Christina Pamporaki1, Barbora Hamplova2, Mirko Peitzsch3, Aleksander Prejbisz4, Felix Beuschlein5, Henri J L M Timmers6, Martin Fassnacht7, Barbara Klink8,9,10,11, Maya Lodish2, Constantine A Stratakis2, Angela Huebner12, Stephanie Fliedner13, Mercedes Robledo14, Richard O Sinnott15, Andrzej Januszewicz4, Karel Pacak2, Graeme Eisenhofer16,3. 1. Departments of Medicine ??I and. 2. The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-2425. 3. Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus at the TU Dresden, D-01307 Dresden, Germany. 4. Department of Hypertension, Institute of Cardiology, 04-628 Warsaw, Poland. 5. Department of Medicine IV, University Hospital of Munich, 80539 Munich, Germany. 6. Department of Internal Medicine, Radboud University Medical Centre, 6525 HP Nijmegen, The Netherlands. 7. Department of Internal Medicine, Division of Endocrinology, University Hospital, University of Wuerzburg, 97070 Wuerzburg, Germany. 8. Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus at the TU Dresden, D-01307 Dresden, Germany. 9. German Cancer Consortium, D-01307 Dresden, Germany. 10. German Cancer Research Center, 69120 Heidelberg, Germany. 11. National Center for Tumor Diseases, D-01307 Dresden, Germany. 12. Pediatrics, and. 13. Department of Medicine, University Medical Center Schleswig-Holstein, 23562 Luebeck, Germany. 14. Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, 28029 Madrid, Spain. 15. Department of Computing and Information, University of Melbourne, 3010 Melbourne, Australia. 16. Departments of Medicine ΙΙI and.
Abstract
CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) in children are often hereditary and may present with different characteristics compared with adults. Hereditary PPGLs can be separated into cluster 1 and cluster 2 tumors due to mutations impacting hypoxia and kinase receptor signaling pathways, respectively. OBJECTIVE: To identify differences in presentation of PPGLs between children and adults. DESIGN: A retrospective cross-sectional clinical study. SETTING: Seven tertiary medical centers. PATIENTS: The study included 748 patients with PPGLs, including 95 with a first presentation during childhood. Genetic testing was available in 611 patients. Other data included locations of primary tumors, presence of recurrent or metastatic disease, and plasma concentrations of metanephrines and 3-methoxytyramine. RESULTS: Children showed higher (P < 0.0001) prevalence than adults of hereditary (80.4% vs 52.6%), extra-adrenal (66.3% vs 35.1%), multifocal (32.6% vs 13.5%), metastatic (49.5% vs 29.1%), and recurrent (29.5% vs 14.2%) PPGLs. Tumors due to cluster 1 mutations were more prevalent among children than adults (76.1% vs 39.3%; P < 0.0001), and this paralleled a higher prevalence of noradrenergic tumors, characterized by relative lack of increased plasma metanephrine, in children than in adults (93.2% vs 57.3%; P < 0.0001). CONCLUSIONS: The higher prevalence of hereditary, extra-adrenal, multifocal, and metastatic PPGLs in children than adults represents interrelated features that, in part, reflect the lower age of disease presentation of noradrenergic cluster 1 than adrenergic cluster 2 tumors. The differences in disease presentation are important to consider in children at risk for PPGLs due to a known mutation or previous history of tumor.
CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) in children are often hereditary and may present with different characteristics compared with adults. Hereditary PPGLs can be separated into cluster 1 and cluster 2 tumors due to mutations impacting hypoxia and kinase receptor signaling pathways, respectively. OBJECTIVE: To identify differences in presentation of PPGLs between children and adults. DESIGN: A retrospective cross-sectional clinical study. SETTING: Seven tertiary medical centers. PATIENTS: The study included 748 patients with PPGLs, including 95 with a first presentation during childhood. Genetic testing was available in 611 patients. Other data included locations of primary tumors, presence of recurrent or metastatic disease, and plasma concentrations of metanephrines and 3-methoxytyramine. RESULTS: Children showed higher (P < 0.0001) prevalence than adults of hereditary (80.4% vs 52.6%), extra-adrenal (66.3% vs 35.1%), multifocal (32.6% vs 13.5%), metastatic (49.5% vs 29.1%), and recurrent (29.5% vs 14.2%) PPGLs. Tumors due to cluster 1 mutations were more prevalent among children than adults (76.1% vs 39.3%; P < 0.0001), and this paralleled a higher prevalence of noradrenergic tumors, characterized by relative lack of increased plasma metanephrine, in children than in adults (93.2% vs 57.3%; P < 0.0001). CONCLUSIONS: The higher prevalence of hereditary, extra-adrenal, multifocal, and metastatic PPGLs in children than adults represents interrelated features that, in part, reflect the lower age of disease presentation of noradrenergic cluster 1 than adrenergic cluster 2 tumors. The differences in disease presentation are important to consider in children at risk for PPGLs due to a known mutation or previous history of tumor.
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