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Genetic Epidemiology of Paget’s Disease of Bone in Italy: sequestosome1/p62 Gene Mutational Test and Haplotype Analysis at 5q35 in a Large Representative Series of Sporadic and Familial Italian Cases of Paget’s Disease of Bone
Families affected by Paget’s disease of bone frequently harbor mutations in the SQSTM1/p62 gene. In this multicentric study we collected 345 sporadic and 12 familial PDB cases throughout Italy, identifying 12 different mutations, 5 of which are newly reported and 3, D335E , A381V , and Y383X , exter...
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Published in: | Calcified tissue international 2009, Vol.84 (1), p.20-37 |
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creator | Falchetti, Alberto Di Stefano, Marco Marini, Francesca Ortolani, Sergio Ulivieri, Massimo Fabio Bergui, Simona Masi, Laura Cepollaro, Chiara Benucci, Maurizio Di Munno, Ombretta Rossini, Maurizio Adami, Silvano Del Puente, Antonio Isaia, Giancarlo Torricelli, Francesca Brandi, Maria Luisa |
description | Families affected by Paget’s disease of bone frequently harbor mutations in the
SQSTM1/p62
gene. In this multicentric study we collected 345 sporadic and 12 familial PDB cases throughout Italy, identifying 12 different mutations, 5 of which are newly reported and 3,
D335E
,
A381V
, and
Y383X
, external to the UBA domain. Subjects with truncating mutations,
E396X
, showed a significantly younger age at clinical diagnosis, while the
Y383X
subjects had a higher average number of affected skeletal sites. All the mutants exhibited the
CGTG
-H2 haplotype. In two pairs and one triad of unrelated Italian PDB families from different Italian regions, we detected a common
SQSTM1/p62
mutation for each
P392L
,
M404V
, and
G425R
group. Since the
CGTG
-H2 haplotype frequency was also high in normal subjects, and genetic influence due to migratory fluxes of different ethnic groups exists in the Italian population, to refine the search for a more geographically specific founder effect, we extended the haplotype analysis in these families using polymorphic microsatellite repeat markers, within and flanking the
SQSTM1/p62
locus, from chromosome 5q35, other than the exon 6 and 3′UTR polymorphisms. All mutant carriers from two of the three
M404V
families and from the
G425R
families exhibited common extended chromosome 5q35 haplotypes,
IT01
and
IT02
, respectively, which may be reflecting influences of past migrations. This may be helpful in estimating the true rate of de novo mutations. We confirm the data on the existence of both a mutational hotspot at the UBA domain of SQSTM1/p62 and a founder effect in the PDB population. |
doi_str_mv | 10.1007/s00223-008-9192-8 |
format | article |
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SQSTM1/p62
gene. In this multicentric study we collected 345 sporadic and 12 familial PDB cases throughout Italy, identifying 12 different mutations, 5 of which are newly reported and 3,
D335E
,
A381V
, and
Y383X
, external to the UBA domain. Subjects with truncating mutations,
E396X
, showed a significantly younger age at clinical diagnosis, while the
Y383X
subjects had a higher average number of affected skeletal sites. All the mutants exhibited the
CGTG
-H2 haplotype. In two pairs and one triad of unrelated Italian PDB families from different Italian regions, we detected a common
SQSTM1/p62
mutation for each
P392L
,
M404V
, and
G425R
group. Since the
CGTG
-H2 haplotype frequency was also high in normal subjects, and genetic influence due to migratory fluxes of different ethnic groups exists in the Italian population, to refine the search for a more geographically specific founder effect, we extended the haplotype analysis in these families using polymorphic microsatellite repeat markers, within and flanking the
