Establishing a Molecular Genetic Diagnosis in Children with Differences of Sex Development: A Clinical Approach

Despite distinct underlying aetiologies, the clinical phenotypes and hormonal profiles of children with various differences of sex development (DSD) are often similar, which presents challenges to ascertaining an accurate diagnosis on clinical grounds alone. Associated features and important clinical outcomes can, however, vary significantly in different DSD, thus establishing an accurate molecular diagnosis may have important implications for decision-making and management planning in a given individual.

The wider availability of next-generation sequencing techniques in recent years has led to recommendations for earlier integration of genetic testing in the diagnostic pathway of children with DSD. This review provides a practical overview of the clinical applications, advantages, and limitations of the more commonly available diagnostic genetic tests and outlines a suggested approach to testing. The potential clinical implications of a confirmed genetic diagnosis, subsequent management pathways for individuals with DSD, and challenges that remain to be addressed are also outlined.

Despite significant improvements in our understanding of the complex genetic pathways that underlie DSD, an accurate diagnosis still eludes many affected individuals. Establishing a molecular diagnosis provides aetiological certainty, enabling improved information for families and individualized clinical management, including monitoring or prophylactic intervention where additional health risks exist. A stepwise approach to genomic testing is recommended to afford highest diagnostic yield from available resources. Looking forward, collaborative multicentre prospective studies will be required to assess the true impact of a genetic diagnosis on improving clinical care pathways and health, well-being and patient-reported outcomes for individuals with DSD.