Context: The cause of Paget's disease of bone (PDB) is unknown, but genetic factors, particularly SQSTM1 mutations, and environmental factors are important.
Objective: To investigate the development of PDB in asymptomatic relatives carrying SQSTM1 mutations to determine whether a secular trend towards a less severe phenotype is evident, and to estimate prospectively the rate at which PDB emerged in this genetically susceptible population.
Design: We recruited first-degree relatives of patients with PDB [33 adult offspring (mean age 45) and 1 sibling] with a familial SQSTM1 mutation. We determined the presence of PDB with skeletal scintiscans and confirmatory radiographs. Those negative for PDB on the initial scan were investigated again a mean 5·1 years later.
Results: The initial skeletal scintiscan demonstrated PDB in six subjects; 26 of the remaining 28 unaffected subjects had a second scintiscan, with two new cases of monostotic PDB diagnosed in 134 patient-years of follow-up. In the total eight adult offspring diagnosed with PDB, the age of diagnosis was greater, by at least 10 years, than that in the 21 probands with clinically identified PDB (P = 0·005). In adult offspring who were older at the time of skeletal scintigraphy than their affected parents were at the time of clinical diagnosis, the difference was even more marked (P < 0·001). In adult offspring with PDB, the disease was significantly less extensive than in their affected parent, as judged by alkaline phosphatase and disease extent (P < 0·003).
Conclusion: These findings suggest a substantial gene-environment interaction: the emergence of PDB in offspring inheriting SQSTM1 mutations is delayed by at least a decade, has a substantially attenuated phenotype and occurs at a low rate between the (mean) ages of 45 and 50 years. The nature of the environmental factor is unknown.
© 2015 John Wiley & Sons Ltd.