Congenital Adrenal Hyperplasia - CAH

Diagnosis

Indications for Testing

• Ambiguous genitalia or unexplainable electrolyte results in infancy
• Premature sexual development in older children
• Hirsutism and irregular menses in adult females

Laboratory Testing

• Initial testing
  • 17-OHP
    • If elevated, perform ACTH stimulation (cosyntropin)
      • Often unnecessary when there is marked elevation of 17-OHP
      • 17-OHP remains increased after stimulation in classic CAH
    • If nonclassic form is suspected in adult female, obtain 17-OHP at 0800 hours and during follicular phase of menstrual cycle
    • Further evaluation should include assessment of salt wasting
      • Serum sodium, potassium, and renin activity – expect hyponatremia, hyperkalemia, and increased renin in classic 21-hydroxylase deficiency CAH
• Secondary testing
  • Adrenal steroid quantitative panel – if ACTH stimulation is abnormal or if a marked elevation of 17-OHP is noted
    • 21-hydroxylase deficiency
      • Characterized by markedly elevated plasma 17-OHP
    • 11-beta-hydroxylase deficiency
      • Indicated by increased 11-deoxycorticosterone and 11-deoxycortisol levels
    • 17-hydroxylase (17-OH) deficiency
      • Characterized by increased pregnenolone, 11-deoxycorticosterone, and corticosterone, and decreased 17-hydroxypregnenolone (17-OH-pregnenolone)
    • 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency
      • Indicated by increased pregnenolone, 17-OH pregnenolone, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEAS)
• Testing in infants
  • Karyotyping to rule out chromosomal disorder
  • Pelvic ultrasonography to assess internal genital organs in females
  • Assess glucose, electrolytes, liver function, and blood gases in infants suspected of acute adrenal insufficiency

Differential Diagnosis

• Hirsutism, irregular menses
  • Polycystic ovarian syndrome
  • Cushing syndrome
  • Androgen-secreting tumor
• Salt wasting
  • Adrenal insufficiency
• Ambiguous genitalia
  • Maternal hyperandrogenism
  • Androgen-secreting tumor
  • Chromosomal abnormality
• Premature sexual development
  • Adrenarche
  • Androgen-secreting tumor
  • Cushing syndrome

Screening

• Newborn screening for CAH in most states – 17-OHP
  • Threshold for positive tests is set relatively low to prevent missing true positives
  • False positives common in premature infants, who tend to have increased 17-OHP
    • Markedly increased 17-OHP confirms disease
      • Follow up positive results with ACTH stimulation in all infants
  • False negative may occur if maternal glucocorticoids are administered
• Prenatal diagnosis
  • Chorionic villus sampling or amniocentesis, 90-95% sensitive
  • Allows for prenatal treatment of disease through administration of maternal glucocorticoid​

Monitoring

• For assessment of glucocorticoid replacement
  • 17-OHP, androstenedione, and testosterone
    • Every 3 months during infancy and every 3-6 months thereafter
• For assessment of mineralocorticoid replacement
  • Blood pressure measurement
  • Plasma renin/renin activity
  • Aldosterone and potassium levels may also be helpful

Background

Epidemiology

• Incidence
  • 1/10,000-20,000 (Speiser, Endocrine Society, 2010)
• Sex – M>F
• Ethnicity
  • Caucasians
    • 0.1-0.2% affected with nonclassical forms
  • Ashkenazi Jews
    • 1-2% affected with nonclassical forms
  • Higher prevalence of classic CAH in Alaskan Yupic Eskimos and residents of French island La Réunion

Risk Factors

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

Pathophysiology

• Gene variants cause a block in adrenal glucocorticoid and mineralocorticoid synthesis pathways
• 21-hydroxylase deficiency
  • Defective conversion of 17-OHP to 11-deoxycortisol
  • 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 and premature sexual development in males
• 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-HSD 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-HSD deficiency
  • Feminized males, partial virilization of females
  • Cortisol and aldosterone deficiency signs and symptoms
    • Feeding difficulty
    • Vomiting
    • Hyponatremia
    • Hyperkalemia
• P450 oxidoreductase deficiency
  • Severe virilization in females, severe under virilization in males
  • No mineralocorticoid deficiency
  • Craniofacial abnormalities
• P450scc deficiency
  • May be lethal due to potential insufficiency
  • Defective synthesis of all adrenal hormones