Abstract
BACKGROUND: Hereditary Multiple Exostoses (HME) is a rare autosomal dominant skeletal disorder resulting from loss-of-function variants in the EXT1, EXT2, or EXT3 genes. While malignant transformation into chondrosarcoma is well documented, the incidence and characterization of non-skeletal malignancies in HME remain poorly defined. OBJECTIVE: We aimed to comprehensively review the literature for reported cases of non-skeletal malignancies in individuals with HME and evaluate a potential association with hematologic cancers, particularly in the pediatric population. METHODS: An extensive literature search was conducted in the PubMed database up to August 2025 using search terms related to HME and malignancy. Eligible reports included 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 identified. Fewer than half underwent molecular genetic testing. Six cases occurred in pediatric patients, four of which involved hematologic malignancies, three leukemias and one Burkitt lymphoma. In adults, malignancies affected a range of organ systems, including respiratory, gastrointestinal, nervous, and endocrine. A marked male predominance was observed (11 males vs. 2 females). CONCLUSIONS: Although a definitive causal relationship cannot be established, hematologic malignancies in pediatric HME patients appear to be disproportionately represented among reported cases. This finding highlights the need for further investigation through large-scale, population-based studies incorporating both clinical and genetic data.