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Head and Neck Paragangliomas in Von Hippel-Lindau Disease and Multiple Endocrine Neoplasia Type 2

Departments of Otorhinolaryngology (C.C.B.), Pathology (T.W.), Neuroradiology (J.W.), and Surgery (K.R.); Department of Nephrology (Z.E., H.P.H.N.), Section of Preventive Medicine; and Division of Pediatric Hematology and Oncology (U.K.), Albert-Ludwigs-University, D-79106 Freiburg, Germany; Génétique Oncologique Ecole Pratique des Hautes Estudes-Centre National de la Recherche Scientifique Formation de Recherche en Évolution 2939 (S.R.), Faculté de Médecine Paris Sud, and Réseau National Institut National du Cancer (INCa) and Centre Pilote Tumeurs Rares INCa (S.R.)/Assistance Publique-Hôpitaux de Paris, Service d’Urologie, Hôpital de Kremlin-Bicêtre (S.R.), F-94270 Kremlin-Bicêtre, France; Assistance Publique-Hôpitaux de Paris, Service de Génétique (A.-P.G.-R., N.B.) and Unité d’Hypertension artérielle (P.F.P.), Hôpital Européen Georges Pompidou, and Université Paris Descartes, F-75006 Paris, France; Hereditary Endocrine Cancer Group (A.C., M.R.), Spanish National Cancer Center, Madrid, and Instituto de Salud Carlos III Center for Biomedical Research on Rare Diseases (CIBERER), E-28029 Madrid, Spain; Neurosurgery Department (J.M.d.C.), Fundación Jiménez Díaz, Autonomous University, E-28049 Madrid, Spain; Department of Pathology (F.H.v.N., R.R.d.K., J.G.), Josephine Nefkens Institute, Erasmus MC-University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands; Department of Nuclear Medicine (M.A.W.), University Hospital Basel, CH-4003 Basel, Switzerland; Division of Nephrology and Endocrinology (K.R.), Otto von Guericke University, D-39106 Magdeburg, Germany; Department of Otolaryngology (V.D.), Skull Base Surgery Department, Hôpital Pellegrin, University Victor Segalen Bordeaux 2, F-33000 Bordeaux, France; Laboratoire de Génétique et Réseau National INCa (S.G.), Hôpital Edouard Herriot, F-69437 Lyon, France; and Genomic Medicine Institute (C.E.), Lerner Research Institute, and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195

Address all correspondence and requests for reprints to: Prof. Dr. Hartmut P. H. Neumann, M.D., Department of Nephrology and General Medicine, University of Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany. E-mail: hartmut.neumann{at}uniklinik-freiburg.de.

Background: Head and neck paragangliomas (HNPs) occur as sporadic or familial entities, the latter mostly in association with germline mutations of the SDHB, SDHC, or SDHD (SDHx) genes. Heritable non-SDHx HNP might occur in von Hippel-Lindau disease (VHL, VHL gene), multiple endocrine neoplasia type 2 (MEN2, RET gene), and neurofibromatosis type 1 (NF1, NF1 gene). Reports of non-SDHx HNP presentations are scarce and guidance for genetic testing nonexistent.

Patients and Methods: An international consortium registered patients with HNPs and performed mutation analyses of the SDHx, VHL, and RET genes. Those with SDHx germline mutations were excluded for purposes of this study. Personal and family histories were evaluated for paraganglial tumors, for the major tumor manifestations, and for family history of VHL, MEN2, or NF1.

Results: Twelve patients were found to have hereditary non-SDHx HNPs of a total of 809 HNP and 2084 VHL registrants, 11 in the setting of germline VHL mutations and one of a RET mutation. The prevalence of hereditary HNP is five in 1000 VHL patients and nine in 1000 non-SDHx HNP patients. Comprehensive literature review revealed previous reports of HNPs in five VHL, two MEN2, and one NF1 patient. Overall, 11 here presented HNP cases, and four previously reported VHL-HNPs had lesions characteristic for VHL and/or a positive family history for VHL.

Conclusions: Our observations provide evidence that molecular genetic testing for VHL or RET germline mutations in patients with HNP should be done only if personal and/or family history shows evidence for one of these syndromes.

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				J. Gaal, F. H. van Nederveen, Z. Erlic, E. Korpershoek, R. Oldenburg, C. C. Boedeker, U. Kontny, H. P. Neumann, W. N. M. Dinjens, and R. R. de Krijger Parasympathetic Paragangliomas Are Part of the Von Hippel-Lindau Syndrome J. Clin. Endocrinol. Metab., November 1, 2009; 94(11): 4367 - 4371. [Abstract] [Full Text] [PDF]