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The heredity of the malignant blood disorders, leukemias, lymphomas and myeloma, has so far been largely unknown. The present study comprises genealogical investigations of one hundred and twelve Scandinavian families with unrelated parents and two or more cases of malignant blood disease. For comparison, one large family with related family members and three hundred and forty-one cases of malignant blood disease from the Faroese population was included. The inheritance is non-Mendelian, a combination of genomic parental imprinting and feto-maternal microchimerism. There is significantly more segregation in maternal than in paternal lines, predominance of mother-daughter combinations in maternal lines, and father-son combinations in paternal lines. Chronic lymphocytic leukemia is the most frequent diagnosis in the family material, and chronic lymphocytic leukemia has a transgenerational segregation that is unique in that inheritance of susceptibility to chronic lymphocytic leukemia is predominant in males of paternal lines. Male offspring with chronic lymphocytic leukemia in paternal lines have a birth-order effect, which is manifest by the fact that there are significantly more male patients late in the sibling line. In addition, there is contravariation in chronic lymphocytic leukemia, i.e. lower occurrence than expected in relation to other diagnoses, interpreted in such a way that chronic lymphocytic leukemia remains isolated in the pedigree in relation to other diagnoses of malignant blood disease. Another non-Mendelian function appears in the form of anticipation, i.e. increased intensity of malignancy down through the generations and a lower age at onset of disease than otherwise seen in cases from the Cancer Registers, in acute lymphoblastic leukemia, for example. It is discussed that this non-Mendelian segregation seems to spread the susceptibility genes depending on the gender of the parents and not equally to all children in the sibling line, with some remaining unaffected by susceptibility i.e. "healthy and unaffected", due to a birth order effect. In addition, anticipation is regarded as a non-Mendelian mechanism that can amplify, «preserve» these vital susceptibility genes in the family. Perhaps this segregation also results in a sorting of the susceptibility, as the percentage of follicular lymphoma and diffuse large B-cell lymphoma is lower in the family material than in an unselected material. Although leukemias, lymphomas and myelomas are potentially fatal diseases, this non-Mendelian distribution and amplification hardly play any quantitative role in the survival of Homo sapiens, because these diseases mostly occur after fertile age., (© 2022. The Author(s).)

Malignant blood disorders depend on heritable susceptibility genes and occur in familial aggregations. We suggest a model of transgenerational segregation of the susceptibility genes based on the study of malignant blood disorders in Norwegian and Danish families with unrelated parents, and in the inbred Faroese population with related parents. This model, consisting of parental genomic imprinting and mother-son microchimerism, can explain the male predominance in most of the diseases, the predominance of affected parent-offspring when parents are not related, and the different modes of segregation in males and females. The model displays a specific pattern in the distribution of affected relatives for each diagnosis, viz. a characteristic distribution in the pedigrees of family members with malignant blood disorder related to the proband. Three such patterns, each reflecting a specific transgenerational passage, were identified: (1) alterations in the number of affected relatives in paternal lines alone, e.g. in patterns for probands with multiple myeloma; (2) alterations in the number of affected relatives in both paternal and maternal lines for probands with chronic lymphocytic leukemia; and (3) no alterations in the numbers of male and female affected relatives in the parental lines, e.g. for probands with some types of malignant lymphoma.

Background: The clinical courses of chronic lymphocytic leukaemia (CLL) are very heterogeneous. Biological markers that provide good prognostic information at the time of diagnosis are available. The aim of the study was to determine the prevalence of these markers in a population-based material., Material and Method: Biological markers were examined using standard laboratory methods after obtaining an informed consent statement from patients diagnosed with chronic lymphocytic leukaemia in the period 1.10.2007-31.12.2009., Results: There were 388 new cases of chronic lymphocytic leukaemia during the study period, and 236 patients (61%) were included in the study. Of 222 patients, 178 (80%) were in Binet's stage A, 26 (12%) in stage B and 18 (8%) in stage C. The V(H) gene was mutated in 69% and unmutated in 31% of cases. Cytogenetic aberrations were found in 68%: del(13q14) in 48%, trisomy 12 in 13%, del(11q22) in 10% and del(17p13) in 7%. CD38-positive disease was found in 28% of the patients. The V(H) gene was mutated in 67% of the patients in Binet's stage A, and in the majority of these a mutated V(H) gene was associated with non-expression of CD38 and del(13q14)., Interpretation: At the time of diagnosis, most patients are asymptomatic and do not need treatment. The biological markers that indicate a favourable prognosis occur most frequently in this group. Markers that indicate a poor prognosis occur more frequently in the group that has symptoms at the time of diagnosis.

