Paget's Disease Of Bone Cases Research Articles

Paget's disease: a review of the epidemiology, etiology, genetics, and treatment.

Paget's disease of bone (PDB) is the second most prevalent metabolic bone disorder worldwide, with a prevalence rate of 1.5%-8.3%. It is characterized by localized areas of accelerated, disorganized, and excessive bone production and turnover. Typically, PDB develops in the later stages of life, particularly in the late 50s, and affects men more frequently than women. PDB is a complex disease influenced by both genetic and environmental factors. PDB has a complex genetic basis involving multiple genes, with SQSTM1 being the gene most frequently associated with its development. Mutations affecting the UBA domain of SQSTM1 have been detected in both familial and sporadic PDB cases, and these mutations are often associated with severe clinical expression. Germline mutations in other genes such as TNFRSF11A, ZNF687 and PFN1, have also been associated with the development of the disease. Genetic association studies have also uncovered several PDB predisposing risk genes contributing to the disease pathology and severity. Epigenetic modifications of genes involved in bone remodelling and regulation, including RANKL, OPG, HDAC2, DNMT1, and SQSTM1, have been implicated in the development and progression of Paget's disease of bone, providing insight into the molecular basis of the disease and potential targets for therapeutic intervention. Although PDB has a tendency to cluster within families, the variable severity of the disease across family members, coupled with decreasing incidence rates, indicates that environmental factors may also play a role in the pathophysiology of PDB. The precise nature of these environmental triggers and how they interact with genetic determinants remain poorly understood. Fortunately, majority of PDB patients can achieve long-term remission with an intravenous infusion of aminobisphosphonates, such as zoledronic acid. In this review, we discuss aspects like clinical characteristics, genetic foundation, and latest updates in PDB research.

Epigenetic analysis of Paget's disease of bone identifies differentially methylated loci that predict disease status.

Paget's disease of bone (PDB) is characterized by focal increases in disorganized bone remodeling. This study aims to characterize PDB-associated changes in DNA methylation profiles in patients' blood. Meta-analysis of data from the discovery and cross-validation set, each comprising 116 PDB cases and 130 controls, revealed significant differences in DNA methylation at 14 CpG sites, 4 CpG islands, and 6 gene-body regions. These loci, including two characterized as functional through expression quantitative trait-methylation analysis, were associated with functions related to osteoclast differentiation, mechanical loading, immune function, and viral infection. A multivariate classifier based on discovery samples was found to discriminate PDB cases and controls from the cross-validation with a sensitivity of 0.84, specificity of 0.81, and an area under curve of 92.8%. In conclusion, this study has shown for the first time that epigenetic factors contribute to the pathogenesis of PDB and may offer diagnostic markers for prediction of the disease.

Paget’s disease of bone: A clinical update

Paget's disease of bone (PDB) is a common destructive condition of bone that affects 1-2% of the population, most typically those over the age of 55 years. Itis usually asymptomatic. The aim of this article is to describe theclinical presentation, diagnosis and management of patients with PDB. Most cases of PDB are diagnosed incidentally on radiographs or as an isolated elevation of serum alkaline phosphatase. Symptomatic patients present with bone pain, fractures, arthritis and features of compression neuropathy. Diagnosis is made on the basis of typical radiological features on plain films, while a radionuclide bone scan may be used to assess the extent of disease. The mainstay of treatment for PDB is bisphosphonate therapy, with zoledronic acid being the most effective agent. Asingle infusion of zoledronic acid leads to a sustained reduction in bone pain and markers of bone turnover. However, bisphosphonates should be reserved for symptomatic patients, as treatment with these agents has been associated with an increase in rates of fracture in patients with asymptomatic PDB.

Evolution of Paget's disease of bone in adults inheriting SQSTM1 mutations.

