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Scientific Articles   |    
Genotype-Phenotype Correlation Study in 529 Patients with Multiple Hereditary Exostoses: Identification of “Protective” and “Risk” Factors
Elena Pedrini, PhD1; Ivy Jennes, PhD2; Morena Tremosini, RN1; Annamaria Milanesi, PhD1; Marina Mordenti, PhD1; Alessandro Parra, PhD1; Federica Sgariglia, PhD1; Monia Zuntini, MS1; Laura Campanacci, MD, PhD1; Nicola Fabbri, MD1; Elettra Pignotti, PhD1; Wim Wuyts, PhD2; Luca Sangiorgi, MD, PhD1
1 Department of Medical Genetics and Skeletal Rare Diseases (E. Pedrini, M.T., A.M., M.M., A.P., F.S., M.Z., and L.S.), V Division (L.C. and N.F.), and Task Force Statistics (E. Pignotti), Rizzoli Orthopaedic Institute, Via Pupilli 1, 40136 Bologna, Italy. E-mail address for L. Sangiorgi: luca.sangiorgi@ior.it
2 Department of Medical Genetics, University and University Hospital of Antwerp, Prins Boudewijnlaan 43, 2650 Edegem, Belgium
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Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. None of the authors, or their institution(s), have had any financial relationship, in the thirty-six months prior to submission of this work, with any entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. Also, no author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

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Investigation performed at Rizzoli Orthopaedic Institute, Bologna, Italy

Copyright © 2011 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2011 Dec 21;93(24):2294-2302. doi: 10.2106/JBJS.J.00949
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Abstract

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 as mild (the absence of both aspects), intermediate, or severe (the concurrent presence of both aspects). An identical molecular 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.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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