Congenital Adrenal Hyperplasia - CAH

Congenital adrenal hyperplasia (CAH) is an uncommon group of autosomal recessive disorders caused by several distinct enzymatic defects, usually with subsequent virilization.

Epidemiology

• Incidence
  • Most common adrenal disorder of infancy and childhood (1/3,000-5,000)
  • 1/10,000-20,000 (Endocrine Society, 2010)
• Sex – M>F
• Ethnicity
  • Ashkenazi Jews
    • 1-2% affected with nonclassical forms (11-beta-hydroxylase, late onset 21-hydroxylase deficiency)
  • Remote geographic location populations (eg, Alaskan Yupiks, French island of LaRéunion)

Risk Factors

• Genetic
  • Autosomal recessive inheritance
  • Enzymatic defects include the following
    • 21-hydroxylase (CYP21A2 mutation) – most common defect (>90%)
    • 11-beta-hydroxylase (CYP11B1 mutation)
    • CYP17A1 deficiencies (CYP17A1 mutation)
    • 17,20-lyase deficiencies
    • 3 beta-hydroxysteroid dehydrogenase (HSD3B2 mutation)
    • Cytochrome P450 oxidoreductase deficiency
    • Hexose-6-phosphate dehydrogenase deficiency (H6PD mutation)
    • PAPSS2 deficiency (PAPSS2 mutation)
    • Congenital lipoid adrenal hyperplasia (StAR mutations)
    • P450scc side chain cleavage enzyme deficiency (CYP11A1 mutation)

Pathophysiology

• Mutations cause a block in adrenal glucocorticoid and mineralocorticoid synthesis pathways
• 21-hydroxylase deficiency
  • Defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol
  • Blocked steroid synthesis causes adrenal insufficiency and compensatory elevation of adrenocorticotropic hormone (ACTH)
  • ACTH elevation causes adrenal hyperplasia and additional precursor synthesis
  • Precursor excess is shunted into the androgen synthesis pathway, causing virilization in females, premature sexual development in males, and adrenal insufficiency
• 11-beta-hydroxylase deficiency
  • Impaired conversion of 11-deoxycortisol to cortisol
  • Accumulation of 11-deoxycorticosterone (a potent mineralocorticoid) leads to mineralocorticoid excess with possible hypertension
• 17-alpha-hydroxylase/17,20-lyase deficiency
  • Usually combined deficiency
  • Decreased cortisol production and shunting of precursors into mineralocorticoid pathways
  • Minimal testosterone or estrogen produced
• 3-beta-hydroxysteroid dehydrogenase deficiency
• Synthesis of all active steroid hormones is impaired

Clinical Presentation

• 21-hydroxylase deficiency
  • Classic (more severe)
    • Presents during neonatal period
    • Ambiguous genitalia in females, virilization in males
    • Salt wasting in majority of patients (hyperkalemia, hyponatremia, dehydration)
  • Nonclassic (late onset)
    • No neonatal genital ambiguity
    • Hirsutism
    • Irregular menses in females
    • Short stature
    • Acne
    • Infertility
    • Alopecia
• 11-beta-hydroxylase deficiency
  • Hypertension, hypokalemia, and premature sexual development in males, ambiguous genitalia in females
• 17-alpha-hydroxylase deficiency
  • Hypertension, hypokalemia, hypogonadism, lack of secondary sexual characteristics in females and males
  • Isolated 17,20-lyase deficiency – males with under virilization, females with delayed pubarche
• 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency
  • Feminized males, partial virilization of females
  • Cortisol and aldosterone deficiency signs and symptoms – feeding difficulty, vomiting, hyponatremia, hyperkalimia
• P450
  • Oxidoreductase deficiency
  • Severe virilization in females, severe under virilization in males
  • No mineralocorticoid deficiency
  • Craniofacial abnormalities
• P450scc
  • May be lethal due to potential insufficiency
  • Defective synthesis of all adrenal hormones