Congenital Adrenal Hyperplasia

A 6-week old baby girl presents with vomiting and failure to thrive. On examination, she is hypotensive and has ambiguous genitalia. Blood tests reveal hyponatremia and hyperkalemia.

Pathophysiology

Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders that impact the enzymes responsible for creating aldosterone and cortisol. This leads to insufficient production of adrenal hormones, including glucocorticoids and/or mineralocorticoids. The most common enzyme deficiency, impacting over 90% of cases, is 21-hydroxylase.

Low cortisol levels trigger a rise in adrenocorticotropic hormone (ACTH) secretion, which stimulates adrenal gland growth, leading to adrenal hyperplasia. This enlargement occurs in both adrenal glands. When 21-hydroxylase or 11β-hydroxylase are deficient, steroid precursors build up and are converted into testosterone, causing an excess of testosterone and androstenedione.

Aetiology

CAH is caused by loss-of-function mutations on chromosome 6 that disrupt the enzymes involved in cortisol and aldosterone production. These mutations are inherited in an autosomal recessive manner.

Epidemiology & Risk Factors

CAH is relatively rare, with an overall incidence of roughly 1 in 15,000 births. 21-hydroxylase deficiency, the most prevalent form, affects an estimated 1 in 10,000 to 1 in 20,000 people globally.

Risk factors include:

• Family history: Having a family history of CAH considerably increases the risk.
• Consanguinity: Relationships between second cousins or closer elevate the risk of inheriting two copies of the recessive gene.

Clinical Features

CAH presents with various clinical features depending on the specific enzyme deficiency, its severity, and the age of presentation.

Classic CAH

• Presents during infancy or early childhood.
• Primarily caused by 21-hydroxylase deficiency.
• Symptoms:
  • Salt wasting: Vomiting, dehydration, hyponatremia, hyperkalemia.
  • Ambiguous genitalia in females due to virilization.
  • Precocious puberty in males.

Non-classic CAH

• Presents later in childhood, adolescence, or adulthood.
• Milder form due to a partial enzyme deficiency.
• Symptoms:
  • Hirsutism, acne, and irregular periods in females.
  • Early puberty in males.

Investigations

• Biochemical tests:
  • 17-hydroxyprogesterone (17-OHP) measurement: This steroid precursor is elevated in CAH, particularly with 21-hydroxylase deficiency.
  • Electrolyte levels: Hyponatremia and hyperkalemia may be observed in salt-wasting CAH.
  • ACTH levels: Typically elevated in all forms of CAH due to lack of cortisol feedback.
  • Renin activity: May be elevated in salt-wasting CAH due to volume depletion.
  • Androgen levels: Testosterone and androstenedione levels might be elevated in some forms, particularly with virilization.
• Genetic testing: Can confirm the diagnosis and pinpoint the specific genetic mutation.

Management

CAH management involves lifelong hormone replacement therapy to address hormone deficiencies and suppress excess ACTH.

Medical Management

• Glucocorticoids: Hydrocortisone or prednisolone replace cortisol and suppress ACTH.
• Mineralocorticoids: Fludrocortisone replaces aldosterone in salt-wasting CAH.
• Dosage adjustments: Regular monitoring and adjustments are needed throughout life, particularly during stress, illness or surgery. Patients need education on "sick day rules" for medication adjustment.
• Additional medications: May be needed to address specific symptoms, like anti-androgens for hirsutism in females.

Surgical Management

• Genitoplasty: May be considered for ambiguous genitalia in females to create more typical female external genitalia.

Lifestyle Management

• Stress management: Important to minimize stress as it can worsen symptoms.
• Regular follow-up: Crucial for monitoring hormone levels and adjusting treatment.

Complications & Prognosis

Complications:

• Adrenal crisis: Life-threatening, especially in severe or salt-wasting CAH, if hormone replacement is inadequate. Adrenal insufficiency can also be caused by adrenal hemorrhage. The 4 S's of adrenal crisis management are: Salt, Steroids, Support, and Search for the underlying illness.
• Short stature: From early epiphyseal growth plate closure.
• Infertility: Possible in both sexes, particularly if poorly managed.
• Psychological impact: Social stigma related to ambiguous genitalia and other symptoms can significantly impact mental well-being.

Prognosis:

• Proper management allows for normal life expectancy and good quality of life in individuals with CAH.