Delayed development of Paget's disease in offspring inheriting SQSTM1 mutations

Show simple item record Bolland, Mark en Tong, PC en Naot, Dorit en Callon, KE en Wattie, DJ en Gamble, Gregory en Cundy, Timothy en 2015-06-12T02:47:08Z en 2006-12-12 en 2007 en
dc.identifier.citation Journal of Bone and Mineral Research, 2007, 22 (3), pp. 411 - 415 (5) en
dc.identifier.issn 0884-0431 en
dc.identifier.uri en
dc.description.abstract Familial Paget's disease is associated with mutations in SQSTM1. We compared the age at diagnosis and severity of Paget's disease in parents with SQSTM1 mutations to their offspring who inherited a mutation. At any given age, the offspring were less likely to be diagnosed with Paget's disease and had less severe disease than their parents. Introduction: Mutations in sequestosome 1 (SQSTM1) occur in 25–50% of cases of familial Paget's disease and are thought to be disease-causing. We sought to determine whether there are differences in age at diagnosis and severity of disease in parents and their offspring who share the same genetic predisposition to Paget's disease. Materials and Methods: Eighty-four offspring from 10 families (29 index patients with Paget's disease) with mutations in SQSTM1 were approached, and 58 agreed to participate. The ubiquitin-binding domain region of SQSTM1 was sequenced, and the presence or absence of the known mutation was established. The presence of Paget's disease in offspring who had inherited an SQSTM1 mutation was determined by bone scintigraphy and measurement of serum alkaline phosphatase (ALP). Results: Twenty-three of 58 offspring had inherited a germline mutation in SQSTM1. The mean ALP was 77 U/liter in offspring with mutations and 72 U/liter in those without mutations (p = 0.84). Scintiscans from four offspring (mean age, 45 years; mean ALP, 139 U/liter; mean skeletal involvement, 6%) showed evidence of Paget's disease but were normal in the other 19 (mean age, 44 years; mean ALP, 64 U/liter). In comparison, in the 15 parents of the 23 offspring, the mean age of diagnosis was 48 years, the mean ALP was 850 U/liter, and the mean skeletal involvement was 30%. There was a 63% reduction in the risk of being diagnosed with Paget's disease at a comparable age in the offspring compared with the parents (p = 0.028). Conclusions: Only 17% of offspring inheriting an SQSTM1 mutation had evidence of Paget's disease on scintigraphy, and this was diagnosed at a later age and was less extensive than in their affected parents. SQSTM1 thus shows incomplete penetrance. The data are consistent with the hypothesis that an environmental factor is important in the pathogenesis and clinical phenotype of familial Paget's disease and that exposure to this factor may be falling. en
dc.language eng en
dc.publisher Wiley en
dc.relation.ispartofseries Journal of Bone and Mineral Research en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from en
dc.rights.uri en
dc.subject Paget's disease en
dc.subject sequestosome 1 en
dc.subject diagnosis en
dc.subject penetrance en
dc.title Delayed development of Paget's disease in offspring inheriting SQSTM1 mutations en
dc.type Journal Article en
dc.identifier.doi 10.1359/jbmr.061204 en
pubs.issue 3 en
pubs.begin-page 411 en
pubs.volume 22 en
dc.rights.holder Copyright: Wiley en
dc.identifier.pmid 17181397 en en
pubs.end-page 415 en
pubs.publication-status Published en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 69809 en Medical and Health Sciences en School of Medicine en Medicine Department en
dc.identifier.eissn 1523-4681 en
pubs.record-created-at-source-date 2010-09-01 en
pubs.dimensions-id 17181397 en

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