Tinnitus With Unexpected Spanish Roots

Head and Neck Paragangliomas Caused by SDHAF2 Mutation

Laura Maria Roose; Niels J. Rupp; Christof Röösli; Nadejda Valcheva; Achim Weber; Felix Beuschlein; Oliver Tschopp


J Endo Soc. 2020;4(3) 

In This Article

Abstract and Introduction


It is estimated that up to 40% of all head and neck paragangliomas (HNPGL) have a hereditary background with the most common mutations being found in the succinate dehydrogenase (SDH) genes. SDHAF2 mutation leads to the rare paraganglioma syndrome 2. The authors present the case of a 15-year-old male patient with 2, non-secretory HNPGLs, presenting with left-sided, pulsatile tinnitus, and hearing loss. Imaging led to the suspicion of a jugulotympanic paraganglioma on the left, as well as a carotid body tumor on the right. After resection of the jugulotympanic tumor, histology confirmed the presence of a paraganglioma; immunohistochemistry furthermore suggested a loss of SDHB expression. Genetic testing revealed a rare germline, loss-of-function mutation in the SDHAF2 gene, previously described to cause hereditary paraganglioma syndrome 2. Twenty months after the first operation, the patient underwent a resection of the right carotid body paraganglioma. Plasma-free metanephrines/catecholamines always remained within the reference range; the patient is under regular follow-up, and his relatives will be screened. Our findings emphasize the relevance of genetic testing in patients with HNPGL, also with negative family history, especially when the patients present at a young age and with multiple lesions.


Head and neck paragangliomas (HNPGL) are a subtype of pheochromocytoma/paraganglioma (Pheo/PGL) and originate from the extra-adrenal ganglia of the autonomous nervous system. In contrast to abdominal and thoracic Pheo/PGL, HNPGL are usually nonsecretory, exclusively have a parasympathetic origin, and only rarely metastasize.[1] The initial manifestation of HNPGL depends on the localization and the secretory pattern of the tumor. Tinnitus and hearing loss are typical for tympanal HNPGL and should prompt further evaluation.

Although HNPGL may occur as sporadic tumors, it is estimated that up to 50% of all Pheo/PGL have a hereditary background that may influence the therapeutic strategies, follow-up of affected patients, and screening of family members.[2,3] The most common mutations are found in the succinate dehydrogenase (SDH) genes with the highest prevalence of mutations in SDHD, followed by SDHB and SDHC.[1]

SDH is a membrane-bound, mitochondrial enzyme and part of the tricarboxylic acid cycle, as well as of the electron transport chain. It plays a key role in energy metabolism.[4] The enzymes of the tricarboxylic acid cycle in general are considered tumor suppressors, and mutations in the corresponding genes are associated with tumorigenesis in different tissues.[5] Several of the mutations associated with hereditary Pheo/PGL cause a disturbed cellular response to hypoxia, leading to a condition called pseudohypoxia. Interestingly also with actual, chronic hypoxia a high incidence of Pheo/PGL occurs. This association was observed in populations living in high-altitude regions, as well as in patients with cyanotic congenital heart disease. It suggests an etiological link between the cellular responses to hypoxia and the development of Pheo/PGL.[6]