Context: Cytochrome P450c17 (P450c17) is a bifunctional enzyme necessary for the production of glucocorticoids (17-hydroxylase activity) and sex steroids (17,20-lyase activity). Isolated 17,20-lyase deficiency is a rare condition characterized by a deficient production of androgens resulting in 46,XY disorders of sex development (DSD) while the production of glucocorticoids is intact. Several missense mutations in the CYP17A1 gene are known to cause this condition. Cytochrome b5(CytB5) is an important factor in 17,20-lyase activity, probably by acting as an allosteric factor. Objective: The aim of this study was to investigate the role of CytB5 in a patient with defective 17,20-lyase activity. Setting: We conducted the study in a pediatric outpatient clinic of a University Hospital. Patients: We studied a 46,XY DSD patient with 17,20-lyase deficiency without missense mutation in the CYP17A1 gene and his parents. Main Outcome Measures: We sequenced the CYB5 gene and measured steroid hormone levels. Results: Analysis of the CYB5 gene in our patient revealed a homozygous W27X mutation, leading to the formation of a premature stop codon; his parents were both heterozygous carriers of this mutation. This mutation results in the absence of residues E48 and E49 of CytB5, which are necessary for an intact 17,20-lyase activity. Conclusion: We demonstrated 17,20-lyase deficiency due to an aberrant CytB5. Our findings thus provide evidence for an alternative etiology for this disorder. Copyright,
Journal of Clinical Endocrinology and Metabolism
Erasmus MC: University Medical Center Rotterdam

Kok, R., Timmerman, M., Wolffenbuttel, K., Drop, S., & de Jong, F. (2010). Isolated 17,20-lyase deficiency due to the cytochrome b5 mutation W27X. Journal of Clinical Endocrinology and Metabolism, 95(3), 994–999. doi:10.1210/jc.2008-1745