A Genotype-Phenotype Study of Multiple Hereditary Exostoses in Forty-Three Patients

Area of Science:

• Genetics
• Orthopedics
• Medical Genetics

Background:

• Multiple hereditary exostoses (MHE) is a rare autosomal dominant skeletal disorder.
• Clinical manifestations of MHE are diverse, necessitating standardized severity assessment.
• Genetic mutations, particularly in EXT1 and EXT2 genes, are primary causes of MHE.

Purpose of the Study:

• To evaluate the clinical phenotypic severity of MHE using a novel scoring system.
• To identify risk factors associated with severe clinical phenotypes in MHE patients.
• To analyze the correlation between specific gene mutations (EXT1/EXT2) and disease severity.

Main Methods:

• Analysis of 43 patients from 30 families with MHE.
• Mutation identification via direct sequencing and multiplex ligation-dependent probe amplification.
• Phenotypic severity assessment using a custom scoring system based on deformity, exostoses count, leg length discrepancy, and functional limitations.

Main Results:

• 90.7% of patients had EXT1 or EXT2 mutations, with EXT1 mutations being more prevalent.
• Patients with EXT1 mutations exhibited significantly more severe phenotypes and higher deformity scores compared to EXT2 or no-mutation groups (p=0.005).
• The custom scoring system demonstrated reliable results in classifying MHE severity.

Conclusions:

• Genetic mutations in EXT1 and EXT2 are key determinants of MHE phenotype.
• The developed scoring system effectively assesses MHE severity, highlighting deformity extent as a critical factor.
• Patients with high deformity scores require close monitoring for potential severe disease progression.