The cause of Paget's disease of bone (PDB) is unknown, but genetic factors, particularly SQSTM1 mutations, and environmental factors are important. To investigate the development of PDB in asymptomatic relatives carrying SQSTM1 mutations to determine whether a secular trend towards a less severe phenotype is evident, and to estimate prospectively the rate at which PDB emerged in this genetically susceptible population. We recruited first-degree relatives of patients with PDB [33 adult offspring (mean age 45) and 1 sibling] with a familial SQSTM1 mutation. We determined the presence of PDB with skeletal scintiscans and confirmatory radiographs. Those negative for PDB on the initial scan were investigated again a mean 5·1 years later. The initial skeletal scintiscan demonstrated PDB in six subjects; 26 of the remaining 28 unaffected subjects had a second scintiscan, with two new cases of monostotic PDB diagnosed in 134 patient-years of follow-up. In the total eight adult offspring diagnosed with PDB, the age of diagnosis was greater, by at least 10 years, than that in the 21 probands with clinically identified PDB (P = 0·005). In adult offspring who were older at the time of skeletal scintigraphy than their affected parents were at the time of clinical diagnosis, the difference was even more marked (P < 0·001). In adult offspring with PDB, the disease was significantly less extensive than in their affected parent, as judged by alkaline phosphatase and disease extent (P < 0·003). These findings suggest a substantial gene-environment interaction: the emergence of PDB in offspring inheriting SQSTM1 mutations is delayed by at least a decade, has a substantially attenuated phenotype and occurs at a low rate between the (mean) ages of 45 and 50 years. The nature of the environmental factor is unknown.

Targeted sequencing of the Paget's disease associated 14q32 locus identifies several missense coding variants in RIN3 that predispose to Paget's disease of bone.

Paget's disease of bone (PDB) is a common disorder with a strong genetic component characterized by increased but disorganized bone remodelling. Previous genome-wide association studies identified a locus on chromosome 14q32 tagged by rs10498635 which was significantly associated with susceptibility to PDB in several European populations. Here we conducted fine-mapping and targeted sequencing of the candidate locus to identify possible functional variants. Imputation in 741 PDB patients and 2699 controls confirmed that the association was confined to a 60 kb region in the RIN3 gene and conditional analysis adjusting for rs10498635 identified no new independent signals. Sequencing of the RIN3 gene identified a common missense variant (p.R279C) that was strongly associated with the disease (OR = 0.64; P = 1.4 × 10−9), and was in strong linkage disequilibrium with rs10498635. A further 13 rare missense variants were identified, seven of which were novel and detected only in PDB cases. When combined, these rare variants were over-represented in cases compared with controls (OR = 3.72; P = 8.9 × 10−10). Most rare variants were located in a region that encodes a proline-rich, intrinsically disordered domain of the protein and many were predicted to be pathogenic. RIN3 was expressed in bone tissue and its expression level was ∼10-fold higher in osteoclasts compared with osteoblasts. We conclude that susceptibility to PDB at the 14q32 locus is mediated by a combination of common and rare coding variants in RIN3 and suggest that RIN3 may contribute to PDB susceptibility by affecting osteoclast function.

Modifications to nano- and microstructural quality and the effects on mechanical integrity in Paget's disease of bone.

Paget's disease of bone (PDB) is the second most common bone disease mostly developing after 50 years of age at one or more localized skeletal sites; it is associated with severely high bone turnover, bone enlargement, bowing/deformity, cracking, and pain. Here, to specifically address the origins of the deteriorated mechanical integrity, we use a cohort of control and PDB human biopsies to investigate multiscale architectural and compositional modifications to the bone structure (ie, bone quality) and relate these changes to mechanical property measurements to provide further insight into the clinical manifestations (ie, deformities and bowing) and fracture risk caused by PDB. Here, at the level of the collagen and mineral (ie, nanometer-length scale), we find a 19% lower mineral content and lower carbonate-to-phosphate ratio in PDB, which accounts for the 14% lower stiffness and 19% lower hardness promoting plastic deformation in pathological bone. At the microstructural scale, trabecular regions are known to become densified, whereas cortical bone loses its characteristic parallel-aligned osteonal pattern, which is replaced with a mosaic of lamellar and woven bone. Although we find this loss of anisotropic alignment produces a straighter crack path in mechanically-loaded PDB cases, cortical fracture toughness appears to be maintained due to increased plastic deformation. Clearly, the altered quality of the bone structure in PDB affects the mechanical integrity leading to complications such as bowing, deformities, and stable cracks called fissure fractures associated with this disease. Although the lower mineralization and loss of aligned Haversian structures do produce a lower modulus tissue, which is susceptible to deformities, our results indicate that the higher levels of plasticity may compensate for the lost microstructural features and maintain the resistance to crack growth.

