Differences in sex development

Question 1

Describe how DSDs emerge

Answer 1

• Differentiation of indifferent gonad into ovaries or testes starts around Wk 6 (~1 month after LMP)
• Tightly regulated by serial time-specific interaction of transcription factors, growth factors, and differentiating factors
• Critical windows of gene expression
• Proliferation, differentiation, and apoptosis need to be in balance.
• As common as congenital hypothyroidism (depending on diagnostic groups included)

Question 2

Describe the different factors involved in sex development

Answer 2

• Chromosomal sex
• Genes (most genetic conditions are not all or none – genes interact and may have partial function, therefore, its a spectrum)
• Gonads morphology and physiology
• Hormones and factors that interact with them (either fetally derived, maternal, exogenous)
  
  • steroid hormones are taken into the cell and act at the nuclear level
  • interact with chaperone molecules that may stimulate or suppress the effect
• Hormone responsiveness/resistance

Question 3

Describe genetic gonadal determination

Answer 3

• SRY (on Y chromosome) and SOX9 (homeobox gene) are key regulators
• Mutual antagonism of each pathway is seen by key regulators
• Early genes are all transcription factors.
• Expression of key genes is both time-critical and time-limited
• The ovary requires the presence of genes to drive its differentiation and maintenance without which it doesn’t develop.
  
  • not just solely dependent on the absence of testosterone

Question 4

Describe steroid biosynthesis and DSD

Answer 4

• Some compartmentalisation of this - some enzymes present only in the gonad, some only in adrenal gland and some present outside both of these (e.g. aromatase in fat cells convert weak androgens into oestrogen)
• Compartmentalisation important for phenotypic changes
  
  • Defects more proximal in pathway will have more severe clinical phenotype e.g. abnormal gonadal function and abnormal adrenal function

Question 5

Describe disorders of 46 XY - gonadal development

Answer 5

• Ovotesticular DSD
  
  • Complete or partial gonadal dysgenesis
  • Monogenic forms (caused by mutations in SRY, SF1, WT1, and others)
  • Syndromic forms

Question 6

Describe disorders of 46 XY: androgen synthesis

Answer 6

• Syndromic (e.g., Smith–Lemli–Opitz syndrome)
  
  • Congenital adrenal hyperplasia and early androgen biosynthetic defects (e.g., mutations and/or deficiencies in StAR, P450(scc), 3β-HSD II, P450R, and CYP17A1)
  • Sole androgen biosynthetic defects (e.g., mutations and/or deficiencies in SRD5A2 and HSD17B3)
  • Associated with endocrine disruption by environmental chemical exposure (e.g., Bisphenols and Phthalates)

Question 7

Describe disorders of 46 XY: androgen action and unclassified disorders

Answer 7

• Disorders of androgen action
  
  • Complete and partial androgen insensitivity
• Unclassified disorders
  - Hypospadias of unknown genetic origin
  - Epispadias
  - Complex syndromic disorders

Question 8

List disorders of 46XX

Answer 8

• Unclassified disorders
  - Mayer–Rokitansky–Küster–Hauser syndrome
  - Complex syndromic disorders
  
  • Disorders of gonadal development
    
    • Ovotesticular DSD
    • Testicular DSD
    • Syndromic forms
  • Disorders of androgen excess
    
    • Congenital adrenal hyperplasia (mostly CYP21 deficiency)
    • Aromatase deficiency
    • Luteoma
    • Iatrogenic (maternal androgen exposure or high-dose progesterone)

Question 9

Describe chromosomal DSDs

Answer 9

• 45,X (Turner syndrome and variants)
  - Varying abnormalities of 2nd X chromosome usually resulting in loss of that chromosome
  - almost all have some level of mosaicism - likely that they have small numbers of cell lines elsewhere
  - if the second cell line happens to be a Y-chromosome derivative, there may be a high incidence of gonadal neoplasia
  
  • 45X/46,XY (mixed gonadal dysgenesis)
  • 47,XXY (Klinefelter syndrome and variants)
    
    • most don’t actually have abnormalities of genitalia and may have mosaicism
  • Other complex chromosomal rearrangements including mosaicism and chimerism

Question 10

List and describe some common DSDs

Answer 10

• The answer depends on which conditions are included in the classification of DSD.
  