SQSTM1/p62
locus, from chromosome 5q35, other than the exon 6 and 3′UTR polymorphisms. All mutant carriers from two of the three
M404V
families and from the
G425R
families exhibited common extended chromosome 5q35 haplotypes,
IT01
and
IT02
, respectively, which may be reflecting influences of past migrations. This may be helpful in estimating the true rate of de novo mutations. We confirm the data on the existence of both a mutational hotspot at the UBA domain of SQSTM1/p62 and a founder effect in the PDB population.</description><identifier>ISSN: 0171-967X</identifier><identifier>EISSN: 1432-0827</identifier><identifier>DOI: 10.1007/s00223-008-9192-8</identifier><identifier>PMID: 19067022</identifier><language>eng</language><publisher>New York: Springer-Verlag</publisher><subject>Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - physiology ; Aged ; Aged, 80 and over ; Biochemistry ; Biogeography ; Biomedical and Life Sciences ; Bone diseases ; Cell Biology ; Chromosomes, Human, Pair 5 - genetics ; DNA Mutational Analysis ; Endocrinology ; Epidemiology ; Exons ; Female ; Founder Effect ; Genetic disorders ; Genetic Predisposition to Disease ; Genetic Testing ; Genotype ; Haplotypes - genetics ; Humans ; Introns ; Italy - epidemiology ; Life Sciences ; Male ; Middle Aged ; Molecular Epidemiology ; Mutation ; Orthopedics ; Osteitis Deformans - epidemiology ; Osteitis Deformans - genetics ; Pedigree ; Phenotype ; Polymorphism, Single Nucleotide ; Sequestosome-1 Protein</subject><ispartof>Calcified tissue international, 2009, Vol.84 (1), p.20-37</ispartof><rights>Springer Science+Business Media, LLC 2008</rights><rights>Springer Science+Business Media, LLC 2009</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c400t-49f113b780339393ca69e7cd06b2157541ca3dc6d63c4e68ebee8cddeadfb62e3</citedby><cites>FETCH-LOGICAL-c400t-49f113b780339393ca69e7cd06b2157541ca3dc6d63c4e68ebee8cddeadfb62e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19067022$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Falchetti, Alberto</creatorcontrib><creatorcontrib>Di Stefano, Marco</creatorcontrib><creatorcontrib>Marini, Francesca</creatorcontrib><creatorcontrib>Ortolani, Sergio</creatorcontrib><creatorcontrib>Ulivieri, Massimo Fabio</creatorcontrib><creatorcontrib>Bergui, Simona</creatorcontrib><creatorcontrib>Masi, Laura</creatorcontrib><creatorcontrib>Cepollaro, Chiara</creatorcontrib><creatorcontrib>Benucci, Maurizio</creatorcontrib><creatorcontrib>Di Munno, Ombretta</creatorcontrib><creatorcontrib>Rossini, Maurizio</creatorcontrib><creatorcontrib>Adami, Silvano</creatorcontrib><creatorcontrib>Del Puente, Antonio</creatorcontrib><creatorcontrib>Isaia, Giancarlo</creatorcontrib><creatorcontrib>Torricelli, Francesca</creatorcontrib><creatorcontrib>Brandi, Maria Luisa</creatorcontrib><creatorcontrib>GenePage Project</creatorcontrib><creatorcontrib>On Behalf of the GenePage Project</creatorcontrib><title>Genetic Epidemiology of Paget’s Disease of Bone in Italy: sequestosome1/p62 Gene Mutational Test and Haplotype Analysis at 5q35 in a Large Representative Series of Sporadic and Familial Italian Cases of Paget’s Disease of Bone</title><title>Calcified tissue international</title><addtitle>Calcif Tissue Int</addtitle><addtitle>Calcif Tissue Int</addtitle><description>Families affected by Paget’s disease of bone frequently harbor mutations in the
SQSTM1/p62
gene. In this multicentric study we collected 345 sporadic and 12 familial PDB cases throughout Italy, identifying 12 different mutations, 5 of which are newly reported and 3,
