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CHERUBISM
Cynthia Kerska – Fall, 2004
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
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.htm#slide0026.htm
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
CLINICAL PHENOTYPE:
Familial Analysis
Tiziani, V., et al. 1999. Figure 1.
• Hereditary
• Autosomal dominant
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.
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/cherubism/sld001.htm
ASSOCIATED COMPLICATIONS
• Complications resulting from Cherubism:
– Delayed dentition
– Dental root reabsoprtion
– Malalignment of teeth
– Impacted teeth
– Displacement of orbital contents
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
STUDY PARTICIPANTS
• 15 patients (10♂, 5♀) from 4 families
• Focus: Family A
– 3 generation family, 8 affected members
Tiziani, V., et al. 1999. Figure 1.
• Collected blood samples and isolated DNA
• Identification Process: POSITIONAL CLONING
STEP #1: GENOTYPING
• Used polymorphic microsatellite markers
(SSRPs)
• PCR amplified genome DNA using γ-[32P]-ATP
end-labeled primers
• Separated DNA via denaturing polyacrylamide
gels
• Performed autoradiography
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)
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
Tiziani, V., et al. 1999. Table 2.
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…”
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
OVERALL RESULTS
Tiziani, V., Y. Ueki, et al. 2001. Figure 1d.
THE ROLE OF SH3BP2
Tiziani, V., Y. Ueki, et al. 2001. Figure 1c.
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
MOLECULAR DIAGNOSIS
AND TREATMENT
• Diagnosis: DNA sequencing
• Treatment:
– Usually unnecessary
– Reasons:
• Pain
• Associated complications
• Cosmetic reasons
REFERENCES
Cong, M., and T. Ton. Cherubism. Found at:
http://www.dental.mu.edu/oralpath/spresent/cherubism/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?articlekey=9508.
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.