Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia

 

Congenital adrenal hyperplasia is an uncommon autosomal recessive genetic disorder that is 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)
    • More frequent in eastern European Jews (1/27 affected with nonclassical 21-hydroxylase deficiency)
    • 21-hydroxylase deficiency is the most common defect (90%)

Risk Factors

  • Genetic
    • Enzymatic defects include:
      • 21-hydroxylase (CYP21A2), 11-beta-hydroxylase (CYP11B1), 17-alpha-hydroxylase/17,20-lyase (CYP17), 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) and the very rare mitochondrial cholesterol side chain cleavage enzyme (P450scc)
      • Mutations cause a block in adrenal glucocorticoid and mineralocorticoid synthesis

Pathophysiology

  • 21-hydroxylase
    • Blocked steroid synthesis causes adrenal insufficiency and compensatory elevation of 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 – 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
    • Rare disorder
    • Decreased cortisol production and shunting of precursors into mineralocorticoid pathways
    • Minimal testosterone or estrogen made

Clinical Presentation

  • 21-hydroxylase
    • Ambiguous genitalia (female), premature sexual development (male), salt wasting (hyperkalemia, hyponatremia, dehydration)
  • 11-beta-hydroxylase
    • Premature sexual development (male), hypertension and hypokalemia
  • 17-alpha-hydroxylase
    • Hypertension, hypokalemia, hypogonadism, lack of secondary sexual characteristics in females and males
  • 3 beta-HSD2
    • Feminized male, partial virilization of female
  • Mitochondrial cholesterol side chain cleavage enzyme (P450scc)
    • Very rare disorder
  • Adult females present with milder forms of any of the diseases – classically present with hyperandrogenism at the time of puberty

Diagnosis

  • Laboratory testing
    • Initial testing – adrenal steroid quantitative panel
      • 21-hydroxylase
        • Plasma 17-hydroxyprogesterone markedly increased
      • 11-beta-hydroxylase
        • 11-deoxycorticosterone and 11-deoxycortisol levels increased
      • 17-hydroxylase (17-OH)
        • Elevated pregnenolone
        • Decreased 17-hydroxypregnenolone (17-OH-pregnenolone)  

Treatment

  • Steroids to suppress pituitary ACTH secretion

See Also