Congenital Adrenal Hyperplasia - CAH

Diagnosis

Indications for Testing

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

Screening

  • Newborn screening for CAH in most states (17-OHP)
    • False positives common in premature infants (tend to have elevated 17-OHP)
      • Markedly elevated 17-OHP – disease confirmed
      • Threshold for positive tests is set relatively low to prevent missing true positives 
        • Follow up positive results with ACTH stimulation in all infants
  • Prenatal diagnosis – via chorionic villus sampling or amniocentesis, 90-95% sensitive
    • Allows for prenatal treatment of disease through administration of maternal glucocorticoid

Monitoring

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

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
  • 11-beta-hydroxylase deficiency
    • Premature sexual development in males, hypertension, and hypokalemia
  • 17-alpha-hydroxylase deficiency
  • 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
Test Name and Number Recommended Use Limitations Follow Up
Congenital Adrenal Hyperplasia Panel, 11-Beta Hydroxylase Deficiency 2002282
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Screen for 11-beta hydroxylase deficiency

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

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

Screen for 21-hydroxylase deficiency

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

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

Screening panel for classic and nonclassic CAH

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

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

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

Monitoring of patients with diagnosis of CAH

Component serum tests are 11-deoxycortisol quantitative; 17-OHP quantitative by MS/MS; 17-hydroxypregnenolone quantitative by MS/MS, and pregnenolone by MS/MS

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Cytogenomic SNP Microarray 2003414
Method: Genomic Microarray (Oligo-SNP Array)

First-tier test for intellectual disability (ID), developmental delay (DD), dysmorphic features, congenital anomalies, and autism

Specimen – blood

Cytogenomic SNP Microarray Buccal Swab 2006267
Method: Genomic Microarray (Oligo-SNP Array)

First-tier test for indication of ID, DD, dysmorphic features, congenital anomalies, and autism

Specimen – buccal (requires use of Oracollect collection kit)

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

11-Deoxycortisol Quantitative by HPLC-MS/MS, Serum or Plasma 0092331
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Detect enzyme deficiencies causing CAH

11-Deoxycorticosterone Quantitative by HPLC-MS/MS, Serum or Plasma 2008458
Method: Quantitative High Performance 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 HPLC-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