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.
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.
Clinical, biochemical, pathological attributes, and outcomes in the MEN-PCC group were correlated with the genotype, and further compared with non-MEN, apparently sporadic adrenal-PCCs (n = 132, excluding 37 extra-adrenal and 15 VHL/NF1/SDH-associated PCC).
Despite these figures, the screening of phaeochromocytomas and paragangliomas for mutations in the SDH genes to detect phaeochromocytoma-paraganglioma syndrome is rarely done because of time and financial constraints.
Finally, discovery of a shared activation of the hypoxic response in pheochromocytomas with mutations in VHL and SDH genes and uncovering of a common JunB-mediated apoptosis defect in the major hereditary groups of pheochromocytoma have provided a mechanistic basis for the clinical similarities between these distinct syndromes.
Genetic analysis for PHEO/paraganglioma genes (SDH A-D, SDHAF2, RET, VHL, TMEM127, and MAX), and pituitary-related genes (AIP, MEN1, and p27) were negative.
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.
Global transcription analysis of KIF1B beta mutant pheochromocytomas revealed that these tumors are transcriptionally related to pheochromocytomas with RET and NF1 mutations but independent from SDH- and VHL-associated tumors.
IDH1 and IDH2 mutations are found in many neoplasms, and germline alterations in SDH genes and FH predispose to pheochromocytoma/paraganglioma and other cancers.
In this study, we investigated mutations of SDH genes in six HPPS patients from four Japanese pedigrees using peripheral blood lymphocytes (from one patient with pheochromocytoma and five patients with neck paraganglioma) and tumor tissues (from two patients with paraganglioma).
It is now recognized that all of the SDH genes are involved in the tumorigenesis of not only paragangliomas/pheochromocytomas, but also other tumor types, most notably gastrointestinal stromal tumors.
Metabolome profiling by HRMAS NMR spectroscopy of pheochromocytomas and paragangliomas detects SDH deficiency: clinical and pathophysiological implications.
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.
Mutations of the SDH gene are associated with many tumors, such as renal cell carcinoma, wild type gastrointestinal stromal tumors (WT GISTs) and hereditary paragangliomas/pheochromocytomas.
Patients with germline mutations in one of the SDH genes are at substantially increased risk of developing paragangliomas, pheochromocytomas (pheos), and other tumors (all combined referred to as SDH-related tumors).
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.
Recent studies indicate that succinate dehydrogenase (SDH) genes B, C, or D are, at least partly, involved in the pathogenesis of pheochromocytoma or paraganglioma.
The SDH mutation database: an online resource for succinate dehydrogenase sequence variants involved in pheochromocytoma, paraganglioma and mitochondrial complex II deficiency.
The aim of this study was to investigate interobserver variability among seven expert endocrine pathologists using a web-based virtual microscopy approach in a large multicenter pheochromocytoma/paraganglioma cohort (n=351): (1) 73 SDH mutated, (2) 105 non-SDH mutated, (3) 128 samples without identified SDH-x mutations, and (4) 45 with incomplete SDH molecular genetic analysis.
The differing effect of the SDHD p.Pro81Leu on HNPGL and pheochromocytoma risks suggests differing mechanisms of tumorigenesis in SDH-associated HNPGL and pheochromocytoma.