Congenital Adrenal Hyperplasia - CAH

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by several distinct enzymatic defects that result in changes in steroidogenesis. These disruptions cause irregular genital and sexual characteristics, and interfere with electrolyte balance. Newborn screening detects elevations in 17-hydroxyprogesterone (17-OHP). Other forms of CAH without significant 17-OHP increases are often not identified until later in life due to their more subtle clinical presentations. Initial testing generally involves 17-OHP testing and, if 17-OHP is increased, adrenocorticotropic hormone (ACTH) testing.


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


  • 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​


  • 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



  • 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)


  • 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
  • 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

ARUP Laboratory Tests

Primary Tests

Detect enzyme deficiencies causing CAH

Screen for 21-hydroxylase deficiency, the most common congenital adrenal insufficiency

Components include androstenedione; 17-OHP; 17-hydroxypregnenolone, quantitative by LC-MS/MS; and dehydroepiandrosterone​

Screen for 11-beta hydroxylase deficiency

Components include androstenedione; 17-OHP; testosterone; 11-deoxycortisol, quantitative by LC/MS-MS; and dehydroepiandrosterone

Detect accumulation of specific steroids as a result of enzyme deficiencies in CAH

Monitor patients with CAH

Components include 11-deoxycortisol, quantitative; 17-OHP, quantitative by MS/MS; 17-hydroxypregnenolone, quantitative by MS/MS; and pregnenolone by MS/MS

Use to monitor treatment of individuals with classic or nonclassic CAH

Total testosterone values may not reflect optimal concentrations in all individuals

Components include androstenedione; 17-OHP, quantitative by LC-MS/MS; and testosterone, females or children

Related Tests

Use to diagnose and manage diabetes mellitus and other carbohydrate metabolism disorders

The combined aldosterone/renin tests are preferred when screening for hyperaldosteronism

Refer to aldosterone/renin activity ratio or aldosterone and renin, direct with ratio

Initial screening for hepatobiliary inflammation

Panel includes albumin; alkaline phosphatase; aspartate aminotransferase; alanine aminotransferase; bilirubin, direct; protein, total; and bilirubin, total


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