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.

Anaemia may be multifactorial in origin. We present a woman with autoimmune hepatitis and secondary warm autoimmune haemolytic anaemia and most likely also concomitant anaemia of chronic disease. A relapse of autoimmune haemolysis was successfully treated with steroids and high-dose intravenous immunoglobulin. At the same time, bleeding from angiodysplasia in the coecum was masked by unauthorised perorally administrated iron. No other cause of bleeding was found. During that period, she required extensive blood transfusions, up to several times per month. Surgical or endoscopic treatment of the bleeding angiodysplasia was not possible. Alloimmunisation developed as a complication to the large number of transfusions, despite the use of steroids. Treatment with somatostatin analogue markedly reduced the need of our patient for blood transfusions for a follow-up period of more than one year, and she has not experienced any side effects. We do not know how long the haemostasis achieved will last, however, we believe that this treatment may be an alternative for other patients as bleeding from angiodysplasia is not uncommon and is often difficult to eradicate.

From 2005 to 2010, eight families with clustering of Hodgkin's lymphoma and other lymphoproliferative disorders were found: Hodgkin's lymphoma 9 cases, chronic lymphocytic leukemia 8, non-Hodgkin's lymphoma 3, and multiple myeloma 1 case. Seven cases of Hodgkin's lymphoma, all males, were seen in pleiotropic pairs of affected family members from two successive generations; two patients were sisters. Five of the seven pairs showed sign of anticipation. The 7 males with Hodgkin's lymphoma were found in 5 patrilineal pairs and 2 matrilineal pairs; 6 parent-offspring pairs and 1 uncle-nephew pair. In contrast to the matrilineal pairs, all patrilineal pairs, apart from one family with an only child, had healthy older siblings in accordance with a birth-order effect. The association among Hodgkin's lymphoma, males, and other lymphoproliferative disorders undoubtedly reflects genotypic traits of the susceptibility. A non-Mendelian segregation is discussed comprising genomic parental imprinting and incomplete penetrance susceptibility in both familial and solitary cases.

Fifty-one parent-offspring pairs with chronic lymphocytic leukemia (CLL) or other lymphoproliferative disorders (nonCLL) such as malignant lymphoma, multiple myeloma, or other types of lymphocytic leukemia than CLL were ascertained independently in 38 families. There were 30 CLL-CLL parent-offspring pairs and 21 pairs with nonCLL in parents and/or in offspring. The median age of onset of disease was 13 years lower in the offspring than in the parents when comparing all 51 pairs (P < 0.001). This difference was mainly caused by a significantly lower age at onset in offspring with parental nonCLL (P < 0.001) where paternal disease was transferred especially to sons, while affected offspring to parents with CLL have the same age at debut of disease than their parents (P = 0.130) and a nearly equal transfer to sons and daughters. The low-malignant follicular small B-cell lymphoma was the predominant diagnosis within nonCLL. Anticipation is pointed out as one likely mechanism behind the lower age at onset of disease in offspring than in parents, even if a part of this difference is ascribed to a generally earlier diagnosis with modern technology in offspring than in parents.

Aim: To investigate the genetics of chronic lymphocytic leukemia (CLL)., Materials and Methods: In 56 (7%) out of 800 CLL patients with concomitant malignant hematological disease, 51 families and 141 cases were ascertained., Result: 106 cases (75%) of CLL, 27 cases (19%) of nonCLL and 8 cases (6%) of myeloproliferative disorders. Paternal disease was transmitted primarily to the youngest sons in the sibship while maternal disease was transmitted equally to all sibs, demonstrated by means of matrix conjugation and confirmed with Cox regression on parity and birth order (maternal-offspring combination: relative risk (RR), 95% confidence interval (CI)=1.47 (0.89 - 2.43), p=0.12, compared with paternal-offspring combination: RR=3.25, 95% CI=(1.57-6.72), p<0.001). The B-cell expression in familial and sporadic CLL was indistinguishable., Conclusion: Parental genomic imprinting is pointed out as one possible mechanism behind this non-Mendelian genomic output.

