OR05-3 Utility of Genomic work-up for 46XY Disorder of Sex Development Patients with Severe Hypospadias

Abstract

Abstract Background Hypospadias is a common human congenital anomaly occurring in ∼1: 200 to 1: 300 live male births in the USA, with an unexplained doubling in incidence over previous decades. Historically, 46XY Differences of Sex Development (DSD) patients, with severe hypospadias have lacked a genetic diagnosis. With the advent of commercially available DSD genomic panels, this is now changing (GeneDX. Neonatal 46 2021, In-vitae 2021). The goal of this study is to review the anatomical characteristics of severe hypospadias that can accurately define patients that have 46XY DSD and to determine the practical utility of performing a genomic workup in these rare 46XY DSD patients with severe hypospadias.Patients: 14 patients seen in disorders of sexual development clinic between 2018–2020 with severe hypospadias defined by an ectopic urethral meatus typically in the scrotum or perineum, an abnormally small glans penis size (<14 mm at maximal width in the first year of life), severe curvature and associated foreskin fusion or penoscrotal transposition were enrolled in the study. Methods Patients who met the criteria for 46XY disorder of sexual development and severe hypospadias were offered a genomic work-up in consultation with pediatric genetics. Patients were identified through chart review. Data extracted included karyotype, hypospadias phenotype including stretched penile length at diagnosis, age at genetic diagnosis/genomic workup, gene defect/ pathologic variant, gender identity, and clinical course.Main Outcome Measurements: The main outcome measured was the presence of a genetic mutation that can be linked to the disorder of sexual development. Secondary outcomes measured included gender identity, clinical course, and histological findings if a biopsy was obtained. Results Of the 14 patients that underwent genomic analysis, 8 had documented pathologic variants known to cause hypospadias. Pathologic genetic variants include defects in the AR (3), SRD5A2 (1), NR5A1 (2), WT1 (1), and ARTX (1). Five had no evidence of pathologic variants based on the Invitae and GeneDx commercial 46XY DSD panel (see Table 2 for genes tested). One had a genetic variant of unknown significance, FREM2. The patient with WT1 was consequently found to have a Wilms tumor and the patients with SRD5A2 are now undergoing adrenal insufficiency surveillance after their genetic testing. Conclusions Patients with 46XY DSD and severe hypospadias can benefit from genetic evaluation as their underlying disorders may unveil mutations that could have potentially life-altering consequences and change surveillance and monitoring. Presentation: Saturday, June 11, 2022 12:00 p.m. - 12:15 p.m.