Ambiguous genitalia

Question 1

Congenital adrenal hyperplasia:

What is the incidence of CAH?

Answer 1

Incidence 1 in 10,000

Question 2

Congenital adrenal hyperplasia:

What is the most common type of CAH?

Answer 2

90% is due to 21-hydroxylase deficiency.

Question 3

Congenital adrenal hyperplasia:

What is the pathophysiology of 21-hydroxlyase deficiency CAH?

Answer 3

• 21-hydroxylase is an enzyme integral to the corticosteroid production pathway.
• Deficiency of 21-hydroxylase interrupts production of:
  
  • Cortisol
  • Aldosterone
• Low cortisol levels leads to an increase in ACTH which causes hyperplasia of the adrenal gland.
• Increased levels of 17-hydroxyprogesterone (17-OHP) are made and shunted towards production of androgens leading to hyperandrogenism and virilisation.

Question 4

Congenital adrenal hyperplasia:

What clinical features or presentation would you expect with CAH?

Answer 4

• Ambiguous genitalia: clitoromegaly, increased rugosity of the labial majora, single urogenital sinus.
  
  • Vagina can join posterior wall of urethra.
• Salt-losing crisis
• Late-onset CAH during puberty: similar presentation to PCOS.

Question 5

Congenital adrenal hyperplasia:

Describe the test results for these investigations:

• 17-hydroxyprogesterone level
• Synacthen (synthetic ACTH) test with measurement of cortisol and 17-OHP measured 30 and 60 mins after administration of synacthen.

Answer 5

• 17-OHP level: HIGH
• Synacthen test: increased 17-OHP but not increased cortisol level.

Question 6

5 alpha-reductase deficiency:

What is the pathophysiology of 5 alpha-reductase deficiency?

Answer 6

• Autosomal recessive 46XY.
• Have bilateral testes and normal production of testosterone but 5 alpha-reductase deficiency prevents conversion of testosterone to DHT which is needed for fetal virilisation.
• Ambiguous or female external genitalia at birth.
• AMH production normal leading to absence of Müllerian duct structures.
• Internal urogenital tract is male: epididymis, vas deferens, seminal vesicle, ejaculatory ducts empty into blind-ending vagina.
• Virilisation at puberty

Question 7

5 alpha-reductase deficiency:

What investigation would you perform to diagnosis 5 alpha-reductase deficiency?

Answer 7

• Basal and/or hCG-stimulated serum testosterone and DHT levels:
  
  • Normal testosterone levels
  • Increased testosterone to DHT ratio >20.

Question 8

5 alpha-reductase deficiency:

Outline your management for a patient with 5 alpha-reductase deficiency who will be raised female:

Answer 8

• Psychosexual counselling and support.
• Genetics counselling
• Gonadectomy before puberty:
  
  • To prevent virilisation during puberty.
  • To reduce risk of malignancy.
• Oestrogen therapy to start at puberty to induce and maintain feminisation:
  
  • Breast development
  • Osteoporosis prevention

Question 9

5 alpha-reductase deficiency:

Outline your management for a patient with 5 alpha-reductase deficiency who will be raised MALE:

Answer 9

• Psychosexual counselling and support
• Genetics counselling
• Surgery to correct:
  
  • Hypospadias
  • Cryptorchidism

Question 10

Complete and partial androgen insensitivity syndrome:

Describe the pathophysiology of CAIS and PAIS:

Answer 10

• Defect in androgen receptor function. Coded by single-copy gene on X-chromosome (Xq11-12).
• Normal testicular production of androgens.
• Incomplete or absent virilisation of external genitalia
• Normal functioning testes produce AMH leading to regression of Müllerian structures (no uterus, tubes or upper 2/3rds of vagina).

Question 11

Complete and partial androgen insensitvity syndrome:

Describe the clinical presentation of a patient with CAIS:

Answer 11

• Female phenotype
• Normal breast development
• Primary amenorrhoea
• Scant or no pubic and axillary hair
• Normal external female genitalia
• Blind-ending vaginal pouch.
• Absent uterus but testes present in abdomen or inguinal region.

Question 12

Complete and partial androgen insensitvity syndrome:

Describe the clinical presentation of a patient with PAIS:

Answer 12

• Varying degrees of virilisation:
  
  • Hypospadias
  • Ambiguous genitalia
  • Spermatogeneis defects (absent to severe impairment)
• Location of gonads: inguinal or scrotal
• Some virilisation occurs at puberty (which does not occur with CAIS):
  
  • Ranging from gynaecomastia to brest development.
  • Sparse or slightly diminished pubic and axillary hair.

Question 13

Complete and partial androgen insensitvity syndrome:

What is the incidence of CAIS/PAIS?

Answer 13

1 in 20,000

Question 14

Complete and partial androgen insensitivity syndrome:

What investigations would you perform in your work up for this condition?

Answer 14

• Karyotype: 46 XY
• Testosterone level: normal
• LH level: normal to elevated.
• Inhibin B level: normal (functioning Sertoli cells)
• Ultrasound or MRI abdo/pelvis: to locate gonads.
  
  • Absence of Müllerian structures.
• hCG stimulation test of testerone level: normal rise in testosterone level.

Question 15

Complete and partial androgen insensitivity syndrome:

What is your management plan for a patient with CAIS?

Answer 15

• Disclosure and psychosexual counselling and support.
  
  • Will never menstruate or be able to bear children.
• Post-pubertal gonadectomy: to prevent germ cell tumours.
  
  • No risk of virilisation as complete androgen insensitivity.
• Oestrogen therapy at puberty:
  
  • Osteoporosis prevention.
• Sexual function: vaginal dilators.
• Fertility referral: options include adoption or gamete donation + surrogacy.