Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics: Clinical Principles and Applications

Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics

Clinical Principles and Applications

Seventh Edition

Editors

Reed E. Pyeritz

Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Bruce R. Korf

University of Alabama at Birmingham, Birmingham, AL, United States

Wayne W. Grody

UCLA School of Medicine, Los Angeles, CA, United States

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Preface to the Seventh Edition of Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics

Preface to Clinical Principles and Applications

1. A Clinical Approach to the Dysmorphic Child

1.1. Introduction

1.2. Prenatal Versus Postnatal Onset of Developmental Problems

1.3. Prenatal-Onset Problems in Development

1.4. Postnatal-Onset Problems in Development

1.5. Conclusion

2. Clinical Teratology

2.1. Introduction

2.2. Evaluating the Patient and Her Exposure

2.3. Recognized Teratogenic Exposures

2.4. Paternal Exposures and Maternal Exposures Before or Shortly After Conception

2.5. Future Perspective

2.6. Conclusion

3. Neurodevelopmental Disabilities: Global Developmental Delay, Intellectual Disability, and Autism

3.1. Intellectual Disability and Global Developmental Delay

3.2. Global Developmental Delay

3.3. Definition of a Diagnosis

3.4. Whole Exome Sequencing

3.5. Whole Genome Sequencing

3.6. Phenotyping

3.7. Genetic Mechanisms of ID

3.8. Diagnostic Testing of Patients With ID of Unknown Cause

3.9. Cytogenomic Copy Number Abnormalities

3.10. X-Linked ID

3.11. Fragile X Syndrome

3.12. Autism Spectrum Disorders

3.13. Inborn Errors of Metabolism and ID

3.14. CNS Malformations, Intellectual Disability and Brain Imaging

3.15. Summary

4. Abnormal Body Size and Proportion

Glossary

4.1. Introduction

4.2. Approach to the Patient With Abnormal Stature

4.3. Mechanisms of Growth

4.4. Pathologic Short Stature

4.5. Pathologic Overgrowth

4.6. Conclusion

Chapter 5. Cytogenetic Analysis

5.1. Introduction

5.2. Milestones in Human Cytogenetics

5.3. Indications for Cytogenetic Analysis

5.4. Tissue Samples and Cell Culture

5.5. Chromosome Banding

5.6. Normal Human Karyotype

5.7. Chromosome Abnormalities

5.8. In Situ Hybridization

6. Diagnostic Molecular Genetics

6.1. Introduction

6.2. Indications for Molecular Genetic Testing

6.3. Technical Approaches to Molecular Genetic Testing

6.4. Molecular Genetic Diagnosis of Some Commonly Tested Diseases

6.5. Mitochondrial DNA Disorders

6.6. Other Targets of Molecular Genetic Screening

6.7. Pharmacogenetic Testing

6.8. Quality Assurance, Reimbursement, and Regulatory Issues

6.9. Internet Resources for Molecular Genetic Testing

6.10. Societal Impact of the New Genetic Technology

6.11. Future Directions

7. Therapies for Lysosomal Storage Diseases

7.1. Introduction

7.2. Enzyme Replacement Therapy

7.3. Bone Marrow Transplantation

7.4. Substrate Reduction Therapy

7.5. Pharmacologic Chaperone Therapy

7.6. Emerging Therapies: Gene Therapy and Genome Editing

8. Transplantation Genetics

8.1. The Major Histocompatibility Complex

8.2. Historical Iter Toward Histocompatibility Definition

8.3. Currently Most Used Methods for HLA Typing

8.4. Clinical Significance of HLA Molecular Typing

8.5. Stem Cells and Transplantation

8.6. Concluding Remarks

9. Genetic Evaluation for Common, Chronic Disorders of Adulthood

9.1. Background

9.2. Outcomes of Genetic Services

9.3. The Process of Genetic Consultation for Common, Chronic Diseases of Adulthood

9.4. Genetic Healthcare Models

Summary

10. Carrier Screening and Heterozygote Testing

Glossary

10.1. Introduction

10.2. Carrier Screening in Clinical Practice

10.3. Carrier Screening in Individuals of Defined Subpopulation Groups

10.4. Therapeutic Implications for Heterozygotes

10.5. Sensitivity and Specificity

10.6. Cost and Feasibility

10.7. Genetic Counseling and Informed Consent

10.8. Conclusions

11. Circadian Rhythms and Disease

11.1. Introduction

11.2. Molecular Mechanisms

11.3. Central and Peripheral Clocks

11.4. Circadian Diseases

11.5. Metabolic and Cardiovascular Disorders

11.6. Cancer

11.7. Psychologic and Neurologic Diseases and Circadian Rhythms

11.8. Chronotherapy

11.9. Concluding Remarks

12. The Genomic Health Record: Current Status and Vision for the Future

12.1. Introduction

12.2. Conclusion

13. Ethical and Social Issues in Clinical Genetics

13.1. Introduction

13.2. The Historical Context

13.3. Genetic Counseling, Testing, and Screening

13.4. Diagnostic Genetic Testing

13.5. Predictive Genetic Testing

13.6. Confidentiality

13.7. Genetic Testing in Childhood

13.8. Population Genetic Screening

13.9. Other Challenges in Genetic Counseling

14. Genetics and Genomics in Public Health

14.1. What Is Public Health Genetics/Genomics?

14.2. The Purposes of Public Health

14.3. The Public Health System Infrastructure

14.4. Evolution and Convergence of Two Fields of Science—Public Health and Genetics/Genomics

14.5. Future Direction for Public Health Genetics/Genomics

15. Implementation of Genomic Medicine: An International Perspective

15.1. Introduction

15.2. Large-Scale Genomic Medicine Initiatives

15.3. National Genomic Medicine Initiatives

15.4. Large-Scale Regional Genome Initiatives

15.5. Corporate Genomic Medicine Initiatives

15.6. Studying Founder Populations

15.7. Conclusions and Future Perspectives

15.8. Competing Interests

Index

Copyright

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List of Contributors

Sura Alwan,     Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

Angus John Clarke

Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff, Wales, United Kingdom

Institute of Medical Genetics, School of Medicine, Heath Park, Cardiff, Wales, United Kingdom

Kenneth H. Astrin

Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, United States

Department of Preclinical Sciences, New York College of Podiatric Medicine, New York, NY, United States

Marina Bartsakoulia,     University of Patras School of Health Sciences, Department of Pharmacy, Patras, Greece

Deepika D’Cunha Burkardt,     Medical Genetics Resident, Center for Human Genetics, University Hospitals/Case Western Reserve University, Cleveland, OH, United States

Constantina Chalikiopoulou,     University of Patras School of Health Sciences, Department of Pharmacy, Patras, Greece

Joshua L. Deignan,     Departments of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, United States

Robert J. Desnick,     Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, United States

Shweta U. Dhar,     Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, United States

Debra Lochner Doyle,     Washington State Department of Health Screening and Genetics, Kent, WA, United States

Malcolm A. Ferguson-Smith,     Cambridge Resource Centre for Comparative Genomics, Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom

Jan M. Friedman,     Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

John M. Graham Jr.

