ESPE Abstracts

Introduction: Advances in diagnostic capability in the field of DSD hold great promise but need a regular review.

Objectives: To study the range of endocrine and molecular genetic variation in a group of boys undergoing investigation for XY DSD.

Methods: 157boys with median age of 0.9yrs (range,0,18) evaluated by the DSD Diagnostic Board in Glasgow from 2016to 2021 were included. Sequence variants were classified according to ACMG guidelines and, in addition to pathogenic and likely pathogenic variants, variants of uncertain significance (VUS) were assigned as causative or coincidental, depending on whether the phenotype was consistent with genotype, or not.

Results: The median external masculinization score (EMS) was 8.5(2,12). Of 157boys, an endocrine abnormality was present in 34(22%) with a median EMS of 8.3(2,12) including a disorder of gonadal development(DGD) in 20(13%), LH deficiency(LHD) in 9 (6%), disorder of androgen synthesis(DAS) in 2(1%) and disorder of androgen action(DAA) in 1(0.5%). In the remaining 121(78%) with non-specific DSD(NS-DSD), the median EMS was 9(2,12). Of the 107boys who had molecular genetic analysis by a combination of methods, variants were found in 8/56(14%) by Sanger sequencing of 7genes, 1/6(17%) by NGS of 21genes, and 39/80(49%) by NGS of 56genes. Of 17boys with DGD who were tested, 4had VUS with no phenotypic consistency (FGFR1,LHB,CYP11A1,NROB1). Molecular genetic diagnosis was reached in 1/1(100%) patient with DAS identifying variant in HSD3B3 and in 1/1(100%) patient with DAA with variants in AR and MAMLD1. Among boys with LHD, 3/8(38%) had ANOS1,GNRHR,CHD7 and FGF8 variants. In 23/79(29%) of boys with NS-DSD who had genetic analysis, causative variants were detected in MAMLD1,DHCR7,NR5A1,WDR11,HSD17B3,ANOS1,CHD7,DHCR7,POR,HSD3B2, KISS1R,CYP17A1,PROK2,SPRY4,AR and FGF8. Of these 23boys, 10 coincidental VUS were also detected in 6 (PROKR2,POR,SOX10,MAP3K1,SPRY4,DHCR,HSD17B3 and CYP11A1). One patient who had not had biochemical evaluation also harboured a VUS in GATA4 and this was consistent with his phenotype. In total, 19coincidental VUS were identified in 18boys with median EMS of 8.8(2,11)(NS-DSD,14;DGD,4). EMS in boys harbouring causative variants and normal (NS-DSD,23) or abnormal (DGD,2;LHD,3) endocrine tests was 6(2,12) and 8.5(2,12), respectively.

Conclusions: The degree of undermasculinisation in boys with DSD appears unrelated to the presence of genetic or endocrine abnormalities. Coincidental VUS are commonly encountered in patients with XY DGD and NS-DSD who have no evidence of a gonadal dysfunction or disorder of androgen synthesis, and this requires a careful and standardised interpretation.