  • 47XXY Klinefelter Syndrome incidence 1:500-800
  • Turner Syndrome and variants incidence ~ 1:4500
• Congenital Adrenal Hyperplasia
  
  • 90% of them are Cyp21, second commonest is Cyp11, all others are rare
  • Incidence 1:10 000 but higher in some population groups
• Hypospadias
  
  • Affects 1:200 boys
  • If testes are normal size and position, not usually considered a DSD
    
    • May just have deficiency in ventral part of foreskin where urethral opening is at tip of fallus or may have tethering of fallus at base of fallus i.e. big spectrum of severity
  • The LGBTIQ community does, however, consider this a DSD

Question 11

Describe investigation and management of DSDs

Answer 11

• Initial investigation - family Hx and clinical assessment
• Ultrasound of internal structures - may be difficult to ascertain what the internal genitalia are
  
  • Presence/absence of Mullerian-derived uterus, fallopian tubes and upper part of vagina
• Measure for CAH using 17-OHP and adrenal steroid profile in urine
  
  • Foetal adrenal zone is part of adrenal cortex only present in utero - involutes first weeks post-natally
    
    • Can interfere with assessment of steroid profile
• Other imaging techniques may be necessary e.g. MRI
• Karyotype for chromosomal sex
• Other biochemistry
  
  • AMH and inhibin B can give prediction of Sertoli cellfunction
  • LH/FSH indicate end-organ function e.g. baby with gonadal dysgenesis (46XX and ↑ LH/FSH) implies problem with ovary itself

Question 12

Describe the darlington statement

Answer 12

• Developed by group fo people who identify as Intersex and allies
• Covers issues related to Human Rights
  
  • Aims to ban all genital surgery
  • Free access to medical records for affected people
  • Stop unnecessary examinations
• Peer support importance
• Appropriate lifelong support and follow-up where this is needed
• Seeks to have Government endorse the statement
• Evidence for/against early surgical management of children with
  DSD
  
  • Where should the line be drawn in diagnostic terms?
• How does the approach fit with what is used for other congenital
  paediatric disorders e.g. cleft palate, limb deformities,
  craniofacial syndromes

Question 13

Describe the approach to managing people born with DSD

Answer 13

• Multidisciplinary Management in Centres of Excellence
  
  • Ethicist
  • Clinical Geneticist
  • Paediatric Endocrinologist
  • Urologist/Paediatric Surgeon/Gynaecologist
  • Psychologist and Social Worker
• Decision Making Informed by:
  
  • Accurate diagnosis including the use of modern genetics (whole exome sequencing)
  • Long-term outcomes for specific conditions (where available)

Question 14

Describe the approach to managing people born with DSD - considerations

Answer 14

• Human rights principles
• Enabling fulfilling sexual function
• Optimizing psychological/mental health outcomes
  
  • Ensuring psychological trauma is minimized by avoiding unnecessary exams
  • Risk of gender dysphoria for a specific condition
• Potential for fertility where possible
• Impact of androgens on brain/behavior
• Delaying procedures where doing so enables patient autonomy, especially if doing so does not adversely affect:
  
  • Physical health (e.g., malignancy risk, operative outcomes at different ages – functionally and cosmetically)
  • Psychological health (impact of growing up without an operation)
• Respectfully considers cultural/religious expectations and ensures respect for parental rights.

Question 15

Describe the approach to managing people born with DSD - ACT considerations

Answer 15

• Legislation being drafted to require all children with conditions determined (by a public service LGBTIQ team) to be intersex to be overseen by a regulatory/oversight committee.
• Proposal to penalize medical staff and parents who attempt to undertake medical or surgical treatments within or outside the ACT with jail time of 1-2 years.
• Key issue has been the definition of what is defined as “intersex variations”
  
  • Circumcision excluded
  • Hypospadias dependent on severity or presence of other features
  • Hypogonadism – to be included.
    
    • Including Turner Syndrome and Klinefelter Syndrome and potentially acquired forms (e.g., post-treatment for childhood cancer with chemotherapy).**