Consultant in Clinical Genetics and Dysmorphology, Cedars-Sinai Medical Center, Los Angeles, CA, United States

Consultant in Clinical Genetics and Dysmorphology, Harbor-UCLA Medical Center, Torrance, CA, United States

Professor Emeritus of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States

Daniel Graziano,     Tissue Typing Laboratory, Allegheny Health Network, Allegheny General Hospital, Pittsburgh, PA, United States

Wayne W. Grody,     UCLA School of Medicine, Los Angeles, CA, United States

Rachel Irving,     Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff, Wales, United Kingdom

Kenneth L. Jones

Department of Pediatrics, University of California, San Diego, CA, United States

Rady Children’s Hospital, San Diego, CA, United States

Marilyn C. Jones

Department of Pediatrics, University of California, San Diego, CA, United States

Rady Children’s Hospital, San Diego, CA, United States

Theodora Katsila,     University of Patras School of Health Sciences, Department of Pharmacy, Patras, Greece

Muin J. Khoury,     The Centers for Disease Control and Prevention, Office of Public Health Genomics, Atlanta, GA, United States

Matthew J. McGinniss,     Principal Consultant, Trinitas Genomics Inc., San Diego, CA, United States

Molly A. McGinniss,     Senior Market Development Manager, Illumina Inc., San Diego, CA, United States

John B. Moeschler,     Professor of Pediatrics, Medical Genetics, Geisel School of Medicine at Dartmouth College, Hanover, NH, United States

Angeliki Panagiotara,     University of Patras School of Health Sciences, Department of Pharmacy, Patras, Greece

George P. Patrinos

University of Patras School of Health Sciences, Department of Pharmacy, Patras, Greece

Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates

Maren T. Scheuner

Department of Pediatrics, Division of Medical Genetics, University of California San Francisco, San Francisco, CA, United States

Department of Medicine, Division of Hematology-Oncology, University of California San Francisco, San Francisco, CA, United States

San Francisco VA Healthcare System, San Francisco, CA, United States

Edward H. Schuchman,     Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, United States

Amita Sehgal

Chronobiology Program at Penn, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Howard Hughes Medical Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Efthymios Skoufas,     University of Patras School of Health Sciences, Department of Pharmacy, Patras, Greece

Nancy B. Spinner

The Children’s Hospital of Philadelphia, Pennsylvania, PA, United States

Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Pennsylvania, PA, United States

Massimo Trucco,     Institute of Cellular Therapeutics, Allegheny Health Network, Allegheny General Hospital, Pittsburgh, PA, United States

Evangelia-Eirini Tsermpini,     University of Patras School of Health Sciences, Department of Pharmacy, Patras, Greece

Marc S. Williams,     Genomic Medicine Institute, Geisinger, Danville, PA, United States

Shirley L. Zhang

Chronobiology Program at Penn, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Howard Hughes Medical Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Preface to the Seventh Edition of Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics

The first edition of Emery and Rimoin’s Principles and Practice of Medical Genetics appeared in 1983. This was several years prior to the start of the Human Genome Project in the early days of molecular genetic testing, a time when linkage analysis was often performed for diagnostic purposes. Medical genetics was not yet a recognized medical specialty in the United States, or anywhere else in the world. Therapy was mostly limited to a number of biochemical genetic conditions, and the underlying pathophysiology of most genetic disorders was unknown. The first edition was nevertheless published in two volumes, reflecting the fact that genetics was relevant to all areas of medical practice.

Thirty-five years later we are publishing the seventh edition of Principles and Practice of Medical Genetics and Genomics. Adding genomics to the title recognizes the pivotal role of genomic approaches in medicine, with the human genome sequence now in hand and exome/genome-level diagnostic sequencing becoming increasingly commonplace. Thousands of genetic disorders have been matched with the underlying genes, often illuminating pathophysiological mechanisms and in some cases enabling targeted therapies. Genetic testing is becoming increasingly incorporated into specialty medical care, though applications of adequate family history, genetic risk assessment, and pharmacogenetic testing are only gradually being integrated into routine medical practice. Sadly, this is the first edition of the book to be produced without the guidance of one of the founding coeditors, Dr David Rimoin, who passed away just as the previous edition went to press.

The seventh edition incorporates two major changes from previous editions. The first is publication of the text in 11 separate volumes. Over the years the book had grown from two to three massive volumes, until the electronic version was introduced in the previous edition. The decision to split the book into multiple smaller volumes represents an attempt to divide the content into smaller, more accessible units. Most of these are organized around a unifying theme, for the most part based on specific body systems. This may make the book more useful to specialists who are interested in the application of medical genetics to their area but do not wish to invest in a larger volume that covers all areas of medicine. It also reflects our recognition that genetic concepts and determinants now underpin all medical specialties and subspecialties. The second change might seem on the surface to be a regressive one in today’s high-tech world—the publication of the 11 volumes in print rather than strictly electronic form. However, feedback from our readers, as well as the experience of the editors, indicated that access to the web version via a password-protected site was cumbersome, and printing a smaller volume with two-page summaries was not useful. We have therefore returned to a full print version, although an eBook is available for those who prefer an electronic version.

One might ask whether there is a need for a comprehensive text in an era of instantaneous internet searches for virtually any information, including authoritative open sources such as Online Mendelian Inheritance in Man and GeneReviews. We recognize the value of these and other online resources, but believe that there is still a place for the long-form prose approach of a textbook. Here the authors have the opportunity to tell the story of their area of medical genetics and genomics, including in-depth background about pathophysiology, as well as giving practical advice for medical practice. The willingness of our authors to embrace this approach indicates that there is still enthusiasm for a textbook on medical genetics; we will appreciate feedback from our readers as well.

The realities of editing an 11-volume set have become obvious to the three of us as editors. We are grateful to our authors, many of whom have contributed to multiple past volumes, including some who have updated their contributions from the first or second editions. We are also indebted to staff from Elsevier, particularly Peter Linsley and Pat Gonzalez, who have worked patiently with us in the conception and production of this large project. Finally, we thank our families, who have indulged our occasional disappearances into writing and editing. As always, we look forward to feedback from our readers, as this has played a critical role in shaping the evolution of Principles and Practice of Medical Genetics and Genomics in the face of the exponential changes that have occurred in the landscape of our discipline.

Preface to Clinical Principles and Applications

This volume of Principles and Practice of Medical Genetics and Genomics presents topics focused on fundamental principles that underlie clinical applications of genetics and genomics. Some of the authors (Robert J. Desnick, John M. Graham, Kenneth Lyons Jones, and Marilyn Jones) have composed and updated their chapters since the first or second editions of this treatise. Due to the recognition of the evolution of genomic, not just genetic, application, a number of new chapters have been added since the sixth edition. The knowledge and perspectives gained from the chapters in this volume provide the foundation for interpreting and applying the information contained in all subsequent volumes.

Reed E. Pyeritz, MD, PhD

1

A Clinical Approach to the Dysmorphic Child

Kenneth L. Jones¹,², and Marilyn C. Jones¹,²     ¹Department of Pediatrics, University of California, San Diego, CA, United States     ²Rady Children’s Hospital, San Diego, CA, United States

Abstract

This chapter outlines a clinical approach to the child with structural defects, defines many terms used in dysmorphology, and presents a parsimonious approach to genetic testing.

Keywords

Malformation; Deformation; Disruption; DysplasiaSingle primary defect; Sequence; Multiple malformation syndrome; Etiology; Pathogenesis; Prognosis; Recurrence risk; Chromosome; Comparative genomic hybridization; Whole exome sequencing

1.1. Introduction

The purpose of this chapter is to present a clinical approach to the child with structural defects. The approach is predicated on the concept that the nature of the structural defects presents clues to the time of onset, mechanism of injury, and probable etiology of the problem, all of which determine the direction of the evaluation. It presumes that the dysmorphic child represents an experiment in human development, which, if interpreted correctly, can provide answers regarding the etiology of various structural defects, as well as permit insights into mechanisms of normal and abnormal morphogenesis. The method on which this approach is based has been most articulately set forth by Sir Arthur Conan Doyle’s fictional character Sherlock Holmes, who showed how much an observant man might learn by accurate and systematic examination of all that came within his way [1]. This chapter adapts this method to the evaluation of the child with structural defects. By sharpening the faculties of observation, the clinician can narrow systematically the diagnostic possibilities so that the laboratory and the literature can be consulted in a rational fashion to arrive at an accurate diagnosis. The precise cause of many malformations and malformation syndromes is not known. However, careful clinical evaluation in combination with an expanded range of cytogenetic, cytogenomic, and molecular testing has allowed the elucidation of the mechanism underlying a growing list of clinical disorders. The separation between genetic and environmental factors as well as cytogenetic (copy number) and single gene abnormalities is somewhat arbitrary. However, the approach is intended to be practical and to facilitate detection and prevention of human malformations. Gorlin’s Syndromes of the Head and Neck [2] and Smith’s Recognizable Patterns of Human Malformation [3] are particularly useful. In recent years, computerized databases available online and on CD-ROM have become useful adjuncts to diagnosis (London Dysmorphology Database [Face2Gene]; Possum Web [4]; Online Mendelian Inheritance in Man [5]; and Decipher [6]).

1.2. Prenatal Versus Postnatal Onset of Developmental Problems

A method of approach to children with structural defects is set forth diagrammatically in Fig. 1.1. Although the lists of exceptions is growing, a history and physical examination usually make it possible to determine if the structural abnormality is of prenatal or postnatal onset. In this chapter, prenatal onset designates structural abnormalities that are present at birth, and postnatal onset designates structures that have previously developed and differentiated normally. Whereas the genetic alteration responsible for many of the disorders included under postnatal-onset structural defects is present at the time of conception, the structural manifestations of that genetic alteration do not become obvious until postnatal life. On the basis of this distinction, a more rational approach to the problem can be developed, as this determination narrows considerably the diagnostic probabilities and, it is hoped, permits a more judicious selection of adjunctive laboratory tests.

Generally speaking, prenatal-onset problems in development are a consequence of genetic or chromosomal (copy number) alterations that cause programming problems in the development and/or differentiation of structure or are the result of factors unique to the pregnancy itself, such as environmental agents, abnormalities of placentation, or mechanical constraint. Although always evident at birth, most prenatal-onset problems remain static or improve postnatally without evidence of neurologic deterioration. By contrast, postnatal-onset problems in development usually result in deterioration in structure or function that has previously been normal. Deterioration may reflect postnatal accumulation of a toxic metabolic product (as in phenylketonuria), progressive storage of a metabolite (as in Hurler syndrome), deteriorating energy production (as in mitochondrial myopathies), or ongoing infection (as in deafness from cytomegalovirus). Children with postnatal problems usually appear to have thrived in utero. The structural and functional consequences of the problem manifest after the newborn period.

Figure 1.1  Approach to a child with structural defects.

Certain historical information can be particularly helpful in determining onset of the problem. Structural defects of prenatal onset are frequently associated with the following abnormalities noted by the mother during pregnancy and at the time of delivery, whereas, by contrast, with postnatal-onset structural defects, the pregnancy and delivery usually are normal.

Alterations of pregnancy associated with prenatal onset of developmental problems are as follows:

1. Alterations in gestational timing (prematurity or postmaturity). As discussed in several other chapters, the majority of conceptuses do not survive to be born at 40weeks’ gestation. Much of this loss occurs in the very early part of pregnancy and is the result of gross chromosomal abnormities and/or malformation. Numerous studies have documented an increased frequency of chromosomal and genetic abnormalities in losses from the second and third trimesters. Thus, premature delivery may reflect late fetal wastage rather than maternal disease. Postmaturity rarely occurs today because of improved fetal monitoring techniques. In years before the widespread use of ultrasound, anencephaly typically presented in pregnancies that continued well beyond the due date because the fetal pituitary-adrenal axis is involved in the triggering of labor.

2. Alterations in onset of fetal activity, nature of fetal activity, or both. Although it is clear that fetal activity begins much earlier, it is usually not felt by the mother until about 18weeks of gestation. Fetal activity increases in amount and intensity from that time, reaches a maximum between the 29th and 38th weeks, and then decreases somewhat until delivery. Discussion with mothers who have given birth to babies with structural defects suggests that certain structural defects are often associated with delayed onset and/or decreased intensity of fetal activity. Moreover, fetal movement may be localized to one particular quadrant of the abdomen, for example, when the defect represents deformation due to intrauterine compression in a previously normally formed structure. Other examples are defects in brain development and meningomyelocele, conditions in which the decreased fetal activity is secondary to neurologic impairment.

3. Abnormalities in amount of amniotic fluid, for example, polyhydramnios or oligohydramnios. During the latter part of gestation, amniotic fluid is maintained in equilibrium by fetal urination and fetal swallowing. Polyhydramnios occurs when the fetus has difficulty swallowing amniotic fluid; for example, early problems in central nervous system development or upper gastrointestinal obstruction. Oligohydramnios is usually present after chronic leakage of amniotic fluid or whenever fetal urinary excretion is decreased, such as renal agenesis, infantile polycystic kidney disease, or urethral obstruction.

