Purpose: 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 highaltitude paraganglioma. We postulated that SDH mutations might play a role in these tumors.Experimental Design: 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. Paragangliomas of the head and neck (HN-PGL; also referred to as chemodectomas) are rare, mostly benign tumors of the parasympathetic nervous system. They occur most commonly in the carotid body, the main peripheral sensor of physiologic hypoxia (low oxygen levels). Paragangliomas of the sympathetic nervous system (sPGL) arise in the adrenal medulla or in the extra-adrenal paraganglia of the thorax and abdomen, and are often referred to as pheochromocytomas or extra-adrenal paragangliomas.A genetic basis for HN-PGL was established with the identification by Baysal et al. (1) of germ line mutations in the succinate dehydrogenase, subunit D gene (SDHD). Other subunits of SDH and related proteins were subsequently shown to be involved in HN-PGL and sPGL (2-4). These genes encode subunits or associated proteins of the succinate dehydrogenase complex, which plays a central role in energy metabolism as both an enzyme of tricarboxylic acid cycle and as complex II of the mitochondrial respiratory chain, involved in oxidative phosphorylation.In recent years, there has been a revival of interest in metabolic adaptations of solid tumors, specifically the very high rate of glycolysis and decline in tricarboxylic acid cycle activity, often referred to as the "Warburg effect" (5, 6). The Warburg effect is fundamental to a broad range of tumors and is now the basis for the widely used technique of 18 F-fluorodeoxyglucose positron emission tomography tumor imaging (7). The discovery ...