Paget disease of bone: A classic case report

Paget disease of bone (PDB) is a chronic progressive disease of the bone of uncertain etiology, characterized initially by an increase in bone resorption, followed by a disorganized and excessive formation of bone, leading to pain, fractures, and deformities. It can manifest as a monostotic or polyostotic disease. The prevalence of PDB is common in the Anglo-Saxon population, but relatively rare in India. The disease is often asymptomatic and commonly seen in an aging population. The diagnosis of the disease is mostly based on radiological examination and on biochemical markers of bone turnover. Markedly elevated serum alkaline phosphatase (SAP) is a constant feature while calcium and phosphate levels are typically within normal limits. It is being successfully treated by biphosphonates, a group of anti-resorptive drugs, thereby decreasing the morbidity and mortality associated with the disease. We report a classic case of PDB with craniofacial involvement resulting in Leontiasis Ossea (lion like face), cotton wool appearance of the skull and elevated SAP.

Giant cell tumor occurring in familial Paget's disease of bone: Report of clinical characteristics and linkage analysis of a large pedigree

Neoplastic degeneration represents a rare but serious complication of Paget's disease of bone (PDB). Although osteosarcomas have been described in up to 1% of PDB cases, giant cell tumors are less frequent and mainly occur in patients with polyostotic disease. We recently characterized a large pedigree with 14 affected members of whom four developed giant cell tumors at pagetic sites. The high number of affected subjects across multiple generations allowed us to better characterize the clinical phenotype and look for possible susceptibility loci. Of interest, all the affected members had polyostotic PDB, but subjects developing giant cell tumors showed an increased disease severity with a reduced clinical response to bisphosphonate treatment and an increased prevalence of bone pain, deformities, and fractures. Together with an increased occurrence of common pagetic complications, affected patients of this pedigree also evidenced a fivefold higher prevalence of coronary artery disease with respect to either the unaffected family members or a comparative cohort of 150 unrelated PDB cases from the same geographical area. This association was further enhanced in the four cases with PDB and giant cell tumors, all of them developing coronary artery disease before 60 years of age. Despite the early onset and the severe phenotype, PDB patients from this pedigree were negative for the presence of SQSTM1 or TNFRSF11A mutations, previously associated with enhanced disease severity. Genome-wide linkage analysis identified six possible candidate regions on chromosomes 1, 5, 6, 8, 10, and 20. Because the chromosome 8 and 10 loci were next to the TNFRSF11B and OPTN genes, we extended the genetic screening to these two genes, but we failed to identify any causative mutation at both the genomic and transcription level, suggesting that a different genetic defect is associated with PDB and potentially giant cell tumor of bone in this pedigree.

Archaeological skeletons support a northwest European origin for Paget's disease of bone

The strong genetic component in the etiology of Paget's disease of bone (PDB), together with marked geographic variation in its prevalence, with high frequencies in British populations, has led some to suggest that the disease originated in Britain and spread around the world in recent times by the migration and admixture of British populations. This study aims to investigate this hypothesis by studying the world geographic distribution of PDB cases identified in ancient skeletons excavated from archaeological sites. The methodology is a review of PDB cases described in the literature. There were 109 cases that met modern diagnostic criteria. All came from Western Europe, 94% from England. These data support the hypothesis that PDB originated in this geographic region.

Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone

Paget’s disease of bone (PDB) is a common disorder with a strong genetic component characterised by focal increases in bone turnover which in some cases is caused by SQSTM1 mutations. To identify additional susceptibility genes we performed a genome wide association study in 750 PDB cases without SQSTM1 mutations and 1002 controls and identified three candidate loci for the disease which were replicated in an independent set of 500 cases and 535 controls. The strongest signal was with rs484959 on 1p13 close to the CSF1 gene (P = 5.38 × 10−24) and significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 × 10−13) and with rs3018362 on 18q21 close to the TNFRSF11A gene (P = 5.27 × 10−13). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as novel candidate genes for disease susceptibility.

Founder Effect in Different European Countries for the Recurrent P392L SQSTM1 Mutation in Paget’s Disease of Bone

Paget's Disease of Bone (PDB) is one of the most frequent metabolic bone diseases, affecting 1-5% of Western populations older than 55 years. Mutations in the sequestosome1 (SQSTM1) gene cause PDB in about one-third of familial PDB cases and in 2.4-9.3% of nonfamilial PDB cases, with the 1215C-->T (P392L) mutation being the most frequent one. We investigated whether a founder effect of the P392L SQSTM1 mutation was present in Belgian (n = 233), Dutch (n = 82), and Spanish (n = 64) patients without a PDB family history. First, direct sequencing analysis of exon 8 in these three populations showed that the P392L mutation occurred in 17 Belgian patients (7.3%), three Dutch patients without a family history (3.7%), and two Dutch patients with a family history. In the Spanish population, 15.6% of patients (n = 10) had the P392L mutation, including one homozygous mutant. This is by far the highest mutation frequency of all populations investigated so far. Next, we examined the genetic background of 33 mutated chromosomes by analyzing haplotypes. We genotyped four single-nucleotide polymorphisms (SNPs) in exon 6 and the 3'-untranslated region of SQSTM1 (rs4935C/T, rs4797G/A, rs10277T/C, and rs1065154G/T) and used software programs WHAP and PHASE to reconstruct haplotypes. Finally, allele-specific primers allowed us to assign the mutation to one of the two haplotypes from each individual. Sequencing results revealed that all 33 P392L mutations were on the CGTG (H2) haplotype. The chance to obtain this result due to 33 independent mutation events is 3.97 x 10(-14), providing strong evidence for a founder effect of the P392L SQSTM1 mutation in Belgian, Dutch, and Spanish patients with PDB.

Paget's Disease of Bone in Italy

Epidemiological studies of Paget's disease of bone (PDB) suggest a pronounced geographical variation in the prevalence of the disease and a decrease in prevalence and clinical severity over time. To analyze epidemiological and clinical features of PDB in Italy, we recently established a registry of Italian PDB cases and performed radiological, biochemical, and bone scan surveys in the towns of Siena and Turin. The overall prevalence of PDB in Italy varied between 0.7% and 2.4%. Prevalence rates increased with age and were higher in men than in women. We observed clinically confirmed familial aggregation in 15-26% of cases. Pedigree analysis indicated an autosomal dominant pattern of inheritance with variable penetrance. SQSTM1 gene analysis in two Italian studies revealed the presence of at least three different mutations accounting for both familial and sporadic cases. Interestingly, no decrease in the prevalence of PDB over time was observed, the opposite of what is described in populations of British descent. However, clinical severity of PDB cases included in the Registry in 2002-2004 seemed reduced with respect to that of PDB patients from the previous epidemiological studies, including a 1950-1956 Italian study. Of interest, a consistent association between PDB and animal-related factors and a significantly higher prevalence of the disease in rural than in urban districts were observed. These findings are in keeping with an important role of the environment in the pathogenesis of PDB, perhaps facilitating the expression of the disease in genetically susceptible subjects. Finally, there was also preliminary evidence indicating regional clustering of PDB in Italy, with a concentration of cases in rural districts of Campania and Tuscany. These districts may represent high prevalence areas of PDB in Italy, similar to what has been observed in other countries. Extrapolation estimates suggest that approximately 150,000-300,000 subjects may be affected with PDB in our country. These results confirm PDB to be the most common bone remodeling disorder in elderly people in Italy, excluding osteoporosis.

