
The double-helix structure of DNA was elucidated in 1953.3 mRNA. Therefore, the information from the intronic sequences
Hydrogen bonds zip up the complementary strands of DNA is not typically represented in the final protein product. Exonic
in which A pairs with T, and C pairs with G. Because of the sequences determine the amino acid sequence of the protein.
complementary sequence of the two strands of DNA, there is Most genes contain at least one and usually numerous introns.
redundancy in the information content, increasing the fidelity of The total length of the introns makes up a far greater proportion
the code. Replication of the double-stranded structure of DNA of a gene’s total length for most genes. Genes are also flanked
molecules requires a separation of the two strands followed by by additional sequences that are transcribed but untranslated,
the synthesis of two new complementary strands. In contrast to known as the 5′ and 3′ untranslated regions, which play a role in
DNA, RNA molecules are single-stranded and short-lived. RNA stability and gene expression.
1
2 SECTION I — Genetics and Embryology
The human genome contains noncoding DNA sequences that MOSAICISM

act as regulatory elements. These sequences include promoters, Mosaicism is the presence of at least two cell populations derived
enhancers, silencers, and locus control regions. They coordinate the from the same zygote. Mitotic nondisjunction, trisomy rescue, or
regulation of genes in space and time. They include sequences for occurrence of a somatic new mutation can lead to the development
proteins called transcription factors to bind to and either increase of genetically different cell lines within the body. Mosaicism can
or repress transcription. Promoter regions are responsible for the affect any cells or tissue within a developing embryo at any point
initiation of transcription and are typically found 5′ or upstream of after conception to adulthood. If the mosaic cells are found only
a gene. Enhancers and silencers can be located either 5′ or 3′ of a in the placenta and absent in the embryo, this known as confined
gene, within the introns or sometimes farther away in neighboring placental mosaicism (CPM) (Fig. 1.2A).7 CPM may be detectable
genes. Promoters are binding sites for proteins that increase or on a chorionic villus sample and may be associated with
repress transcription. Besides genes that are transcribed and made intrauterine growth restriction but not with congenital anomalies
into proteins, there are genes known as non-coding RNAs (ncRNAs), or neurodevelopmental disorders if the genetic anomaly is not
whose functional product is RNA. Some ncRNAs can be quite long present in the fetus. Somatic mosaicism is the presence of two or
(long ncRNAs or lncRNAs) and play roles in gene regulation.5 more cell lineages in tissues that may have a clinically observable
There are also small non-coding RNAs, known as short interfering phenotype in the part of the body with the genetic aberration (see
RNAs (siRNAs) and microRNAs (miRNAs), that control gene Fig. 1.2B). In gonadal mosaicism, the mosaic cells are restricted to
expression. MicroRNAs are short, non-coding RNAs, approximately the gametes and do not have a clinically observable phenotype but
22 nucleotides in length, which post-transcriptionally regulate can be passed onto the next generation.
mRNA expression,6 usually by decreasing expression. siRNAs are
homologous to specific mRNAs and degrade the mRNA to decrease MEIOSIS
the expression of the target gene. Meiosis is the process by which gametes are formed. In contrast
More than half of the human genome consists of various types with mitosis, in which a single cell division and an exact
of repeat sequences that are either clustered together or evenly duplication of the genetic material occurs, meiosis involves two
distributed throughout the genome. These sequences can be cell divisions, starting with a diploid parental cell and random
short and consist of only a few nucleotides or can be as long reassortment and reduction of genetic material so that each of
as 5000 to 6000 nucleotides. The two best-studied dispersed the four daughter cells has the haploid DNA content (i.e., 23
repetitive elements are the Alu family and the long interspersed chromosomes). In this way, meiosis yields four haploid gametes
nuclear element (LINE) family. The Alu family makes up at least (sperm or eggs). In female meiosis, the second meiotic division is
10% of human DNA, and the LINE family accounts for nearly 20% completed only after fertilization, and advancing maternal age is
of the genome. Segmental duplications are another repeat and associated with nondisjunction of the chromosomes. A polar body,
are highly conserved and make up 5% of the human genome. containing a complete set of chromosomes, is extruded, leaving
When these duplicated sequences include genes, structural the egg with a single remaining haploid set of chromosomes. The
rearrangements can cause genetic diseases. second polar body is useful for preimplantation genetic diagnosis.
CELL DIVISION RECOMBINATION

Transmission of the genetic information from one generation During the prophase of the first meiotic division, homologous pairs
to the next relies on accurate replication of DNA during of chromosomes are held together by the synaptonemal complex,
reproduction. Mitosis is used during somatic cell division to which extends along the entire length of the paired chromosomes.
support the development and cellular differentiation. In mitotic Recombination between chromatids of the homologous
division, the usual complement of 46 chromosomes is maintained chromosomes occurs at this stage, resulting in the exchange of DNA
through a process of DNA replication and subsequent separation between the original parental chromosomes (Fig. 1.3). In males, the
of the chromosomes. In contrast, meiosis occurs only in cells X and Y chromosomes are physically associated only at the tips of
that become gametes, each of which has only 23 chromosomes their short arms during meiotic prophase. This short region is called
(haploid genome).Thus errors in cell division in either somatic or the pseudoautosomal region because recombination between
germline cells can cause abnormalities of chromosome number the X and Y chromosomes occurs there (and thus it behaves as
or structure that can be clinically significant. an autosome in terms of Mendelian inheritance). Recombination
enhancer promoter exon intron exon intron exon

