title: Rare presentation of familial paraganglioma without evidence of mutation in the SDH, RET and VHL genes: towards further genetic heterogeneity.
abstract: OBJECTIVE
  Mutations in genes encoding succinate dehydrogenase and its anchoring subunits (SDH genes) are at the origin of hereditary head and neck paraganglioma (PGL) and a subset of apparently sporadic pheochromocytoma.
  
  
  METHODS
  We describe a family including three patients harbouring bilateral head and neck PGL diagnosed before 25 years of age. Multiple hypervascular hepatic lesions were subsequently discovered in two of them. In both, liver biopsy confirmed the diagnosis of PGL. In addition, in one patient, MRI disclosed multiple target-like lesions of the spine, highly suggestive of metastatic PGL. Family history was compatible with autosomal dominant inheritance with possible maternal imprinting.
  
  
  RESULTS
  Combined single-strand conformation polymorphism and heteroduplex analysis followed by sequencing did not show any mutation of the coding parts of SDHB, SDHC, SDHD, RET or VHL genes. Screening of copy number alterations and loss of heterozygosity in the three affected family members showed no deletion or amplification of the SDH, RET and VHL genes. Furthermore, succinate dehydrogenase activity measured in a liver PGL sample was not significantly decreased in the affected patient as compared with controls, underscoring the exclusion of the SDH genes.
  
  
  CONCLUSIONS
  To our knowledge, this is the first reported family of hereditary head and neck PGL with metastatic dissemination in the liver and the spine. A large body of evidence supports the absence of mutations in SDH, RET and VHL genes, which suggests the existence of a yet unknown gene at the origin of this particular form of familial PGL.
authors.affiliation: Cardiology Unit, Cliniques Universitaires Saint Luc, Université catholique de Louvain, Brussels, Belgium. alexandre.persu@card.ucl.ac.be
authors.forename: Alexandre
authors.initials: A
authors.lastname: Persu
authors.forename: Mustapha
authors.initials: M
authors.lastname: Amyere
authors.forename: Ilse
authors.initials: I
authors.lastname: Gutierrez-Roelens
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.forename: Christine
authors.initials: C
authors.lastname: Sempoux
authors.forename: Frédéric E
authors.initials: FE
authors.lastname: Lecouvet
authors.forename: Bernard E
authors.initials: BE
authors.lastname: Van Beers
authors.forename: Yves
authors.initials: Y
authors.lastname: Horsmans
authors.forename: Jean-François
authors.initials: JF
authors.lastname: De Plaen
authors.lastname: MarcHamoir
authors.forename: Miikka
authors.initials: M
authors.lastname: Vikkula
mesh_terms: D006801:Humans; D008279:Magnetic Resonance Imaging; D009154:Mutation; D010235:Paraganglioma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D013385:Succinate Dehydrogenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C497446:VHL protein, human