Alterations noted at delivery associated with prenatal onset of developmental problems are as follows:

1. Increased incidence of breech presentation. Breech presentation occurs in 3.1% of normal deliveries at 40weeks’ gestation. However, it occurs much more frequently in some disorders that adversely affect the form and/or function of the fetus. Defects of form include structural abnormalities such as hydrocephalus, which would be less compatible with the vertex position because of the large head, and joint dislocations, which may limit the capacity of the fetus to alter its position. Defects of function include some conditions associated with neuromuscular dysfunction, for example, the trisomy 18 syndrome and Smith–Lemli–Opitz syndrome associated with hypertonia and the Prader–Willi syndrome and Zellweger syndrome associated with hypotonia.

2. Prenatal onset growth deficiency. Drillen [7] studied the incidence of malformations, intellectual disability, and/or neurologic defects in 180 children who were 1year old, whose birth weight was 2000g or less, and who were small for gestational age (SGA). She documented an increased incidence of prenatal onset malformations as weight-for-gestational age decreased. In addition, she showed a marked increase in suspected mental and neurologic defects in those SGA children who had some structural anomaly. The association between both prematurity and SGA has more recently been confirmed in a population-based registry study in which birth defects were present in 17.2% of SGA infants as opposed to 7.8% of controls [8].

3. Difficulty with neonatal adaptation. Children with prenatal-onset structural defects frequently have problems with neonatal respiratory adaptation, probably secondary to malformations of brain structure. Therefore, one should always be cautious when attributing intellectual disability to a perinatal insult in a child who has associated prenatal-onset structural malformations. Intellectual disability in such patients may well be related to a problem in brain development of prenatal onset.

Other historical information that will be useful in determining etiology includes:

1. Family history with attention to any health, developmental, or functional issues in first-, second-, or third-degree relatives as well as the presence or absence of consanguinity;

2. Past obstetrical history with attention to unexplained fetal losses;

3. Maternal health and exposure history in that mothers with diabetes, epilepsy, and certain immunological conditions may have a higher risk for adverse outcomes. Certain drugs, chemicals, and infections are known to increase risk.

The most helpful way to determine whether a structural defect is of prenatal or postnatal onset is a careful physical examination [9]. In the vast majority of situations, the nature of the problem will determine the direction the diagnostic evaluation should take. The physical examination should focus on delineating the pattern of major and particularly minor malformations. Major malformations are birth defects which have significant cosmetic and/or functional consequences to the individual concerned. About 15%–20% of stillborn babies and 2%–3% of all liveborns have a major malformation with the addition of an additional 2% as occult cardiac, renal and nervous system malformations become manifest by age 5  years. Major anomalies are often what brings an individual to clinical attention, but they rarely lead to an etiologic diagnosis.

Minor malformations, on the other hand, have no functional or cosmetic consequences for the affected individual. Minor malformations include such things as complete 2–3 syndactyly of the toes or a single transverse palmar crease. By definition, minor malformations occur in less than 4% of the general population. Although these anomalies themselves have few adverse implications, the presence of two or more minor anomalies greatly increases the likelihood of a major anomaly. In addition, certain minor anomalies (such as a preauricular tag) may be associated with specific major anomalies (such as hearing loss). Moreover, most syndromes are diagnosed based upon the pattern of minor malformations rather than the major malformations with which they occur. For example, a diagnosis of Down syndrome may be suspected in an infant with upslanting palpebral fissures, epicanthal folds, small ears, a flat face, loose nuchal skin, a single transverse palmar crease, and wide spaces between toes 1 and 2 regardless of the presence of a cardiac defect. Last, minor malformations may provide clues as to the timing of the insult in development. For example, the interphalangeal flexion creases develop at about 9  weeks’ gestation in response to movement across the joint. Hand contractures associated with absent palmar creases suggest that the fetal hand was not moving at 9  weeks’ gestation, whereas contractures in the face of normal creases suggest that early hand movement was normal.

Table 1.1

In addition to structure, posture, tone, and behavior may all provide diagnostic clues as in the high pitched cry of the neonate with deletion 5p (cri du chat) syndrome, the overfriendliness and lack of stranger anxiety in the toddler with Williams syndrome, or the hand-wringing behavior of the youngster with Rett syndrome.

1.3. Prenatal-Onset Problems in Development

Once a given problem has been determined to be of prenatal onset, a distinction should be made between those that are single primary defects in development and those that are multiple malformation syndromes. Although the concepts are not totally analogous, separation of prenatal problems into these two categories permits some practical generalizations that can be extremely helpful in counseling about recurrence risk.

Conceptually, single primary defect in development is an anatomic or morphogenetic designation. In most cases, the defect involves only a single structure, and the child is otherwise completely normal. Table 1.1 sets forth the seven most common single primary defects in development. For most of them, the specific etiology is unknown, making definitive recurrence risk counseling difficult. However, from a practical standpoint, most single primary defects are explained on the basis of multifactorial inheritance, which is thought to carry a recurrence risk for first-degree relatives of between 2% and 5%. Thus, recognition that a child’s structural defect represents a single primary defect in development usually enables the clinician to suggest recurrence risk percentages between 2% and 5% for unaffected parents with one affected child.

The multifactorial model is a theoretical construct that was developed to explain the observed 2%–5% risk for first-degree relatives, the twin discordance, and gender inequality observed for many common single defects. The model stipulates that expression of a given characteristic represents the interaction between genetic susceptibility to a given biologic error and a threshold beyond which a given characteristic is expressed (later volumes will address such and such topic more fully). Susceptibility is depicted as a normal distribution in the population. The threshold may be manipulated by environmental factors, which may either increase or decrease the likelihood that a defect will be evident. The extent to which multifactorial inheritance contributes to the etiology of some of the less common single defects in development is at present unclear. The fact that single primary defects are etiologically heterogeneous implies that some will have a clearly environmental etiology, whereas others will result from dominantly or recessively inherited single altered genes. Craniosynostosis secondary to in utero constraint is an example of the former, and postaxial polydactyly illustrates the latter. Before multifactorial risk figures are used for counseling, references Online Mendelian Inheritance in Man [5] or Harper’s Practical Genetic Counselling [10] should be consulted to determine if other risk figures have been reported. Currently available genetic tests such as comparative genomic hybridization (CGH) array and whole exome sequencing (WES) rarely identify the etiology of most single defects in development.

