Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

268 Section II • Clinical Endocrinology

genital anatomy and psychological factors, such as delayed psychosexual development and decreased sexual activity, also contribute. 177 In one study of quality of life in women with classical CAH, half reported that their disease adversely affected their sexual life and most were less than satisfied with their genital anatomy and function, regardless whether they had received reconstructive surgery; vaginal stenosis or narrowing were commonly observed. 178 Women with classi cal CAH also had a later sexual debut and fewer pregnancies and children. Fertility rates correlate with the severity of the disorder and are significantly lower in women with salt wast ing than in those with the simple virilizing form of classical CAH. 179 However, outcomes of pregnancies among women with classical CAH who conceive are normal except for an increased incidence of gestational diabetes. 177 Children born to mothers with classical CAH have normal birth weight, have no increased incidence of malformations, and exhibit normal intellectual and social development. 177,180 Although maternal serum androgen concentrations can increase significantly during pregnancy and should be monitored, the high capacity of placental aromatase activity effectively protects the female fetus from the masculinizing effects of maternal hyperandrogenism. 180

enzyme deficiency (compound heterozygote). Compound heterozygotes having two variant alleles can exhibit the fea tures of nonclassical CAH but are not at risk for having a child with classical CAH. Although phenotype does not reliably predict genotype, the effect of a given mutation generally can be predicted by site-directed mutagenesis and expression and by analysis of enzyme activity in vitro. 138,147,153–156,158–165 ● ● The salt-wasting form of classical 21-hydroxylase defi ciency usually is associated with large gene deletions or a mutation that affects splicing and results in no enzyme activity. ● ● Patients with the simple virilizing form of classical 21-hydroxylase deficiency most often have point muta tions that result in low but detectable enzyme activity (e.g., 1–2% of normal) that supports adequate aldosterone and cortisol production. ● ● Those with the nonclassical form of 21-hydroxylase defi ciency usually are compound heterozygotes, having one classic mutation and one variant allele or two variant alleles; the phenotype of compound heterozygotes usually correlates with the less severe of the two mutations. 150 ● ● Heterozygotes may exhibit biochemical abnormalities but typically have no clinically significant endocrinopathy. 166,167 Females with classical 21-hydroxylase deficiency (both salt-wasting and simple virilizing forms) present at birth with ambiguous genitalia (adrenogenital syndrome) . 168–170 Boys with salt-wasting CAH typically present as neonates or during early infancy with symptoms of adrenal insufficiency (failure to thrive, dehydration, hyponatremia, hyperkale mia), and those with simple virilizing CAH not identified by neonatal screening generally present as young children with early virilization. Females with the nonclassical “late-onset” form of 21-hydroxlyase deficiency have normal external genitalia and present later, during childhood or early ado lescence with precocious puberty, or as young adults with other signs of hyperandrogenism such as hirsutism. As discussed earlier in this chapter in reference to the sexual differentiation of the CNS, females with classical CAH tend to exhibit greater interest in male-typical toys and play and more cross-gender and aggressive behavior than do unaffected healthy women. 4,106–111 Studies of cognitive func tion in women with classical CAH have yielded inconsis tent results. Whereas some have suggested that such women exhibit lower 171,172 or higher intelligence 173 and differences in verbal learning and memory, 174,175 compared to unaffected women, others have found no evidence to indicate that prenatal androgen exposure has a consistent or predictable effect on cognition in women with CAH. 176 Fertility in women with classical CAH is lower than that in normal women, 3,111 primarily due to chronic anovula tion relating to excess production of adrenal androgens and progestogens (progesterone, 17-OHP) and disordered patterns of gonadotropin secretion 151 ; abnormalities of

Diagnosis of 21-hydroxylase deficiency is based on a high serum concentration of 17-OHP, the primary substrate for the enzyme. In neonates with either salt-wasting or simple virilizing CAH, 17-OHP levels typically are greater than 3,500 ng/dL 129,181 ; levels in normal newborns generally are below 100 ng/dL. 147 To distinguish 21-hydroxylase deficiency from other causes of CAH (11 β -hydroxylase and 3 β -HSD deficiencies), serum concentrations of 11-deoxycortisol and 17 α -hydroxypregnenolone also should be measured. When the diagnosis is suspected but uncertain, it can be confirmed by performing an ACTH stimulation test, obtaining blood samples before and 60 minutes after administering cosyn tropin (synthetic ACTH 1–24; 1 mg/m 2 or 0.25 mg) 182 ; in affected infants, stimulated 17-OHP levels typically exceed 10,000 ng/dL. 168 Diagnosis also can be confirmed by geno typing, which can detect approximately 95% of mutations. 183 In couples known to be at risk for having an affected child (affected sibling, both partners carriers for a clas sic mutation), prenatal diagnosis is possible by genotyping amniocytes or, preferably, cells obtained by chorionic vil lus sampling (CVS). 139,152 Early prenatal diagnosis offers the option for intervention, before the most critical period of fetal genital differentiation, in efforts to avoid severe mascu linization of the external genitalia in affected female fetuses. Neonatal screening programs measure 17-OHP in blood samples dried on filter paper, comparing results to established reference values that vary with weight and gestational age. 184,185 Antenatal corticosteroid treatment can decrease 17-OHP lev els and increase the risk for a false-negative result, particularly when administered repeatedly 186 ; screening can be repeated at 1–2 weeks of age, with careful monitoring in the interim, or genotyping can be performed on the dried blood sample. 187 Copyright © 2019 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited.