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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.
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By the Health On the Net Foundation. Click here to verify.# HON Conduct 282463 and is linked on the NIH
National Library of Medicine, Directory of Health Organizations (SIS) website, as well as the link for Patient
Information on The Diseases Database a cross-referenced index of human disease, and the 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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