Hereditary thrombocytosis caused by MPLSer505Asn is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis

Abstract

The online version of this article has a supplementary appendix. BackgroundThe MPL Ser505Asn mutation has been reported to be a cause of hereditary thrombocythemia. Recently, we detected this mutation in a large proportion of children with familial thrombocythemia, suggesting that in Italy the incidence of MPL Ser505Asn mutation could be underestimated. Design and MethodsWe extended the search for this mutation to all patients with essential thrombocythemia who had a positive family history for thrombocytosis or essential thrombocythemia. We identified eight Italian families positive for the MPL Ser505Asn mutation. Clinical and hematologic data were available for members of seven families, including 21 patients with a proven mutation and 20 relatives with thrombocytosis. ResultsFifteen major thrombotic episodes, nine of which were fatal, were recorded among 41 patients. The thrombotic manifestation was stroke in four cases, myocardial infarction in seven cases, fetal loss in two cases, deep vein thrombosis of the leg in one case and Budd Chiari syndrome in one case. Almost all patients over 20 years old had splenomegaly and bone marrow fibrosis, while these were rarely observed in patients under 20 years old, suggesting that these manifestations are associated with aging. Finally, the life expectancy of family members with thrombocytosis was significantly shorter than that of members without thrombocytosis (P=0.003). Conclusions Patients with familial thrombocytosis caused by a MPLSer505Asn mutation have a high risk of thrombosis and, with aging, develop splenomegaly and bone marrow fibrosis, significantly affecting their life expectancy. Key words: MPL Ser505Asn, hereditary thrombocytosis, splenomegaly, bone marrow fibrosis. Citation: Teofili L, Giona F, Torti L, Cenci T, Ricerca BM, Rumi C, Nunes V, Foà R, Leone G, Martini M, and Larocca LM. Hereditary thrombocytosis caused by MPLSer505Asn is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis. Haematologica. 2010; 95:65-70. doi:10.3324/haematol.2009 This is an open-access paper. Hereditary thrombocytosis caused by MPL

Clinical utility gene card for: Hereditary thrombocythemia

“…No increased risk for progression to acute leukemia in THCYT2. Low risk for progression to myelofibrosis and/or acute leukemia in THCYT3/hereditary ET; similar risk as in sporadic ET 11,20,21 .…”

“…13 Adult and elderly patients, but not children with MPL S505N-positive THCYT2, have frequently developed myelofibrosis. 11 These cases are indistinguishable from other BCR-ABL-negative PMF. Neoplastic THCYT3/hereditary ET have a low but nevertheless elevated risk to develop myelofibrosis and/or acute leukemia.…”

“…11,20,22,23 Sporadic ET but not hereditary thrombocythemia with MPL codon W515 mutations have not been described so far. 13 Adult and elderly patients, but not children with MPL S505N-positive THCYT2, have frequently developed myelofibrosis.…”

“…9 G1073A/S505N (germline alteration). [10][11][12] Codon W515 mutations have not yet been reported in hereditary cases but in sporadic essential thrombocythemia (ET). 13 JAK2 (THCYT3): G1894T/V617F (somatic mutation in THCYT3 and sporadic ET).…”

“…3 In an affected Italian family with THPO 1-BP DEL, 3252G distal unilateral limb defects were present; presumably secondary defects (grandfather without limb defects; father with absence of right forearm and hand and absence of right foot, one of three male children with absence of the right foot, the calcaneus and astragalus; a second child with absence of the last phalange of 2nd digit and last 2 phalanges of 3rd to 5th digits; the third child had no limb defects). 5 Hereditary thrombocythemia cases with associated MPL alterations (THCYT2) have been described in Japan, 10 Italy 11,12 North America (African Americans) 8 and Arabia. 9 Regional/ethnic association is known for MPL K39N (B7% of African Americans are heterozygous for MPL K39N, n ¼ 12/161) and MPL P106L (B5% in Arab population, n ¼ 11/213; B1% are homozygous and B4% are heterozygous for MPL P106L).…”