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 screen – 17 hydroxyprogesterone (17-OHP)
  • If elevated, perform ACTH stimulation (cosyntropin); however, this is often unnecessary with marked elevation of 17-OHP
    • 17-OHP remains elevated after stimulation in classic CAH
  • If nonclassic form is suspected in adult female, obtain 17-OHP at 0800 hours value and during follicular phase of menstrual cycle
  • Further evaluation should include assessment of salt wasting
    • Serum sodium, potassium, and renin activity – expect decreased sodium, increased potassium, and increased renin in classic 21-hydroxylase deficiency CAH
• Infants – karyotype 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 (important)
• Adrenal steroid quantitative panel if ACTH stimulation is abnormal or if a marked elevation of 17-OHP is noted
  • 21-hydroxylase deficiency
    • Plasma 17-OHP markedly increased
  • 11-beta-hydroxylase deficiency
    • 11-deoxycorticosterone and 11-deoxycortisol levels increased
  • 17-hydroxylase (17-OH) deficiency
    • Elevated pregnenolone, 11-deoxycorticosterone, corticosterone
    • Decreased 17-hydroxypregnenolone (17-OH-pregnenolone)
  • 3 beta-HSD deficiency
    • Elevated pregnenolone, 17-OH pregnenolone, DHEA and DHEAS

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
  • Premature adrenarche
  • Androgen-secreting tumor
  • Cushing syndrome

Screening

Monitoring

Clinical Background

Congenital adrenal hyperplasia (CAH) is an uncommon autosomal recessive genetic disorder 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)
  • Classic CAH – 1/16,000-20,000
  • Nonclassic CAH – 1/500-1,000
• Sex – M>F
• Ethnicity – more common in Ashkenazi Jews
  • 1/27 affected with nonclassical (21-hydroxylase deficiency)

Risk Factors

• Genetic
  • Enzymatic defects include the following
    • 21-hydroxylase (CYP21A2 mutation) – most common defect (90%)
    • 11-beta-hydroxylase (CYP11B1 mutation)
    • 17-CYP17 alpha-hydroxylase/17,20-lyase
    • 3 beta-hydroxysteroid dehydrogenase
    • Mitochondrial cholesterol side chain cleavage enzyme (P450scc) – very rare

Pathophysiology

• Mutations cause a block in adrenal glucocorticoid and mineralocorticoid synthesis pathway
• 21-hydroxylase deficiency
  • 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
  • Rare disorder
  • Decreased cortisol production and shunting of precursors into mineralocorticoid pathways
  • Minimal testosterone or estrogen produced

Clinical Presentation

• 21-hydroxylase deficiency
  • Classic (more severe)
    • Ambiguous genitalia in females, virilization in males
    • Salt wasting in about 75% (hyperkalemia, hyponatremia, dehydration)
  • Nonclassic (milder)
    • Hirsutism
    • Irregular menses in females
    • Short stature
    • Acne
    • Infertility
    • Alopecia 
• 11-beta-hydroxylase deficiency
  • Premature sexual development in males, hypertension, and hypokalemia
• 17-alpha-hydroxylase deficiency
  • Hypertension, hypokalemia, hypogonadism, lack of secondary sexual characteristics in females and males
• 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency
  • Feminized males, partial virilization of females
• P450scc deficiency – very rare disorder
  • Defective synthesis of all adrenocortical hormones; can be lethal

Treatment

• Steroids to suppress corticotropin-releasing hormone and ACTH secretion
  • May require both gluco- and mineralocorticoid therapy
• Acute adrenal insufficiency is a medical emergency
  • Fluid resuscitation and stress doses of hydrocortisone are mainstays of treatment
• Prenatal treatment
  • If disease is recognized early during gestation of a female fetus, dexamethasone therapy is used for duration of pregnancy

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Cytogenomic SNP Microarray 2003414 Method: Genomic Microarray (Oligo-SNP Array)
Cytogenomic SNP Microarray Buccal Swab 2006267 Method: Genomic Microarray (Oligo-SNP Array)
Glucose, Plasma or Serum 0020024 Method: Quantitative Enzymatic	Assess for glucose abnormalities
Electrolyte Panel 0020410 Method: Quantitative Ion-Selective Electrode/Enzymatic	Assess for electrolyte abnormalities
Hepatic Function Panel 0020416 Method: Quantitative Enzymatic/Quantitative Spectrophotometry	Assess for hepatic abnormalities
17-Hydroxyprogesterone 0070005 Method: Quantitative Radioimmunoassay	Detect enzyme deficiencies causing CAH
11-Deoxycortisol Quantitative by LC-MS/MS, Serum or Plasma 0092331 Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry	Detect enzyme deficiencies causing CAH
Deoxycorticosterone (DOC), Serum 2007206 Method: Liquid Chromatography/Tandem Mass Spectrometry	Detect enzyme deficiencies causing CAH
Pregnenolone by LC-MS/MS, Serum or Plasma 0092334 Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry	Detect enzyme deficiencies causing CAH
17-Hydroxyprogesterone Quantitative by LC-MS/MS, Serum or Plasma 0092332 Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry	Detect enzyme deficiencies causing CAH
17-Hydroxypregnenolone Quantitative by LC-MS/MS, Serum or Plasma 0092333 Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry	Detect enzyme deficiencies causing CAH