CHERUBISM

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CHERUBISM

• Cynthia Kerska Fall, 2004

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OUTLINE

• 1. Cherubism A Definition
• 2. Clinical Phenotype
• A. Physical Description
• B. Familial Analysis
• C. Radiological Analysis
• D. Histopathological Analysis
• 3. Associated Complications
• 4. The Quest to Identify the Cherubism Mutation
• A. Study Participants
• B. Positional Cloning
• C. Overall Results
• D. The Role of SH3BP2
• 5. Molecular Diagnosis and Treatment

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CHERUBISM A Definition

• DEFINITION Cherubism is the hereditary form of
  polyostotic fibrous dysplasia that causes
  characteristic deformity in the lower half of the
  face due to the degeneration of maxilla and
  mandible bone tissue and its replacement with
  excessive amounts of fibrous tissue.
• Jones 1933
• Maxilla and
  mandible

http//www.toddthomsen.com/powerpoints/Dental
Emergencies_files/frame.htmslide0026.htm
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CLINICAL PHENOTYPE Physical Description

• Bilateral swelling of the jaw
• Painless
• Premature loss of primary teeth
• Impaired development and eruption of permanent
  teeth
• Onset 4-10 years
• Stabilizes after puberty
• Spontaneous regression 25-30 years

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CLINICAL PHENOTYPE Familial Analysis
Tiziani, V., et al. 1999. Figure 1.

• Hereditary
• Autosomal dominant

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CLINICAL PHENOTYPE Radiological Analysis

• Multilocular radiolucencies
• Note absence of solid bone
  structure and enlarged jaw
  region

Tiziani, V., et al. 1999. Figure 3.
Ueki, Y., V. Tiziani, et al. 2001. Figure 1b.
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CLINICAL PHENOTYPE Histopathological Analysis

• Multinucleated giant cells osteoclasts
• Note fibrous tissue and bone formation

EARLY STAGE
LATE STAGE
http//www.dental.mu.edu/oralpath/spresent/cherubi
sm/sld001.htm
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ASSOCIATED COMPLICATIONS

• Complications resulting from Cherubism
• Delayed dentition
• Dental root reabsoprtion
• Malalignment of teeth
• Impacted teeth
• Displacement of orbital contents

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THE QUEST TO IDENTIFY THE CHERUBISM MUTATION

• Initial Research
• J. Mangion, et al., 1999
• V. Tiziani, et al., 1999
• Subsequent Research
• Y. Ueki, V. Tiziani, et al., 2001

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STUDY PARTICIPANTS

• 15 patients (10?, 5?) from 4 families
• Focus Family A
• 3 generation family, 8 affected members
• Collected blood samples and isolated DNA
• Identification Process POSITIONAL CLONING

Tiziani, V., et al. 1999. Figure 1.
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STEP 1 GENOTYPING

• Used polymorphic microsatellite markers (SSRPs)
• PCR amplified genome DNA using ?-32P-ATP
  end-labeled primers
• Separated DNA via denaturing polyacrylamide gels
• Performed autoradiography

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STEP 1 GENOTYPING

• Linkage Analysis
• Pairwise linkage analysis
• Used MLINK program of LINKAGE package computer
  software
• Excluded several potential candidate gene loci
• Switched to random mapping of entire genome (360
  polymorphic microsatellite markers)

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STEP 1 GENOTYPING

• Linkage Analysis Results
• Haplotype analysis showed no recombination on
  chromosome 4p
• LOD Scores
• Combined LOD score 4.21, 22cM
• Family A ZMAX 3.31
• Family B ZMAX 0.60
• Family C ZMAX 0.30
• Family D ZMAX 0.30

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Tiziani, V., et al. 1999. Table 2.
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STEP 2 LOCATION IDENTIFICATION

• Linkage assigned to chromosome 4p16
• Between markers D4S2936 D4S2949
• According to physical map, interval spans 22 cM
  unit
• Note Candidate Genes
• Summary The disease develops in a time frame
  coinciding with many different events of tooth
  development

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STEP 3 IDENTIFYING THE GENE SH3BP2

• Study participants
• 66 individuals
• 15 families
• Linkage and haplotype analysis
• Results coincide with initial study
• Sequenced cDNA and genomic DNA
• Overall results
• Point mutations
• SH3-binding domain
• SH3BP2

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OVERALL RESULTS
Tiziani, V., Y. Ueki, et al. 2001. Figure 1d.
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THE ROLE OF SH3BP2
Tiziani, V., Y. Ueki, et al. 2001. Figure 1c.
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THE ROLE OF SH3BP2

• SH3BP2 Src Homology 3 Binding Protein 2
• Small protein domain, including
• SH3 Binding Domain
• SH2 Binding Domain
• Pleckstrin Homology Domain
• Mediate
• Protein-protein associations
• Regulate cytoplasmic signaling

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MOLECULAR DIAGNOSIS AND TREATMENT

• Diagnosis DNA sequencing
• Treatment
• Usually unnecessary
• Reasons
• Pain
• Associated complications
• Cosmetic reasons

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REFERENCES

• Cong, M., and T. Ton. Cherubism. Found at
  http//www.dental.mu.edu/oralpath/spresent/cherubi
  sm/sld001.htm.
• Henry, F., et al. Cherubism the value of imaging
  and preoperative embolization. J. Radiol. 2003
  (Nov.) 84 1774-1778.
• Lewis, C. R. Cherubism. Found at
  http//clearinghouse.mwsc.edu/manuscripts/163.asp.
  
• Lo, B., et al. Novel mutation in the gene
  encoding c-Abl-binding protein SH3BP2 causes
  cherubism. Am. J. Med. Genet.. 2003 (Aug.)
  121A(1) 37-40.
• Mangion, J., et al. The gene for cherubism maps
  to chromosome 4p16.3. Am. J. Hum. Genet. 1999
  65 151-157.
• Medterms Website. Cherubism. Found at
  http//www.medterms.com/script/main/art.asp?articl
  ekey9508.
• Online Mendelian Inheritance in Man (OMIM). Found
  at http//www.ncbi.nlm.nih.gov/Omim, for
  Cherubism MIM 118400, FGFR3 MIM 134934, MSX1
  MIM 142983, and SH3BP2 MIM602104.
• Schultze-Mosgali, S., L. M. Holbach, and J.
  Wiltfang. Cherubism clinical evidence and
  therapy. J. Craniofac. Surg. 2003 (March) 14(2)
  201-206
• Tiziani, V., et al. The gene for cherubism maps
  to chromosome 4p16. Am. J. Hum. Genet. 1999 65
  158-166.
• Ueki, Y., V. Tiziani, et al. Mutations in the
  gene encoding c-Abl binding protein SH3BP2 cause
  cherubism. Nature Genet. 2001 28 125-126.