A 48-year-old Caucasian lady, an elementary school teacher from Minnesota, was noted to have erythrocytosis while undergoing a kidney donor evaluation. Hgb and Hct were 19.4 g/dl and 57%, respectively, with normal leukocyte and platelet count. The patient had a history of persistent erythrocytosis with Hgb/Hct of 19.3 g/dl/58%, documented two decades prior to her diagnosis. Her medical history was significant for hypertension, optimally controlled with lisinopril; tobacco use, vascular events, or microvascular symptoms were absent in her medical history. Importantly, both her mother and brother were previously noted to have erythrocytosis. Initial laboratory evaluation included EPO (1.1 mIU/mL; normal reference range 2.6–18.5) and peripheral blood JAK2 mutational screen (wild-type for both exons 12 and 14). Based on family history and subnormal EPO, EPOR mutation screen was pursued and revealed a heterozygous c.1316G>A, p.(Trp439*) mutation in exon 8 that caused a premature stop codon and truncated the 70 C-terminal amino acids resulting in a gain of function []; the altered C-terminal increases EPOR stability at the cell surface resulting in pre-activation of both receptor and constitutive JAK2 signaling similar to what is seen in PV []. This EPOR mutation has been shown to be associated with autosomal dominant erythrocytosis [] and also reported as a de novo alteration [, ]. Taken together, this information supported a diagnosis of autosomal dominant hereditary or familial erythrocytosis type 1. Most patients with EPOR mutations are asymptomatic; with isolated cases experiencing cardiovascular complications and deep vein thrombosis []. While phlebotomy may benefit some patients in alleviating symptoms, it does not appear to have a protective effect with regards to cardiovascular events []. In terms of management, optimal hypertension control with lisinopril was emphasized and low-dose aspirin initiated. Since our patient was asymptomatic, routine phlebotomy was not recommended, however, phlebotomy prior to kidney donation was a consideration.
A 41-year old male presents with a 5-year history of erythrocytosis and high hematocrit levels. Laboratory test at presentation disclose high Hb (17.8 g/dL) and Hct (54%), normal WBC (6.7 × 109/L) and platelet counts (203 × 109/L), and erythropoietin (Epo) levels below local laboratory ranges (3.9 mU/mL [4.3–29]). A JAK2 mutation with 2.8% variant allele frequency (VAF) is detected on peripheral blood granulocytes (data on exon 12 and/or additional exon 14 mutations not available). The overall clinical presentation is suspected for PV and prompts a BM evaluation. A BM biopsy () features cellularity within age-related limits, preserved maturation of erythroid and myeloid lineages, and only a minor increase in megakaryocytes. The latter are sparse in distribution, with predominant mature-type morphology and only rare, scattered large forms. Thus, the lack of clear-cut major criterion 2 () does not allow a diagnosis of PV and warrants a provisional characterization as MPN-U.\nIn the present case, the histology is not inconsistent with the clinical diagnosis of PV, but it is not robust (particularly, some clustering of megakaryocytes with scattered large forms are disputable). A pre-morphologic diagnosis of MPN (i.e., a diagnosis made without full-blown MPN histology) is not common []. Indeed, it may occur in clinical settings where awareness of early phase MPNs suggests comprehensive laboratory and molecular screening, including quantitative PCR for low-burden driver gene mutations []. In such a context, it is worth noting that low VAF of JAK2 may be due to multiple base mutations in exon 14, which may hamper primer annealing and affect the quantification of the mutational burden []. Thus, searching for additional exon 14 mutations may be justified in cases with inexplicably low burdens of JAK2.