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.
- CAH is caused by autosomal recessive defects in enzymes that are responsible for the production of cortisol.
- There are three subtypes of CAH:
- Low levels of cortisol → lack of negative feedback to the pituitary → increased ACTH → adrenal hyperplasia and increased synthesis of adrenal precursor steroids
- Depending on which enzyme is affected, the following endocrine changes are seen:
|Enzyme deficiency||Cortisol||Aldosterone||11-Deoxycorticosterone (DOC)||Androgens|
|21β-hydroxylase|| || || || |
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.
|Blood pressure||XX (female) genotype||XY (male) genotype|
- → vomiting and diarrhea → dehydration
- Failure to thrive
- Hyperpigmentation in areas that are not exposed to sunlight (e.g., palm creases, mucous membranes of the oral cavity, genitalia) is a common feature in all forms of CAH.
|Classic CAH||Nonclassic CAH|
|21β-hydroxylase deficiency|| || |
|Detection by neonatal screening|| || |
|Prevalence|| || |
|Onset of symptoms|| || |
|Clinical manifestations|| |
|Ethnic predisposition|| || |
The differential diagnoses listed here are not exhaustive.
- Increased 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.
|Laboratory findings||Adrenal enzyme deficiencies|
|17-Hydroxyprogesterone|| || || |
|11-Deoxycorticosterone (DOC)|| || || |
|Corticosterone|| || || |
|Sodium|| || || |
|Potassium|| || || |
- General approach
- 21β-hydroxylase deficiency
- 11β-hydroxylase deficiency
- 17α-hydroxylase deficiency
- Salt-wasting CAH
- Nonclassic CAH
- Additional considerations
Prenatal diagnosis and treatment of CAH
- Prenatal testing is recommended in mothers who have previously given birth to a child with 21β-hydroxylase deficiency.
- If a defect in 21β-hydroxylase is diagnosed prenatally: