A novel TMEM127 mutation in a patient with familial bilateral pheochromocytoma

Burnichon, Nelly; Lepoutre-Lussey, Charlotte; Laffaire, Julien; Gadessaud, Noémie; Molinié, Vincent; Hernigou, A.; Plouin, Pierre‐François; Jeunemaı̂tre, Xavier; Favier, Judith; Gimenez-Roqueplo, Anne-Paule

doi:10.1530/eje-10-0758

Cited by 42 publications

(32 citation statements)

References 14 publications

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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.

106

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

confidence: 99%

Pheochromocytoma and paraganglioma syndromes: genetics and management update

Lefebvre¹,

Foulkes²

2013

Curr. Oncol.

106

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“…An association between TMEM127 mutation and pheochromocytoma was initially discovered through global expression profiling and high-density copy number mapping, with TMEM127 mutations being identified in almost one-third of familial cases. 21,81 Subsequent direct sequencing analyses have now demonstrated that 2%-4% of individuals with SHN-PG possess TMEM127 mutations. 63,74 Although the exact mechanism by which TMEM127 mutations result in paraganglioma tumorigenesis is the focus of current research, preliminary studies indicate it is a negative regulator of mTOR (mammalian target of rapamycin), a cellular growth and proliferation protein of the PI3-kinase family.…”

Section: Tmem127 and Maxmentioning

confidence: 99%

Molecular genetics of paragangliomas of the skull base and head and neck region: implications for medical and surgical management

Hussain¹,

Husain²,

Baredes

et al. 2014

JNS

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Paragangliomas are rare neuroendocrine tumors derived from neural crest cells of the autonomic nervous system. Tumors occurring in the thorax, abdomen, and pelvis are usually derived from sympathetic paraganglia, which are associated with catecholaminemia, headaches, and resistant hypertension. Pheochromocytomas, arising from chromaffin cells of the adrenal medulla, are histologically similar to sympathetic paragangliomas and can have identical clinical presentations. In contrast to these tumors, skull base and head and neck region paragangliomas (SHN-PGs) are usually derived from parasympathetic paraganglia and rarely secrete catecholamines. These tumors can present in a variety of locations, most commonly arising from glomus Type I (chief) cells of the carotid body. Less commonly they arise in regions of the temporal bone including the middle ear (glomus tympanicum) and jugular fossa (glomus jugulare) (Fig. 1A), as well as along the length of the vagus nerve (glomus vagale) and in the nose and paranasal sinuses (sinonasal paraganglioma). 60,69,75,77,93,99 These tumors Paragangliomas are rare, slow-growing tumors that frequently arise in the head and neck, with the carotid bodies and temporal bone of the skull base being the most common sites. These neoplasms are histologically similar to pheochromocytomas that form in the adrenal medulla and are divided into sympathetic and parasympathetic subtypes based on functionality. Skull base and head and neck region paragangliomas (SHN-PGs) are almost always derived from parasympathetic tissue and rarely secrete catecholamines. However, they can cause significant morbidity by mass effect on various cranial nerves and major blood vessels. While surgery for SHN-PG can be curative, postoperative deficits and recurrences make these lesions challenging to manage. Multiple familial syndromes predisposing individuals to development of paragangliomas have been identified, all involving mutations in the succinate dehydrogenase complex of mitochondria. Mutations in this enzyme lead to a state of "pseudohypoxia" that upregulates various angiogenic, survival, and proliferation factors. Moreover, familial paraganglioma syndromes are among the rare inherited diseases in which genomic imprinting occurs. Recent advances in gene arrays and transcriptome/exome sequencing have identified an alternate mutation in sporadic SHN-PG, which regulates proto-oncogenic pathways independent of pseudohypoxia-induced factors. Collectively these findings demonstrate that paragangliomas of the skull base and head and neck region have a distinct genetic signature from sympathetic-based paragangliomas occurring below the neck, such as pheochromocytomas. Paragangliomas serve as a unique model of primarily surgically treated neoplasms whose future will be altered by the elucidation of their genomic complexities. In this review, the authors present an analysis of the molecular genetics of SHN-PG and provide future directions in patient care and the development of novel therapies. 321Abbreviations used in ...

