Familial paraproteinemia: hyper-responsive B-cells as endophenotype

The prevalence of paraproteinemias or monoclonal gammopathies increases with age. No other major risk factors have been recognized, but significant associations have been reported with chronic antigen exposure, agricultural environment, and family history. In around 130 families reported worldwide, IgG or IgA monoclonal gammopathy of undetermined significance (MGUS) occurs with multiple myeloma (MM) whereas Waldenström's macroglobulinemia (WM) is linked to IgM MGUS. Of the 8 multi-case families described here, 5 are remarkable for including both IgG/IgA and IgM type disorders. In the remaining 3 families IgG/IgA MGUS and MM occurred with Hodgkin disease and T-cell malignancies. These different patterns of familial paraproteinemia indicate different genetic backgrounds. A previously described functional phenotype of hyper-responsive B lymphocytes fulfils criteria for being an endophenotype and may be related to raised serum IgM. Identifying an endophenotype is important to ensure correct classification of affected family members and thus enhance the power of genetic studies.