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Paget's disease of bone

Written2013-04Stuart H Ralston
Rheumatic Diseases Unit, Institute of Genetics, Molecular Medicine, University of Edinburgh, Scotland

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Identity

Other namesosteitis deformans
Atlas_Id 10057
Genes implicated inSQSTM1  
Inheritance Autosomal dominant; polygenic.

Clinics

Note A family history is found in approximately 15% of cases. In such families, the disease is inherited as an autosomal dominant trait with about 80-90% penetrance by the age of 70. About 50% of patients with familial PDB have a mutation in the SQSTM1 gene and in others there is linkage to a locus on chromosome 10p13 (Lucas et al., 2008). The gene responsible in this locus remains to be identified. There also may be familial clustering without a clear patten of inheritance consistent with polygenic inheritance. Common genetic variants at seven loci have been identified that predispose to Paget's disease (Albagha et al., 2011; Albagha et al., 2010), but the causal variants have not been identified. Overall relatives of patients with Paget's have 7-fold increase risk of developing the disease as compared with the general population.
Phenotype and clinics The disease is characterised by focal bone lesions in which there is increased osteoclastic bone resorption coupled with increase and disorganised new bone formation (Ralston, 2013). The axial skeleton is predominantly affected. The most common sites are the pelvis, spine, femurs, skull and tibia. Many patients are asyptomatic and a common mode of presentation is with an abnormal serum alkaline phosphatase picked up on routine blood tests or an abnormal radiograph. The most common complaint in patients who come to medical attention is bone pain. Other common complications include pathological fractures, bone deformity, deafness (when the base of the skull is involved), secondary osteoarthritis, and nerve compression syndromes (van Staa et al., 2002). Rare complications include hypercalcaemia which can occur if the patient is immobilised and dehydrated and high output cardiac failure due to increased blood flow through affected bone.
Neoplastic risk The risk of osteosarcoma is increased and it has been estimated to occur in about 0.3% of patients (Mangham et al., 2009). This represents more than one thousand fold increase in risk as compared with adults in the general population (van Staa et al., 2002). The osteosarcoma arises in affected bones.
Treatment Paget's disease can be treated with bisphosphonates which supress the elevated bone turnover and can improve pain. Orthopaedic surgery may be required for the treatment of fractures, secondary osteoarthritis and spinal stenosis. Surgical excision and chemotherapy may be required for osteosarcoma.
Prognosis Bisphosphonates are often effective at helping bone pain but it is uncertain at present if they alter the natural history of Paget's or prevent complications. The prognosis is poor for patients who develop osteosarcoma, even with agressive treatment (Sharma et al., 2005).

Cytogenetics

Note No cytogenetic abnormalities have been identified in Paget's.
Cytogenetics of cancer Multiple chromosomal abberations have been described in osteosarcoma, but none are specific for Paget's disease.

Genes involved and Proteins

Gene NameSQSTM1 (sequestosome 1)
Location 5q35.3
DNA/RNA
Note The human gene contains 8 exons and spans 31.6 Kb of genomic DNA. There are three mRNA transcripts. The predominant transcript is NM_003900 which comprises 2923 bp. Two other transcripts have been identified. One (NM_001142298.1) of 2931 bp differs from NM_003900 in the 5' UTR, lacks a portion of the 5' coding region, and initiates translation from an in-frame downstream start codon compared to another variant 1. This results in an isoform with a shorter N-terminus compared to NM_003900. A third transcript (NM_001142299) of 2848 bp differs from NM_001142298.1 in the 5'UTR, but encodes the same protein isoform.
Protein
Description The p62 protein contains 440 amino acids and has a mass of 47 Kda. It contains several domains, uncluding a TRAF-6 binding domain, a ubiquitin associated domain and SH2 domains.
Expression Widely expressed in many cells and tissues.
Function The p62 protein is an adaptor protein involved in NFkB signalling downstream of the RANK receptor, TNF receptor, IL-1 receptor and NGF receptor. In RANK signaling is responsible for recruiting CYLD to the intracellular receptor complex and this requires a functional UBA domain.
Mutations
Note More than 25 mutations of SQSTM1 have been described in Patients with Paget's disease and most of these affect the UBA domain (Ralston and Layfield, 2012). Functional analysis indicates that most mutations impair the ability of the UBA domain to bind ubiquitin chains (Goode and Layfield, 2010).

Bibliography

Genome-wide association identifies three new susceptibility loci for Paget's disease of bone.
Albagha OM, Wani SE, Visconti MR, Alonso N, Goodman K, Brandi ML, Cundy T, Chung PY, Dargie R, Devogelaer JP, Falchetti A, Fraser WD, Gennari L, Gianfrancesco F, Hooper MJ, Van Hul W, Isaia G, Nicholson GC, Nuti R, Papapoulos S, Montes Jdel P, Ratajczak T, Rea SL, Rendina D, Gonzalez-Sarmiento R, Di Stefano M, Ward LC, Walsh JP, Ralston SH; Genetic Determinants of Paget's Disease (GDPD) Consortium.
Nat Genet. 2011 May 29;43(7):685-9. doi: 10.1038/ng.845.
PMID 21623375
 
Recent advances in understanding the molecular basis of Paget disease of bone.
Goode A, Layfield R.
J Clin Pathol. 2010 Mar;63(3):199-203. doi: 10.1136/jcp.2009.064428. Epub 2009 Oct 26. (REVIEW)
PMID 19858527
 
Identification of a major locus for Paget's disease on chromosome 10p13 in families of British descent.
Lucas GJ, Riches PL, Hocking LJ, Cundy T, Nicholson GC, Walsh JP, Ralston SH.
J Bone Miner Res. 2008 Jan;23(1):58-63.
PMID 17907922
 
Sarcoma arising in Paget's disease of bone: declining incidence and increasing age at presentation.
Mangham DC, Davie MW, Grimer RJ.
Bone. 2009 Mar;44(3):431-6. doi: 10.1016/j.bone.2008.11.002. Epub 2008 Nov 19.
PMID 19064007
 
Pathogenesis of Paget disease of bone.
Ralston SH, Layfield R.
Calcif Tissue Int. 2012 Aug;91(2):97-113. doi: 10.1007/s00223-012-9599-0. Epub 2012 Apr 29. (REVIEW)
PMID 22543925
 
Clinical practice. Paget's disease of bone.
Ralston SH.
N Engl J Med. 2013 Feb 14;368(7):644-50. doi: 10.1056/NEJMcp1204713. (REVIEW)
PMID 23406029
 
Sarcomatous change in the Pagetoid tibiae.
Sharma H, MacDuff E, Jane MJ, Reid R.
Int Orthop. 2005 Oct;29(5):319-25. Epub 2005 Aug 11.
PMID 16094541
 
Incidence and natural history of Paget's disease of bone in England and Wales.
van Staa TP, Selby P, Leufkens HG, Lyles K, Sprafka JM, Cooper C.
J Bone Miner Res. 2002 Mar;17(3):465-71.
PMID 11878305
 

Citation

This paper should be referenced as such :
Ralston, SH
Paget's disease of bone
Atlas Genet Cytogenet Oncol Haematol. 2013;17(10):726-727.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Tumors/PagetDiseaseID10057.html


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