Management of Paragangliomas in the Netherlands: The Importance of Genetics in Clinical Decision Making

Since the year 2000, our insights into the genetics of head and neck paragangliomas has dramatically increased. Before, our knowledge was limited to the VHL, RET and NF1 genes causing the VHL, MEN type 2 and NF1 tumor syndromes, of which paragangliomas can, on rare occasions, be a part. To date, 19 different genes have been identified that are all associated with paraganglioma formation. The best known are the genes encoding subunits of the succinate dehydrogenase complex (SDH): SDHA, SDHAF2, SDHB, SDHC and SDHD. Today, it is estimated that 30-40% of the paragangliomas are hereditary, most frequently associated with SDHB and SDHD. There are important regional differences however. In the Netherlands, it is estimated that 60-80% of head and neck paraganglioma patients have a genetic predisposition, and that even the majority of paraganglioma patients with a negative family history carry a germ line mutations in an SDH- associated gene, mostly founder mutations in SDHD. Because the penetrance (i.e. the risk of acquiring a paraganglioma upon inheritance of a predisposing gene mutation), the mode of inheritance, as well as the risk of multiple tumors, metastases, and associated tumors depend on the causative gene involved, genetic counseling and testing are considered an essential aspect of the diagnostic work up of paraganglioma patients. In a multidisciplinary process, tumor factors (such as size, localization, growth rate and catecholamine secretion), patients factors (such as age, neurological deficits and comorbidity) but certainly also the genetic predispostion are weighed in order to achieve individualized treatment strategies.