Prenatal Diagnosis E-Book

Miriam S. DiMaio

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 362

Veröffentlichungsjahr: 2011

Beschreibung

How can prenatal testing help your patients? In utero diagnosis has undergone an amazing revolution in recent years. More tests are available; the indications for prenatal diagnosis have expanded - you can now advise your patients about disorders you could not have previously detected. Medical training for obstetricians, medical geneticists, and genetic counselors has not kept pace with these developments. Clinical exposure to common and unusual problems in prenatal diagnosis is limited. Prenatal Diagnosis: Clinical Cases and Challenges, based on the authors' several decades of experiences, fills this gap. Real cases portray diagnostic problems as a route to the underlying biology, the available testing options, and the results that might be obtained. The authors discuss the challenges of management, interpretation, and counseling. Cases used throughout emphasize three types of clinical problems: * Chromosomal abnormalities * Mendelian disorders * Fetal structural abnormalities The decision to enter the world of prenatal diagnosis should be very carefully considered by any prospective mother. Prenatal Diagnosis: Clinical Cases and Challenges will help you discuss the issues in an informed manner with your patients.

Leseprobe

Contents

Cover

Title Page

Copyright

Preface

Chapter 1: Cytogenetic Abnormalities

Chapter 2: Mendelian Inheritance

Introduction to Mendelian Inheritance

Autosomal Dominant Disorders

Autosomal Recessive Disorders

X-Linked disorders

Skeletal Dysplasias

Chapter 3: Non-Mendelian Inheritance

Introduction to Non-Mendelian Inheritance

Mitochondrial Inheritance

Imprinting Disorders

Multifactorial Inheritance

Autism

Chapter 4: First and Second Trimester Screening

Chapter 5: Abnormal Ultrasound Findings

Chapter 6: Common Issues in Prenatal Diagnosis

Introduction to Common Issues in Prenatal Diagnosis

Infertility

Family History

Consanguinity

Non-paternity

Chapter 7: Fetal Infection and Teratogens

Appendix

Index

This edition first published 2010, © 2010 by Miriam S. DiMaio, Joyce E. Fox and Maurice J. Mahoney

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ISBN: 9781405191432

A catalogue record for this book is available from the British Library and the Library of Congress.

01 2010

Preface

The advent of mid-trimester amniocentesis in the mid-1960s initiated the era of prenatal diagnosis, a new window into fetal development, health and disease. At that time, the molecular basis of almost all Mendelian disorders was unknown, and few genetic disorders could be tested for prenatally. Initially, fetal diagnosis was largely restricted to chromosomal abnormalities, the few single gene disorders for which molecular or biochemical testing could be performed on amniocytes or amniotic fluid supernatant, and fetal abnormalities that could be identified by ultrasound examination. For some rare disorders, more invasive and riskier testing by fetal blood or skin sampling or fetoscopy could provide information about the fetus.

In the ensuing decades, the explosion of knowledge about the human genome and the molecular pathogenesis of many human diseases, the availability of rapid and highly accurate molecular diagnostic techniques, and the refinement of ultrasound imaging techniques have transformed the field of prenatal diagnosis. Furthermore, maternal serum analyte testing and carrier screening for genetic disorders based on ethnic background, family history or population risk have improved our ability to identify women who are appropriate candidates for diagnostic testing. Next on the horizon will be the diagnosis of fetal disease states using fetal nucleic acids (RNA or DNA) recovered from the maternal circulation. This will markedly alter the current state of prenatal diagnosis and will probably supplant many of our current approaches.

The rapid advances in understanding the molecular basis of human disease have also revealed genetic complexities and mechanisms that were only postulated or even unimagined a generation ago. We now recognize that for some disorders, different mutations in a single gene can result in markedly disparate clinical presentations. Such disorders, once defined by narrow clinical criteria, are now known to have remarkable variation in their manifestations and age of onset depending on the nature of specific mutation(s) in a single gene. Conversely, the same or similar clinical phenotype can result from mutations in more than one gene. In addition, non-Mendelian mechanisms such as uniparental disomy, trinucleotide repeat expansions, and epigenetic phenomenona such as imprinting add another level of complexity when considering an underlying diagnosis.

A problem that often complicates counseling in prenatal diagnosis is the difficulty of making precise predictions about the severity of a disorder that has been diagnosed in utero. This is most common when chromosomal mosaicism is diagnosed in chorionic villi or amniotic fluid and where the possible outcomes range from a disabling condition to normal or near normal. Counseling is also difficult for disorders which have highly variable severity among members of the same family, are of mid-life onset, have a wide range in age of onset, or have reduced penetrance.

For some fetal abnormalities diagnosed on ultrasound examination, there is insufficient information to establish a diagnosis. Questions about the etiology of the fetal abnormalities and their recurrence in subsequent children may have to be resolved after delivery following examination of the baby or by the results of pathological examination that allow a more focused approach to molecular or other testing. Sometimes, however, an underlying diagnosis will not be established, and providing precise information about risk of recurrence is not possible. Empiric data may be available and provide some guidance. Such data, however, reflect the experience of many families and represent an average risk with some families having a much higher or lower risk.

