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Normal Thrombopoietin and Its Receptor Genes in 6 Children with Essential Thrombocythemia



Normal Thrombopoietin and Its Receptor Genes in 6 Children with Essential Thrombocythemia



Blood 100(11): Abstract No. 4932



We have observed and studied 6 cases of thrombocytosis presenting in children and meeting the criteria for ET according to Polycythemia Vera Study Group criteria This condition is very rare in pediatric age and some evidences are available in the literature, suggesting that ET in childhood may be a non-clonal disease or at least a possible variant of the classical ET described in adults. The children in our series were 5 girls and 1 boy, with a median age of 7,5 years (9 moths-11years) at the time of diagnosis. Their platelet counts ranged from 1.112 to 3.178 x 109/l. A girl had presented with inferior vena cava thrombosis, 3 children complained of frequent headache episodes, but other major complication were not observed. One girl used IFNalpha treatment for some time, with only temporary and partial reduction of platelets number. Two patients were under aspirin treatment and one under warfarin therapy. The median follow up is now 101 months (range 48-208 months) and none of the children showed any resolution of the thrombocytosis. Chromosomal rearrangements, myelofibrosis, abnormalities of platelets function or spontaneous growth of precursor from peripheral and marrow blood were absent. Serum levels of erithropoietin and thrombopoietin (TPO) were normal. In particular no transformation into acute leukemia or myelofibrosis has been recognized to date. In keeping with the observation of familial cases of polycythemia with abnormalities of the erythropoietin receptor, we have analyzed molecular structure of TPO and its receptor (c-mpl) or of their regulatory pathway as possible causes for increased platelet numbers. Primers for amplification were chosen based on published sequences. The DNA extracted from peripheral blood leukocytes was screened for the presence of the activating splice mutation in intron 3 of the TPO gene using a modification of the technique described by Wiesner (Nature Genetics,1998;18:49-52), based on the loss of a Bsr I restriction site in mutated allele. Both TPO and c-mpl genes were investigated for the presence of other point mutations by direct sequencing of PCR fragments on genetic analyzer (373 Perkin Elmer cetus). We could not demonstrate any alteration of the c-mpl nor of TPO; however, in one case we observed an already known polymorphism in untranslated regions of TPO. This is in keeping with similar observation in adult ET. Therefore, more studies are needed to elucidate the pathophysiology of childhood ET: in particular, clonality has to be confirmed and TPO-c-mpl regulatory pathways are to be studied.

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