Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) refers to any of several autosomal recessive diseases resulting from defects in steps of the synthesis of cortisol from cholesterol by the adrenal glands. Most of these diseases involve excessive or defective production of sex steroids and can pervert or impair development of primary or secondary sex characteristics in affected infants, children, and adults. Only a small minority of people with CAH can be said to have an intersex condition, but this attracted American public attention in the late 1990s and many accounts of varying accuracy have appeared in the popular media. more...

Examples of problems caused by various forms of CAH:

• ambiguous genitalia such that it is difficult to determine sex
• vomiting leading to dehydration and death in early infancy
• early pubic hair and rapid growth in childhood
• precocious puberty or failure of puberty to occur
• excessive facial hair, virilization, and/or menstrual irregularity in adolescence
• infertility due to anovulation

Overview of the multiple types of CAH

Cortisol is an adrenal steroid hormone necessary for life; production begins in the second month of fetal life. Inefficient cortisol production results in rising levels of ACTH, which in turn induces overgrowth (hyperplasia) and overactivity of the steroid-producing cells of the adrenal cortex. The defects causing adrenal hyperplasia are congenital (i.e., present at birth).

Cortisol deficiency in CAH is usually partial, and not the most serious problem for an affected person. Synthesis of cortisol shares steps with synthesis of mineralocorticoids such as aldosterone, androgens such as testosterone, and estrogens such as estradiol. The resulting excessive or deficient production of these three classes of hormones produce the most important problems for people with CAH. Specific enzyme inefficiencies are associated with characteristic patterns of over- or underproduction of mineralocorticoids or sex steroids.

In all its forms, congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for about 95% of diagnosed cases of CAH. Unless another specific enzyme is mentioned, "CAH" in nearly all contexts refers to 21-hydroxylase deficiency.

• Severe 21-hydroxylase deficiency causes salt-wasting CAH, with life-threatening vomiting and dehydration occurring within the first weeks of life. Severe 21-hydroxylase deficiency is also the most common cause of ambiguous genitalia due to prenatal virilization of genetically female (XX) infants.
• Moderate 21-hydroxylase deficiency is referred to as simple virilizing CAH; and typically is recognized by causing virilization of prepubertal children.
• Still milder forms of 21-hydroxylase deficiency are referred to as non-classical CAH and can cause androgen effects and infertility in adolescent and adult women.

CAH due to deficiencies of other enzymes than 21-hydroxylase present many of the same management challenges as 21-hydroxylase deficiency, but some involve mineralocorticoid excess or sex steroid deficiency.

• Lipoid congenital adrenal hyperplasia
• Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency
• Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency
• Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Further variability is introduced by the degree of enzyme inefficiency produced by the specific alleles each patient has. Some alleles result in more severe degrees of enzyme inefficiency. In general, severe degrees of inefficiency produce changes in the fetus and problems in prenatal or perinatal life. Milder degrees of inefficiency are usually associated with excessive or deficient sex hormone effects in childhood or adolescence, while the mildest form of CAH interferes with ovulation and fertility in adults.

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