Delayed development of Paget's disease in offspring inheriting SQSTM1 mutations.
Familial Paget's disease is associated with mutations in SQSTM1. We compared the age at diagnosis and severity of Paget's disease in parents with SQSTM1 mutations to their offspring who inherited a mutation. At any given age, the offspring were less likely to be diagnosed with Paget's disease and had less severe disease than their parents.


BACKGROUND
Mutations in sequestosome 1 (SQSTM1) occur in 25-50% of cases of familial Paget's disease and are thought to be disease-causing. We sought to determine whether there are differences in age at diagnosis and severity of disease in parents and their offspring who share the same genetic predisposition to Paget's disease.


METHODS
Eighty-four offspring from 10 families (29 index patients with Paget's disease) with mutations in SQSTM1 were approached, and 58 agreed to participate. The ubiquitin-binding domain region of SQSTM1 was sequenced, and the presence or absence of the known mutation was established. The presence of Paget's disease in offspring who had inherited an SQSTM1 mutation was determined by bone scintigraphy and measurement of serum alkaline phosphatase (ALP).


RESULTS
Twenty-three of 58 offspring had inherited a germline mutation in SQSTM1. The mean ALP was 77 U/liter in offspring with mutations and 72 U/liter in those without mutations (p=0.84). Scintiscans from four offspring (mean age, 45 years; mean ALP, 139 U/liter; mean skeletal involvement, 6%) showed evidence of Paget's disease but were normal in the other 19 (mean age, 44 years; mean ALP, 64 U/liter). In comparison, in the 15 parents of the 23 offspring, the mean age of diagnosis was 48 years, the mean ALP was 850 U/liter, and the mean skeletal involvement was 30%. There was a 63% reduction in the risk of being diagnosed with Paget's disease at a comparable age in the offspring compared with the parents (p=0.028).


CONCLUSIONS
Only 17% of offspring inheriting an SQSTM1 mutation had evidence of Paget's disease on scintigraphy, and this was diagnosed at a later age and was less extensive than in their affected parents. SQSTM1 thus shows incomplete penetrance. The data are consistent with the hypothesis that an environmental factor is important in the pathogenesis and clinical phenotype of familial Paget's disease and that exposure to this factor may be falling.
Bolland
Mark J
MJ
Department of Medicine, University of Auckland, New Zealand. m.bolland@auckland.ac.nz
Tong
Pak Cheung
PC
Naot
Dorit
D
Callon
Karen E
KE
Wattie
Diana J
DJ
Gamble
Greg D
GD
Cundy
Tim
T
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D017668:Age of Onset; D000469:Alkaline Phosphatase / Q000097:blood; D004781:Environmental Exposure; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010001:Osteitis Deformans / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D000071456:Sequestosome-1 Protein
D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D000469:Alkaline Phosphatase