The incidence of classic 21-hydroxylase deficiency is about 1 in 15,000 among various white populations. Nonclassic CAH may occur with an incidence of 1 in 50 in certain populations. The gene for 21-hydroxylase lies on the short arm of chromosome 6; the genotype may be determined in a proband, permitting prenatal diagnosis in a subsequent pregnancy.
Deficient 21-hydroxylase activity (P-450c21 deficiency) impairs the conversion of 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol and in the salt-losing form, of progesterone to deoxycorticosterone, a mineralocorticoid proximal in the pathway to the production of aldosterone. The decreased production of cortisol causes hypersecretion of ACTH, which stimulates the synthesis of steroids immediately proximal to the block and shunting of these to overproduction of androgens. The primary clinical manifestation is the virilization of the external genitalia of the affected female fetus; the development of the uterus, ovaries, and fallopian tubes remains unaffected by the androgens. The degree of virilization varies, ranging from mild clitoromegaly to complete fusion of labioscrotal folds, with severe clitoromegaly simulating a phallus (see Chapter 177). A male infant with this defect appears normal at birth, although penile enlargement may be apparent thereafter. The deficiency in aldosterone, found in about 75% of patients, causes salt wasting with shock and dehydration until the diagnosis is established and appropriate treatment is given.
The treatment of 21-hydroxylase deficiency requires hydro-cortisone and fludrocortisone in the case of the salt-losing form. Therapy must be adjusted throughout childhood at regular intervals. Overtreatment will cause growth stunting and weight gain (cushingoid features), whereas undertreatment will cause excessive height gain, skeletal advance, and early appearance puberty, ultimately jeopardizing adult height potential.
Late-onset CAH is typically noted years after birth. Affected subjects have milder manifestations without ambiguous genitalia, but they may have acne, hirsutism, and in girls irregular menstrual cycles or amenorrhea. Late-onset CAH in girls may be confused with polycystic ovarian syndrome.
Biochemical diagnostic studies show elevated levels of serum 17-OHP, the substrate for the defective 21-hydroxylase enzyme activity. In newborns with CAH, the values are elevated a hundredfold to a thousandfold. In late-onset CAH, an ACTH stimulation test is necessary to show an abnormally high response of 17-OHP. Serum cortisol and aldosterone levels (in salt losers) are low, renin levels are high, whereas the testosterone level is elevated because it is derived from 17-OHP.