Genetic Analysis in the Diagnosis of Familial Paragangliomas

Abstract

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 front‐line diagnostic role, leading to more timely and cost‐effective patient management.

Tumors of the Jugular Foramen

“…22,23 The overall familial incidence may be as high as 20%. 24 Both sporadic and familial paragangliomas are associated with deletions at chromosomes 11q13 and 11q22-23. 24,25 As with other jugular foramen tumors, the clinical presentation may vary depending on the site of origin in the jugular foramen and routes of extension from the primary site.…”

“…24 Both sporadic and familial paragangliomas are associated with deletions at chromosomes 11q13 and 11q22-23. 24,25 As with other jugular foramen tumors, the clinical presentation may vary depending on the site of origin in the jugular foramen and routes of extension from the primary site. Glomus jugular tumors grow along neural and vascular pathways as well as through the aircell tracts, skull base foramina, fissures, and recesses.…”

Etiopathogenesis and clinical presentation of carotid body tumors

“…Currently, the proportion of familial CBTs has been estimated to be 10% (Grufferman et al, 1980) to 50% (van der Mey et al, 1989) of all cases. Genetic mapping studies on the familial forms of CBTs were performed mostly in the last 10 years to uncover the underlying genes (Heutink et al, 1992(Heutink et al, , 1994Mariman et al, 1993;Baysal et al, 1997Baysal et al, , 1999Milunsky et al, 1997;Petropoulos et al, 2000;Niemann et al, 2001). Currently, four loci have been identified: three encode the subunits of mitochondrial complex II, SDHB (PGL4) (Astuti et al, 2001a), SDHC (PGL3) (Niemann and Muller, 2000), and SDHD (PGL1) .…”

Large Paraganglioma of the Abdominal Cavity: A Case Report and Review of the Literature

“…Paragangliomas (synonyms: chemodectoma, aortic-body tumor, carotid-body tumor, glomus jugulare tumor) derive fromautonomicnervouscellswithanestimatedincidenceof 1:30,000 [1], some cases are familiar forms [2], but 80% of cases occur sporadically [3]. Overall, 69% occur in the head andneck [4],buttheorganofZuckerkandlandothersitesof theparaganglionsystem [5]havebeenreportedassitesoforiginaswell.Abdominalparagangliomasoftenoriginatefrom theorganofZuckerkandlwiththehighestincidencenearthe inferiormesentericartery [6],butmayalsobelocatedatthe aortorenal ganglion and the bladder wall.…”