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

Clinical Principles and Applications

Reed E. Pyeritz, Bruce R. Korf, Wayne W. Grody

• Publisher: Academic Press
• Year: 2018
• ISBN:
  9780128126844
• Edition: 7
• Topic: Biological Sciences
• Subtopic: Genetics & Genomics
• Index: Biological Sciences

For decades, Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics has served as the ultimate resource for clinicians integrating genetics into medical practice. With detailed coverage in contributions from over 250 of the world's most trusted authorities in medical genetics and a series of 11 volumes available for individual sale, the Seventh Edition of this classic reference includes the latest information on seminal topics such as prenatal diagnosis, genome and exome sequencing, public health genetics, genetic counseling, and management and treatment strategies to complete its coverage of this growing field for medical students, residents, physicians, and researchers involved in the care of patients with genetic conditions. This comprehensive yet practical resource emphasizes theory and research fundamentals related to applications of medical genetics across the full spectrum of inherited disorders and applications to medicine more broadly.Clinical Principles and Applications thoroughly addresses general methods and approaches to genetic counseling, genetic diagnostics, treatment pathways, and drug discovery. Additionally, new and updated chapters explore the clinical implementation of genomic technologies, analytics, and therapeutics, with special attention paid to developing technologies, common challenges, patient care, and ethical and legal aspects.With regular advances in genomic technologies propelling precision medicine into the clinic, the seventh edition of Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics bridges the gap between high-level molecular genetics and practical application and serves as an invaluable clinical tool for the health professionals and researchers.

• Fully revised and up-to-date, this new edition introduces genetic researchers, students, and health professionals to general principles of genetic counseling, genetic and genomic diagnostics, treatment pathways, drug discovery, and the application of genomic technologies, analytics, and therapeutics in clinical practice
• Examines key topics and developing areas within clinical genomics, including genetic evaluation of patients, clinical trials and drug discovery, genetic health records, cytogenetic analysis, diagnostic molecular genetics, small molecule genetic therapeutics, gene product replacement, clinical teratology, transplantation genetics, and ethical and legal aspects of genomic medicine
• Includes color images supporting identification, concept illustration, and method processing
• Features contributions by leading international researchers and practitioners of medical genetics

1

A Clinical Approach to the Dysmorphic Child

Kenneth L. Jones^1,2, and Marilyn C. Jones^{1,2 1}Department 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 40 weeks’ 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 18 weeks 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 40 weeks’ 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 1 year old, whose birth weight was 2000 g 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. ...

Table of contents

• Cover image
• Title page
• Table of Contents
• 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
• 2. Clinical Teratology
• 3. Neurodevelopmental Disabilities: Global Developmental Delay, Intellectual Disability, and Autism
• 4. Abnormal Body Size and Proportion
• Chapter 5. Cytogenetic Analysis
• 6. Diagnostic Molecular Genetics
• 7. Therapies for Lysosomal Storage Diseases
• 8. Transplantation Genetics
• 9. Genetic Evaluation for Common, Chronic Disorders of Adulthood
• 10. Carrier Screening and Heterozygote Testing
• 11. Circadian Rhythms and Disease
• 12. The Genomic Health Record: Current Status and Vision for the Future
• 13. Ethical and Social Issues in Clinical Genetics
• 14. Genetics and Genomics in Public Health
• 15. Implementation of Genomic Medicine: An International Perspective
• Index