Sequestosome 1: Mutation Frequencies, Haplotypes, and Phenotypes in Familial Paget's Disease of Bone

Mutations of the SQSTM1/p62 gene are commonly observed in PDB. Screening an updated sample from Quebec and using previously published data from other populations, we compared frequency estimates for SQSTM1/p62 mutations and haplotype distribution. The P392L mutation was the most prevalent, embedded in two different haplotypes, possibly shared by other populations. We also examined the phenotype and penetrance of P392L. There is accumulating evidence that supports a contribution of genetic factors in the etiology of Paget's disease of bone (PDB), and several genetic loci have been suggested for the disorder. The sequestosome1/p62 (SQSTM1/p62) gene was the first gene identified to have a role in PDB, with 14 mutations reported to date. To evaluate the importance of the SQSTM1/p62 mutations in PDB, we recruited, sequenced, and genotyped a total of 123 carriers from 20 families in addition to 214 unrelated PDB patients. We compared the frequency of SQSTM1/p62 mutations in familial and unrelated cases among different populations. Finally, we examined the phenotypic expression and penetrance of the P392L mutation in the Quebecois families. The 14 mutations reported in SQSTM1/p62 all affect the ubiquitin-associated domain of the protein. The P392L mutation is the most commonly observed mutation in PDB patients and was consistently found in unrelated and familial PDB cases in the populations tested. Analysis of adjacent polymorphisms suggests that P392L is associated with two different haplotypes in the Quebecois patients, similar to what has been observed in European populations. In Quebec, both haplotypes had similar frequencies in unrelated P392L carriers, whereas one haplotype was predominant in the other populations studied. These data suggest that these two haplotypes, possibly introduced by European founders in the Quebecois population, were equally distributed in the succeeding generations. Finally, the P392L mutation is transmitted as an autosomal dominant trait in the Quebecois families, with a high but incomplete penetrance peaking after age 60. The large phenotypic variability and similarity between unrelated and familial cases, respectively, remain unexplained and require further research.

Evidence for Increased Clinical Severity of Familial and Sporadic Paget's Disease of Bone in Campania, Southern Italy

The analysis of 236 Italian patients with Paget's bone disease showed higher clinical severity and greater frequency of neoplastic degeneration among patients who live or descend from individuals living in the Campania region (southern Italy). A prevalent involvement of the spine and the skull, the sites preferentially involved in giant cell tumors complicating Paget's disease, was also shown in familial cases from this geographical region. The Campania region in southern Italy has been recently indicated as a high prevalence area for Paget's disease of bone (PDB), and most pagetic families with multiple occurrence of neoplasms in affected members were from this geographical region. We evaluated the PDB epidemiological characteristics in 125 patients from Campania in comparison with 111 patients from other Italian regions. Twenty-three patients from Campania and 26 patients from other Italian areas had at least one first-degree relative affected by PDB (familial cases). The remaining patients made up the sporadic cases. Among subjects from Campania, the patients in the familial group tended to come from larger families and showed at diagnosis higher serum total alkaline phosphatase, larger extension of disease, and earlier mean age with respect to patients with PDB of the sporadic group. The skull, spine, and humerus were the sites preferentially involved in the familial cases. In contrast, no such differences were observed between familial and sporadic PDB cases among patients from the other geographical areas, except for a lower age at diagnosis. An increased PDB clinical severity was finally observed in the PDB cohort from Campania in comparison with patients from other Italian regions. Neoplastic degeneration of pagetic bones (osteosarcoma and giant cell tumor) was exclusively observed in patients with polyostotic PDB from Campania. We showed a higher clinical severity of PDB with occurrence of neoplastic degeneration in the high prevalence area of Campania, with its maximum expression in cases with familial disease. This peculiar pattern might be traced to genetic predisposition and/or to the abnormal impact of a still undefined environmental trigger.

