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While the clinical core phenotype is well established and mainly consists of bone deformities, limb length discrepancies, multiple benign bone neoplasms, and increased risk of chondrosarcoma, the association of HMO with malignancies remains undefined. Only two cases have been reported to date. We report a third patient with HMO and leukemia. New research suggests that EXT1 and EXT2 genes may influence leukemogenesis through several mechanisms, including protein\u2013protein interactions with leukemia\u2010associated genes and modulation by specific microRNAs (miRNAs). Dysregulation of heparan sulfate biosynthesis, a pathway involving exostosin proteins, may disrupt the bone marrow microenvironment, impacting hematopoietic cell growth and differentiation.<\/jats:p>","DOI":"10.1002\/ajmg.a.64052","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T12:51:01Z","timestamp":1742302261000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hereditary Multiple Osteochondromas and Acute Lymphoblastic Leukemia: A Possible Role for <scp>EXT1<\/scp> and <scp>EXT2<\/scp> in Hematopoietic Malignancies"],"prefix":"10.1002","volume":"197","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8525-3041","authenticated-orcid":false,"given":"Francesco","family":"Comisi","sequence":"first","affiliation":[{"name":"Pediatric Clinic and Rare Diseases Microcitemico Hospital \u201cA. 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