title: Malignant phenotype and two SDHD mutations in a family with paraganglioma syndrome type 1.
abstract: BACKGROUND
  Paraganglioma syndrome type 1 (PGL1) is a rare autosomal dominant syndrome associated with multiple, overwhelmingly benign, pheochromocytomas and paragangliomas, attributed to SDHD gene mutations.
  
  
  OBJECTIVE
  Clinically and molecularly characterize a family with uncommon malignant phenotype of paragangliomas attributed to two seemingly pathogenic SDHD germline mutations.
  
  
  METHODS
  The proband presented with large bilateral carotid body tumours and family history of cervical masses in his five siblings. All family members underwent clinical examination, imaging studies (18F-FDG PET/CT) and genotyping of relevant genes. The proband was diagnosed with locally advanced paraganglioma; his hypertensive, otherwise asymptomatic father, had locally advanced pheochromocytoma and his three siblings showed multiple head and neck masses, confirmed to be paragangliomas with local metastasis. All affected patients carried two germline mutations in the SDHD gene; a previously reported nonsense mutation in exon 1 (p.Trp5X) and a novel missense mutation in exon 2 (p.Pro53Leu), highly deleterious by in silico analysis. Allelic loss at the SDHD locus was not shown for any of the analysed tumours.
  
  
  CONCLUSIONS
  This is a rare case of malignant PGL1 with seemingly double pathogenic mutations in the SDHD gene, highlighting the possibility that the presence of both mutations is associated with the more aggressive phenotype.
authors.affiliation: Department of Surgery,Universidade Federal de Minas Gerais,Belo Horizonte,30130-100,Brazil.
authors.forename: Franciele B
authors.initials: FB
authors.lastname: Leidenz
authors.affiliation: Universidade Federal de Juiz de Fora,Campus Governador Valadares,35010-177,Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Bastos-Rodrigues
authors.affiliation: Department of Surgery,Universidade Federal de Minas Gerais,Belo Horizonte,30130-100,Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Oliveira
authors.affiliation: Department of Anatomy and Imaging,Universidade Federal de Minas Gerais,Belo Horizonte,30130-100,Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Mamede
authors.affiliation: Department of Medicine,Universidade Federal de Minas Gerais,Belo Horizonte,30130-100,Brazil.
authors.forename: Marta
authors.initials: M
authors.lastname: Sarquis
authors.affiliation: The Susanne Levy Gertner Oncogenetics Unit,Chaim Sheba Medical Center,Tel-Hashomer,52621,Israel.
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
authors.affiliation: Department of Surgery,Universidade Federal de Minas Gerais,Belo Horizonte,30130-100,Brazil.
authors.forename: Luiz
authors.initials: L
authors.lastname: de Marco
mesh_terms: D000328:Adult; D001483:Base Sequence; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005192:Family Health; D017809:Fatal Outcome; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010235:Paraganglioma / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D010673:Pheochromocytoma / Q000235:genetics* / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000235:genetics*; D013577:Syndrome
chemical_list: D018389:Codon, Nonsense; C491545:SDHD protein, human; D013385:Succinate Dehydrogenase
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