Serum OPG and RANKL levels before and after intravenous bisphosphonate treatment in Paget's disease of bone

Paget's disease of bone (PDB) is a focal disorder of bone remodeling characterized by increased osteoclast-mediated bone resorption. Even though increasing evidence indicates enhanced nuclear factor-kB (NF-kB) signaling as a common mechanism involved in PDB and other related disorders, few studies investigated circulating osteoprotegerin (OPG) and receptor of activator of NF-kB-ligand (RANKL) levels in PDB patients. In this study we explored the relationships between OPG or RANKL levels and bone turnover markers in a group of patients with PDB, before and after intravenous bisphosphonate treatment (pamidronate 60 mg). Both OPG and RANKL were markedly elevated in PDB patients with respect to control groups (healthy or osteoporotic postmenopausal women and elderly men) and were positively associated with bone turnover markers. Higher levels of these cytokines were observed in polyostotic than monostotic PDB cases. The ratio between RANKL and OPG was more than 3-fold higher in PDB patients than in controls. Interestingly, in the group of patients treated with pamidronate, we found an increase in OPG levels that become statistically significant after 3 and 6 months from treatment. A trend toward a decrease in RANKL levels after treatment was also observed. The RANKL/OPG ratio was significantly reduced after 3 and 6 months of therapy. In contrast, in patients classified as non-responders, OPG and RANKL levels after pamidronate infusion did not significantly differ with respect to pre-treatment values. Thus, the positive effect of amino bisphosphonates in the treatment of PDB may be due to either direct or indirect suppression of RANKL-induced bone resorption through decreased RANKL and increased OPG production.

Prevalence of Paget's Disease of Bone in Italy

We examined the prevalence of PDB in Italy from radiological, scintigraphic, and biochemical surveys in two Italian towns. Prevalence rates varied from 0.7% to 2.4%, were higher in males than in females, and slightly differed between the two towns. Unlike previous studies in populations of British descent, no secular trend for a decreasing prevalence emerged. Clinical, radiological, and necropsy data from different countries suggested pronounced geographical variations in the prevalence of Paget's disease of bone (PDB). Despite the impact of the disease on the population, there are limited data on the prevalence of PDB in Italy. The objective of this study was to estimate the prevalence of PDB in the district of Siena (Central Italy) and Turin (Northern Italy) from radiological, biochemical, and scintigraphic surveys. We examined a sample of 1778 consecutive pelvic radiographs performed between 1999 and 2000 at the Hospital Radiology Unit in Siena and 6609 pelvic radiographs performed in 1986-1987, 1992-1993, and 1999-2002 from the Radiology Department of Molinette Hospital in Turin. In Siena, 7906 consecutive (99m)TC-MDP bone scans performed over a 4-year period (January 2000 to May 2004) were also screened for the presence of PDB, and the prevalence of elevated alkaline phosphatase (ALP) levels (>300 UI/liter) was estimated from 7449 computerized medical records over a 3-year period (January 2000 to February 2003). The finding of PDB on the pelvic radiograph and bone scan was based on standardized radiological criteria. At the end of the radiological surveys, 16/1778 pelvic PDB cases (8 males and 8 females) were observed in Siena and 41/6609 (27 males and 14 females) in Turin. The crude prevalence of the disease was 0.89% in Siena and 0.62% in Turin. Given that pelvic involvement is commonly described in 60-90% of PDB patients, the estimated overall prevalence of PDB ranged from 1.0% to 1.5% in Siena and from 0.7% to 1.0% in Turin. No decrease in the prevalence of PDB was evident after comparison of prevalence rates from different periods. Biochemical analyses showed 296/7449 subjects with elevated ALP levels and normal liver enzymes, 87 of whom had confirmed diagnosis of PDB. The estimated prevalence of biochemical PDB was 1.5%. The scintigraphic survey showed a PDB prevalence of 194/7906 (2.4%), which was significantly higher than the radiological and biochemical estimates. Our surveys suggest that PDB in Italy has an estimated prevalence of at least 1%, comparable with that observed in United States and other European countries, but lower than that described in Britain and New Zealand. No secular trend for a decreasing prevalence of PDB was observed.