In contrast to the anatomic concept of the single primary defect in development, the designation multiple malformation syndrome indicates that all the observed structural defects have the same cause. The defects themselves usually include a number of anatomically unrelated errors in morphogenesis. Multiple malformation syndromes are caused by gross chromosomal abnormalities, smaller copy number abnormalities resulting in microdeletions and duplications, teratogens, and single-gene defects usually inherited in Mendelian patterns. Recurrence risk depends on an accurate diagnosis and ranges from zero in cases that represent fresh gene mutations or are caused by one-time teratogen exposures to 100% for the unusual case of a child with the Down syndrome in which one parent is a balanced 21/21 translocation carrier. To review, recognition that a child has a prenatal-onset single primary defect in development suggests a 2%–5% risk; recognition that a child has a multiple malformation syndrome is not helpful with respect to recurrence risk counseling unless a specific diagnosis can be made.

1.3.1. Single Primary Defect in Development

Single primary defects can be subcategorized, as shown in Table 1.1, according to the nature of the error in morphogenesis that has produced the observed structural defect Thus, single primary defects involve either malformation, deformation, disruption, or dysplasia of developing structure. A malformation implies a primary structural defect arising from a localized error in morphogenesis. A deformation should be thought of as an alteration, usually through compression, in shape and/or structure of a part that has differentiated normally; the term disruption is used for a structural defect resulting from destruction of a previously normally formed part. The term dysplasia refers to an abnormal organization of cells and the structural consequences. Dysplasias may be localized or generalized. Localized dysplasias (e.g., hemangiomas) are generally single primary defects in development. However, generalized dysplasias such as connective tissue disorders usually present as multiple malformation syndromes in that a variety of structures are involved because of the widespread distribution of the dysplastic tissue.

Table 1.1 sets forth the most common single primary defects in development. Four are malformations, the result of a localized error in morphogenesis. Two (congenital hip dislocation and talipes equinovarus) are the result of intrauterine molding and thus represent deformation of previously normally formed structures. One (pyloric stenosis) is a dysplasia resulting from abnormal muscular hypertrophy at the gastric outlet. Each of these seven anomalies occurs with a frequency of 0.5–1 per 1000 live-born infants. The major reason for separating single defects in development into malformation, deformation, disruption, and dysplasia is to gain information that can be helpful relative to prognosis. Of the deformations noted at birth, 90% will correct spontaneously; of those that do not, the vast majority can be corrected with early postural interventions, such as casting or bracing. Conversely, spontaneous correction of both malformations and disruptions almost never occurs, and, when correction is possible, surgery is virtually always necessary. Because dysplasias involve abnormal organization and localized deregulation of growth in affected structures, many change over time with involution occurring in some and malignant transformation taking place in others.

1.3.2. Malformations

Most children with a localized malformation in development, such as a cardiac septal defect or cleft lip and palate, are otherwise completely normal. After appropriate reconstruction, prognosis is excellent. In those cases in which Mendelian inheritance has not been previously documented, multifactorial recurrence risk figures (2%–5%) can be given to unaffected parents. If the malformation in development involves a structure that is not amenable to surgical correction, such as the brain, the long-term prognosis may be poor. The environmental factors that modify the threshold for expression of most malformations are for the most part unknown. For neural tube malformations, however, folic acid supplementation before conception substantially reduces the risk for recurrence [11].

1.3.3. Deformations

Most deformations involve the musculoskeletal system and are believed to be caused by intrauterine molding [12]. The pressure required to produce such molding may be intrinsic (e.g., neuromuscular imbalance within the fetus) or more likely be extrinsic (e.g., fetal crowding). In either case, the ability of the fetus to kick is impaired, resulting in decreased fetal movement, an important factor in the development of a normal musculoskeletal system. This is particularly true with respect to joint development because motion is essential for normal development of the joints. In addition, because of fetal plasticity, marked positional deformation of any body part can occur when the fetus is unable to change position and thus alter the direction along which potentially deforming extrinsic forces are being directed.

1.3.3.1. Intrinsically Derived Prenatal-Onset Deformations

Disorders involving muscle degeneration, such as the Steinert myotonic dystrophy, and disorders involving motor neurons, such as Werdnig–Hoffmann disease, are uncommon causes of positional deformations. Early defects in development of the central nervous system are more common causes and should be seriously considered whenever a structural defect is thought to be an intrinsically derived prenatal-onset deformation.

1.3.3.2. Extrinsically Derived Prenatal-Onset Deformations

Fetal crowding, the common pathway in extrinsically derived postural deformations, is usually due to a decreased volume of amniotic fluid, a situation that occurs normally during the later weeks of gestation when the fetus undergoes extremely rapid growth. However, it also occurs abnormally when fetal urinary output is diminished and in cases of chronic leakage of amniotic fluid. Other extrinsic factors associated with the development of deformations include breech presentation and the shape of the amniotic cavity. When a fetus is held in the breech position, the legs may be trapped between the body and the uterine wall. In that position, the fetus is unable to kick optimally and therefore is immobilized and more susceptible to molding and deformation. Breech presentation is associated with a 10-fold increase in the incidence of deformations. The shape of the amniotic cavity, which has a profound influence on the shape of the fetus that lies within it, is influenced by many factors, among which are the following: uterine shape; volume of amniotic fluid; size and shape of the fetus; presence of more than one fetus; site of placental implantation; presence of uterine tumors; shape of the abdominal cavity, which is influenced by the pelvis, sacral promontory; and neighboring abdominal organs; and tightness of the abdominal musculature.

The various forms of talipes and congenital hip dislocation are the most frequently observed congenital postural deformities. Most children with these deformations are otherwise completely normal, and their prognosis is excellent. Correction usually occurs spontaneously. However, recognition that a structural defect represents a deformation does not always imply fetal crowding and should lead to careful consideration of other etiologic possibilities that might have far greater importance to the child. For example, because decreased fetal movement can be secondary to serious neurologic abnormalities, multiple joint contractures should always alert the clinician to the possibility of a malformation in central nervous system development. Although the most common deformational single primary defects—congenital hip dislocation and talipes—have a 2%–5% recurrence risk, most deformations are the result of physiologic crowding and have virtually no recurrence risk. Deformations that are due to pathologic crowding (e.g., uterine tumors or malformation) have a much higher recurrence risk unless the factors leading to crowding are altered before subsequent pregnancies. Deformations that are the result of an underlying malformation (e.g., renal agenesis) have a recurrence risk similar to that for the underlying malformation.

1.3.4. Disruptive Defects

Disruptive defects occur when there is destruction of a previously normally formed part. There are at least two basic mechanisms believed to produce disruption. One involves entanglement followed by renting, amputation, or both of a normally developed structure, usually a digit, arm, or leg, by strands of amnion floating within amniotic fluid (amniotic bands) [13].

