Genetic Steroid Disorders - 1st Edition - ISBN: 9780124160064, 9780123914675

Genetic Steroid Disorders

1st Edition

Editors: Maria I. New Oksana Lekarev Alan Parsa Tony Yuen Bert O'Malley Gary Hammer
eBook ISBN: 9780123914675
Hardcover ISBN: 9780124160064
Imprint: Academic Press
Published Date: 24th September 2013
Page Count: 406
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Description

This is a comprehensive book addressing steroid disorders from hormonal, genetic, psychological, and surgical perspectives. It is meant to educate adult and pediatric endocrinologists, clinical geneticists, genetic counselors, reproductive endocrinologists, neonatologists, urologists, and psychoendocrinologists. It will assist these specialists in the diagnosis and treatment of steroid disorders. The book is written for postgraduate and faculty-level physicians. The content consists of steroid disorders, genetic bases for the disorder and case presentations of each disorder.

Key Features

  • Provides a common language for professionals to discuss and diagnose genetic steroid disorders
  • Includes the very latest details on genetic tests and diagnoses
  • Offers a strong understanding of the molecular basis for the diseases and therefore correct diagnosis and treatment of steroid disorders
  • Presents insight into which medications to use based on the genetic makeup of a patient
  • Teaches the best strategies and most effective use of genetic information in the patient counseling setting

Readership

Adult and pediatric endocrinologists, academic and clinical researchers in endocrinology and clinical genetics, geneticists, genetic counselors, and psychoendocrinologists.

Table of Contents

Dedication

Preface

Contributors

Chapter 1. Introduction

Abstract

References

Chapter 2. Adrenal Development

Abstract

Introduction

Adrenal Organogenesis

Molecular Mechanisms That Regulate Adrenal Development

Adrenal Diseases

References

Chapter 3A. Congenital Adrenal Hyperplasia Owing to 21-Hydroxylase Deficiency

Abstract

Introduction

Endocrine Function of the Adrenal Cortex

The Adrenal Cortex as Two Glands

Pathogenesis of 21-Hydroxylase Deficiency

Classical CAH

Non-Classical CAH

Diagnosis (Hormonal and Genetic)

Molecular Mechanisms Creating Cyp21a2 Genetic Defects

Clinical Features

Treatment

Prenatal Diagnosis and Treatment

References

Chapter 3B. The History of Prenatal Diagnosis of Congenital Adrenal Hyperplasia

Abstract

Introduction

Hormonal Measurements in Amniotic Fluid

Molecular Genetics

Dexamethasone Treatment and Controversy

Non-Invasive Prenatal Diagnosis

Fetal Sex Determination

Future Directions

Summary

References

Chapter 3C. Growth Hormone Therapy to Improve Adult Height in Patients with Congenital Adrenal Hyperplasia

Abstract

Introduction

Adult Height in CAH

Factors Affecting Adult Height in CAH

Studies with Growth Hormone Treatment to Improve Adult Height in CAH

Conclusion

References

Chapter 3D. Steroid 11β-Hydroxylase Deficiency and Related Disorders

Abstract

Acknowledgments

Introduction

Biochemistry of Adrenal Steroid Biosynthesis

Genetics of Steroid 11β-Hydroxylase Isozymes

Steroid 11β-Hydroxylase Deficiency

Aldosterone Synthase (Corticosterone Methyloxidase) Deficiency

Glucocorticoid-Suppressible Hyperaldosteronism

References

Chapter 3E. Ambiguous Genitalia in Newborns

Abstract

Introduction

Typical Sex Determination and Differentiation

Disorders of Sex Development (DSD)

Other Categories of Ambiguous Genitalia

Work-Up of Newborns with Ambiguous Genitalia

Differential Diagnosis

Gender of Rearing

Parents and Caregivers of Children with Ambiguous Genitalia

Conclusions

References

Chapter 3F. 3β-Hydroxysteroid Dehydrogenase Deficiency

Abstract

The 3β-HSD Family: Amino Acid Sequences and Activities

Epidemiology

Clinical Forms

Biological Diagnosis

Molecular Diagnosis

Relationship between Genotype and Phenotype of Patients

Puberty and Fertility

Structure–Function Relationship

Treatment

References

Chapter 3G. Genetic Deficiencies of Cytochrome P450c17 (CYP17A1): Combined 17-Hydroxylase/17,20-Lyase Deficiency and Isolated 17,20-Lyase Deficiency