D335E
,
A381V
, and
Y383X
, external to the UBA domain. Subjects with truncating mutations,
E396X
, showed a significantly younger age at clinical diagnosis, while the
Y383X
subjects had a higher average number of affected skeletal sites. All the mutants exhibited the
CGTG
-H2 haplotype. In two pairs and one triad of unrelated Italian PDB families from different Italian regions, we detected a common
SQSTM1/p62
mutation for each
P392L
,
M404V
, and
G425R
group. Since the
CGTG
-H2 haplotype frequency was also high in normal subjects, and genetic influence due to migratory fluxes of different ethnic groups exists in the Italian population, to refine the search for a more geographically specific founder effect, we extended the haplotype analysis in these families using polymorphic microsatellite repeat markers, within and flanking the
SQSTM1/p62
locus, from chromosome 5q35, other than the exon 6 and 3′UTR polymorphisms. All mutant carriers from two of the three
M404V
families and from the
G425R
families exhibited common extended chromosome 5q35 haplotypes,
IT01
and
IT02
, respectively, which may be reflecting influences of past migrations. This may be helpful in estimating the true rate of de novo mutations. We confirm the data on the existence of both a mutational hotspot at the UBA domain of SQSTM1/p62 and a founder effect in the PDB population.</description><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - physiology</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Biochemistry</subject><subject>Biogeography</subject><subject>Biomedical and Life Sciences</subject><subject>Bone diseases</subject><subject>Cell Biology</subject><subject>Chromosomes, Human, Pair 5 - genetics</subject><subject>DNA Mutational Analysis</subject><subject>Endocrinology</subject><subject>Epidemiology</subject><subject>Exons</subject><subject>Female</subject><subject>Founder Effect</subject><subject>Genetic disorders</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic Testing</subject><subject>Genotype</subject><subject>Haplotypes - genetics</subject><subject>Humans</subject><subject>Introns</subject><subject>Italy - epidemiology</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Molecular Epidemiology</subject><subject>Mutation</subject><subject>Orthopedics</subject><subject>Osteitis Deformans - epidemiology</subject><subject>Osteitis Deformans - genetics</subject><subject>Pedigree</subject><subject>Phenotype</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Sequestosome-1 Protein</subject><issn>0171-967X</issn><issn>1432-0827</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><recordid>eNqFks-K1TAUxoMoznX0AdxIcOGuTv60aetuvM4_uKI4I7graXLuJUPbdHJaoTtfw9dz4XOYeC8MCCqBBE6-8zsfh4-Q55y95oyVJ8iYEDJjrMpqXousekBWPJciY5UoH5IV4yXPalV-OSJPEG8Z47lS6jE54jVTZexdkZ8XMMDkDD0bnYXe-c7vFuq39KPewfTj23ek7xyCRkjFt34A6gZ6NelueUMR7mbAyaPvgZ-MStBEo-_nSU_OD7qjN_Gb6sHSSz12flpGoKexvqBDqida3Mki8TTd6LAD-gnGAAhD6v8K9BqCA0yDr0cftI02E-tc965zkZ5sOD3QdbSH_zT9lDza6g7h2eE9Jp_Pz27Wl9nmw8XV-nSTmZyxKcvrLeeyLSsmZR2P0aqG0limWsGLssi50dIaZZU0OagKWoDKWAvablslQB6TV3vuGPzv3TS9QwNdpwfwMzZKlbVK9P8JBSuEVFUVhS__EN76OcQdRg2XrIxXovG9yASPGGDbjMH1OiwNZ02KSrOPShOj0qSoNAn84gCe2x7sfcchG1Eg9gKMX8MOwv3kv1N_Ae6-zUM</recordid><startdate>2009</startdate><enddate>2009</enddate><creator>Falchetti, Alberto</creator><creator>Di Stefano, Marco</creator><creator>Marini, Francesca</creator><creator>Ortolani, Sergio</creator><creator>Ulivieri, Massimo Fabio</creator><creator>Bergui, Simona</creator><creator>Masi, Laura</creator><creator>Cepollaro, Chiara</creator><creator>Benucci, Maurizio</creator><creator>Di