3.9 Familial CLL in Norway

A total of 388 cases of CLL (234 males and 154 females) were recorded by the National Norwegian CLL Registry during a period of 27 months from Oct. 1st 2007 to Dec. 31st 2009. This is a 100 per cent statutory registration of new cases based on flow cytometric documentation according to consensus diagnostic criteria of CLL. Cross-check of all 388 cases with the Norwegian Cancer Registry revealed 42 CLL patients (11%, 26 males and 16 females) who had 1 (30) or more than 1 (12) family members with malignant hematological disease (MHD) in 3 or 4 generations related to the CLL proband. Self-reported pedigrees, available in 236 (61%) of the 388 cases, were used to identify older family members who died in the first part of the nineteenth century before the civil registration number came into use. A total of 60 relatives to the 42 CLL probands had MHD: lymphoproliferative disease (49) and myeloproliferative disease (11) in the following combinations: CLL proband – Parents (n = 17): CLL-CLL 6, CLL-NHL IN 3, CLL-NHL AG 1, CLL-NHL NOS 1, CLL-HL 2, CLL-HCL 1, CLL-MM 2, CLL- AML 1. CLL proband – Grandparents (n = 8): CLL-CLL 3, CLL-MM 1, CLL-leukemia NOS 2, CLL-AML 1, CLL-CML 1. CLL proband – Children (n = 1): CLL-NHL AG 1. CLL proband – Grandchildren (n = 1): CLL-NHL AG 1. CLL proband – Aunt, uncle, cousin or nephew, etc. (n = 25): CLL-CLL 4, CLL-NHL IN 3, CLL-NHL AG 2, CLL-NHL NOS 1, CLL- Tcell-NHL 1, CLL-ALL 2, CLL-HL 2, CLL-MM 2, CLL-AML 4, CLL-CML 2, CLL-myeloid leukemia NOS 1, CLL-leukemia NOS 1. Sib concordance, viz. more affected sibs (n = 8): CLL-CLL 3, CLL-NHL IN 1, CLL-NHL AG 2, CLL-MM 1, CLL-AML 1. Abbreviations: ALL acute lymphoblastic leukemia, AML acute myeloid leukemia, CLL chronic lymphocytic leukemia, CML chronic myeloid leukemia, HL Hodgkin's lymphoma, HCL hairy cell leukemia, MM multiple myeloma, NHL non-Hodgkin lymphoma, NOS not otherwise specified, IN indolent, AG aggressive. Based on detailed pedigrees from each of the 42 CLL probands, the position of affected family members in either the father's or mother's line could be determined in 36 cases (19 patrilineal, 17 matrilineal) while in 6 cases both lines were involved. Haldane-Smith's test for birth order effect 1 Emery A.E.H. Parental age and birth order. in: Emery A.E.H. Methodology in medical genetics. 2nd Edition. Churchill Livingstone, Edinburgh, London1986: 140-153 Google Scholar was used for calculation of the mean rank by age in the sibship of each CLL proband. The birth order of the CLL probands differed between patrilineal and matrilineal lines in terms of Haldane-Smith adjusted mean (‘6A') and its 95% confidence interval: Patrilineal (n = 19): 288 (192 - 282), p = 0.02, mean sibship size = 2.9. In patrilineal lines, the CLL proband is nearly never first in the sibship having a higher birth order range with healthy older sibs. Matrilineal (n = 17): 216 (186-278), p = 0.7, mean sibship size = 2.9. In matrilineal lines, the CLL probands occur randomly in the sibship. Conclusion: Familial CLL (11%, 42 of 388 cases) is related to a wide pleiotypic repertoire of both lymphoproliferative and myeloproliferative disorders. In the 42 families with 42 CLL probands in addition to 60 affected relatives with MHD, the mean number of patients is 2.4 per family. CLL-CLL and CLL- B-cell NHL kindred are the most frequent combinations, both seen in 16 (27%) of the 60 combinations, respectively. CLL-myeloproliferative disease is seen in 11 (18%) of the 60 combinations predominated by AML (7 of 11 cases). This cross-checked Norwegian material confirms a patrilineal birth order effect in CLL while no such birth order could be seen in matrilineal transmissions. Epigenetic segregation of the MHD-susceptibility is one possible explanation of this difference.