Gene
(DNA)
Transcription
Splicing
Transcript
Fig. 1.1 Gene structure (top) and (RNA) Capping, Polyadenylation
the flow of genetic information from Transport to cytoplasm
DNA to protein. Tan boxes indicate
AUG Stop
the regions of exons that do not en-
code amino acid sequences; gray
boxes indicate posttranscriptional
modifications. AUG is a codon that
specifies the amino acid methionine Translation
and is also used to specify the first
amino acid of a protein. Protein
CHAPTER 1 — Basic Genetic Principles 3
involves the exchange of genetic material between the two homologs The boundary between the introns and exons consists of a
during meiosis I, and it is also critical for proper chromosome 5′ donor GT dinucleotide and a 3′ acceptor AG dinucleotide.
segregation during meiosis. Failure to recombine correctly can lead Besides the canonical splice sequences, there are also splicing
to nondisjunction of the chromosomes in meiosis I and is a frequent regulatory elements such as exonic splicing enhancers (ESEs)
cause of aneuploidy (incorrect chromosome number) leading to and exonic splicing silencers (ESSs). ESEs and ESSs correspond
pregnancy loss and congenital anomalies. to six to eight nucleotides that serve as docking sites for splicing
activator or splicing repressor proteins, thereby influencing the
recruitment and activity of the splicing machinery.8 Most human
HOW GENES FUNCTION genes undergo alternative splicing and hence encode more than
one protein for each gene. Alternative polyadenylation creates
FLOW OF GENETIC INFORMATION further diversity. Some genes have more than one promoter, and
TRANSCRIPTION these alternative promoters may result in tissue-specific isoforms.
The first step in gene expression is the production of an RNA Alternative splicing of exons is also seen with individual exons
molecule from the DNA template. The RNA acts as a molecular present in only some isoforms.
messenger, carrying the genetic information out of the nucleus
to the cytoplasm. The synthesis of mRNA is called transcription TRANSLATION
because the genetic information in DNA is transcribed. During The production of protein from a mRNA template is called
transcription, the two DNA strands separate, and one functions translation because the genetic information that is encoded in
as a template for the synthesis of single-stranded RNA molecules DNA is translated into a sequence of amino acids in the protein.
by RNA polymerases. The initial RNA transcripts are quite long The genetic information is stored in the genetic code. Each of the
because they include both introns and exons from the gene. three adjacent nucleotides is a unit of information called a codon
The intronic sequences are cut out, and the remaining exons and specifies an amino acid or the start or stop of translation.
are spliced together. To form the mature mRNAs that leave the The linear codons in the DNA sequence specify the sequence
nucleus, a methylated guanine nucleotide called a cap is added to of amino acids in a protein. Because each of the three sites in
the 5′ end, and a string of 200 to 250 adenine (polyA tail) bases is a codon can be one of four possible nucleotides, a total of 43,
added to the 3′ end. The cap is necessary for ribosomal binding or 64, different codons are possible. Three of these 64 possible
to initiate protein synthesis, and the polyadenosine stretch at the codons, UAA, UAG, and UGA, are called termination codons. The
3′ end increases the stability of the mRNA. remaining 61 codons specify one of the 20 amino acids, leading to
Transcriptional control is central for the development some degeneracy in coding certain amino acids. A consequence
and proper functioning of every organism. Transcriptional of degeneracy is that some DNA variants do not result in a change
regulation is accomplished by modifying the DNA (e.g., cytosine in the amino acid sequence (synonymous variants).
methylation) or by protein binding to specific DNA sequences
to activate or repress transcription of a gene. There are many EPIGENETICS
sequence-specific transcription factors that are differentially In addition to the classic transcription factors that bind to specific
active by cellular and tissue type and time in development. Several sequence elements in genes, gene expression is controlled by
regulatory sequences have been identified in promoters that are enzymes that modify DNA-bound proteins and DNA itself. The
important for transcriptional initiation by RNA polymerase II,
including the TATA box, so-called because it consists of a run of
T and A base pairs. The TATA box is located approximately 30
bases before the transcription start site and functions as the
binding site for a large, multisubunit complex of transcription
factors (including RNA polymerase). A second conserved region,
the so-called CAT box, is a few dozen base pairs farther upstream.
Specific sequence elements that form promoters and enhancers
are required for binding the ∼1400 sequence-specific proteins Fig. 1.3 Recombination. In this simplified view of recombination, the
that bind to DNA and regulate transcription. Mutations in these two members of a homologous pair of chromosomes line up during
regulatory sequence elements can lead to significant alterations the first meiotic prophase. Segments of the two chromosomes “cross
in transcription and also can lead to genetic disorders. over,” and breakage and rejoining of the DNA strands occur.
A B
Fig. 1.2 Mosaicism. (A) Confined placental mosaicism. Presence of mutant cells only in the placental tissue, not in the fetus. (B) Somatic mosai-
cism. Presence of two or more mutant cell lineages in tissues and may have a clinically observable phenotype in the part of the body with the
genetic aberration.
principal mechanism by which DNA is modified is by methylation an increase in the number of copies of triplet repeats in the
of cytosine residues adjacent to guanosine. Methylation of these coding or noncoding region of a gene. These disorders include
CpG dinucleotides by DNA methylases leads to transcriptional myotonic dystrophy, fragile X syndrome, and Huntington disease.
inactivation, while demethylation by demethylases alters the The repeat size can increase with successive generations, and
conformation of chromatin, leading to transcriptional activation. as the repeat number increases, the age of onset of the disease
Histone proteins are extensively modified by many enzymes, decreases, giving rise to the phenomenon of anticipation.
including acetylases, kinases, and methylases. The pattern of
histone modification, particularly on lysine residues, controls HOW MANY MENDELIAN CONDITIONS ARE THERE?
whether a particular region of chromatin will be transcriptionally There are 8319 Mendelian phenotypes described. A total of 5489
active or inactive. of them (66%) have an associated known underlying gene. A total
Modifications of chromatin proteins and DNA can be inherited of 20% (3912/19,580) of human genes are known to underlie
through multiple cell divisions. Such alterations that do not a Mendelian phenotype.9 This information is curated in Online
change the DNA sequence itself and are called epigenetic. Genetic Mendelian Inheritance in Man (OMIM),10 which is a continuation
diseases that affect this process exemplify the importance of of Mendelian Inheritance in Man (MIM), published between 1966
epigenetics. For example, mutations in MeCP2, a protein that and 1998.
binds to methylated DNA to repress the expression of associated
genes, cause Rett syndrome, an X-linked neurodegenerative CHROMOSOMAL MUTATIONS
disease. Rubinstein-Taybi syndrome is caused by mutations in Mutations in chromosome structure include deletions, dupli-
the CBP gene, encoding CREB-binding protein, which acts to cations, inversions, and translocations. Because chromosomal
acetylate the histone proteins that are major components of alterations usually result in the disruption of multiple genes,
chromatin. they often have profound clinical consequences that include
more than one organ system (see Fig. 1.4B).
If the total amount of genetic material is normal (just simply
GENETIC VARIATION rearranged), then the karyotype is balanced. A deletion is the
loss of a part of a chromosome and results in monosomy for
A locus is a particular position on a chromosome for a specific that segment of the chromosome. An insertion is the addition
gene and related DNA elements. Alleles refer to an alternative of a segment of DNA into a chromosome. An insertion is often
version of the DNA sequence at a locus. Generally, one of the associated with an unbalanced chromosome complement.
alternative alleles is found in more than half of the population and An inversion is a two-break rearrangement involving a single
is called is the major allele. The other versions of that gene refer
to variants or minor alleles. Allele frequencies vary significantly A. Single-Gene Mutations
in different populations. If an allele frequency is greater than 1%,
it is said to be a polymorphism (multiple forms). ATG · CTA · CGC · TGG · ACA · AGC
Mutation is generally meant to signify a DNA sequence that is Normal
Met · Leu · Arg · Try · Thr · Ser
deleterious and associated with a human disease. Mutations can
be germline and inherited from one or both parents, or somatic ATG · CCA · CGC · TGG · ACA · AGC
and acquired over the life of an individual. Mutations can vary Missense
Met · Pro · Arg · Try · Thr · Ser
by the size of the altered DNA sequence. The size of mutations
can range from a single nucleotide to the rearrangements of an ATG · CTT · CGC · TGG · ACA · AGC
entire chromosome. By convention, we have a reference genome Silent
Met · Leu · Arg · Try · Thr · Ser
that is used to compare genetic variants. This reference genome
is updated as we understand the human genome better. ATG · CTA · CGC · TGA · ACA · AGC
Nonsense
Met · Leu · Arg · (Stop)
SINGLE NUCLEOTIDE VARIATIONS
ATG · CGT · ACG · CTG · GAC · AAG · C
When a “point mutation” of one or a small number of nucleotides Frameshift (insertion)
Met · Arg · Thr · Leu · ASD · Lys
occurs in a part of the gene that codes for a protein and alters the
protein by changing the codon of which it is a part, it is called
a nonsynonymous variant (Fig. 1.4A). Because the genetic B. Chromosomal Mutations
code is degenerate, it is possible to have a point mutation that
Normal Deletions Duplication Inversions Translocation
does not change the amino acid that is encoded. This is called a
synonymous variant. Insertion or deletion of a nucleotide in the A A A A A A A 1
B B B B B D B 2
protein-coding portion of a gene is called a frameshift mutation C
C 3
C C C C C
because it changes the entire reading frame of the gene at every D G D D D B D 4
E H E E G E E G
codon distal to the site of the mutation. Nonsense mutations F F D F F F H
are those point mutations that result in one of the three codons G E E G 5
H F H H 6
(UAA, UAG, UGA) that do not code for amino acids but rather G 7
truncate proteins, often producing proteins with little or no H
activity if they occur early enough in the protein. Point mutations Fig. 1.4 Mutation. (A) Single-gene mutations. A prototypical nor-
occurring at the boundaries between introns and exons can mal gene sequence is shown on the first line, with the corresponding
cause improper splicing of RNA precursors, resulting in aberrant amino acid sequence. Examples of four types of common mutations
splicing or RNA instability. also are shown. The substituted or inserted nucleotides are indicated
Regulation of gene expression can be affected by mutations by arrows, and the affected amino acids are underlined. (B) Chro-
occurring in control elements, such as promoters and enhancers; mosomal mutations. A prototype normal chromosome is shown, with
the effect of such mutations is to quantitatively affect the amount genes A through H. Examples of gross chromosomal mutations are
of protein produced, such as occurs in some forms of thalassemia. shown to the right, and their effects on gene content and arrangement
A different mutational mechanism involves the expansion are indicated. In the translocation example, the two chromosomes are
of triplet repeat sequences (dynamic mutations), caused by not members of a homologous pair.
chromosome in which a segment is flipped and reversed in be helpful in predicting recurrence risk for the parents. Some
position. If the inversion segment includes the centromere, it is deletions and insertions involve only a few nucleotides and are
termed a pericentric inversion. If it involves only one arm of the generally most easily detected by sequencing the relevant part of
chromosome and does not involve the centromere, it is known the genome. In other cases, a large segment of a gene, an entire
as a paracentric inversion. A translocation refers to the transfer gene, or several adjacent genes are deleted, duplicated, inverted,
of genetic material from one chromosome to another. If two or translocated and create a novel arrangement. Depending on
different chromosome breaks and the chromosome segments the exact nature of the deletion, insertion, or rearrangement, a
are exchanged, it is called a reciprocal translocation. If the variety of different laboratory approaches can be used to detect
translocation occurs between two acrocentric chromosomes the genomic alteration, including karyotype, fluorescent in situ
or chromosomes with redundant genetic material on the p arm, hybridization (FISH), chromosome microarray, or sequencing
it is called a Robertsonian translocation. Similar to inversions, methods.
translocations can be balanced or unbalanced. Individuals
who carry translocations but who have a normal amount of ANEUPLOIDY
genetic material are called balanced translocation carriers. Aneuploidy refers to missing or additional individual
Translocations can have severe effects on offspring if the progeny chromosomes in the cell (a number other than 46 chromosomes).
has an unbalanced complement. When counseling a carrier of a Aneuploidies of chromosomes 13, 18, and 21 are among the
balanced reciprocal translocation or Robertsonian translocation, most clinically important of the chromosome abnormalities.
it is necessary to consider the particular rearrangement to They consist of monosomy (the presence of only one copy of
determine what the probability is that it could result in the birth a chromosome in an otherwise diploid cell) and trisomy (three
of an abnormal baby. Translocation carriers are at increased risk copies of a chromosome). Nondisjunction causes errors in
of miscarriage of unbalanced products of conception. chromosome segregation and leads to aneuploidies. Multiple
A ring chromosome is formed when a break occurs on each congenital anomalies, growth restriction, and intellectual
arm of a chromosome leaving two “sticky” ends on the central disability are the most common phenotypes of these trisomies.
portion of the chromosome that reunite as a ring. The two distal Nevertheless,each has a reasonably unique neonatal phenotype
chromosomal fragments are lost, so if the involved chromosome that is recognizable by an experienced clinician. Trisomy 13 and
is an autosome, the effects are usually severe. 18 are both less common than trisomy 21, and survival beyond
Structural variant (SV) refers to genomic rearrangements the first year is rare for trisomy 13 and 18. In contrast, individuals
and includes deletions, insertions, inversions, duplications, and with Down syndrome have a life expectancy of over 50 years.
translocations. Copy number variation (CNV) describes a group Most other autosomal trisomies result in early pregnancy loss,
of DNA sequence variants (including deletions and duplications) with trisomy 16 being a particularly common finding in first-
that result in an abnormal number of copies of segments of trimester spontaneous miscarriages.
DNA.11 Trisomy 21, which causes Down syndrome, is the most common
autosomal aneuploidy seen among live births.The most common
features include intellectual disability, hypotonia, gastrointestinal
GENETIC DISORDERS obstruction, congenital heart defects, and dysmorphic facial
features. In approximately 90% of cases, the third chromosome
CHROMOSOMAL DISORDERS 21 is of maternal origin. About 95% of Down syndrome cases
Chromosome disorders compose an important category of are caused by nondisjunction, and Robertsonian translocations
genetic disease, occurring in approximately 1 out of every 150 cause most of the remaining cases. Mosaicism is seen in 2% to 4%
live births.12 They are a common cause of intellectual disability of Down syndrome cases and is often associated with a milder
and pregnancy loss. Chromosomal disorders can be divided into phenotype.The most frequent cause of mosaicism in trisomies is
two groups: numerical and structural abnormalities. Numerical a trisomic conception followed by loss of the extra chromosome
abnormalities result from one or more chromosome gains or during mitosis in some embryonic cells (trisomic rescue).
losses, referred to as an aneuploidy (e.g., trisomy, monosomy, Trisomy 13 and 18 are sometimes compatible with survival to
tetrasomy) or the addition of one or more complete haploid term, although 95% or more of affected fetuses are spontaneously
genomes, referred to as polyploidy (e.g., triploidy, tetraploidy). aborted. These trisomies produce more severe disease than
In addition to the loss or gain of whole chromosomes, parts of trisomy 21, with 90% to 95% mortality during the first year of life.
chromosomes can be lost or duplicated as gametes are formed, Turner syndrome is most commonly associated with 45, X.
and the arrangement of portions of chromosomes can be altered. Although this disorder is common at conception, it is relatively
Structural chromosome abnormalities may be unbalanced (the rare among live births, reflecting a high rate of spontaneous
rearrangement causes a gain or loss of chromosomal material) abortion. Mosaicism, including confined placental mosaicism,
or balanced (the rearrangement does not produce a loss or appears to increase the probability of survival to term. Klinefelter
gain of chromosome material). Molecular methods including syndrome occurs in men who receive two X chromosomes in
chromosome microarrays are often helpful to sensitively detect addition to the Y chromosome. The presence of an extra sex
gains, losses, and rearrangements that may be missed by standard chromosome (X or Y) has only mild phenotypic effects.
karyotype alone. Unlike aneuploidy and polyploidy, balanced
structural abnormalities less frequently produce serious health GENOMIC DISORDERS (MICRODELETION AND
consequences, and many are compatible with normal health and DUPLICATION SYNDROMES, STRUCTURAL VARIATIONS,
behavior. However, unbalanced abnormalities of chromosome COPY NUMBER VARIATIONS)
structure and even some that are balanced but that disrupt key Chromosomal deletions and duplications are an important
genes can create severe disease in individuals or their offspring. cause of human malformations and intellectual disability. Those
The phenotype associated with the chromosome disorder tends caused by submicroscopic changes were not easily detectable
to run true in the family when inherited, so testing the parents to with a standard karyotype (with a resolution of approximately
determine if a chromosome disorder is inherited or de novo is often 5 to 10 Mb). With the advent of high-resolution banding, it
recommended by a geneticist. Some structural alterations can be has become feasible to identify smaller deletions. Advances in
caused by translocations (reciprocal or Robertsonian), insertion, molecular genetics, mainly the FISH and chromosome microarray
deletion, or rearrangement of DNA sequences, so examination techniques, have permitted the detection of deletions that are
of the parents of a child with a complex rearrangement may often too small to be observed microscopically (i.e., <5 Mb).
Because these syndromes generally involve the deletion or the gene/gene(s) that are imprinted. The imprint is maintained
duplication of a series of adjacent genes, it is sometimes referred throughout the life of the organism, in virtually all tissues; however,
to as a contiguous gene syndrome. Recent studies show that germ cells erase and then reset imprints for transmission to the
this is caused by the presence of flanking repeat sequences, next generation. Imprinting disorders can be caused by:

termed low-copy repeats (also termed segmental duplications),
(a) sequence mutation of the relevant gene (UBE3A for Angel-
at the deletion borders. These repeat sequences favor unequal
man syndrome),
crossing-over, which then produces duplications and deletions of
(b) deletion or duplication of imprinted genes,
the region bounded by the repeat elements. These disorders are
(c) UPD, or
collectively called genomic disorders.13
(d) epigenetic errors in imprinting centers causing faulty imprint-
Some of well-known genomic disorders and their associated
ing.
clinical features are shown in Table 1.1.
Prader-Willi syndrome, Angelman syndrome, and Beckwith-