Munno, Ombretta</creator><creator>Rossini, Maurizio</creator><creator>Adami, Silvano</creator><creator>Del Puente, Antonio</creator><creator>Isaia, Giancarlo</creator><creator>Torricelli, Francesca</creator><creator>Brandi, Maria Luisa</creator><general>Springer-Verlag</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>2009</creationdate><title>Genetic Epidemiology of Paget’s Disease of Bone in Italy: sequestosome1/p62 Gene Mutational Test and Haplotype Analysis at 5q35 in a Large Representative Series of Sporadic and Familial Italian Cases of Paget’s Disease of Bone</title><author>Falchetti, Alberto ; Di Stefano, Marco ; Marini, Francesca ; Ortolani, Sergio ; Ulivieri, Massimo Fabio ; Bergui, Simona ; Masi, Laura ; Cepollaro, Chiara ; Benucci, Maurizio ; Di Munno, Ombretta ; Rossini, Maurizio ; Adami, Silvano ; Del Puente, Antonio ; Isaia, Giancarlo ; Torricelli, Francesca ; Brandi, Maria Luisa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c400t-49f113b780339393ca69e7cd06b2157541ca3dc6d63c4e68ebee8cddeadfb62e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adaptor Proteins, Signal Transducing - physiology</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Biochemistry</topic><topic>Biogeography</topic><topic>Biomedical and Life Sciences</topic><topic>Bone diseases</topic><topic>Cell Biology</topic><topic>Chromosomes, Human, Pair 5 - genetics</topic><topic>DNA Mutational Analysis</topic><topic>Endocrinology</topic><topic>Epidemiology</topic><topic>Exons</topic><topic>Female</topic><topic>Founder Effect</topic><topic>Genetic disorders</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetic Testing</topic><topic>Genotype</topic><topic>Haplotypes - genetics</topic><topic>Humans</topic><topic>Introns</topic><topic>Italy - epidemiology</topic><topic>Life Sciences</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Molecular Epidemiology</topic><topic>Mutation</topic><topic>Orthopedics</topic><topic>Osteitis Deformans - epidemiology</topic><topic>Osteitis Deformans - genetics</topic><topic>Pedigree</topic><topic>Phenotype</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Sequestosome-1 Protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Falchetti, Alberto</creatorcontrib><creatorcontrib>Di Stefano, Marco</creatorcontrib><creatorcontrib>Marini, Francesca</creatorcontrib><creatorcontrib>Ortolani, Sergio</creatorcontrib><creatorcontrib>Ulivieri, Massimo Fabio</creatorcontrib><creatorcontrib>Bergui, Simona</creatorcontrib><creatorcontrib>Masi, Laura</creatorcontrib><creatorcontrib>Cepollaro, Chiara</creatorcontrib><creatorcontrib>Benucci, Maurizio</creatorcontrib><creatorcontrib>Di Munno, Ombretta</creatorcontrib><creatorcontrib>Rossini, Maurizio</creatorcontrib><creatorcontrib>Adami, Silvano</creatorcontrib><creatorcontrib>Del Puente, Antonio</creatorcontrib><creatorcontrib>Isaia, Giancarlo</creatorcontrib><creatorcontrib>Torricelli, Francesca</creatorcontrib><creatorcontrib>Brandi, Maria Luisa</creatorcontrib><creatorcontrib>GenePage Project</creatorcontrib><creatorcontrib>On Behalf of the GenePage Project</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>ProQuest Nursing & Allied Health Database</collection><collection>Proquest Health & Medical Complete</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Calcified tissue international</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Falchetti, Alberto</au><au>Di Stefano, Marco</au><au>Marini, Francesca</au><au>Ortolani, Sergio</au><au>Ulivieri, Massimo Fabio</au><au>Bergui, Simona</au><au>Masi, Laura</au><au>Cepollaro, Chiara</au><au>Benucci, Maurizio</au><au>Di Munno, Ombretta</au><au>Rossini, Maurizio</au><au>Adami, Silvano</au><au>Del