Concurrent heterozygous Von-Hippel-Lindau and transmembrane-protein-127 gene mutation causing an erythropoietin-secreting pheochromocytoma in a normotensive patient with severe erythrocytosis

Aurelio Negro, Gallia Graiani, Davide Nicoli, Enrico Farnetti, Bruno Casali, Ignazio Verzicco, Stefano Tedeschi, Angelo Ghirarduzzi, Valentina Cannone, Loredana D.E. Marco, Angela Filice, Giuseppe Gemelli, Alessandro Giunta, Aderville Cabassi

Research output: Contribution to journalArticle

Abstract

Background:Mutations of genes related to Krebs cycle enzymes, kinases or to pseudohypoxic signaling pathways, including Von-Hippel-Lindau (VHL) and transmembrane-protein-127 predispose to pheochromocytoma and paraganglioma development. Homozygous loss of function mutation of VHL (VHL 598C>T) gene can associate with polycythemia because of an altered hypoxia sensing.Patient:A 19-year-old normotensive man presented with headache, fatigue associated with severe erythrocytosis (hematocrit 76%), high hemoglobin (25.3 g/dl) in normoxic condition. Bone marrow biopsy showed marked hyperplasia of erythroid series. The Janus kinase 2 (V617F) mutation was absent. Abdominal computed tomography scan showed a 8-mm left adrenal pheochromocytoma with tracer uptake on 68GaDOTA-octreotate PET. Twenty-four-hour urinary metanephrine excretion was slightly increased, while normetanephrine, 3-methoxytyramine were normal. Adrenal veins sampling showed high left-side erythropoietin secretion.Results:Next-generation sequencing genetic analysis evidenced two concurrent heterozygous mutation of VHL598C>T and of transmembrane-protein-127 c.268G>A. Left side adrenalectomy improved symptoms, erythrocytosis, hemoglobin, and erythropoietin circulating levels. Adrenal histologic sections showed a pheochromocytoma with extensive immunostaining for erythropoietin, but also coexpression of chromogranin A, a marker of chromaffin tissue.Conclusion:Congenital polycythemia was clinically diagnosed, mimicking Chuvash polycythemia. Chuvash polycythemia is an autosomal recessive disorder that usually harbors a homozygous mutation of VHL598C>T but not predispose to pheochromocytoma development; in contrast our patient showed for the first time that the concurrent heterozygous VHL and TMEM mutations, resulted in a clinical phenotype of a normotensive patient with polycythemia due to erythropoietin-secreting pheochromocytoma that improved after adrenalectomy.

Original languageEnglish (US)
Pages (from-to)340-346
Number of pages7
JournalJournal of hypertension
Volume38
Issue number2
DOIs
StatePublished - Feb 1 2020

Keywords

  • Chuvash polycythemia
  • Von-Hippel-Lindau
  • erythrocytosis
  • erythropoietin
  • normotension
  • pheochromocytoma
  • transmembrane-protein-127

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Negro, A., Graiani, G., Nicoli, D., Farnetti, E., Casali, B., Verzicco, I., Tedeschi, S., Ghirarduzzi, A., Cannone, V., Marco, L. D. E., Filice, A., Gemelli, G., Giunta, A., & Cabassi, A. (2020). Concurrent heterozygous Von-Hippel-Lindau and transmembrane-protein-127 gene mutation causing an erythropoietin-secreting pheochromocytoma in a normotensive patient with severe erythrocytosis. Journal of hypertension, 38(2), 340-346. https://doi.org/10.1097/HJH.0000000000002253