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P450c17 Deficiency: Clinical and Molecular Characterization of Six Patients

University Children’s Hospital Zürich (S.R., C.D., M.M., M.L.-M., E.J.S., A.B.-L.), 8032 Zürich, Switzerland; Ospedale Umberto I (G.B., M.B.), 60020 Ancona, Italy; Division of Pediatric Endocrinology and Metabolism (A.K.T.), Faculty of Medicine, Cukurova University, 01330 Adana, Turkey; and Clinica Medica III (F.F., L.Z., R.M.) and Department of Medical and Surgical Sciences (F.M.), Division of Endocrinology, University of Padova, 35122 Padova, Italy

Address all correspondence and requests for reprints to: Anna Biason-Lauber, University Children’s Hospital, Division of Endocrinology and Diabetology, Steinwiesstrasse, 75, 8032 Zurich, Switzerland. E-mail: anna.lauber{at}kispi.unizh.ch.

Context: The characteristics of P450c17 deficiency include 46,XY disorder of sex development, hypertension, hypokalemia, and lack of pubertal development.

Objective: To better understand this rare enzymatic deficiency, we analyzed the CYP17A1 gene in six affected patients.

Design and Patients: We examined six patients, five 46,XY, and one 46,XX (age 9–29 yr) with complete lack of masculinization (female infantile external genitalia, no uterus) and delayed puberty, respectively, and different degrees of hypertension.

Main Outcome Measurements: Genotype-phenotype correlation was measured.

Results: Four homozygote mutations were identified by direct sequencing of the CYP17A1 gene corresponding to an alanin 302-proline (A302P) exchange; the loss of lysine 327 (K327del); the deletion of glutamate 331 (E331del); and the replacement of arginine 416 with a histidine (R416H). Both P450c17 activities were abolished in all the mutant proteins, except one, when expressed in COS1 cells. The E331del-mutated P450c17 retained 17-hydroxylase activity. The mutant proteins were normally expressed, suggesting that the loss of enzymatic activity is not due to defects of synthesis, stability, or localization of P450c17 proteins.

Conclusion: These studies confirm lack of masculinization in 46,XY individuals as the pathognomic sign of the complete P450c17 deficiency. In XX individuals P450c17 deficiency should be considered in cases of delayed puberty. Age of onset and the severity of hypertension do not seem to be constant. Careful examination of long-term follow-ups in two of our patients suggested to us that estrogen treatment in P450c17-deficient patients might worsen the enzymatic defect, leading to aggravation of the hypertension.

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