Ambiguous genitalia Flashcards
Congenital adrenal hyperplasia:
What is the incidence of CAH?
Incidence 1 in 14,000
Commonest cause of ambiguous genitalia
(RCOG E-learning)
Congenital adrenal hyperplasia:
What is the most common cause of CAH?
90% is due to 21-hydroxylase deficiency.
Congenital adrenal hyperplasia:
What is the pathophysiology of 21-hydroxlyase deficiency CAH?
- 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.
Congenital adrenal hyperplasia:
What clinical features or presentation would you expect with CAH?
- Classic salt-losing
- classic non salt-losing
- Non-classical (late onset)
Females:
- Classic: Ambiguous genitalia - clitoromegaly, increased rugosity of the labial majora, single urogenital sinus. (Vagina can join posterior wall of urethra.)
- Salt-losing crisis within first 7-14 days of life (dehydration, hyponatremia, hyperkalemia)
- Late-onset CAH during puberty: similar presentation to PCOS.
Males:
- Hyperpigmented scrotum, enlarged phallus
- Salt losing crisis
- In non-salt-losing cases - may only be noted when develop early virilisation at 2-4 years (pubic hair/axillary hair/adult body odour etc)
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.
- 17-OHP level: HIGH
- Synacthen test: increased 17-OHP but not increased cortisol level.
5 alpha-reductase deficiency:
What is the pathophysiology of 5 alpha-reductase deficiency?
- 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
5 alpha-reductase deficiency:
What investigation would you perform to diagnosis 5 alpha-reductase deficiency?
- Basal and/or hCG-stimulated serum testosterone and DHT levels:
- Normal testosterone levels
- Increased testosterone to DHT ratio >20.
5 alpha-reductase deficiency:
Outline your management for a patient with 5 alpha-reductase deficiency who will be raised female:
- 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
- Vaginal dilators +/- vaginal reconstructive surgery
- HRT until age of menopause
- Will never be able to carry children - will require donor oocytes and surrogate OR adoption
5 alpha-reductase deficiency:
Outline your management for a patient with 5 alpha-reductase deficiency who will be raised MALE:
- Psychosexual counselling and support
- Genetics counselling
- Surgery to correct:
- Hypospadias
- Cryptorchidism
Complete and partial androgen insensitivity syndrome:
Describe the pathophysiology of CAIS and PAIS:
- Defect in androgen receptor function, causing complete or partial insensitivity to androgens.
- Coded by single-copy gene on X-chromosome (Xq11-12).
- Normal testicular production of androgens.
- Incomplete or absent virilisation of external genitalia - causing female or ambiguous genitalia
- Normal functioning testes produce AMH leading to regression of Müllerian structures (no uterus, tubes or upper vagina).
- Mesonephric ducts regress in majority therefore no epididymus, vas deferens, seminal vesical or prostate.
- The excess amounts of androgens can be converted to estrange by peripheral aromatase action, causing female phenotype including normal breast development.
- The undescended testis may be abdominal, pelvic or present as inguinal hernia or labial.
Complete and partial androgen insensitvity syndrome:
Describe the clinical presentation of a patient with CAIS:
- Usually ot diagnosed till puberty, when primary ammenorrhea triggers medical assessment
- Female external genitalia
- Blind-ending vaginal pouch.
- Absent uterus and other mullerian structures
- Undescended testes present in abdomen or inguinal region - may present with inguinal hernia
- Slow pubertal development, but can get breast development (due to peripheral aromatisation of androgens to estrone)
- Primary amenorrhoea (no uterus)
- Scant or no pubic and axillary hair (androgen controlled)
Describe the clinical presentation of a patient with partial androgen insensitvity syndrome:
- Often diagnosed soon after birth as presents with ambiguous genitalia
- Varying degrees of virilisation:
- Micropenis
- Hypospadias
- Ambiguous genitalia
- Spermatogeneis defects (infertility)
- Location of gonads: inguinal or scrotal
- Some virilisation occurs at puberty (which does not occur with CAIS):
- Ranging from gynaecomastia to breast development.
- Sparse or slightly diminished pubic and axillary hair.
Complete and partial androgen insensitvity syndrome:
What is the incidence of CAIS/PAIS?
1 in 20,000-40,000
Complete and partial androgen insensitivity syndrome:
What investigations would you perform in your work up for this condition?
- Karyotype: 46 XY
- Testosterone level: normal
- LH level: normal to elevated.
- hCG stimulation test of testerone level: normal rise in testosterone level
- Normal testosterone:dihydrotestosterone ratio (normal 5a-reductase activity)
- Inhibin B level: normal (functioning Sertoli cells)
- Ultrasound or MRI abdo/pelvis
- To locate gonads.
- Absence of Müllerian structures.
- Molecular genetic testing for x-linked mutation for androgen receptors
Complete and partial androgen insensitivity syndrome:
What is your management plan for a patient with CAIS?
- 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 for puberty induction
- HRT until menopause
- Osteoporosis and CVD prevention.
- Sexual function: vaginal dilators +/- reonstructive surgery
- Fertility referral: options include adoption or gamete donation + surrogacy.
