Novel insights into the polycythemia-paraganglioma-somatostatinoma syndrome.
Worldwide, the syndromes of paraganglioma (PGL), somatostatinoma (SOM) and early childhood polycythemia are described in only a few patients with somatic mutations in the hypoxia-inducible factor 2 alpha (HIF2A). This study provides detailed information about the clinical aspects and course of 7 patients with this syndrome and brings into perspective these experiences 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 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.
Section on Medical NeuroendocrinologyEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Roland
R
Därr
Section on Medical NeuroendocrinologyEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Joan
J
Nambuba
Section on Medical NeuroendocrinologyEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Jaydira
J
Del Rivero
Section on Medical NeuroendocrinologyEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Ingo
I
Janssen
Laboratory of PathologyNational Institutes of Health, Bethesda, Maryland, USA.
Maria
M
Merino
Institute of HematologyClinical Center of Serbia and Medical Faculty University of Belgrade, Belgrade, Serbia.
Milena
M
Todorovic
Institute of Transfusiology and Hemobiology of Military Medical Academy and Institute for Medical ResearchUniversity of Belgrade, Belgrade, Serbia.
Bela
B
Balint
Section on Medical NeuroendocrinologyEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.|1st Department of Internal MedicineFaculty of Medicine, Pavol Jozef Safarik University in Kosice, Kosice, Slovakia.
Ivana
I
Jochmanova
Division of HematologyUniversity of Utah, Salt Lake City, Utah, USA.
Josef T
JT
Prchal
Tupper Research Institute and Department of MedicineDivision of Endocrinology, Diabetes and Metabolism, Tufts Medical Center, Boston, Massachusetts, USA.
Ronald M
RM
Lechan
Department of Pathology and Laboratory MedicineTufts Medical Center, Boston, Massachusetts, USA.
Arthur S
AS
Tischler
Institute of EndocrinologyClinical Center of Serbia, Medical Faculty, University Belgrade, Belgrade, Serbia.
Vera
V
Popovic
Institute of EndocrinologyClinical Center of Serbia, Medical Faculty, University Belgrade, Belgrade, Serbia.
Dragana
D
Miljic
Section on Medical NeuroendocrinologyEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Karen T
KT
Adams
Department of OphthalmologyEugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.
F Ryan
FR
Prall
Department of Radiology and Imaging SciencesClinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Alexander
A
Ling
Division of Child NeurologyDepartment of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Meredith R
MR
Golomb
Riley Hospital for Children at Indiana University HealthIndianapolis, Indiana, USA.
Michael
M
Ferguson
Endocrine Oncology BranchNational Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Naris
N
Nilubol
Division of Nuclear MedicineDepartment of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Clara C
CC
Chen
Division of Epidemiology and Clinical ApplicationsNational Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
Emily
E
Chew
Department of Nuclear MedicineLa Timone University Hospital & CERIMED & Inserm UMR1068 Marseille Cancerology Research Center, Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France.
David
D
Taïeb
Division of Intramural ResearchEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Constantine A
CA
Stratakis
Medical Oncology BranchNational Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Tito
T
Fojo
Neuro-Oncology BranchCenter for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Chunzhang
C
Yang
Endocrine Oncology BranchNational Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Electron
E
Kebebew
Neuro-Oncology BranchCenter for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Zhengping
Z
Zhuang
Section on Medical NeuroendocrinologyEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA karel@mail.nih.gov.
Karel
K
Pacak
D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000150:complications / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy; D000328:Adult; D002648:Child; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary / Q000150:complications / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000150:complications / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy; D010235:Paraganglioma / Q000150:complications / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy; D011086:Polycythemia / Q000150:complications / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy; D012189:Retrospective Studies; D013005:Somatostatinoma / Q000150:complications / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy; D013577:Syndrome; D055815:Young Adult
HIF2A mutation; paraganglioma; pheochromocytoma; polycythemia; somatostatinoma
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