The second mechanism through which disruption occurs involves the interruption of blood supply to a developing part, leading to infarction, necrosis, and resorption of structures distal to the insult. If interruption of blood supply occurs early in gestation, the disruptive defect seen at term usually involves atresia or absence of a particular part. If the infarction occurs later, necrosis is more likely to be present. Examples of disruptive single primary defects for which infarctive mechanisms have been implicated include nonduodenal intestinal atresia [14], gastroschisis [15], porencephaly, and transverse limb reduction defects [16]. The extent to which disruption of developing structures plays a role in dysmorphogenesis is unknown [7].

Because disruptions typically do not involve programing errors intrinsic to the fetus, genetic factors appear to play a minor role in their pathogenesis. Thus, most disruptive defects are sporadic events in otherwise normal families. Cocaine is an environmental agent whose mechanism of action is vascular disruption. Multiple disruptive defects have been seen in the offspring of women who abuse this agent in pregnancy [9]. The prognosis for a disruptive defect is determined entirely by the extent and location of the tissue loss. Thus, a child with a limb amputation has an excellent prognosis for normal function but a child with porencephaly does not.

Figure 1.2  Infant with the Robin malformation sequence. (A) Micrognathia. (B) U-shaped palatal cleft.

1.3.5. Dysplasia

The causes of many localized dysplasias have recently been elucidated and reflect somatic mutation in specific tissues. Mosaicism is consistent with the observation that empirical recurrence risks for localized dysplasias are low. Germline mutations in the genes responsible for many localized dysplasias are likely embryonic lethals. The process of dysplasia typically involves deregulation of growth; hence, most dysplasias change over time. Capillary hemangiomas become involuted (the bathing trunk nevus illustrated in Fig. 1.5 carries a risk for malignant transformation). Knowledge of the natural history of a lesion is critical in the long-term follow-up of children with localized dysplasias.

1.3.6. Sequence

Sequence describes the pattern of multiple anomalies that occurs when a single primary defect in early morphogenesis produces multiple abnormalities through a cascading process of secondary and tertiary errors in morphogenesis [17]. When evaluating a child with multiple anomalies, it is extremely important from the standpoint of recurrence risk counseling to differentiate between multiple anomalies secondary to a single localized error in morphogenesis (a sequence) and a multiple malformation syndrome. In a sequence, recurrence risk counseling for the multiple anomalies depends entirely on the recurrence risk for the initiating, localized error. The words malformation, deformation, disruption, and dysplasia sequence are used if the nature of the initiating error in morphogenesis is known.

The patient depicted in Fig. 1.2 has mandibular hypoplasia, glossoptosis, and cleft palate, an example of multiple anomalies secondary to a single localized error in morphogenesis. The primary defect in this case is mandibular hypoplasia, a malformation. Because the tongue is relatively large for the oral cavity, it drops back (glossoptosis), blocking closure of the posterior palatal shelves, resulting in a U-shaped cleft palate. This condition has previously been referred to as the Pierre Robin syndrome. However, because both the glossoptosis and cleft palate are secondary to mandibular hypoplasia, the disorder is now understood as the Robin malformation sequence. Recognition that all of the observed defects are due to a single localized error in morphogenesis (mandibular hypoplasia) permits recurrence risk counseling based on the etiology of the single defect, which could be a localized malformation of the mandible or a consequence of a genetic abnormality as in Stickler syndrome [18]. The patient depicted in Fig. 1.3 has bathrocephaly, torticollis, facial asymmetry, a dislocated right hip, and valgus anomalies of both feet. All of the structural defects are the result of compression of developing fetal parts. The pattern of abnormalities in this patient is referred to as the breech deformation sequence. Intrauterine crowding in this situation was the result of a large infant with a birth length of 54  cm, birth weight of 3.9  kg, and head circumference of 36  cm, delivered from a breech position to a small, primigravida mother. Recurrence risk is therefore negligible. Recognition of the deformational nature of the abnormalities is helpful with respect to prognosis. All of the problems should resolve spontaneously or with postural therapy.

Figure 1.3  Newborn infant with breech deformation sequence. Note the deformed cranial shape and positional deformities at the hips and feet.

The patient depicted in Fig. 1.4 has the amnion rupture sequence. All of the craniofacial and limb defects are secondary to multiple fibrous strands of amnion extending from the placental insertion of the umbilical cord to the surface of the amnion-denuded chorion or floating freely within the chorionic sac. These strands of amnion, which result from disruption of the normally formed membrane, cause secondary defects through any one or more of the following mechanisms. Malformations occur if a strand of amnion interferes with the normal sequence of embryologic development. For example, a strand of amnion could interrupt fusion of the facial processes so that a cleft lip would result. Disruptions, on the other hand, are secondary to tearing apart of structures that have previously developed normally. As such, an amniotic band might act to cleave areas in the developing craniofacies along a line not conforming to the normal planes of facial closure. Deformations due to fetal compression occur secondary to oligohydramnios, tethering of a fetal part, or both. The former situation may result from rupture of both amnion and chorion, leading to chronic leakage of amniotic fluid. Tethering occurs when the fetus or one of its parts becomes immobilized by the constraining effect of an amniotic band such that it is unable to change position and thus alters the direction along which potentially deforming forces are being directed.

Figure 1.4  Infant with amniotic band disruption sequence. Note the asymmetrical encephalocele, severe disruption of facial development, and digital anomalies.

Figure 1.5  Infant with neurocutaneous melanosis. Note the bathing trunk nevus. This infant also had seizures, presumably from melanocytic infiltration of the pia and arachnoid.

When used in conjunction with the word sequence, malformation, deformation, disruption, and dysplasia describe only the initiating error in morphogenesis of the sequence. The nature of the individual secondary defects that ensue from the initiating event depend on the manner in which the initiating error alters subsequent morphogenesis. In the case of the amnion rupture sequence, the initiating event, disruption, can lead to multiple structural defects through three of the mechanisms listed above.

The child depicted in Fig. 1.5 has a neurocutaneous melanosis sequence. In this dysplasia sequence, melanocytic hamartosis of the skin occurs in conjunction with similar changes in the pia and arachnoid. Affected individuals are at risk for malignant degeneration within the hamartoses and are also at risk for neurologic sequelae, including seizures and intellectual disability. The cause of this condition, in most cases, is somatic mosaicism for mutations in NRAS Proto-Oncogene, GTPase (NRAS) [19]. The patchy phenotype is a function of which tissues harbor the mutation.

Finally, a sequence, like any other single defect in development, can occur by itself in an otherwise normal individual or may be one feature in a multiple malformation syndrome. Stickler syndrome, cerebrocostomandibular syndrome, and spondyloepiphyseal dysplasia congenita are examples of multiple malformation syndromes in which the Robin malformation sequence represents one feature [18]. In this situation, recurrence risk counseling is based on the etiology of the overall condition.

