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

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 GaDOTA-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.

Intraprocedural cortisol measurement increases adrenal vein sampling success rate in primary aldosteronism.

BACKGROUND: Adrenal venous sampling (AVS) is the gold standard for the identification of unilateral primary aldosteronism (PA), but is technically difficult. The aim of our study was to assess whether intraprocedural cortisol measurement (IPCM) increases AVS success rate. METHODS: Twenty-five consecutive PA patients underwent cosyntropin-stimulated AVS. Cortisol was measured immediately in a first set of samples drawn from adrenal veins and inferior vena cava. The selectivity criterion was an adrenal vein-to-inferior vena cava cortisol ratio ≥5. If bilateral selectivity was not achieved in a first set of samples, a second set was obtained during the same radiological session. PA was judged as unilateral if the gradient of cortisol-corrected aldosterone between dominant and nondominant side was >3.5. Twenty-five consecutive PA patients who had previously been submitted to AVS without IPCM served as historical controls. Lateralizing patients who underwent unilateral adrenalectomy were followed for 2 years after surgery. RESULTS: Bilateral selectivity using IPCM was achieved in 19/25 patients in the first set of samples, and in an additional four cases in the second set (92% vs. 76%; P = 0.06). The final rate of bilateral selectivity was higher than that obtained in the historical series (23/25 vs. 16/25, P = 0.04), whereas bilateral selectivity in the first set of samples was not different from that achieved in the historical series. Nineteen lateralizing patients (13 of the present series, six of the historical series) were submitted to adrenalectomy, resulting in reversal of PA. CONCLUSIONS: IPCM increases the success rate of AVS.