Clinical and Genetic Evaluation of Undervirilized Boys With Bifid Scrotum

Bifid scrotum and hypospadias suggest undervirilization, yet boys presenting with these findings often do not receive a genetic diagnosis. Some of these individuals fall on the spectrum toward genital ambiguity, which often has an identifiable genetic etiology. In some cases, identifying an underlying genetic diagnosis can help optimize clinical care. The objectives of this work include characterizing current practice for genetic evaluation for patients with bifid scrotum, identifying approaches with a good diagnostic yield, as well as using whole-exome sequencing to study ten undervirilized 46,XY subjects with bifid scrotum. These studies demonstrate that the majority of individuals with bifid scrotum do not receive a genetic diagnosis on clinical workup. Over a third of subjects did not have any genetic testing, even though karyotype analysis and androgen receptor sequencing were both relatively high yield for identifying a genetic etiology. Increased utilization of traditional genetic approaches could significantly improve the ability to find a genetic diagnosis. Furthermore, using whole-exome sequencing on ten 46,XY boys with bifid scrotum identified two novel NR5A1 variants, both impacting exon 7. One of these variants demonstrated significant genotype-phenotype variability in the setting of a rare instance of paternal inheritance from an unaffected father.