Congenital adrenal hyperplasia
D E FI N I T ION
Inherited disorders of adrenal steroid synthesis.
AE T IOLOGY
Autosomal recessive genetic defects in the steroid synthesis pathway result in
# cortisol (and, in some cases, # aldosterone) synthesis. This produces a secondary rise in
pituitary ACTH secretion causing hyperplasia of the adrenal glands and build-up of precursor
steroids and in most cases androgenic steroids. Common defective enzymes include 21-
hydroxylase (most common), 11b-hydroxylase and 17a-hydroxylase.
E P IDEMIOLOGY
Annual incidence of 21-hydroxylase deficiency and 11b -hydroxylase
deficiency are one in 10 000 and one in 100 000, respectively. The rest are less common.
H ISTORY AND EXAMI N AT ION
21-Hydroxylase deficiency (# aldosterone, " androgens):
Classic: Salt-losing crisis in infants (hypotension, hyponatraemia, hyperkalaemia). Females:
Ambiguous genitalia (cliteromegaly, fused labia). Males: Precocious puberty.
Non-classic or late-onset CAH: Hirsutism, acne and menstrual irregularity in young women,
early pubarche or sexual precocity in school age children, or there may be no symptoms.
11 b-Hydroxylase deficiency ("11-deoxycorticosterone: a mineralocorticoid, " androgens):
Hypertension, hypokalaemia.
Females: Ambiguous genitalia. Males: Precocious puberty.
17a-Hydroxylase deficiency (" aldosterone, # androgens): Hypertension, hypokalaemia.
Females: Failure to develop secondary sexual characteristics at puberty. Males: Ambiguous
genitalia.
INVE S T I G A T IONS
Blood: 9 a.m. follicular phase 17OH-progesterone (" in 21-hydroxylase
deficiency and 11b-hydroxylase deficiency), testosterone, LH, FSH, U&Es. ACTH stimulation
test: Inappropriately elevated 17OH-progesterone levels after IM synthetic ACTH. Karyotyping:
Confirms gender of infantwith ambiguous genitalia. Genetic analysis may be performed
to identify specific CYP21 mutations. Men who desire future fertility: Serum testosterone
level, semen analysis and testicular ultrasound.
MANAGEMENT
Acute salt-losing crisis: IV saline, dextrose and hydrocortisone.
Glucocorticoid replacement with dexamethasone or hydrocortisone. Fludrocortisone in saltlosers.
Monitor growth in children, serum 17OH-progesterone, DHEAS, androstenedione and
testosterone (goal: slightly above the normal range). Monitor plasma renin activity and
U&Es in patients on mineralocorticoids.
Children with ambiguous genitalia: Careful evaluation by an experienced team of paediatric
endocrinologists, geneticists and paediatric surgeons (reconstructive surgery at age 2–6
months). Psychosocial support.
Non-classic CAH: If not pursuing fertility, oral contraceptives or cyproterone acetate (antiandrogen).
Those who desire fertility should receive glucocorticoids; if do not ovulate add
clomiphene citrate. Males do not usually require treatment unless they have testicular
masses (see Complications) or oligospermia (in a man desiring fertility).
CAH and pregnancy: The male partner must be screened for CAH. If 17OH-progesterone
levels are elevated, genotyping must be done. If the male partner is heterozygote, then
the foetus is at risk of inheriting CAH and developing virilization. Thus pre-natal
dexamethasone is given to the mother as soon as the pregnancy is recognized.
COM P L IC A T I ONS
Reduced fertility (caused by hyperandrogenaemia due to inadequate
glucocorticoid therapy or structural abnormalities due to androgen excess in utero or
suboptimal surgical reconstruction). Short final adult height (because of pre-mature epiphyseal
closure). Testicular adrenal rests (ectopic adrenal tissue which is stimulated by the
increased ACTH).
PROGNOSIS
Undiagnosed infants may die from salt-losing crisis. Otherwise, quality of life
is usually good
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