Erythrocytosis associated with cerebral hemangiomas and multiple venous anomalies
Authors: Naseema Gangat, Animesh Pardanani, Ayalew Tefferi
Journal: American Journal of Hematology (2020)

A previously healthy 17-year-old Caucasian male was referred for evaluation of unexplained erythrocytosis. His main symptoms over the last year included nausea, vomiting for up to five episodes per day, and upper abdominal pain with associated weight loss of 20 pounds. Furthermore, he endured severe fatigue, headaches, cold hands and feet with numbness and tingling, hyperhidrosis, and palpitations, with occasional itching. 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. Serial blood counts revealed a consistent elevation in hemoglobin (> 165 g/L) and hematocrit, with normal leukocyte and platelet count. Peak hemoglobin/hematocrit values were 183 g/L and .52 respectively. A workup for erythrocytosis was initiated with JAK2V617F/exon 12 mutational screen which was negative, and erythropoietin level which was elevated at 22.6 mIU/mL (normal range; 2.6-18.5 mIU/mL) ruling out polycythemia vera (PV).1 Bone marrow aspirate/biopsy was normocellular without stigmata of a myeloproliferative neoplasm. A hereditary erythrocytosis evaluation2 was undertaken given his young age; an abnormal hemoglobin variant was not detected. Moreover, gene sequencing studies for 2,3-bisphosphoglycerate Mutase (BPGM), erythropoietin receptor (EPOR), and oxygen sensing pathway proteins, hypoxia-inducible factor-2 alpha(HIF2A), prolyl hydroxylase domain-2 (PHD2), and Von Hippel- Lindau (VHL) did not reveal molecular aberrations. Abdominal imaging (CT angiography, MRI, ultrasound) was unrevealing for vascular pathology, hepatic/renal tumors or lymphadenopathy. Spleen was mildly enlarged at 14 cm. Furthermore, CT of the chest was without significant findings. Given the constellation of systemic symptoms, hormonal dysfunction namely thyroid, adrenal, and pheochromocytoma were excluded. Transthoracic echocardiogram with shunt study was unremarkable. This case serves to highlight the varied symptomatology encountered in patients with erythrocytosis and the intricacies involved in the clinical evaluation of JAK2 unmutated erythrocytosis. A systematic approach is key once PV has been excluded by an elevated erythropoietin level and a negative JAK2 mutational screen.3 In the absence of a satisfying explanation, central nervous system (CNS) imaging was pursued. Intriguingly, MRI of the brain revealed multiple cerebrovascular malformations; a moderate sized developmental venous anomaly was located within the parasagittal anterior left frontal lobe (Figure 1A), and another within the left temporal region (Figure 1B). A third smaller developmental venous anomaly was located within the left frontal lobe and associated with a 5 mm focus of hemosiderin deposition. An additional punctate focus of hemosiderin deposition was noted within the deep white matter of the right frontal lobe representing a cavernous hemangioma (Figure 1C). Moreover, spine imaging was without vascular anomalies. Based on our evaluation, the cerebrovascular malformations identified were a plausible link to the erythrocytosis. Neurology and neurosurgical consultations were sought with recommendations for repeat imaging in a year. He was initiated on phlebotomies with marked improvement in symptoms. Cerebrovascular malformations encompass several abnormalities ranging from arteriovenous malformations (AVM), cavernous hemangiomas, and telangiectasias, to developmental venous anomalies (Table S1). Mixed malformations, namely cavernous hemangiomas and developmental venous anomalies, such as in our patient have not been previously reported in the context of erythrocytosis. A meticulous literature review yielded a solitary case of cerebral arteriovenous malformation (AVM) resulting in erythrocytosis.4 In the latter instance, presence of an AVM was felt to induce alterations in cerebral blood flow creating a “steal” phenomenon and shunting resulting in increased erythropoietin production; surgical resection of the AVM led to a rapid decline in erythropoietin level and prompt resolution of erythrocytosis.4 Alternatively, astrocytes may ramp up erythropoietin production in the face of local hypoxia (AVM induced vascular steal) with systemic release of erythropoietin facilitated by vascular endothelial growth factor mediated breakdown of the blood brain barrier.5, 6 In line with CNS vascular malformations and erythrocytosis, a predilection for vertebral hemangiomas in Chuvash polycythemia patients with homozygous germ line VHL mutations deserves mention.7 Similarly, a multitude of cases linking erythrocytosis and cerebellar hemangioblastoma have been reported. Moreover, elevated erythropoietin in the tumor fluid confirms it as a site of ectopic erythropoietin production8 with resection of the tumor resulting in resolution of erythrocytosis. In addition, hemangiomas involving the lung, kidneys, and liver have been reported in association with erythrocytosis. A comprehensive review of the literature in regards to vascular malformations associated with erythrocytosis is provided in Table S2. In summary, we report a novel observation of cerebrovascular malformations specifically mixed malformations (cavernous hemangiomas and developmental venous anomalies) and secondary erythrocytosis occurring in the absence of VHL syndrome. Together, our findings underscore the need to consider CNS imaging in the evaluation of JAK2 unmutated erythrocytosis with elevated erythropoietin level. We thank Gary M Miller M.D. from radiology for his assistance in providing MRI images. The authors declare no potential conflict of interest. Table S1 Types of cerebrovascular malformations Table S2 Vascular malformations and erythrocytosis Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.