BC Children's Hospital & Health Centre.
http://www.bcchildrens.ca/Services/SurgeryAndSurgSuites/OrthopaedicSurgery/Whatwedo/Hereditarymultipleexostosesclinic.htm
http://www.bcchildrens.ca/Services/SurgeryAndSurgSuites/OrthopaedicSurgery/Whatwedo/Hereditarymultipleexostosesclinic.htm
| Christine Alvarez, M.D. |
Research authored by Dr. Alvarez
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List of Publications via PubMed
(NIH National Library of Medicine)
List of Publications via PubMed
(NIH National Library of Medicine)
Defining the Severity of Hereditary Multiple Exostosis
Abstract 2005 MHE Conference
Christine Alvarez
Department of Orthopaedics, University of British Columbia,
British Columbia’s Children’s Hospital, Canada.
Introduction: Hereditary Multiple Exostoses (HME) is a genetic disorder with a wide phenotypic expression involving limb
alignment, limb lengths and height, lesion factors, and potential for sarcomatous transformation.
The clinical impact of HME is likely related to number of lesions a patient has. It remains unclear what factors are predictive of
the number of lesions an individual becomes riddled with. However, these factors are likely related to the patient’s genotype.
HME results from mutations in the exostoses genes: EXT1 and EXT2. The function of these genes involves controlling physeal
chondrocyte proliferation and differentiation. Mutation of either gene results in loss of control of the physeal maturation
gradient which eventually leads to excess chondrocyte proliferation and presumptive osteochondroma formation. EXT 1 has a
more dominant role in this mechanism and therefore an EXT 1 mutation would likely have greater impact and result in a greater
loss of chondrocyte regulation in the zone of proliferation and thus, more potential for exotosis formation.
Previous work examining the potential for a genotype phenotype relationship showed that EXT1 patients showed a worse
phenotype. This study however had a small sample size and though trends in many of the 58 phenotypic parameters tested
were identified statistical significance was not uniformly met. Other studies also have found a similar relationship of EXT 1 being
worse phenotypically but phenotypic parameters were incomplete, in some studies the sample was still small, and in some cases
genotypic was based on linkage analysis only and not definite mutations. Thus, a more descriptive and extensive clinically
significant evaluation of these patients is required as well as a study involving a greater number of patients to provide sufficient
power to address issues of statistical and clinical significance.
Purpose:
The purpose of this study was to build on the original studies on genotype phenotype correlation in HME. This project was
designed to establish an extensive phenotype profile, define genotype and have large sample size. This study will then therefore
define the genotype phenotype relationship in HME.
Materials and Methods:
Genotyping was performed at the Molecular Diagnostic Laboratory at BC Children’s Hospital. EXT1 and EXT2 mutations were
analyzed by direct sequencing of entire gene coding regions, including flanking intronic sequences. Phenotyping was performed
at the HME Clinic and involved collection of radiographic and clinical parameters divided across three categories of lesion quality,
limb segment lengths, and limb alignment.
Results:
Sixty-eight affected individuals with HME participated in the study. Genotype data was collected for all participants. Phenotype
data including lesion number and quality (17 parameters), limb segment lengths (6 parameters x 2 side), longitudinal height,
and limb alignment (28 parameters) were collected.Baseline demographics were established considering number of patients
affected with EXT 1 vs. EXT 2 mutations, gender, and age (classified into four age categories: 0-5, 6-10 11-15 and +16 years).
The primary premise, that more lesion cause worse severity, was established, and then applied to the principal hypothesis that
EXT 1 mutations produce a worse phenotype.
Abstract 2005 MHE Conference
Christine Alvarez
Department of Orthopaedics, University of British Columbia,
British Columbia’s Children’s Hospital, Canada.
Introduction: Hereditary Multiple Exostoses (HME) is a genetic disorder with a wide phenotypic expression involving limb
alignment, limb lengths and height, lesion factors, and potential for sarcomatous transformation.
The clinical impact of HME is likely related to number of lesions a patient has. It remains unclear what factors are predictive of
the number of lesions an individual becomes riddled with. However, these factors are likely related to the patient’s genotype.
HME results from mutations in the exostoses genes: EXT1 and EXT2. The function of these genes involves controlling physeal
chondrocyte proliferation and differentiation. Mutation of either gene results in loss of control of the physeal maturation
gradient which eventually leads to excess chondrocyte proliferation and presumptive osteochondroma formation. EXT 1 has a
more dominant role in this mechanism and therefore an EXT 1 mutation would likely have greater impact and result in a greater
loss of chondrocyte regulation in the zone of proliferation and thus, more potential for exotosis formation.
Previous work examining the potential for a genotype phenotype relationship showed that EXT1 patients showed a worse
phenotype. This study however had a small sample size and though trends in many of the 58 phenotypic parameters tested
were identified statistical significance was not uniformly met. Other studies also have found a similar relationship of EXT 1 being
worse phenotypically but phenotypic parameters were incomplete, in some studies the sample was still small, and in some cases
genotypic was based on linkage analysis only and not definite mutations. Thus, a more descriptive and extensive clinically
significant evaluation of these patients is required as well as a study involving a greater number of patients to provide sufficient
power to address issues of statistical and clinical significance.
Purpose:
The purpose of this study was to build on the original studies on genotype phenotype correlation in HME. This project was
designed to establish an extensive phenotype profile, define genotype and have large sample size. This study will then therefore
define the genotype phenotype relationship in HME.
Materials and Methods:
Genotyping was performed at the Molecular Diagnostic Laboratory at BC Children’s Hospital. EXT1 and EXT2 mutations were
analyzed by direct sequencing of entire gene coding regions, including flanking intronic sequences. Phenotyping was performed
at the HME Clinic and involved collection of radiographic and clinical parameters divided across three categories of lesion quality,
limb segment lengths, and limb alignment.
Results:
Sixty-eight affected individuals with HME participated in the study. Genotype data was collected for all participants. Phenotype
data including lesion number and quality (17 parameters), limb segment lengths (6 parameters x 2 side), longitudinal height,
and limb alignment (28 parameters) were collected.Baseline demographics were established considering number of patients
affected with EXT 1 vs. EXT 2 mutations, gender, and age (classified into four age categories: 0-5, 6-10 11-15 and +16 years).
The primary premise, that more lesion cause worse severity, was established, and then applied to the principal hypothesis that
EXT 1 mutations produce a worse phenotype.
| Dr. Alvarez's research |
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Click here to verify.# HON Conduct 282463 and is the patient support link on the US Government Genetics Home Reference (http://ghr.nlm.nih.gov)
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Intute: health & life sciences a free online service providing access to the very best Web resources for education and research located in the UK
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