GENOMIC IMPRINTING Wiedemann syndrome are the best-studied examples of the role
There are regions of the genome with parent-of-origin effects of genomic imprinting in human disease.
as a result of genomic imprinting. Genomic imprinting is
an epigenetic term describing monoallelic gene expression UNIPARENTAL DISOMY
according to parental origin. This epigenetic “mark” or imprint Uniparental disomy (UPD) refers to the presence of a disomic
affects the chromatin structures and silences expression of cell line containing two chromosomes that are inherited from
only one parent, rather than one chromosome being inherited
from the mother and the other from the father. If the disomic
chromosomes are received from identical sister chromatids,
Table 1.1 Examples of Microdeletion Syndromes. it is called isodisomy (the same copy of two chromosomes);
if both homologs come from one parent, the situation is
Chromosomal heterodisomy.
Syndrome Locus Major Clinical Features
Trisomy rescue is the mechanism of loss of a chromosome that
Deletion 1p36 1p36 Intellectual disability, restores a disomic state and escape from trisomy. If it happens,
Syndrome seizures, hearing loss, the resulting cell might show UPD.
heart defects, growth
If UPD occurs and includes a chromosome with an imprinted
failure, behavioral
symptoms region such as chromosome 15, this may cause disease. For
Wolf-Hirschhorn 4p16.3 Pre- and postnatal growth example, Angelman syndrome is due to mutations/deletions in
Syndrome failure, iris coloboma, the maternally expressed gene UBE3A or paternal UPD 15, such
seizure, microcephaly that there is no functional UBE3A allele, as the maternal allele
Cri-du-chat 5p High-pitched cat-like cry, is missing. Angelman syndrome can also be due to epigenetic
Syndrome microcephaly, hypotonia, modifications of the imprinting center on chromosome 15q11,
developmental delay, which results in the loss of expression of UBE3A.
low-set ears
Williams-Beuren 7q11.23 Supravalvular aortic SEX CHROMOSOME ABNORMALITIES
Syndrome stenosis, hypercalcemia,
periorbital fullness, thick Sex chromosome aneuploidies are common and may not be
lips, friendly personality diagnosed for decades, if ever. Males with Klinefelter syndrome
WAGR 11p13 Wilms tumor, aniridia, (47, XXY) are taller than average, may have slightly reduced IQ,
Syndrome genitourinary and are usually infertile. The 47, XXX and 47, XYY karyotypes
abnormalities, intellectual are present in about 1/1000 female and male births, respectively.
disability, obesity Each involves a slight reduction in IQ and potentially behavioral
Prader-Willi 15q11– Intellectual disability, issues, including attention deficit hyperactivity disorder, but are
Syndrome q13 short stature, obesity, associated with few physical or medical problems.
hypotonia, characteristic
facies, small feet X INACTIVATION
Angelman 15q11– Intellectual disability, ataxia,
Syndrome q13 behavioral abnormalities, The principle of X inactivation is that in somatic cells in
seizures, hypotonia, normal females (but not in normal males), one X chromosome
wide-based gait is inactivated early in development, thus equalizing the
Rubinstein- 16p13.3 Intellectual disability, broad expression of X-linked genes in the two sexes. In normal
Taybi thumbs and great toes, female development, because the choice of which X
Syndrome vertebral and sternal chromosome is to be inactivated is random and then clonally
abnormalities, heart maintained, females are mosaic with respect to X-linked gene
defects
Smith-Magenis 17p11.2 Intellectual disability,
expression. In patients with extra X chromosomes (whether
Syndrome hyperactivity, male or female), additional X chromosomes are randomly
dysmorphic features, inactivated, leaving only one active X per cell. Thus all diploid
self-destructive behavior somatic cells in both males and females have a single active
Miller-Dieker 17p13.3 Lissencephaly, X chromosome, regardless of the total number of X or Y
Syndrome microcephaly, seizures, chromosomes present.
growth retardation, The X chromosome contains approximately 1000 genes, but
facial dysmorphism, not all of them are subject to inactivation. Notably, the genes that
early death
continue to be expressed from the inactive X are not distributed
DiGeorge/VCF 22q11.2 Characteristic facies, cleft
Syndrome palate, heart defects,
randomly along the X chromosome. Many of the genes that
hypocalcemia, thymic “escape” inactivation are on distal Xp (as many as 50%) rather
hypoplasia than on Xq (just a few percent). This finding has important
implications for genetic counseling in cases of a partial X
chromosome aneuploidy, because imbalance for genes on Xp
may have greater clinical significance than imbalance for genes same mutation (intrafamilial variation). Pleiotropy is when a
on Xq, where the effect is mostly normalized by X inactivation. mutation in a single gene has effects on the body in more than
one way (e.g., congenital heart disease and intellectual disability).
SINGLE-GENE DISORDERS The proportion of cases resulting from new (de novo)
A trait or disorder that is determined by a gene on an autosome is mutations varies considerably between different AD conditions.
said to show autosomal inheritance, whereas a trait or disorder In some disorders, the de novo mutation rate is high (nearly 100%
determined by a gene on one of the sex chromosomes is said to of cases), whereas for some other conditions, a new mutation is
show sex-linked inheritance. For autosomal loci, the genotype unusual.
of a person at a locus consists of both of the alleles occupying In many AD disorders, reproductive fitness is zero, (i.e.,
that locus on the two homologous chromosomes. If two alleles mutation carriers do not reproduce). Such a condition is
are the same for a particular locus, the genotype is homozygous. maintained in the population entirely by new mutations, and
When the alleles are different, and one of the alleles is the the majority of cases are due to de novo mutations (although
reference allele (common variant in the population), it is called parental germline mosaicism may sometimes lead to recurrence
heterozygous. If the two alleles are different and neither is in a sibling). Many other AD disorders have only modest effects
the reference allele, it is called compound heterozygote. The on reproductive fitness.
term hemizygous refers to one abnormal allele located on the
X chromosome in a male. Mitochondrial loci are present in AUTOSOMAL RECESSIVE DISORDERS
thousands of copies per cell; thus the terms mentioned herein Autosomal recessive (AR) conditions occur when the mutant
are not used to describe mitochondrial genotypes. allele is present in both copies of the gene. Heterozygous
There are two types of genetic heterogeneity. Allelic individuals are said to be carriers for that condition and are
heterogeneity is when many different mutations in one gene cause asymptomatic (see Fig. 1.5B).
similar phenotypes. Locus heterogeneity is when mutations in
several different genes all cause a similar phenotype. Phenotype Principles of Autosomal Recessive Inheritance
is the expression of genotype as a morphologic, clinical, cellular, • D isease is expressed only in homozygotes and compound
or biochemical trait, which may be clinically observable or may heterozygotes.
only be detected by blood or tissue testing. The phenotype can • Parents are obligate carriers.
be discrete or can be a measured quantity, such as body mass • Risk to carrier parents for having an affected child is 1 in 4.
index or blood glucose levels. • Healthy siblings of affected individuals have a two-thirds risk
of being a carrier.
AUTOSOMAL DOMINANT DISORDERS • Males and females are affected equally.

Autosomal dominant (AD) disorders manifest in heterozygous
individuals who have a single copy of the mutant allele. Many
molecular mechanisms are associated with AD inheritance,
including haploinsufficiency (loss of function of one amorphic Autosomal dominant Autosomal recessive
allele), hypomorphic alleles with decreased function,
hypermorphic alleles exhibiting gain of function (constitutive
protein activity), neomorphic alleles that acquire a new function
(such as altered substrate specificity), and toxic (antimorphic)
effects of a protein, leading to dominant-negative (DN)
mechanisms (Fig. 1.5A). A B
Principles of Autosomal Dominant Inheritance
• M ales and females are affected equally. X-linked recessive X-linked dominant
• Males and females can both transmit the disorder.
• There is a 50% risk to offspring in any pregnancy in which one
parent carries a mutation.
• The severity of the disorder in the offspring may vary, being
similar, more severe, or less severe than in the parent.
• Many AD disorders are due to de novo mutations. C D

Dominant diseases show the same phenotype in either the Mitochondrial inheritance
X-linked dominant, male lethality
heterozygous or homozygous state. The majority of AD disorders
are incompletely dominant or semidominant, which means
homozygous individuals have a more severe phenotype than
heterozygous individuals. In codominant inheritance, both alleles
are phenotypically expressed (e.g., ABO blood group).
Penetrance is the percentage of individuals who carry the E F
relevant genotype and have signs or symptoms of the disorder.
If all individuals who have a disease genotype show the disease Normal male
phenotype, then the disease is said to be “fully penetrant,” or Normal female
to have a penetrance of 100%. Many dominant disorders show Affected male
age-dependent penetrance. Some conditions show incomplete
Affected female
penetrance (i.e., not all mutation carriers will manifest the
Carrier
disease during a natural lifespan).
Abortion
Expressivity is the difference in the severity of a disorder in
individuals who have inherited the same disease alleles. Many Fig. 1.5 (A–F) Pedigrees for disorders exhibiting the various men-
genetic conditions show a striking difference between families delian and mitochondrial modes of inheritance. These are idealized
(interfamilial variation) and also within families carrying the pedigrees, assuming full penetrance and no new mutations.
Consanguinity is a significant risk factor for AR disorders.

The founder effect is often responsible for a higher preva- GENETIC DIAGNOSIS
lence of a recessive genetic disorder in an isolated population,
because multiple individuals of the population are descended VALUE OF A DIAGNOSIS AND NEED FOR A
from a common ancestor who carried a disease-causing DIAGNOSIS
mutation. Genetic disorders can be classified as Mendelian (monogenic),
oligogenic, chromosomal, and multifactorial. In this section, we
X-LINKED RECESSIVE DISORDERS will limit ourselves to rare diseases. Rare diseases are described
as those that affect fewer than 200,000 people in the United
Principles of X-Linked Recessive Inheritance
States. There are more than 7,000 rare diseases, approximately
See Fig. 1.5C. 80% of which are thought to have a genetic cause.10 The majority

• M ales carrying the mutation are more severely affected; (50% to 75%) of rare diseases affect children.14 Making an
females carrying the mutation are generally either unaffected accurate diagnosis is fundamental to good patient care. Molecular
or more mildly affected than males, and severity in females diagnoses for patients with rare disorders are important for
depends on the X-inactivation pattern. patients and their families to refine prognosis, management,
• When a carrier female conceives, there are four possible recurrence risk, and reproductive options; identify other families
outcomes, each equally likely: a normal daughter, a carrier with the same condition; and participate in research for new
daughter, a normal son, and an affected son. sources of support and therapies.15 It is important to diagnose
• The pedigree shows no male-to-male transmission. rare diseases early in the disease course, when the medical and
• An affected male transmits the mutation to all his daughters. financial burdens to families are fairly minimal, and then proceed
with treatment.16 Increasingly, genomic diagnostic methods
are more comprehensive and support more facile diagnoses of
X-LINKED DOMINANT DISORDERS
genetic conditions.
Principles of X-Linked Dominant Inheritance
See Fig. 1.5D. CLINICAL APPROACH TO CONGENITAL ANOMALIES
AND THE DYSMORPHIC CHILD

• Males carrying the mutation are severely affected, often

leading to spontaneous pregnancy loss or neonatal death of Dysmorphology is the study of congenital anomalies and
affected males (see Fig. 1.5E). developmental disorders. The term is used to describe visible
• Female heterozygotes are affected but have less severe malformations or distinctive structural features of the face or
features than males. X-inactivation patterns determine the other parts of the body.
degree to which females express the disorder. A clinical geneticist is often consulted for one or more of the
• When a heterozygous affected female conceives, there are following reasons:

four genetic possibilities at conception, each equally likely: • to examine the patient, gather the clinical and familial
a normal daughter, an affected daughter, a normal son, and information, and plan the genetic tests to order and interpret
an affected son. to make a diagnosis;
• The pedigree shows no male-to-male transmission. • to interpret an existing genetic test result, particularly one
• When an affected male has a child, all of his daughters will that is not definitive;
inherit the mutation, and none of his sons will be affected • to discuss the genetic basis of the condition with the family;
(unless their mother is a carrier). • to recommend studies to evaluate for disease manifestations
• Males who are born with features of a severe and usually once a genetic diagnosis is made;
lethal XLD condition might have Klinefelter syndrome or an • to consult on the prognosis, management, and therapeutic
additional X chromosome disorder. options;
• Females with unusually severe features of an XLD disorder • to discuss the risk of recurrence and reproductive options;
may have this as a consequence of: • to coordinate prenatal/preimplantation genetic testing; and
• unfavorably X-inactivation, • to discuss genetic test results with other members of the
• Turner syndrome (45, X), or extended family and arrange for genetic testing for relatives.
• X-autosome translocation.
MITOCHONDRIAL DISORDERS PHYSICAL EXAMINATION, FAMILY HISTORY, AND

PEDIGREE INFORMATION
PRINCIPLES OF MITOCHONDRIAL INHERITANCE
See Fig. 1.5F A genetic consultation differs in the ability to examine the patient
in the prenatal versus neonatal timeframe. In this section, we will
• The condition can only be transmitted by females in the focus on how a clinical geneticist evaluates a child. Although
maternal line. the same strategy applies to the prenatal setting, there is less
• Males do not transmit mitochondrial inherited disorders, clinical data available in the prenatal setting because the physical
with extremely rare exceptions. examination is limited to ultrasound and magnetic resonance
• A mitochondrial inherited condition can affect either sex. images, and because blood samples cannot be readily obtained.
• If the mother is heteroplasmic for a mutation, the A genetic consultation includes a review of medical records;
proportion of mutant mtDNA in her offspring can vary interviews with the family to review prenatal exposures; a three-
considerably between offspring and between tissues in the generation family history, including ancestry and any history
same offspring. of consanguinity; and physical examination of the child and, in
some cases, the parents. The geneticist will develop a differential
MULTIFACTORIAL DISORDERS diagnosis and order appropriate genetic tests to evaluate the
If mutations in two different genes are necessary to cause a possible conditions. This usually requires a biologic sample from
phenotype, the inheritance is digenic. If a disease is the result the fetus/neonate and may require samples from the parents for
of contributions on a few genes, it is oligogenic. If a disease is comparison. The genetic testing may yield a definitive diagnosis
the result of the combination of many genes, it is polygenic. If a or, in some cases, will suggest a possible diagnosis for which the
disease is the result of the combination of many genes and the geneticist must reassess the patient and determine whether the
environment, it is multifactorial. diagnosis fits the phenotype. If the test does not yield a diagnosis,
continued follow-up is important because additional clinical indication for testing (incidental findings such as mutations for
features may become apparent over time and aid in making hereditary cancer or hereditary causes of sudden cardiac death).
the diagnosis; in addition, clinical diagnostic lab methods may When the laboratory systematically and intentionally looks for
continue to evolve and improve. variants in a prespecified set of genes unrelated to the primary
indication, these are termed secondary findings. The consent
DIAGNOSTIC METHODS IN CLINICAL GENETICS process is important to determine which findings the patient
There are many methods for clinical genetic testing, each of which would like to receive. Thus the generally accepted approach for
has been developed for particular clinical scenarios, including incidental findings is to examine the exome/genome data for
carrier screening, non-invasive prenatal testing, newborn pathogenic/likely pathogenic variants in 59 genes.20
screening, and diagnostic testing, with chromosome analyses to A summary comparing the different clinical genetic testing
detect copy number variants and cytogenetic rearrangement and methods is provided in Table 1.2.
sequence-based tests.17
Many types of chromosomal abnormalities have been NEED FOR VARIANT REINTERPRETATION OVER TIME
clinically and cytogenetically described and are diagnosed using A significant challenge associated with the clinical implementation
conventional karyotyping, FISH, and chromosomal microarray of next-generation sequencing for large panels and exomes/
(CMA). CMA is routinely performed as part of the comprehensive genomes is the large number of variants identified. Distinguishing
diagnostic testing for patients with unexplained developmental which of these variants is pathogenic is difficult since many of
delay/intellectual disability, autism spectrum disorders, or the variants identified are rare or novel and little is known about
multiple congenital anomalies.18 CMA is now routinely performed them. In addition, because not all disease genes have yet been
as oligoarrays, with single nucleotide polymorphism (SNP) identified, a diagnosis may be missed, despite comprehensive
probes to provide high resolution for copy number variants and exome/genome sequencing, because the condition has not yet
identify UPD and long stretches of homozygosity in families with been scientifically recognized. Re-evaluation of sequence data
consanguinity.19 over time may clarify the pathogenicity of variants and yield
Sanger sequencing was the primary genetic test for the additional diagnoses as scientific understanding of genetic variants
diagnosis for monogenic disorders due to sequence variants; and additional genetic conditions advances.Thus reanalyzing and
however, the decreased cost and increased throughput of reinterpreting clinical sequence data is inevitable. The ordering
massive parallel next-generation sequencing has significantly healthcare provider, clinical geneticist, clinical laboratory, and
increased the number of conditions that can simultaneously be patient/family each may have a role regarding reinterpretation
tested and can now include an entire genome. For conditions of genetic results.21,22 These expectations should be clearly
that are genetically heterogeneous, rather than selecting a outlined as part of the informed consent process.
single gene to test, it is now routine to test for a panel of genes
causing a particular phenotype/disease. In addition, whole
exome sequencing (WES), of all coding segments of almost all FUTURE DIRECTIONS IN CLINICAL
genes, and whole genome sequencing (WGS) are feasible and GENETICS
can even be performed within 1 to 2 weeks. As the number
of genes assessed increases, the number of genetic variants EARLIER DIAGNOSIS, INCREASINGLY PRENATAL
that could be pathogenic also increases. The laboratory may Making a genetic diagnosis earlier in life has a greater impact
issue a report with several variants in several genes as possible on medical care and may afford more effective treatment
diagnoses and then rely on the geneticist to further assess the opportunities and minimize harm by decreasing the number of
likelihood of the possibilities. Additionally, not all variants are unnecessary diagnostic procedures or ineffective interventions.
detectable by exome/genome sequencing. Triplet repeats and Rapid diagnosis in the neonatal or even prenatal period allows
somatic mutations can be particularly difficult or impossible providers and parents to make more informed decisions about
to detect based upon current sequencing methods and read care, obtain more accurate prognostic information, and draw
depth. upon experience with the genetic condition. Rapid diagnosis of
As the amount of genetic data generated increases with genetic acutely ill patients in neonatal intensive care unit is increasingly
testing, such as WES and WGS, there is a chance of identifying gene common and decreases costs and length of stay.23 One of the
variants of clinical relevance that were not related to the primary most common uses of NGS is non-invasive prenatal screening
Table 1.2 Comparison of Clinical Genetic Testing Methods.
Chromosome Sanger Sequencing Exome Genome

