Germ-line mutations in nonsyndromic pheochromocytoma.
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.
Neumann
Hartmut P H
HP
Department of Nephrology and Hypertension, Albert Ludwigs University, Freiburg, Germany. neumann@mm41.ukl.uni-freiburg.de
Bausch
Birke
B
McWhinney
Sarah R
SR
Bender
Bernhard U
BU
Gimm
Oliver
O
Franke
Gerlind
G
Schipper
Joerg
J
Klisch
Joachim
J
Altehoefer
Carsten
C
Zerres
Klaus
K
Januszewicz
Andrzej
A
Eng
Charis
C
Smith
Wendy M
WM
Munk
Robin
R
Manz
Tanja
T
Glaesker
Sven
S
Apel
Thomas W
TW
Treier
Markus
M
Reineke
Martin
M
Walz
Martin K
MK
Hoang-Vu
Cuong
C
Brauckhoff
Michael
M
Klein-Franke
Andreas
A
Klose
Peter
P
Schmidt
Heinrich
H
Maier-Woelfle
Margarete
M
Peçzkowska
Mariola
M
Szmigielski
Cesary
C
Eng
Charis
C
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
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