Familial occurrence of chronic lymphocytic leukaemia in Norway.

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.

Chronic lymphocytic leukaemia in Norway--incidence and prognostic markers at diagnosis.

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.

Familial Hodgkin's lymphoma in Scandinavia.

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.

Familial chronic lymphocytic leukemia in Norway and Denmark. Comments on pleiotropy and birth order.

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.

Anticipation in families with chronic lymphocytic leukemia and other lymphoproliferative disorders.

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.

Possible imprinting and microchimerism in chronic lymphocytic leukemia and related lymphoproliferative disorders.

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.

[Catheter-directed thrombolysis of iliofemoral venous thrombosis]. / Kateterbasert trombolytisk behandling av bekkenvenetrombose.

BACKGROUND: Although a success rate of 80% has been reported in patients with iliofemoral venous thrombosis treated with catheter-based thrombolysis, the possible long-term benefit of this treatment is not known. MATERIAL AND METHOD: 28 consecutive patients referred for catheter-based thrombolysis of iliofemoral venous thrombosis were treated with infusion of alteplase into the thrombus for two to five days. Following thrombolysis, warfarin was given for at least one year. All patients were examined every six months with colour duplex scanning and air pletysmography. RESULTS: 100% thrombolysis was achieved in eight patients, 75-99% in ten, 50-74% in nine and < 50% in one patient. Angioplasty (four) or stent implantation (four) was successful in eight out of twelve patients with stenosis of the left common iliac vein. Early recurrence of thrombosis (< 7 days) occurred in three patients, pulmonary embolism in one, and bleeding at the insertion site in six. After a mean follow-up of 2.5 years, 17 patients were free of symptoms, seven had a mild degree and four a moderate degree of postthrombotic syndrome. Eighteen patients had normal venous physiology, nine deep venous reflux, and three functional obstruction of deep veins. Postthrombotic syndrome was associated with deep venous reflux and/or functional obstruction of the iliofemoral segment. INTERPRETATION: Catheter-based thrombolysis is a safe and effective treatment of proximal deep venous thrombosis and might reduce the occurrence of postthrombotic syndrome compared to treatment with anticoagulation alone.