Congenital Adrenal Hyperplasia - CAH

  • Diagnosis
  • Screening
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

Laboratory Testing

  • Initial test – 17-hydroxyprogesterone (17-OHP)
    • If elevated, perform ACTH stimulation (cosyntropin); however, this is often unnecessary when there is 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 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
  • 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
  • Adrenal steroid quantitative panel if ACTH stimulation is abnormal or if a marked elevation of 17-OHP is noted
    • 21-hydroxylase deficiency
      • Markedly elevated plasma 17-OHP
    • 11-beta-hydroxylase deficiency
      • Elevated 11-deoxycorticosterone and 11-deoxycortisol levels
    • 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

  • 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 (tend to have elevated 17-OHP)
      • Markedly elevated 17-OHP – disease confirmed
        • Follow up positive results with ACTH stimulation in all infants
    • False negative may occur if maternal glucocorticoids are administered
  • Prenatal diagnosis – via 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

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
  • 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

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.

Congenital Adrenal Hyperplasia Panel, 21-Hydroxylase Deficiency 2002283
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Congenital Adrenal Hyperplasia Panel, 11-Beta Hydroxylase Deficiency 2002282
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Congenital Adrenal Hyperplasia Treatment Panel 2002029
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Adrenal Steroid Quantitative Panel by HPLC-MS/MS, Serum or Plasma 0092330
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Related Tests

Guidelines

Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF L, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC, Endocrine Society. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010; 95(9): 4133-60. PubMed

General References

Antal Z, Zhou P. Congenital adrenal hyperplasia: diagnosis, evaluation, and management. Pediatr Rev. 2009; 30(7): e49-57. PubMed

Krone N, Arlt W. Genetics of congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab. 2009; 23(2): 181-92. PubMed

Lambert SM, Vilain EJ N, Kolon TF. A practical approach to ambiguous genitalia in the newborn period. Urol Clin North Am. 2010; 37(2): 195-205. PubMed

Nimkarn S, New MI. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: A paradigm for prenatal diagnosis and treatment. Ann N Y Acad Sci. 2010; 1192: 5-11. PubMed

Nimkarn S, New MI. Prenatal diagnosis and treatment of congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Nat Clin Pract Endocrinol Metab. 2007; 3(5): 405-13. PubMed

Trakakis E, Basios G, Trompoukis P, Labos G, Grammatikakis I, Kassanos D. An update to 21-hydroxylase deficient congenital adrenal hyperplasia. Gynecol Endocrinol. 2010; 26(1): 63-71. PubMed

Witchel SFeldman. Nonclassic congenital adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes. 2012; 19(3): 151-8. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Kushnir MM, Neilson R, Roberts WL, Rockwood AL. Cortisol and cortisone analysis in serum and plasma by atmospheric pressure photoionization tandem mass spectrometry. Clin Biochem. 2004; 37(5): 357-62. PubMed

Kushnir MM, Rockwood AL, Roberts WL, Pattison EG, Owen WE, Bunker AM, Meikle W. Development and performance evaluation of a tandem mass spectrometry assay for 4 adrenal steroids. Clin Chem. 2006; 52(8): 1559-67. PubMed

Mao R, McDonald J, Cantwell M, Tang W, Ward K. The implication of de novo 21-hydroxylase mutation in clinical and prenatal molecular diagnoses. Genet Test. 2005; 9(2): 121-5. PubMed

Rogers MA, Liu J, Kushnir MM, Bryleva E, Rockwood AL, Meikle W, Shapiro D, Vaisman BL, Remaley AT, C Y Chang C, Chang T. Cellular pregnenolone esterification by acyl-CoA:cholesterol acyltransferase. J Biol Chem. 2012; 287(21): 17483-92. PubMed

Schwarz E, Liu A, Randall H, Haslip C, Keune F, Murray M, Longo N, Pasquali M. Use of steroid profiling by UPLC-MS/MS as a second tier test in newborn screening for congenital adrenal hyperplasia: the Utah experience. Pediatr Res. 2009; 66(2): 230-5. PubMed

Medical Reviewers

Last Update: April 2016