title: Germ-line mutations in nonsyndromic pheochromocytoma.
abstract: BACKGROUND
  The group of susceptibility genes for pheochromocytoma that included the proto-oncogene RET (associated with multiple endocrine neoplasia type 2 [MEN-2]) and the tumor-suppressor gene VHL (associated with von Hippel-Lindau disease) now also encompasses the newly identified genes for succinate dehydrogenase subunit D (SDHD) and succinate dehydrogenase subunit B (SDHB), which predispose carriers to pheochromocytomas and glomus tumors. We used molecular tools to classify a large cohort of patients with pheochromocytoma with respect to the presence or absence of mutations of one of these four genes and to investigate the relevance of genetic analyses to clinical practice.
  
  
  METHODS
  Peripheral blood from unrelated, consenting registry patients with pheochromocytoma was tested for mutations of RET, VHL, SDHD, and SDHB. Clinical data at first presentation and follow-up were evaluated.
  
  
  RESULTS
  Among 271 patients who presented with nonsyndromic pheochromocytoma and without a family history of the disease, 66 (24 percent) were found to have mutations (mean age, 25 years; 32 men and 34 women). Of these 66, 30 had mutations of VHL, 13 of RET, 11 of SDHD, and 12 of SDHB. Younger age, multifocal tumors, and extraadrenal tumors were significantly associated with the presence of a mutation. However, among the 66 patients who were positive for mutations, only 21 had multifocal pheochromocytoma. Twenty-three (35 percent) presented after the age of 30 years, and 17 (8 percent) after the age of 40. Sixty-one (92 percent) of the patients with mutations were identified solely by molecular testing of VHL, RET, SDHD, and SDHB; these patients had no associated signs and symptoms at presentation.
  
  
  CONCLUSIONS
  Almost one fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations; routine analysis for mutations of RET, VHL, SDHD, and SDHB is indicated to identify pheochromocytoma-associated syndromes that would otherwise be missed.
authors: Department of Nephrology and Hypertension, Albert Ludwigs University, Freiburg, Germany. neumann@mm41.ukl.uni-freiburg.de
authors: Hartmut P H
authors: HP
authors: Neumann
authors: Birke
authors: B
authors: Bausch
authors: Sarah R
authors: SR
authors: McWhinney
authors: Bernhard U
authors: BU
authors: Bender
authors: Oliver
authors: O
authors: Gimm
authors: Gerlind
authors: G
authors: Franke
authors: Joerg
authors: J
authors: Schipper
authors: Joachim
authors: J
authors: Klisch
authors: Carsten
authors: C
authors: Altehoefer
authors: Klaus
authors: K
authors: Zerres
authors: Andrzej
authors: A
authors: Januszewicz
authors: Charis
authors: C
authors: Eng
authors: Wendy M
authors: WM
authors: Smith
authors: Robin
authors: R
authors: Munk
authors: Tanja
authors: T
authors: Manz
authors: Sven
authors: S
authors: Glaesker
authors: Thomas W
authors: TW
authors: Apel
authors: Markus
authors: M
authors: Treier
authors: Martin
authors: M
authors: Reineke
authors: Martin K
authors: MK
authors: Walz
authors: Cuong
authors: C
authors: Hoang-Vu
authors: Michael
authors: M
authors: Brauckhoff
authors: Andreas
authors: A
authors: Klein-Franke
authors: Peter
authors: P
authors: Klose
authors: Heinrich
authors: H
authors: Schmidt
authors: Margarete
authors: M
authors: Maier-Woelfle
authors: Mariola
authors: M
authors: Peçzkowska
authors: Cesary
authors: C
authors: Szmigielski
authors: Charis
authors: C
authors: Eng
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D029721:Drosophila Proteins; D042963:Electron Transport Complex II; D005260:Female; D018095:Germ-Line Mutation; D005918:Glomus Tumor / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000235:genetics*; D008025:Ligases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics*; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics; D020125:Mutation, Missense; D010088:Oxidoreductases / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*; D021122:Protein Subunits; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics*; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; D007506:Iron-Sulfur Proteins; C000715470:MAS1 protein, human; D009097:Multienzyme Complexes; D021122:Protein Subunits; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D042963:Electron Transport Complex II; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; D008025:Ligases; C497446:VHL protein, human