Based on the concept that the tumorogenesis in chronic lymphocytic leukaemia comprises both an initial, inherited mutation and subsequent somatic mutations, the pleiotypic diversity of familial chronic lymphocytic leukaemia and related malignant lymphoproliferative disorders is generally explained by a repertoire of monoallelic polygenes in the initial mutation. Epigenetic genomic imprinting is a likely mechanism behind of the asynchroneous replicating monoallelic polygenes which is discussed in the light of pleiotrophy and birth order effect. Furthermore, it is discussed that one possible mechanism available for the epigenetic transfer of these genes could be the physiological pregnancy-related microchimerism between mother and fetus.

The notion that inherited predisposition contributes to the development of haematological malignancies is generally thought of as being a relatively new idea. However, Videbaek made a clear enunciation of such a hypothesis in 1947, from a study of tumour incidence in relatives of patients with different leukaemias. To gain further insight into inherited susceptibility to chronic lymphocytic leukaemia (CLL), we followed up the descendants of Videbaek's 'Pedigree 14' series of families. Using the Danish medical and pedigree databases, complete tracing of 222 descendants of the original 57 family members was achieved. To date, 10 family members have been diagnosed with CLL, one with T-cell lymphoma and 17 with nonhaematological cancers, including five with breast cancer. The detailed follow up of this family provides further support for inherited predisposition to CLL and illustrates the value of follow-up studies of previously published family material for genetic analyses.

Unlabelled: Changes in the amount and distribution of amyloid lesions have been difficult to monitor because they can usually be demonstrated only by evident symptoms or from a biopsy. The recent progress in the treatment of amyloidosis stresses the need for an early diagnosis and the need for noninvasive monitoring during the course of treatment. To validate (99m)Tc-aprotinin scintigraphy, we studied 23 consecutive patients with known or suspected amyloidosis., Methods: (99m)Tc-Aprotinin (500-700 MBq) was injected intravenously and whole-body scans, regional images, and SPECT tomograms were obtained 90 min after tracer injection., Results: Focal accumulations of (99m)Tc-aprotinin were seen in different organs of 22 patients with a total of 90 lesions, of which 20 were confirmed by biopsy or autopsy. Scintigraphy revealed "silent" amyloid deposits in at least 5 patients who later developed clinical symptoms. Physiologic uptake or excretion in liver and kidneys could not be differentiated from pathologic lesions in those organs., Conclusion: (99m)Tc-Aprotinin scintigraphy appears to be a fairly sensitive and specific diagnostic modality in patients with suspected amyloidosis. The technique is noninvasive, and it entails a minimal stress to the patient and is useful for detection of a wide range of lesions.

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.

A sister and a brother with a progressive mixed axonal and demyelinating polyneuropathy were found to have a monoclonal IgM gammopathy of kappa and lambda type, respectively. Sural nerve and cutaneous nerve specimens obtained by biopsy showed deposits of IgM on myelin sheets. Sera from both patients contained antibodies directed to bovine peripheral nerve myelin as determined by ELISA technique and to normal human peripheral nerve myelin as demonstrated by indirect immunofluorescence histochemistry. These siblings may have a genetic predisposition to the formation of autoantibodies with peripheral nerve myelin as the target for the immune attack.

During a one year period acute pericarditis was diagnosed in 16 consecutive patients without acute infarction or malignancy. In two of these patients with both pericarditis and pneumonia Legionella infection was present. One case was caused by Legionella longbeachae and the other by both Legionella longbeachae and Legionella jordanis. When pericarditis is associated with pneumonia Legionella infection should be sought so that effective treatment with erythromycin may be started early.