Genetics of Paget's disease of bone

PDB (Paget's disease of bone) is a common condition characterized by focal increases in bone turnover affecting one or more sites throughout the skeleton. Genetic factors are important in the pathogenesis of PDB and many families have been described where PDB is inherited in an autosomal-dominant fashion. Several candidate loci for susceptibility to PDB and related syndromes have been identified by genome-wide scans and recent evidence suggests that mutations in genes that encode components of the RANK [receptor activator of NF-kappaB (nuclear factor-kappaB)]/NF-kappaB signalling pathway play an important role in the pathogenesis of this group of diseases. Insertion mutations in the TNFRSF11A gene encoding RANK have been identified as the cause of familial expansile osteolysis, some cases of early onset PDB and expansile skeletal hyperphosphatasia. Inactivating mutations in the TNFRSF11B gene that encodes OPG (osteoprotegerin) have been found to cause the syndrome of juvenile PDB. Polymorphisms in OPG also appear to increase the risk of developing PDB. The most important causal gene for classical PDB is Sequestosome 1 (SQSTM1), which is a scaffold protein in the NF-kappaB signalling pathway, and mutations affecting the UBA (ubiquitin-associated) domain of this protein occur in between 20-50% of familial and 10-20% of sporadic PDB cases. The rare syndrome of IBMPFD (inclusion body myopathy, PDB and fronto-temporal dementia) is due to mutations in the VCP gene and these also cluster in the domain of VCP that interacts with ubiquitin, suggesting a common disease mechanism with SQSTM1-mediated PDB.

Characteristics and Familial Aggregation of Paget's Disease of Bone in Italy

This study examined the characteristics of 147 PDB cases from Italy. Our data showed a reduced clinical severity of PDB with respect to other populations and provided further support of the importance of environmental factors (rural area of residence and animal contact) in the pathogenesis of PDB. Familial aggregation was observed in 15% of cases. The etiology of Paget's disease of bone (PDB) remains unknown. Current evidence suggests that interactions among genetic or exogenous factors seem to be necessary for disease expression. Major epidemiological studies were performed in the United Kingdom and in other populations of British descent. To date, there are no reliable data on PDB characteristics among the Italian population, and its frequency in different areas of the country remains unknown. In an attempt to evaluate clinical characteristics, the proportion of familial cases and the influence of environmental features on the occurrence of the disease, we studied 147 consecutive PDB patients. For all subjects, a detailed medical history was obtained, and constitutional features were recorded. Characteristics of PDB patients were compared with those obtained from 323 consecutive non-Pagetic outpatient control subjects. Of the 147 PDB patients, 22 (15%) had at least one other family member affected, 19 (13%) reported one family member with suspected features of PDB, and 106 (72%) were classified as sporadic PDB. Even though we observed a reduced clinical severity of PDB with respect to other populations (mean number of affected sites, 2.2 +/- 1.6), we did not find any evidence of a decreased severity of the disease over time. We also found an association of PDB with animal contact (odds ratio [OR], 2.22; p < 0.0005) and a significant prevalence of PDB in rural versus urban districts (OR, 2.42; p < 0.0005). Osteoarthritis (45%), fractures (14%), hearing loss (14%), and valvular calcifications (15%) were the most observed complications. Interestingly, the geographical distribution of PDB showed a concentration of cases in rural areas of Campania and Tuscany. These areas may indicate local clustering of PDB cases in Italy, similar to that observed in other countries.

Ubiquitin-Associated Domain Mutations of SQSTM1 in Paget's Disease of Bone: Evidence for a Founder Effect in Patients of British Descent

