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

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Criteria for Diagnosis of Non-SDHx Heritable Neoplasia Syndromes The criteria for non-SDHx heritable HNPs are absence of germline mutations in the genes SDHB, SDHC and SDHC analyzed as shown above and presence of clinical or molecular genetic evidence for MEN 2, VHL or NF 1. VHL was diagnosed, if the patient was found to have a germline VHL mutation and/or had at least one of the tumors of the VHL component spectrum of hemangioblastoma of the eye or central nervous system (CNS), renal cell carcinoma (RCC) or pheochromocytoma. MEN 2 was diagnosed if the patient was found to carry a germline RET mutation or a first degree relative had a medullary thyroid carcinoma and a pheochromocytoma. NF 1 was diagnosed, if the patient had at least two of the following clinical features: multiple neurofibromas, plexiform neurofibroma, axillary freckling, café au lait spots and Lisch nodules of the iris and/or a first degree relative with confirmed NF 1 (8, 15-17). Approval and Consent The study design was approved by the ethical committee of the University of Freiburg and all participating centers accordingly. All participants gave written informed consent. The study was performed in accordance with the guidelines of the Helsinki Declaration of 1975, as revised in 1983. RESULTS By March 1, 2009, the International Non-SDHx HNP Consortium registered 12 patients with HNPs who showed characteristics suggesting a non-SDHx-related heritable tumor syndrome. Eleven of the 12 patients were found to carry germline mutations in the VHL gene, and one in the RET gene. Six of the patients originate from France, two from Germany, two from Spain and one each from The Netherlands and Switzerland. To estimate the prevalence of HNP in VHL individuals, we used the country-specific registries to provide a denominator. For VHL, the French VHL registry comprises 886 registrants, the German VHL Registry based in Freiburg 844, the Spanish VHL registry 296, and the Dutch VHL registry 58 registrants respectively as of January 1, 2009. 8
Regarding VHL, the prevalence of HNP in the national registries was 2/844 or 2/1,000 in Germany, 2/296 or 7/1,000 in Spain, and 6/886 or 7/1,000 in France, respectively. In the Netherlands, the VHL registry comprises 58 cases, but none of the registrants had HNP (18). In total, prevalence of HNP amongst VHL cases was 10/2085 or 5/1,000. Regarding HNP, the European Australian American Head and Neck Paraganglioma Registry counts 513 registrants, the Rotterdam HNP registry 147 registrants and the French HNP registry 149 registrants in whom SDHx mutations have been excluded. Regarding HNP prevalence in the European Australian American HNP Registry, which includes Germany, Spain and Switzerland among other countries but not the Netherlands and France, was 5/513 or 10/1,000 registrants in whom SDHx mutations have been excluded. In the Netherlands and France, the prevalence of hereditary non-SDHx HNP was 1/147 or 7/1,000 and 1/149 or 7/1,000, respectively. In total, among all 809 registrants, prevalence was 9/1,000. Case reports: Case 1 In 1997, a 7-year old boy was diagnosed with a malignant extraadrenal pheochromocytoma of the left retroperitoneum with regional lymph node metastases. These were treated with resection of the primary tumor, lymphadenectomy and chemotherapy according to the protocol GPOH-MET 97 (19). At age 9, there was a local recurrence, which was treated with resection and external radiotherapy of 20 Gy. At age 13, a right adrenal pheochromocytoma was resected. At age 15, a left carotid body tumor was clinically detected and removed, but this recurred at age 16 and again resected. At age 17, a pheochromocytoma at the renal pelvis was diagnosed on a routine MRI and resected. At age 18, he is disease-free except for a lesion in the L1 vertebral body suggestive of hemangioma or pheochromocytoma, a lesion first diagnosed in 2004 but unchanged over the last 5 years. The family history was initially negative for VHL. Molecular genetic testing revealed the mutation VHL p.Tyr98His. Predictive testing was offered to the patient’s family and revealed that the mother and other relatives were positive. Clinical investigations of these relatives showed retinal 9
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: MATERIAL AND METHODS Subjects The i
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

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

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