Purpose: Germline SDHB, SDHC and/or SDHD mutations have been reported in familial and apparently sporadic paragangliomas (PGLs). There is, however, some variation in the prevalence, penetrance and phenotypic expression of the succinate dehydrogenase (SDH) mutated gene among different populations. We sought to determine whether germline mutations in SDHB, SDHC and/or SDHD play a role in cervical PGLs from Northern Spain, where this disorder is particularly frequent, and whether there is any difference with respect to the data published in other populations.

Design: Thirty-six sporadic cervical PGLs and four familial PGLs were investigated by PCR/SSCP/sequencing. Computational biology was applied to address the structural-conformational changes behind missense mutations and, simultaneously, infer the possible consequences in protein function.

Results: Eight sporadic cases(22.2%) carried pathogenic germline mutations, six of which were in SDHB and two in SDHD. Three families had mutations in SDHD and one in SDHB. Seven of eleven(64%) different pathogenic mutations affected SDHB. Ten mutations were novel. Missense mutations were primarily found in SDHB and frameshift mutations in SDHD. Missense SDHB mutations seemed to alter the enzymatic activity by hampering the electron transfer. SDH-linked tumors occurred mainly in males(p=0.0033), at a younger age(p<0.0001), were usually multifocal(p=0.0011) and exhibited a larger size(p=0.0341).

Conclusions: A significant proportion of sporadic cervical PGLs arise as a consequence of intrinsic genetic factors. At variance with previous reports, SDHB is frequently mutated in sporadic cervical PGLs and the mutations do not entail a deleterious behavior. Therefore, SDHB genetic testing may be considered in all subjects presenting with solitary cervical PGL and no family history.