Abstract

Structure of the Gene and Mapping in the Human Genome

Genetic Defects – Mutation

Hormonal Abnormalities

Diagnosis Based on Structure of the Gene and Mutations

Epidemiology

Ethnic Diversity and Clusters of the Defect

Psychoendocrine Abnormalities Resulting from the Enzymatic Defect

Treatment: Medical and Surgical

Long-Range Outcome: Medical and Psychological (Gender, Cognition)

Life Careers

Prismatic Cases

Prenatal Diagnosis and Treatment

References

Chapter 3H. P450 Oxidoreductase Deficiency (PORD)

Abstract

Acknowledgments

Introduction

The Biological Function of POR

Clinical Spectrum of PORD

The Steroid Metabolom of PORD and Diagnostic Pitfalls

POR Structure to Steroid Function Correlations

PORD and Skeletal Malformations

POR and Drug Metabolism

Heme Oxygenase

Cytochrome b5 and Small Molecules

POR Variants in the Human Population

Regulation of POR Gene Expression

Conclusions and Perspectives

References

Chapter 3I. Disorders in the Initial Steps in Steroidogenesis

Abstract

Intracellular Cholesterol Trafficking

Disorders of Intracellular Cholesterol Trafficking

Mitochondrial Cholesterol Import and the Acute Regulation of Steroidogenesis

References

Chapter 3J. Aromatase Deficiency and Aromatase Excess

Abstract

Acknowledgments

Introduction

Case Reports

Clinical Characteristics

Genetics

Pathophysiology

Differential Diagnosis

Treatment

Aromatase Inhibitors

Aromatase Excess Syndrome

Conclusion

References

Chapter 3K. 46,XY DSD due to 17β-Hydroxysteroid Dehydrogenase 3 Deficiency

Abstract

Acknowledgments

Introduction

Clinical Aspects

Gender Role

Biochemical Diagnosis

Histological Aspects

Molecular Findings

References

Chapter 4A. Steroid 5α-Reductase 2 Deficiency

Abstract

Introduction

The Enzymatic Reaction

Role of Dihydrotestosterone in Androgen Physiology

Why Dihydrotestosterone?

Role of Dihydrotestosterone in Male Sexual Development

Steroid 5α-Reductase 2 Deficiency

Diagnosis

Molecular Genetics

Management

Summary

References

Chapter 4B. Marsupial Pathway in Humans

Abstract

Acknowledgments

Role of Androgens in Fetal Male Differentiation

Sexual Development and Sexual Differentiation

The “Classic” Pathway of Androgen Biosynthesis

The Alternative “Backdoor” Pathway of Androgen Synthesis

Aldo Keto Reductases (AKR) and Steroidogenesis

Significance for Sexual Development

AKR1C2 Mutations Show that the Backdoor Pathway is Essential in Humans

Activities of the AKR1C2 Mutants

An Unrelated Individual Confirms the Key Role of AKR1C2

Modeling Studies

Sites of DHT Synthesis

Conclusions

References

Chapter 5. Androgen Insensitivity Syndrome

Abstract

Introduction

Androgen Action: Structure and Function of The AR

Clinical Features of AIS

Diagnosis of AIS

Phenotype–Genotype Correlations of AR Mutations

Management of AIS

Sex of Rearing

Conclusion

References

Chapter 6A. Apparent Mineralocorticoid Excess

Abstract

Background

Molecular Genetics

Clinical Presentation and Diagnosis

Treatment

Summary

References

Chapter 6B. The History, Biology, and Pathophysiology of Apparent Mineralocorticoid Excess

Abstract

Acknowledgments

References

Chapter 6C. Glucocorticoid-Remediable Aldosteronism

Abstract

Introduction

Pathophysiology and Genetic Basis of GRA

Epidemiology

Clinical Presentation

Biochemical Features

Other Forms of Familial Hyperaldosteronism

Diagnostic Approach

Treatment

Conclusion

References

Chapter 7. The Genetics of Ovotesticular Disorders of Sex Development

Abstract

Introduction

Phenotypic Features of OT-DSD

Genotypes of OT-DSD

Animal Models

Conclusion

References

Chapter 8. The Persistent Müllerian Duct Syndrome

Abstract

Introduction

AMH and The Müllerian DUCT: The Basics

The Patient with PMDS

Biology

Differential Diagnosis

AMH Gene Mutations

AMH Receptor Mutations

Idiopathic and Non-Characterized PMDS

References

Chapter 9. Treatment and Outcome of Congenital Adrenal Hyperplasia: Current Reconstructive Surgery

Abstract

Preoperative Evaluation

Endoscopy

Surgical Technique

Outcomes

References

Chapter 10. Psychoendocrinology of Congenital Adrenal Hyperplasia

Abstract

Introduction

Gender

General Cognitive Development

Psychiatric Outcome

Sexuality

Quality of Life

Implications for the Organization of Health Services for CAH

References

Chapter 11. Nuclear Receptor Co-regulators

Abstract

Introduction

Molecular Features of Co-Activators

Co-Activators Exist in Multiprotein Complexes

Co-Activators are Master Regulators of Gene Expression Programs

The Relationship Between Co-Regulators and Human Genetic Disorders

Co-Repressors and Genetic Disease

Co-Regulators and Cancer

Co-Activators and Resistance to Chemotherapy

Co-Activators as Drug Targets

Co-Regulator ‘Omics’: Using High-Throughput Data to Connect Co-Regulator Biology to Human Disease

Co-Activators, Our Environment and Human Evolutionary History

Co-Activators as Weakly Penetrant Disease Risk Alleles

Conclusions

References

Chapter 12. Genetics of Adrenal Tumors

Abstract

Genetics of Adrenocortical Tumors

Genetic Syndromes

Genes Frequently Dysregulated in Sporadic ACCs

Multistep Model of Adrenocortical Tumorigenesis – Evidence from Clinical Observations, Molecular Studies, and Animal Models

Histology does not Tell Everything – Genome-Wide Expression Profiles

Conclusion

References

Chapter 13A. Animal Models of Adrenal Genetic Disorders

Abstract

Introduction

Mouse Models for Congenital Adrenal Hypoplasia

Mouse Models for Familial Glucocorticoid Deficiency (ACTH Resistance Syndromes)

Mouse Models for Congenital Adrenal Hyperplasia

Mouse Models of Congenital Lipoid Adrenal Hyperplasia

Genetically Modified Mouse Models Displaying an Adrenal Tumor Phenotype

Mouse Models with Targeted Deletions Inducing Adrenal Tumors

References

Chapter 13B. The Impact of Genetic Steroid Disorders on Human Fertility

Abstract

Introduction

Adrenal Steroid Enzyme Deficiencies

Steroidogenic Acute Regulatory Protein (STAR)

Gonadal Steroid Enzyme Defects

Conclusion

References

Chapter 13C. Preimplantation Diagnosis and Other Modern Methods for Prenatal Diagnosis

Abstract

Introduction and Overview

Treatment

Expanding the Diagnostic Range in Prenatal Genetic Diagnosis by CGH in Chromosomal Microarrays (Array CGH)

Preimplantation Genetic Diagnosis

Changing Approaches in Prenatal Detection of Mendelian Disorders: Cell-Free Fetal DNA

Cell-Free Fetal DNA in Maternal Blood to Determine Gender

Cell-Free Fetal DNA in Maternal Blood to Detect Mendelian Disorders Showing Qualitative Maternal–Fetal Differences

Cell-Free Fetal DNA in Maternal Blood for Detection of CAH (21-Hydroxylase Deficiency)

Intact Fetal Cells in Maternal Blood: Earlier Detection of Fetal Mendelian Disorders?