1.3.7. Multiple Malformation Syndromes

The category of multiple malformation syndromes includes patients in whom a primary developmental anomaly of two or more systems has occurred, all of which are thought to be due to a common etiology. Other than Down syndrome, which has an incidence of 1:660, and XXY syndrome (1:500 males), few of these disorders occur more frequently than 1 in 3000 live births.

As shown in Fig. 1.1, multiple malformation syndromes can be categorized on the basis of etiology.

1.3.8. Chromosomal (Copy Number) Abnormalities

The ability to perform chromosomal studies and, more recently, CGH arrays has led to the recognition of a number of multiple malformation syndromes due to copy number abnormalities secondary to gross chromosomal rearrangements or more subtle deletions or duplications. Certain generalizations are important to consider when deciding whether a copy number abnormality should be suspected. First, because chromosomes are present in most cells of the body, a chromosome aberration may be expected to affect adversely many parts of the body. Consequently, a person with only an incurved fifth finger and a heart defect is very unlikely to have those features on the basis of a copy number abnormality. Second, some sex-chromosome disorders (e.g., XXX, XXY, and XYY) have few, if any, defects recognizable at birth and may present as postnatal problems in development associated with learning difficulties and behavioral challenges. In addition, as more experience is gained with copy number abnormalities involving very small deletions and duplications it has become increasingly clear that prenatal growth deficiency and intellectual disability should not be the only requirements for this type of testing.

The most common disorder associated with a chromosomal abnormality is Down syndrome (trisomy 21). The principal features of the disorder (flat facies with upward slant to the palpebral fissures, hypotonicity, and small ears) are usually present at birth, making a clinical diagnosis possible in the newborn period. Ear length is measured by the maximum distance from the superior aspect to the inferior aspect of the ear. Aase and colleagues [20] documented decreased ear length as a consistent feature in newborn infants with Down syndrome. In their series, no full-term white infant with Down syndrome had an ear length greater than 3.4  cm (mean 3  cm), and no normal full-term white infant had an ear length less than 3.2  cm (mean 3.8  cm).

Until recently, the most commonly performed screening test to define the etiology of an unrecognized, prenatal-onset multiple malformation syndrome was a high-resolution chromosome analysis (>550-band resolution). Chromosome analysis as a first-tier test has effectively been replaced by array technologies combining CGH and single nucleotide polymorphism (SNP) platforms. Array-based CGH identifies copy number variation (either duplication or deletion) across the entire genome at high resolution. The most broadly available arrays use fluorescence techniques to compare DNA content in two differentially labeled genomes. Thousands of individual DNA sequences can be simultaneously interrogated, providing precise information about copy number at specific genomic locations. SNP arrays have the capacity to detect areas of homozygosity that could suggest unknown or undisclosed consanguinity or uniparental disomy. Arrays vary in resolution and coverage. Most currently provide less than 1-Mb resolution and dense coverage in areas of known clinical significance. A recent meta-analysis of diagnostic yield of array GCH in the evaluation of individuals with learning disabilities and congenital anomalies has suggested a 10% rate of causal copy number abnormalities. The down side of the technology is that it also detects copy number abnormalities that will eventually be determined to be noncausal (usually based on parental studies) at almost the same rate—7%, the false-positive rate [17]. Most practice guidelines have advocated that array CGH should be a first-line diagnostic test in the evaluation of a child with a multiple malformation syndrome given the ability of the technology to identify causal copy number changes that might not be specifically suspected on clinical grounds alone as well as all of the aneuploid anomalies identified on routine chromosome analysis and fluorescent in situ hybridization testing for specific microdeletion syndromes [21,22]. Arguments against the routine use of array CGH focus primarily on cost, the false-positive rate (which adds cost if parental studies are required), and the inability of the technology to detect balanced rearrangements. When using array CGH as a first-line test, it must be borne in mind that the technology cannot detect balanced rearrangements such as translocations and inversions that may relate directly to the phenotype or represent a predisposing factor to rearrangement.

Recurrence risk counseling for copy number abnormalities depends on the nature of the cytogenetic abnormality identified. Risk is usually low in aneuploidy; however, the risk for certain trisomies (21, 18, XXX, and XXY) may increase with increasing maternal age. In case of an unbalanced translocation, parental karyotypes are warranted before specific risks are cited. In cases of de novo abnormalities, the risk is usually low except for the rare circumstance of gonadal mosaicism in a parent. Most microdeletion and microduplication syndromes are mediated by low copy repeats or inversions and carry a low risk for recurrence [23].

1.3.9. Disorders With Known Genetic Etiology

A single mutant allele or a pair of mutant alleles has been implicated as the cause of some recognizable multiple malformation syndromes of prenatal onset. Testing technology has dramatically altered the ability of the laboratory to assist the clinician when the pattern of malformation is not clinically recognized. A family history of a similarly, affected individual can be extremely helpful in suspecting that a single gene might be operative. However, many patients with multiple malformation syndromes of genetic etiology represent simplex events as a result of fresh gene mutation or the first presentation of an autosomal recessive disorder in a family. In such situations, family history will be noncontributory although older paternal age might suggest fresh gene mutation or parental consanguinity the effects of an autosomal recessive mutation. For many multiple malformation syndromes in which the abnormalities reflect perturbation of a specific system, such as the skeletal system in bone dysplasias, adjunctive testing might first involve radiographs or tissue histopathology. Increasingly, laboratories are offering platforms that include panels of genes, mutations in which produce overlapping phenotypes such as for lethal skeletal dysplasias or aortopathies that resemble Marfan syndrome. For multiple malformation syndromes with no known copy number abnormality, WES or whole genome sequencing (WGS) may be a viable approach. Although these platforms sequence the whole exome or genome, interpretation reflects analysis of variants in genes known to relate to the phenotype in question. As the technology improves, WGS may replace array technology as a methodology that can identify both copy number abnormalities and single gene variants.

In addition to Mendelian patterns of inheritance, some multiple malformation syndromes may arise as a consequence of dosage imbalance of a gene. At some loci in the genome, only one copy of a gene is active even though two copies are normally present. Inactivation of one member of a gene pair involves the process of imprinting. Parent of origin effects are evident at imprinted sites where it is possible in a normal individual to document that either the maternally inherited copy of the gene or the paternally inherited copy of the gene is active. Prenatal-onset multiple malformation syndromes may occur if an abnormality in the imprinting process causes both the maternal and paternal genes to be active (or inactive) at a specific locus or if an affected individual inherits two copies of a gene from one parent and none from the other. The latter situation is termed uniparental disomy (UPD). Each of these mechanisms accounts for some cases of the Beckwith–Wiedemann syndrome. The extent to which imprinting and UPD play a role in the etiology of genetically determined multiple malformation syndromes is at present unknown.

