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.
What are 3 causes of ambiguous genitalia with a normal female karyotype?
Congenital adrenal hyperplasia
Exposure in utero to increased maternal androgens
Aromatase deficiency
What is the incidence of ambiguous genitalia?
1/4000
Almost half of the newborns with ambiguous genitalia suffer with ___ and are at risk of ______________________
CAH
Salt-losing crisis
Hypoglycaemia and electrolyte disturbances should be assessed and treated urgently
Lifelong steroid treatment will be required
What are five causes of ambiguous genitalia in an infant with a normal male karyotype?
Partial gonadal dysgenesis
Complete androgen insensitivity syndrome
Partial androgen insensitivity syndrome
Defect in testosterone biosynthesis
5-alpha reductase deficiency
What is the incidence of 5alpha reductase deficiency?
Unknown
Geographical variation reported
Increases with consanguinity
How is 5-alpha reductase deficiency diagnosed?
Normal basal testosterone and after HCG stimulation
Increased testosterone:DHT ratio after HCG stimulation test
Molecular genetic tesing for mutation
What is the Prader Staging System and the Stages
Staging system for degree of sexual ambiguity- typically in CAH
- Isolated clitoromegaly, otherwise female appearing genitalia
- Narrow vestibule with separate urethral and vaginal opening
- Single urogenital sinus / labia majora partially fused
- Empty scrotum, phallus present, hypospadius, complete labial fusion
- Isolated crypto-orchidism, otherwise male appearing genitalia
What are the genetics of Swyer syndrome?
46XY Mutation in SRY gene in 10%
Swywer syndrome:
What is the pathophysiology of Swyer syndrome?
- 46XY with complete gonadal dysgenesis / failure of testicular development.
- Caused by mutation on SRY gene leading to failure of the indifferent gonad to differentiate into a testis.
- No testosterone production leading to:
- Failure for Wolffian ducts to develop.
- No DHT and failure to virilise external genitalia; normal female external genitalia.
- No AMH production leading to persistance of Müllerian ducts and presence of uterus, tubes, cervix and upper vagina.
What is the presentation of Swyer syndrome?
- Phenotypically female
- Female external genitalia
- Presence of uterus, fallopian tubes, cervix, vagina
- Tall stature
- Absence of pubertal development due to complete gonadal dysgenesis:
- Absence of breast development
- Primary amenorrhoea
- Sparse pubic hair
- 30% risk of developing gonadal malignancy.
What investigations are appropriate for Swyer syndrome?
- FSH and LH levels: elevated
- Karyotype
- Pelvic imaging: uterus, tubes, no ovaries
- Assessment for mutation in SRY gene
What is the management of Swyer syndrome?
- Induction of puberty
- Gonadectomy as risk of malignancy
- Long-term HRT
- Childbearing is possible with ovum donation and HRT.
What is the definition of ambiguous genitalia?
Genitalia are considered ambiguous when they have an atypical appearance and it is impossible to determine the sex of the baby by inspecting them
With ambiguous genitalia and hyperpigmentation, what diagnosis should be suspected?
CAH
Excessive production of melanocyte-stimulating hormone
What is the risk of gonadal malignancy in CAIS?
3%
Gonads can be left in situ until after puberty, and decision made with patient
