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Background: The only known risk factor for chronic lymphocytic leukaemia (CLL) is occurrence of the disease in close relatives. The aim of this study was to determine the frequency of familial chronic lymphocytic leukaemia., Material and Method: All patients with chronic lymphocytic leukaemia notified to the Cancer Registry in the period 1.10.2007-31.12.2009 were asked to report occurrences of malignant disease in siblings, parents, grandparents and children. The information about malignant haematological disease was verified with the Cancer Registry., Results: We found malignant haematological disease in close relatives of 42 of the 236 included patients (18%). CLL and lymphoma were the most common diagnoses. On average, 16 family members were identified in each family. The relative risk of developing CLL was six times higher in those who had close relatives with the disease (16 of a total of 3,776 family members) than among those who did not have close relatives who were affected (76 cases among 107,223 family members of 38,159 control subjects). The increased risk of disease was also associated with other lymphoproliferative diseases. With patrilinear, but not matrilinear inheritance, we found a birth order effect, with affection of younger men in a group of siblings, while the eldest escaped., Interpretation: Malignant haematological disease is common in the family members of patients with CLL. CLL is the most common disease, but there is extensive pleiotropy.

Rank order of affected offspring in a sibship can inform on epigenetic factors in disease susceptibility. Here we report an analysis of birth order in 32 families segregating chronic lymphocytic leukaemia (CLL) and other B-cell lymphoproliferative disorders. A paternal-offspring, but not a maternal-offspring birth rank order was observed. Cox regression analysis provided relative risks (RR) for paternal and maternal transmission of 3.60 (CI 95%: 1.54 - 8.42; P = 0.0005) and 1.64 (CI 95%: 0.90 - 3.01; P = 0.096), respectively. The significance of paternal and maternal transmission of CLL-CLL pairs employing Haldane and Smith's test were 0.006 and 0.63, respectively. There was no evidence of a relationship between parental age and birth order. The genetic mechanism behind the birth order effect observed is discussed in the light of non-Mendelian imprinting and pregnancy related microchimerism.

Lymphoproliferative disorders, especially chronic lymphocytic leukaemia (CLL), non-Hodgkin's lymphomas, Hodgkin's lymphoma and multiple myeloma are regarded as a hereditary entity with pleiotropic clustering in families, although the genuine alleles have not been found so far. The world-wide highest incidence of CLL and the existence of a systematic cancer registration since 1943 make Denmark a perfect place for epidemiological and genealogical investigations in the search for the genetics of the lymphoproliferative disorders. In Scandinavia, we see no signs of anticipation but marked linkage between parents and children, where the combination CLL in parent and CLL in child is more predominant than CLL in parent and a child with any other type of lymphoproliferative disorder. This same conservative pattern is also seen in parent-children transportation of non-Hodgkin's lymphomas and Hodgkin's lymphoma. That no certain linkage to other cancers can be significantly detected is discussed. A non-Mendelian mode of inheritance seems not unlikely in the familial clustering of the lymphoproliferative disorders.

Objective: To examine the relationship between autoimmunity and extranodal lymphocytic infiltrates in different lymphoproliferative disorders with immunoglobulin alterations., Subjects and Design: A clinical review combined with a retrospective cohort study of 380 patients, 28 with monoclonal gammopathy of undetermined significance, three with common variable immunodeficiency, 147 with chronic lymphocytic leukaemia, 57 with Waldenström's macroglobulinaemia and 145 with non-Hodgkin's malignant lymphoma., Setting: A university hospital and The State Serum Institute in Copenhagen., Intervention: Clinical examination of each patient with special attention to chronic inflammatory and autoimmune manifestations. Biopsies were taken from non-infectious infiltrates, some of which were additionally tested with PCR analysis for gene rearrangements. Serological screening with a test battery for various autoantibodies was used in combination with techniques for the detection of M-components and monoclonal B-cell proliferation., Main Outcome Measures: Clinical and/or serological autoimmune manifestations, M-component and other immunoglobulin alterations, and inflammatory tissue changes were studied in patients with chronic inflammatory, polyclonal or oligoclonal pseudolymphomas and in monoclonal, malignant extranodal lymphomas., Results: In 380 consecutive patients, 49 (12.9%) had extranodal manifestations, of whom 47 also had autoimmune manifestations. Nearly half of the 47 patients had more than one autoimmune manifestation. There was a strong correlation between clinical signs and corresponding autoantibodies such as anti-SSA and -SSB antibodies in Sjögren's syndrome (10 cases), antithyroid peroxidase antibodies in thyroiditis and Graves' disease (10 cases), and parietal cell antibodies in gastric ulcers with maltoma (12 cases). Clinical and serological signs of autoimmunity correlated strongly with female sex (34, 72% women; and 13, 28% men) and with immunoglobulin alterations., Conclusions: To our knowledge this is the first systematic review of B-lymphoproliferative and autoimmune disorders indicating that pseudolymphoma and malignant lymphomas, including maltomas, may develop in the context of a permanent autoantigenic drive.

The lymphoid component of skin infiltrates from 6 cases of mycosis fungoides and 2 cases of T cell chronic lymphatic leukaemia consisted almost exclusively of T lymphocytes with abnormally high E receptor expression. Such T cells were also found to dominate the skin infiltrates from 10 patients with severe atopic dermatitis. Blood T lymphocyte counts from all types of patients were within the normal range, but even the blood T lymphocytes of the patients had a strong E receptor expression. The bone marrow in atopic dermatitis and in mycosis fungoides showed normal T cell counts with normal E receptor expression. Supported by basic lymphocyte-kinetic considerations it is likely that the skin in T lymphoproliferative diseases is characterized by an abnormal ability to home and/or to trap T lymphocytes with strong E receptor expression.

2 cases of malignant T-lymphoproliferative disease are reported. The proliferating cell was a large blast expressing E and Fc gamma receptors but no helper or suppressor phenotypes and no SmIg. Skin infiltrates were the dominant clinical sign with conspicuous perivascular aggregations of T, E, Fc gamma lymphocytes, though both patients initially had disseminated disease with mild lymphadenopathy, splenomegaly and, in case 2, also hepatic infiltrations. Accordingly, DNA measurements on skin biopsies, taken early in the course, showed a dominating hypotetraploid clone (case 1) and a pronounced population in S-phase (case 2). The patients were alive for 6 and 2 yr, respectively, with a final fatal course of about 6 months duration involving a rather sudden progression of the skin infiltrates, increasing lymphadenopathy and splenomegaly, leukaemic transformation of the neoplastic T, E, Fc gamma lymphocyte and practically no response to cytostatic treatment.