Hereditary Multiple Osteochondromas and Acute Lymphoblastic Leukemia: A Possible Role for EXT1 and EXT2 in Hematopoietic Malignancies

Hereditary multiple osteochondromas (HMO) is an autosomal dominant disorder caused by heterozygous deleterious variants in the EXT1 or EXT2 genes. 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–protein interactions with leukemia-associated 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.