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17-Hydroxylase/17,20-Lyase Deficiency Caused by a Novel Homozygous Mutation (Y27Stop) in the Cytochrome CYP17 Gene

Department of Endocrinology, Metabolism, and Pathobiochemistry (K.M., S.K., F.M., G.S., H.-U.H., F.J.S., B.G.), University Hospital of Internal Medicine, University of Tübingen, D-72076, Tübingen, Germany; Department of Pharmacology (C.M.G.), Steroid Laboratory, University of Heidelberg, D-69120 Heidelberg, Germany; and Steroid Research Unit (M.F.H., S.A.W.), Center of Child and Adolescent Medicine, Justus Liebig University of Giessen, D-35392 Giessen, Germany

Address all correspondence and requests for reprints to: Dr. Karsten Müssig, M.D., Medizinische Klinik IV, Universitätsklinikum Tübingen, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany. E-mail: karsten.muessig{at}med.uni-tuebingen.de.

Context: 17-Hydroxylase/17,20-lyase deficiency, a rare autosomal recessive form of congenital adrenal hyperplasia, is caused by mutations in the cytochrome P450c17 (CYP17) gene. We report on a case of complete 17-hydroxylase/17,20-lyase deficiency due to a novel homozygous mutation of CYP17.

Design: A 20-yr-old female Turkish patient (46,XX) presented with primary amenorrhea, sexual infantilism, and easy fatigability.

Results: The patient’s steroid metabolism showed increased levels of mineralocorticoid precursors and low or undetectable plasma concentrations of 17-hydroxycorticoids, androgens, and estrogens before and after ACTH stimulation. The gas chromatography-mass spectrometry urinary steroid profile was dominated by metabolites of corticosterone and its precursors, while cortisol and C₁₉-steroid metabolites were lacking. ACTH, FSH, and LH levels were elevated. These hormonal findings were consistent with a combined and total 17-hydroxylase/17,20-lyase deficiency. A therapy with hydrocortisone and a cyclic estrogen/gestagen substitution was initiated.

Conclusion: The CYP17 gene analysis revealed homozygosity of the mutation Y27Stop (TACTAA) in exon 1, a mutation that has not been previously described. This novel mutation leads to a stop codon causing a total loss of 17-hydroxlyase/17,20-lyase activity, as reflected biochemically by the detected concentrations of the steroid metabolites.