| Research Abstract |
1. Genotype-phenotype correlation of cytochrome P450 oxidoreductase(POR) deficiency(PORD) Clinical and molecular studies were performed on 33 Japanese cases with PORD. A total of 12 mutations were identified, with R457H accounting for 〜70% of mutant alleles. Clinical features of 33 cases included abnormal skeletal development and adrenal dysfunction in patients of both sexes, undermasculinization during fetal and pubertal periods in male patients(46, XY disorders of sex development; 46, XY DSD), and virilization during fetal life and poor pubertal development in female patients(46, XX DSD) Genotype-phenotype correlation analysis revealed that skeletal abnormalities clearly depended on mutation types, and adrenal dysfunction and 46, XY DSD were partially correlated to the genotypes. By contrast, 46, XX DSD were present in almost all cases irrespectively to mutation types.
2. Urine Steroid hormone analysis To obtain evidence for the presence of an alternative pathway for androgen synthesi
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s(the "backdoor" pathway) in PORD, urine steroid profile analysis was performed by gas chromatography/mass spectrometry. In the PORD patients, the urine steroid ratios reflecting CYP17A1 and CYP21A2 activities were decreased throughout the examined age. Furthermore, etiocholanolone and 11-hydroxyandrosterone, that should originate almost exclusively in the conventional "frontdoor" pathway, were grossly normal or somewhat decreased since early infancy, whereas androsterone, that can derive not only via the conventional "frontdoor" pathway but also from 5α- pregnane-3α, 17α-diol-20-one in the "backdoor" pathway, was increased during the early infancy and remained grossly normal thereafter. Thus, the androsterone/etiocholanolone ratio was increased during the early infancy and remained grossly normal thereafter. The increased androsterone excretion as compared with the etiocholanolone and 11-hydroxyandrosterone excretions in the early infancy would suggest the presence of the "backdoor" pathway.
3. Conclusion The present study suggests that 46, XX DSD in POR would be ascribed to defective androgen conversion in the placenta due to aromatase deficiency, and androgen overproduction via the "backdoor pathway". Less
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