Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasias (CAH) are a group of heritable disorders associated with an inability or deficiency in the ability to produce cortisol. In affected individuals, the disease begins early in gestation and leads to disease that is manifest at birth. Without cortisol, there is a failure of negative feedback and excessive secretion of corticotropin-releasing hormone from the hypothalamus and ACTH from the anterior pituitary. Continued secretion of ACTH causes unremitting stimulation of the adrenal cortex, leading to hyperplasia (an increase in the number of cells in that tissue).

In the most common cases, adrenal hyperplasia also involves a deficiency in aldosterone, which results in mild to severe loss of body sodium. In some individuals, the disorder also involves overproduction of adrenal androgens, which, in affected females, often results prenatal virilization with an ambiguous or male-like external genital tract at birth.

Mutations in at least five different genes can result in adrenal hyperplasia, all of which are transmitted as autosomal recessive traits.

CAH Due to 21-Hydroxylase Deficiency

Greater than 90% of the cases of CAH are the result of deficiency in the enzyme steroid 21-hydroxylase. Absolute or partial deficiency in this enzyme leads to two problems:

1. Deficiency in production of cortisol and aldosterone: Aldosterone is necessary for normal retention of sodium by the kidney, and in its absense, a "salt wasting" disorder occurs.
2. Shunting of steroid precursors to form androgens: In the absence of 21-hydroxylase, concentrations of 17-hydroxyprogesterone increase substantially and is converted to androgens including testosterone and dihydrotestosterone. The resulting secretion of relative large quantities of androgens early in life leads to virilization of female fetuses and abnormal development in male children.

Incidence and Clinical Presentation

CAH due to 21-hydroxylase deficiency is seen in roughly 1 of every 15,000 live births worldwide; it is a relatively common disorder in humans. Clinically, it is seen in three primary manifestations:

• Simple virilizing form: Excessive prenatal production of androgens in affected females results in masculinization of the reproductive tract to a point that the sex of the newborn is not clear ("ambiguous genitalia") or appears male-like. Affected males are usually normal at birth. In both sexes, linear growth in childhood is accelerated, but the epiphyses fuse early, leading to short stature. The simple virilizing form of CAH is seen in approximately 25% of those with 21-hydroxylase deficiency.
• Salt-wasting form: Roughly 75% patients are unable to synthesize adequate amounts of aldosterone, which is essential for sodium homeostasis. Such individuals lose large amounts of sodium in urine, which leads to potentially fatal electrolyte and water imbalance. Individuals with severe deficiency usually present with "adrenal crisis" between 1 and 4 weeks of age; signs are often non-specific, but can include poor appetite, vomiting and failure to grow. Replacement therapy is mandatory in such patients.
• Non-classical form: This form of the disease is mild and usually manifest as some type of androgen excess later in life. Aldosterone deficiency is not usually observed.

Genetics

The 21-hydroxylase enzyme is encoded by the CYP21 gene. More than 50 different mutations of CYP21 have been identified, of which about 15 account for a large majority of 21-hydroxylase cases. Most mutations appear to be the result of a recombination between CYP21 and a pseudogene (CYP21P). One consequence of this multitude of mutations is that there is considerable variability in the clinical presentation of disease, ranging from severe salt-wasting or virilizing disease to milder syndromes. This disorder is seen as a simple autosomal recessive trait.

Diagnosis and Prenatal Screening

Most commonly, 21-hydroxylase deficiency is first suspected in a newborn infant with "ambiguous genitalia". Finding elevated blood levels of 17-hydroxyprogesterone, in conjuction with ultrasound examination of the abdomen and genital tract usually leads to a rapid diagnosis. Disorders that must be differentiated in such cases include true hermaphorditism, pseudohermaphroditism and certain types of sex chromosome abnormalities, none of which should have high concentrations of 17-hydroxyprogesterone.

Treatment

All patients with CAH, regardless of form, are treated with glucocorticoid replacment therapy. This not only alleviates glucocorticoid (i.e. cortisol) deficiency, but more importantly, provides negative feedback to suppress ACTH secretion and prevent continued adrenal stimulation. As a result, excessive 17-hydroxyprogesterone is not available as a substrate for excessive androgen production.

Patients with the salt-wasting form of deficiency must also receive mineralocorticoid therapy to normalize the abnormalities in sodium balance associated with aldosterone deficiency.

Prenatal treatment of the mother with glucocorticoids can prevent or reduce that the virilizing effects of fetal 21-hydroxylase deficiency. This procedure has been used in cases where couples have previously had a child with virilizing CAH. In such cases, it is known that both parents are carriers, and since only female children require prenatal treatment, the probability that the current fetus is affected is 1 in 8. Treatment of the mother with glucocorticoids must begin at 6 to 7 weeks of gestation, at which time it is almost never known whether the fetus is affected. Hence, in 7 of 8 cases, the fetus does not actually require therapy. The long term effect and safety of this procedure is poorly defined.

A number of surigical procedures have been developed to correct the genital abnormalities of girls with the virilizing form of CAH. These procedures are complicated by concerns about when the surgery should be performed, gender identity of the patient and other factors.

CAH Due to Other Mutations

Mutations in four genes other than CYP21 are recognized to cause forms of CAH. Three of these induce a deficiency in enzymes involved in steroidogenesis. The fourth involves the steroid acute-regulatory protein (StAR), which is promotes transport of cholesterol into mitochondria.

References and Reviews

• Lee H: CYP21 mutations and congenital adrenal hyperplasia. Clin Genetics 59:293-301, 2001.
• Meyer-Bahlburg HF: Gender and sexuality in classic congenital adrenal hyperplasia. Endocrin Metab Clinics North Amer 30:155-171, 2001.
• Ritzen EM: Prenatal dexamethasone treatment of fetuses at risk for congenital adrenal hyperplasia: benefits and concerns. Seminars Neonatology 6:357-362, 2001.
• Spiser PW, White PC: Congenital adrenal hyperplasia. New Eng J Med 349:776,788, 2003.
• Therrell BL: Newborn screening for congenital adrenal hyperplasia. Endocrin Metab Clinics North Amer 30:15-30, 2001.
• White PC, Speiser PW: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocrine Reviews 21:245-291, 2000.

Advanced and Supplemental Topics

• Steroidogenesis