Congenital JAK2^V617F polycythemia vera: where does the genotype-phenotype diversity end?

To the editor:

A previously healthy 7-month-old girl was admitted to her local hospital with tonsillitis. Full blood count showed polycythemia (Hb 190 g/L) 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 normal. Serum erythropoietin was low. No mutations were identified in exons 7 and 8 of the EPO receptor gene, the Von Hippel-Lindau tumor suppressor gene and the Prolyl hydroxylase domain 2 gene. Bone marrow examination showed hypercellularity, megakaryocyte hyperplasia with clustering and erythroid hyperplasia, and absence of the BCR/ABL fusion. Spontaneous erythroid colonies were demonstrated. The JAK2^V617F mutation was identified in her blood and Guthrie card taken at 2 days of age. Both parents and 2 of her siblings had normal full blood counts. There is no known family history of myeloproliferative disorders (MPDs). 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 to maintain her hematocrit less than 45%. Aspirin (45 mg once daily) was started when her platelet count rose above 1500 × 10⁹/L. Due to the long-term risks of malignant transformation and thromboembolism, she underwent an uneventful sibling (JAK2^V617F-negative) allogeneic bone marrow transplantation. Complete donor chimerism and undetectable JAK2^V617F mutation have been observed from day +14 to present. She remains clinically well and in molecular remission after hematopoietic stem cell replacement.

Although polycythemia vera (PV) is extremely rare in young children, to the best of our knowledge this is the first report of prenatal JAK2^V617F PV and further highlights the genotype-phenotype diversity that is seen among this group of JAK2^V617F-positive myeloproliferative neoplasms. The frequency of the mutation in pediatric PV has been variably reported in the literature but our observation proves that it can occur at all ages.¹  The absence of the mutation in either parent or the oral mucosa of the child shows that this was most 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.²  Analysis of another single large family with PV showed the presence of JAK2^V617F in affected family members but not in an obligate carrier.³  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 toward the acquisition in utero of the somatic JAK2^V617F mutation in our particular case, but such events also may have influenced the relatively rapid evolution to the polycythemic phenotype in this infant compared with the estimated time it takes for a JAK2^V617F mutation to develop into clinical PV in adult patients.