Introduction: The degree of consistency between the findings from next generation sequencing (NGS) and detailed endocrine assessment is unclear in boys with XY DSD.
Objectives: Examine the range of endocrine and molecular genetic variation in boys undergoing evaluation for XYDSD.
Methods: Boys with XYDSD who were evaluated in Glasgow from 2016 to 2018 were included. Sequence variants were classified according to ACMG guidelines; Class 3 variants of uncertain clinical significance that were not reported clinically were divided into 3A and 3B, depending on the level of consistency of the phenotype with the genetic findings.
Results: 115 boys with median age of 0.9 yrs (range, 0.00,16.93) and median external masculinization score (EMS) of 8 (2,12) were identified. Endocrine assessment revealed an abnormality in 29 (25%) boys with a median EMS of 8.5 (2,11). The range of endocrine abnormalities consisted of disorder of gonadal development (DGD) in 19 (17%), LH-deficiency (LHD) in 8 (7%) and disorder of androgen synthesis (DAS) in 2 (2%). In the remaining 85 (75%) boys with non-specific DSD (NS-DSD), the median EMS was 8 (2,12). Of the 65 boys who had molecular genetic analysis by a combination of methods, variants were found in 8/55 (15%) by Sanger sequencing of seven genes and 16/40 (40%) by NGS of fifty-six genes. Of the 16 boys who had NGS-variants with a median EMS of 6.5 (2,12), 4 had Class 5, 1 had Class 4, 3 had a combination of Class 5/3A/3B, 5/3A and 5/3B, 5 had Class 3A only and 3 had Class 3A/3B combination. These included ANOS1, AR, CHD7, DHCR7, FGF8, GATA4, HSD3B2, HSD17B3, MAMLD1, NR5A1, POR, PROK2, WDR11. Median EMS in boys with Class 5 and Class 4 variants was 5 (2,9) and 3 (3), respectively. Of 7 boys with Class 5 variants, 5 had normal and 2 had abnormal endocrine tests. One boy with Class 4 variant in ANOS1 also had normal endocrine tests. Median EMS in 8 boys with Class 3A variants was 8.8 (2,12), of whom 5 had normal endocrine tests. There were 3 boys (NS-DSD,2; DGD,1) with a median EMS of 8.5 (7,10.5) who had Class 3B variants in FGFR1, CYP11B1 or RSPO1.
Conclusions: Although the use of NGS increases the likelihood of a pathological variant, the extent of harmony with phenotypic features including endocrinology is variable. The clinical significance of Class 3 variants needs further research and there is a need to pool results from similar parallel activities worldwide.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology