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Kim B, Lee SH, Ahn CH, Jang HN, Cho SI, Lee JS, Lee YM, Kim SJ, Sung TY, Lee KE, Lee W, Koh JM, Seong MW, Kim JH. Genetic Landscape and Clinical Manifestations of Multiple Endocrine Neoplasia Type 1 in a Korean Cohort: A Multicenter Retrospective Analysis. Endocrinol Metab (Seoul) 2024; 39:956-964. [PMID: 39552147 PMCID: PMC11695471 DOI: 10.3803/enm.2024.2008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/08/2024] [Accepted: 07/24/2024] [Indexed: 11/19/2024] Open
Abstract
BACKGRUOUND Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors in multiple endocrine organs, caused by variants in the MEN1 gene. This study analyzed the clinical and genetic features of MEN1 in a Korean cohort, identifying prevalent manifestations and genetic variants, including novel variants. METHODS This multicenter retrospective study reviewed the medical records of 117 MEN1 patients treated at three tertiary centers in Korea between January 2012 and September 2022. Patient demographics, tumor manifestations, outcomes, and MEN1 genetic testing results were collected. Variants were classified using American College of Medical Genetics and Genomics (ACMG) and French Oncogenetics Network of Neuroendocrine Tumors propositions (TENGEN) guidelines. RESULTS A total of 117 patients were enrolled, including 55 familial cases, with a mean age at diagnosis of 37.4±15.3 years. Primary hyperparathyroidism was identified as the most common presentation (84.6%). The prevalence of gastroenteropancreatic neuroendocrine tumor and pituitary neuroendocrine tumor (PitNET) was 77.8% (n=91) and 56.4% (n=66), respectively. Genetic testing revealed 61 distinct MEN1 variants in 101 patients, with 18 being novel. Four variants were reclassified according to the TENGEN guidelines. Patients with truncating variants (n=72) exhibited a higher prevalence of PitNETs compared to those with non-truncating variants (n=25) (59.7% vs. 36.0%, P=0.040). CONCLUSION The association between truncating variants and an increased prevalence of PitNETs in MEN1 underscores the importance of genetic characterization in guiding the clinical management of this disease. Our study sheds light on the clinical and genetic characteristics of MEN1 among the Korean population.
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Affiliation(s)
- Boram Kim
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Hun Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chang Ho Ahn
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Han Na Jang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Im Cho
- Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jee-Soo Lee
- Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Yu-Mi Lee
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Su-Jin Kim
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Tae-Yon Sung
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyu Eun Lee
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Woochang Lee
- Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jung-Min Koh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Moon-Woo Seong
- Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jung Hee Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
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Snezhkina AV, Pavlov VS, Krasnov GS, Kalinin DV, Pudova EA, Stolbovskaya OV, Dunshina AV, Fedorova MS, Kudryavtseva AV. Non-Susceptibility Gene Variants in Head and Neck Paragangliomas. Int J Mol Sci 2024; 25:12762. [PMID: 39684472 DOI: 10.3390/ijms252312762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 11/21/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Head and neck paragangliomas (HNPGLs) are rare neoplasms that, along with pheochromocytomas and extra-adrenal paragangliomas, are associated with inherited mutations in at least 12 susceptibility genes in approximately 40% of cases. However, due to the rarity of HNPGLs, only a series of small-scale studies and individual cases have reported mutations in additional genes that may be involved in tumorigenesis. Consequently, numerous disease-causing mutations and genes responsible for the pathogenesis of HNPGLs remain poorly investigated. The aim of this study was to gain a deeper understanding of the genetic basis of HNPGLs by focusing on variants in genes that were not previously identified as well-known drivers. A whole-exome data analysis was conducted on a representative set of 152 HNPGLs. In 30% of the tumors examined, 53 potentially deleterious variants were identified in 36 different genes. The analysis identified pathogenic or likely pathogenic variants in the ARNT, IDH2, L2HGDH, MYH3, PIK3CA, and TERT genes. A functional network analysis of the mutated genes revealed numerous associations and a list of metabolic pathways (e.g., the TCA cycle, carbon metabolism, pyruvate metabolism, etc.) and signaling pathways (e.g., HIF1, PI3K-Akt, FoxO, AMPK, MAPK, etc.) that may play an important role in the development of HNPGLs. The identified range of genetic alterations affecting multiple genes and, potentially, influencing diverse cellular pathways provides an enhanced molecular genetic characterization of HNPGLs.
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Affiliation(s)
- Anastasiya V Snezhkina
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Vladislav S Pavlov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - George S Krasnov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Dmitry V Kalinin
- Vishnevsky Institute of Surgery, Ministry of Health of the Russian Federation, 117997 Moscow, Russia
| | - Elena A Pudova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Olga V Stolbovskaya
- Department of Human Anatomy, Ulyanovsk State University, 432017 Ulyanovsk, Russia
| | | | - Maria S Fedorova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Anna V Kudryavtseva
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
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Tsoy UA, Sokolnikova PS, Kravchuk EN, Ryazanov PA, Kozyreva AA, Fomicheva YV, Aramisova LS, Karonova TL, Kostareva AA, Grineva E. A Comprehensive Target Panel Allows to Extend the Genetic Spectrum of Neuroendocrine Tumors. Neuroendocrinology 2024:1-21. [PMID: 39536727 DOI: 10.1159/000542223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 09/17/2024] [Indexed: 11/16/2024]
Abstract
INTRODUCTION Neuroendocrine tumors (NETs) frequently have a genetic basis, and the range of genes implicated in NET development continues to expand. Application of targeted gene panels (TGPs) in next-generation sequencing is a central strategy for elucidating novel variants associated with NET development. METHODS In this study, we conducted comprehensive molecular genetic analyses using TGP on a cohort of 93 patients diagnosed with various NETs subtypes, mainly accompanied by various endocrine syndromes: insulinoma (n = 26), pheochromocytoma and paraganglioma (PPGL) (n = 38), parathyroid adenoma (n = 18, including three with insulinoma), and NETs of other locations (n = 14). The TGP encompassed genes linked to diverse NETs and other hereditary endocrine disorders, with subsequent variant classification according to the American College of Medical Genetics and Genomics guidelines. RESULTS Among the identified variants, 20 were found in genes previously linked to specific tumor types, and 10 were found in genes with a limited likelihood and unclear molecular mecanisms of association with observed NETs. Remarkably, 13 variants were discovered in genes not previously associated with the NETs observed in our patients. These genes, such as ABCC8, KCNJ11, KLF11, HABP2, and APC, were implicated in insulinoma; ZNRF3, GNAS, and KCNJ5 were linked with PPGL; parathyroid adenomas were related to variants in SDHB and TP53; while NETs of other locations displayed variants in APC and ABCC8. CONCLUSION Our study demonstrates that utilizing broad TGP in examining patients with various functioning NETs facilitates the identification of new germinal variants in genes that may contribute to the diseases. The verification of revealed findings requires research in vaster sample.
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Affiliation(s)
- Uliana A Tsoy
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Polina S Sokolnikova
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Ekaterina N Kravchuk
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Pavel A Ryazanov
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Alexandra A Kozyreva
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Yulia V Fomicheva
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Liana S Aramisova
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Tatiana L Karonova
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Anna A Kostareva
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
- Department of Women's and Children's Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Elena Grineva
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
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Lingas EC. Non-Functional Yet Terminal: A Case of Asymptomatic Retroperitoneal Paraganglioma With Distant Metastasis. Cureus 2023; 15:e43004. [PMID: 37551290 PMCID: PMC10404458 DOI: 10.7759/cureus.43004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/29/2023] [Indexed: 08/09/2023] Open
Abstract
Retroperitoneal paraganglioma remains an extremely rare type of tumor that arises from either sympathetic or parasympathetic neural crest cells. It could be functional or non-functional. Non-functional paraganglioma may present as a diagnostic challenge since patients are usually asymptomatic and tend to present to the hospital with complications from the invasion of the tumor. Malignancy is usually determined by the degree of metastasis. The gold standard of diagnosis is biopsy and obtaining a sample for histological examination. This author presents a case of asymptomatic, non-functional retroperitoneal paraganglioma with distant metastasis.
