Hereditary multiple exostoses patients carry heterozygous mutations in the heparan sulfate (HS)-synthesizing enzymes EXT1 or EXT2, but studies suggest that EXT haploinsufficiency and ensuing partial HS deficiency are insufficient for exostosis formation.
We hypothesized that loss of function of EXT1 or EXT2 in subjects with hereditary multiple exostoses (HME) affects pancreatic insulin secretion capacity and development.
In our cohort of patients, variables such as female sex (odds ratio = 1.840; 95% confidence interval, 1.223 to 2.766), fewer than five skeletal sites with exostoses (odds ratio = 7.588; 95% confidence interval, 3.479 to 16.553), EXT2 mutations (odds ratio = 2.652; 95% confidence interval, 1.665 to 4.223), and absence of EXT1/2 mutations (odds ratio = 1.975; 95% confidence interval, 1.051 to 3.713) described patients with a mild phenotype; in contrast, a severe phenotype was associated with male sex (odds ratio = 2.431; 95% confidence interval, 1.544 to 3.826), EXT1 mutations (odds ratio = 6.817; 95% confidence interval, 1.003 to 46.348), and more than twenty affected skeletal sites (odds ratio = 2.413; 95% confidence interval, 1.144 to 5.091).
In this study, we have characterized exostosis chondrocytes from three patients with HME (one with EXT1 and two with EXT2 germline mutations) and from one individual with a non-HME, isolated exostosis.
Two homologous genes, EXT1 and EXT2, responsible for the development of benign multiple cartilagenous bone tumors (exostoses) on the long bones, have been identified in the past 2 years.
Finally, we performed lineage tracing to show that exostoses and enchondromas in mice likely contain mixtures of wild-type and SHP2-deficient chondrocytes.
Hereditary multiple exostoses patients carry heterozygous mutations in the heparan sulfate (HS)-synthesizing enzymes EXT1 or EXT2, but studies suggest that EXT haploinsufficiency and ensuing partial HS deficiency are insufficient for exostosis formation.
We hypothesized that loss of function of EXT1 or EXT2 in subjects with hereditary multiple exostoses (HME) affects pancreatic insulin secretion capacity and development.
Three subtypes have been described: TRPS I, caused by mutations in TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses.
In our cohort of patients, variables such as female sex (odds ratio = 1.840; 95% confidence interval, 1.223 to 2.766), fewer than five skeletal sites with exostoses (odds ratio = 7.588; 95% confidence interval, 3.479 to 16.553), EXT2 mutations (odds ratio = 2.652; 95% confidence interval, 1.665 to 4.223), and absence of EXT1/2 mutations (odds ratio = 1.975; 95% confidence interval, 1.051 to 3.713) described patients with a mild phenotype; in contrast, a severe phenotype was associated with male sex (odds ratio = 2.431; 95% confidence interval, 1.544 to 3.826), EXT1 mutations (odds ratio = 6.817; 95% confidence interval, 1.003 to 46.348), and more than twenty affected skeletal sites (odds ratio = 2.413; 95% confidence interval, 1.144 to 5.091).
EXT1 mutations were more commonly observed in those with shoulder exostoses (odds ratio [OR], 20.6; 95% confidence interval [CI], 11.2-28.5; P = .001).
Among the novel mutations in EXT1, c.1004T>G-associated HME exhibited overriding toes and scoliosis, c.1883+2T>A-associated HME exhibited brachydactyly, and c.459_460delCT-associated exostosis arising from vertebra T4 caused spinal cord compression.
Patients with EXT1-linkage and patients with undetermined linkage (EXT?) were more severely affected, underwent more surgeries, and showed a higher number of exostoses at follow-up.
Patients with EXT 1 mutation were found to have more exostoses, more limb malalignment with shorter limb segments and height, and more pelvic and flatbone involvement.