Disorders|Differences of Sex Development: An Integrated Approach to Management

Description

The new, fully updated edition of this successful book, brings together the combined experience of a leading dedicated unit over 25 years in delivering expert medical and surgical care to children with DSD (Disorders of Sex Development) in a holistic environment. It documents the most recent advances in the molecular biology and embryology of sex development, and describes each disorder in detail. The main focus of the book is on patients with problems with their anatomy and hormone function. New chapters describe the developments in the field in terms of definitions and incidence, the mental health of DSD patients and discuss the perspectives of patients families and support groups. The clinical presentation and approach to diagnosis are described both for babies and for children presenting later in childhood or at adolescence. The chapters on management highlight all the latest knowledge and include the shared wisdom of the authors on current controversies, such as the timing of surgical treatment. Finally, the authors describe their short-, medium-, and long-term outcomes, which demonstrate the strengths of holistic team management. Preface for the Second Edition Acknowledgements for the Second Edition Contents About the Editors 1: Introduction: Changing Landscapes 1.1 Background 1.1.1 Terminology 1.1.2 Recent History of DSD 1.1.3 Clinical Definition of DSD 1.1.4 Incidence of DSD 1.1.5 Clinical Care: Historical Perspective and Changes Over Time 1.1.6 Human Rights and DSD: Where to from Here? References 2: The Molecular Basis of Sex Determination and Differentiation: Implications for Understanding DSD 2.1 Formation of the Bi-potential Gonad 2.2 Testis Determination and Development 2.2.1 SRY 2.2.2 SOX (SRY Box) Transcription Factors 2.3 Regulators of Sry Expression 2.3.1 GATA Genes and ZFPM2 2.3.2 NR5A1 Gene encodes Steroidogenic Factor 1 (SF1) 2.3.3 WT1 2.3.4 Mitogen-Activated Protein Kinase Pathway 2.4 The Hedgehog Signalling Pathway 2.5 DMRT1 2.6 Epigenetic Regulation of Testis Determination 2.7 Ovarian Differentiation 2.7.1 Forkhead Box L2 (Foxl2) 2.7.2 Wnt4, Rspo1 and β-catenin 2.8 Internal Genital Tract Development 2.9 External Genitalia Development 2.10 Genetics and DSD 2.11 Conclusion References 3: Embryology of the Human Genital Tract 3.1 The Urogenital Ridge 3.1.1 Wolffian and Müllerian Duct Development 3.2 Sexual Differentiation 3.2.1 Testosterone 3.2.2 Anti-Müllerian Hormone (AMH or MIS) 3.2.3 Insulin-Like Hormone (INSL3) 3.3 External Genitalia 3.4 Gonadal Descent References 4: Hormones Regulating Sex Development 4.1 Introduction 4.2 Testicular Hormones 4.2.1 Testosterone Synthesis 4.2.2 Androgen Receptor 4.2.3 Control of Testosterone Levels 4.2.4 Anti-Müllerian Hormone (AMH) 4.2.5 Insulin-Like Hormone 3 (INSL3) 4.3 Ovarian Hormones 4.4 The Placenta 4.5 The Foetal Hypothalamic–Pituitary Axis 