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Torres-Costa M, Flores B, Torregrosa N, González M, Ríos A, Febrero B, Flores D, Rodríguez P, Carbonell P, Ortuño MI, Rodríguez JM. Malignant prediction in paragangliomas: analysis for clinical risk factors. Langenbecks Arch Surg 2021; 406:2441-2448. [PMID: 34101001 DOI: 10.1007/s00423-021-02222-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 06/01/2021] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Paragangliomas are infrequent neuroendocrine tumours whose only criterion for malignancy is presence of metastases; thus, all paragangliomas show malignant potential. Actually, different risk factors have been analyzed to predict metastases but they remain unclear. PURPOSE To analyze clinical, histological, and genetic factors to predict the occurrence of metastasis. PATIENTS AND METHOD A multicentre retrospective observational analysis was performed between January 1990 and July 2019. Patients diagnosed with paraganglioma were selected. Clinical, histological, and genetic features were analyzed for the prediction of malignancy. RESULTS A total of 83 patients diagnosed with paraganglioma were included, of which nine (10.8%) had malignant paraganglioma. Tumour size was greater in malignant tumours than in benign (6 cm vs. 4 cm, respectively; p = 0.027). The most frequent location of malignancy was the thorax-abdomen-pelvis area observed in six cases (p = 0.024). No differences were observed in histological differentiation, age, symptoms, and catecholaminergic production. The most frequent genetic mutation was SDHD followed by SDHB but no differences were observed between benign and malignant tumours. In the univariate analysis for predictive factors for malignancy, location, tumour size, and histological differentiation showed statistical significance (p = 0.025, p = 0.014, and p = 0.046, respectively); however, they were not confirmed as predictive factors for malignancy in the multivariate analysis. CONCLUSION In this study, no risk factors for malignancy have been established; therefore, we recommend follow-up of all patients diagnosed with paraganglioma.
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Affiliation(s)
- Miquel Torres-Costa
- Department of Surgery, Hospital Clínico Universitario Virgen de La Arrixaca, Murcia, Spain.
| | - Benito Flores
- Department of Surgery, Hospital General Universitario Morales Meseguer, Murcia, Spain
| | - Nuria Torregrosa
- Department of Surgery, Hospital General Universitario Santa Lucía, Cartagena, Spain
| | - Miguel González
- Department of Surgery, Hospital Universitario Reina Sofía, Murcia, Spain
| | - Antonio Ríos
- Department of Surgery, Hospital Clínico Universitario Virgen de La Arrixaca, Murcia, Spain
| | - Beatriz Febrero
- Department of Surgery, Hospital Clínico Universitario Virgen de La Arrixaca, Murcia, Spain
| | - Diego Flores
- Department of Surgery, Hospital General Universitario Morales Meseguer, Murcia, Spain
| | - Pablo Rodríguez
- Department of Surgery, Hospital General Universitario Santa Lucía, Cartagena, Spain
| | - Pablo Carbonell
- Center for Biochemistry and Clinical Genetics, Hospital Clínico Universitario Virgen de La Arrixaca, Murcia, Spain
| | - María Isabel Ortuño
- Department of Pathology, Hospital Clínico Universitario Virgen de La Arrixaca, Murcia, Spain
| | - José Manuel Rodríguez
- Department of Surgery, Hospital Clínico Universitario Virgen de La Arrixaca, Murcia, Spain
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Pedro J, Cunha FM, Neto V, Hespanhol V, Martins DF, Guimarães S, Varela A, Carvalho D. Coexistence of DIPNECH and carotid body paraganglioma: is it just a coincidence? Endocrinol Diabetes Metab Case Rep 2020; 2020:EDM190141. [PMID: 32408270 PMCID: PMC7274547 DOI: 10.1530/edm-19-0141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 04/21/2020] [Indexed: 01/10/2023] Open
Abstract
SUMMARY We describe the case of a 56 year-old woman with the almost simultaneous appearance of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and a carotid body paraganglioma. Of interest, 6 years earlier, the patient underwent total thyroidectomy due to papillary thyroid carcinoma and, in the meantime, she was submitted to mastectomy to treat an invasive ductal carcinoma of the breast. In order to explain these lesions, an extensive genetic study was performed. Results showed positivity for the presence of the tumor suppressor gene PALB2, whose presence had already been detected in a niece with breast cancer. The patient underwent different procedures to treat the lesions and currently she is symptom-free over 2 years of follow-up. LEARNING POINTS The presence of two rare neoplasms in a single person should raise the suspicion of a common etiology. To the best of our knowledge, this is the first case that shows the coexistence of DIPNECH and paraganglioma. The contribution of the PALB2 gene in the etiology of these rare neoplasms is a possibility.
