title: Phenotypic variability and risk of malignancy in SDHC-linked paragangliomas: lessons from three unrelated cases with an identical germline mutation (p.Arg133*).
abstract: BACKGROUND
  Mutations in the four subunits of succinate dehydrogenase (SDH) are the cause for the hereditary paraganglioma (PGL) syndrome types 1-4 and are associated with multiple and recurrent pheochromocytomas and PGLs. SDHC mutations most frequently result in benign, nonfunctional head-and neck PGLs (HNPGLs). The malignant potential of SDHC mutations remains unclear to date.
  
  
  OBJECTIVE
  We report a patient with malignant PGL carrying a SDHC mutation and compare her case with two others of the same genotype but presenting with classic benign HNPGLs. Loss of heterozygosity (LOH) was demonstrated in the malignant PGL tissue.
  
  
  METHODS
  In three unrelated patients referred for routine genetic testing, SDHB, SDHC, and SDHD genes were sequenced, and gross deletions were excluded by multiplex ligation-dependent probe amplification (MLPA). LOH was determined by pyrosequencing-based allele quantification and SDHB immunohistochemistry.
  
  
  RESULTS
  In a patient with a nonfunctioning thoracic PGL metastatic to the bone, the lungs, and mediastinal lymph nodes, we detected the SDHC mutation c.397C>T predicting a truncated protein due to a premature stop codon (p.Arg133*). We demonstrated LOH and loss of SDHB protein expression in the malignant tumor tissue. The two other patients also carried c.397C>T, p.Arg133*; they differed from each other with respect to their tumor characteristics, but both showed benign HNPGLs.
  
  
  CONCLUSIONS
  We describe the first case of a malignant PGL with distant metastases caused by a SDHC germline mutation. The present case shows that SDHC germline mutations can have highly variable phenotypes and may cause malignant PGL, although malignancy is probably rare.
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine (J.K.B., S.S., K.J.L., H.R.), Institute of Pathology (A.S., E.S.), Department of Endocrinology and Metabolism, I Medical Department (M.M.W., C.F.), Department of Otorhinolaryngology (K.P., D.K., W.J.M.), Department of Endocrine Surgery (T.J.M.), Department of Nuclear Medicine (M.M.), and Institute of Human Genetics (O.B.), University Medical Center Mainz, 55131 Mainz, Germany.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Bickmann
authors.forename: Stefanie
authors.initials: S
authors.lastname: Sollfrank
authors.forename: Arno
authors.initials: A
authors.lastname: Schad
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Musholt
authors.forename: Erik
authors.initials: E
authors.lastname: Springer
authors.forename: Matthias
authors.initials: M
authors.lastname: Miederer
authors.forename: Oliver
authors.initials: O
authors.lastname: Bartsch
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Papaspyrou
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Koutsimpelas
authors.forename: Wolf J
authors.initials: WJ
authors.lastname: Mann
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Weber
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Lackner
authors.forename: Heidi
authors.initials: H
authors.lastname: Rossmann
authors.forename: Christian
authors.initials: C
authors.lastname: Fottner
mesh_terms: D001120:Arginine / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D005925:Glomus Jugulare Tumor / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000473:pathology; D006338:Heart Neoplasms / Q000235:genetics / Q000556:secondary; D006801:Humans; D019656:Loss of Heterozygosity; D008159:Lumbar Vertebrae; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010235:Paraganglioma / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D012307:Risk Factors; D013125:Spinal Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D008565:Membrane Proteins; C108096:SDHC protein, human; D001120:Arginine