Exposure to common and unusual clinical problems in prenatal diagnosis should be an integral component in the training of obstetricians, medical geneticists, and genetic counselors. A major shortcoming of such training is that the clinical experience is usually limited to a short period of time in which few complex cases will arise. Physicians and genetic counselors in training are therefore not exposed to the broad range of diagnostic problems and dilemmas that occur in the field of prenatal diagnosis, and they finish their training programs with only superficial clinical exposure. We hope that this book will serve as a supplement to clinical training in the field of prenatal diagnosis.

This book is a product of our own clinical experience over several decades. We have used cases from our own practice and from colleagues elsewhere, some of which have been modified, and present them as vignettes to portray diagnostic problems in prenatal diagnosis. We recognize that our case material reflects predominantly the experience of prenatal diagnosis in the United States and Canada and that medical centers in other parts of the world may have a different experience. Our presentations also reflect, to some degree, protocols that have been developed at our own medical centers.

The format of the book includes a brief synopsis of each case followed by a discussion of the problem, an explanation of the underlying biology, the available testing options, and the results that might be obtained. These cases illustrate approaches to management, including pedigree interpretation, probability, laboratory and technical analysis, and counseling. This book is not a comprehensive reference about prenatal diagnosis and is not intended to provide in-depth information about the genetic disorders that are discussed. In the interest of presenting cases in a straightforward way, our discussions may lack some of the complexities and nuances that would be found in more comprehensive sources. Some of the cases presented in the book include clinical situations or laboratory results that are rarely encountered in a general prenatal genetics practice. We have chosen to use these unusual cases because they illustrate important concepts about disease causation which have applicability to other more common problems in prenatal diagnosis. As we experience the rapid changes in laboratory methods of genetic diagnosis and in imaging technology, it is easy to predict that diagnostic approaches described herein will become outdated and replaced by newer methods.

The cases emphasize three types of clinical problems which are currently the primary focus of prenatal diagnosis: chromosomal abnormalities, Mendelian disorders, and fetal structural abnormalities that can be diagnosed by ultrasound examination. Multifactorial disorders, other than those associated with structural birth defects, are neglected because their etiology is, at present, not well understood. As our understanding of the molecular and other bases of this class of disorders increases, we anticipate that there will be interest in the prenatal diagnosis of severely disabling conditions.

We have not focused on the counseling aspects of prenatal testing and the psychological impact of abnormal test results. Whether to interrupt or continue a pregnancy is one of the most wrenching decisions that a couple can face. Recognition of the different choices that parents make when confronted with the same fetal disease state reinforces the importance of impartial and non-directive counseling after a diagnosis has been established.

There are excellent web-based resources that are available and provide comprehensive information about the field. Information about many of the genetic disorders which are discussed in this book were obtained from GeneTests, which is a web based medical genetics information resource for health care providers. GeneTests provides authoritative and comprehensive peer reviewed articles that are written by experts in the field and are updated frequently. GeneTests also contains a directory of clinical and research based genetics laboratories worldwide and the genetic disorders for which testing is available. Another indispensable web based resource is Online Mendelian Inheritance in Man(OMIM), an online catalog of Mendelian traits and disorders, now numbering over 12,000 that includes their clinical presentations and underlying molecular and biochemical bases.

Chapter 1

Cytogenetic Abnormalities

Introduction

The diagnosis of a common trisomy by chorionic villus sampling or amniocentesis is the most frequent reason for referral for genetic counseling in the setting of prenatal diagnosis. There is an abundance of information available in the literature about these situations to provide accurate counseling about the spectrum of structural and functional abnormalities that could be present.

This section includes cases which illustrate the challenges in counseling about several of the less common and more vexing results that can arise from prenatal diagnostic testing. Of these, chromosomal mosaicism in chorionic villi or amniotic fluid is among the most troublesome. Prenatally diagnosed chromosomal mosaicism raises the questions of whether the abnormal cell line is also present in the fetus and, if present, whether there will be fetal damage. Although further diagnostic testing can provide more information, the interpretation of additional evaluations is complicated by phenomena such as tissue-specific mosaicism, uniparental disomy, placental mosaicism with adverse effects on the placenta, fetus or both, and the lack of long-term follow-up of surviving children. Another obstacle is that each case is unique; each case has different percentages of abnormal cells in fetal tissues that make extrapolation from the experience of case reports in the literature problematic.

Structural chromosomal rearrangements also present challenges to providing definitive prognostic information. In this situation, questions about whether the normal functioning of gene(s) has been disrupted by a translocation or inversion cannot be answered satisfactorily with current testing methods. Some rearrangements involving chromosomes which have imprinted genes raise concern about uniparental disomy which must also be addressed.

Cases involving a discrepancy between the phenotypic and chromosomal sex illustrate the possibilities of laboratory error, fetal disease states, and the limitations of ultrasonographic imaging.

Uncertainties about recurrence risks are heightened when a woman has had more than one trisomic conception, raising the possibilities of gonadal mosaicism in a parent or a predisposition to non-disjunction. Finally, when a diagnosis of a trisomic fetus is made by pathologic examination alone (i.e., without karyotypic confirmation), providing definitive information about risk of recurrence is problematic. This section presents cases of both common and rare prenatally diagnosed chromosomal abnormalities to illustrate the counseling dilemmas that can arise.