- Clinical science
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.
- CAH is a result of autosomal recessive defects in enzymes that are responsible for the production of cortisol. The most common defects are:
- Low levels of cortisol → lack of negative feedback to the pituitary → ↑ 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|
|Deficient enzyme||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, and/or genitalia) is a common feature in all forms of CAH.
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!
|Disease manifestations||Classic form||Nonclassic CAH|
|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:
|Ethnic predisposition|| |
|Ashkenazi Jews, whites|
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|
- For all forms: lifelong glucocorticoid replacement therapy
- 21β-hydroxylase deficiency: lifelong fludrocortisone therapy (aldosterone substitution)
- 11β-hydroxylase deficiency:
- 17α-hydroxylase deficiency
- Counseling may be considered for potential gender identity issues
- Genital reconstruction surgery may be considered in children with ambiguous genitalia.