Karyotype SNP Microarray FISH Sequencing Panel Sequencing Sequencing
Single nucleotide X X X X
variations (SNVs)
Copy number X X +/− X
variations (CNVs)
Balanced X X +/−
chromosomal
rearrangement
Identification of new X X
disease genes
Incidental findings X X
Cost Low Low Low Modest Modest High High
FISH, Fluorescence in situ hybridization; SNP, single nucleotide polymorphism.
(NIPS) to noninvasively identify pregnancies with a high In Vivo Ex Vivo

likelihood of chromosomal aneuploidies using a maternal blood
sample and enriching for and analyzing fragmented fetal DNA
within the sample. With an amniocentesis or chorionic villus
sample, karyotype, chromosome microarray, single/panel gene
tests, WES, and WGS can be used to prenatally diagnose genetic Transplant into
diseases when there is an aberrant ultrasound finding or based original or other site
upon a family history of a genetic condition, carrier screening,
or NIPS result. Direct injection of
transducing vector
FUTURE OF NEWBORN SCREENING

Newborn screening (NBS) is carried out via various large public- Remove tissue
health genetic-screening programs. The scope of NBS programs has Culture and transduce
increased with advances in technology. Current NBS programs in cell in vitro
the United States consist of approximately 50 conditions and rely
heavily on tandem mass spectrometry to detect inborn errors of
metabolism. Molecular methods have been increasingly integrated
as second-tier tests for cystic fibrosis or as first-tier tests for
immunodeficiencies (TREC assay) and spinal muscular atrophy. In Fig. 1.6 Models for human gene therapy. In vivo gene therapy in-
the future, it is possible that NBS will be expanded even further to volves direct introduction of a transducing vector into the patient.
screen for classes of genetic disorders that can only be diagnosed Ex vivo gene therapy involves removal of tissue and transduction
with sequencing methods such as glucose transport (GLUT1) in vitro.
deficiency syndrome or retinoblastoma. Recent pilot studies of
sequencing-based methods are not as sensitive as biochemical
screening. Therefore, the utilization of sequence-based methods Table 1.3 Therapeutic Methods for Genetic
will first require greater accuracy in variant interpretation in these Diseases.
genes across diverse ethnicities to maximize clinical sensitivity.
Method Example
THERAPEUTIC APPROACHES FOR MONOGENIC Dietary for errors of PKU and some other inborn errors of
DISEASES metabolism metabolism
There is an increased demand for therapies of monogenic Enzyme replacement Pompe, CLN2, MPS I, MPS IVA, MPS
diseases with the improvement of diagnostic methods described therapy (ERT) VIA
in previous sections. Most of the inborn errors of metabolism Pharmacologic Pompe, Fabry, Gaucher
rely on dietary changes, enzyme replacement therapies (ERTs), or chaperone therapy
(PCT)
liver or bone marrow transplant. Transplantation also works for
Recombinant peptide Achondroplasia (Vosoritide [clinical
other genetic conditions beyond the inborn error of metabolism analog trial continue] is a C-type
(e.g., bone marrow transplant for hematologic conditions and natriuretic peptide analog that
immunodeficiencies). However, therapies are only available for a stimulates enchondral ossification
fraction of genetic diseases. and inhibits the FGFR3-mediated
Therapeutic options for monogenic diseases may significantly MAPK signaling pathway.)
expand in the next decade. Gene editing has advanced, Gene therapy Retinal dystrophy (RPE65, AAV vector),
specifically with the use of Crispr-Cas9 for gene editing. There SMA (Zolgensma, AAV vector)
is no safe and efficient, approved gene editing for humans yet, Gene editing Hemoglobinopathies, sickle cell, DMD,
immuno-oncology (all in clinical trials)
but it is an active area of research. Gene therapy trials began Antisense and SMA (Nusinersen), hATTR
in the 1990s but were limited by safety issues, including other therapeutic amyloidosis (Tegsedi), trinucleotide
immunologic responses to viral vectors and genomic integration oligonucleotides repeat disorders
activating proto-oncogenes, leading to fatal leukemias. With the Monoclonal X-linked hypophosphatemia (XLH)
advent of safer viral vectors without genomic integration and antibodies (Burosumab is a fully human
with trophism for a greater range of tissues, there have been monoclonal IgG1 antibody against
significant advances in gene therapy for monogenic diseases FGF23 protein.)
(Fig. 1.6). The European Medicines Agency (EMA) and the US
Food and Drug Administration (FDA) have approved six gene
therapy products since 2016,24 including gene therapy for
spinal muscular atrophy, a common genetic cause of death in
infants. In addition to gene replacement or gene addition, there conditions, and early organ failure. We are entering the next
are improving technologies for somatic gene editing. Numerous exciting era, going beyond the diagnosis, toward the treatment
gene-therapy clinical trials for monogenic diseases, including of genetic diseases. We need to continue to understand the
particularly hematologic, immunologic, and hepatic diseases, are basic mechanisms of human genes to develop rational treatment
ongoing (Table 1.3). Longer-term outcome studies of safety and strategies. Moreover, transformational platforms to deliver or
durability are still needed, but gene therapy is likely to play a alter genes may enable the treatment of whole classes of genetic
greater role in treatment in the future. diseases and offer new treatment opportunities to patients.
SUGGESTED READINGS
CONCLUSION Nussbaum R, McInnes R, Willard H. Thompson & Thompson Genetics In Medicine.
8th ed. Elsevier; 2016.
The Human Genome Project has had a significant impact on Turnpenny P, Ellard S. Emery’s Elements of Medical Genetics. 15th ed.
Elsevier; 2017.
medicine and especially neonatology. We routinely use genomic Jorde L, Carey J, Bamshad M. Medical Genetics. 6th ed. Elsevier; 2019.
methods and data to diagnose genetic diseases in newborns, Firth H, Hurst J. Oxford Desk Reference Clinical Genetics and Genomics. 2nd ed.
especially those associated with congenital anomalies, neurologic Oxford University Press; 2017.
CHAPTER 2 — Epigenetics 11
REFERENCES 14. European Organisation for Rare Diseases. Rare diseases: understanding this pub-
lic health priority. Eurordis. 2005.
1. Venter JC, Adams MD, Myers EW, et al.The sequence of the human genome. Sci- 15. Wright CF, FitzPatrick DR, Firth HV. Paediatric genomics: diagnosing rare dis-
ence. 2001;291(5507):1304–1351. https://doi.org/10.1126/science.1058040. ease in children. Nat Rev Genet. 2018;19(5):253–268. https://doi.org/10.1038/
2. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human nrg.2017.116.
genome. Nature. 2001;409(6822):860–921. https://doi.org/10.1038/35057062. 16. Boycott KM, Rath A, Chong JX, et al. International cooperation to enable the
3. Watson JD, Crick FH. Molecular structure of nucleic acids; a structure for deoxy- diagnosis of all rare genetic diseases. Am J Hum Genet. 2017;100(5):695–705.
ribose nucleic acid. Nature. 1953;171(4356):737–738. https://doi.org/10.1016/j.ajhg.2017.04.003.
4. Tukiainen T, Villani AC, Yen A, et al. Landscape of X chromosome inactiva- 17. Katsanis SH, Katsanis N. Molecular genetic testing and the future of clini-
tion across human tissues. Nature. 2017;550(7675):244–248. https://doi. cal genomics. Genomic Precis Med Found Transl Implement Third Ed.
org/10.1038/nature24265. 2016;14(6):263–282. https://doi.org/10.1016/B978-0-12-800681-8.00018-9.
5. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in 18. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal micro-
the human genome. Nature. 2012;489(7414):57–74. https://doi.org/10.1038/ array is a first-tier clinical diagnostic test for individuals with developmental
nature11247. disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749–764.
6. Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. https://doi.org/10.1016/j.ajhg.2010.04.006.
Cell. 2009;136(4):642–655. https://doi.org/10.1016/j.cell.2009.01.035. 19. Harel T, Lupski JR. Genomic disorders 20 years on-mechanisms for clinical mani-
7. Kalousek DK, Vekemans M. Confined placental mosaicism. J Med Genet. festations. Clin Genet. 2018;93(3):439–449. https://doi.org/10.1111/cge.13146.
1996;33(7):529–533. 20. Kalia SS, Adelman K, Bale SJ, et al. Recommendations for reporting of second-
8. Soukarieh O, Gaildrat P, Hamieh M, et al. Exonic splicing mutations are ary findings in clinical exome and genome sequencing, 2016 update (ACMG
more prevalent than currently estimated and can be predicted by using in SF v2.0): a policy statement of the American College of Medical Genetics
silico tools. PLoS Genet. 2016;12(1):1–26. https://doi.org/10.1371/journal. and Genomics. Genet Med. 2017;19(2):249–255. https://doi.org/10.1038/
pgen.1005756. gim.2016.190.
9. Centers for Mendelian Genomics. Mendelian traits by the numbers. 21. David KL, Best RG, Brenman LM, et al. Patient re-contact after revision of
http://mendelian.org/mendelian-traits-numbers. Accessed September 18, 2020. genomic test results: points to consider—a statement of the American College
10. Amberger JS, Bocchini CA, Scott AF, Hamosh A. OMIM.org: leveraging knowledge of Medical Genetics and Genomics (ACMG). Genet Med. 2018;0(0):1–3. https://
across phenotype-gene relationships. Nucleic Acids Res. 2019;47(D1):D1038– doi.org/10.1038/s41436-018-0391-z.
D1043. https://doi.org/10.1093/nar/gky1151. 22. Bombard Y, Brothers KB, Fitzgerald-Butt S, et al. The responsibility to recontact
11. Alkan C, Coe BP, Eichler EE. Genome structural variation discovery and genotyp- research participants after reinterpretation of genetic and genomic research
ing. Nat Rev Genet. 2011;12(5):363–376. https://doi.org/10.1038/nrg2958. results. Am J Hum Genet. 2019;104(4):578–595. https://doi.org/10.1016/j.
12. Hsu L. Prenatal Diagnosis of Chromosomal Abnormalities Through Amnio- ajhg.2019.02.025.
centesis in Genetic Disorders and the Fetus. 3rd ed. Baltimore: Johns Hopkins 23. Farnaes L, Hildreth A, Sweeney NM, et al. Rapid whole-genome sequencing
University Press; 1992. decreases infant morbidity and cost of hospitalization. Npj Genomic Med.
13. Lupski JR. 2018 Victor A. McKusick Leadership Award: Molecular Mecha- 2018;3(1). https://doi.org/10.1038/s41525-018-0049-4.
nisms for Genomic and Chromosomal Rearrangements. Am J Hum Genet. 24. High KA, Roncarolo MG. Gene therapy. N Engl J Med. 2019;381(5):455–464.
2019;104(3):391–406. https://doi.org/10.1016/j.ajhg.2018.12.018. https://doi.org/10.1056/NEJMra1706910.
Epigenetics 2
William Schierding | Mark H. Vickers | Justin M. O’Sullivan | Wayne S. Cutfield
PRINCIPLES OF EPIGENETICS can lead to up- or down-regulation of gene activity.This definition

