Characteristics of Early Paget's Disease in SQSTM1 Mutation Carriers: Baseline Analysis of the ZiPP Study Cohort

Abstract

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 AE SE age of 50.1 AE 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 AE 9.1 versus 49.8 AE 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 AE 0.69 versus 0.42 AE 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.

Clinical phenotype of adult offspring carriers of the p.Pro392Leu mutation within the SQSTM1 gene in Paget's disease of bone

“…In a 16-year period of follow-up in a Dutch cohort, one (12.5%) carrier of a mutation within the SQSTM1 gene developed the disease, but the bone scan was performed in this study only in participants who had raised levels of ALP or P1NP or both ( Peeters et al, 2019 ). The recent study of Cronin et al reported 20 participants (9%) carriers of a SQSTM1 mutation with asymptomatic PDB, based on bone scan only as radiographs of bones displaying uptake on bone scan were not performed in this study ( Cronin et al, 2020 ) ( Table 3 ).…”

Updates on Paget’s Disease of Bone

“…In this study, adults with a family history of PDB underwent genetic testing for SQSTM1 mutations, and those who tested positive were invited to participate in the randomized controlled trial of zoledronic acid or placebo to determine the treatment efficacy in preventing the onset of PDB [68]. Interestingly, the majority of individuals with lesions exhibited normal levels of the biochemical indicators of bone remodeling [69], as determined by an analysis of the baseline features. Guay-Belanger et al [70] combined a genetic screening test for SQSTM1 mutations with a test for biochemical markers associated with PDB as an alternative method.…”

Genetic Determinants of Paget’s Disease of Bone

“…In this study, adults who had a family history of PDB were offered genetic testing for SQSTM1 mutations, and those that tested positive were invited to take part in a randomised controlled trial of zoledronic acid or placebo with the aim of determining whether treatment was effective at preventing the development of PDB [ 92 ]. Analysis of baseline characteristics showed that about 9% of SQSTM1 mutation carriers had signs of PDB on bone scan but were asymptomatic, and interestingly, most people with lesions had normal levels of biochemical markers of bone remodelling [ 93 •]. The study remains in progress but is due to report during 2021.…”