Germline Mutations of the TMEM127 Gene in Patients with Paraganglioma of Head and Neck and Extraadrenal Abdominal Sites

Neumann, Hartmut P. H.; Sullivan, Maren; Winter, Aurelia; Malinoc, Angelica; Hoffmann, Michael M.; Boedeker, Carsten C.; Bertz, Hartmut; Walz, Martin K.; Moeller, Lars C.; Schmid, Kurt Werner; Eng, Charis

doi:10.1210/jc.2011-0114

Cited by 92 publications

(102 citation statements)

References 11 publications

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“…Another study revealed one additional PCC patient with a TMEM127 mutation . No TMEM127 mutations were detected in 129 sympathetic and 60 parasympathetic PGLs (Yao et al 2010b), but in a recent study, germline missense variants were detected in two out of 48 patients with multiple PGLs (Neumann et al 2011), one of which also displayed bilateral PCC. Summarizing the 23 reported patients, all but one (96%) had PCC and 39% had bilateral PCC (Table 1).…”

Section: Tmem127-associated Pccs and Pglsmentioning

confidence: 92%

Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas

Welander¹,

Söderkvist²,

Gimm³

2011

Endocrine-Related Cancer

311

321

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Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors of the adrenal glands and the sympathetic and parasympathetic paraganglia. They can occur sporadically or as a part of different hereditary tumor syndromes. About 30% of PCCs and PGLs are currently believed to be caused by germline mutations and several novel susceptibility genes have recently been discovered. The clinical presentation, including localization, malignant potential, and age of onset, varies depending on the genetic background of the tumors. By reviewing more than 1700 reported cases of hereditary PCC and PGL, a thorough summary of the genetics and clinical features of these tumors is given, both as part of the classical syndromes such as multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease, neurofibromatosis type 1, and succinate dehydrogenase-related PCC-PGL and within syndromes associated with a smaller fraction of PCCs/PGLs, such as Carney triad, Carney-Stratakis syndrome, and MEN1. The review also covers the most recently discovered susceptibility genes including KIF1Bb, EGLN1/PHD2, SDHAF2, TMEM127, SDHA, and MAX, as well as a comparison with the sporadic form. Further, the latest advances in elucidating the cellular pathways involved in PCC and PGL development are discussed in detail. Finally, an algorithm for genetic testing in patients with PCC and PGL is proposed.

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Section: Tmem127-associated Pccs and Pglsmentioning

confidence: 92%

Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas

Welander¹,

Söderkvist²,

Gimm³

2011

Endocrine-Related Cancer

311

321

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“…Through both germline and somatic tumor testing of individuals with PGL, the prevalence of germline susceptibility genes altered in HNPGL is now ~30 to 40%, involving predominantly genes encoding subunits of succinate dehydrogenase ("SDHx" genes) [3,5]. In addition to SDHx, VHL, NF1 and RET, genes including MAX [6], TMEM127 [7] fumarate hydratase [8] and HIF2A [9] have now been associated with HNPGL in rare cases. The clinical implications of hereditary disease have led the Endocrine Society to recommend referring all patients diagnosed with PGL for clinical genetic testing regardless of site of origin or lack of familial events [10].…”

Section: Geneticsmentioning

confidence: 99%

Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Paragangliomas

Williams

Tischler

2017

Head and Neck Pathol

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“…The typical presentation is a unilateral adrenal pheo in patients with no prior family history. Recently, however, bilateral pheo, extraadrenal pgl, and hnpgl have been described 27,28 . The penetrance is unknown.…”

Section: Genetics Of Pheo-pgl: Non-syndromic Causesmentioning

confidence: 99%

Pheochromocytoma and paraganglioma syndromes: genetics and management update

Lefebvre¹,

Foulkes²

2013

Curr. Oncol.

103

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hypertension, perspiration, or pallor. He was referred to genetics because of a family history of pheochromocytoma (pheo): his maternal cousin's daughter had been diagnosed with an abdominal extra-adrenal paraganglioma (pgl). She and her mother underwent genetic testing and were both found to be positive for a SDHB mutation, c.343C>T, p.Arg115*. Our patient's deceased maternal uncle was presumed to be a carrier, because his wife (the affected woman's maternal grandmother) was tested and did not carry the mutation. The patient was tested and was found to be a carrier of the familial mutation, as were his three unaffected children. Case 2A 49-year-old French Canadian man was diagnosed with bilateral neck pgls. He did not report ataxia, skin problems, or other tumours, and the family history was negative for relevant illnesses. Magnetic resonance imaging showed bilateral masses in the carotid spaces. On the left side, the tumour extended from the post-styloid parapharyngeal space, splaying the carotid arteries anteriorly and the internal jugular vein posteriorly. The mass, which arose from the vagus nerve, measured 72×38×46 mm. On the right side, the tumour, which arose from the carotid body, was located in the right carotid bifurcation. It measured 11×14 mm. Because surgery was not possible, the patient was treated with radiotherapy.The genetic work-up included SDHB and SDHD sequencing, the results of which were normal. A deletion and duplication analysis of SDHB, SDHC, and SDHD by multiplex ligation-dependent probe amplification was also normal. On a research basis, SDHAF2 and SDHC sequencing were then done. We identified a SDHC mutation, c.397C>T, p.Arg133*, which is a probable French Canadian founder mutation 1 . Case 3A 67-year-old woman of Ashkenazi Jewish inheritance had a history of a mass in the neck for about 20 ABSTRACT Pheochromocytomas (pheos) and paragangliomas (pgls) are rare tumours of the autonomic nervous system, originating from paraganglia, which are dispersed neuroendocrine organs characterized by catecholamine and peptide-producing cells derived from the neural crest. Medical textbooks have traditionally suggested that 10% of pheos are heritable. However, the frequency of heritable pheo has been underestimated. Three syndromic conditions-Von Hippel-Lindau (vhl), multiple endocrine neoplasia type 2 (men2), and neurofibromatosis type 1 (nf1)-and three genes-subunits of the succinate dehydrogenase (SDH) complex: SDHB, SDHC, and SDHD-are established causes of hereditary pheo-pgl. In the last few years, four new genes (SDHA, SDHAF2, MAX, and TMEM127) have been found to be associated with predisposition to these tumours. The present review, illustrated by three case reports, gives an update of the genetic basis of pheo-pgl and of the parent-of-origin effect implicated in the transmission of SDHD and SDHAF2. We discuss the referral criteria that should guide the decision to offer genetic testing to affected patients. We also specify the genes that are most likely implicated-based on particular featur...

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Germline Mutations of the TMEM127 Gene in Patients with Paraganglioma of Head and Neck and Extraadrenal Abdominal Sites

Cited by 92 publications

References 11 publications

Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas

Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas

Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Paragangliomas

Pheochromocytoma and paraganglioma syndromes: genetics and management update

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