Congenital JAK2 V617F Polycythaemia Vera Cured with Sibling Allogeneic Bone Marrow Transplantation
Authors: Kelly Kevin R , McMahon Corrina , Langabeer Stephen , Eliwan Hassan , O’Marcaigh Aengus , Smith Owen P. 
Published: April 2020

Abstract
Polycythaemia vera (PV) is extremely rare in young children. The Janus Kinase 2 V617F mutation is present in 95 % of adult PV patients. Testing is now widely available and has simplified the diagnostic workup. A previously healthy 7 month old girl was admitted to her local hospital with tonsillitis. Full blood count showed polycythaemia (Hb 19 g/dl) along with an elevated platelet (946 ×109/L) and white cell count (19.7 ×109/L). Oxygen saturations, arterial blood gases, chest x-ray, abdominal ultrasound and P50 were all normal. Serum erythropoietin was low. No mutations were identified in exons 7 and 8 of the EPO receptor gene, the Von Hipple Lindau tumour suppressor gene and the Prolyl hydroxylase domain 2 gene. Bone marrow aspirate and biopsy were showed hypercellularity, megakaryocyte hyperplasia and clustering along with erythroid hyperplasia. Cytogenetic analysis was normal. Spontaneous erythroid colonies were demonstrated. The JAK2 V617F mutation was found by polymerase chain reaction in her blood and in her Guthrie card taken at 2 days of age. Both parents and two of her siblings had normal full blood counts. Two further siblings have not had full blood counts. There is no known family history of myeloproliferative disorders. The JAK2 V617F mutation was not detected in the peripheral blood or the oral mucosa of either parent or in the oral mucosa of the patient. She was treated with regular venesection and aspirin 45mg OD was started when her platelet count rose above 1,500 × 109/L. Her clinical course and laboratory parameters remained stable with this treatment and no thromboembolic complications occurred. Due to the long term risks of malignant transformation and thromboembolism a sibling allogeneic bone marrow transplantation was performed with her 6 year old brother as a fully HLA matched, JAK2 V617F negative donor with a normal full blood count. A total nucleated count of 13 ×108 per kg recipient body weight, bone marrow was infused. The conditioning regimen was busulphan (4mg/kg/day × 5 days) and cyclophosphamide (50mg/kg/day × 4 days). Neutrophils rose to 2.6 ×109/L by day 24. No venous occlusive disease or graft versus host disease occurred. Complete donor chimerism and undetectable JAK2 V617F mutation have been observed from day + 14 to present. She remains in remission 15 months post transplant. She now has a normal full blood count and has not suffered any adverse sequelae. To the best of our knowledge this is the first report of prenatal JAK2 V617F PV. It further highlights the genotype-phenotype diversity that is seen amongst this group of JAK2 V617F positive myeloproliferative neoplasms. The frequency of the mutation in pediatric PV has been variably reported in the literature but this report proves that it can occur at all ages. The absence of the mutation in either parent or the oral mucosa of the child shows that this was likely an acquired somatic event that occurred in utero. The JAK2 V617F mutation is thought to be acquired in both familial and sporadic MPD. In a study of 22 families with PV the mutation was present in variable amounts in affected members and absent in unaffected members. Analysis of another single large family with PV showed the presence of JAK2 V617F in affected family members but not in an obligate carrier. This suggests that other genetic abnormalities, possibly inherited, precede the acquisition of the JAK2 V617F mutation. Inheritance of as yet unknown germline mutations may have predisposed towards the in utero acquisition of the somatic JAK2 V617F mutation in our particular case.
Young children with PV face a considerable lifetime risk of arterial and venous thrombosis and of malignant transformation. Hemopoetic stem cell transplantation normalises the full blood count and eradicates the pre malignant clone thereby reducing these risks and should be considered early if a suitable donor is available.