Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas

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 includingKIF1Bβ, EGLN1/PHD2, SDHAF2, TMEM127, SDHA, andMAX, 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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Perioperative outcomes of syndromic paraganglioma and pheochromocytoma resection in patients with von Hippel-Lindau disease, multiple endocrine neoplasia type 2, or neurofibromatosis type 1

Surgery ◽

10.1016/j.surg.2017.08.002 ◽

2017 ◽

Vol 162 (6) ◽

pp. 1259-1269 ◽

Cited By ~ 7

Author(s):

James J. Butz ◽

Qi Yan ◽

Travis J. McKenzie ◽

Toby N. Weingarten ◽

Alexandre N. Cavalcante ◽

...

Keyword(s):

Neurofibromatosis Type 1 ◽

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Neurofibromatosis Type ◽

Perioperative Outcomes ◽

Von Hippel Lindau ◽

Endocrine Neoplasia ◽

Von Hippel Lindau Disease

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Novel genotype–phenotype correlations in five Chinese families with Von Hippel–Lindau disease

Endocrine Connections ◽

10.1530/ec-18-0167 ◽

2018 ◽

Vol 7 (7) ◽

pp. 870-878 ◽

Cited By ~ 4

Author(s):

Qiuli Liu ◽

Gang Yuan ◽

Dali Tong ◽

Gaolei Liu ◽

Yuting Yi ◽

...

Keyword(s):

Malignant Neoplasms ◽

Missense Mutations ◽

Chinese Families ◽

Von Hippel Lindau ◽

Disease Phenotypes ◽

Mri Scans ◽

Von Hippel Lindau Disease ◽

Vhl Disease

Context Von Hippel–Lindau (VHL) disease manifests as a variety of benign and malignant neoplasms. Previous studies of VHL disease have documented several genotype–phenotype correlations; however, many such correlations are still unknown. Increased identification of new mutations and patients with previously described mutations will allow us to better understand how VHL mutations influence disease phenotypes. Patients and design A total of 45 individuals from five unrelated families were evaluated, of which 21 patients were either diagnosed with VHL disease or showed strong evidence related to this disease. We compared the patients’ gene sequencing results with their medical records including CT or MRI scans, eye examinations and laboratory/pathological examinations. Patients were also interviewed to obtain information regarding their family history. Results We identified four missense mutations: c.239G>T (p.Ser80Ile), linked with VHL Type 2B, was associated with renal cell carcinoma, pheochromocytoma and hemangioma in the cerebellum; c.232A>T (p.Asn78Tyr) manifested as RCC alone and likely caused VHL Type 1; c.500G>A (p.Arg167Gln) mutation was more likely to cause VHL Type 2 than Type 1 as it preferentially induced Pheo and HB in the retina, cerebellum and spinal cord; c.293A>G (p.Try98Cys) was associated with Pheo and thus likely induced VHL Type 2. Conclusions Characterizing VHL disease genotype–phenotype correlations can enhance the ability to predict the risk of individual patients developing different VHL-related phenotypes. Ultimately, such insight will improve the diagnostics, surveillance and treatment of VHL patients. Precis Four missense mutations in VHL have been identified in 21 individuals when five unrelated Chinese families with VHL disease were analyzed; VHL mutations are highly associated with unique disease phenotypes.

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Inherited endocrine syndromes and MEN

10.1093/med/9780198851899.003.0010 ◽

2021 ◽

pp. 651-702

Author(s):

Paul Newey

Keyword(s):

Renal Calculi ◽

Cowden Syndrome ◽

Carney Complex ◽

Endocrine Disorders ◽

Mccune Albright Syndrome ◽

Von Hippel Lindau ◽

Von Hippel Lindau Disease ◽

Albright Syndrome

This chapter begins with genetic testing for monogenic endocrine disorders, and then goes on to define the diagnosis, treatment, and management of McCune-Albright syndrome, neurofibromatosis, von Hippel-Lindau disease, Carney complex, Cowden syndrome, and POEMS syndrome. It then goes on to the clinical features and management of MEN type 1 and MEN type 2, and MEN type 4. Inherited primary hyperparathyroidism, phaeochromocytoma-paraganglioma syndromes, and renal calculi.

