Genotype-phenotype correlation study in 529 patients with multiple hereditary exostoses: Identification of "protective" and "risk" factors

Elena Pedrini, Ivy Jennes, Morena Tremosini, Annamaria Milanesi, Marina Mordenti, Alessandro Parra, Federica Sgariglia, Monia Zuntini, Laura Campanacci, Nicola Fabbri, Elettra Pignotti, Wim Wuyts, Luca Sangiorgi

Research output: Contribution to journalArticlepeer-review


Background: Multiple hereditary exostoses is an autosomal dominant skeletal disorder characterized by wide variation in clinical phenotype. The aim of this study was to evaluate whether the severity of the disease is linked with a specific genetic background. Methods: Five hundred and twenty-nine patients with multiple hereditary exostoses from two different European referral centers participated in the study. According to a new clinical classification based on the presence or absence of deformities and functional limitations, the phenotype of the patients was assessed asmild (the absence of both aspects), intermediate, or severe (the concurrent presence of both aspects). An identicalmolecular screening protocol with denaturing high-performance liquid chromatography and multiplex ligation-dependent probe amplification was performed in both institutions. Results: 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). Malignant transformation was observed in 5% of patients, and no evidence of association between chondrosarcoma onset and EXT mutation, sex, severity of disease, or number of lesions was detected. Conclusions: The identified "protective" and "risk" factors, as well as the proposed classification system, represent helpful tools for clinical management and follow-up of patients with multiple hereditary exostoses; moreover, homogeneous cohorts of patients, useful for studies on the pathogenesis of multiple hereditary exostoses, have been identified. Level of Evidence: Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.

Original languageEnglish
Pages (from-to)2294-2302
Number of pages9
JournalJournal of Bone and Joint Surgery - Series A
Issue number24
Publication statusPublished - Dec 21 2011

ASJC Scopus subject areas

  • Surgery
  • Orthopedics and Sports Medicine


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