4.6 Postnatal Hormone Levels and Implications (Fig. 4.4) References 5: Embryology in DSD 5.1 Sex Determination 5.2 46,XY Complete Gonadal Dysgenesis 5.3 Incomplete Testicular Differentiation (and Mixed Gonadal Dysgenesis) 5.4 Anatomy of Caudal Internal Ducts in DSD 5.5 Placental Failure 5.6 Failure of the Hypothalamic–Pituitary–Gonadal Axis 5.7 Failure of Hormone Action 5.7.1 INSL3 5.7.2 AMH 5.7.3 Androgen 5.8 Morphogenesis of the Genitalia (See Also Chap. 9) 5.9 Internal Genital Tract 5.9.1 Wolffian Ducts 5.9.1.1 In the Female 5.9.1.2 In the Male Epididymis Vas Deferens Seminal Vesicles (SV) Cysts Agenesis and Hypoplasia 5.9.2 Müllerian Ducts 5.9.2.1 In the Female Anomalies of Development Aplasia and Hypoplasia Unicornuate Uterus Anomalies of Fusion Uterus Didelphys Bicornuate Uterus Anomalies of Septal Reabsorption Septate Uterus Arcuate Uterus 5.9.2.2 In the male 5.10 External Genitalia 5.10.1 Gonads 5.10.2 Genital Folds 5.10.3 Genital Tubercle and Urogenital Sinus References 6: 46,XX DSD 6.1 Clinical Presentations of Individuals with 46,XX DSD 6.2 Congenital Adrenal Hyperplasia (CAH) 6.2.1 21-Hydroxylase Deficiency 6.2.1.1 Clinical Features 6.2.1.2 Diagnosis 6.2.1.3 Genetics 6.2.1.4 Monitoring of Treatment 6.2.1.5 Gender Identity and Sexuality in 46,XX Individuals with CAH 6.2.1.6 Bilateral Adrenalectomy in the Treatment of CAH 6.2.2 11β-Hydroxylase Deficiency 6.2.3 3β-Hydroxysteroid Dehydrogenase Deficiency 6.2.4 P450 Oxidoreductase Deficiency 6.2.5 17α-Hydroxylase Deficiency 6.2.6 Lipoid Congenital Adrenal Hyperplasia 6.3 Steroidogenic Factor-1 Deficiency 6.4 46,XX Gonadal Dysgenesis 6.5 46,XX Premature Ovarian Insufficiency (POI) 6.6 Müllerian Duct Agenesis 6.7 46,XX Testicular DSD 6.8 46,XX Ovo-Testicular DSD 6.9 Cloacal Exstrophy and Bladder Exstrophy References 7: 46,XY DSD 7.1 Clinical Presentation 7.2 Incidence 7.3 Undefined 46,XY DSD (Hypospadias and Cryptorchidism) 7.3.1 Management 7.4 46,XY Gonadal Dysgenesis 7.4.1 Management 7.4.2 46,XY Testicular Regression Syndrome 7.5 Hormonal causes of 46,XY DSD 7.5.1 Gonadotrophin deficiency or resistance 7.5.2 Management 7.5.3 Altered Androgen Biosynthesis 7.5.4 Androgen Insensitivity Syndrome 7.5.4.1 Management 7.5.5 Persistent Müllerian Duct Syndrome 7.6 Additional Management Considerations 7.6.1 Germ Cell Tumours 7.6.1.1 Germ Cell Tumour Risk in AIS 7.6.2 Fertility 7.6.3 Hormonal and Sexual Function 7.6.4 Urinary Function 7.6.5 Psychosocial Considerations 7.6.6 Genetic Counselling and Disclosure 7.7 Conclusion References 8: Sex Chromosome DSD 8.1 Introduction 8.2 45,X/46,XY Mosaicism 8.2.1 Phenotype of 45,X/46,XY DSD 8.2.2 Malignancy Risk and Risk Management 8.2.3 Management 8.3 Ovo-Testicular DSD 8.3.1 Management of Ovo-Testicular DSD 8.4 Klinefelter Syndrome: 47,XXY and Variants 8.5 Turner Syndrome: Monosomy X and Variants 8.5.1 Detecting Mosaicism in Turner Syndrome References 9: Non-hormonal DSD 9.1 Introduction 9.2 Internal Genitalia 