Head and Neck Paragangliomas in Von Hippel-Lindau Disease and ...

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INTRODUCTION Head and neck paragangliomas (HNPs) are highly vascularized tumors of the autonomic nervous system, mainly arising from the carotid body or the glomus jugulare, tympanicum or vagale. HNPs occur as sporadic as well as hereditary entities (1, 2). Hereditary HNPs have attracted interest in particular from 2000, when a first susceptibility gene for the so called ”paraganglioma syndromes” (PGL) was detected (PGL 1) (3). This gene, SDHD, located on 11q23, encodes subunit D of the enzyme succinate dehydrogenase or mitochondrial complex II. Subsequently, two other PGL susceptibility genes, encoding the B and C subunits of SDH, were described, SDHB (PGL4) and SDHC (PGL3) (4, 5). A fourth susceptibility gene, for PGL 2, has been mapped to 11q13, but has not yet been identified (6). These three known PGL susceptibility genes will be collectively referred to here as SDHx. In contrast, SDHA gene mutations do not predispose to PGL (7). Because of intense clinical investigation subsequent to 2000, we know that HNP is a major component tumor of the syndromes characterized by germline SDHx mutations (1, 2, 8, 9). Studies from us and others have shown that patients with SDHx mutations are not only at risk for HNPs, but also for other tumors of the paraganglial system including adrenal pheochromocytoma and extraadrenal pheochromocytoma of the retroperitoneum, pelvis and thorax (1, 2, 8, 10, 11). However, HNPs occurring in the non-SDHx heritable disorders have been anecdotal. In order to examine the clinical context of non-SDHx heritable HNPs, we adopted and updated the European Australian American HNP Registry in which we previously studied the characteristics and prevalence of HNPs (12) and proposed to different groups to join us. As the Non-SDHx HNP Consortium, we then proceeded to study the prevalence of HNPs and other salient clinical features and family histories in registrants found to have von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2) and type 1 neurofibromatosis (NF 1). 6
MATERIAL AND METHODS Subjects The international Non-SDHx-HNP-Consortium was constituted in 2008 in order to identify and to clinically and genetically characterize patients with HNP with heritable syndromes in the absence of germline SDHx mutations. We paid particular attention to additional component tumors suggestive of VHL, MEN 2 or NF 1. We adopted and updated the registrants from the European Australian American HNP Registry including symptomatic and asymptomatic HNPs as of March 1, 2009 which included a total of 513 subjects. In particular, centers dedicated to clinical care and molecular genetic diagnosis of HNPs in 26 countries including Germany, Spain, The Netherlands, Italy, Hungary, Ukraine, Serbia, Greece, Poland, Sweden, Finland, Denmark, Belgium, France, Switzerland, Austria, Turkey, Iran, China, Japan, the USA, Brazil, Chile, Argentina, Australia and New Zealand were recontacted. Separately to the European Australian American HNP Registry, the Netherlands and France have national HNP registries with 147 and 149 registrants in whom SDHx mutations have been excluded, respectively. This aimed to identify unrecognized patients with HNP for case registration and for updating the HNP registry for prevalence estimations. For prevalence estimations in VHL, we used the national population-based registries for Germany, France, Spain, and the Netherlands. Genetic Analysis All registrants provided 10 ml EDTA-anticoagulated blood for molecular genetic analyses. The analyses comprised testing of the VHL (RefSeq:NM_000551.2) and RET (RefSeq:NM_020975.4) genes for germline mutations. DNA extraction, primers, PCR conditions and sequencing methods followed published protocols of international standards (1, 2, 10, 11). Of note, analyses also included screening for large deletions or rearrangements of the VHL gene, since such mutations have been described in VHL patients with pheochromocytoma (13, 14). Overall, 809 HNP patients (513+147+149) of the European Australian American HNP Registry, the French HNP Registry and the Rotterdam HNP Registry combined were subjected to the above described analyses. 7
Page 1 and 2: Head and Neck Paragangliomas in Von
Page 3 and 4: disclaims any responsibility or lia
Page 5: ABSTRACT Background Head and neck p
Page 9 and 10: Regarding VHL, the prevalence of HN
Page 11 and 12: eceptor scintigraphy revealed a hot
Page 13 and 14: In 1994, a 34-year old woman withou
Page 15 and 16: involved in a pheochromocytoma pres
Page 17 and 18: ACKNOWLEDGMENTS We thank the member
Page 19 and 20: 8. Neumann HP, Bausch B, McWhinney
Page 21 and 22: 19. Pawlowsky T BP 2000 Aktueller S
Page 23: Abbreviations: HNP, head and neck p

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