Familial Paget*s disease of bone: Long-term follow up of index families in the Netherlands

Paget*s disease of bone is a focal disorder of bone remodeling that progresses
slowly, leads to changes in the shape and size of affected bones and is
associated with to articular and vascular complications. The precise etiology
of the disease is unknown and the current view is that the disease is caused by
interactions between environmental and genetic factors, the nature of which
remains to be determined. In the only epidemiologic study conducted in the
Netherlands, which was performed by our group between 2000 and 2003, we
demonstrated that first-degree relatives of patients with Paget*s disease of
bone have a 10-fold higher risk of being affected by the disease, a risk
increase similar to that found in epidemiologic studies conducted in the UK and
the USA. In our study, we identified mutations in the SQSTM1 gene in 38.9% of
266 members of 20 families with Paget*s disease(LUMC protocol number P202/98
and P00-088-3). However, the disease was documented in a minority of these
subjects, particularly those who were older. It is well established that
Paget*s disease of bone seldom presents before the age of 45 years and that the
prevalence of the disease increases with age. We, therefore, hypothesize that
the identified younger subjects harboring the mutation will be more likely to
develop the disease in the course of time than subjects without the mutation.
In the present study we propose to test this hypothesis by re-evaluating all
subjects for the appearance of PDB 15 years after the initial assessment.
Furthermore since 2003 additional mutations have been identified and these
mutations will be checked in the subjects in whom no mutation was identified in
2003.

1. To investigate the presence of PDB in asymptomatic relatives of patients
with familial PDB who were investigated for a SQSTM1 mutation 10-15 years
previously but had no evidence of PDB .
2. To compare the risk of developing the disease between members of families
with PDB who are carriers versus non-carriers of a SQSTM1 mutation.
3. To asses the genetics of the non cariers with the current mutations known in
PDB.

cohort study

This is a follow-up study of previously investigated subjects. The study
requires a single visit to the LUMC for medical history taking, clinical
examination, filling in of disease-specific questionnaires, laboratory
investigations and skeletal scintigraphy and.