Congenital adrenal hyperplasia
Congenital adrenal hyperplasia
(CAH) is a family of disorders character-ized by enzyme defects in the
steroidogenic pathways that lead to the bio-synthesis of cortisol, aldosterone,
and androgens. The relative decrease in cortisol production, acting via the
classic negative feedback loop, results in increased secretion of ACTH from the
anterior pituitary gland and to sub-sequent hyperplasia of the adrenals. All
forms of CAH are inherited in an autosomal recessive manner, and their clinical
manifestation is determined by the effects produced by the particular hormones
that are deficient and by the excess production of steroids unaffected by the
enzymatic block.
The causes of CAH include
deficiencies in the following steroidogenic pathway enzymes:
· 21A-hydroxylase (CYP21);
· 11B-hydroxylase (CYP11);
· 3B-hydroxysteroid dehydrogenase;
· 17A-hydroxylase/17–20 lyase (CYP17);
· side-chain cleavage (SCC/StAR).
Deficiency of the 21-hydroxylase
enzyme is the most common form of CAH, accounting for over 90% of cases.
CAH due to deficiency of the 21A-hydroxylase enzyme arises as a
result of deletions or deleterious mutations in the active gene (CYP21) located on chromosome 6p. Many
different mutations of the CYP21 gene
have been identified, causing varying degrees of impairment of 21A-hydroxylase ac-tivity that result
in a spectrum of disease expression. CAH can be classified according to
symptoms and signs and to age of presentation.
· Classic
CAH: includes a severe
‘salt wasting’ form that usually presents
with acute adrenal crisis in early infancy (usually males at 7–10 days of
life), and a ‘simple virilizing’ form in which patients demonstrate
masculinization of the external genitalia (females at birth) or signs of
virilization in early life in males.
· Non-classic
(late onset) CAH: this
presents in females with signs and symptoms
of mild androgen excess at or around the time of puberty.
The incidence of CAH due to 21A-hydroxylase deficiency has been
reported to be in the region of 1 in 10,000–17,000 in Western Europe and the
USA, with an overall worldwide figure of approximately 1/14,000 births.
‘Classic’ CAH is diagnosed by
demonstrating characteristic biochemical abnormalities, which are present
regardless of severity, age, and sex of the infant:
· elevated plasma
17-hydroxyprogesterone levels;
· elevated plasma 21-deoxycortisol
levels;
· increased urinary
adrenocorticosteroid metabolites.
Note:
It may be difficult to distinguish
elevated androgen levels from the physiological
hormonal surge that occurs in the first 2 days of life. These tests should be
postponed or repeated after 48hr of age.
In the ‘salt-wasting’ form, the
aldosterone deficiency results in hyponat-raemia, hyperkalaemia, and metabolic
acidosis. However, these are not specifi c fi ndings and can cause diagnostic
confusion with children present-ing with more common causes of renal tubular
dysfunction, such as acute pyleonephritis.
Required in all patients. In
addition to treating cortisol deficiency, this therapy also suppresses the
ACTH-dependent excess adrenal androgen production. Standard therapy usually
consists of: hydrocortisone: oral 15mg/m2/day in 3 or 4 divided
doses.
As in other disorders associated
with cortisol insufficiency, during peri-ods of stress and illness increased
amounts (e.g. double or triple dose) of glucocorticoid therapy are required.
For the salt-wasting form of CAH
only: fludrocortisone: oral 50–300mi-crograms/day.
Resistance to mineralocorticoid
therapy is usually seen in infancy. Sodium chloride supplements are often
required during this period of life to main-tain normal electrolyte balance.
Once a normal solid diet is established salt supplements may be discontinued.
Sodium
chloride solution: oral,
added to feed, 2–10mmol/kg/day in divided
doses.
Reconstructive surgery (clitoral
reduction and vaginoplasty) is usually per-formed in infancy in females with
significant virilization of the external genitalia.
Regular monitoring of patients by
a specialist team is required in order to ensure the child’s optimal growth and
development.
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