title: Parasympathetic paragangliomas are part of the Von Hippel-Lindau syndrome.
abstract: BACKGROUND
  Von Hippel-Lindau (VHL) disease, caused by germline mutations in the VHL gene, is a hereditary tumor syndrome manifested by hemangioblastomas, clear cell renal cell carcinomas, and pheochromocytomas. In addition, a multitude of other rare tumors, including parasympathetic paragangliomas, can occur and even be the sole manifestation of VHL disease. The VHL gene is a bona fide tumor suppressor gene with biallelic inactivation contributing to tumor formation. However, in parasympathetic paragangliomas occurring in VHL disease, biallelic inactivation of the VHL gene has not been demonstrated to date.
  
  
  METHODS
  The head and neck paragangliomas of two VHL patients were analyzed for mutations by direct sequencing of the VHL gene. In addition loss of heterozygosity analysis was performed for three microsatellite loci near the VHL gene. To rule out other underlying genetic causes of the parasympathetic paragangliomas, mutation analysis of the SDHB, SDHC, and SDHD genes was also performed.
  
  
  RESULTS
  Apart from germline VHL mutations, no additional mutations were found in the paraganglioma-related tumor suppressor genes SDHB, SDHC, and SDHD. Analysis of paraganglioma tissue revealed loss of the VHL wild-type allele in both tumors, indicating that in these tumors biallelic VHL gene inactivation occurred.
  
  
  CONCLUSIONS
  These findings indicate that parasympathetic paragangliomas in VHL disease, although rare, are part of the syndrome and related to VHL gene inactivation. Clinicians should be aware of the potential occurrence of parasympathetic paragangliomas in VHL disease.
authors.affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands. j.gaal@erasmusmc.nl
authors.forename: José
authors.initials: J
authors.lastname: Gaal
authors.forename: Francien H
authors.initials: FH
authors.lastname: van Nederveen
authors.forename: Zoran
authors.initials: Z
authors.lastname: Erlic
authors.forename: Esther
authors.initials: E
authors.lastname: Korpershoek
authors.forename: Rogier
authors.initials: R
authors.lastname: Oldenburg
authors.forename: Carsten C
authors.initials: CC
authors.lastname: Boedeker
authors.forename: Udo
authors.initials: U
authors.lastname: Kontny
authors.forename: Hartmut P
authors.initials: HP
authors.lastname: Neumann
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
mesh_terms: D019943:Amino Acid Substitution; D002292:Carcinoma, Renal Cell / Q000453:epidemiology; D002353:Carrier State; D002648:Child; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D020868:Gene Silencing; D018095:Germ-Line Mutation; D006801:Humans; D007680:Kidney Neoplasms / Q000453:epidemiology; D008297:Male; D010235:Paraganglioma / Q000453:epidemiology* / Q000209:etiology; D010673:Pheochromocytoma / Q000453:epidemiology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D055815:Young Adult; D006623:von Hippel-Lindau Disease / Q000150:complications* / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human