Mutation of SDHB is a cause of hypoxia-related high-altitude paraganglioma.
OBJECTIVE
Paragangliomas of the head and neck are neuroendocrine tumors and are associated with germ line mutations of the tricarboxylic acid cycle-related genes SDHB, SDHC, SDHD, and SDHAF2. Hypoxia is important in most solid tumors, and was directly implicated in tumorigenesis over 40 years ago when it was shown that dwelling at high altitudes increases the incidence of carotid body hyperplasia and paragangliomas. Although recent research has now elucidated several pathways of hypoxia in paragangliomas, nothing is currently known of the genetics or of gene-environment interactions in high-altitude paraganglioma. We postulated that SDH mutations might play a role in these tumors.


METHODS
Patients from a Mexican family, originating and resident in Guadalajara, were tested for mutations of SDHD, and subsequently, for mutations of SDHB followed by immunohistochemical confirmation of SDHB loss.


RESULTS
Two patients, born and resident at altitudes of between 1,560 and 2,240 m, were found to have head and neck paragangliomas, including a remarkably aggressive recurrent tumor. Mutation analysis identified a pathogenic missense mutation in exon 7 of SDHB, c.689G>A, p.Arg230His, and loss of the SDHB protein was confirmed by immunohistochemistry.


CONCLUSIONS
This is the first report of a SDH gene mutation in paraganglioma at high altitude. A rapidly recurrent head and neck paraganglioma is a very rare finding in an SDH mutation carrier, suggesting a gene-environment interaction. Neither patient showed evidence of sympathetic paraganglioma.
Cerecer-Gil
Nidia Y
NY
Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Mexico.
Figuera
Luis E
LE
Llamas
Francisco J
FJ
Lara
Mauricio
M
Escamilla
José G
JG
Ramos
Ruben
R
Estrada
Gerardo
G
Hussain
A Karim
AK
Gaal
José
J
Korpershoek
Esther
E
de Krijger
Ronald R
RR
Dinjens
Winand N M
WN
Devilee
Peter
P
Bayley
Jean Pierre
JP
D000368:Aged; D000531:Altitude; D002345:Carotid Body Tumor / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006258:Head and Neck Neoplasms / Q000209:etiology / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D009378:Neoplasms, Multiple Primary / Q000473:pathology; D010051:Ovarian Neoplasms / Q000473:pathology; D010375:Pedigree; D016133:Polymerase Chain Reaction; D013385:Succinate Dehydrogenase / Q000235:genetics*
C108095:SDHB protein, human; D013385:Succinate Dehydrogenase