Genetics of pheochromocytoma and paraganglioma in Spanish patients.
BACKGROUND
The presence of familial history in pheochromocytoma/paraganglioma patients, including syndromic antecedents, leads in the majority of cases to a positive genetic testing for mutations in one of the major susceptibility genes described so far. Furthermore, it has been reported that in the absence of familial antecedents, about 11-24% of patients also carry a mutation in one of these related genes. In these cases, other clinical aspects like bilaterality, multiplicity, location of the tumors, or age at onset can help to recognize the underlying genes involved.


OBJECTIVE
The objective of the study was to discuss clinical criteria helpful in the genetic diagnosis, placing special emphasis on apparently sporadic cases.


METHODS
Two hundred thirty-seven nonrelated probands were analyzed for the major susceptibility genes: VHL, RET, SDHB, SDHC, and SDHD. Genetic characterization included both point mutation analysis and gross deletions in the SDH genes performed by multiplex PCR.


RESULTS
As expected, all syndromic probands were genetically diagnosed with a mutation affecting either RET or VHL. A total of 79.1% (19 of 24) and 18.4% (31 of 168) of patients presenting with either nonsyndromic familial antecedents or apparently sporadic presentation were found to carry a mutation in one of the susceptibility genes. Finally, we found a Spanish founder effect for two mutations: SDHB c.166_170delCCTCA and SDHD c.129G>A.


CONCLUSIONS
Germline mutations are rare in apparently sporadic probands diagnosed after age 40 yr (3.9% in our series) and mainly involve SDHB. Therefore, we recommend prioritizing SDHB genetic testing in patients developing isolated tumors at any age, especially those with extraadrenal location or malignant behavior.
Cascón
Alberto
A
Hereditary Endocrine Cancer Group, Institute de Salud Carlos III Center for Biomedical Research on Rare Diseases, Madrid, Spain.
Pita
Guillermo
G
Burnichon
Nelly
N
Landa
Iñigo
I
López-Jiménez
Elena
E
Montero-Conde
Cristina
C
Leskelä
Susanna
S
Leandro-García
Luis Javier
LJ
Letón
Rocío
R
Rodríguez-Antona
Cristina
C
Díaz
José Angel
JA
López-Vidriero
Emilio
E
González-Neira
Anna
A
Velasco
Ana
A
Matias-Guiu
Xavier
X
Gimenez-Roqueplo
Anne-Paule
AP
Robledo
Mercedes
M
D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D000328:Adult; D017668:Age of Onset; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000453:epidemiology / Q000235:genetics; D010235:Paraganglioma / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D010673:Pheochromocytoma / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation; D013030:Spain / Q000453:epidemiology; D055815:Young Adult; D006623:von Hippel-Lindau Disease / Q000453:epidemiology / Q000235:genetics