Puente, Antonio</au><au>Isaia, Giancarlo</au><au>Torricelli, Francesca</au><au>Brandi, Maria Luisa</au><aucorp>GenePage Project</aucorp><aucorp>On Behalf of the GenePage Project</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic Epidemiology of Paget’s Disease of Bone in Italy: sequestosome1/p62 Gene Mutational Test and Haplotype Analysis at 5q35 in a Large Representative Series of Sporadic and Familial Italian Cases of Paget’s Disease of Bone</atitle><jtitle>Calcified tissue international</jtitle><stitle>Calcif Tissue Int</stitle><addtitle>Calcif Tissue Int</addtitle><date>2009</date><risdate>2009</risdate><volume>84</volume><issue>1</issue><spage>20</spage><epage>37</epage><pages>20-37</pages><issn>0171-967X</issn><eissn>1432-0827</eissn><abstract>Families affected by Paget’s disease of bone frequently harbor mutations in the
SQSTM1/p62
gene. In this multicentric study we collected 345 sporadic and 12 familial PDB cases throughout Italy, identifying 12 different mutations, 5 of which are newly reported and 3,
D335E
,
A381V
, and
Y383X
, external to the UBA domain. Subjects with truncating mutations,
E396X
, showed a significantly younger age at clinical diagnosis, while the
Y383X
subjects had a higher average number of affected skeletal sites. All the mutants exhibited the
CGTG
-H2 haplotype. In two pairs and one triad of unrelated Italian PDB families from different Italian regions, we detected a common
SQSTM1/p62
mutation for each
P392L
,
M404V
, and
G425R
group. Since the
CGTG
-H2 haplotype frequency was also high in normal subjects, and genetic influence due to migratory fluxes of different ethnic groups exists in the Italian population, to refine the search for a more geographically specific founder effect, we extended the haplotype analysis in these families using polymorphic microsatellite repeat markers, within and flanking the
SQSTM1/p62
locus, from chromosome 5q35, other than the exon 6 and 3′UTR polymorphisms. All mutant carriers from two of the three
M404V
families and from the
G425R
families exhibited common extended chromosome 5q35 haplotypes,
IT01
and
IT02
, respectively, which may be reflecting influences of past migrations. This may be helpful in estimating the true rate of de novo mutations. We confirm the data on the existence of both a mutational hotspot at the UBA domain of SQSTM1/p62 and a founder effect in the PDB population.</abstract><cop>New York</cop><pub>Springer-Verlag</pub><pmid>19067022</pmid><doi>10.1007/s00223-008-9192-8</doi><tpages>18</tpages></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0171-967X |
ispartof | Calcified tissue international, 2009, Vol.84 (1), p.20-37 |
issn | 0171-967X 1432-0827 |
language | eng |
recordid | cdi_proquest_miscellaneous_66796803 |
source | Springer Nature |
subjects | Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - physiology Aged Aged, 80 and over Biochemistry Biogeography Biomedical and Life Sciences Bone diseases Cell Biology Chromosomes, Human, Pair 5 - genetics DNA Mutational Analysis Endocrinology Epidemiology Exons Female Founder Effect Genetic disorders Genetic Predisposition to Disease Genetic Testing Genotype Haplotypes - genetics Humans Introns Italy - epidemiology Life Sciences Male Middle Aged Molecular Epidemiology Mutation Orthopedics Osteitis Deformans - epidemiology Osteitis Deformans - genetics Pedigree Phenotype Polymorphism, Single Nucleotide Sequestosome-1 Protein |
title | Genetic Epidemiology of Paget’s Disease of Bone in Italy: sequestosome1/p62 Gene Mutational Test and Haplotype Analysis at 5q35 in a Large Representative Series of Sporadic and Familial Italian Cases of Paget’s Disease of Bone |
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