Genetics of pheochromocytoma and paraganglioma in Spanish pediatric patients

Cascón, Alberto; Inglada-Pérez, Lucía; Comino-Méndez, Iñaki; Cubas, Aguirre A. de; Letón, Rocío; Mora, Jaume; Marazuela, Mónica; Galofré, Juan Carlos; Quesada-Charneco, Miguel; Robledo, Mercedes

doi:10.1530/erc-12-0339

Cited by 49 publications

(73 citation statements)

References 17 publications

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“…This population-based frequency was even higher than expected compared with published data from smaller pediatric series of 22-70% (Ciftci et al 2001, Neumann et al 2002, Barontini et al 2006, De Krijger et al 2006, Cascon et al 2013. The affected genes are dominated by VHL followed by SDHB, SDHD, and NF1.…”

Section: Discussionmentioning

confidence: 53%

Long-term prognosis of patients with pediatric pheochromocytoma

Bausch¹,

Wellner²,

Bausch³

et al. 2013

Endocrine-Related Cancer

136

180

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A third of patients with paraganglial tumors, pheochromocytoma, and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127, and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-PheochromocytomaParaganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy were performed in patients diagnosed at !18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1, and one patient each in RET, SDHA, and SDHC. A second primary paraganglial tumor developed in

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Section: Discussionmentioning

confidence: 53%

Long-term prognosis of patients with pediatric pheochromocytoma

Bausch¹,

Wellner²,

Bausch³

et al. 2013

Endocrine-Related Cancer

136

180

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“…52,95 The majority of SHN-PGs are diagnosed in middleaged adults, with younger patients and children more likely to have a recognized predisposing genetic mutation. 24,70,79 Diagnosis is usually achieved by CT or MRI, but for extremely rare secretory SHN-PG, measurement of urine or plasma fractionated metanephrines, radionuclide scintigraphy, and PET can be used for confirmation. 23,44 When these tumors occur in the jugular foramen and temporal bone region of the skull base, it is important to distinguish them from schwannomas and meningiomas, which can have similar presentations and imaging findings.…”

mentioning

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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“…За последние годы установлено, что до 35% случаев развития ФХ/ПГ обусловлено наследуемыми мутациями (для детской по-пуляции этот показатель достигает 70%), а не ограничивается 10%, как считали ранее [4,21,22]. Приблизительно 40% всех насле-дуемых ФХ/ПГ развиваются при трех семей-ных (наследственных) синдромах:…”

Section: злокачественная феохромоцитома/ параганглиомаunclassified

Personalized diagnostics of chromaffin tumors (pheochromocytoma, paraganglioma) in oncoendocrinology

et al. 2018

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Central Military Clinical Hospital named after P.V. Mandryko, Moscow, Russian FederationФеохромоцитомы и параганглиомы (ФХ/ПГ) -редкие катехоламин-секретирующие нейроэндокринные опухоли, почти в 40% случаев имеющие наследственную природу. Заболеваемость колеблется от 2 до 8 случаев на 1 млн человек в год, с пиком заболеваемости в 30-50 лет. Согласно последней классификации, хромаффинные опухоли отнесены к злокачественным новообразованиям. Частота метастазирования ФХ -10%, ПГ -25%. Клинические проявления ФХ и ПГ обусловлены избытком катехоламинов. Известно более 20 наследуемых генов, мутации в которых провоцируют развитие ФХ/ПГ. С точки зрения молекулярной клеточной патофизиологии известный на сегодня пул мутаций можно разделить на два кластера: первый (SDHх, SDHAF2 -фактор сборки SDH, FH, MDH2) нарушает функционирование цикла Кребса и энергетической транспортной цепи митохондрий, второй (RET, NF1, TMEM127, MAX) -мутации генов рецепторов трансмембранных белков-протеинкиназ (тирозинкиназ), активирующие внутриклеточные сигнальные пути (PI3K-AKT-mTOR и MYC), ответственные за клеточный рост, регуляцию роста и дифференцировку клеток. В итоге происходят стабилизация HIF-транскрипционных факторов (оксидативный стресс), изменение метилирования ДНК, приводящие в итоге к глубоким нарушениям экспрессии генов и опухолевой трансформации клетки. Выделяют три основных секреторно-биохимических фенотипа ФХ/ПГ: норадренергический, адренергический и допаминергический. В зависимости от типа секреции опухоли, возраста пациента и семейного анамнеза назначаются комплементарные генетические исследования и методы молекулярной визуализации. В клинической практике биохимический фенотип опухоли, стадия, семейный анамнез и особенно генетический "паспорт" опухоли позволяют подобрать оптимальный алгоритм молекулярной визуализации (ОФЭКТ/ПЭТ) в целях персонализации тактики лечения и клинического прогноза.Ключевые слова : хромаффинные опухоли, феохромоцитома, параганглиома, радионуклидная диагностика, молекулярная визуализация, генетика, эндокринология, онкология, радиология, онкоэндокринология. Pheochromocytomas and paragangliomas (PPGLs) are rare catecholamine-secreting neuroendocrine tumours, up to 40% of which occur in the setting of a hereditary syndrome. The incidence is 2 to 8 per million persons per year. The peak incidence occurs in the third to fifth decades of life. According to the most recent classification, chromaffin tumours refer to malignant neoplasms. The incidence of metastasis in pheochromocytomas is 10%; in paragangliomas it is 25%. Clinical manifestations of PPGLs are caused by the excess of catecholamines. More than 20 hereditary gene mutations are known to result in PPGLs development. According to the molecular and cellular pathophysiology, all currently known mutations can be divided intoThe article can used under the CC BY-NC-ND 4.0 license. Статья может быть использована на условиях международной лицензии CC BY-NC-ND 4.0.

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Genetics of pheochromocytoma and paraganglioma in Spanish pediatric patients

Cited by 49 publications

References 17 publications

Long-term prognosis of patients with pediatric pheochromocytoma

Long-term prognosis of patients with pediatric pheochromocytoma

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

Personalized diagnostics of chromaffin tumors (pheochromocytoma, paraganglioma) in oncoendocrinology

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