46,XX testicular disorder of sex development with RSPO1 intron 4 mutation: A rare genetic variant

Abstract Sex reversal in a 46,XX individual is quite uncommon. Typically, this condition involves a translocation of the sex-determining region Y (SRY) gene. However, there are very few cases where the SRY gene is not involved. Our case reinforces the idea that a single gene disorder in the ovarian development pathway can lead to male gonadal development. Additionally, it supports the notion that ovary development is not a passive process. We present a complex case of genital ambiguity that challenges traditional concepts of sexual development. A 1 year 6-month old child exhibited penoscrotal hypospadias and micropenis. Although gonads descended bilaterally, the karyotype report came as 46,XX. Genetic analysis revealed a homozygous 3′ splice site pathogenic variant (c.286 + 1G>A) in intron 4 of the RSPO1 gene, implicating it in testicular differentiation. This case underscores the importance of early genetic diagnosis in predicting the outcomes and guiding counseling for XX male individuals, who may face complications such as hypergonadotropic hypogonadism and infertility. The complexity of sexual development extends beyond the traditional male–female dichotomy, highlighting the role of single-gene mutations in determining phenotypic outcomes.