9.3 External Genitalia 9.4 Lower Abdominal Wall Defects 9.5 Perineal Anomalies 9.6 Cloacal Maldevelopment References 10: Multiple Malformation Syndromes in DSD 10.1 Hormonal DSD 10.1.1 Gonadal Dysgenesis 10.1.1.1 WAGR Syndrome (OMIM #194072) 10.1.1.2 Denys-Drash Syndrome (OMIM #194080) (Fig. 10.1) 10.1.1.3 Frasier Syndrome (OMIM #136680) 10.1.1.4 Hand-Foot-Genital Syndrome (OMIM #140000) 10.1.1.5 Alpha-Thalassaemia/Mental Retardation Syndrome, X Linked (OMIM #301040) 10.1.1.6 Opitz G/BBB Syndrome (OMIM #300000) 10.1.1.7 Turner Syndrome 10.1.1.8 Complete Gonadal Dysgenesis (Swyer Syndrome) (OMIM #400044) 10.1.2 Hypogonadism 10.1.2.1 Klinefelter Syndrome 10.1.2.2 Noonan Syndrome (OMIM #163950) 10.1.2.3 Kallman Syndrome (OMIM #308700) 10.1.2.4 CHARGE Syndrome (OMIM #214800) 10.1.2.5 Prader-Willi Syndrome (OMIM #176270) 10.1.2.6 Congenital Adrenal Hypoplasia (OMIM #300200) 10.1.2.7 Rubinstein-Taybi Syndrome (OMIM #180849) 10.1.2.8 Axenfeld-Rieger Syndrome (OMIM #180500) 10.1.2.9 Deletion 4p Syndrome 10.1.2.10 Fraser Syndrome (OMIM #219000) 10.1.3 Abnormal Cholesterol Metabolism (Fig. 10.2) 10.1.4 Abnormal Steroid Metabolism 10.1.5 Abnormal Hormonal Function 10.1.5.1 Robinow Syndrome (OMIM #180700 and 268310) 10.1.5.2 Aarskog-Scott Syndrome (OMIM #305400) 10.2 Non-hormonal DSD 10.2.1 Affecting Internal Genitalia 10.2.1.1 Wolffian Duct Anomalies 10.2.1.2 Müllerian Duct Anomalies Mayer-Rokitansky-Küster-Hauser Syndrome Herlyn-Werner-Wunderlich Syndrome 10.2.2 Affecting External Genitalia 10.2.2.1 Prune Belly Syndrome (OMIM #100100) 10.2.2.2 Lower Abdominal Wall Defects 10.2.2.3 Perineum Defects 10.2.2.4 Cloacal Anomalies 10.2.2.5 Caudal Regression Syndrome 10.2.2.6 Sirenomelia References 11: The Foetus 11.1 Prenatal Diagnosis 11.2 Preimplantation Genetic Testing References 12: The Neonate with Atypical Genitalia 12.1 Introduction 12.2 Diagnostic Rules and Clinical Significance 12.3 Clinical Approach to a New Baby with Atypical Genitalia 12.3.1 History 12.3.2 Clinical Examination 12.4 Investigations 12.4.1 Ultrasonography 12.4.1.1 Congenital Adrenal Hyperplasia 12.4.2 Genitogram 12.4.3 Magnetic Resonance Imaging and Computerised Tomography 12.4.4 Endoscopy 12.4.5 Laparoscopy (See Chap. 17) 12.4.6 Initial Laboratory Investigations References 13: DSD Later in Childhood 13.1 Introduction 13.2 Inguinal Hernia 13.2.1 DSD Identified at Herniotomy in Girls: Complete Androgen Insensitivity Syndrome 13.2.2 DSD Found at Herniotomy in Boys 13.3 Cryptorchidism 13.4 DSD Found at Laparoscopy 13.5 DSD Found with Hypospadias 13.6 DSD Found at Cystoscopy 13.7 Precocious Puberty References 14: The Adolescent or Young Adult with DSD 14.1 Introduction 14.2 Phenotypic Females 14.2.1 Precocious Puberty 14.2.2 Virilisation at Puberty 14.2.3 Groin Lump 14.2.4 Delayed Puberty 14.2.5 Primary Amenorrhoea 14.2.6 Secondary Sex Characteristics 14.2.7 Cyclical Abdominal Pain 14.2.8 Difficulties with Sexual Intercourse 14.2.9 Infertility 