FaCD Online Syndrome Fact Sheet

Last updated: 18 Mar 2009

Name: Polycythemia Vera, Familial

Mode of Inheritance: AD?/AR?

Genes

JAK2, mapped to 9p24

Tumor features (possible)

leukemia, acute
leukemia, chronic myeloid (CML)
multiple myeloma (Kahler's disease)

Non-tumor features

pancytosis
polycythemia

Comment

Clinical hallmarks are increased red blood cell mass due to increased red blood cell production. Frequently white blood cell and platelet count are also elevated (pancytosis). Common symptoms are due to disturbed cerebral circulation (including headache, vertigo, disturbed vision, syncope), disturbed peripheral circulation manifests as thrombosis or bleeding. The disease usually begins in late middle life and has a slowly progressive course. About 1/5 of patients progress to bone marrow fibrosis, splenomegaly and anemia. There is a somewhat elevated risk to develop hematological malignancies including chronic and acute leukemia, lymphomas and multiple myeloma. Familial clustering has been observed[1-5]. Polycythemia vera (PV) is one of the chronic myeloproliferative disorders (CMDs, or myeloproliferative neoplasms), others are hereditary/essential thrombocytosis (ET), erythrocytosis and myelofibrosis (MF). At least 7,6% of CMD cases is familial[5].

Najean et al[6] studied the family history of 842 polycythemia vera cases. They observed a small but significant excess of myeloproliferative diseases and leukemia in the first-degree relatives of these patients.
In a recent study of the Swedish population[7], relatives of CMD patients had significantly increased risks of PV(RR=5.7; 3.5-9.1), ET (RR=7.4; 3.7-14.8), and CMD NOS (RR=7.5; 2.7-20.8). Analyses stratified by type of first-degree relative suggested recessive inheritance. Relatives of CMD patients had a borderline increased risk of chronic myeloid leukemia (CML) (RR=1.9; 0.9-3.8; p=0.09). Acquired JAK2 V617F mutations are seen in virtually all cases of PV, sporadic or familial, but not necessarily in relatives of PV patients who have other types of CMDs[8,9]. Particular germline JAK2 variants/haplotypes appear to increase the risk of acquiring somatic oncogenic JAK2 mutations[10-12].

References

[1] Levin WC, Houston EW, Ritzmann SE. Polycythemia vera with Ph1 chromosomes in two brothers. Blood 1967; 30(4):503-512.
[2] Manoharan A, Garson OM. Familial polycythaemia vera: a study of 3 sisters. Scand J Haematol 1976; 17:10-16.
[3] Ratnoff WD, Gress RE. The familial occurence of polycythemia vera: report of a father and son,,with consideration of the possible etiologic role of exposure to organic solvents, including tetrachloroethylene. Blood 1980; 56(2):233-236.
[4] Rumi E. Familial chronic myeloproliferative disorders: the state of the art. Hematological oncology 2008; .
[5] Hemminki K, Jiang Y. Familial polycythemia vera: results from the Swedish Family-Cancer Database. Leukemia 2001; 15(8):1313-5.
[6] Najean Y, Rain JD, Billotey C. Epidemiological data in polycythaemia vera: a study of 842 cases. Hematol Cell Ther 40[4], 159-165. 1998.
[7] Landgren O, Goldin LR, Kristinsson SY, Helgadottir EA, Samuelsson J, Bjorkholm M. Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24577 first-degree relatives of 11039 patients with myeloproliferative neoplasms in Sweden. Blood 2008; epub ahead of print.
[8] Cario H, Goerttler PS, Steimle C, Levine RL, Pahl HL. The JAK2V617F mutation is acquired secondary to the predisposing alteration in familial polycythaemia vera. British journal of haematology 2005; 130(5):800-1.
[9] Pardanani A, Lasho T, McClure R, Lacy M, Tefferi A. Discordant distribution of JAK2V617F mutation in siblings with familial myeloproliferative disorders. Blood 2006; 107(11):4572-3.
[10] Kilpivaara O, Mukherjee S, Schram AM, Wadleigh M, Mullally A, Ebert BL, Bass A, Marubayashi S, Heguy A, Garcia-Manero G, Kantarjian H, Offit K, Stone RM, Gilliland DG, Klein RJ, Levine RL. A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms. Nat Genet. 2009 Mar 15. [Epub ahead of print]
[11] Olcaydu D, Harutyunyan A, Jäger R, Berg T, Gisslinger B, Pabinger I, Gisslinger H, Kralovics R. A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet. 2009 Mar 15
[12] Jones AV, Chase A, Silver RT, Oscier D, Zoi K, Wang YL, Cario H, Pahl HL, Collins A, Reiter A, Grand F, Cross NC. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet. 2009 Mar 15