Mutations in the UBA domain of SQSTM1 are a common cause of Paget's disease of bone. Here we show that the most common disease-causing mutation (P392L) is carried on a shared haplotype, consistent with a founder effect and a common ancestral origin. Paget's disease of bone (PDB) is a common condition with a strong genetic component. Mutations affecting the ubiquitin-associated (UBA) domain of sequestosome 1 (SQSTM1) have recently been shown to be an important cause of PDB. The most common mutation results in a proline to leucine amino acid change at codon 392 (P392L), and evidence has been presented to suggest that there may be a recurrent mutation rather than a founder mutation on an ancestral chromosome. Because marked geographical differences exist in the prevalence of PDB, we have investigated the frequency of SQSTM1 mutations in different populations and looked for a founder effect on chromosomes bearing SQSTM1 UBA domain mutations. We conducted mutation screening of SQSTM1 and performed haplotype analysis using the PHASE software program in 83 kindreds with familial PDB, recruited mainly through clinic referrals in the United Kingdom, Australia, and New Zealand. Similar studies were conducted in 311 individuals with PDB who did not have a family history and 375 age- and sex-matched controls from the United Kingdom. The proportion of patients with familial PDB who had SQSTM1 UBA domain mutations varied somewhat between referral centers from 7.1% (Sydney, Australia) to 50% (Perth, Australia), but the difference between centers was not statistically significant. Haplotype analysis in 311 British patients with PDB who did not have a family history and 375 age- and sex-matched British controls showed that two common haplotypes accounted for about 90% of alleles at the SQSTM1 locus, as defined by common single nucleotide polymorphisms (SNPs) in exon 6 (C916T, G976A) and the 3'UTR (C2503T, T2687G). These were H1 (916T-976A-2503C-2687T) and H2 (916C-976G-2503T-2687G). There was no significant difference in haplotype distribution in PDB cases and controls, but the P392L mutation was found on the H2 haplotype in 25/27 cases (93%), which is significantly more often than expected given the allele frequencies in the normal population (odds ratio, 13.2; 95% CI, 3.1-56.4; p < 0.0001). Similar findings were observed in familial PDB, where 12/13 (92%) of P392L mutations were carried on H2 (odds ratio 17.2; 95% CI, 2.2-138; p = 0.001). These results provide strong evidence for a founder effect of the SQSTM1 P392L mutation in PDB patients of British descent, irrespective of family history. Our results imply that these individuals share a common ancestor and that the true rate of de novo mutations may be lower than previously suspected.

Susceptibility to Paget's disease of bone is influenced by a common polymorphic variant of osteoprotegerin.

To clarify the role of the TNFRSF11B gene encoding osteoprotegerin (OPG), in Paget's disease of bone (PDB) we studied TNFRSF11B polymorphisms in an association study of 690 UK subjects and in a worldwide familial study of 66 kindreds. We found that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to both sporadic and familial PDB. Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of bone turnover. Genetic factors are important in the pathogenesis of PDB, and studies have shown that inactivating mutations of the TNFRSF11B gene, encoding osteoprotegerin (OPG), cause the rare syndrome of juvenile Paget's disease. In this study, we sought to determine whether polymorphisms of the TNFRSF11B gene contribute to the pathogenesis of classical PDB. We screened for polymorphisms of the TNFRSF11B gene by DNA sequencing of the proximal promoter, coding exons, and intron-exon boundaries in 20 PDB patients and 10 controls. Informative single nucleotide polymorphisms (SNPs), including a G1181C SNP, which predicts a lysine-asparagine substitution at codon 3 of the OPG signal peptide and haplotypes, were related to the presence of PDB in 312 cases compared with 378 controls and to transmission of PDB in 140 affected offspring from 66 kindreds with familial PDB. The G1181 allele was significantly over-represented in PDB patients (chi(2) = 5.7, df = 1, p = 0.017, adjusted alpha = 0.024), equivalent to an odds ratio for PDB of 1.55 (95% CI: 1.11-2.16). The distribution of TNFRSF11B haplotypes significantly differed in sporadic PDB cases and controls (chi(2) = 30.2, df = 9, p < 0.001) because of over-representation of haplotypes containing the G1181 allele in cases. The family study showed that the most common haplotype containing the G1181 allele was transmitted more frequently than expected to 140 individuals with familial PDB (chi(2) = 7.35, df = 1, p < 0.01), and the transmission disequilibrium was even more pronounced in a subgroup of 78 familial PDB patients who did not carry mutations of the SQSTM1 gene (chi(2) = 8.44, df = 1, p < 0.005). We conclude that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to the development of sporadic PDB and familial PDB that is not caused by SQSTM1 mutations.