Paediatrics: Congenital adrenal hyperplasia

2021-03-03 12:00 AM

Congenital adrenal hyperplasia (CAH) is a family of disorders characterized by enzyme defects in the steroidogenic pathways that lead to the biosynthesis of cortisol, aldosterone, and androgens.

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.

21α-hydroxylase deficiency

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 presentswith 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 andsymptoms 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.

Diagnosis

‘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.

Treatment

Glucocorticoid replacement therapy

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.

Mineralocorticoid therapy

For the salt-wasting form of CAH only: fludrocortisone: oral 50–300mi-crograms/day.

Sodium chloride therapy

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.

Urogenital surgery

Reconstructive surgery (clitoral reduction and vaginoplasty) is usually performed in infancy in females with significant virilization of the external genitalia.

Long-term management and monitoring

Regular monitoring of patients by a specialist team is required in order to ensure the child’s optimal growth and development.