Pheochromocytoma and paraganglioma: implications of germline mutation investigation for treatment, screening, and surveillance

Abstract

Objective: Paraganglioma (PGL) and pheochromocytoma (PCC) are rare neuroendocrine tumors that were considered to be predominantly sporadic. However, with the identification of novel susceptibility genes over the last decade, it is currently estimated that up to 40% of cases can occur in the context of a hereditary syndrome. We aimed to characterize PGL/PCC families to exemplify the different scenarios in which hereditary syndromes can be suspected and to emphasize the importance for patients and their families of making an opportune genetic diagnosis. Materials and methods: Retrospective analysis of patients diagnosed with PGL/PCC. Germline mutations were studied using next-generation sequencing panels including SDHA, SDHB, SDHC and SDHD. Clinical data were collected from clinical records, and all patients received genetic counseling. Results: We describe 4 families with PGL/ PCC and germline mutations in SDH complex genes. 2 families have SDHB mutations and 2 SDHD mutations. The clinical presentation of the patients and their families was heterogeneous, with some being atypical according to the literature. Conclusions: PGL/PCC are more commonly associated with a germline mutation than any other cancer type, therefore, all individuals with these types of tumors should undergo genetic risk evaluation. NGS multigene panel testing is a cost-effective approach given the overlapping phenotypes. Individuals with germline mutations associated with PGL/PCC should undergo lifelong clinical, biochemical and imaging surveillance and their families should undergo genetic counseling. For all these reasons, it is critical that all medical staff can suspect and diagnose these inherited cancer predisposition syndromes.

SDHB-Associated Paraganglioma Syndrome in Africa—A Need for Greater Genetic Testing

“…Loss of SDHB staining was present in 19 specimens (36%), suggesting the presence of SDHB -associated PPGL in these cases [ 12 ]. The prevalence noted in this study is similar to that reported globally and serves to illustrate that many cases of heritable PPGL likely remain undetected in sub-Saharan Africa [ 13 , 14 ]. The paucity of reports from sub-Saharan Africa may be attributed to the limited health care resources and the lack of availability of genetic testing in the region [ 7-9 , 11 ].…”

Head and Neck Paragangliomas are not so Rare after All: A Single-Center Experience in 3 Years

“…Genetic testing is gaining popularity among the specialists treating PGN, because 20-40% of them have hereditary mutations 12 . Succinate dehydrogenase genes (SDHx A to F), MAX, and TMEM127 are novel genes have been related to "emerging hereditary PHEO/PGN syndromes, " which may be more frequent than the traditionally known genes that cause cancer susceptibility syndromes, such as VHL, NF-1 (neurofibromin 1), and RET (ret proto-oncogene) 23 . New algorithms suggest that HNPGN should be tested for SDHD, SDHC, VHL, SDHB, or SDHAF2 sequentially, unless other characteristics are present (multicentricity, specific syndrome, or family history or malignant behavior) 24 .…”

Familial SDHB gene mutation in disseminated non-hypoxia-related malignant paraganglioma treated with [⁹⁰Y]Y/[¹⁷⁷Lu]Lu-DOTATATE

“…In our patient, genetic testing revealed PGL4 syndrome associated with the Arg230His mutation in the SDHB gene. The mutation was reported previously (21), including in familial cases, although to date, there are only a few families bearing the Arg230His mutation described in the literature (22)(23)(24)(25).…”