Characteristics of early Paget's disease in SQSTM1 mutation carriers: Baseline analysis of the ZiPP study cohort

Owen Cronin, Deepak Subedi, Laura Forsyth, Kirsteen Goodman, Steff C. Lewis, Catriona Keerie, Allan Walker, Mary Porteous, Roseanne Cetnarskyj, Ranganath Lakshminarayan, Peter Selby, Geeta Hampson, Rama Chandra, Shu Ho, Jon Tobias, Steven Young Min, Malachi McKenna, Rachel Crowley, William D. Fraser, Jonathan TangLuigi Gennari, Rannuccio Nuti, Maria-Luisa Brandi, Javier Del Pino-Montes, Jean-Pierre Devogelaer, Anne Durnez, Giovanni Carlo Isaia, Marco Di Stefano, Josep Blanch Rubio, Nuria Guanabens, Markus Seibel, John P. Walsh, Mark A. Kotowicz, Geoffrey C. Nicholson, Emma L. Duncan, Gabor Major, Ann Horne, Nigel Gilchrist, Stuart H. Ralston (Lead / Corresponding author)

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    Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB), but little is known about the clinical characteristics of those with early disease. Radionuclide bone scans, biochemical markers of bone turnover, and clinical characteristics were analyzed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study. We studied 222 individuals, of whom 54.9% were female, with mean ± SE age of 50.1 ± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu, which was present in 141 of 222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%), ten of whom (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 versus 49.8 ± 8.9; p = .07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years versus 59 years, p = .17). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalized to the upper limit of normal in each center were higher in those with lesions (0.75 ± 0.69 versus 0.42 ± 0.29 arbitary units; p < .0001). Similar findings were observed for other biochemical markers of bone turnover, but the sensitivity of ALP and other markers in detecting lesions was poor. Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow-up of this cohort will provide important information on the natural history of early PDB and its response to treatment. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

    Original languageEnglish
    Pages (from-to)1246-1252
    Number of pages7
    JournalJournal of Bone and Mineral Research
    Issue number7
    Early online date16 Mar 2020
    Publication statusPublished - 1 Jul 2020


    • Paget's disease of bone
    • radionuclide imaging
    • SQSTM1
    • genetics


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