Measurement of 17-OHP should be performed in patients presenting with precocious puberty, and a subsequent ACTH stimulation test is recommended if basal 17-OHP is greater than 200 ng/dL.
The need for screening patients with hirsutism for adult-onset adrenal hyperplasia depends on the patient population. The frequency of some form of the disorder varies by ethnicity and is estimated at 0.1% of the general population, 1% to 2% of Hispanics and Yugoslavs, and 3% to 4% of Ashkenazi Jews (175).
Genetics of 21-Hydroxylase Deficiency 1.
The 21-hydroxylase gene is located on the short arm of chromosome 6, in the midst of the HLA region.
2.
The 21-hydroxylase gene is now termed CYP21. Its homologue is the pseudogene CYP21P (176).
3.
Because CYP21P is a pseudogene, the lack of transcription renders it nonfunctional. The CYP21 is the active gene.
4.
The CYP21 gene and the CYP21P pseudogene alternate with two genes called C4B and C4A, both of which encode for the fourth component (C4) of serum complement (176).
5.
The close linkage between the 21-hydroxylase genes and HLA alleles allowed the study of 21-hydroxylase inheritance patterns in families through blood HLA typing (e.g., linkage of HLA-B14 was found in Ashkenazi Jews, Hispanics, and Italians) (177).
Women with congenital and adult-onset forms of the disorder are at a significant risk for having affected infants, owing to the high frequency of 21-hydroxylase mutations in the general population. This presents an important rationale for screening hyperandrogenic women for this disorder when they anticipate childbearing. In families at risk for CAH and in instances where one partner expresses the congenital or adult onset form of the disease, first-trimester prenatal screening using chorionic villus sampling is advocated (176). The fetal DNA is used for specific amplification of the CYP21 gene using polymerase chain reaction (PCR) amplification (178). When the fetus is at risk for CAH, maternal dexamethasone treatment can suppress the fetal HPA axis and prevent genital virilization in affected females (179). The dose is 20 μg/kg in three divided doses administered as soon as pregnancy is recognized and no later than 9 weeks of gestation. This is done prior to performing chorionic villus sampling or amniocentesis in the second trimester. Dexamethasone crosses the placenta and suppresses ACTH in the fetus. If the fetus is determined to be an unaffected female or a male, treatment is discontinued. If the fetus is an affected female, dexamethasone therapy is continued.
The practice of prenatal dexamethasone treatment for women whose fetuses are at risk for CAH is controversial; seven of eight pregnancies will be treated with dexamethasone unnecessarily, albeit brieﬂy, to prevent one case of ambiguous genitalia. The efficacy and safety of prenatal dexamethasone treatment is not established, and long-term follow-up data on the offspring of treated pregnancies are lacking (180).
Numerous studies in experimental animal models showed that prenatal dexamethasone exposure could impair somatic growth, brain development, and blood pressure regulation. A human study of 40 fetuses at risk for CAH who were treated prenatally with dexamethasone to prevent virilization of affected females reported long-term effects on neuropsychological functions and scholastic performance (179,181).