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Affiliation(s)
- J Pedro
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
- Faculty of Medicine of Universidade do Porto, Porto, Portugal
| | - F M Cunha
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal
| | - V Neto
- Department of Pneumology, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - V Hespanhol
- Faculty of Medicine of Universidade do Porto, Porto, Portugal
- Department of Pneumology, Centro Hospitalar Universitário de São João, Porto, Portugal
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - D F Martins
- Faculty of Medicine of Universidade do Porto, Porto, Portugal
- Department of Pathology, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - S Guimarães
- Department of Pathology, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - A Varela
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
- Faculty of Medicine of Universidade do Porto, Porto, Portugal
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - D Carvalho
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
- Faculty of Medicine of Universidade do Porto, Porto, Portugal
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
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Aaquist T, Medhus JB, Thomassen A, Detlefsen S. Synchronous detection of SDHA-related gallbladder paraganglioma and pancreatic neuroendocrine tumor. Pathol Res Pract 2020; 216:153006. [PMID: 32534711 DOI: 10.1016/j.prp.2020.153006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 01/17/2023]
Abstract
Primary gallbladder paragangliomas (PGLs) are exceedingly rare. PGLs are extraadrenal neuroendocrine tumors that are morphologically inseparable from intraadrenal pheochromocytomas. PGLs and pheochromocytomas are some of the most heritable tumor types in the body and are often associated with other tumors or part of a genetic syndrome. We report a case of gallbladder PGL presenting synchronously with pancreatic neuroendocrine tumor (NET) and pulmonary IgG4-related disease in a 74-year old male patient with disseminated prostate adenocarcinoma. Due to the high rate of germline mutations and the possible syndromal manifestation of PGLs as well as pancreatic NETs, this patient was offered genetic testing, and a pathogenic SDHA germline mutation was found. Immunohistochemically, there was loss of SDHA and SDHB in the PGL but neither in the NET nor in the prostate adenocarcinoma. To our knowledge, this case is the first report of gallbladder PGL associated with pancreatic NET. It is likely that the identified SDHA germline mutation played a role in the development of gallbladder PGL in this patient.
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Affiliation(s)
- Trine Aaquist
- Department of Pathology, Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark
| | | | - Anders Thomassen
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark
| | - Sönke Detlefsen
- Department of Pathology, Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
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Tepede AA, Welch J, Lee M, Mandl A, Agarwal SK, Nilubol N, Patel D, Cochran C, Simonds WF, Weinstein LS, Jha A, Millo C, Pacak K, Blau JE. 18F-FDOPA PET/CT accurately identifies MEN1-associated pheochromocytoma. Endocrinol Diabetes Metab Case Rep 2020; 2020:EDM190156. [PMID: 32130200 PMCID: PMC7077596 DOI: 10.1530/edm-19-0156] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 02/11/2020] [Indexed: 12/13/2022] Open
Abstract
SUMMARY Pheochromocytoma (PHEO) in multiple endocrine neoplasia type 1 (MEN1) is extremely rare. The incidence is reported as less than 2%. We report a case of a 76-year-old male with familial MEN1 who was found to have unilateral PHEO. Although the patient was normotensive and asymptomatic, routine screening imaging with CT demonstrated bilateral adrenal masses. The left adrenal mass grew from 2.5 to 3.9 cm over 4 years with attenuation values of 9 Hounsfield units (HU) pre-contrast and 15 HU post-contrast washout. Laboratory evaluation demonstrated an adrenergic biochemical phenotype. Both 18F-fluorodeoxyglucose (18F-FDG) PET/CT and 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy demonstrated bilateral adrenal uptake. In contrast, 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET/CT demonstrated unilateral left adrenal uptake (28.7 standardized uptake value (SUV)) and physiologic right adrenal uptake. The patient underwent an uneventful left adrenalectomy with pathology consistent for PHEO. Post-operatively, he had biochemical normalization. A review of the literature suggests that adrenal tumors >2 cm may be at higher risk for pheochromocytoma in patients with MEN1. Despite a lack of symptoms related to catecholamine excess, enlarging adrenal nodules should be biochemically screened for PHEO. 18F-FDOPA PET/CT may be beneficial for localization in these patients. LEARNING POINTS 18F-FDOPA PET/CT is a beneficial imaging modality for identifying pheochromocytoma in MEN1 patients. Adrenal adenomas should undergo routine biochemical workup for PHEO in MEN1 and can have serious peri-operative complications if not recognized, given that MEN1 patients undergo frequent surgical interventions. MEN1 is implicated in the tumorigenesis of PHEO in this patient.
