Introduction:
Variations in Sexual Characteristics (VSC), also known as intersex traits and previously referred to as Disorders or Differences in Sex Development (DSD), represent complex conditions affecting chromosomal, gonadal, or anatomical sex development. While traditional classification systems have provided valuable diagnostic frameworks, emerging evidence suggests that VSC features may be more prevalent across genetic conditions than currently recognized. This study aimed to systematically evaluate the presence of VSC-related phenotypes across genetic conditions to determine if current diagnostic frameworks adequately capture the full spectrum of VSC presentations.

Methods:
We leveraged the Human Phenotype Ontology (HPO) to systematically identify VSC-related phenotypic terms. Through computational analysis of HPO annotations and expert clinical review, we developed a Focused Genitourinary VSC Glossary (FGV Glossary) of 103 VSC-related terms. We then analyzed the prevalence of these terms across all conditions in Online Mendelian Inheritance in Man (OMIM) to establish their distribution patterns. Robinow syndrome was examined as a case study to illustrate how conditions not traditionally classified as VSC may consistently present with VSC features.

Results:
Analysis of phenotype annotations revealed that 536 of 8,326 OMIM conditions (6.4%) were associated with FGV Glossary terms. Notably, many of these conditions are not traditionally classified as VSC disorders, suggesting that VSC features appear in a broader range of conditions than currently acknowledged in clinical practice. The systematic review identified consistent patterns of VSC features in conditions primarily classified under other diagnostic categories, including skeletal, neurological, and developmental disorders.

Conclusion:
This study provides evidence that VSC features occur more frequently across genetic conditions than previously recognized, supporting the need for an expanded diagnostic framework. These findings have significant implications for genetic testing strategies and clinical care, suggesting that VSC features should be actively considered in patient evaluation regardless of primary diagnosis. We propose revised criteria for genetic testing and provide recommendations for clinical practice that reflect this broader understanding of VSC manifestation across genetic conditions. This expanded framework has important implications for diagnostic approaches, genetic counseling, and the clinical management of patients presenting with VSC features.