leaves out the concept of inheritance, instead emphasizing the
INTRODUCTION TO EPIGENETICS effect on the final cell type and how small nongenetic changes
The publication of the majority of the human genome sequence in development can lead to measurable differences in adult
in 20011,2 was the precursor to many important discoveries. phenotype. Recently, epigenetics has been redefined, first by Riggs
However, the human genome sequence has not provided as “the study of mitotically and/or mitotically heritable changes
researchers with the codex to fully understand the genome’s in gene function that cannot be explained by changes in DNA
functionality or to predict its response to environmental cues sequence”7 and more recently by Cavalli and Heard as “the study
(such as nutritional challenges). One reason why this is the case is of molecules and mechanisms that can perpetuate alternative
that the human genome is more complicated than was originally gene activity states in the context of the same DNA sequence.”8
postulated. Counterintuitively, this complexity partially arises Therefore, epigenetics is any element with permanent (or at
from the finding that the human genome only has approximately least semi-permanent) changes in gene expression or cellular
one third of the predicted number of genes.3 Fewer genes phenotype.9 This encompasses transgenerational inheritance
means that those genes that are present are more complex, and the persistence of gene activity or chromatin states
producing multiple different messenger RNAs. As a result, the through extended periods of time. Throughout this chapter we
regulatory processes that control the expression of these genes will discuss epigenetics in the context of this more modern
are complex,4,5 involving multiple layers of regulation, much of definition, but it should be noted that epigenetics is a term that
which still remains to be discovered and described. has many different definitions, with “mitotically stable” and
Traditionally, it had been assumed that inherited genes control “epigenetic memory” being points of controversy.
gene expression and, ultimately, phenotype. In the early 1940s
Waddington introduced the concept of epigenetics (“on to top FROM GENETICS TO EPIGENETICS
of” or “in addition to” genes) to describe the way in which genes Double-stranded DNA is an efficient and reliable mechanism to
interact with their surroundings to produce a phenotype during pass information from one generation to another, given that it is
the differentiation of cells over the course of development stable and there are a number of repair systems that have evolved
(without a change in gene sequence).6 Thus, environmental cues to maintain it. Thus, genetic changes tend to occur slowly, taking
REFERENCES 14. European Organisation for Rare Diseases. Rare diseases: understanding this pub-
lic health priority. Eurordis. 2005.
1. Venter JC, Adams MD, Myers EW, et al.The sequence of the human genome. Sci- 15. Wright CF, FitzPatrick DR, Firth HV. Paediatric genomics: diagnosing rare dis-
ence. 2001;291(5507):1304–1351. https://doi.org/10.1126/science.1058040. ease in children. Nat Rev Genet. 2018;19(5):253–268. https://doi.org/10.1038/
2. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human nrg.2017.116.
genome. Nature. 2001;409(6822):860–921. https://doi.org/10.1038/35057062. 16. Boycott KM, Rath A, Chong JX, et al. International cooperation to enable the
3. Watson JD, Crick FH. Molecular structure of nucleic acids; a structure for deoxy- diagnosis of all rare genetic diseases. Am J Hum Genet. 2017;100(5):695–705.
ribose nucleic acid. Nature. 1953;171(4356):737–738. https://doi.org/10.1016/j.ajhg.2017.04.003.
4. Tukiainen T, Villani AC, Yen A, et al. Landscape of X chromosome inactiva- 17. Katsanis SH, Katsanis N. Molecular genetic testing and the future of clini-
tion across human tissues. Nature. 2017;550(7675):244–248. https://doi. cal genomics. Genomic Precis Med Found Transl Implement Third Ed.
org/10.1038/nature24265. 2016;14(6):263–282. https://doi.org/10.1016/B978-0-12-800681-8.00018-9.
5. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in 18. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal micro-
the human genome. Nature. 2012;489(7414):57–74. https://doi.org/10.1038/ array is a first-tier clinical diagnostic test for individuals with developmental
nature11247. disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749–764.
6. Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. https://doi.org/10.1016/j.ajhg.2010.04.006.
Cell. 2009;136(4):642–655. https://doi.org/10.1016/j.cell.2009.01.035. 19. Harel T, Lupski JR. Genomic disorders 20 years on-mechanisms for clinical mani-
7. Kalousek DK, Vekemans M. Confined placental mosaicism. J Med Genet. festations. Clin Genet. 2018;93(3):439–449. https://doi.org/10.1111/cge.13146.
1996;33(7):529–533. 20. Kalia SS, Adelman K, Bale SJ, et al. Recommendations for reporting of second-
8. Soukarieh O, Gaildrat P, Hamieh M, et al. Exonic splicing mutations are ary findings in clinical exome and genome sequencing, 2016 update (ACMG
more prevalent than currently estimated and can be predicted by using in SF v2.0): a policy statement of the American College of Medical Genetics
silico tools. PLoS Genet. 2016;12(1):1–26. https://doi.org/10.1371/journal. and Genomics. Genet Med. 2017;19(2):249–255. https://doi.org/10.1038/
pgen.1005756. gim.2016.190.
9. Centers for Mendelian Genomics. Mendelian traits by the numbers. 21. David KL, Best RG, Brenman LM, et al. Patient re-contact after revision of
http://mendelian.org/mendelian-traits-numbers. Accessed September 18, 2020. genomic test results: points to consider—a statement of the American College
10. Amberger JS, Bocchini CA, Scott AF, Hamosh A. OMIM.org: leveraging knowledge of Medical Genetics and Genomics (ACMG). Genet Med. 2018;0(0):1–3. https://
across phenotype-gene relationships. Nucleic Acids Res. 2019;47(D1):D1038– doi.org/10.1038/s41436-018-0391-z.
D1043. https://doi.org/10.1093/nar/gky1151. 22. Bombard Y, Brothers KB, Fitzgerald-Butt S, et al. The responsibility to recontact
11. Alkan C, Coe BP, Eichler EE. Genome structural variation discovery and genotyp- research participants after reinterpretation of genetic and genomic research
ing. Nat Rev Genet. 2011;12(5):363–376. https://doi.org/10.1038/nrg2958. results. Am J Hum Genet. 2019;104(4):578–595. https://doi.org/10.1016/j.
12. Hsu L. Prenatal Diagnosis of Chromosomal Abnormalities Through Amnio- ajhg.2019.02.025.
centesis in Genetic Disorders and the Fetus. 3rd ed. Baltimore: Johns Hopkins 23. Farnaes L, Hildreth A, Sweeney NM, et al. Rapid whole-genome sequencing
University Press; 1992. decreases infant morbidity and cost of hospitalization. Npj Genomic Med.
13. Lupski JR. 2018 Victor A. McKusick Leadership Award: Molecular Mecha- 2018;3(1). https://doi.org/10.1038/s41525-018-0049-4.
nisms for Genomic and Chromosomal Rearrangements. Am J Hum Genet. 24. High KA, Roncarolo MG. Gene therapy. N Engl J Med. 2019;381(5):455–464.
2019;104(3):391–406. https://doi.org/10.1016/j.ajhg.2018.12.018. https://doi.org/10.1056/NEJMra1706910.
Epigenetics 2
William Schierding | Mark H. Vickers | Justin M. O’Sullivan | Wayne S. Cutfield
PRINCIPLES OF EPIGENETICS can lead to up- or down-regulation of gene activity.This definition

leaves out the concept of inheritance, instead emphasizing the
INTRODUCTION TO EPIGENETICS effect on the final cell type and how small nongenetic changes
The publication of the majority of the human genome sequence in development can lead to measurable differences in adult
in 20011,2 was the precursor to many important discoveries. phenotype. Recently, epigenetics has been redefined, first by Riggs
However, the human genome sequence has not provided as “the study of mitotically and/or mitotically heritable changes
researchers with the codex to fully understand the genome’s in gene function that cannot be explained by changes in DNA
functionality or to predict its response to environmental cues sequence”7 and more recently by Cavalli and Heard as “the study
(such as nutritional challenges). One reason why this is the case is of molecules and mechanisms that can perpetuate alternative
that the human genome is more complicated than was originally gene activity states in the context of the same DNA sequence.”8
postulated. Counterintuitively, this complexity partially arises Therefore, epigenetics is any element with permanent (or at
from the finding that the human genome only has approximately least semi-permanent) changes in gene expression or cellular
one third of the predicted number of genes.3 Fewer genes phenotype.9 This encompasses transgenerational inheritance
means that those genes that are present are more complex, and the persistence of gene activity or chromatin states
producing multiple different messenger RNAs. As a result, the through extended periods of time. Throughout this chapter we
regulatory processes that control the expression of these genes will discuss epigenetics in the context of this more modern
are complex,4,5 involving multiple layers of regulation, much of definition, but it should be noted that epigenetics is a term that
which still remains to be discovered and described. has many different definitions, with “mitotically stable” and
Traditionally, it had been assumed that inherited genes control “epigenetic memory” being points of controversy.
gene expression and, ultimately, phenotype. In the early 1940s
Waddington introduced the concept of epigenetics (“on to top FROM GENETICS TO EPIGENETICS
of” or “in addition to” genes) to describe the way in which genes Double-stranded DNA is an efficient and reliable mechanism to
interact with their surroundings to produce a phenotype during pass information from one generation to another, given that it is
the differentiation of cells over the course of development stable and there are a number of repair systems that have evolved
(without a change in gene sequence).6 Thus, environmental cues to maintain it. Thus, genetic changes tend to occur slowly, taking
Box 2.1 Nature Versus Nurture, Genes

Wheels Cars
Versus the Environment
There has been a longstanding debate as to whether health Wheels Cars (2) Wheels Cars
is determined by “nature” or “nurture.”20-22 It is clear that
phenotypic traits exist on a continuum, where some are Wheels Cars
predominantly controlled by genetics (e.g., height) and oth- (1) (3)
ers by environmental factors (e.g., obesity). However, the
influence of genes and environment in the development of Fig. 2.1 Epigenetic machinery. The following analogy can be used to
phenotypic traits is not mutually exclusive, but rather is a illustrate this point. Security guards can use keys to lock and unlock
result of their constant interaction. For example, twin stud- doors according to instructions they are receiving from another source.
ies suggest that genetic factors have a substantial effect (1 and 3) At the beginning and end of each working day, the guards go
on variations in body weight, particularly in children and through their routine of unlocking or locking doors. (2) By locking and
adolescents. Nonetheless, the fact that obesity is rapidly unlocking doors in a factory, the guards are not changing the structure
increasing worldwide shows that environment also plays a of the factory, but rather this system is akin to epigenetic modifications
significant role in the likelihood of becoming obese. Thus that limit the workers’ (i.e., the transcription factors, DNA binding pro-
in most cases the resulting manifestation of non-commu- teins, and RNA polymerases) access to the equipment and informa-
nicable disease is a combination of nature and nurture. tion within the factory. If there is an error in the unlocking routine for
Importantly, this interaction between the environment and example, part of the factory would remain off-limits to the workers for
genetic inheritance is mediated through epigenetics. one cycle of 12 hours. Thus, if the factory is a car assembly line and
the section where the wheels are stored (i.e., the gene) remains locked,
then no workers are able to access this area and the final product (i.e.,
many generations for a single mutation to become dominant in a the phenotype) is cars without wheels. (3) However, when the correct
population. By contrast, epigenetic changes can occur in a more set of keys has opened the correct factory doors, the cars and wheels
rapid timeframe.This means that epigenetics provides a mechanism will both be accessible, and the cars will be made.
for rapid responses to environmental changes. Consistent with
this, studies have shown that de novo epigenetic “mutation” is
one to two orders of magnitude more frequent than de novo THE STRUCTURE OF THE (EPI)GENOME
somatic DNA mutation.10 This difference in “mutation rates” is Eukaryotes use multiple systems to initiate and regulate changes
due to a reduction in the fidelity of maintenance of epigenetic in gene expression. In total, genes are regulated by hundreds
features, when compared to genetic features, throughout the cell of functional DNA elements, controlling when and how much
cycle.11 For example, the genetic code is copied (replicated) with protein is produced. This regulatory control occurs through
an error rate of less than 1 base in 107 to 108 bases copied.12 mechanisms that utilize epigenetic signals to affect nuclear
By contrast, epigenetic mechanisms, such as methylation, have an (e.g., transcription and mRNA processing) and cytoplasmic
error rate that has been estimated to be between 1% and 4%.4,11,13 (e.g., translation) processes (Fig. 2.1). These mechanisms include
Developmental plasticity is a genotype’s or individual’s ability DNA methylation (with or without ubiquitination),23 histone
to respond to changes in environmental conditions through modifications (i.e., acetylation, phosphorylation, sumoylation,
changes in its phenotypes. All developmental plasticity is, by methylation),24 chromatin folding,25-30 non-coding RNA (ncRNA
definition, epigenetic in origin, as the genotype of the responding and miRNA),31,32 and prions.33 Epigenetic effects on transcription
individual remains unaltered in the process. The plasticity of are well documented and will therefore form the main focus
the epigenome is important for its contribution to the dynamic of the remainder of this chapter.34-36 A summary of how these
coordination of the genome’s responses to environmental signals. various epigenetic processes are analyzed is shown in Table 2.1.
However, changing to suit the present environment can result It should be noted that epigenetic effects such as DNA
in a suboptimal phenotype for tomorrow’s environment (the methylation do not turn a gene on or off permanently. Rather,
mismatch hypothesis).14 In developmental terms, the epigenome most epigenetic mechanisms lead to semi-permanent changes.
can change to enhance fitness in response to an environmental As such, epigenetic modifications need to be continually
cue (e.g., reduced placental nutrient supply) during a small maintained by the recruitment of the required enzymes and
window in early development. Subsequent changes to the proteins to accurately replenish the epigenetic marks, and
environmental conditions (e.g., overabundance of high-energy thus contribute to the maintenance of the appropriate state of
food) mean that the epigenetic changes, which have been stably transcription.9 Epigenetic modifications only “contribute to the
maintained through the remainder of development, may become maintenance of the correct state of transcription”; other factors
detrimental over the course of the individual’s lifespan by (e.g., DNA-binding proteins and RNA polymerases) are ultimately
increasing the risk for metabolic and cardiovascular diseases.15 responsible for reading and transcribing the gene.
HOW GENES LEARN FROM EXPERIENCE DNA METHYLATION

