ESPE Abstracts (2019) 92 RFC10.3

Level of Uncertainty in Diagnostic Evaluation of Boys With XY Disorders of Sex Development (DSD)

Malika Alimussina1, Louise A Diver2, Jane D McNeilly3, Angela K Lucas-Herald1, Edward S Tobias2,4, Martin McMillan1, Ruth McGowan1,2, S Faisal Ahmed1


1Developmental Endocrinology Research Group, University of Glasgow, Royal Hospital for Children, Glasgow, United Kingdom. 2West of Scotland Clinical Genetics Service, Queen Elizabeth University Hospital, Glasgow, United Kingdom. 3Biochemistry Department, Queen Elizabeth University Hospital, Glasgow, United Kingdom. 4Academic Medical Genetics and Pathology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, United Kingdom


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.

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