46,XX ovotesticular difference of sex development

46,XX ovotesticular difference of sex development (DSD), formerly known as 46,XX true hermaphroditism, is a rare condition in which an individual has a 46,XX karyotype but possesses both ovarian tissue (containing follicles) and testicular tissue (containing seminiferous tubules) within the gonads. These may exist as separate ovary and testis (lateral), combined as an ovotestis on one or both sides, or in various combinations. The condition affects the reproductive and endocrine systems, leading to ambiguous genitalia at birth in most cases. Clinical features can include variable degrees of genital ambiguity such as a micropenis or enlarged clitoris, hypospadias, cryptorchidism, and the presence of both Müllerian (uterus, fallopian tubes) and Wolffian duct derivatives. Breast development may occur at puberty, and some individuals may menstruate. Fertility is rare but has been reported, particularly in those with sufficient ovarian tissue. The underlying genetic mechanisms are heterogeneous. In some cases, the condition results from translocation of the SRY gene onto an X chromosome, but many 46,XX ovotesticular DSD cases are SRY-negative, suggesting involvement of other genes in the sex-determination pathway, such as SOX9 duplications, RSPO1 mutations, or dysregulation of WNT signaling pathways. Most cases appear to be sporadic, though rare familial occurrences have been described, sometimes with autosomal recessive inheritance (particularly in cases linked to RSPO1 mutations). Management is individualized and typically involves a multidisciplinary team including endocrinologists, urologists or gynecologists, psychologists, and geneticists. Treatment considerations include gender assignment (ideally guided by the patient's own gender identity when possible), surgical management of ambiguous genitalia if desired, gonadectomy of discordant gonadal tissue to reduce malignancy risk, and hormone replacement therapy as needed. Psychological support is an essential component of care. Long-term monitoring for gonadal tumors, particularly in dysgenetic testicular tissue, is recommended.

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