Key Facts

CAH is the commonest cause of ambiguous genitalia in 46,XX neonates and the commonest adrenal cause of virilisation. The key management challenge is balancing adequate cortisol replacement to suppress androgen excess without causing growth retardation from glucocorticoid excess.

Epidemiology

Classic CAH: ~1 in 15,000. Non-classic: ~1 in 200-1,000 (commoner in certain ethnic groups — Ashkenazi Jewish, Hispanic, Italian). Carrier frequency ~1 in 60.

Aetiology

21-hydroxylase deficiency (~95%): impaired conversion of 17-OHP → 11-deoxycortisol (cortisol pathway) and progesterone → 11-deoxycorticosterone (aldosterone pathway). Other rare types: 11β-hydroxylase deficiency (~5%), 17α-hydroxylase deficiency (<1%), 3β-HSD deficiency.

Pathophysiology

21-hydroxylase block → cortisol deficiency → loss of negative feedback → ACTH elevation → adrenal hyperplasia → accumulation of precursors proximal to block (17-OHP) → shunting into androgen pathway → excess androgens (androstenedione, testosterone) → virilisation. In salt-wasting form: aldosterone deficiency also → renal sodium wasting, hyperkalaemia, dehydration, metabolic acidosis → salt-wasting crisis.

Classic Salt-Wasting (~75% of Classic CAH)

• 46,XX neonates: ambiguous genitalia (clitoromegaly, labial fusion, urogenital sinus) — most common presentation
• 46,XY neonates: normal genitalia; may present with salt-wasting crisis at 1-3 weeks (vomiting, dehydration, shock, hyperkalaemia, hyponatraemia)
• Salt-wasting crisis: medical emergency

Classic Simple Virilising

• 46,XX: ambiguous genitalia at birth (milder than salt-wasting) or progressive virilisation
• 46,XY: premature adrenarche, accelerated growth, advanced bone age; short adult height
• Both sexes: precocious puberty (peripheral)

Non-Classic (Late-Onset)

• Presents in adolescence/adulthood (especially females)
• Hirsutism, acne, menstrual irregularity, subfertility
• Often misdiagnosed as PCOS
• Males may be asymptomatic

Red Flags

• Ambiguous genitalia in neonate → urgent endocrinology (karyotype, 17-OHP)
• Neonatal collapse with hyperkalaemia/hyponatraemia → salt-wasting crisis

Biochemical

• 17-hydroxyprogesterone (17-OHP): markedly elevated in classic CAH (>300 nmol/L neonatal; >30 nmol/L in non-classic); mildly elevated in non-classic (may need ACTH stimulation test)
• ACTH stimulation test: 250μg Synacthen; measure 17-OHP at 0 and 60 minutes; exaggerated 17-OHP rise confirms CAH
• Serum cortisol: low or inappropriately normal
• Electrolytes: hyponatraemia, hyperkalaemia (salt-wasters)
• Renin: elevated (salt-wasters)
• Androgens: elevated androstenedione, testosterone

Genetics

• CYP21A2 gene sequencing: confirms diagnosis, genotype-phenotype correlation, carrier testing, prenatal diagnosis

Imaging

• Pelvic USS: in neonates with ambiguous genitalia (uterus present?)
• Bone age X-ray: advanced in virilising forms
• Adrenal CT/MRI: not routine (may show bilateral hyperplasia)

Glucocorticoid Replacement

• Children: hydrocortisone 10-15 mg/m²/day in 3 divided doses (lowest effective dose to suppress androgens while allowing normal growth)
• Adults: hydrocortisone 15-25 mg/day or prednisolone 2.5-5 mg/day or dexamethasone 0.25-0.5 mg ON (dexamethasone most potent at suppressing ACTH/androgens but higher SE risk)

Mineralocorticoid (Salt-Wasters)

• Fludrocortisone 50-200 μg OD
• Sodium chloride supplementation in infancy

Sick-Day Rules

• Double/triple hydrocortisone dose during illness
• IM hydrocortisone if vomiting
• Steroid emergency card + MedicAlert

Monitoring

• 17-OHP, androstenedione, testosterone (target: normal range — not over-suppressed)
• Growth velocity, bone age (annually in children)
• Avoid over-treatment (Cushingoid features, growth suppression) and under-treatment (androgen excess, advanced bone age, virilisation)

Surgical

• Feminising genitoplasty for severely virilised 46,XX: timing controversial; MDT decision with family

Non-Classic CAH

• May not need glucocorticoids if asymptomatic
• Hydrocortisone or low-dose dexamethasone if symptomatic (hirsutism, subfertility)
• OCP for menstrual regulation and anti-androgen effect

Referral Criteria

• Paediatric endocrinology: all neonatal/childhood cases
• Adult endocrinology: transition, non-classic CAH
• DSD MDT: ambiguous genitalia

With appropriate treatment, most patients with classic CAH lead normal lives. Final adult height: often reduced by 1-2 SD despite treatment (advanced bone age, glucocorticoid effects). Fertility: reduced in classic CAH women (~60-80% pregnancy rate with good management); men generally fertile. Non-classic CAH: excellent prognosis; subfertility treatable. Testicular adrenal rest tumours: may develop in undertreated males (ACTH-driven — respond to increased glucocorticoid dose).

CAH Subtypes

Classic vs Non-Classic CAH