• Clinical science

Congenital adrenal hyperplasia


Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive defects in enzymes that are responsible for cortisol, aldosterone, and, in very rare cases, androgen synthesis. All forms of CAH are characterized by low levels of cortisol, high levels of ACTH, and adrenal hyperplasia. The exact clinical manifestations depend on the enzyme defect. The most common form of CAH, which is caused by a deficiency of 21β-hydroxylase, presents with hypotension, ambiguous genitalia, and virilization (in the female genotype), and/or precocious puberty (in both males and females). It is further characterized by hyponatremia, hyperkalemia, and metabolic acidosis. Increased levels of 17-hydroxyprogesterone confirm the diagnosis of 21β-hydroxylase deficiency. All newborn infants in the United States are screened for 21β-hydroxylase deficiency by measuring 17-hydroxyprogesterone in a blood sample obtained from a heel prick. Treatment of CAH involves lifelong glucocorticoid replacement therapy. Patients with a 21β-hydroxylase deficiency also require mineralocorticoid replacement with fludrocortisone. Certain rare forms of CAH (e.g., 11β-hydroxylase and 17α-hydroxylase deficiencies) present with symptoms of mineralocorticoid excess (e.g., hypertension) and therefore require spironolactone (aldosterone receptor inhibitor) in addition to glucocorticoid replacement. Patients with gender identity issues may benefit from counseling. Surgical reconstruction of the genitals may be considered in cases of ambiguous genitalia. Complications of CAH include severe hypoglycemia, adrenal insufficiency, and/or a failure to thrive.


Enzyme deficiency Cortisol Aldosterone 11-Deoxycorticosterone (DOC) Androgens




Clinical features

Deficient enzyme Blood pressure XX (female) genotype XY (male) genotype


  • Hypotension



As a result of both severe dehydration associated with an adrenal crisis and salt-wasting associated with hypoaldosteronism, infants with 21β-hydroxylase deficiency can present with shock within the first few weeks of life!

Different types of mutations on the CYP21A2 gene (which codes for 21β-hydroxylase) are associated with different levels of disease severity.

Disease manifestations Classic form Nonclassic CAH
21β-hydroxylase deficiency Severe Mild
Detection by neonatal screening Yes No
Prevalence Less common More common
Onset of symptoms Early onset (during the neonatal period or early infancy) Late onset (presents during late childhood, adolescence or adulthood)
Clinical manifestations

Two clinical subtypes exist:

  • Salt-wasting type
  • Non-salt-wasting type (simple virilizing)
    • ∼ 33% of all classic forms
    • No signs of shock
    • Males present with precocious puberty at age 2–4
    • Females present with ambiguous genitalia
Ethnic predisposition


Ashkenazi Jews, whites


Differential diagnoses

The differential diagnoses listed here are not exhaustive.


  • ↑ Specific steroid precursors in blood and/or urine samples (see the table below)
  • Hypocortisolism is seen in all forms of CAH and cortisol levels remain low even after administration of cosyntropin.
  • Specific patterns of electrolyte and/or acid-base disorders are associated with specific enzyme deficiencies.
Deficient enzyme Steroid precursors Additional laboratory findings




All newborns in the US are screened for CAH by measuring changes in 17-hydroxyprogesterone levels from a heel prick blood sample!References:[2][10][9][11]


The dose of glucocorticoids must be increased during periods of stress (e.g., sepsis)!References:[4][7][9][12]