Twin studies exemplify the epigenetic changes that occur during a DNA methylation is a fundamental and evolutionarily conserved
lifetime of interactions between the environment and the genome epigenetic modification involved in gene regulation and
(reviewed in Bell and Spector16). In simple terms, genetically other biologic processes (e.g., see He and colleagues37). In
identical monozygotic twins are epigenetically indistinguishable mammals, DNA methylation is restricted to sites where a
when they are born.17 However, as they age, the twins begin to cytosine nucleotide is followed by a guanine nucleotide (CpG,
display differences in the overall phenotype, due to their cumulative Fig. 2.2). In most mammalian species, 90% to 98% of CpG sites
individual exposure to environmental signals.17 As previously are methylated,24 and the methylation status and density of CpG
mentioned, it is through the epigenetic changes that each individual sites is associated with gene regulation.38 Therefore, measuring
modifies their phenotype to better suit the environment they the methylation status of particular genes within a cell type can
have experienced. Collectively, these changes alter the individual provide researchers with information as to which RNA species
twin’s risk factors for obesity and a number of non-communicable are likely to be transcribed, albeit there are exceptions to this
diseases such as type 2 diabetes mellitus (Box 2.1).18,19 rule (as will be discussed later.)
Table 2.1 Measuring Epigenetic Profiles.
Single Locus Analysis Global (Whole Genome) Analysis

Epigenetic Process Function Platform Cost Time Platform Cost Time
DNA Methylation Repress gene Bisulfite conversion Low Low Bisulfite conversion High High
activity followed by various followed by various
targeted sequencing whole-genome
opt ions sequencing opt ions
DNMT1a. Methylation
DNMTlb maintenance
(across cell
divisions)
DNMT3a. De novo DNA
DNMT3b methylation
Historic Chromatin Low Low Chromatin High High
modifications immunoprecipitation immunoprecipitation
followed by qPCR followed by
Next Generation
Sequencing (ChIP-
seq) or hybridization
to a microarray (ChIP-
chip)
Post- Repress gene qRT-PCR, Targeted Low Low Microarray or Next High High
transcriptional activity Sequencing, or Generation
Regulators Microarray Sequencing (RNAseq)
(miRNA,
ncRNA)
Chromatin 10,000× Chromatin Medium Medium Global chromatin Very High
Structure and Companion, conformation conformation capture high
Function (3D DNA activity capture (3C, 4C, or (5C or Hi-C), FISH,
Genome) regulation GCC) and FISH and ChIA-PET.
Various techniques are used to characterize epigenetic modifications. The use of antibody precipitation to isolate pieces of DNA that are methylated or
unmethylated, or are associated with modified histones is central to many of the techniques that are used to study epigenetic modifications on the local and
global scale (e.g., chromatin immunoprecipitation, ChIP-chip ChIP-seq; ChIA-PET; MeDIP).171 Modifications of methylation of cytosine in CpGs are also studied
using bisulfite conversion, which changes the 5me-C residue to a uracil.172 Finally, chromatin organization (which DNA sequences are nearby or contacting each
other within the nucleus) and the effects of epigenetic modifications on this is determined by methods that range from FISH methodologies methodologies,173,174
differential centrifugation,175 or chromosome conformation capture based technologies (e.g., 3C 3C,176 4C,177 GCC,178 or 5C179).
Gene activation is typically associated with tracts of largely two copies of the core histones H2A, H2B, H3, and H4 (see
unmethylated CpG, known as CpG islands. The majority (60%) Fig. 2.2).44 Nucleosomes are separated by exposed linker DNA
of these CpG islands occur in or near gene promoters.36,38 that is typically 20 to 50 base pairs in length.45 Only about 75% to
Methylation (a mark of down-regulation) inside or within ∼2 90% of DNA in eukaryotes is bound within a nucleosome at any
kb of these CpG islands39 contributes to the control of gene time in the cell cycle.46
expression.24 DNA methylation status is mostly controlled Nucleosomes are the targets of a wide range of post-
by the family of genes known as DNA methyltransferases translational modifications (e.g., acetylation, phosphorylation,
(DNMT). Briefly, DNMT1 controls maintenance of methylation sumoylation, and methylation) that combine to form an
(transmission from mother to daughter cells).40 DNMT 3a and epigenetic (histone) code.47 Each of the core histones (H3 and
3b are responsible for de novo methylation (establishment H4) features a long amino acid “tail,” where posttranslational
of methylation without a template or changes in methylation modifications may occur to affect gene expression. Enzymes
state),41,42 while DNMT3L is largely involved in the methylation deposit (“write”) or remove (“erase”) these histone marks of
of maternally imprinted genes (see later) during oogenesis.43 phosphorylation, acetylation, and methylation. Proteins that bind
Placental growth and development are regulated in part to modified histones (“readers”) are part of larger, multisubunit
by epigenetic mechanisms such as DNA methylation. During protein complexes that exert downstream functions (note: these
gestation, embryonic development is associated with the complexes often recognize combinations of different histone
establishment of distinct DNA methylation differences between marks simultaneously).
the trophectoderm and inner cell mass. The trophectoderm Post-translational modifications of the histone tails, or to
(ultimately placenta) becomes significantly less methylated than the central histone structure itself,34 can (1) directly affect
the inner cell mass (ultimately embryo/somatic tissues). Overall, the compaction and assembly of the chromatin by regulating
whole-term placental lysates have 14% to 25% less global DNA the interaction between the DNA and each histone within the
methylation when compared to somatic tissues. nucleosome or the between nucleosomes themselves46; or (2)
For a more exhaustive review on epigenetic marks in serve as binding sites for recruitment of other proteins that
development, see the review by Ficz and colleagues.36 themselves contribute to the regulation of transcription and
other nuclear functions.35 These modifications of the histone
HISTONE MODIFICATIONS residues (“marks”) have been correlated with various important
The most basic unit of chromatin structure is the nucleosome, genetic elements in the regulation of gene expression. Promoters
which consists of approximately 147 base pairs of DNA wrapped of transcriptionally active genes are associated with enriched
1.67 times around a barrel-shaped histone octamer containing trimethylation on histone H3 lysine 4 (H3K4me3), and lysine
Me
C
G
G DNA methylation
C • Methyl marks repress gene activity (usually at a
cytosine residue)
Me Histone modification
Me • Different chemical groups in combination bind to
the tails of the histones and alter DNA activity
• There are more than 200 post-translational
C
modifications
G
Nucleosome 3D structure
Histone • DNA is tightly compacted around histones into chromatin
Histone tails • Chromatin can be in an open (active) or closed (inactive)
conformation
• Chromatin packaging necessitates between- and within-
Open Closed chromosome contacts that are dynamic and non-random
chromatin chromatin • Connections work to repress or activate certain regions
of the genome
Chromosome
Fig. 2.2 Fundamentals of epigenetics.
acetylation (H3K9ac, H3K27ac). For example, an enhancer is a CHROMATIN FOLDING AND 3D STRUCTURE
genomic switch that, when activated (“turned on”), increases the A non-linear consideration of DNA is important to understand
likelihood of transcription of a particular gene. These enhancer the establishment and maintenance of enhancer-promoter
elements are defined by having both H3K27ac and H3K4me1. interactions in space and time. Nucleosomes are the lowest form
Repressed genes have a higher density of nucleosomes of structural scaffolds for DNA, which, when packaged with
(i.e., heterochromatin) and are usually marked by H3K9me, other proteins and RNA components, form compacted chromatin
H3K27me3, and H4K20me3.48 structures. The compaction levels for chromatin are not fixed
Polycomb complexes remodel chromatin to maintain but vary as the cell moves through the cell cycle. This ultimately
developmentally or environmentally programmed expression results in the structures we recognize as chromosomes, in which
states. DNA-binding proteins (or noncoding RNAs) recruit the DNA has been compacted up to 10,000-fold (see Fig. 2.2).46
polycomb-group proteins to specific regions of the genome for The dynamic process of changing the compaction level of the
epigenetic silencing of genes.For Polycomb Repressive Complex 2, DNA within a nucleus is an important component of the regulation
histone methyltransferase enzyme EZH2 regulates trimethylation of genes.52,53 At a gross level, chromatin compaction is thought
of lysine 27 on histone H3 (H3K27me2/3). Processes affected by to contribute to the two dominant types of chromatin within
polycomb complexes include X-chromosome inactivation and eukaryotic cells: (1) heterochromatin, the tightly compacted
Hox gene silencing, through modulation of chromatin structure form of chromatin that is largely transcriptionally silent; and (2)
during embryonic development.49 euchromatin, the less condensed, more transcriptionally active
According to the modern definition of epigenetics, epigenetic form of chromatin.46 However, closer inspection using new
changes must be mitotically stable. This leads to considerable molecular techniques reveals that DNA packaging also creates
controversy over the underlying changes that must be present local chromatin structures that contribute to the establishment
and as to how expression levels of consistently activated genes are of cell-type identity and lineage specificity.46,54 Briefly, each
maintained when the original activation signal has passed.46 Some chromosome folds up into a structure that promotes physical
histone modifications (e.g., H3K36 methylation) have not been connections between regulatory elements that would be
shown to be “mitotically stable” across several generations, while otherwise separated by long distances in the DNA sequence.55-60
methylation marks located on H3K4, H3K9, and H3K27 have been The organized three-dimensional (3D) chromatin structure
shown to be mitotically transmissible.50Also,some epigenetic changes within the nucleus (i.e., functional framework between
are only a transient phenomenon, such as the phosphorylation of regulatory elements and distant genes) gets substantially
a variant of histone H2A (i.e., H2AX) during DNA double-strand reorganized in disease (Fig. 2.3). This restructuring induces an
breaks.51 On many levels, this would classify as an epigenetic mark, aberrant exposure of gene promoters to inappropriate regulatory
but it disappears once the break is repaired. Thus, these types of elements, resulting in enhanced pro-disease (e.g., oncogenes)
marks will never be classified as stably inherited effects and cannot or silenced anti-disease genes (e.g., tumor suppressors). In
meet the modern definition of being epigenetic. Therefore, while development, Rubinstein syndrome and brachydactyly–mental
they are generally called epigenetic, not all methylation and histone retardation are both linked to defects in the management of
modifications are epigenetic in the modern definition.9 the local chromatin state. In Rubinstein-Taybi syndrome, defects
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Title: Bang vir die lewe
Author: Henry Bordeaux
Translator: Jan F. E. Celliers
Release date: December 6, 2023 [eBook #72345]
Language: Afrikaans
Original publication: Cape Town: Nasionale Pers Bpk, 1925
Credits: Kobus Meyer, Emmanuel Ackerman and the Online

Distributed Proofreading Team at https://www.pgdp.net
*** START OF THE PROJECT GUTENBERG EBOOK BANG VIR

DIE LEWE ***
Bang vir die Lewe
Bang vir die Lewe
Uit die oorspronklike Frans van Henri Bordeaux

ná die 137e Franse uitgaaf vir Suid-Afrika
vertaal en bewerk
deur
JAN F. E. CELLIERS
(Derde Druk.)
Die Nasionale Pers, Beperk, Drukkers en Uitgewers, Kaapstad,
Stellenbosch, Bloemfontein en Pietermaritzburg.
1925.
VOORWOORD AAN DIE LESER.
Hierdie verhaal het, as vervolgstorie, in „Die Brandwag” verskyn,
van die allereerste nommer af.
Baie boeke van die buiteland, en veral romans, behandel
toestande, persone en insigte wat vir die gewone Afrikaanse leser
vreemd en dus onverstaanbaar en ongenietbaar is. Dit kan van
hierdie boek nie gesê word nie: wat hier aan ons vertoon word, is
algemeen-menslik—sulke persone en hartstogte en gevoelens en
kontraste tref ons by ons net so aan.
Sonder dat die outeur as sedemeester optree, gaan daar ’n sterk
morele invloed van sy boek uit, deurdat hy ons op meesterlike wyse
die teëstelling laat sien tussen swakkelinge—ryk en bedorwe
sywurms wat bang is vir die lewe en stryd en strewe daarvan—en ’n
famielie van staatmakers wat sout en krag in hulself het.
Die sentrale figuur is ongetwyfeld die brawe ou moeder Kibert—vir
haar vergeet ons nooit weer nie as ons die verhaal gelees het. En
ons dink daarby aan die talryke Afrikaanse moeders en dogters wat
agtien jaar gelede op so treffende wyse aan die wêreld getoon het
hoe min hulle vir die lewe bang was—en vir die dood. Hulle rus daar
op ons velde vandag, dog die dag sal kom dat Afrikaanse skrywers
ook uit hul lewe stof sal haal vir roerende en opbouende verhale.
Dog die gewone lewe lewer daartoe al stof genoeg op; hierdie
skrywer—soos elke goeie skrywer—maak die gewone vir ons
interessant en het geen kunsies, soos intrigue en sulke goed, nodig
nie.
Hierdie verhaal is goed inmekaargesit. Die skrywer gee nie
onnodige praatjies en beskrywinge nie; ook sy natuurbeskrywinge is
net van pas op die toestande wat voorgestel word en nie
plesiertuintjies waar die outeur in verdwaal en die verband van sy
storie versteur nie.
Die Vertaler.
INHOUD.
Hoofstuk. Bls.
Deel I.
I. Terugkoms van Marcel Kibert 1
II. Broer en Suster 17
III. Die Blommefees 31
IV. ’n Agtermiddag op Chenée 39
V. Die Geheim van Alida 55
VI. Meneer en Mevrou Delourens 70
VII. Die Huweliksaanvraag 86
VIII. Planne 101
IX. Afskeid 113
X. Vertrek 121
Deel II.
I. Dertien aan Tafel 130
II. Die Boodskap van die Veldwagter 148
III. Haar Laaste Kind 154
IV. Roubeklag 162
V. Jan 173
VI. Isabella 187
VII. Die Geheim van Paula 201
VIII. Mevrou Kibert 214
IX. Haar Laaste Kind 223
X. Kalme Berusting 233
Bang vir die Lewe.
Uit die oorspronklike Frans van Henri Bordeaux na die 137e Franse
uitgaaf vir Suid-Afrika vertaal en bewerk deur Jan F. E. Celliers.
I.
TERUGKOMS VAN MARCEL KIBERT.[1]
Klaar om te vertrek, in haar een hand haar sambreel, alhoewel dit

