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

A germline mutation is identified in almost 40% of Pheochromocytoma-Paraganglioma (PPGL) Syndromes. Genetic testing and counselling are essential for the management of index cases as well as pre-symptomatic identification and pre-emptive management of affected family members. Mutations in the genes encoding the mitochondrial enzyme succinate dehydrogenase (SDH) are well described in patients with hereditary PPGL. Amongst patients of African ancestry the prevalence, phenotype, germline mutation spectrum and penetrance of SDH mutations is poorly characterized. We describe a multifocal paraganglioma in a young African male with an underlying mis-sense SDHB mutation, with a history of three first-degree relatives who demised at young ages from suspected cardiovascular causes. The same SDHB mutation, Class V variant c.724C>A p.(Arg242Ser), was detected in one of his asymptomatic siblings. As there is limited data describing hereditary PPGL syndromes in Africa this report of an SDHB associated PPGL is a notable contribution to the literature in this growing field. Due to the noteworthy clinical implications of PPGL mutations, it highlights the existing need for broader genetic screening amongst African patients with PPGL despite the limited healthcare resources available in this region.

Hereditary pheochromocytoma/paraganglioma syndrome with a novel mutation in the succinate dehydrogenase subunit B gene in a Japanese family: two case reports

Background Pheochromocytoma and paraganglioma caused by succinate dehydrogenase gene mutations is called hereditary pheochromocytoma/paraganglioma syndrome. In particular, succinate dehydrogenase subunit B mutations are important because they are strongly associated with the malignant behavior of pheochromocytoma and paraganglioma . This is a case report of a family of hereditary pheochromocytoma/paraganglioma syndrome carrying a novel mutation in succinate dehydrogenase subunit B. Case presentation A 19-year-old Japanese woman, whose father died of metastatic paraganglioma, was diagnosed with abdominal paraganglioma, and underwent total resection. Succinate dehydrogenase subunit B genetic testing detected a splice-site mutation, c.424-2delA, in her germline and paraganglioma tissue. Afterwards, the same succinate dehydrogenase subunit B mutation was detected in her father’s paraganglioma tissues. In silico analysis predicted the mutation as “disease causing.” She is under close follow-up, and no recurrence or metastasis has been observed for 4 years since surgery. Conclusions We detected a novel succinate dehydrogenase subunit B mutation, c.424-2delA, in a Japanese family afflicted with hereditary pheochromocytoma/paraganglioma syndrome and found the mutation to be responsible for hereditary pheochromocytoma/paraganglioma syndrome. This case emphasizes the importance of performing genetic testing for patients with pheochromocytoma and paraganglioma suspected of harboring the succinate dehydrogenase subunit B mutation (that is, metastatic, extra-adrenal, multiple, early onset, and family history of pheochromocytoma and paraganglioma) and offer surveillance screening to mutation carriers.

An aggressive and expanded phenotype in a kindred with a c.57delG SDHD mutation

Summary Familial paraganglioma syndrome type 1 (PGL-1) is maternally imprinted, caused by SDHD mutations on the paternally inherited allele, and presents with paragangliomas and pheochromocytomas that are usually benign. We describe a kindred with a germline c.57delG SDHD mutation that demonstrates an aggressive and possibly expanded phenotype. Eight individuals across four generations were heterozygous for the c.57delG SDHD mutation. The three with known paternal inheritance were clinically affected. The aggressive phenotype was manifested by a neck paraganglioma with distant metastases, and to a lesser degree a neck paraganglioma infiltrating into local connective tissue and a pheochromocytoma presenting at age 8 y. A pulmonary capillary hemangioma may expand the SDHD phenotype. We conclude that the c.57delG SDHD mutation may confer a more aggressive and possibly expanded phenotype than other SDHD mutations. Learning points The c.57delG SDHD mutation may confer a more aggressive phenotype than other mutations associated with familial paraganglioma syndrome type 1. A capillary hemangioma, a component of other pseudohypoxia states, was observed in the lung of a single member of the c.57delG SDHD kindred. This report supports the hypothesis of others that mutations found near the beginning of the SDHD open reading frame are more likely to demonstrate an aggressive phenotype.

Paraganglioma of the Urinary Bladder Metastatic to the Lung in a Patient with SDHB Gene Mutation: A Case Report

Introduction/Objective Paragangliomas are tumors originating from the neural crest. Most tumors are benign and arise from various locations in the body. Extra-adrenal paragangliomas arise as sporadic cases in most settings or as part of heredofamilial syndromes in about one-quarter of cases. Succinate dehydrogenase subunit B (SDHB) gene mutations are associated with an aggressive clinical disease course of pheochromocytoma/paraganglioma. Methods We present a 41-year-old male former smoker with a history of a growing right upper lung nodule on chest imaging. He had no cough or respiratory symptoms. Twenty-seven months prior the patient underwent a cystoprostatectomy due to paraganglioma of the bladder. Genetic testing identified a pathogenic mutation in SDHB gene, c.166_170delCCTCA (p.Pro56Tyrfs*5). He underwent a wedge resection of the lung nodule. Results Sectioning of the lung wedge revealed a well circumscribed, firm tan nodule. Microscopically there were nests of large neoplastic cells with round nuclei and eosinophilic granular cytoplasm. Tumor cells were positive for synaptophysin and chromogranin and negative for pan-cytokeratin. S100 highlighted sustentacular cells. The pulmonary neoplasm was morphologically similar to the prior tumor of the bladder. These features are consistent with a metastatic urothelial paraganglioma to the lung, in a background of a hereditary paraganglioma syndrome. Conclusion Extra-adrenal paraganglioma occurring in a setting of hereditary paraganglioma syndrome has a higher risk of metastasis. Lifelong surveillance even after prompt resection of primary tumor with negative margins is required to ensure early detection of metastasis and prevention of complications associated with it.

Molecular characterization of CNS paragangliomas identifies cauda equina paragangliomas as a distinct tumor entity

Paragangliomas/pheochromocytomas are rare neuroendocrine tumors that arise from the adrenal gland or ganglia at various sites throughout the body. They display a remarkable diversity of driver alterations and are associated with germline mutations in up to 40% of the cases. Comprehensive molecular profiling of abdomino-thoracic paragangliomas revealed four molecularly defined and clinically relevant subtypes. Paragangliomas of the cauda equina region are considered to belong to one of the defined molecular subtypes, but a systematic molecular analysis has not yet been performed. In this study, we analyzed genome-wide DNA methylation profiles of 57 cauda equina paragangliomas and show that these tumors are epigenetically distinct from non-spinal paragangliomas and other tumors. In contrast to paragangliomas of other sites, chromosomal imbalances are widely lacking in cauda equina paragangliomas. Furthermore, RNA and DNA exome sequencing revealed that frequent genetic alterations found in non-spinal paragangliomas—including the prognostically relevant SDH mutations—are absent in cauda equina paragangliomas. Histologically, cauda equina paragangliomas show frequently gangliocytic differentiation and strong immunoreactivity to pan-cytokeratin and cytokeratin 18, which is not common in paragangliomas of other sites. None of our cases had a familial paraganglioma syndrome. Tumors rarely recurred (9%) or presented with multiple lesions within the spinal compartment (7%), but did not metastasize outside the CNS. In summary, we show that cauda equina paragangliomas represent a distinct, sporadic tumor entity defined by a unique clinical and morpho-molecular profile.