Background: Disorders of Sex Development (DSD) comprise several phenotypes due to dysfunction in genes involved in human sexual determination and differentiation. The most frequent aetiologies among 46,XY DSD are androgen insensitivity syndrome and 5-alpha-reductase type 2 deficiency due mutations in AR and SRD5A2 genes, respectively.
Objective and hypotheses: The purpose of this study was to investigate mutations in AR and SRD5A2 genes in 21 paediatric patients classified as 46,XY DSD. For cases without mutation in these genes, complementary analysis of NR5A1 or HSD17B3 genes was performed, according to clinical and hormonal characteristics.
Method: Genomic DNA was obtained from blood samples. Molecular alterations were investigated by sequencing exons and exon-intron junctions. Each fragment was amplified by polymerase chain reaction and used for direct sequencing. The sequences obtained were analysed and compared with the reference sequence for each gene.
Results: Six alterations were identified: p.Ala475Val and p.Leu57Gln in AR; p.Gly183Ser in SRD5A2; p.Arg39Cys in NR5A1; and, p.Ala203Val and p.Gly262Val in HSD17B3.
Conclusion: Individuals with 46,XY DSD show significant overlap of clinical and hormonal features, which make it difficult to reach diagnosis, to indicate treatment and to perform genetic counselling. In the casuistic here analysed, six patients revealed sequence variations in AR, SRD5A2, NR5A1 and HSD17B3. However, 15 patients did not show any abnormality indicating that other genes may be involved in the aetiology. The p.Arg39Cys alteration identified in NR5A1 and p.Gly262Val in HSD17B3, are firstly described here. Although these findings are relevant to diagnostic elucidation, investigation of in vitro functional effects of novel mutations is crucial.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology