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Utility of Genetic Work-Up for 46,XY Patients with Severe Hypospadias
Laurence Baskin, MD, Priya Srivastava, MD, Jessica Tenney, MD, Maya Lodish, MD, Anna Slavotinek, MD/PHD.
UCSF, San Francisco, CA, USA.

BACKGROUND: Hypospadias is a common congenital abnormality that has been increasing in prevalence over the last decades. Historically, 46,XY patients with severe hypospadias have frequently lacked a genetic diagnosis. Platforms for molecular genetic testing have become more readily available and can offer an insight into underlying genetic causes of severe hypospadias. The goal of this study was to review the anatomical characteristics of severe hypospadias that can accurately define patients with 46,XY severe hypospadias and determine the practical utility of performing molecular genetic testing in this group of patients. METHODS: Over a two year period (2000-2021) patients who met the criteria for 46,XY severe hypospadias were offered a molecular genetic work-up in consultation with pediatric genetics. Severe hypospadias was 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 often associated with a ventral penile skin tethering such as a short urethral plate or fusion of the foreskin to the scrotum with associated penoscrotal transposition (Figure 1). Data extracted included karyotype, hypospadias phenotype including stretched penile length at diagnosis, age at genetic diagnosis, molecular genetic testing, pathogenic gene variant(s), gender identity, and clinical course. All patients underwent clinical genetic testing via 46,XY Disorders of Sexual Development (DSD) panels offered by Invitae, GeneDx, or Blueprint Genetics.
RESULTS: Of the 14 patients (out of 20 with severe hypospadias) that underwent genetic testing, there were 5 previously published and 3 novel pathogenic or likely pathogenic variants in genes associated with 46,XY severe hypospadias. Pathogenic variants were identified in AR (3), SRD5A2 (1), NR5A1 (2), WT1 (1), and ARTX (1). Two patients had a variant of unknown significance, one in FREM2 and another in CEP41. Four had negative gene panels. The patient with the WT1 pathogenic variant was subsequently found to have developed a Wilms tumor and the patients with NR5A1 pathogenic variants are now undergoing adrenal insufficiency surveillance (Figure 2).
CONCLUSIONS: Patients with 46,XY severe hypospadias can benefit from molecular genetic testing as their underlying disorders may reveal pathogenic variants that could have potentially life-altering consequences and change surveillance and monitoring.


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