14.2.10 Secondary Amenorrhoea 14.3 Males 14.3.1 Haematuria 14.3.2 Abdominal/Pelvic Tumour 14.3.3 Altered Pubertal Development 14.3.4 Infertility 14.4 Imaging 14.4.1 Imaging in Girls During Late Childhood and Early Adolescence References 15: Ethical Principles for the Management of DSD 15.1 Introduction 15.2 Methodology 15.3 Ethical Principles for DSD 15.4 Basis and Application of the Principles 15.4.1 Minimise Physical Risk 15.4.2 Maximise Psychosocial Well-being 15.4.3 Preserving Potential for Fertility 15.4.4 Preserving or Promoting Capacity to Have Satisfying Sexual Experiences 15.4.5 Leaving Options Open for the Future 15.4.6 Respecting the Parents’ Wishes and Beliefs 15.4.7 Consider the Views of Children and Adolescents 15.5 Using Ethical Principles in Clinical Practice 15.6 Conclusion References 16: Medical Management of DSD 16.1 Introduction 16.2 Classification System 16.3 Clinical Diagnosis 16.4 Common Causes 16.4.1 46,XX DSD: Congenital Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency 16.4.2 46,XY DSD: Androgen Insensitivity Syndrome (AIS) 16.4.3 Mixed Sex Chromosome (Aneuploidy) DSD: Mixed Gonadal Dysgenesis 16.5 Summary of Management Concepts During Childhood 16.6 Gender Dysphoria in Relation to DSD 16.7 Management During Transition to Adulthood 16.8 Existential Issues 16.9 Medical Issues in Adolescence (Table 16.5) 16.9.1 Oestrogens 16.9.2 Progestogens 16.9.3 Fertility 16.9.4 Male 16.10 Holistic Care Through Adolescence (Table 16.7) 16.11 Conclusions References 17: Surgical Management in DSD 17.1 Introduction 17.2 Feminising Genitoplasty 17.2.1 Clitoroplasty 17.2.2 Vaginoplasty in the Setting of Virilised Genitalia 17.3 Masculinising Genitoplasty 17.4 Laparoscopy 17.5 Indications for Laparoscopy 17.5.1 Diagnosis of Internal Genital Anatomy 17.5.1.1 Androgen Insensitivity Syndrome 17.5.1.2 45,X/46,XY Mixed Gonadal Dysgenesis 17.5.1.3 Ovo-Testicular DSD 17.5.1.4 Pure Gonadal Dysgenesis/46,XY Complete Gonadal Dysgenesis (Previously Called Swyer Syndrome) 17.5.1.5 Persistent Müllerian Duct Syndrome 17.5.1.6 Primary Amenorrhoea 17.5.1.7 Hypothalamic Hypogonadism 17.5.2 Biopsy/Excision of Intra-Abdominal Gonads 17.5.3 Excision of Internal Genital Ducts 17.5.4 Cloacal Anomalies 17.6 Vaginoplasty 17.6.1 Mayer-Rokitansky-Küster-Hauser Syndrome and Complete Androgen Insensitivity Syndrome 17.6.2 Partial Müllerian Agenesis References 18: Gynaecological Management 18.1 Introduction 18.2 Neonatal Period 18.2.1 Talking with Parents 18.2.2 Surgical Input 18.2.3 Timing of Surgery 18.2.4 Reproductive Prognosis 18.3 Childhood 18.4 Adolescence 18.4.1 General Issues 18.4.2 Genital Appearance and Function 18.4.3 Vaginal Surgery 18.4.4 Genital Sensation and Sexual Function 18.5 Gonadal Surgery 18.6 Conclusion References 19: Psychosocial Support 19.1 Psychosocial Support 19.2 Development of Psychosocial Systems and Sharing Information 19.3 Psychosocial Implications of DSD 19.4 What Is Psychosocial Support? 