Clinical, genetic and functional characteristics of three novel CYP17A1 mutations causing combined 17alpha-hydroxylase/17,20-lyase deficiency.

BACKGROUND: P450c17 has two distinct activities: 17alpha-hydroxylase activity and 17,20-lyase activity. Combined 17alpha-hydroxylase/17,20-lyase deficiency leads to a severe defect in the production of cortisol and sex steroids. In affected males this results in impaired masculinization with ambiguous or female external genitalia. Female patients have normal genitalia but show a lack of pubertal development in adolescence. An increased production of mineralocorticoids often leads to hypertension and hypokalemia in both sexes. METHODS: To better understand the mechanisms of P450c17 deficiency, we studied 2 patients (both 46,XY) with combined 17alpha-hydroxylase/17,20-lyase deficiency of different severity: one with complete lack of masculinization and one with ambiguous genitalia. RESULTS: Four mutations were identified by sequencing of the CYP17A1 gene: I332T and A355T in the less severely affected patient; G111S and R440H in the patient with complete lack of masculinization. The three novel mutations were expressed in COS1 cells and all mutant proteins except I332T showed a complete loss of both enzymatic activities. I332T retained some residual 17alpha-hydroxylase as well as 17,20-lyase activity. CONCLUSION: We identified 2 patients with the phenotypical spectrum of P450c17 deficiency. Three novel mutations in the CYP17A1 gene were identified and their functional characterization provided a good phenotype-genotype correlation. The location of the mutated residues in the three-dimensional model of P450c17 gave some additional insights into its structure-function relationship.

Is a testis located at the superficial inguinal pouch (Denis Browne pouch) comparable to a true cryptorchid testis?

In a clinical study 96 prepubertal boys with 100 testes located in the superficial inguinal pouch underwent routine orchiopexy. Of 65 patients 45 (69%) who had received hormonal treatment before the surgical procedure had a closed processus vaginalis compared with only 11 of 35 (31%) who had not (p less than 0.0002). A normal epididymis was also present significantly more often in those patients receiving hormonal treatment than in those who did not (p less than 0.039). While those testes located in the superficial inguinal pouch had significantly better histology and a greater number of germ cells than those located in a high inguinal or abdominal position (p less than 0.01), the number of germ cells per tubule was nonetheless lower than that seen in the normal controls (p less than 0.01). In conclusion, a testis located at the superficial inguinal pouch behaves as a true cryptorchid testis. Furthermore, hormonal treatment before surgery has a significant effect on epididymal development and closure of the processus vaginalis.