Parasympathetic paragangliomas are part of the Von Hippel-Lindau syndrome.
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.
Gaal
José
J
Department of Pathology, Josephine Nefkens Institute, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands. j.gaal@erasmusmc.nl
van Nederveen
Francien H
FH
Erlic
Zoran
Z
Korpershoek
Esther
E
Oldenburg
Rogier
R
Boedeker
Carsten C
CC
Kontny
Udo
U
Neumann
Hartmut P
HP
Dinjens
Winand N M
WN
de Krijger
Ronald R
RR
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*
D004273:DNA, Neoplasm; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human