In order to characterize phenotypic effects of these mutations, the present study investigated the immunohistochemical expression of the catalytic subunits of complex II (flavoprotein and iron protein), SDH enzyme activity, and mitochondrial morphology in a series of 22 head and neck paragangliomas.
Germline mutations in FH predispose individuals to leiomyomas and renal cell cancer (HLRCC), whereas mutations in SDH cause paragangliomas and phaeochromocytomas (HPGL).
The SDH mutation database offers a valuable tool and resource for clinicians involved in the treatment of patients with paraganglioma-pheochromocytoma, clinical geneticists needing an overview of current knowledge, and geneticists and other researchers needing a solid foundation for further exploration of both these tumor syndromes and SDHA-related phenotypes.
Mutation screening of genes associated to VHL (VHL), MEN (RET), and familial PGL (SDH-B, -C, and -D) showed that all cases had germline deletions in the SDHB gene.
An intriguing hypothesis proposes that mutations of RET, NF1, VHL, or SDH predispose to hereditary pheochromocytoma/ paraganglioma by causing defective apoptotic culling of cells that would normally be destroyed during embryogenesis.
Inactivating mutations of the mitochondrial complex II succinate dehydrogenase (SDH) enzyme subunits SDHB, SDHC, and SDHD are found in PGLs, gain-of-function mutations of c-kit (KIT), and platelet-derived growth factor receptor A (PDGFRA) in GISTs.
Approximately 10% to 15% of paragangliomas are caused by mutations in the succinate dehydrogenase (SDH) genes B, C, or D. These are often multifocal as part of paraganglioma syndromes and hormone secreting, and malignant particularly associated with mutations in SDHB.
Recent studies have demonstrated that SDH gene mutations in germ line occur in at least 11% of non-familial head and neck paragangliomas, 8% of non-familial pheochromocytomas, 28% of malignant pheochromocytomas and 33% of extra-adrenal pheochromocytomas.
Mutations in genes encoding succinate dehydrogenase and its anchoring subunits (SDH genes) are at the origin of hereditary head and neck paraganglioma (PGL) and a subset of apparently sporadic pheochromocytoma.
These data suggest that inactivating germline SDH mutations and somatic deletions of SDH genes as a "second hit" are involved in a subset, but not in all PGLs.
SDH genetic testing, including tests for large genomic deletions, is indicated in all patients with head and neck and/or thoracic-abdominal or pelvic paraganglioma and can be targeted according to clinical criteria.
Germline mutations in SDH genes are responsible for 6% and 9% of sporadic paragangliomas and phaeochromocytomas, respectively, 29% of paediatric cases, 38% of malignant tumours and more than 80% of familial aggregations of paraganglioma and phaeochromocytoma.
Recent studies indicate that succinate dehydrogenase (SDH) genes B, C, or D are, at least partly, involved in the pathogenesis of pheochromocytoma or paraganglioma.
We investigated whether SDHB immunohistochemistry could effectively discriminate between SDH-related and non-SDH-related phaeochromocytomas and paragangliomas in large retrospective and prospective tumour series.
The paraganglioma-pheochromocytoma syndrome is caused by germline-inactivating mutations in the mitochondrial succinate dehydrogenase (SDH) genes SDHB, SDHC, SDHD, or SDHAF2, and VHL is the result of inactivating VHL gene mutations.
As SDH mutations are virtually always germline, we conclude that approximately 15% of all pheochromocytomas or paragangliomas are associated with germline SDH mutation and that immunohistochemistry can be used to triage genetic testing.
Analysis of the SDH genes was performed in 29 patients and one kindred with familial PGL to identify germline mutations in the SDHB, SDHC, and SDHD genes by direct DNA sequencing.