Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20-lyase deficiency

J Clin Endocrinol Metab. 2008 Sep;93(9):3584-8. doi: 10.1210/jc.2008-0051. Epub 2008 Jun 17.


Context: Very few patients have been described with isolated 17,20-lyase deficiency who have had their mutations in P450c17 (17alpha-hydroxylase/17,20-lyase) proven by DNA sequencing and in vitro characterization of the mutations. Most patients with 17,20-lyase deficiency have mutations in the domain of P450c17 that interact with the electron-donating redox partner, P450 oxidoreductase (POR).

Objective: Our objective was to clarify the genetic and functional basis of isolated 17,20-lyase deficiency in familial cases who were previously reported as having 17,20-lyase deficiency.

Patients: Four undervirilized males of an extended Bedouin family were investigated. One of these has previously been reported to carry mutations in the CYP17A1 gene encoding P450c17 causing isolated 17,20-lyase deficiency.

Methods: Serum hormones were evaluated before and after stimulation with ACTH. Urinary steroid metabolites were profiled by gas chromatography-mass spectrometry. Exons 1 and 8 of CYP17A1 previously reported to harbor mutations in one of these patients and all 15 coding exons of POR were sequenced.

Results: Gas chromatography-mass spectrometry (GC-MS) urinary steroid profiling and serum steroid measurements showed combined deficiencies of 17,20-lyase and 21-hydroxylase. Sequencing of exons 1 and 8 of CYP17A1 in two different laboratories showed no mutations. Sequencing of POR showed that all four patients were homozygous for G539R, a previously studied mutation that retains 46% of normal capacity to support the 17alpha-hydroxylase activity but only 8% of the 17,20-lyase activity of P450c17.

Conclusion: POR deficiency can masquerade clinically as isolated 17,20-lyase deficiency.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Hyperplasia, Congenital / diagnosis*
  • Adrenal Hyperplasia, Congenital / genetics*
  • Adult
  • Arginine / genetics
  • Base Sequence
  • Consanguinity
  • DNA Mutational Analysis
  • Diagnosis, Differential
  • Family*
  • Glycine / genetics
  • Homozygote
  • Humans
  • Male
  • NADPH-Ferrihemoprotein Reductase / genetics*
  • Pedigree
  • Point Mutation
  • Steroid 17-alpha-Hydroxylase / genetics*


  • Arginine
  • Steroid 17-alpha-Hydroxylase
  • NADPH-Ferrihemoprotein Reductase
  • Glycine