Background: Main diagnosis of 46,XY disorders of sex development (DSD) with normal testosterone secretion Androgen insensivity sydrome (AIS) or 5α-reductase deficiency (5α-RD). In prepubertal period, AIS and 5α-RD present indistinguishable phenotypes that necessitate the molecular analyses for the definitive diagnosis.
Objective and hypotheses: Clinical, hormonal and genetic investigation of 46,XY DSD patients who considered as PAIS or 5α-RD, to understand the causes underlining the phenotype for suitable follow up, prognosis and management.
Method: Eighty-seven patients, who diagnosed as AIS or 5α-RD according to clinic and hormonal evaluations, were investigated. Severity of ambiguous genitalia (AG), LH, FSH, T, dihydrotestosterone (DHT) levels were determined. Short-term hCG test was applied in proper cases and T/DHT ratios were evaluated. SRD5A2 mutations were investigated in the cases that had T/DHT ratio of above 20, whereas AR mutations were investigated when the ratio under 20. Sanger DNA sequencing was used for molecular analysis.
Results: The mean age of cases on application was 1.9 years (±3.5). Mutations that can lead to disease were detected in 21 (n=%24.1) patients (n=12 for AR, n=9 for SRD5A2). Eight of patients were found to have homozygous and one was found to have compound heterozygous mutations in SRD5A2. Three novel SRD5A2 mutations in homozygous form were detected in four patients (c.269A>C, c.468-470delAAT, c.453delC). Furthermore, three novel mutations were detected in four patients with AR gene mutations (c.2585delAGCTCCTG, c.2676T>A, c.2084C>T). Three patients were found to have Klinefelter Syndrome (n=1SRD5A2 mutation, n=2 AR mutation, n=1 undetermined genetic cause).One patient had 47,XYY karyotype with AR mutation. Except one, all other cases with AR mutations had T/DHT ratio under 20. This ratio was below 20 in two of the SRD5A2 cases.
Conclusion: Novel SRD5A2 and AR mutations were identified in study. T/DHT ratio in diagnosis of AIS and 5α-RD is an important hormonal criterion, but in some cases, T/DHT ratio may lead to diagnostic confusion. So, molecular diagnosis is important for the robust diagnosis of 46,XY DSD patients correctly.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology