LARS2-Related Perrault Syndrome in Siblings With 46,XY Differences of Sex Development

Perrault syndrome is a heterogeneous phenotype that generally encompasses the findings of sensorineural hearing loss in both 46,XX and 46,XY individuals and varying degrees of abnormal ovarian function in 46,XX individuals. In this case report, we present two brothers with LARS2-related Perrault syndrome who have undervirilization. In addition to bilateral profound sensorineural hearing loss, both brothers had bilateral undescended testes that required surgical intervention. In addition, the younger affected brother had hypospadias with chordee. Quad exome sequencing on both brothers was consistent with 46,XY and revealed the same biallelic pathogenic variants in LARS2, a gene known to be associated with Perrault syndrome. No other variants were reported on exome analysis. To date, undervirilization in 46,XY individuals who have Perrault syndrome has only rarely been reported, although the number of reported males with Perrault syndrome continues to be small. Pathogenic variants in LARS2 have been found to lead to ovarian dysgenesis in 46,XX individuals and complete infertility due to failure to produce germ cells in Caenorhabditis elegans ( C . elegans ), indicating that LARS2 is expressed in gonadal tissue and can impact gonadal development. Undervirilization in affected males is likely an underrecognized component of the LARS2-related Perrault syndrome. In this article, we suggest that LARS2 be included in the differential diagnosis of both 46,XX and 46,XY individuals with DSD conditions and should be considered in 46,XY individuals with hearing loss and evidence of undervirilization.