Familial Paget's Disease in The Netherlands: Occurrence, Identification of New Mutations in the Sequestosome 1 Gene, and Their Clinical Associations

Objective. To estimate the occurrence of familial Paget's disease of bone in The Netherlands, to examine the prevalence of mutations of the sequestosome 1 gene (SQSTM1) in identified families, and to assess potential genotype-phenotype associations. Methods. We performed a case-control study of patients with Paget's disease and a mutation analysis of the SQSTM1 gene of index patients with familial disease and of the relatives of those with a mutation. Serum alkaline phosphatase (AP) activity was assessed, and bone scintigraphy was performed. Results. Five percent of patients had at least 1 first-degree relative with the disease, compared with 0.5% of the controls (relative risk 10; 95% confidence interval 1.3-75.6). In 38.9% of patients with familial disease, heterozygous mutations in the SQSTM1 gene were identified. These were the previously described P392L mutation, which was present in 22.2% of patients, and 3 new mutations, S399P, G425R, M404T, 9 of which were present in 3 different families. All mutations were located in the ubiquitin-associated domain of the gene. There was a relationship between serum AP activity, as a marker of the disease, and the presence or absence of the G425R and P392L mutations, the subject's age, and the presence of Paget's disease. Conclusion. Our data provide further evidence of a causal role of SQSTM1 gene mutations in the pathogenesis of Paget's disease and allow the design of a strategy based on measurements of serum AP activity and age for investigating asymptomatic relatives of patients with familial Paget's disease of bone.