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 17-year-old Caucasian male, a high school student from Missouri was referred for evaluation of unexplained erythrocytosis. He reported a myriad of symptoms including nausea, vomiting, abdominal pain, weight loss, fatigue, headaches, cold hands and feet with numbness and tingling, hyperhidrosis, palpitations, and pruritus. He was a non-smoker without illicit drug or hormone use. Family history was unremarkable. On physical examination, no cutaneous, abdominal or neurological abnormalities were noted. A review of serial blood counts showed a consistent elevation in Hgb >16.5 g/dl, with peak Hgb/Hct of 18.3 g/dl/52.4% and normal leukocyte and platelet counts. PV was excluded with a negative JAK2V617F/exon 12 mutation screen and elevated EPO at 22.6 mIU/mL (normal range; 2.6–18.5 mIU/mL). Bone marrow aspirate/biopsy was without features of a MPN. Hereditary erythrocytosis evaluation did not reveal high-affinity Hgb variants or mutations in 2,3-Bisphosphoglycerate Mutase (BPGM)(exons 1–4), EPOR (exon 8), or oxygen-sensing pathway proteins, including hypoxia-inducible factor 2 α (HIF2A) encoded by endothelial PASS domain protein 1 (EPAS1) (exons 9 and 12), prolyl hydroxylase 2 (PHD2) encoded by egl-9 family hypoxia-inducible factor 1(EGLN1)(exons 1-5), von Hippel Lindau (VHL) (three coding exons and intron/exon boundaries). Chest/abdominal imaging, arterial blood gas, transthoracic echocardiogram with shunt study, urinary catecholamines/metanephrines were unremarkable. Interestingly, MRI brain/spine revealed multiple cerebrovascular malformations; both developmental venous anomalies and cavernous hemangiomas in the frontal and temporal regions. Accordingly, the cerebrovascular malformations were hypothesized to be a plausible link to the patient’s erythrocytosis. Surgical intervention was not feasible due to the presence of multiple anomalies. He was initiated on phlebotomies with marked improvement in symptoms; thereafter, need for periodic phlebotomies was determined by symptoms rather than a target Hct value. This previously published case underscores the importance of a systematic diagnostic approach to JAK2 unmutated erythrocytosis [].