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DEFINITION/CLASSIFICATION

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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.

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ETIOLOGY

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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.

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EPIDEMIOLOGY

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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.

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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

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CLINICAL MANIFESTATIONS

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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 ...

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