Abstract
Background
Polycythemia vera (PV) is defined as an increase in red blood cells reflected as an increase in hemoglobin (Hgb) and/or hematocrit (Hct), an acquired JAK2 mutation, and a bone marrow biopsy that shows hypercellularity with panmyelosis. Literature has shown that applying these guidelines to pediatric patients can lead to misdiagnosis and improper management. Pediatric PV presents with nonspecific clinical manifestations such as headaches, general weakness, pruritus in upper extremities, fatigue, splenomegaly, and a low frequency of JAK2 mutations. This series describes diagnostic approaches, management, and outcomes of three pediatric patients diagnosed with PV.
Case Series
Patient A: A 16-year-old male with a history of severe hypertension and gross hematuria was referred to hematology for elevated hemoglobin since the age 2. He reported dizziness, syncope, and transient hand flushing. Upon presentation, labs showed Hgb 18.1 g/dL, Hct 52.5%, and a normal erythropoietin (EPO) level of 11mU/mL. Gene sequencing revealed a variant of unknown significance (VUS) in SH2B3 p.R425C, a gene with pathogenic variants that have been associated with erythrocytosis, thrombocytosis, and myelofibrosis. A bone marrow biopsy showed normocellular marrow with trilineage hematopoiesis, no evidence of MDS or neoplasia, and genetic VUS in SH2B3 and BCOR p.P126L, which is a transcription factor regulating hematopoiesis and lymphoid development. He has been treated with aspirin and phlebotomy with significant symptom improvement.
Patient B: A 10-year-old female presented with a six-month history of fatigue, thrombocytosis, and post-shower pruritus. Labs showed Hgb 16.3 g/dL, Hct 52.2%, a low EPO level of 1 mU/mL, and she was found to have an increase in erythroid precursor cells on bone marrow biopsy and JAK2 V617F pathogenic mutation. The patient was treated with aspirin and phlebotomy. Phlebotomy frequency decreased after one year and was discontinued after three years due to symptom improvement. After 5 years, hemoglobin remains elevated however symptoms have resolved.
Patient C: A 2-year-old male had persistently elevated hemoglobin since birth along with facial flushing, fatigue, and headaches. Hemoglobin at 2 years of age was 13.4 g/dL, Hct 38.4%, and EPO 14. Gene sequencing revealed a VUS in EPAS1 p.P643S which encodes for a hypoxia induced transcription factor and pathogenic variants associated with erythrocytosis. The patient has started aspirin 81 mg however, as his symptoms have resolved without further treatment, family has elected to forego additional treatment or bone marrow biopsy unless symptoms recur.
Discussion
This series highlights genetic variability and clinical heterogeneity seen in pediatric PV. All patients underwent a diagnostic evaluation that included evaluation for non-hematologic causes of erythrocytosis including renal, cardiac, and erythropoietin pathway etiologies. Hematologic evaluation should include a hemoglobin electrophoresis to assess for high oxygen affinity hemoglobin variants. Diagnostic evaluation should not only include testing for mutations in JAK2, CALR, and MPL but consider additional genetic testing for more rare genetic causes of polycythemia including EPAS1 and SH2B3. Utilizing a modified NCCN diagnostic and risk stratification framework, all patients were classified as low-risk and managed with low-dose aspirin (81 mg) to reduce the risk of thrombosis and, when indicated by symptom severity, phlebotomy every 6-8 weeks to maintain a hematocrit of <45%.
ConclusionGuidelines for diagnosis and treatment of PV in pediatric populations are not well defined. Applying adult guidelines for treatment did not show significant hematologic improvement, although symptom relief was observed in this series of patients. This series further supports the need for additional research into pediatric-specific diagnostic and management criteria for PV that incorporates clinical and genetic variability.
