A Rare Case of JAK2 V617F Positive Polycythemia Vera in a Child with Neurofibromatosis Type I.
Authors: Berman Jason N. , Greer Wenda L. , Loh Mignon , Riddell Christie , Morash Barbara , Dumas Nadine , Fernandez Conrad V. , Ludman Mark 
Published: October 2019

Polycythemia vera (PV), is a myeloproliferative disease (MPD) originating in a hematopoietic stem cell resulting in clonal expansion of erythroid progenitors. It is associated with thromboses and malignant transformation. Recently the V617F alteration arising from a mutation in JAK2 has been identified in greater than 90% of cases of PV in adults. PV is rare in children and the frequency of the common JAK2 mutation is significantly lower than in adult patients, indicating that alternative genetic events are involved in the pathogenesis of this disease. We have identified a child diagnosed with PV at the age of 15 months, the youngest described in the literature to date. Initial laboratory values demonstrated a WBC of 33 x109/L, hemoglobin 181 g/L, and platelet count of 579 x109/L. Bone marrow cytogenetics were normal. Erythroid colony forming units demonstrated erythropoietin-independent growth. Peripheral blood, buccal swab and saliva analysis revealed the presence of the common JAK2 V617F mutation, but a B lymphocyte cell line and skin-fibroblast-culture from this patient were negative, indicating that the JAK2 mutation was somatic. Peripheral blood from her parents and older brother demonstrated normal blood counts and wild type JAK2 status. This child was also diagnosed with Neurofibromatosis type 1 (NF1) based on meeting NIH consensus diagnostic criteria diagnostic criteria, having the requisite number of appropriately sized café-au-lait macules and Lisch nodules. NF1 and PV have no previously known association, however NF1 is associated with another MPD, juvenile myelomonocytic leukemia (JMML). Patients with NF1 and JMML demonstrate loss of heterozygosity (LOH) at the NF1 locus while 60% of JMML patients without NF1 alternatively demonstrate somatic mutations in NRAS, KRAS2 or PTPN11. Taken together, these genetic lesions result in hyperactivation of the RAS/MAPK pathway. Low density single nucleotide polymorphism arrays performed on peripheral blood from this patient failed to demonstrate obvious LOH at the NF1 locus. NF1 gene sequencing failed to identify the cause of the NF1 phenotype. Mutations were not identified in the commonly mutated regions of NRAS, KRAS2 or PTPN11. This case reveals the presence of the most commonly acquired somatic JAK2 mutation in a young child with PV and indicates that buccal swabs and saliva are unreliable sources of unaffected tissue for assessing the presence of germline mutations in PV patients. Moreover, it suggests that some patients with clinical NF1 are at risk for developing other MPDs besides JMML. For this patient, a novel unidentified genetic abnormality resulting in the clinical phenotype of NF1 may serve as a predisposing genetic event accounting for the unusually young age of presentation. The investigation of rare children with PV has the potential to provide valuable insight into the molecular interactions underlying the pathogenesis of MPDs.