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

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four sons were found to carry the mutation. Clinical screening of all 3 disclosed a 2.4 cm abdominal paraganglioma in one of them, but no lesion in the other brothers. Summary of Case Reports In summary, of the 12 non-SDHx HNP arising in VHL and MEN 2 patients, 8 are female and 4 are male, with ages at diagnosis 15-42 (mean 28). Eleven had an VHL mutations and one an RET mutations. Eight of the 11 VHL mutations and also the RET mutation were missense mutations. Three cases were identified at an asymptomatic stage, whereas nine had symptoms of a local mass or due to dysfunction of the vestibular-cochlear nerve. All but one of the VHL cases had carotid body tumors. The other VHL case had a vagal paraganglioma and the case with the RET mutation had a jugular paraganglioma. All cases had a single HNP. Family history was suggestive for VHL in 6 cases. Additional tumors have been previously diagnosed in 8 cases. Thus, all cases with VHL had clinical manifestations and/or a suggestive family history for VHL. In addition to those meeting the criteria for heritable non-SDHx-HNP for this study, there are 31 out of 809 registrants who have the stigmata of inherited HNP. Eight had a family history for paraganglial tumors in relatives, and 5 HNP patients also had abdominal paraganglial tumors. Furthermore is note worthy that 20 of the HNP patients had multiple tumors. All these patients had no germline mutation in the genes SDHB, SDHC, SDHD, RET and VHL, and no clinical signs for NF1. DISCUSSION Paraganglial tumors can be divided into nearly always vasoactive abdominal, pelvic and thoracic pheochromocytomas (here all classified as pheochromocytomas) and nearly always non-vasoactive but space-occupying tumors of the head and neck paraganglia (here all classified as paragangliomas or HNPs). Several studies over the last 7 years have shown that approximately one third of symptomatic presentations of pheochromocytomas, even in the absence of other syndromic features or family history, are caused by germline mutations.(1, 2, 8, 10, 11, 16) The prevalence of susceptibility genes 14
involved in a pheochromocytoma presentation, in decreasing order of frequency, of VHL, SDHB, RET, NF1 and SDHD is 41%, 18%, 17%, 13%, and 11% respectively.(16) Given the data that even apparently sporadic pheochromocytomas have a relatively high frequency of germline mutations, most clinicians would offer gene testing, in the setting of genetic counselling, to all patients presenting with a pheochromocytoma irrespective of other features or family history. Knowledge of the relative prevalence of a specific gene involved associated with certain clinical features allows some type of prioritisation of which gene(s) to begin testing with. In contrast to relatively high prevalences of VHL, RET and NF1 involved in pheochromocytoma presentations, our recent international molecular genetic study on nearly 600 unrelated patients with symptomatic HNPs showed that virtually all patients with HNPs due to germline mutations have the mutation in one of the following genes: SDHB, SDHC and SDHD (12). Additionally, certain clinical features in HNP patients can accurately help prioritize which gene to begin testing (12). The occurrence of HNP in the non-SDHx PGL syndromes, mainly VHL and MEN 2, has been anecdotal (20-27). The literature provides little guidance as to the prevalence of VHL, MEN 2 and NF 1 in HNP presentations. It also provides little guidance in regard to associated clinical features and family history in patients with non-SDHx-related heritable HNP. Our present study addresses these issues relevant to clinical practice in several subspecialties. First, among all symptomatic HNP presentations, we were able, after exclusion of SDHx germline mutation- associated cases, to estimate that 5/1,000 actually have VHL. Second, we could estimate that among individuals with VHL, 8/1,000 will have HNP. Third, VHL has the highest prevalence among non- SDHx hereditary HNP with 11 out of 12 cases in our study. In the literature, 5 of 8 cases had VHL, and 2 had MEN 2 (20-25, 27). All but three VHL patients showed germline VHL missense mutations. NF 1 was the etiology of non SDHx heritable HNP in one case in the literature, but not in our series (26). Sixteen out of 20 patients, 10 from our study and 6 in the literature, presented with a carotid body tumor (20-23, 25, 27). One of our patients and one from literature had a glomus jugulare, one of our patients a glomus vagale tumor and one from the literature a glomus tympanicum tumor (Table 1) (24, 26). Remarkably, 15 of the 16 VHL-HNP patients had clinical features suggestive of VHL, with classical VHL lesions or a family history diagnostic for VHL. All but one of the HNPs were benign. In 15
Page 1 and 2: Head and Neck Paragangliomas in Von
Page 3 and 4: disclaims any responsibility or lia
Page 5 and 6: ABSTRACT Background Head and neck p
Page 7 and 8: MATERIAL AND METHODS Subjects The i
Page 9 and 10: Regarding VHL, the prevalence of HN
Page 11 and 12: eceptor scintigraphy revealed a hot
Page 13: In 1994, a 34-year old woman withou
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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