Pituitary Adenoma With Paraganglioma/Pheochromocytoma (3PAs) and Succinate Dehydrogenase Defects in Humans and Mice

Xekouki, Paraskevi; Szarek, Eva; Bullova, Petra; Giubellino, Alessio; Quezado, Martha; Mastroyannis, Spyridon A.; Mastorakos, Panagiotis; Wassif, Christopher A.; Raygada, Margarita; Rentia, Nadia; Dye, Louis; Cougnoux, Antony; Koziol, Deloris E.; Sierra, Maria de la Luz; Lyssikatos, Charalampos; Belyavskaya, Elena; Malchoff, Carl D.; Moline, Jessica; Eng, Charis; Maher, L. James; Pacák, Karel; Lodish, Maya; Stratakis, Constantine A.

doi:10.1210/jc.2014-4297

Cited by 131 publications

(121 citation statements)

References 54 publications

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“…However, unlike the rest of the CTr patients who are overwhelmingly female, those with SDHx defects were disproportionately male (50% versus 8%, Po0.05) following the pattern of other diseases associated with SDHx mutations that typically have no gender predilection. 9,18,21 The other interesting finding was the association with other neural crest tumors that have not previously been associated with CTr: ganglioneuroma in one patient with SDHC variation and NB in the nephew of another, in association with the same SDHB defect; in this family, no other patient had CTr: the obligate carriers had PGL or PHEO. In other words, in accordance with all known CTr patients in whom the disease appears sporadically, even in these patients where SDHx mutations were present, CTr was never inherited in its full form.…”

Section: Discussionmentioning

confidence: 64%

Carney triad can be (rarely) associated with germline succinate dehydrogenase defects

et al. 2015

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Carney triad, the association of paragangliomas/pheochromocytomas, gastrointestinal stromal tumors and pulmonary chondromas, is a sporadic condition that is significantly more frequent in females; its genetic etiology remains unknown. Carney triad is distinct from the dyad of paragangliomas/pheochromocytomas and gastrointestinal stromal tumors, known as Carney-Stratakis syndrome, which is inherited in an autosomal-dominant manner and is almost always caused by succinate dehydrogenase subunit mutations. In the present study, we investigated the largest cohort of Carney triad patients that is available internationally: 63 unrelated patients. Six patients (9.5%) were found to have germline variants in the SDHA, SDHB or SDHC genes. All six patients, except one, had multifocal gastrointestinal stromal tumors, chondromas and/or paragangliomas. A patient with Carney triad and SDHC variant had a ganglioneuroma. One of the patients with Carney triad and SDHB mutation had a nephew with the same sequence defect, who developed a neuroblastoma. Other relatives, carriers of the identified SDHA, SDHB or SDHC mutations, have not developed any of the components of Carney triad or Carney-Stratakis syndrome. None of the other 57 Carney triad patients had any genomic defects of SDHA, SDHB or SDHC genes. We conclude that, in rare occasions, Carney triad can be allelic to Carney-Stratakis syndrome. Although for the vast majority of patients with Carney triad the causative defect(s) remain(s) unknown, testing for SDHA, SDHB or SDHC variations should be offered, as carriers may develop isolated paragangliomas/pheochromocytomas and occasionally other tumors.

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Section: Discussionmentioning

confidence: 64%

Carney triad can be (rarely) associated with germline succinate dehydrogenase defects

et al. 2015

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“…In vivo estimation of succinate could help classifying a dubious lesion detected during surveillance and to demonstrate the causality of SDH deficiency in tumors identified in SDHx-mutated patients. This would be particularly helpful in cases for which surgery is not necessary, such as prolactin-secreting pituitary adenomas recently described in SDHx mutation carriers (37). Because of the small size of these tumors, the feasibility of SUCCESS may however be more difficult in these cases.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma

Lussey-Lepoutre

Bellucci

Morin

et al. 2016

Clinical Cancer Research

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International audiencePurpose: Germline mutations in genes encoding mitochon-drial succinate dehydrogenase (SDH) are found in patients with paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and renal cancers. SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite and which levels, assessed on surgically resected tissue are a highly specific biomarker of SDHx-mutated tumors. The aim of this study was to address the feasibility of detecting succinate in vivo by magnetic resonance spectroscopy. Experimental Design: A pulsed proton magnetic resonance spectroscopy (1 H-MRS) sequence was developed, optimized, and applied to image nude mice grafted with Sdhb À/À or wild-type chromaffin cells. The method was then applied to patients with paraganglioma carrying (n ¼ 5) or not (n ¼ 4) an SDHx gene mutation. Following surgery, succinate was measured using gas chromatography/mass spectrometry, and SDH protein expression was assessed by immunohistochemistry in resected tumors. Results: A succinate peak was observed at 2.44 ppm by 1 H-MRS in all Sdhb À/À-derived tumors in mice and in all paragangliomas of patients carrying an SDHx gene mutation, but neither in wild-type mouse tumors nor in patients exempt of SDHx mutation. In one patient, 1 H-MRS results led to the identification of an unsus-pected SDHA gene mutation. In another case, it helped define the pathogenicity of a variant of unknown significance in the SDHB gene. Conclusions: Detection of succinate by 1 H-MRS is a highly specific and sensitive hallmark of SDHx mutations. This non-invasive approach is a simple and robust method allowing in vivo detection of the major biomarker of SDHx-mutated tumors. Clin Cancer Res; 22(5); 1120–9. Ó2015 AACR

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“…In terms of the molecular pathogenesis of the syndrome, constitutional inactivating mutations of SDHB, SDHC or SDHD have been confirmed in the vast majority of CSS patients (Benn et al 2006, McWhinney et al 2007. Additionally, the syndrome of pituitary adenomas, paragangliomas and pheochromocytomas (3PAs) has also been reported to be associated with SDH subunit germline mutations (Xekouki et al 2015).…”

Section: Carney-stratakis Syndromementioning

confidence: 98%

Classification of gastrointestinal stromal tumor syndromes

Gopie

Faber

et al. 2018

Endocrine-Related Cancer

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, thought to derive from neoplastic outgrowth of the interstitial cells of Cajal. Building on recent advances in recognition, classification and diagnosis, the past two decades have seen a changing paradigm with molecular diagnostics and targeted therapies. KIT and PDGFRA mutations account for 85-90% of GIST carcinogenesis. However, the remaining 10-15% of GISTs, which until recently were called KIT/PDGFRA wild-type GISTs, have been found to have one of the several mutations, including in the SDHA, B, C, D, BRAF and NF1 genes. Though most of such GISTs are sporadic, a number of families with high incidence rates of GISTs and other associated clinical manifestations have been reported and found to harbor germline mutations in KIT, PDGFRA, SDH subunits and NF1. The goal of this review is to describe the mutations, clinical manifestations and therapeutic implications of syndromic and inherited GISTs in light of recent studies of their clinicopathologic range and pathogenesis.

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Pituitary Adenoma With Paraganglioma/Pheochromocytoma (3PAs) and Succinate Dehydrogenase Defects in Humans and Mice

Cited by 131 publications

References 54 publications

Carney triad can be (rarely) associated with germline succinate dehydrogenase defects

Carney triad can be (rarely) associated with germline succinate dehydrogenase defects

In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma

Classification of gastrointestinal stromal tumor syndromes

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