Congenital adrenal hyperplasia (CAH) is a group of inherited disorders of the adrenal gland, small triangular organs located on top of the kidneys that secrete hormones. CAH is caused by abnormalities in the enzymes required for the production of the steroid hormones cortisol and/or aldosterone.
In the adrenal gland, cholesterol is turned into a precursor called pregnenolone and then several enzymes complete the production of aldosterone, cortisol, and androgens. If one or more of these enzymes is deficient or dysfunctional, then abnormal amounts of the final products are produced. Because low levels of cortisol cause levels of a pituitary hormone that stimulates adrenal growth and hormone production (adrenocorticotropic hormone, or ACTH) to become elevated, the adrenal gland increases in size (CAH). However, the increased size and activity cannot overcome the block in cortisol production. In some forms of CAH, other steroid hormones known as androgens (such as 17-hydroxyprogesterone) will be produced in excess. The vast majority of CAH cases are due to a deficiency in the enzyme 21-hydroxylase (classical CAH), so this type will be the main focus of this article.
With CAH, the enzyme deficiency can cause a decrease in cortisol and/or aldosterone and, in some cases, an increase in androgens, a group of "male hormones." Excess androgens can result in changes in genital structures in female infants (virilization), which is often noticed at birth. A baby girl's external sex organs may be ambiguous (not clearly female or male). While it is a rare disorder, CAH is the most common cause of ambiguous external sex organs (genitals) in newborns.
Males with this condition will appear normal at birth but may have early puberty due to the excess androgens. Females may develop excess hair on the face and body (hirsutism) and other signs of excess androgens (acne, clitoral enlargement) during childhood and adolescence and have irregular menstruation. In both male and females with classical CAH, growth is also affected. Children grow more rapidly than expected, they often have early puberty and may have shorter stature as an adult if left untreated. CAH may also lead to infertility in adults.
CAH enzyme deficiencies are due to mutations in specific genes. They are autosomal recessive, which means that it takes two copies of the gene mutation, one inherited from each parent, before a person will be affected by CAH. A person with one copy will be a carrier but will not typically have any symptoms. Many different mutations have been identified.
About 90% of CAH cases are due to a 21-hydroxylase deficiency, which is caused by a mutation in the CYP21A2 gene. Those affected may have a classic (more severe) or nonclassic (less severe) type. About 75% of those with a classic deficiency will have a "salt-wasting" form that includes decreased aldosterone and leads to an excess loss of fluids, low sodium, and high potassium that can be life-threatening.
The National Institute of Child Health and Human Development estimates that classic CAH affects about one in 15,000 babies worldwide, while nonclassic CAH affects about one in 1,000 people. CAH can occur in people of all ethnicities but is more common among Ashkenazi Jews, Yupik Eskimos, and those of Hispanic, Slavic, or Italian descent.
Several other rare inherited enzyme deficiencies can also cause CAH. Of these, 11-beta-hydroxylase deficiency is the most common, accounting for about 5-8% of CAH cases, and 17-alpha-hydroxylase and 3 beta-hydroxysteroid dehydrogenase occur to a lesser degree. The signs and symptoms that are experienced by males and females with CAH will depend upon which enzymes are deficient and the severity of the deficiencies.
For more information on these less common types of CAH, see the links in Related Content below.