Sex Development Disorders and Precocious Puberty Flashcards
What is the inheritance of Congenital Adrenal Hyperplasia?
Autosomal recessive
What is the most frequent enzyme deficiency in Congenital Adrenal Hyperplasia and what proportion of cases does it constitute?
21-hydroxylase deficiency
>90% of cases
What is the function of 21-hydroxylase?
- Catalyzes the conversion of 17-hydroxyprogesterone to 11-deoxycortisol, a precursor of cortisol
- Catalyzes the conversion of progesterone to deoxycorticosterone, a precursor of aldosterone
How does a lack of 21-hydroxylase explain the phenotype?
- Excess cortisol precursors - diverted into sex hormone synthesis, ie excess androgens
- Aldosterone deficiency - salt wasting (75%)
- Postnatal virilization, precocious puberty and rapid somatic growth (ie short stature) if inadequately treated
NB spectrum of the above
How many births are detected with classic 21-hydroxylase deficiency?
1 in 16,000
What do the female and male genitalia look like in CAH?
Female:
Ambiguous - large clitoris, common urogenital sinus, partially fused labia majora but normal uterus, fallopian tubes, ovaries. No Wolffian duct.
Male:
Usually subtle hyperpigmentation and penile enlargement
What are the fertility rates in women with CAH?
80% simple virilizing disease
60% salt wasting disease
How is classic CAH diagnosed?
Elevated 17-hydroxyprogesterone
ACTH stimulation test (high dose)
What is the treatment of CAH?
Glucocorticoids (hydrocortisone)
Fludrocortisone if salt wasting type
Surgical correction of ambiguous genitalia
At what age is precocious puberty defined?
Devlopment of secondary sex characteristics < age 8
What is the incidence of precocious puberty?
1:5000-10,000
F:M 10:1
What is the biochemical mechanism of puberty?
- Increased pulsatile GnRH
- Increased LH and FSH during sleep, then 24 hrs
- Ovarian follicles -> oestrogen
What is adrenarche and when is its onset?
Androgen-dependent signs of puberty (pubic/axillary hair, greasy hair, skin, etc)
Precedes gonadarche
Begins by 6-8 years
How long after thelarche is menarche and what is the median age of menarche in the UK?
Usually occurs within 2-3 years
Median age - 13
What are the 3 classifications of premature sexual development?
- Central, true - gonadotrophin-dependent
- Peripheral, pseudo - gonadotrophin-independent
- Isolated variants - precocious pubarche, thelarche or menarche
What are the causes of central precocious puberty?
NB always isosexual
- Idiopathic (75%)
- CNS pathology/lesion (Harmatomas, tumours, congenital e.g. hydrocephalus, acquired e.g. post-irradiation, trauma, infection, meningitis)
- Secondary to peripheral precocious puberty
What are the causes of peripheral precocious puberty?
- Ovarian
- Oestrogenic e.g. granulosa tumour, cyst
- Androgenic e.g. Sertoli-Leydig cell tumour, arrhenoblastoma (contrasexual) - Adrenal
- CAH (contrasexual)
- Cushing syndrome
- Neoplasm - Exogenous sex hormones
- McCune-Albright syndrome
- Severe long-standing hypothyroidism
What is the growth pattern in precocious puberty?
Initial tall stature and accelerated growth
Then get premature fusion of epiphyses and end up with compromised final height
How is Central precocious puberty diagnosed?
LH and FSH measured sequentially after GnRH analogue - LH>FSH ratio >1
What is the treatment of central precocious puberty?
Depends on brain lesion - often conservative or GnRH analogues dependent on age of onset.
What is McCune-Albright syndrome and what is its treatment?
Caused by activating mutations of GNAS1 gene
Polyostotic fibrous dysplasia (bone cysts)
Cafe au lait spots
Peripheral precocious puberty
May see raised prolactin levels in some - pituitary adenomas associated
Rx: Suppression of gonadal steroidogenesis with aromatase inhibitors
How are androgen-producing adrenal tumours diagnosed biochemically?
Raised serum DHEAS
May see very elevated urinary 17-ketosteroid levels
What is the phenotype of Mayer-Rokitansky-Kuster-Hauser syndrome and why does it happen?
- Congenital absence upper 2/3 vagina (caudal part)
- Absent/rudimentary uterus (mid part)
- Normal secondary sex characteristics
- Ovaries absent/hypoplastic in 10%
- Often associated renal abnormalities (up to 40%) - 12% absent kidney
- Skeletal abnormalities (12-20%) incl Klippel-Fiel anomaly
- Auditory malformations 10-25%
- 46XX
Agenesis/hypoplasia of Mullerian (paramesonephric duct)
(Fuse 12th week)
What are the eponymous surgical procedures recommended for MRKH syndrome?
Vecchieti - dilating ‘olive’ suspended intraperitoneally and gradual traction to create neovagina. Removed and maintained by dilators/regular SI
Davydov - neovagina from woman’s own peritoneal lining - postop mould and dilators for 6/52
What is the inheritance of androgen insensitivity syndrome?
And the karyotype/phenotype of CAIS?
X linked recessive - mutation in AR gene on Xq11-13
Karyotype - 46XY
Phenotype - External female genitalia with male testes; no fallopian tubes/uterus/proximal vagina (as normal AMH), no pubic/axillary hair
How is CAIS differentiated from 5-alpha reductase deficiency?
CAIS/PAIS have normal production of testosterone and conversion to dihydrotestosterone (DHT)
NB 5-ARD is autosomal recessive
What is the incidence of AIS?
1 in 20,400
In which sex devlopment disorder should gonadectomy be performed to reduce the risk of malignancy?
Complete Androgen Insensitivity Syndrome
Risk 0-22% of developing gonadoblastoma
From which embryological layers does the urogenital system develop?
Intermediate mesothelium of the peritoneal cavity and the endoderm of the urogenital sinus
At what gestation do primordial germ cells form?
By week 4
Migrate to developing ovary by week 6 and differentiate into oogonia
What is the incidence of MRKH syndrome?
1 in 5000 female births
What is the incidence of transverse vaginal septum?
1 in 30,000-50,000
What is the biochemical profile in CAH?
- Insufficient cortisol
- Stimulates CRH (hypothalamic)
- Chronically elevated ACTH
- Stimulates adrenal gland - hyperplastic
