Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive defects in the enzymes that are responsible for cortisol, aldosterone, and, in very rare cases, androgen synthesis. All forms of CAH are characterized by low levels of cortisol, high levels of ACTH, and adrenal hyperplasia. The exact clinical manifestations depend on the enzyme defect. The most common form of CAH is caused by a deficiency of 21β-hydroxylase and manifests with hypotension, ambiguous genitalia, virilization (in the female genotype), and/or precocious puberty (in both males and females). All newborn infants in the US are screened for 21β-hydroxylase deficiency by measuring 17-hydroxyprogesterone in a blood sample obtained from a heel prick. CAH treatment involves lifelong glucocorticoid and fludrocortisone replacement therapy. Certain rare forms of CAH (e.g., 11β-hydroxylase and 17α-hydroxylase deficiencies) manifest with symptoms of mineralocorticoid excess (e.g., hypertension) and therefore require spironolactone (aldosterone receptor inhibitor) in addition to glucocorticoid replacement. Individuals with a virilizing form of CAH have an increased likelihood of experiencing gender dysphoria. Intersex medical interventions may be considered in cases of ambiguous genitalia. Complications of CAH include severe hypoglycemia, adrenal insufficiency, and failure to thrive.

• CAH is caused by autosomal recessive defects in enzymes that are responsible for the production of cortisol.
• There are three subtypes of CAH:
  • 21β-hydroxylase (∼ 95% of CAH)
  • 11β-hydroxylase (∼ 5% of CAH)
  • 17α-hydroxylase (rare)
• Low levels of cortisol → lack of negative feedback to the pituitary → increased ACTH → adrenal hyperplasia and increased synthesis of adrenal precursor steroids
• Depending on which enzyme is affected, the following endocrine changes are seen:

A deficiency in both 17α-hydroxylase and 11β-hydroxylase results in the overproduction of mineralocorticoid precursors with mineralocorticoid activity like DOC. Increased mineralocorticoid activity leads to suppression of the RAAS, which results in low aldosterone levels. “1 DOC:” If the deficient enzyme starts with 1 (11β-, 17‑), there is increased DOC.
“AND 1:” If the deficient enzyme ends with 1 (21-, 11β‑), androgens are increased.

References:^{[1][2][3][4][5]}

• Hypoglycemia
• Adrenal crisis → vomiting and diarrhea → dehydration
• Failure to thrive
• Hyperpigmentation in areas that are not exposed to sunlight (e.g., palm creases, mucous membranes of the oral cavity, genitalia) is a common feature in all forms of CAH.

Infants with 21β-hydroxylase deficiency can present with shock within the first few weeks of life because of severe dehydration due to an adrenal crisis and salt-wasting due to hypoaldosteronism.

Different types of mutations on the CYP21A2 gene (which codes for 21β-hydroxylase) are associated with different levels of disease severity.

Individuals with a virilizing form of CAH have an increased likelihood of experiencing gender dysphoria.

References:^{[3][4][5][6][7][8][9][10]}

• Precocious pseudopuberty
• Primary adrenal insufficiency
• PCOS
• Hyperprolactinemia
• Cushing Syndrome

The differential diagnoses listed here are not exhaustive.

• Increased specific steroid precursors in blood and/or urine samples (see the table below)
  • Screening is conducted by measuring 17-hydroxyprogesterone (also for newborns).
  • If steroid precursors are not elevated at baseline but CAH is still suspected, administer exogenous ACTH (cosyntropin) and measure again (see ACTH stimulation test).
• Hypocortisolism is seen in all forms of CAH, and cortisol levels remain low even after administration of cosyntropin.
• Specific patterns of electrolyte and/or acid-base disorders are associated with specific enzyme deficiencies.

All newborns in the US are screened for CAH by measuring changes in 17-hydroxyprogesterone levels from a heel prick blood sample.References:^{[2][9][11][12]}

• General approach
  • Therapy aims to replace deficient hormones and reduce excess androgen production.
  • Glucocorticoid replacement therapy is indicated in all forms of CAH.
    • Lifelong daily regimen
      • Hydrocortisone in neonates and children
      • Prednisolone or dexamethasone in adolescents and adults
    • Steroid stress dosing
• Specific treatment
  • 21β-hydroxylase deficiency
    • Lifelong fludrocortisone therapy (aldosterone substitution)
    • Sodium chloride (salt) supplements, especially during infancy and childhood
  • 11β-hydroxylase deficiency
    • Spironolactone to block mineralocorticoid receptors
    • Reduced dietary sodium intake
  • 17α-hydroxylase deficiency
    • Spironolactone to block mineralocorticoid receptors
    • Estrogen replacement therapy for female genotype; may be started in early puberty
    • Reduced dietary sodium intake
  • Salt-wasting CAH
    • Fluid resuscitation with intravenous normal saline
    • Intravenous dextrose in patients with significant hypoglycemia
    • Immediate administration of glucocorticoid replacement therapy
  • Nonclassic CAH
    • Symptomatic children: hydrocortisone replacement therapy until 2–3 years postmenarche for girls and early to mid-puberty for boys
    • Women: combined oral contraceptives are first-line treatment (alternatively glucocorticoid therapy)
    • Men: usually no treatment required
• Additional considerations
  • Intersex medical intervention may be considered in children with ambiguous genitalia.
  • Patients that experience gender dysphoria may benefit from counseling.

The dose of glucocorticoids must be increased during severe infection, critical illness, and perioperatively to meet increased demands to prevent adrenal crisis.

References:^{[4][7][9][13]}

• Prenatal testing is recommended in mothers who have previously given birth to a child with 21β-hydroxylase deficiency.
  • Chorionic villus sampling
  • Increased 17α-hydroxyprogesterone in amniotic fluid
• If a defect in 21β-hydroxylase is diagnosed prenatally:
  • Prophylactic treatment of the mother with dexamethasone soon after conception
  • Dexamethasone therapy should be discontinued if the fetus has a male genotype (revealed by karyotyping).