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Homozygous Mutation G539R in the Gene for P450 Oxidoreductase in a Family Previously Diagnosed as Having 17,20-Lyase Deficiency

Pediatric Endocrinology and Metabolic Unit (E.H, N.L), Soroka Medical Center, Beer Sheva 84101, Israel; Department of Developmental Genetics and Virology (R.P), Faculty of Health Sciences and the National Institute of Biotechnology Negev, Ben Gurion University of the Negev, Beer Sheva 84105, Israel; Steroid Research Unit (S.A.W., M.F.H.), Center of Child and Adolescent Medicine, Justus Liebig University, 35390 Giessen, Germany; and Department of Pediatrics (L.G.G., W.L.M.), University of California San Francisco, San Francisco, California 94143

Address all correspondence and requests for reprints to: Prof. Eli Hershkovitz, Pediatric Endocrinology and Metabolic Unit, Soroka University Medical Center, P.O. Box 151, Beer Sheva 84101, Israel. E-mail: elih{at}bgu.ac.il.

Context: Very few patients have been described with isolated 17,20-lyase deficiency who have had their mutations in P450c17 (17-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 17-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.