Novel insights into the polycythemia-paraganglioma-somatostatinoma syndrome

Abstract

The syndrome of paraganglioma (PGL), somatostatinoma (SOM), and early childhood polycythemia in patients with somatic mutations in the hypoxia-inducible factor 2 alpha ( HIF2A) gene is described in only a few patients worldwide. The present study provides detailed information about the clinical aspects and course of 7 patients with this syndrome and brings these experiences into perspective with the pertinent literature. Six females and one male presented at a median age of 28 years (range 11–46). Two were found to have HIF2A somatic mosaicism. No relatives were affected. All patients were diagnosed with secondary polycythemia before age 8 and before PGL/SOM developed. PGLs were found at a median age of 17 years (range 8–38) and SOMs at 29 years (range 22–38). PGLs were multiple, recurrent, and metastatic in 100%, 100%, and 29% of all cases, and SOMs in 40%, 40%, and 60%, respectively. All PGLs were primarily norepinephrine producing. All patients had abnormal ophthalmologic findings and those with SOMs had gallbladder disease. Computed tomography (CT) and magnetic resonance imaging revealed cystic lesions at multiple sites and hemangiomas in 4 patients (57%), previously thought to be pathognomonic for von Hippel-Lindau disease. The most accurate radiopharmaceutical to detect PGL appeared to be [ ¹⁸F]-fluorodihydroxyphenylalanine ([ ¹⁸F]-FDOPA). Therefore, [ ¹⁸F]-FDOPA PET/CT, not [ ⁶⁸Ga]-(DOTA)-[Tyr3]-octreotate ([ ⁶⁸Ga]-DOTATATE) PET/CT is recommended for tumor localization and aftercare in this syndrome. The long-term prognosis of the syndrome is unknown. However, to date no deaths occurred after 6 years follow-up. Physicians should be aware of this unique syndrome and its diagnostic and therapeutic challenges.