mooi weer is, terwyl die ander die swart kripsluier wegskuiwe wat
van haar hoedjie afhang oor haar gesig, staan mevrou Kibert te wag
in haar voorkamer op Maupas, moeite doende om geduldig te bly.
En nadat sy al verskeie kere na die horlosie gekyk het, staan sy op
en loop met langsaam, swak stappies deur die kamer; dan gaan sy
meteens weer sit, nie op een van die lekker sagte leuningstoele nie,
dog op ’n rottingstoel, waarvan sy gou kan opstaan sonder alte veel
moeite. Mevrou Kibert is al taamlik oud, kort en dik, en haal
langsaam asem. Haar gelaat vertoon sagtheid sowel as beslistheid.
Haar oë is helder-blou, en sy kyk daar so teer en droefgeestig uit,
dat dit lyk of daar trane in is—getuiende van ’n skroomvallige en
liefhebbende geaardheid, wat maklik skrik aan te ja is deur omgang
met die wêreld; maar haar vierkantige ken en haar gesette, stewige
postuur, gee weer ’n indruk van geeskrag en weerbaarheid. Haar
wange het, ondanks haar jare, nog fris gebly, duidende op edel
bloed en goeie gesondheid.
Na ’n bietjie aarseling, besluit sy om ’n deur oop te maak en te
roep:
—Paula, kom jy nou? Dis tyd om te gaan.
’n Helder en suiwer stem gee antwoord:
—Ag, ma, ons het nog baie tyd.
—Dis al sewenuur op die horlosie, sê die ou vrou, maar sonder
haarself op te win.
—Ma weet dat die horlosie drie-kwartier voor is.
—Ja, maar hy kan miskien meteens agtergebly het, hy is so vol
nukke.
Die jongmeisie antwoord met ’n skaterlag, maar uitlag is dit darem
glad nie. Spoedig laat sy daarop volg:
—Ek sit nou my hoed op, ma, en ek kom.
Getroos gaan mevrou Kibert weer sit. Sy laat haar oë gaan deur
haar voorkamertjie (hulle woon buite die dorp), oor die wit gordyne,
onlangs skoon gewas en gestryk, waar die lig dowwerig deur val,
reeds versag deur die nuwe somergroen van die groot bome buite.
Die meubels is oud en stemmig, en daar is nie onnodige opskik nie.
Dis die roostyd, en sy sit ’n vaas met rose aldag daar, as ’n
offerande aan die portrette van die geliefdes aan die muur—oorsaak
van al haar vreugde en smarte; die vergrote portret van haar man,
dokter Maurits Kibert, gestorwe die jaar vantevore as slagoffer van
sy plig gedurende die koorssiekte wat geheers het; en die portret
van haar dogter Thérèse, ’n klein meisie van twaalf jaar, na God
geroep in die daeraad van haar jeug en skoonheid. Daar is ’n
groepie van haar kinders op één portret bymekaar: Etienne, haar
oudste seun, ingenieur in Tonkin; Marcel, offisier; Magreet,
pleegsuster; Frans, by sy broer in die verre Oos; dan Paula, die
laaste wat nog vir haar oorgebly het. Ag, hoeveel maal het sy al
moet afskeid neem—en vir altyd—in sestig jaar tyds! Maar dit lyk of
hulle haar toelag vandag—’n feesdag in haar huis van rou.
Haar twede seun, Marcel, is terug in die land. Hy het deelgeneem
aan die oorlog in Madagaskar tot onderwerping van die inboorlinge.
Op agtienjarige leeftyd was hy reeds kaptein. Hy het die erekruis
gewin en kom nou terug, fris en gesond, na afwesigheid van drie
jaar. ’n Telegram, vanmôre ontvang, wat sy al gelees en herlees het,
lê nog oop op die tafel, en het haar te kenne gegee dat hy sal
aankom op Chamberie vanaand met die trein van half-ag. En dis
daarom dat mevrou Kibert haar vandag twee ure te vroeg klaar
gemaak het om na die naburige dorp, Chamberie, te ry en haar seun
by die stasie te ontmoet. Haar gedagtes loop haar al vooruit op die
treinspoor waar hy langs moet kom. Maar sy voorsien by die
ontmoeting ’n ontroering wat al haar moed sal verg. Daar ver in die
vreemde land het Marcel gehoor van sy pa se dood. As die dood in
die verte diegene tref wat ons liefhet, hoe bitter en wreed is dan sy
slae! Met die eerste oogopslag sal Marcel haar rouklere sien en die
vermeerderde tekens van haar ouderdom. Daar sal ’n skaduwee van
die dode oprys tussen haar en haar seun. Sy beproef haar kragte,
en sê by haarselwe:
—Sy kinders het nog nooit teruggekom met die trein van hier of
daar nie, of hy was altyd self by die stasie om hulle te verwelkom. Ek
sal nou daar wees in sy plek.
Paula kom nou die kamer in. Haar fraai blinkend-swart hare omlys
haar ronde dofkleurige gesig. Haar swart klere laat haar dun lyk,
maar sy lyk nie swak nie. Uit haar fiere houding en vaste uitkyk
straal beslistheid en dapperheid. Hierdie kind van twintig jaar het al
geweet wat lye is, op ’n leeftyd dat die lewe sy hoogste geur en fleur
het. Om nie ’n swakkeling te wees nie, het sy haarself skrap gesit,
en die gevolge van die stryd kom uit in haar houding.
Paula het ’n nuwe hoedjie in haar hand wat sy stilletjies klaar
gemaak het die dag vantevore.
—Sit nou eers stil, ma. Ma moet mooi lyk as Marcel vandag kom.
Kyk wat ’n mooi hoedjie het ek klaar gemaak; daardie een wat ma op
het, is te afgedra.
Haar ma wil eers teënstribbel, maar laat haar dan begaan.
—Maar nou word dit darem regtig tyd, my kind.
—Ja, sê Paula, ek gaan Trelas roep.
Trelas is die kneg, wat sal leisels hou op die pad na Chamberie.
Paula kyk nog ’n keer op die horlosie en sê:
—Ons sal nog ’n uur by die stasie moet wag.
—My kind, ek sou tog nie te laat wil wees nie.
Met moeite klim sy van die stoep in die rytuig. Noudat sy sit,
probeer sy te glimlag met Paula, en die onvoleindigde glimlag gee vir
’n oomblik aan haar gesig die frisse saligheid terug, wat die bekoring
van haar jeug was. Paula spring vlugtig in die rytuig, en gaat naas
haar sit.
—Laat loop maar, Trelas, en ’n bietjie gou, hoor; maar moenie alte
baie slaan nie, en pasop by die afdraands.
—Tyd genoeg, sê Trelas drogies.
Hul ry onder die laning van swaargeblaarde kastaiingbome en
plataanbome deur, verby die eikebosse. Die ou merrie begin haar
bene te kry en so hard te draf dat mevrou Kibert bangerig word.
Agter die bult is die son al ondergegaan, dog die blonde lig van die
someraand verlig die velde nog lank.
—Ma, kyk tog na die berge, sê Paula.
In ’n groot sirkel lê die berge om Chamberie, hul rotsagtige toppe
helder-rooskleurig getint, terwyl op hul voet, en langs hul kante, soos
’n fyn sluier die blouagtige waas hang, wat mooi weer voorspel.
Maar mevrou Kibert is te besorg om na die sonnegloeie op die toppe
van die berge te kyk; meteens kom dit uit waaroor sy sit en prakseer:
—Sê nou die trein was te vroeg! En hoewel sy dit mènens gesê
het, is sy die eerste wat glimlag oor so ’n nuwe veronderstelling. Sy
sien hoe die tere en ligte skaduwee stadig die berge uitklim, terwyl ’n
oomblik die toringkruisie van die dorp helder daarteen afsteek. Sy
wys dit aan haar dogter, as ’n beeld van stralende geloof. En nou
daal dieselfde stille vrede neer op die hele natuur, en ook vir die
eerste keer, sedert lank, op die gesigte van die twee vroue in rou.
Naby Chamberie kom ’n rytuig, met twee pragtige harddrawers
bespan, hul agterop, en ry hul verby.
—Dis die rytuig van die famielie Delourens, sê Paula. Hulle het
ons nie gegroet nie.
—Hul het ons seker nie herken nie.
—O ja, ma, maar vandat ons ons geld verloor het deur ons oom te
help, groet hul ons amper nie meer nie.
Sy praat van ’n famielie-ramp wat voorgeval het kort voor die dood
van haar vader. Mevrou Kibert neem die hand van haar dogter.
—Dis maar niks nie, my kind; dink tog daaraan dat ons netnou vir
Marcel sal sien.
Maar na ’n oomblik stilte vra Paula;
—Was dit nie pa wat vir Alida Delourens gedokter en gesond
gemaak het nie toe die koorssiekte so geheers het, waaraan pa ook
self gesterwe het?
—Ja, fluister die ou vrou, en al haar plesier is weg as sy daaraan
dink. En sonder klag voeg sy sag daarby:
—Ja, en hul het nog altyd vergeet om die rekening te betaal. So
maak die ryk mense baie maal. Hul weet nie dat ’n mens geld moet
verdien om te lewe nie.
—Dis omdat hul aan niks anders as aan tydkorting dink nie.
Mevrou Kibert sien ’n bitter trek op die nog jong gesig.
—Luister, my kind, ons moet hul nie beny nie. Onder die
verstrooiing vergeet hul om te lewe. Sou hul selfs weet dat die lewe
iets kosbaars is? Hul weet nie wat ’n mens se hart kan vervul en dit
harder laat klop nie. Ek sal gou sestig jaar oud wees.—Ek kan my
gestorwene en my opofferinge tel. Ek het my dogter Thérèse verloor,
en my man, wat my krag was. Jou ouer suster, Magreet, is
sendelinge, en ek het haar in vyf jare nie gesien nie. Etienne en
Frans is in Asië, in Tonkin, en ek ken nie eens my kleinkind wat daar
in die verre land gebore is nie. Marcel kom terug vandag, nadat sy
afwesigheid my drie jare van onrus besorg het. Maar ek het darem
tog ’n skone deel ontvang. Ek prys die Heer, Wat my beproef het
nadat Hy my met weldade oorstelp het. Elke dag van my lewe het ek
gevoel hoe goed Hy is. Selfs in my ellende het Hy my ’n steun gegee
—en dis jy.
Met haar klein handjie, sonder handskoen, druk Paula die
verrimpelde en gekerfde hand van haar moeder.
—Ja, dit is so, ma, ek sal nie meer kla nie.
Hul is eindelik by Chamberie, na die rit van drie myle. Trelas laat
die vroue afklim by die stasie en gaan opsy met die rytuig.
Paula kyk op die horlosie en sien met verbasing dat dit tien minute
oor sewe aanwys. Haar ma sien dat sy verwonderd lyk:
—Het ek jou nie gesê ons sou te laat kom nie?
Die jongmeisie glimlag:
—Te laat, omdat ons nie meer as twintig minute sal moet wag nie?
Hul gaan na die wagkamer. Net soos mevrou Kibert die deur
oopmaak, wil sy weer terugtree. Maar Paula druk haar saggies
binne-toe. Die kamer is vol deftig aangeklede mense. Dis die hoë
mense van Chamberie wat wag op ’n trein wat hul na die komedie
sal neem. Paula en haar ma herken die famielie Delourens.
Mevrou Kibert voel ongemaklik en wil uitgaan; sy fluister in Paula
haar oor:
—Laat ons in die wagkamer van die derde klas gaan: dis beter
daar.
—Waarom? sê Paula.
Op dié oomblik verlaat ’n aansienlike jongman ’n klompie vroue
wat daar staan, en stap na hulle toe. Hul herken in hom luitenant Jan
Berlier,[2] ’n vriend van Marcel. Hy groet hul op die vriendelike
manier wat ’n mens dadelik eie laat voel.
—U wag op die kaptein, is dit nie so nie, mevrou, want u hou tog
nie van reis nie.
—O, nee!
—Hoe bly sal hy wees om u netnou te ontmoet!
—Vroeër, sê die ou vrou aan die jongman, wat sy al as kind geken
het, was dit sy vader wat hom altyd ontmoet het, weet u!
—Ja, ek weet.
En om nou nie verder op ’n publieke plek oor die sterfgeval uit te
wy nie, laat Jan Berlier daarop volg:
—Ek sal Marcel ook nog die hand kan druk, eerdat ons trem
weggaan.
—Kom soek hom op by ons huis. Gaan u op reis?
—Vir vanaand. Ons gaan na die stad. Daar word vanaand ’n nuwe
komedie-stuk opgevoer. Maar u stel daar nie belang in nie.
Altyd openhartig, antwoord mevrou Kibert:
—Ek is nog nooit in ’n komedie gewees nie. En om u die waarheid
te sê, ek het daar ook nie spyt van nie.
Alhoewel sy saggies praat, het twee jongmeisies in ligte klere haar
gehoor, en een van hulle, met bruin hare en brutale blik, bars uit van
die lag. Dit kan wees dat ’n luitenant wat met hulle staan en praat,
die lag verwek het.
Paula bekyk die meisie wat lag, veragtelik, van bo tot onder met
haar swart oë, wat ’n snelle blits uitskiet.
—Moenie hier so bly staan nie, sê Jan.
Die ou vrou gaan sit in ’n donker hoekie, op ’n stoel wat naas ’n
leë leuningstoel staan, net soos iemand wat hom nederig en
bangerig voel.
—Maar neem dan tog die leuningstoel, ma, sê Paula ’n bietjie
ongeduldig. Sy beantwoord drogies ’n groet van die ander
jongmeisie van die twee—wat nie met haar saam gelag het nie,
maar gebloos.
Die jonkman praat nog ’n paar woorde met hulle en gaan dan
terug na sy eie geselskap. Paula kyk hom na en hoor hoe hy aan
mevrou Delourens sê:
—Ja, dis mevrou Kibert. Sy verwag haar seun uit Madagaskar.
—Watter een? Sy het so baie.
—Maar die offisier, Marcel!
—Watter rang het hy?
—Kaptein—dié wat die eremedalje gewin het—beroemd, sê Jan
haastig, ’n bietjie ongeduldig oor die uitvra, want die meisie met die
bruin hare roep hom.
Maar mevrou Delourens wil nou meer hoor:
—Beroemd? Wat het hy gedoen?
—Weet u dan niks van die slag van Audriba, waar sy kommando-
afdeling die oorwinning behaal het nie?
—Is jy seker daarvan?
—So seker as iets. Die hele land praat van Marcel Kibert.
Mevrou Delourens is dadelik vol belangstelling, en tree op mevrou
Kibert toe. Tot selfs in haar verval word die ou weduwee nou
belangwekkend, omdat haar seun so ’n naam gemaak het.
—Kom die kaptein vanaand tuis, mevrou? Ag, ons het hom almal
met ons harte gevolg, daar in die verre land en in die vreeslike
oorlog, waar hy sy land eer aangedaan het. In die koerante het ons
gelees wat hy alles volbring het in die slag van Audriba.
Agter sy vrou staan mnr. Delourens, ’n baie onderdanige en
hoflike klein mannetjie, en met ’n hoofbeweging bevestig hy al wat sy
vrou sê.
Mevrou Kibert voel haar in dié omgewing baie ongemaklik. Hoe
steek haar armoedige rouklere af (alhoewel deur haar dogter
opgeknap) by hul deftige aandkleding; sy voel dat sy geen enkele
gedagte gemeen het met hierdie mense van die wêreld nie. Almal
kom rondom haar staan en wens haar geluk. Na mevrou Delourens
kom mevrou Orlandi haar gelukwens. Laasgenoemde is ’n ou
Italiaanse gravin wat stil lewe in Chamberie en gedokter was vir haar
senuwees deur oorlede dokter Kibert. Meneer De Marthenay, ’n
luitenantjie, kyk die ou vrou op ’n byna brutale manier deur sy
oogglasie aan. Bangerig beantwoord sy hulle met enkele woorde;
die bloed styg in haar wange op, haar dogter Paula merk dit, en kom
haar te hulp. Paula is meer op haar gemak en, selfs ’n bietjie styf,
ondanks die lieftalligheid wat die twee jong meisies haar betoon—die
bruine Isabella Orlandi, wat in haar woorde net so aanstellerig is as
in haar houding, en veral die ander meisie, die blonde Alida
Delourens, wat van nature vriendelik is. Sy oorlaai Paula met
beleefdheidjies en voorkomendheid, haar stem is sangerig en
breierig, sy versag die hardklinkende woorde en praat met ’n
aangename soetvloeiendheid.
—So, dan kom jou broer vandag? Jy is seker bly? Dis al jare
gelede dat ek hom laas gesien het. Weet jy nog toe ons almal saam
gespeel het in julle tuin by Maupas, of in ons syne by Chenée.
—Ja, sê Paula, en nou speel ons nie meer saam nie. Die tuin by
Maupas lê woes, en dié by Chenée is weer alte mooi versorg.
—Maar waarom kom jy nie meer na ons toe nie? Jy moet regtig
kom.
En Paula vra haarself af waarom haar vriendin van vroeër dae—
deur lewensomstandighede van haar geskei—nou so vriendelik vir
haar is. Sy kyk na haar eie swart rok, so eenvoudig en glad, en
bewonder dan, sonder afguns, Alida haar ligblou lyfie, opgemaak
met wit kant en ’n bietjie laag in die hals—’n wit, dun hals, wat lyk
soos ’n tere blom. Paula beskou dan verder haar gelaat, waarvan die
trekke fyn en suiwer is, en die ligrose gelaatskleur sonder ’n vlekkie.
Sy kan nie help om te sê nie:
—Hoe mooi is jy tog, Alida!
Die fris wange word meteens purperrooi. Alida gaan opsy om
iemand te laat verbykom, en Paula merk dat selfs haar slap-
sleperige stap iets bydra om haar dooierig-tingerige bekoorlikheid te
voltooi: naas haar voel Paula beter haar eie jong krag. . . .
—Nee, Paula, dis jy wat mooi is. . .
Daar kom die trein aan en breek al die gesprekke meteens af.
Almal storm die wagkamer uit. Die famielie Delourens en hul
geselskap soek eersteklas rytuie in die trein, wat nou stilhou. Die
mense wat uit die trein stap, loop al haastig na die uitgangsdeur. Die
voorste van almal is ’n lang jonkman, skraal en regop; hy hou sy
hoof fier omhoog. In sy hand dra hy ’n sabel, in groen baai. Net soos
hy mevrou Kibert opmerk, hardloop hy na haar toe, en is in haar
arms.
—My kind! sê sy, en ondanks haar besluit om sterk te bly, bars sy
in snikke los.
En hy, hy rig hom weer op ná die omhelsing, en teer kyk hy sy
moeder aan, wat die merke dra van haar beproewing. Sy
songebrande, byna hardvogtige gelaat, vertoon ’n ontroering. ’n
Naam wat hulle nie nodig het om uit te spreek nie, beef op hulle
lippe, en een selfde eerbiedige nagedagtenis roer hul harte. Die
vreug van sy terugkoms gee iets treffend nuuts aan die smart wat
hulle al lank gevoel het.
Met versagte blik kyk Paula haar groot broer en haar ma aan.
Voor die deurtjie van die trein draai Alida Delourens en Isabella
Orlandi om, en sien die verwelkoming van die jong offisier; en
Isabella kyk mevrou Kibert met spotlaggende oë aan, omdat sy so
dik is en nog huil daarby.
Jan Berlier staan opsy en wag eerbiedig. Hy kom na Paula toe.
—Hoe gelukkig is hulle tog!
En met iets treurigs in sy stem voeg hy daar nog by:
—As ek van ver af terugkom, is daar niemand wat my verwag nie.
Marcel omhels ook sy suster.
Jan kom laggend nader:
—Ek wil nou ook my beurt hê.
—So, Jan, is dit jy?!
En as warme vriende druk die twee mekaar hartlik die hand. Jan is
’n oomblik ontroerd, dog glimlag nou weer:
—Tot weersiens. My trein gaat weg: ek moet hardloop.
—Waar gaat jy?
Al lopende draai die jonkman half om en sê:
—Ons gaan na die komedie in die stad. En hy wys met sy hand na
die mense wat by die trein staan.
Marcel Kibert laat haastig sy oog oor die deftig uitgedoste mense
gaan. Maar Paula draai nog ’n keer om en sien hoe Alida haar groet
uit die treinraampie. Sy groet terug, haastig, en nie besonder
vriendelik nie, net of sy ’n soort wantroue of bygelowige vrees voel
vir daardie verleidelike verskyning. Haar jong vurige siel het, deur
vroegtydige leed, ’n soort van trotse gevoeligheid oorgehou.
Waarom was Alida so tegemoetkomend? dink Paula. Haar oë volg

