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

Paget's disease of bone (PDB) is a common chronic bone disorder. In the French-Canadian population, the p.Pro392Leu mutation within the SQSTM1 gene is involved in 46% of familial forms. In New Zealand, the emergence of PDB in offspring inheriting SQSTM1 mutations was reported to be delayed by a decade compared to their parents. We aimed at assessing the clinical phenotype of offspring carriers of this mutation in our French-Canadian cohort. We reviewed research records from adult offspring carriers of this mutation aged <90 years and their affected parents. In parents, we collected data on sex, age at diagnosis, number of affected bones, total serum alkaline phosphatase levels (tALPs) at diagnosis. In offspring, PDB extended phenotype assessment relying on tALPs, bone specific alkaline phosphatase levels (bALPs), procollagen type 1 amino-terminal propeptide (P1NP), whole body bone scan and skull and pelvis radiographs, was performed at inclusion from 1996 to 2009 and updated in 2016 to 2018, if not done during the past 8 years. The results showed that among the 36 offspring with an updated phenotype, four of them developed a clinical phenotype of PDB characterized by monostotic or polyostotic increased bone uptake associated with typical radiographic lesions in the affected sites, representing an incidence of 1.83 per 1000 person-years. Moreover, the age at PDB diagnosis was delayed by at least 10 years in the adult offspring carriers of the p.Pro392Leu mutation versus their affected parents. Our findings support the utility of a regular monitoring of the adult offspring without PDB but carriers of this mutation.