Familial Paragangliomas: Genetic Grounds

Abstract

About 10 to 50% of paragangliomas are familial and they may present as a solitary tumor or as multiple tumors, as occurs in 30 to 40% of familial paragangliomas. These tumors are generally confined to the head and neck region, but occasionally they are accompanied by adrenal or extra-adrenal paragangliomas. Paragangliomas also may be part of different syndromes, such as multiple endocrine neoplasia type 2 (over-representation of mutant RET), von Hippel-Lindau disease (VHL germline mutation and wildtype allelic deletion), and neurofibromatosis type 1. It now appears that germline inactivating heterozygous mutations in SDHB, SDHC, and SDHD, which encode subunits of mitochondrial complex II (succinate dehydrogenase, succinate-ubiquinone oxidoreductase), are responsible for 70% of familial cases and approximately 8% of nonfamilial cases. On the other hand, mutations in the subunit SDHA display a phenotype resembling other mitochondrial and Krebs cycle gene defects, which are often characterized by hypotonia, growth retardation, cardiomyopathy, myopathy, neuropathy, and metabolic derangement. In SDHB (1p36)- and SDHC (1q21)-linked families, disease inheritance is autosomal dominant. In SDHD (11q23)-linked families, the disease phenotype is expressed only upon paternal transmission of the mutation, consistent with maternal imprinting or with a somatic genetic mechanism targeting both the SDHD gene on 11q23 and a paternally imprinted gene on 11p15.5. In addition, loss of heterozygosity (LOH) on chromosome 11, mainly in 11q23 (PGL1), has been observed. A two-hit model comprising both LOH and point mutation appears to be the pathophysiologic basis for sporadic tumor development. Loss of chromosome 11 regions, including the deletion of PGL1 and PGL2 loci, may result in a more severe phenotype, as exemplified by the development of multiple tumors. In contrast with SDHD mutation carriers who have more frequent multifocal paragangliomas, SDHB mutation carriers are more likely to develop malignant disease and possibly extraparaganglial neoplasias, including renal cell and thyroid carcinomas.