Phenotypic Description of Familial Chronic Myeloproliferative Disorders.

Abstract

Abstract Chronic myeloproliferative disorders (CMPD) are rare diseases of the bone marrow characterised by a clonal proliferation of one or several myeloid lineages. Familial clustering are regularly reported suggesting a role for inherited factors. To adress this issue, we collected with the help of a large network of haematologists clinical data and blood samples of 78 families defined by the presence of at least two affected subjects with one of the four CMPD: polycythemia vera, essential thombocythemia, chronic myeloid leukemia and agnogenic myeloid metaplasia. A total of 176 affected subjects including 83 polycythemia vera, 70 essential thrombocythemia, 12 chronic myeloid leukemia and 11 agnogenic myeloid metaplasia were recruited. 449 asymptomatic relatives, mainly first-degrees, were collected and among them 11%were carriers of endogenous erythroid colonies with normal blood counts. Phenotypic spectrum within families was either homogenous (46/78) or heterogeneous (32/78) and the main association (25/32) was polycythemia vera and essential thrombocythemia. A few cases of changes in disease phenotype was also observed during the course of CMPD. Clinical and haematological data of affected subjects at diagnosis and during the course of the disease were similar to sporadic CMPD. However, a marked anticipation of approximatively 20 years/generation at onset age was observed. No excess of carcinomas was noted either in affected subjects or relatives. An excess of acute leukemias, however, was noted in relatives. We did not show evidence of known environmental factors such as exposition to ionic radiations or chemical solvents. Familial cases were restricted to a single generation in 33 families. Occurence was vertical in 45 families involving 2 generations in 36 and 3 generations in 9. In those familial cases consistent with a dominant inheritance, we exluded molecular abnormalities of VHL and EpoR genes involved in particular forms of familial and congenital polycythemia. In conclusion, the analysis of these 78 familial CMPD cases highlights that (i) the observation of mixed phenotypes in a large proportion is consistent with the theory that MPD arise from clonal expansion of a pluripotent hematopoietic precursor cell (ii) no environmental factor is clearly involved in the onset of CMPD and (iii) the observation of familial aggregations and the low incidence of the pathology suggest the implication of genetic predisposition factors in the occurence of myeloproliferative disorders. This large collection of multiplex families enables us to initiate genome-wide linkage analysis.