Mutations in AR or SRD5A2 genes: clinical findings, endocrine pitfalls, and genetic features of children with 46,XY DSD

Objective: androgen insensivity syndrome (AIS) and 5 alpha-reductase deficiency (5 alpha-RD) present with indistinguishable phenotypes among the 46,XY disorders of sexual development (DSD) that usually necessitate molecular analyses for the definitive diagnosis in the prepubertal period. The aim was to evaluate the clinical, hormonal and genetic findings of 46,XY DSD patients who were diagnosed as AIS or 5 alpha-RD. Methods: patients diagnosed as AIS or 5 alpha-RD according to clinical and hormonal evaluations were investigated. Sequence variants of steroid 5-alpha-reductase type 2 were analyzed in cases with testosterone/dihydrotestosterone (T/DHT) ratio of >= 20, whereas the androgen receptor (AR) gene was screened when the ratio was <20. Stepwise analysis of other associated genes were screened in cases with no causative variant found in initial analysis. For statistical comparisons, the group was divided into three main groups and subgroups according to their genetic diagnosis and T/DHT ratios. Results: a total of 128 DSD patients from 125 non-related families were enrolled. Birth weight SDS and gestational weeks were significantly higher in 5 alpha-RD group than in AIS and undiagnosed groups. Completely female phenotype was higher in all subgroups of both AIS and 5 alpha-RD patients than in the undiagnosed subgroups. In those patients with stimulated T/DHT <20 in the prepubertal period, stimulated T/DHT ratio was significantly lower in AIS than in the undiagnosed group, and higher in 5 alpha-RD. Phenotype associated variants were detected in 24% (n=18 AIS, n=14 5 alpha-RD) of the patients, revealing four novel AR variants (c.94G>T, p.Glu32*, c.330G>C, p.Leu110=; c.2084C>T, p.Pro695Leu, c.2585_2592delAGCTCCTG, p.(Lys862Argfs*16), of these c.330G>C with silent status remained undefined in terms of its causative effects. Conclusion: T/DHT ratio is an important hormonal criterion, but in some cases, T/DHT ratio may lead to diagnostic confusion. Molecular is for the
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