Congenital Adrenal Hyperplasia Flashcards
Define
Most common non-iatrogenic cause of low cortisol and MR secretion
- Incidence 1 in 17,000 births
- Multiple forms of CAH – 90% are a deficiency of 21-hydroxylase enzyme
- Autosomal recessive
The foetal gonads are initially bipotential
* In males, a testis-determining gene on the Y chromosome (SRY gene) is responsible for the differentiation of the gonad into the testis
* The subsequent production of testosterone and dihydrotestosterone results in the development of male genitalia
* In the absence of SRY, the gonads become ovaries and the genitalia become female
Causes of disorders of sex development
* Excessive androgens producing virilisation in a female – e.g. due to CAH
* Most common non-iatrogenic cause of low cortisol and MR secretion
* Incidence 1 in 17,000 births
* Multiple forms of CAH – 90% are a deficiency of 21-hydroxylase enzyme
Autosomal recessive
* Inadequate androgen action, producing under-virilisation in males
* Due to inability to respond to androgens (a receptor problem- androgen insensitivity syndrome, which may be complete or partial)
* Due to inability to convert testosterone to dihydrotestosterone (5a-reductase deficiency)
* Abnormalities of the synthesis of androgens from cholesterol
Gonadotrophin insufficiency
* Seen in Prader-Willi syndrome and congenital pituitary dysfunction
* Leads to small penis and cryptorchidism
* Ovotesticular DSD (aka hermaphroditism)
Caused by the presence of both XX-containing cells and XY-containing cells in the foetus leading to the presence of BOTH testicular and ovarian tissue
Types
Signs and symptoms
Signs & symptoms (more obvious in girls than boys):
Virilisation of external genetalia
- Female infants -> clitoromegaly, fusion of labia
- Male infants -> enlarged penis and scrotum pigmented [much harder to see]
Salt-losing crisis [often the 1st sign in boys]
* Week 1 to 3 of age – more common in boys (in girls, virilisation is noted early and CAH treated)
* Vomiting, WL, hypotonia, circulatory collapse
Tall stature
* Occurs in 20% of “non-salt losers”
* Excess androgens -> muscular build, adult body odour, pubic hair, acne
Acne, hirsutism, accelerated growth and increased skeletal maturation due to XS androgens
Precocious puberty
Testes
bilateral enlargement = gonadotrophin release from intracranial lesion
unilateral enlargement = gonadal tumour
small testes = adrenal cause (tumour or adrenal hyperplasia)
Family history of neonatal death
Investigations
Initial (ambiguous genetalia, no external gonads) -> USS [examine internal genetalia]
o Confirmatory (CAH) -> raised plasma 17a-hydroxyprogesterone (cannot do in a newborn)
* The mother’s levels will often obscure the reading in a newborn
* An USS for internal genetalia may often be the best first investigation of a newborn
Biochemical abnormalities [FBC]:
* Salt-losing crisis -> low sodium, high potassium
* Metabolic acidosis -> low bicarbonate
* Hypoglycaemia -> low glucose from low cortisol
Other confirming tests:
Karyotyping
High urea (dehydrated)
Beta-hCG
Management
Management:
Corrective surgery – for affected females on the external genetalia
* Girls are raised as girls (they have a uterus and ovaries)
* Definitive surgery often delayed until early puberty
Long-term management:
* Life-long glucocorticoids (hydrocortisone) to suppress ACTH levels (and hence testosterone)
* Mineralocorticoids (fludrocortisone) if there is salt loss
* Monitoring growth, skeletal maturity, plasma androgens and 17a-hydroxyprogesterone levels
* Additional hormone replacement at times of illness or surgery [i.e. double hydrocortisone]
Salt-losing crisis -> IV hydrocortisone, IV saline, IV dextrose
Complications
Complications
* Reduced female fertility
* Short stature (premature epiphyseal closure secondary to steroid therapy
* Steroid side effects
* Death can occur from adrenal crisis at the time of illness or injury
* Some females experience psychosexual problems which may relate to high androgen levels experienced IU prior to diagnosis
* Obesity, insulin resistance and hypertension are more common
Prognosis
Good if diagnosed early
Undiagnosed infants die from salt-losing crisis
Other sex developing conditions
5a-reductase deficiency
Testosterone is required IU to allow differentiation of the Wolffian ducts into the normal male phenotypic internal reproductive tract
Differentiation of the indifferent external genital slit into the penis, prostate and scrotum does NOT require testosterone
Congenital absence of 5a reductase in these external tissues will result in feminisation
If left untreated, affected individuals are generally phenotypically female until puberty
At puberty, increased amounts of testosterone result in virilisation (known as ‘penis-at-twelve’ syndrome)
If discovered early, male gender assignment can be supported with the administration of dihydrotestosterone to increase the penis size
If discovered after infancy, a female gender assignment can be supported with administration of oestrogen substitution therapy and prophylactic orchidectomy.
Androgen Insensitivity Syndrome
X linked recessive
Due to end organ resistance to testosterone causing genotypically male children (46XY) to have a female phenotype
Features
- Primary amenorrhoea
- Undescended testes causing groin swellings
- Gonads in these patients are testes rather than ovaries and up to 90% develop inguinal hernias containing the immature testes.
- Breast development may occur as a result of a conversion to testosterone to oestradiol
Diagnosis
- Buccal smear or chromosomal analysis to reveal 46XY genotype
Management
- Counselling- raise child as female?
- Bilateral orchidectomy (increased risk of testicular cancer due to undescended testes)
- Oestrogen therapy
Complete androgen resistance
The external genitalia is feminised but neither the female-type nor the male-type internal tracts develop
In the absence of the androgen receptor, the Wolffian ducts will degenerate.
There is also degeneration of the Mullerian ducts due to the normal effect of testicular Mullerian regression factor
