Congenital adrenal hyperplasia (CAH) is a family of inherited, autosomal recessive disorders of adrenal steroidogenesis due to an abnormality in a step necessary for conversion of cholesterol to cortisol in the adrenal cortex (Figure 46-1). Of all CAH cases, 95% are caused by 21-hydroxylase deficiency. There are 2 forms of 21-hydroxylase deficiency: classic and nonclassic CAH (also called late-onset CAH). Classic CAH comprises the salt-wasting form (cortisol deficiency and aldosterone deficiency) and simple virilizing form. The salt-wasting form comprises 75% and simple virilizing form 25% of patients with 21-hydroxylase deficiency. The classic form is associated with severe enzyme deficiency, leading to prenatal virilization in girls; the nonclassic form has mild enzyme deficiency that causes postnatal hyperandrogenism but no prenatal virilization.
Adrenal biosynthesis pathway.
The most common form of CAH is caused by mutations in CYP21A2, the gene encoding the adrenal steroid 21-hydroxylase enzyme (P450c21).1 The steroid 21-hydroxylase enzyme catalyzes conversion of 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol and progesterone to deoxycorticosterone, which are precursors of cortisol and aldosterone, respectively. In 21-hydroxylase deficiency, because of deficient cortisol synthesis, progesterone and 17-hydroxyprogesterone are shunted to the androgen synthetic pathway (androstenedione and testosterone). These adrenal androgens are oversecreted in utero, resulting in variable degrees of virilization in the female fetus.
The incidence of classic CAH in the general population, as shown by newborn screening in different populations worldwide, ranges from 1:10,000 to 1:20,000, with an overall incidence of 1:15,000.2, 3 The incidence of CAH in specific populations ranges from 1 in 5000 live births in Saudi Arabia to 1 in 21,270 live births in New Zealand. The newborn screening incidence in the United States and Canada is 1 in 14,203 live births, with Brazil at 1 in 1863 live births and Japan at 1 in 18,827. A high frequency of CAH exists among Yupik Eskimos from western Alaska: 1 in 282 live births.
The prevalence of nonclassic 21-hydroxylase deficiency CAH in the general heterogeneous population of New York City was estimated to be 1 in 100. Ashkenazi Jews have the highest prevalence at 1/27. Other ethnic groups with a high prevalence of nonclassic CAH include Hispanics (1/40), Slavs (1/50), and Italians (1/300).1
The cardinal feature of classic CAH in newborn females is ambiguous genitalia (Figure 46-2). Clitoromegaly occurs as a result of adrenal androgens binding to genital skin androgen receptors. Females may present with a urogenital sinus (Figure 46-3). Urogenital sinus due to high levels of circulating adrenal androgens beginning at about 7 weeks’ gestation prevent the formation of separate vaginal and urethral canals. Females with classic CAH have normal Müllerian structures (uterus, fallopian tubes). The girl with classic CAH ...