Genetic analysis in the diagnosis of familial paragangliomas

Objectives: In the management of two related patients with multicentric glomus jugulare tumors, given the incidence of 1:30,000 with approximately 20% familial cases, our objective was to review the genetic characteristics and inheritance patterns of these tumors and to determine what molecular genetic screening possibilities exist for the phenotypically normal family members. In addition, our aim was to review the incidence of various multicentric paraganglioma (PGL) tumor location combinations. Methods: Molecular genetic linkage analysis testing was performed on the 2 patients and 14 other unaffected family members. We report the results of this screening and review the literature on the incidence and genetics of paragangliomas. Results: The inheritance pattern in the literature demonstrates autosomal dominant transmission with maternal imprinting (inactivation). The proclivity for multicentric origin increases to 26% in familial cases, as reflected in our patients. In addition to the two patients, four unaffected family members demonstrated the presence of the disease haplotype at chromosome band 11q23, which indicates a very high likelihood of developing a paraganglioma, given the highly penetrant nature of the disease. Conclusions: It is clear that the familial PGL gene locus is situated at chromosome 11q23. The gene itself and its exact degree of penetrance, however, still await identification. Since early detection of paragangliomas reduces the incidence of morbidity and mortality, genotypic analysis as a screening tool in families of affected patients should play a bent-line diagnostic role, leading to more timely and cost-effective patient management.