1.3.10. Disorders Caused by Teratogens

Disorders caused by teratogens include multiple malformation syndromes due to the effect of specific infections and drugs or chemical agents with which the embryo or fetus has come into contact (later volumes will address such and such topic more fully). These disorders take on special importance because they represent the only group of dysmorphologic conditions in which prevention before conception may be feasible. This is particularly true in the case of drugs and chemicals if the mother is aware that the agent in question can affect her baby. It is difficult, on the other hand, for a pregnant woman to avoid contact with all infectious agents. Immunization of at-risk individuals may assist in prevention of birth defects caused by specific viral infections (e.g., rubella or varicella-zoster virus).

A careful history of drug intake, chemical exposure, and, in some cases, travel should be obtained from the parents of all children with multiple malformation syndromes. This is particularly true when the etiology of the disorder is unknown. An excellent source of information regarding what is known about various exposures in pregnancy is MotherToBaby (https://mothertobaby.org/). In addition, several online databases are available through subscription, including Reprotox (https://reprotox.org) and TERIS (http://depts.washington.edu/terisdb/teriswerb/index.html).

Although a specific and easily distinguishable phenotype does not exist for each of the infectious agents that are commonly associated with altered fetal development, intrauterine infection can be suspected, based on the overall pattern of malformation. Any SGA patient with microcephaly or hydrocephalus, ocular findings including microphthalmia, chorioretinitis, cataracts, and/or glaucoma, or hepatosplenomegaly and thrombocytopenia, and who is developmentally delayed may be suspected of having had an intrauterine infection. It should be emphasized that each of these intrauterine infections has a wide spectrum, from fetal death, to the severely affected newborn infant with multiple malformations, to the child with no malformation disabilities. The latter situation is illustrated by a study by Hanshaw and coworkers [24] indicating a significant increase in school failure and deafness after clinically unapparent congenital cytomegalovirus infection (another exception to the prenatal–postnatal distinction set forth at the beginning of the chapter).

1.3.11. Recognized Patterns

Many multiple malformation syndromes are diagnosed based on the pattern of malformation in the affected individual, specifically the pattern of minor malformations. As the molecular basis for many syndromes is elucidated, etiologic heterogeneity has become the rule rather than the exception. A case in point is Rubenstein–Taybi syndrome (RTS). This disorder is a well-recognized pattern of malformation associated with prenatal and postnatal growth deficiency, intellectual disability, typical craniofacial features that change over time, and distinctive limb anomalies. Most cases of RTS are produced by functional loss of one copy of the gene encoding the transcriptional coactivator CREB-binding protein (CREBBP) on chromosome 16p13.3 [25]. Microdeletions of this region, first thought to be causal in the majority of cases, actually account for only 10% of affected cases and produce a more severe phenotype than point mutations in the gene, which account for the majority of cases. Moreover, mutations in a second gene, EP300 on chromosome 22q13, also produce a similar phenotype. Thus, RTS is both a chromosomal and a single gene disorder. RTS is typical of a growing number of recognized patterns of malformation in which different genetic mechanisms may produce the same phenotype. As a note of caution, array CGH testing will identify the deletion cases but not those due to point mutation in the gene. As the technology of WGS advances and the cost decreases, it may be possible for one test to detect both the copy number abnormality cases and those with a single gene mutation.

Array CGH and WES have both allowed delineation of the molecular basis of previously unrecognized patterns of malformation, such as the Potock–Lupski syndrome [26] and mandibulofacial dysostosis with microcephaly [27]. It is interesting that, in many cases, the distinguishing phenotype has not been delineated until after the molecular cause was known. In some newly described disorders, defined first in the laboratory, the phenotype appears to be so nonspecific as to be unrecognizable.

The molecular basis of many multiple malformation syndromes remains unknown although most will likely be determined to be a consequence of altered copy number, single gene mutation, epigenetic factors that alter expression or function of existing genes, or as yet unrecognized environmental exposure.

1.4. Postnatal-Onset Problems in Development

Most children with postnatal-onset malformation problems are normal at birth, having appeared to thrive in utero. Neurologic problems frequently begin within the first week of life, and deterioration is often rapid. A specific pattern of malformation is typically not present at birth; structural abnormalities develop as the result of neurologic deterioration, storage of metabolites, or progressive loss of function in a specific tissue. In disorders with a known metabolic aberration, other manifestations of the metabolic defect such as cataracts, sparse hair, coarse facies, unusual skin pigmentation, and hepatosplenomegaly are frequently present. As set forth in Fig. 1.1, these disorders can be categorized on the basis of etiology.

1.4.1. Genetic

1.4.1.1. Metabolic

Most metabolic conditions are the result of deficiency of a specific enzyme, transporter, or cofactor. Because of the possibility that early institution of dietary or enzyme replacement therapy may help to prevent intellectual disability, these disorders are of particular interest, and newborn screening is offered for an expanding list of these conditions throughout the United States. Because the placenta is able to compensate for the metabolic deficiency, affected infants are typically normal at birth (e.g., aminoacidurias and organic acidurias). Most of these conditions have an autosomal recessive mode of inheritance. Their incidence is extremely low. Phenylketonuria (1:14,000) is the most common and represented, in its untreated state, about 1% of most institutionalized populations surveyed before newborn screening programs were instituted. A second group of metabolic conditions produces a phenotype through abnormal accumulation or storage of material in various tissues in the body. Although the placenta does not compensate for the enzymatic deficiency, the phenotype does not manifest until a period of time has passed during which accumulation of metabolites occurs (e.g., glycogen storage diseases and mucopolysaccharidoses). Consequently, there is usually a postnatal presentation.

1.4.1.2. Central Nervous System Degenerative States

A genetic etiology is increasingly known for many of these disorders. The clinical diagnosis has previously relied on imaging and histopathology. However, genetic panel testing and WES have significantly changed the rate and ease of diagnosis in these conditions.

1.4.1.3. Myopathies and Connective Tissue Disorders

Myopathies and connective tissue disorders represent a group of conditions in which structures deteriorate with wear and tear over time—hence, the typically postnatal presentation. A diagnosis may be suspected by the communality of the involved tissue (i.e., wound-healing problems and ligamentous laxity for connective tissue disorders or cardiomyopathy and weakness for muscle disorders). The ability to sequence mitochondrial and genomic DNA using panels or whole exome platforms has greatly facilitated diagnosis in all of these disorders.

1.4.2. Environmental Factors

Trauma, infection, hypoxia, and metabolic derangements can result in severe neurologic impairment. Progressive joint immobility, abnormal positioning, and paralysis secondary to central nervous system deterioration are the most frequent structural anomalies resulting from this type of injury. Deafness and cataract may also be seen.

1.5.