How has genetics changed the diagnosis and the management of differences of sex development?

Rare differences of sex development (DSD) encompass all medical situations in which chromosomal sex, gonadal development, or external genitalia are atypical. Genetic investigations of these medical conditions, often diagnosed in the neonatal period, have evolved considerably over the past 20 years. Excluding congenital adrenal hyperplasia, whose diagnosis is clinical and hormonal, a genetic diagnosis is done in 2026 in only approximately 35% of DSD children with 46, XY and 46, XX DSD outside CAH, using next-generation sequencing (NGS) or genome analysis. In 2021, for the first time, a legal framework organizing the care of children with a variation in genital development (VGD), sometimes referred to as "intersex children" or "children with differences in sex development" (DSD), was introduced in France (article L. 2131-6 of the Code of Public Health). The law requires national multidisciplinary case review for any DSD children, except life-saving treatment, and put genetics at the center of the framework. Posterior/proximal hypospadias may, if clinically isolated and with a normal hormonal and genetic profile, fall outside this new framework. Children with 46, XY hypospadias, carrying a pathogenic variant fall within the scope of the law. This subtle distinction, lacking scientific support, makes family care pathways difficult to understand and therefore more distressing.