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“…Ce gène a été identifié en 2010 comme un gène de susceptibilité au PCC grâce à des approches de génomique intégrative, combinant analyse de liaison, étude du transcriptome et analyse du nombre de copies [13]. Les échantillons tumoraux provenant de patients avec une mutation TMEM127 se classent dans le cluster 2 ; il y a systématiquement une perte de l'allèle sauvage qui s'étend souvent sur la totalité du bras 2q [13,29,30]. Les premières données obtenues in vitro suggèrent que TMEM127 pourrait être impliquée dans le trafic protéique intracellulaire et/ou dans le recyclage des protéines de l'endocytose.…”

Section: Les Nouveaux Gènes De Prédisposition Aux Pgl/pccunclassified

La génétique des paragangliomes et des phéochromocytomes

Favier

Gimenez-Roqueplo

2012

Med Sci (Paris)

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> Les paragangliomes et les phéochromocytomes sont des tumeurs rares qui se développent aux dépens des ganglions sympathiques et parasympathiques, ainsi que de la médullosurrénale. La génétique des phéochromocytomes et des paragangliomes a fait des progrès considérables au cours des dix dernières années. Dix gènes de prédisposition (VHL, RET, NF1, SDHA, B, C et D, SDHAF2, TMEM127 et finalement MAX) ont été identifiés, expliquant plus d'un tiers des cas (avec une histoire familiale, mais aussi de pré-sentation apparemment sporadique). Les études transcriptomiques ont par ailleurs conduit à l'identification de mutations somatiques des gènes RET et VHL dans les tumeurs d'environ 15 % des patients atteints d'une forme sporadique de la maladie, apportant ainsi une explication moléculaire dans près de la moitié des cas. Ces découvertes ont conduit à une meilleure compréhension des mécanismes moléculaires de tumorigenèse des phéochromocytomes et des paragangliomes. Il a été montré que le statut génétique des tumeurs était associé à une signature moléculaire particulière, telle que la pseudohypoxie ou l'activation des voies des MAPK ou de mTOR. Ces connaissances ont eu un impact majeur sur le conseil génétique des patients et de leurs familles et permettront à l'avenir une prise en charge médicale, clinique et thérapeutique personnalisée des patients atteints. < et jugulaire), le cou (glomus carotidien et vagal), la médullosurrénale et les ganglions sympathiques thoraco-abdominaux-pelviens. Ces tumeurs peuvent sécréter des catécholamines ; on parle de phéo-chromocytome (PCC) si leur localisation est médullosurrénalienne, ou de PGL fonctionnel si leur localisation est extrasurrénalienne. Elles constituent alors une cause classique de forme secondaire et grave d'hypertension artérielle. Leur prévalence est évaluée à environ 0,1 % des patients hypertendus et 4 % des patients présentant une masse surrénalienne découverte de façon fortuite. Les PGL/ PCC sont des tumeurs très vascularisées, le plus souvent bénignes. Cependant, elles sont malignes dans environ 15 % des cas et, en absence de critère histologique fiable, ce diagnostic de malignité des PGL/PCC repose sur l'apparition d'une métastase à distance d'un site paraganglionnaire (ganglions, os, foie, poumons, etc.). La seule approche thérapeutique efficace est l'ablation chirurgicale de la tumeur, qui peut être à l'origine de nombreuses complications, notamment du fait de la sécrétion hormonale et de l'importante vascularisation de ces tumeurs. Les PGL/PCC posent donc de difficiles problèmes de diagnostic, de pronostic, de traitement et de surveillance à long terme [1]. Au cours des dix dernières années, nous avons assisté à une progression spectaculaire des connaissances sur la génétique des PGL/PCC. On a longtemps considéré que seules 10 % de ces tumeurs étaient génétiquement déterminées, causées par des mutations constitutionnelles des gènes NF1 (neurofibromin) [2] Les paragangliomes (PGL) sont des tumeurs neuroendocrines rares qui se développent aux dépens du tissu...

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A novel TMEM127 mutation in a patient with familial bilateral pheochromocytoma

Cited by 42 publications

References 14 publications

Pheochromocytoma and paraganglioma syndromes: genetics and management update

Pheochromocytoma and paraganglioma syndromes: genetics and management update

Molecular genetics of paragangliomas of the skull base and head and neck region: implications for medical and surgical management

La génétique des paragangliomes et des phéochromocytomes

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