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Familial tumour syndromes

The Neurosurgeon's Handbook ◽

10.1093/med/9780198570677.003.0371 ◽

2010 ◽

pp. 482-493

Author(s):

George Samandouras

Keyword(s):

Tuberous Sclerosis ◽

Giant Cell ◽

Neurofibromatosis Type 1 ◽

Neurofibromatosis Type ◽

Subependymal Giant Cell Astrocytoma ◽

Von Hippel Lindau ◽

Vhl Disease ◽

Giant Cell Astrocytoma

Chapter 8.18 covers familial tumour syndromes, including neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), von Hippel-Lindau (VHL) disease and capillary haemangioblastoma, tuberous sclerosis and subependymal giant cell astrocytoma (SEGA), and Lhermitte-Duclos disease.

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Paragangliomas/Pheochromocytomas: Clinically Oriented Genetic Testing

International Journal of Endocrinology ◽

10.1155/2014/794187 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 28

Author(s):

Rute Martins ◽

Maria João Bugalho

Keyword(s):

Genetic Testing ◽

Somatic Mutations ◽

Parasympathetic Nervous System ◽

Multiple Endocrine Neoplasia Type ◽

Neurofibromatosis Type ◽

Clinical Aspects ◽

Von Hippel Lindau

Paragangliomas are rare neuroendocrine tumors that arise in the sympathetic or parasympathetic nervous system. Sympathetic paragangliomas are mainly found in the adrenal medulla (designated pheochromocytomas) but may also have a thoracic, abdominal, or pelvic localization. Parasympathetic paragangliomas are generally located at the head or neck. Knowledge concerning the familial forms of paragangliomas has greatly improved in recent years. Additionally to the genes involved in the classical syndromic forms:VHLgene (von Hippel-Lindau),RETgene (Multiple Endocrine Neoplasia type 2), andNF1gene (Neurofibromatosis type 1), 10 novel genes have so far been implicated in the occurrence of paragangliomas/pheochromocytomas:SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, EGLN1, HIF2A,andKIF1B. It is currently accepted that about 35% of the paragangliomas cases are due to germline mutations in one of these genes. Furthermore, somatic mutations ofRET, VHL, NF1, MAX, HIF2A,andH-RAScan also be detected. The identification of the mutation responsible for the paraganglioma/pheochromocytoma phenotype in a patient may be crucial in determining the treatment and allowing specific follow-up guidelines, ultimately leading to a better prognosis. Herein, we summarize the most relevant aspects regarding the genetics and clinical aspects of the syndromic and nonsyndromic forms of pheochromocytoma/paraganglioma aiming to provide an algorithm for genetic testing.

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P110 Neurofibromatosis type 1 and von hippel-lindau disease: a possible association

10.1136/archdischild-2017-313273.198 ◽

2017 ◽

Author(s):

Clementina Calabrese ◽

Lucia Soldano ◽

Carmela De Meco ◽

Pasquale Pio Maccarone ◽

Luciana Romaniello ◽

...

Keyword(s):

Neurofibromatosis Type 1 ◽

Neurofibromatosis Type ◽

Von Hippel Lindau ◽

Von Hippel Lindau Disease

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An Update on the Ophthalmologic Features in the Phakomatoses

Journal of Ophthalmology ◽

10.1155/2016/3043026 ◽

2016 ◽

Vol 2016 ◽

pp. 1-15 ◽

Cited By ~ 6

Author(s):

Solmaz Abdolrahimzadeh ◽

Andrea Maria Plateroti ◽

Santi Maria Recupero ◽

Alessandro Lambiase

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Neurofibromatosis Type 1 ◽

Imaging Techniques ◽

Neurofibromatosis Type ◽

Treatment Modalities ◽

Near Infrared Reflectance ◽

Von Hippel Lindau ◽

Von Hippel Lindau Disease

Neurofibromatosis type 1, tuberous sclerosis complex, and Von Hippel-Lindau disease, historically classified as the phakomatoses, are hereditary multisystem disorders characterized by the presence of hamartoma, which carry the risk of malignant transformation. The alteration of tumor suppressor genes seems to be at the basis of their pathophysiogenetic mechanism. Lisch and choroidal nodules in neurofibromatosis type 1, retinal astrocytomas in tuberous sclerosis complex, and retinal capillary hemangioma in Von Hippel-Lindau disease are the principal ophthalmic hamartomatous manifestations. The advent of novel imaging techniques such as near infrared reflectance and optical coherence tomography has provided unprecedented insight on the choroidal and retinal features of these diseases. These methods have improved early diagnosis and the ongoing surveillance in these conditions. Among an array of treatment modalities, antivascular endothelial growth factor therapy has been used in the management of retinal hamartomas but results have been varied. This review is an update on the pathophysiogenetic mechanisms, ophthalmic manifestations, and novel treatment strategies in the phakomatoses with emphasis on the role of imaging techniques.

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