EVIDENCE FOR A HETEROZYGOTE ADVANTAGE IN CONGENITAL ADRENAL-HYPERPLASIA DUE TO 21-HYDROXYLASE DEFICIENCY

21-Hydroxylase deficiency is one of the most common inherited disorder s, with carrier frequencies of approximately 10% in all world populati ons studied to date. The high prevalence of the mutant gene is probabl y due to a flanking pseudogene serving as a reservoir for mutations. D espite the potential for a high rate of de novo mutations, a founder e ffect for specific gene conversions is observed in most populations. W e hypothesized that there was a survival advantage to 21-hydroxylase h eterozygotes, and here we report endocrinological and molecular invest igations to test this hypothesis. We defined 28 carriers and 22 mutati on-negative controls by molecular genotyping and determined ACTH-stimu lated adrenal hormone responses. We found significantly elevated corti sol responses in the carriers compared to controls (30 min cortisol le vels: normal, 24.2 +/- 4.6 mu g/dL; carrier, 28.1 +/- 4.2 mu g/dL; P < 0.005). Cortisol has a crucial role in maintaining homeostasis, influ encing differentiation, suppressing inflammation, and effecting cross- talk among the immune, nervous, and endocrine systems. The brisk corti sol response we have documented in carriers of 21-hydroxylase may enab le a rapid return to homeostasis in response to infectious, inflammato ry, or other environmental stresses and may protect from inappropriate immune responses, such as autoimmune diseases.