title: Genotype-phenotype correlation study in 529 patients with multiple hereditary exostoses: identification of "protective" and "risk" factors.
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.
authors.affiliation: Department of Medical Genetics and Skeletal Rare Diseases, Rizzoli Orthopaedic Institute, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Pedrini
authors.forename: Ivy
authors.initials: I
authors.lastname: Jennes
authors.forename: Morena
authors.initials: M
authors.lastname: Tremosini
authors.forename: Annamaria
authors.initials: A
authors.lastname: Milanesi
authors.forename: Marina
authors.initials: M
authors.lastname: Mordenti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Parra
authors.forename: Federica
authors.initials: F
authors.lastname: Sgariglia
authors.forename: Monia
authors.initials: M
authors.lastname: Zuntini
authors.forename: Laura
authors.initials: L
authors.lastname: Campanacci
authors.forename: Nicola
authors.initials: N
authors.lastname: Fabbri
authors.forename: Elettra
authors.initials: E
authors.lastname: Pignotti
authors.forename: Wim
authors.initials: W
authors.lastname: Wuyts
authors.forename: Luca
authors.initials: L
authors.lastname: Sangiorgi
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016001:Confidence Intervals; D005097:Exostoses, Multiple Hereditary / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D018095:Germ-Line Mutation; D006801:Humans; D015994:Incidence; D008297:Male; D015999:Multivariate Analysis; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D016017:Odds Ratio; D011379:Prognosis; D012189:Retrospective Studies; D018570:Risk Assessment; D018709:Statistics, Nonparametric; D000099065:Exostosin 2; D000099058:Exostosin 1
chemical_list: D017351:N-Acetylglucosaminyltransferases; D000099058:Exostosin 1; D000099065:Exostosin 2