This is the first reported case of simultaneous SDHB and TP53 germline mutations occurring in an individual with a highly aggressive clinical course of pheochromocytoma.
Main characteristics of patients with MPP were: primary pheochromocytoma in 53% of patients; tumor- or hormone-related symptoms in 57% or 58% of cases; positive plasma or urine hormones in 81% of patients; identification of a mutation in SDHB in 42% of cases.
Individuals that tested positive for this novel SDHB gene variant were counselled and additional clinical evaluation was offered for the identification of HNPGL and/or PHEO.
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).
SDHB immunohistochemistry (IHC) has previously been shown to be useful for identifying SDHx-deficient PGL/PCC, however, FH IHC has never been explored in these tumors.
Without the identification of SDHB deficiency, this patient's personal and familial predisposition to PC, PGL, GIST and metachronous RCCs may have gone undetected despite his RCC diagnosis.
The succinate dehydrogenase (SDH) enzyme was proven to be the most important molecular pathway involved in pheochromocytomas, along with several other genes.
Patients harboring germline mutations in the succinate dehydrogenase complex subunit B (SDHB) gene present with pheochromocytomas and paragangliomas (PPGL) that are more likely malignant and clinically aggressive.
Here, for the first time, we evaluated the effects of <i>SDHB</i> silencing in a three dimension (3D) culture using spheroids of a mouse Pheo cell line silenced or not (wild type/wt/control) for the SDHB subunit.
We describe a pediatric patient initially considered to have localized neuroblastoma based on anatomical imaging and <sup>123</sup> I-MIBG scan, but subsequent investigations revealed germline succinate dehydrogenase complex iron sulfur subunit B (SDHB) mutation-associated pheochromocytoma with multiple FDG-avid skeletal metastases.
Succinate dehydrogenase subunit B (SDHB) gene mutations are associated with an aggressive clinical disease course of pheochromocytoma/paraganglioma (PHEO/PGL).
We have shown that SDHAF3 interacts directly with SDHB (residue 242 being key to this interaction), and that a variant in SDHAF3 (c.157 T > C [p.Phe53Leu]) may be more prevalent in individuals with PC/PGL, and is hypomorphic via impaired interaction with SDHB.
Thus, F-FDG PET/CT imaging may be more effective than I-MIBG scintigraphy for the evaluation of pheochromocytomas that are associated with highly malignant characteristics resulting from mutations of the SDHB gene.
Transcriptional profiling analysis classified the tumor within cluster 2 of PCCs/PGLs (without SDH gene mutations) and identified downregulation of genes involved in neuronal development and homeostasis (NLGN4, CD99 and CSF2RA) as well as upregulation of Drosha, an important gene involved in miRNA and rRNA processing.