• Clinical science

Congenital adrenal hyperplasia


Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive defects in the 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 is caused by a deficiency of 21β-hydroxylase and manifests with hypotension, ambiguous genitalia, virilization (in the female genotype), and/or precocious puberty (in both males and females). All newborn infants in the US are screened for 21β-hydroxylase deficiency by measuring 17-hydroxyprogesterone in a blood sample obtained from a heel prick. CAH treatment involves lifelong glucocorticoid and fludrocortisone replacement therapy. Certain rare forms of CAH (e.g., 11β-hydroxylase and 17α-hydroxylase deficiencies) manifest with symptoms of mineralocorticoid excess (e.g., hypertension) and therefore require spironolactone (aldosterone receptor inhibitor) in addition to glucocorticoid replacement. Individuals with a virilizing form of CAH have an increased likelihood of experiencing gender dysphoria. Intersex medical interventions may be considered in cases of ambiguous genitalia. Complications of CAH include severe hypoglycemia, adrenal insufficiency, and failure to thrive.


Enzyme deficiency Cortisol Aldosterone 11-Deoxycorticosterone (DOC) Androgens

A deficiency in both 17α-hydroxylase and 11β-hydroxylase tends to result in overproduction of mineralocorticoids like DOC and underproduction of aldosterone.“1 DOC:” If the deficient enzyme starts with 1 (11β-, 17‑), there is increased DOC.
“AND 1:” If the deficient enzyme ends with 1 (21-, 11β‑), androgens are increased.


Clinical features

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


  • Hypotension



Infants with 21β-hydroxylase deficiency can present with shock within the first few weeks of life because of severe dehydration due to an adrenal crisis and salt-wasting due to hypoaldosteronism.

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

Classic CAH Nonclassic CAH
21β-hydroxylase deficiency
  • Severe
  • Mild
Detection by neonatal screening
  • Yes
  • No
  • Less common
  • More common
Onset of symptoms
  • Early onset (during the neonatal period or early infancy)
  • Late onset (manifests during late childhood, adolescence, or adulthood)
Clinical manifestations
  • 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
  • Inuit and Alaska native populations
  • Ashkenazi and white populations

Individuals with a virilizing form of CAH have an increased likelihood of experiencing gender dysphoria.


Differential diagnoses

The differential diagnoses listed here are not exhaustive.


Laboratory findings Adrenal enzyme deficiencies
21β-hydroxylase 11β-hydroxylase 17α-hydroxylase
  • ↑↑
11-Deoxycorticosterone (DOC)
  • ↑↑
  • ↑↑
Acid-base disorders

All newborns in the US are screened for CAH by measuring changes in 17-hydroxyprogesterone levels from a heel prick blood sample.References:[2][11][9][12]


The dose of glucocorticoids must be increased during severe infection, critical illness, and perioperatively to meet increased demands to prevent adrenal crisis.


Prenatal diagnosis and treatment of CAH