OR15-06 Integrative and Analytical Review of the 5 Alpha Reductase Type 2 Deficiency Worldwide

Abstract

Introduction: The conversion of testosterone into dyhidrotestosterone is catalyzed by the 5 α reductase type 2 enzyme which plays a crucial role in the external genitalia virilization. It is encoded by the SRD5A2 gene. Allelic variants (AV) in this gene cause a 46,XY DSD with no genotype-phenotype relationship. It was firstly reported at early 70’s from isolated clusters. Since then, several cases have been reported. Putting together, it will expand the knowledge about the molecular bases of androgen regulation. Methods: We searched for SRD5A2 AV in the literature (Pubmed, EMBASE, Medline) and websites (ensemble, HGMD, ClinVar). Only cases with AV in both alleles, either in homozygous (HM) or compound heterozygous state (CH) and 5ARD2 phenotype were included. The AV were analyzed according to ethnicity, exon, domain, aminoacid (aa) conservation, age at diagnosis, sex assignment, gender change, external genitalia virilization and functional studies. External genitalia virilization was scored using Sinnecker scale. Conservation analysis was carried out using CONSURF platform. For categorical variables we used X2 test and Cramer’s V. Continuous variables were analyzed by t test or ANOVA. Concordance was estimated by Kappa. Results: We identified 434 cases of 5ARD2 deficiencies from 40 countries. Most came from Turkey (23%), China (17%), Italy (9%), and Brazil (7%). 69% were assigned as female. There were 70% of AV in HM and 30% in CH state. Most were missense variants (76%). However, small indels (11%), splicing (5%) and large deletions (4%) were all reported. They were distributed along all exons with exon 1 (33%) and exon 4 (25%) predominance. AV in the exon 4 (NADPH-binding domain) resulted in lower virilization (F=10.5; p<.0001). The positions 55, 65, 196, 235 and 246 are hotspots making up, 25% of all AV. Most AV (76%) were located at conserved aa. However, AV at non-conserved aa were more frequently indels (28% vs 6%; p<.01). The overall rate of gender change from female to male ranged from 16% to 70%. The lowest rate of gender change occurred in Turkey and the highest in Brazil. Virilization was similar between those who changed and kept their gender. The gender change rate was significantly different across the countries (V=0.44; p<.001) even with similar virilization scores. There was no concordance between genotype and phenotype in all recurrent AV (196, 235 and 246; k 0.6, 0.12 and 0.19). Conclusion: 5ARD2 deficiency has a worldwide distribution. AV at NADPH-ligand region cause lower virilization. Genitalia virilization influenced sex assignment but not gender change which was influenced by cultural aspects across the countries.