Conclusion

References

Chapter 13D. Geographical Endocrinology of Genetic Steroid Disorders

Abstract

Introduction

Epidemiology – Screening Data

Genetic Studies in Various Ethnic Groups

Lessons Learned from “Consanguineous Populations”

Carrier Frequency of CAH in the General Population

Heterozygote Advantage in CAH Caused by 21OHD

Summary

References

Chapter 13E. Debates and Controversies in Genetic Steroid Disorders

Abstract

Controversy No.1: Prenatal Treatment of Virilizing Congenital Adrenal Hyperplasia

Controversy No.2: Genital Surgery

Controversy No.3: Growth Enhancement

References

Chapter 13F. Genetic Factors in Cushing Disease Pathogenesis

Abstract

Introduction

Pituitary Corticotroph Tumors

Animal Models

References

Chapter 13G. Case Reports of Unsolved Mysteries of Steroid Disorders: 46,XY DSD with One Clue

Abstract

Introduction

46,XY Dsd with Low Simulated T/Δ4 Ratio

Leydig Cell Hypoplasia in Two Siblings with 46,XY DSD

References

Index

Color Plates

Details

No. of pages:
406
Language:
English
Copyright:
© Academic Press 2014
Published:
Imprint:
Academic Press
eBook ISBN:
9780123914675
Hardcover ISBN:
9780124160064

About the Editor

Maria I. New

Dr. New received her Bachelors degree from Cornell University and her Doctor of Medicine degree from the University of Pennsylvania, where she was awarded the Distinguished Graduate Award.

She was Chairman of Pediatrics at Weill Medical College of Cornell University from 1980 to 2002 and Founding Director of its Children’s Clinical Research Center, where she also served as Chief of Pediatric Endocrinology from 1964 to 2002.

Dr. Maria New is Professor of Pediatrics, Professor of Genetics and Genomic Sciences, and Director of the Adrenal Steroid Disorders Program at Mount Sinai School of Medicine in New York City. She is also serving as Associate Dean for Clinical Research at the Florida International University Herbert Wertheim College of Medicine.

Former president of the Endocrine Society, Dr. New has edited or co-edited 12 medical textbooks, published more than 600 peer-reviewed papers and served as editor-in-chief of the Journal of Clinical Endocrinology and Metabolism. She has trained more than 100 young physician-scientists who have become chiefs of pediatric endocrinology and leaders in their field.

Her research, clinical work and teaching have taken her around the world. In 2005 and 2006, she led genetics research expeditions to Siberia in collaboration with the School of Medicine, St. Petersburg University, Russia.

Dr. New’s contributions have been recognized by her being selected as one of the few pediatricians in the National Academy of Sciences. She has received numerous honors including: the Robert H. Williams Distinguished Leadership Award; the Rhone-Poulenc Rorer Clinical Investigator Award from the American Endocrine Society; the 1996 Dale Medal, the highest award given by the British Endocrine Society; and the 2003 Fred Conrad Koch Award, the highest award given by the American Endocrine Society. In 2010, she received the Van Wyk Prize, the highest award given in pediatric endocrinology.

She has conducted pioneering research in the area of Congenital Adrenal Hyperplasia, a term used to describe a family of monogenic autosomal recessive disorders of steroidogenesis in which enzymatic defects result in impaired synthesis of cortisol by the adrenal cortex. In addition, Dr. New discovered a new form of hypertension, Apparent Mineralocorticoid Excess, which opened a new field of receptor biology. She was also the first to describe Dexamethasone-Suppressible Hyperaldosteronism, another form of low-renin hypertension. In 1999, she reported what may be the first example of a transcription factor defect in human beings.

Oksana Lekarev

Alan Parsa

Tony Yuen

Assistant Professor of Medicine, Endocrinology, Diabetes and Bone Disease, Department of Pediatrics, Mount Sinai Medical Center, New York, NY, USA

Affiliations and Expertise

Department of Pediatrics, Mount Sinai Medical Center, New York, NY, USA

Bert O'Malley

Gary Hammer

Reviews

"Appropriate for both novice and experienced researchers, this collection demonstrates that the genetic basis has been located for each steroid disorder causing clinical and bioclinical abnormalities in patients. Ten of the 31 chapters describe the symptoms, cause, diagnosis, and treatment of the many disorders resulting from congenital adrenal hyperplasia…the definitive treatise belongs in every medical library."--ProtoView.com, February 2014
"Appropriate for both novice and experienced researchers, this collection demonstrates that the genetic basis has been located for each steroid disorder causing clinical and bioclinical abnormalities in patients…Edited by a professor of pediatric endocrinology at Mount Sinai Hospital, the definitive treatise belongs in every medical library."--Reference & Research Book News, December 2013