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Evolution of Paget's disease of bone in adults inheriting SQSTM 1 mutations
Author(s) -
Cundy Tim,
Rutland Michael D.,
Naot Dorit,
Bolland Mark
Publication year - 2015
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/cen.12741
Subject(s) - protein data bank (rcsb pdb) , paget's disease of bone , offspring , medicine , proband , asymptomatic , population , context (archaeology) , disease , endocrinology , physiology , mutation , biology , genetics , pregnancy , biochemistry , gene , environmental health , paleontology
Summary Context The cause of Paget's disease of bone ( PDB ) is unknown, but genetic factors, particularly SQSTM 1 mutations, and environmental factors are important. Objective To investigate the development of PDB in asymptomatic relatives carrying SQSTM 1 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 SQSTM 1 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 SQSTM 1 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.