Congenital adrenal hyperplasia (CAH)

Definition

• Congenital adrenal hyperplasia comprises a group of autosomal recessive enzyme defects of cortisol synthesis in the adrenal cortex; depending on the defect, there is additionally a deficiency or excess of mineralocorticoids and sex hormones, with androgen excess in the common 21-hydroxylase deficiency.

Classification

• About 90–95% of cases are due to 21-hydroxylase deficiency caused by mutations in the CYP21A2 gene; defects of, for example, 11β-hydroxylase or 3β-HSD are rarer.
• Clinically, classic CAH, either salt-wasting or simple virilising, is distinguished from the milder non-classic form, in which 20–80% of normal 21-hydroxylase activity is preserved.

Occurrence & epidemiology

Epidemiology

• Classic 21-hydroxylase-deficient CAH occurs in about 1 in 10,000 to 20,000 live births, about 75% of them salt-wasting; the non-classic form is more common, at about 1 in 1,000 in White populations and up to about 3% in certain groups such as Ashkenazi Jews.

Aetiopathogenesis

Aetiology and pathogenesis

• Cortisol deficiency increases ACTH secretion via loss of feedback, causing adrenal cortical hyperplasia, accumulation of precursors such as 17-hydroxyprogesterone and excess adrenal androgen production.
• Aldosterone deficiency in severe enzyme defects leads to salt wasting with hyponatraemia and hyperkalaemia.

Clinical features

• In girls with classic CAH, the external genitalia are virilised at birth with clitoral enlargement, labial fusion and a urogenital sinus, while the Müllerian ducts develop normally into the uterus and fallopian tubes.
• If unrecognised, the salt-wasting form can lead to a life-threatening adrenal crisis with hyponatraemia, hyperkalaemia, vomiting, hypoglycaemia, hypovolaemia and shock; aldosterone is low and renin is raised.
• Boys usually have normal genitalia, so the diagnosis may be delayed without screening; androgen excess presents in both sexes with early pubic hair and accelerated growth.
• Non-classic CAH is asymptomatic at birth and usually presents in childhood or adolescence, in girls with premature pubarche, advanced bone age, hirsutism, oligomenorrhoea and acne, resembling PCOS.

Diagnosis

• The key finding is raised 17-hydroxyprogesterone, measured in newborn screening; confirmation shows low cortisol and raised levels of DHEA, androstenedione and testosterone.
• In unclear cases and late presentations, an ACTH stimulation test with hormone measurement before and 60 minutes after ACTH helps; if results remain inconclusive, genotyping of CYP21A2 complements the work-up.

Keep learning in the app

Further reading (selection)

1. MSD Manual Professional: Congenital Adrenal Hyperplasia Caused by 21-Hydroxylase Deficiency
2. StatPearls: Congenital Adrenal Hyperplasia (NCBI Bookshelf)
3. Genetics and Pathophysiology of Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency (J Clin Endocrinol Metab 2025, PubMed Central)

Cross-references