19.5 The Role of the Multidisciplinary Team 19.6 Multidisciplinary Team Clinical Meeting 19.7 Sharing Information About a DSD Diagnosis 19.8 Informing the Parents of Their Child’s Condition/Variation 19.9 Psychosocial Counselling Service for Families of an Infant with  Uncertain Sex 19.10 Celebrating the Birth of a Baby with a DSD to Family and Friends 19.11 Issues Faced by Families of Infants and Young Children with DSD 19.11.1 Adaptation 19.11.2 Parent Pre-existing Issues 19.11.3 Dealing with Uncertainties 19.11.4 Family Issues 19.11.4.1 Decision Regarding the sex of rearing at Day 1 or 2 19.11.5 Other Selected Associations 19.11.6 Discussion 19.11.7 Issues for Families at Subsequent Counselling 19.11.8 What Does the Family Need from Psychosocial Services? 19.11.9 Sharing Information About a of Sex Development to a Child References 20: Psychological Management in Adolescence and Beyond 20.1 Introduction 20.2 Psychosocial and Psychosexual Issues in Adolescents and Adults with DSD 20.3 Psychological Issues in DSD 20.3.1 Psychopathology 20.3.2 Quality of Life 20.3.3 Sports and DSD 20.4 Psychosexual Issues in DSD 20.4.1 Psychosexual Development 20.4.2 Gender Dysphoria 20.4.3 Diagnosing Gender Dysphoria 20.4.4 Psychosexual Outcomes 20.4.4.1 Congenital Adrenal Hyperplasia (CAH) 20.4.4.2 Complete Androgen Insensitivity Syndrome (CAIS) 20.4.4.3 Partial Androgen Insensitivity Syndrome (PAIS) 20.4.4.4 Enzyme Deficiencies 20.4.4.5 Other DSD 20.5 Psychosocial Care in Adolescents and Adults 20.5.1 Initial Diagnosis in Adolescents and Adults 20.5.2 Information Management 20.5.3 Medical Trauma 20.5.4 Puberty and Sexuality 20.5.5 Gender Assignment and Reassignment 20.5.6 Gender Dysphoria and DSD 20.5.7 Infertility 20.5.8 Role of Support Groups 20.6 Future Research Focus 20.7 Summary References 21: Genetic Counselling 21.1 Introduction 21.2 Overview of Genetic Counselling 21.2.1 Diagnostic and Clinical Aspects 21.2.2 Documentation of Family and Pedigree Information 21.2.3 Recognition of Inheritance Patterns and Risk Estimation 21.2.4 Communication 21.2.5 Information on Available Options 21.2.6 Support in Decision-Making and for Decisions Made 21.3 Reproductive Options 21.4 Genetic Testing 21.4.1 Cytogenetics 21.4.2 Gene Testing 21.5 Genetic Counselling for Specific DSD 21.5.1 Sex Chromosome DSD 21.5.1.1 47,XXY 21.5.1.2 45,X 21.5.1.3 45,X/46,XY 21.5.1.4 46,XX/46,XY 21.5.2 46,XY DSD 21.5.2.1 46,XY Complete Gonadal Dysgenesis (Swyer Syndrome) and 46,XY Partial Gonadal Dysgenesis DSD 21.5.2.2 XY Ovarian DSD 21.5.2.3 Complete (CAIS) or Partial Androgen Insensitivity Syndrome (PAIS) 21.5.2.4 Hormone Biosynthetic Defects 21.5.3 Rare Syndromes 21.5.3.1 Campomelic Dysplasia and SOX9 21.5.3.2 WT-1 21.5.4 Isolated Anomalies 21.5.4.1 Hypospadias 21.5.4.2 Cryptorchidism 21.5.5 46,XX DSD 21.5.5.1 XX Testicular DSD 21.5.5.2 46,XX Ovotesticular DSD 21.5.5.3 Congenital Adrenal Hyperplasia 21.5.5.4 Rare Syndromes 21.5.5.5 Isolated Anomalies References 22: Cultural Differences in the Developing World 22.1 DSD Subtypes 22.2 Delayed Presentation 22.3 Investigations 22.4 Treatment 22.5 Sex Assignment 22.6 Socioeconomic and Cultural Influences 22.6.1 Hijra 22.6.2 Influence of Religion 22.7 Legal Issues 22.8 Problems with Compliance and Follow-Up 22.9 Our Experience 22.9.1 Some Stories 22.9.1.1 Story 1 22.9.1.2 Story 2 22.9.1.3 Story 3 22.9.1.4 Story 4 22.9.1.5 Story 5 References 23: Short, Medium and Long-Term Outcomes for DSD at The Royal Children’s Hospital 23.1 Introduction 23.2 Short-Term Results 23.3 Medium-Term Results 23.4 Long-Term Psychosocial and Psychosexual Outcomes in Young Adults References 24: Outcomes of Individuals with DSD: A World View 24.1 Introduction 24.2 Understanding Outcome Studies: Factors Influencing Interpretation 24.2.1 Recruitment 24.2.2 Cohort Participant’s Profile 24.2.3 Health Resources 24.2.4 Regional Cultural Preferences 24.2.5 Cohort: Medical Care and Expertise of Their Carers 24.2.6 Cohort Age—Changes in Care over Time 24.3 Measuring Outcomes 24.3.1 Quality of Life, Well-Being Measures 24.3.2 Gender Outcomes 24.3.3 Risk of Malignancy 24.3.4 Fertility Potential 24.3.5 Measuring Surgical Outcomes 24.4 Outcomes by DSD Classification 24.4.1 46,XX DSD 24.4.1.1 Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency) (CAH) 24.4.1.2 46,XX Ovo-Testicular DSD 24.4.1.3 46,XX Testicular DSD 24.4.1.4 46,XX Müllerian Agenesis Syndrome 24.4.2 46,XY DSD 24.4.2.1 Complete Androgen Insensitivity Syndrome (CAIS) 24.4.2.2 Partial Androgen Insensitivity Syndrome (PAIS) 24.4.2.3 5α-Reductase-2 Deficiency 24.4.2.4 17β-Hydroxysteroid Dehydrogenase (17β-HSD) Deficiency 24.4.2.5 46,XY Lipoid Adrenal Hyperplasia and 46,XY, 17β-Hydroxylase Deficiency 24.4.2.6 46,XY Complete Gonadal Dysgenesis 24.4.2.7 46,XY Partial Gonadal Dysgenesis (GD) 24.4.2.8 Persistent Müllerian Duct Syndrome 24.5 Cloacal Exstrophy 24.6 Sex Chromosome DSD 24.6.1 45,X/46,XY Mixed Gonadal Dysgenesis 24.6.2 47,XXY Klinefelter Syndrome with Atypical Genitalia 24.7 Discussion and Conclusion References 25: Complete Androgen Insensitivity Syndrome: A Guide for Parents and Patients 25.1 Introduction 25.2 How AIS Was First Recognised 25.3 The Nature of AIS 25.4 Hormones 25.4.1 Androgen 25.4.2 Androgen and Masculine Sexual Development 25.4.3 The Internal Reproductive Organs 25.4.4 Androgen Receptor 25.5 The Genetic Basis of AIS 25.5.1 Chromosomes and Genes 25.5.2 The Androgen Receptor Gene 25.5.3 The Inheritance of AIS 25.6 The Diagnosis of CAIS 25.7 Hormonal Changes During Childhood and Adolescence 25.8 Surgery for Individuals with AIS 25.8.1 Testes 25.8.2 The Vagina 25.9 Lack of Pubic and Underarm Hair 25.10 Counselling and Support 25.10.1 Parents of Newly Diagnosed Children 25.10.2 Parents of Children and Teenagers 25.10.2.1 Children Aged 6–11 Years 25.10.2.2 Adolescents with AIS 25.10.3 Adults 25.10.4 Support Groups Further Reading Index