Malignancy Ratio in Pediatric Patients with Hereditary Multi-ple Exostoses: True Association or Reporting Bias?

Background: Hereditary Multiple Exostoses (HME) is a rare autosomal dominant skel-etal disorder resulting from loss-of-function variants in the EXT1, EXT2, or EXT3 genes. While malignant transformation into chondrosarcoma is well documented, the inci-dence and characterization of non-skeletal malignancies in HME remain poorly de-fined. Objective: To comprehensively review the literature for reported cases of non-skeletal malignancies in individuals with HME and evaluate a potential association with he-matologic cancers, particularly in the pediatric population. Methods: A thorough literature search was conducted in the PubMed database up to May 2025 using search terms related to HME and malignancy. Eligible reports includ-ed case descriptions of non-skeletal cancers occurring in patients with confirmed or suspected HME. Extracted data included patient age, sex, cancer type, and available genetic or molecular findings. Results: Thirteen cases of non-skeletal malignancies associated with HME were identi-fied. Fewer than half underwent molecular genetic testing. Six cases occurred in pedi-atric patients, four of which involved hematologic malignancies—three leukemias and one Burkitt lymphoma. In adults, malignancies affected a range of organ systems, in-cluding respiratory, gastrointestinal, nervous, and endocrine. A marked male pre-dominance was observed (11 males vs. 2 females). Conclusions: Although a definitive causal relationship cannot be established, hemato-logic malignancies in pediatric HME patients appear to be disproportionately repre-sented among reported cases. This finding highlights the need for further investigation through large-scale, population-based studies incorporating both clinical and genetic data.