More than 90 percent ofCAH cases are caused by 21-hydroxylase deficiency, which is found in classic and nonclassic forms. he incidence of classic CAH approximates 1: 15000 births overall and is higher in selected populations. For example, it has been reported in approximately 1 :300 Yupik Eskimos (Nimkarn, 2010). Among those with classic CAH, 75 percent are at risk for salt-wasting adrenal crises and require postnatal treatment with mineralocorticoids and glucocorticoids to prevent hyponatremia, dehydration, hypotension, and cardiovascular collapse. The remaining 25 percent with classic CAH have the simple virilizing ype and also require glucocorticoid supplementation. As discussed in Chapter 32 (p. 614), all states mandate newborn screening for CAH.
he eicacy of maternal dexamethasone treatment to suppress fetal androgen overproduction and either obviate or ameliorate virilization of female fetuses has been recognized for more than 30 years (David, 1984; New, 2012). Prenatal corti costeroid therapy is considered successful in 80 to 85 percent of cases (Miller, 2013; Speiser, 2010). The alternative is con sideration of postnatal genitoplasty, a complex and somewhat controversial surgical procedure (Braga, 2009).
he tpical preventive regimen is oral dexamethasone given to the mother at a dosage of 20 Lg/kg/d-up to 1.5 mg per day, divided in three doses. The critical period for external genitlia development is 7 to 12 weeks' gestation, and treatment to pre vent virilization should be initiated by 9 wees-bore it is known whether the etus is at risk. Because this is n autosomal recessive condition, ffected females mke up only 1 in 8 at-risk conceptions.
Typically, carrier parents are identified after the birth of an afected child. Molecular genetic testing is clinically available, initially using sequence analysis of the CP21A2 gene, which encodes the 21-hydroxylase enzyme (Nimkarn, 2016). If this is uninformative, gene-targeted deletion/duplication analy sis is performed, and additional testing such as whole exome sequencing may be considered (Chap. 13, p. 272).
A goal of prenatal diagnosis is to limit dexamethasone expo sure in males and in unafected females. Prenatal diagnosis villi-at 10 to 12 weeks' gestation-or on amniocytes after 15 weeks. Cell-free DNA testing of maternal serum has potential to replace invasive tests such as chorionic villus sampling and amniocentesis for CAH (Chap. 13, p. 273). Determination of (Devaney, 2011). In the research setting, cell-free DNA testing using hybridization probes lanking the CP21A2 gene can be efective as early as 5617 weeks' gestation (New, 2014).
Maternal treatment with dexamethasone has become a topic of signiicant controversy. The Endocrine Society recommends that treatment be given only in the context of research protocols (Miller, 2013; Speiser, 2010). It should be noted that if therapy is initiated shortly before 9 weeks, the dose of dexamethasone used is not considered to have significant teratogenic potential because organogenesis of major organs has already taken place (McCullough, 2010). Ongoing concerns, however, focus on the potential efects of either excess endogenous androgens or excess exogenous dexamethasone on the developing brain. Although maternal dexamethasone has been used for many years to prevent virilization of female fetuses with CAH, longterm safety data are relatively limited.