Carriers for type II 3beta-hydroxysteroid dehydrogenase (HSD3B2) deficiency can only be identified by HSD3B2 genotype study and not by hormone test

Clin Endocrinol (Oxf). 2003 Mar;58(3):323-31. doi: 10.1046/j.1365-2265.2003.01716.x.


Objective: We investigated adrenal steroidogenic function relevant to 3beta-hydroxysteroid dehydrogenase (HSD3B2) activity in vivo and HSD3B2 genotype in clinically normal family members of patients with HSD3B2 genotype-proven HSD3B2 deficiency congenital adrenal hyperplasia (CAH) to determine whether genotype-proven carriers for HSD3B2 deficiency exhibit decreased enzyme activity analogous to the mildly decreased adrenal 21-hydroxylase activity in the carriers of CYP21 gene mutation.

Design/patients: Nineteen adult family members (ages median/range: 37/19-56 years) including 13 females and six males of six unrelated patients with HSD3B2 genotype-proven HSD3B2 deficiency were studied.

Measurements: All family members had HSD3B2 DNA analysis and an ACTH stimulation test (Cortrosyn 0.25 mg IV bolus) for determination of adrenal HSD3B activity.

Results: Ten of 13 females and five of six males were carriers of a proven or predictably deleterious mutation in one allele of the HSD3B2 gene, which was identified in the probands. ACTH-stimulated levels of 17-hydroxypregnenolone (delta5-17P), 17-hydroxyprogesterone (17-OHP), cortisol (F), dehydroepiandrosterone (DHEA) and androstenedione (delta4-A) and ratios of delta5-17P to 17-OHP, delta5-17P to F and DHEA to delta4-A, as well as increments of delta5-17P and DHEA values (ACTH-stimulated - baseline) in the genotype-proven female carriers (age, mean +/- SD: 36 +/- 6.7 years) and male carriers (age, mean +/- SD: 37 +/- 6.7 years) did not differ significantly from age-matched normal females (35 +/- 5.4 years, n = 20) and normal males (35 +/- 6 years, n = 10), respectively. There were no significant differences in any of the ACTH-stimulated hormonal levels or ratios between the female carriers with a seriously deleterious genotype (n = 5) and the female carriers with mildly deleterious genotypes (n = 5). These hormonal levels and ratios in three genotype-normal females and one genotype-normal male overlapped with those of the carriers.

Conclusion: These data suggest that normal adrenal HSD3B2 activity is maintained in the genotype-proven carriers because heterodimers of mutant and wild-type HSD3B2 enzymes may be stable and exhibit similar activity compared to homodimers of wild-type enzymes, possibly by a relatively rate-unlimited effect of haplo-wild-type enzyme activity. However, we cannot preclude entirely the possibility of a limited expression of another HSD3B activity under ACTH stimulation contributing to the normal adrenal HSD3B activity in vivo in the HSD3B2 genotype-proven heterozygotes. Which mechanism plays a role in maintaining normal enzyme activity in the heterozygotes remains to be elucidated. The hormone findings in the genotypic-proven carriers for HSD3B2 deficiency also indicate that carriers for this disorder cannot be detected by a hormone test and can only be detected by HSD3B2 genotype study.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3-Hydroxysteroid Dehydrogenases / deficiency*
  • 3-Hydroxysteroid Dehydrogenases / genetics*
  • Adrenal Glands / enzymology
  • Adrenal Hyperplasia, Congenital / diagnosis*
  • Adrenal Hyperplasia, Congenital / enzymology
  • Adrenocorticotropic Hormone
  • Adult
  • Biomarkers / blood
  • Female
  • Gene Deletion
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Pedigree
  • Polymerase Chain Reaction / methods
  • Predictive Value of Tests
  • Steroid 21-Hydroxylase / blood


  • Biomarkers
  • Adrenocorticotropic Hormone
  • 3-Hydroxysteroid Dehydrogenases
  • Steroid 21-Hydroxylase