Neoplasms

Musculoskeletal Diseases

All Conditions

Diseases and Abnormalities at or Before Birth

Skin and Connective Tissue Diseases

Nutritional and Metabolic Diseases

Symptoms and General Pathology

Rare Diseases

Osteochondroma

Exostoses, Multiple Hereditary

Osteochondromatosis

Exostoses

Osteophyte

Enchondromatosis

Hyperostosis

Bone Diseases

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Osteochondrodysplasias

Mucopolysaccharidosis IV

Bone Diseases, Developmental

Syndrome

Neoplastic Syndromes, Hereditary

Genetic Diseases, Inborn

Hereditary Multiple Osteochondromas

Ollier Disease

Mucopolysaccharidosis Type IV

Christine Alvarez, MD

The purpose of this study is to establish the genetic profile of families in British Columbia with HME.

The purpose of this study is to establish the genetic make-up of families and patients with HME. This will occur as the patient presents to a regular clinic visit. Dr. Alvarez will be introduced to interested patients and their parent(s) and a brief discussion about the project will occur. If the patient and their direct family are interested they will be entered into the study. This will involve interviewing the patients and their direct family. This interview will take about 1 hour. We are interested in identifying all affected family members as far up the family tree as possible. We ask that the idea of the study be introduced to extended family members by the participating family members and then have them call Dr. Alvarez to set up an appointment. Each available member will be interviewed and a physical exam done to determine the location of osteochondromas. In addition, Xrays will be done to determine the location of all osteochondromas. All Xrays will be reviewed. No new ones will be taken unless it is part of the patient's routine care.

To complete the genetic work up DNA analysis will be done on all available family members. This will entail obtaining a blood sample from each family member willing to partake in the study. These blood samples will be used only for the purpose of identifying abnormalities in the genes related to osteochondromas. The blood samples will be taken at British Columbia's Children's Hospital and processed there. DNA samples will be kept confidential.

Establishing the Genetic Profile of Multiple Hereditary Exostoses (HME) in Families of BC

Circle of Care

Vancouver Foundation

Children's & Women's Health Centre of British Columbia

University of British Columbia

Dr. Christine Alvarez

The investigator's goal for this project is to examine the causes of the wide variability of the expression of Hereditary Multiple Exostoses (HME). Previous work completed by our group shows that there exists a correlation between genotype and phenotype such that certain mutations or affected genes cause certain patterns of presentation, symptoms, and signs. The investigators intend to achieve this goal by increasing our study sample size to build upon the results generated from the pilot project of this study, in order to obtain statistical significance. This will be achieved by performing genotype-phenotype analysis on new families presenting with HME in British Columbia.

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.

Demographics:

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 elucidated.

Phenotype:

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.

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.

Gene Mutations and Orthopaedic Symptoms Correlation of Multiple Hereditary Exostoses: Multicentre Project

Genotype-Phenotype Correlation of Multiple Hereditary Exostoses: Multicentre Project

Principle Investigator

Behaviors and Mental Disorders

Quality of Life

The purpose of this study is to assess the health-related quality of life of subjects who have Hereditary Multiple Exostoses and to develop a disease specific quality of life survey. The investigators hypothesize that there are a wide range of quality of life experiences for patients with this syndrome.

At the time of recruitment, subjects will be asked to indicate whether they would like to participate in a one-time survey, or are willing to participate in the initial survey plus two additional questionnaire administrations, thereafter, which will be used to develop the disease-specific quality of life (QOL) score. All participants will complete either the SF-36 survey (for adult HME subjects) or the CHQ PF (for parents of children with HME), as applicable, in addition to a blank form with categorical subheadings (such as recreation, social function, etc.), which they will use to address any issues not covered in the standardized questionnaire. Standardized questionnaires will be scored and analyzed. The items listed on the second form will be compiled and reapplied to subjects that indicated interest in extended participation in survey completion. Subjects will be asked to determine which items apply to them and to rank these applicable items in order of importance. The results from this will be used to develop a 30 question, disease-specific questionnaire. The final step will be to readminister this survey, in conjunction with the SF-36 or CHQ PF, and follow up, in two weeks, with a second administration of the aforementioned surveys, in order to test the variability and validity of the disease-specific, health-related, quality of life score.

The Health-Related Quality of Life in Patients With Hereditary Multiple Exostoses

MHE Coalition

Study title	NCT ID	Conditions	Eligibility	Organization
Establishing the Genetic Profile of Multiple Hereditary Exostoses (HME) in Families of BC	NCT00473850	Exostoses, Mult...	-	University of British Columbia
Gene Mutations and Orthopaedic Symptoms Correlation of Multiple Hereditary Exostoses: Multicentre Project	NCT00474331	Exostoses, Mult...	-	University of British Columbia
Establishing the Genetic Profile of Multiple Hereditary Exostoses (HME) in Families of BC	NCT00473850	Exostoses, Mult...	-	University of British Columbia
The Health-Related Quality of Life in Patients With Hereditary Multiple Exostoses	NCT00474448	Exostoses, Mult...	-	University of British Columbia

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