Evidence for a heterozygote advantage in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Selma F. Witchel, Peter A. Lee, Makiko Suda-Hartman, Massimo Trucco, Eric P. Hoffman

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


21-Hydroxylase deficiency is one of the most common inherited disorders, with carrier frequencies of approximately 10% in all world populations studied to date. The high prevalence of the mutant gene is probably due to a flanking pseudogene serving as a reservoir for mutations. Despite the potential for a high rate of de novo mutations, a founder effect for specific gene conversions is observed in most populations. We hypothesized that there was a survival advantage to 21-hydroxylase heterozygotes, and here we report endocrinological and molecular investigations to test this hypothesis. We defined 28 carriers and 22 mutation-negative controls by molecular genotyping and determined ACTH-stimulated adrenal hormone responses. We found significantly elevated cortisol responses in the carriers compared to controls (30 min cortisol levels: normal, 24.2 ± 4.6 μg/dL; carrier, 28.1 ± 4.2 μg/dL; P < 0.005). Cortisol has a crucial role in maintaining homeostasis, influencing differentiation, suppressing inflammation, and effecting cross-talk among the immune, nervous, and endocrine systems. The brisk cortisol response we have documented in carriers of 21-hydroxylase may enable a rapid return to homeostasis in response to infectious, inflammatory, or other environmental stresses and may protect from inappropriate immune responses, such as autoimmune diseases.

Original languageEnglish (US)
Pages (from-to)2097-2101
Number of pages5
JournalJournal of Clinical Endocrinology and Metabolism
Issue number7
StatePublished - 1997

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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