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Fetal and Neonatal

FETAL AND NEONATAL PHYSIOLOGY: SIXTH EDITION ISBN-13: 978-0-323-71284-2

Library of Congress Control Number: 2021940940

Publisher: Sarah Barth

Last digit is the print number: 9 8 7 6 5 4 3 2 1

And our grandchildren –

Soraya Abbasi, MD Gabriel Altit, MDCM, MSc

Katrina A. Andrews, MB BChir Peter Russell Baker II, MD

Kathryn Beardsall, BSc, MBBS, MD John F. Bertram, BSc, PhD, DSc

Laura Bennet, PhD Joseph M. Bliss, MD, PhD

Laura D. Brown, MD Jill Chang, MD

Douglas G. Burrin, PhD Jennifer R. Charlton, MD

Barbara Cannon, BSc, PhD Sylvain Chemtob, MD, PhD

David A. Clark, MD Amélie Collins, MD, PhD

C.A. Crowther, MBChB, DCH, MD, CMFM Diomel de la Cruz, MD

François Duhamel, BPharm, MSc Melinda Erdős, MD, PhD

Vittorio Gallo, PhD Armond S. Goldman, MD

Emmanouil Grigoriou, MD Gabriel G. Haddad, MD

Jean-Pierre Guignard, MD Cathy Hammerman, MD

Alice Hadchouel, MD, PhD J.E. Harding, MBChB, DPhil

Richard Harding, PhD, DSc William W. Hay, Jr., MD

Peter Hartmann, BSc, PhD Michael A. Helmrath, MD

M. Elizabeth Hartnett, MD Karen D. Hendricks-Muñoz, MD, MPH

Rodrigo Hasbun, MD, MPH Emilio Herrera, PhD

Silvia Iacobelli, MD, PhD Alan H. Jobe, MD, PhD

Deepak Jain, MD Michael Kaplan, MB ChB

Frederick J. Kaskel, MD, PhD Chang-Ryul Kim, MD, PhD

Lorraine E. Levitt Katz, MD Paul S. Kingma, MD, PhD

Susan E. Keeney, MD Torvid Kiserud, MD, PhD

Jay K. Kolls, MD T. Rajendra Kumar, PhD

Yvonne K. Lee, MD Steven Lobritto, MD

Sandra L. Leibel, MD Cynthia A. Loomis, MD

Fangming Lin, MD, PhD Anastasiya Mankouski, MD

Carlos B. Mantilla, MD, PhD Hugo R. Martinez, MD

Karen Mestan, MD Jeremiah D. Momper, PharmD, PhD

Steven P. Miller, MDCM, MAS Paul Monagle, MBBS, MD, MSC

Imran N. Mir, MD Jacopo P. Mortola, MD

Lisa J. Mitchell, DO Louis J. Muglia, MD, PhD

Vivek Narendran, MD, MRCP (UK), MBA Lawrence M. Nogee, MD

Josef Neu, MD Barbara M. O’Brien, MD

Henar Ortega-Senovilla, PhD Francesco Pisani, MD, PhD

Justin M. O’Sullivan, PhD David Pleasure, MD

Anna A. Penn, MD, PhD Martin Post, PhD

Raymond Quigley, MD Timothy R.H. Regnault, PhD

Thomas D. Ryan, MD, PhD George J. Schwartz, MD

Gary C. Sieck, PhD Markus Sperandio, MD

Michael J. Solhaug, MD Lisa Stinson, BSc, MMedSci, PhD

Barbara S. Stonestreet, MD Vadim S. Ten, MD, PhD

Janette F. Strasburger, MD Bernard Thébaud, MD, PhD

Xin Sun, PhD Daniel J. Tollin, PhD

Linda X. Wang, MD Andy Wessels, PhD

Ronald J. Wong, MD Christopher J. Yuskaitis, MD, PhD

1Ince C. Personalized physiological medicine. Crit Care 2017;21:308.

Basic Genetic Principles 1

INTRODUCTION STRUCTURE OF CHROMOSOMES

The human genome contains noncoding DNA sequences that MOSAICISM

CELL DIVISION RECOMBINATION

enhancer promoter exon intron exon intron exon

Prader-Willi syndrome, Angelman syndrome, and Beckwith-

Consanguinity is a significant risk factor for AR disorders.

• Males carrying the mutation are severely affected, often

FETAL AND NEONATAL PHYSIOLOGY: SIXTH EDITION ISBN-13: 978-0-323-71284-2

• Males carrying the mutation are severely affected, often

Box 2.1 Nature Versus Nurture, Genes