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Genotype-Phenotype Correlation of Multiple Hereditary Exostoses: Multicentre Project

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Exostoses, Multiple Hereditary

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Trial Information

Genotype-Phenotype Correlation of Multiple Hereditary Exostoses: Multicentre Project

Subject Recruitment:

New patients presenting with HME will be identified through the offices and clinics of
British Columbia Children's Hospital Orthopaedic Department. All potential participants
will be educated about the study's rationale, purpose, and procedures and informed consent
will be obtained.


All probands (affected patient), their first degree family members and extended family
members willing to participate in the study will be interviewed. Information including age,
gender, ethnic origin, family history, symptoms, complications and previous surgery will be


Affected patients will have their osteochondroma(s) mapped for location, size, morphology,
and symptoms. A total of seventy-five phenotypic parameters divided into four major data
categories will be collected. The first two categories are accumulated from physical
examinations and include stature and limb segment lengths (15 (x2 for left and right). The
other two categories, lesion quality (19 parameters) and limb alignment and deformity (26
parameters) will be drawn from radiographic examinations which are part of the patient's
current care. All available xrays will be reviewed and the exostoses characterized
radiographically. This will establish the patient's genotype.


Each participant whose genotype is unknown will have a 10 cc. blood sample collected at BC
Children's Hospital. This sample will be processed for mutation analysis (DNA extraction
from blood samples, mutation analysis) at the Clinical Molecular Diagnostic Laboratory at BC
Children's Hospital. The techniques used in the pilot study will be implemented with the
exception that microsatellite markers will not be used in order to save cost.

Using EXT 1 and EXT 2 primers (Appendix 1) both strands of a DNA segment are sequenced using
ABI Big Dye chemistry Version 2. The resulting sequencing reaction products are then run on
an ABI 3100 Avant genetic analyzer. Once a sequence is obtained it is analyzed with
SeqScape version 2 software which allows comparison with reference sequence.

Data Analysis:

All information resulting from this research study will be kept strictly confidential. All
documents will be identified by an ID number and kept in locked filing cabinets.
Participants will not be identified by name in any reports of the completed study.
Databases will be stored on project-dedicated laptop computer which is locked in the
research office.

The phenotypic data collected will be used to describe family degrees (designed using
Cyrillic software), phenotypes of affected individuals and mutations in the exostoses genes
of interest (site and type of mutation). Subject heights and segment lengths will be
converted to percentile figures to standardize for age and gender to allow for comparison
amongst groups.

Genotypic data from the mutation analysis of blood samples will include location of the
mutation (early in the gene versus late in the gene), type of mutation (alteration of gene
as missense, frameshift, nonsense or splice site), and the amino acid change that was caused
by the mutation. The data will be analyzed as follows:

Preliminary Analysis

1. EXT 1 versus EXT 2

2. Males versus Females

3. EXT 1 males versus EXT 1 females versus EXT 2 males versus EXT 2 females

Secondary Analysis

4. Types of mutations (Missense versus Nonsense versus Splice site versus Frameshift)

5. Early or late mutation (less than 1700 base pairs versus greater than 1700 base pairs)

With 2-way analyses, an unpaired t-test will be calculated and with greater than 2-way
analyses, an ANOVA will be calculated. Power will be calculated for every comparison due to
the huge variation in sample size. Statistical significance will be set to prior at 0.05
and power of 0.8.

Inclusion Criteria:

- Diagnosed with HME

Type of Study:


Study Design:

Observational Model: Case-Only, Time Perspective: Retrospective

Principal Investigator

Christine Alvarez, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of British Columbia


Canada: Health Canada

Study ID:




Start Date:

June 2004

Completion Date:

June 2023

Related Keywords:

  • Exostoses, Multiple Hereditary
  • DNA sequencing
  • EXT genes
  • Hereditary Multiple Exostoses,
  • also known as Multiple Hereditary Exostoses,
  • also known as Hereditary Multiple Osteochondromas
  • Exostoses
  • Osteophyte
  • Osteochondroma
  • Exostoses, Multiple Hereditary
  • Osteochondromatosis