Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

266 Section II • Clinical Endocrinology

Deficiencies of 11 β -hydroxylase and 3 β -HSD are less common causes of CAH. In all, the pathophysiology relates primarily to decreased cortisol production, which stimulates a compensatory increase in pituitary adreno corticotropic hormone (ACTH) secretion, causing adrenal hyperplasia; increased levels of steroid hormones proxi mal to the enzyme block seek an alternative metabolic pathway, resulting in increased production of androgens. In females, the classic forms of CAH (with and without salt wasting) are characterized by genital ambiguity. Depending on the time, duration, and level of exposure, abnormally high androgen concentrations in utero result in vary ing degrees of clitoral enlargement and labial fusion and abnormalities of the urethra and vagina; generally, the urethra and vagina share a urogenital sinus that opens at the base of the clitoris. The fetal adrenal cortex does not achieve a significant level of function before 10 weeks of gestation, and by that time, the vagina and urethra nor mally have become separated. However, between 10 and 12 weeks, rising androgen levels can promote progressive cli toral enlargement, labial fusion, and even partial closure of the urethra. At birth, the genital anatomy is similar to that in males with hypospadias and bilateral cryptorchidism and can result in incorrect sex assignment. The effects of elevated adrenal androgen levels arising after 12–14 weeks of gesta tion are more limited. Female external genital development normally is not completed until approximately 20 weeks of gestation, and the size of the clitoris depends more on the level than on the timing of excess androgen exposure. Development of the internal genitalia is normal in females with classical CAH because the excess androgen derives from the adrenals and the normal ovaries produce neither AMH nor significant amounts of androgen. Absent AMH and the high local androgen concentrations required to promote wolffian duct development, the fallopian tubes, uterus, and upper vagina develop normally. 21-Hydroxylase (P450c21) Deficiency The enzyme 21-hydroxylase (also designated P450c21 and CYP21A2) mediates the conversion of 17 α -hydrox yprogesterone (17-OHP) to 11-deoxycortisol (the immediate precursor of cortisol) and of progesterone to 11-deoxycorti costerone (an intermediate steroid in aldosterone synthesis). CAH due to 21-hydroxylase deficiency is the most fre quent cause of sexual ambiguity and the most common endocrine cause of neonatal death . The more serious “salt-wasting” variety of classical 21-hydroxylase deficiency is characterized by severe deficiencies of both cortisol and aldosterone, resulting in salt wasting and dehydration, in addition to virilization. In the less severe “simple virilizing” form of the disorder, elevated levels of ACTH are able to drive sufficient glucocorticoid and mineralocorticoid pro duction to prevent circulatory collapse, but excess androgen production in utero results in masculinization of the exter nal genitalia. The third and least severe “nonclassical” form

of 21-hydroxylase deficiency generally does not become apparent until adolescence or early adulthood, when abnor mally high androgen levels cause hirsutism and menstrual irregularities. Data derived from neonatal screening programs for detec tion of classical CAH indicate that prevalence varies widely with ethnicity. Whereas the overall prevalence is approxi mately 1 in 15,000 live births, 132 prevalence ranges from 1 in 28,000 Chinese 133 and between 1 in 5,000 and 1 in 23,000 Caucasians, 134,135 to as high as 1 in 280 Yupik Eskimos. 136 In the United States, the prevalence of classical CAH is lower in African Americans (1 in 42,000) than in Caucasians (1 in 15,500). 137 Approximately two-thirds exhibit salt wasting, and one-third has the simple virilizing form of the disorder (Figure 8.8) . Nonclassical 21-hydroxylase deficiency is one of the most common autosomal recessive diseases, and as in the clas sical form of the disorder, prevalence varies with ethnicity. Nonclassical 21-hydroxylase deficiency affects between 1 in 100 and 1 in 1,000 Caucasians 136–138 and may be even more common among those of Mediterranean, Hispanic, Slavic, and Eastern European Jewish descent. 139 Most affected indi viduals are not identified in neonatal screening programs because their serum levels of 17-OHP are not sufficiently ele vated. 140 Estimates of the carrier frequency (heterozygotes) for nonclassical 21-hydroxylase deficiency generally have ranged between 1 in 60 and 1 in 80 individuals 133,136 but have been as high as 1 in 10 in a European population. 141 All forms of CAH, including 21-hydroxylase deficiency, are transmitted as autosomal recessive disorders. Humans have two CYP21A genes; one is a nonfunctional pseudo gene ( CYP21A1 , also designated CYP21P , encoding an inac tive form of the enzyme), and the other is the active gene ( CYP21A2 ). The two genes have greater than 90% homology and reside in the same region within the HLA histocompat ibility complex on the short arm of chromosome 6 (6p21.3), which provides ample opportunity for recombination during meiosis. 142–145 Most CYP21A2 mutations (approximately 75%) result from nonreciprocal gene conversions in which a seg ment of the CPY21A1 pseudogene is inserted into the active CYP21A2 gene, altering its sequence and resulting in point mutations that yield a defective enzyme. 144–148 Approximately 20% of CYP21A2 mutations result from unequal crossover exchanges between the two genes, yielding a larger fusion gene that produces an enzyme having reduced or no activ ity. 134,139,148,149 About 20 gene conversion mutations account for almost all of the affected alleles observed among various ethnic groups. 147,150–157 The remaining 5% of patients with CYP21A2 mutations have 1 or 2 of the more than 60 differ ent point mutations that have been identified. 147,150–152

Women who carry a classic mutation are at risk for hav ing a child with the severe form of the disorder. They may be asymptomatic, having one classic mutation and one nor mal allele, or exhibit the nonclassical form of CAH, having one classic mutation and a variant allele associated with mild Copyright © 2019 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited.