title: Familial monoclonal gammopathy: hyper-responsive B cells in unaffected family members.
abstract: BACKGROUND
  In Iceland, eight families have been identified with multiple cases of monoclonal gammopathies (MG) and other lymphoproliferative diseases. In one of these families with several cases of monoclonal gammopathy of undetermined significance (MGUS) and Waldenströms macroglobulinemia, in vitro stimulation with poke-weed mitogen revealed hyper-responsive B cells showing increased immunoglobulin production in one-third of disease-free family members.
  
  
  METHODS
  In this study, the families were further traced and the list of names produced was compared with The Icelandic Cancer Registry (ICR) to find all recent cases of lymphoproliferative diseases. First-degree relatives and descendants older than 20yrs of age (n=350) were selected for screening for paraprotein. Selected family members were tested for B-cell hyper-responsiveness and the lymphocyte phenotype was analysed by flow cytometry.
  
  
  RESULTS
  Comparison of the total list of 4370 family members with the ICR revealed 22 new cases and screening for serum paraprotein identified nine new cases of MG, eight being first-degree relatives of known probands. Sixty cases of lymphoproliferative diseases are currently known within the eight families, five of them containing both IgG/A and IgM disorders. Twelve hyper-responders (HR) were identified in four families, eight from one family, of whom four were known already. Stimulated B cells from HR had a significantly higher proportion of CD27(+) memory/plasma cells than controls.
  
  
  CONCLUSIONS
  Identification of new affected family members by screening confirms a hereditary predisposition to B-cell proliferative diseases. Contrary to most studies, IgG/A and IgM disorders occurred together in five families. In four families, enhanced B-cell responsiveness was found in healthy subjects clustered around cases.
authors.affiliation: Department of Clinical Haematology, Landspitali University Hospital, Reykjavik Faculty of Medicine, University of Iceland, Reykjavik, Iceland. hlifst@landspitali.is
authors.forename: Hlíf
authors.initials: H
authors.lastname: Steingrímsdóttir
authors.forename: Helga K
authors.initials: HK
authors.lastname: Einarsdóttir
authors.forename: Vilhelmína
authors.initials: V
authors.lastname: Haraldsdóttir
authors.forename: Helga M
authors.initials: HM
authors.lastname: Ogmundsdóttir
mesh_terms: D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007055:Iceland; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000235:genetics / Q000276:immunology; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology; D010265:Paraproteinemias / Q000235:genetics* / Q000276:immunology*; D010266:Paraproteins / Q000235:genetics / Q000276:immunology; D010375:Pedigree; D012042:Registries; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: D010266:Paraproteins