Congenital Adrenal Hyperplasia

Overview – Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia (CAH) is a group of autosomal recessive disorders affecting adrenal steroidogenesis, with 21-hydroxylase deficiency accounting for over 90% of cases. This enzyme deficiency leads to reduced cortisol and aldosterone synthesis, resulting in compensatory ACTH overproduction and shunting towards androgen synthesis. CAH presents along a spectrum, from life-threatening neonatal salt-wasting crises to ambiguous genitalia and premature puberty. Early diagnosis and hormonal replacement therapy are key to management and preventing long-term complications.

Definition

CAH is a genetic disorder caused by enzymatic defects in adrenal steroid biosynthesis, most commonly due to 21-hydroxylase deficiency, leading to cortisol and aldosterone deficiency with androgen excess.

Aetiology

• Inheritance: Autosomal recessive
• Most common cause: 21-hydroxylase deficiency due to mutations in the CYP21A2 gene

Pathophysiology

• 21-hydroxylase is required for synthesis of both cortisol and aldosterone
• Deficiency leads to:
  • ↓ Cortisol → ↑ ACTH (via negative feedback) → adrenal hyperplasia
  • ↓ Aldosterone → ↓ Na⁺ reabsorption, ↑ K⁺ retention → hypovolaemia, hyponatraemia, hyperkalaemia
  • ↑ 17-hydroxyprogesterone accumulates and is shunted to androgen synthesis → virilisation

Clinical Features

Neonates

• Salt-wasting crisis (common in severe forms):
  • Presents in 1st week of life
  • Hypovolaemic shock, dehydration, vomiting, hypotension
  • Mottled skin, non-arousable
• Ambiguous genitalia in females (enlarged clitoris, labial fusion)
• Normal genitalia in males but may have hyperpigmentation or enlarged genitalia

Older Children / Adolescents

• Signs of androgen excess:
  • Females:
    • Hirsutism
    • Oligomenorrhoea or amenorrhoea
    • Acne
    • Clitoral hypertrophy
  • Males:
    • Precocious puberty
    • Penile enlargement
    • Small testes (due to suppressed gonadotropins)
    • Oligospermia
• Psychosocial & gender identity issues (in severe virilisation)

Investigations

• Serum electrolytes:
  • Hyponatraemia
  • Hyperkalaemia
• Serum 17-hydroxyprogesterone: ↑↑
• ACTH: ↑
• Cortisol and aldosterone: ↓
• Karyotyping (for ambiguous genitalia)
• Ultrasound: Adrenal enlargement, internal genitalia assessment

Management

• Glucocorticoid replacement (e.g. hydrocortisone): suppresses ACTH → ↓ androgen overproduction
• Mineralocorticoid replacement (e.g. fludrocortisone) if salt-wasting
• Salt supplementation in neonates
• Surgical management of ambiguous genitalia (controversial; requires multidisciplinary approach)
• Lifelong follow-up for hormone adjustment, fertility, and psychological support

Complications

• Adrenal crisis (life-threatening salt-wasting)
• Precocious puberty
• Infertility
• Short stature (due to premature epiphyseal closure)
• Psychological distress due to gender ambiguity

Summary – Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia (CAH), most often due to 21-hydroxylase deficiency, leads to cortisol and aldosterone deficiency with androgen excess. It may present in infancy with life-threatening salt-wasting or later with virilisation and puberty disorders. Early diagnosis and hormone replacement therapy are vital for long-term outcomes. For related content, visit our Endocrine Overview.