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 ).…”

Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget’s disease of bone

“…We believe that a bone scan is an essential component of the proposed management pathway since our previous study demonstrated that biochemical markers of bone turnover had poor sensitivity and specificity in detecting PDB-like bone lesions in this patient group. 17 The study has also shown that a single infusion of ZA is well tolerated and that it can favourably modify the raised bone turnover that is characteristic of active disease, as reflected by bone scan appearances and biochemical markers of bone turnover.…”

Diagnosis and treatment of Paget’s disease of bone: position paper from the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases (SIOMMMS)

“…In case high t-ALP levels are identified (or in any case of increased bone turnover), the diagnostic procedure to be followed will be the same described above, in section 4.2.3. Concerning the use of t-ALP for this specific setting, it should be, however, underlined that, albeit it represents a valuable marker, normal t-ALP levels can be also found in patients with PDB, particularly in case of monostotic forms [ 23 ], as well as in asymptomatic cases with early PDB and a positive family history [ 52 ]. In this respect, either uNTx or P1NP demonstrated a better predictive value in identifying early cases with pagetic lesions [ 52 ].…”