The cause of Paget's disease of bone (PDB) is unknown. In an attempt to ascertain the proportion of familial cases and evaluate the influence of genetic factors on the occurrence of the disease, a study was undertaken based on 35 PDB patients from our Unit. Their families were investigated, with the participation of a total of 128 first-degree relatives. Fourteen (40%) of these 35 index cases had at least one other first-degree relative affected with PDB and were defined as "familial." The remaining 21 (60%) were considered "sporadic." The frequency of males in the familial cases (79%) was significantly higher than among the sporadics (29%; p < or = 0.01). Mean age at diagnosis (63.1 +/- 12.6 vs. 71.3 +/- 8.7; p < or = 0.02), proportion of polyostotic cases (85.7% vs. 52.4%, p < or = 0.05), and mean number of involved bones per patient (4.36 +/- 2.50 vs. 2.33 +/- 1.93, p < or = 0.01) differ significantly in the familial and sporadic groups. The disease appears to be transmitted via both paternal and maternal sides, and pedigree analysis suggested an autosomal dominant inheritance or multifactorial mechanism. Apart from green-and-blue eye color, which was clearly associated with familial grouping (OR 6.25, 95% CI 1.15-37.16, p < or = 0.01), crude analysis on several genetically based traits and environmental variables revealed no other significant differences between the groups. The adjusted odds ratio estimated for green-and-blue eye color was 2.92 (95% CI 0.38-22.74).(ABSTRACT TRUNCATED AT 250 WORDS)