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Affiliation(s)
- Aisha A Tepede
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)
| | - James Welch
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)
| | - Maya Lee
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)
| | - Adel Mandl
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)
| | - Sunita K Agarwal
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)
| | - Naris Nilubol
- National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA
| | - Dhaval Patel
- National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA
| | - Craig Cochran
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)
| | - William F Simonds
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)
| | - Lee S Weinstein
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)
| | - Abhishek Jha
- Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA
| | - Corina Millo
- Clinical Center PET Department (CC PET), National Institutes of Health, Bethesda, Maryland, USA
| | - Karel Pacak
- Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA
| | - Jenny E Blau
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)
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Xekouki P, Brennand A, Whitelaw B, Pacak K, Stratakis CA. The 3PAs: An Update on the Association of Pheochromocytomas, Paragangliomas, and Pituitary Tumors. Horm Metab Res 2019; 51:419-436. [PMID: 30273935 PMCID: PMC7448524 DOI: 10.1055/a-0661-0341] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pituitary adenomas (PA) and pheochromocytomas/paragangliomas (PHEO/PGL) are rare tumors. Although they may co-exist by coincidence, there is mounting evidence that genes predisposing in PHEO/PGL development, may play a role in pituitary tumorigenesis. In 2012, we described a GH-secreting PA caused by an SDHD mutation in a patient with familial PGLs and found loss of heterozygosity at the SDHD locus in the pituitary tumor, along with increased hypoxia-inducible factor 1α (HIF-1α) levels. Additional patients with PAs and SDHx defects have since been reported. Overall, prevalence of SDHx mutations in PA is very rare (0.3-1.8% in unselected cases) but we and others have identified several cases of PAs with PHEOs/PGLs, like our original report, a condition which we termed the 3 P association (3PAs). Interestingly, when 3PAs is found in the sporadic setting, no SDHx defects were identified, whereas in familial PGLs, SDHx mutations were identified in 62.5-75% of the reported cases. Hence, pituitary surveillance is recommended among patients with SDHx defects. It is possible that the SDHx germline mutation-negative 3PAs cases may be due to another gene, epigenetic changes, mutations in modifier genes, mosaicism, somatic mutations, pituitary hyperplasia due to ectopic hypothalamic hormone secretion or a coincidence. PA in 3PAs are mainly macroadenomas, more aggressive, more resistant to somatostatin analogues, and often require surgery. Using the Sdhb +/- mouse model, we showed that hyperplasia may be the first abnormality in tumorigenesis as initial response to pseudohypoxia. We also propose surveillance and follow-up approach of patients presenting with this association.
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Affiliation(s)
- Paraskevi Xekouki
- Department of Endocrinology, King’s College Hospital, London, UK
- Division of Diabetes & Nutritional Sciences, King’s College London, London, UK
| | - Ana Brennand
- Division of Diabetes & Nutritional Sciences, King’s College London, London, UK
| | - Ben Whitelaw
- Department of Endocrinology, King’s College Hospital, London, UK
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA
| | - Constantine A. Stratakis
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA
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Alzahrani AS, Alswailem M, Albattal S, Qasem E, Murugan AK, Al-Hindi H. Familial paraganglioma due to a novel SDHB mutation: familial phenotypic heterogeneity and a potentially novel manifestation. INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2019. [DOI: 10.2217/ije-2018-0003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Non-paraganglioma (PGL) tumors are rare manifestations of familial PGL syndromes. Primary hyperparathyroidism has not been described in PGL syndromes. We present a 36-year-old man with a history of right carotid body tumor at 24 years and an abdominal PGL at 31 years of age. At 35 years, he developed hypercalcemia (serum Ca 2.65–2.72 mmol/l), and high parathyroid hormone of 92–131 ng/l (normal range, 15–65) and a Tc99 Sestamibi scan showed a single parathyroid adenoma which was confirmed on histopathological examination of parathyroidectomy. Recently, he was diagnosed with a left glomus jugulare which has not been operated on yet. His family history is strongly positive for PGLs. Genetic testing revealed a novel SDHB mutation (p.K137E) but the phenotype and penetrance were variable in different family members.
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Affiliation(s)
- Ali S Alzahrani
- Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
- Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Meshael Alswailem
- Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Shatha Albattal
- Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Ebtesam Qasem
- Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | | | - Hindi Al-Hindi
- Department of Pathology & Laboratory Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
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11
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Kamilaris CDC, Stratakis CA. An update on adrenal endocrinology: significant discoveries in the last 10 years and where the field is heading in the next decade. Hormones (Athens) 2018; 17:479-490. [PMID: 30456751 PMCID: PMC6294814 DOI: 10.1007/s42000-018-0072-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 08/28/2018] [Accepted: 09/20/2018] [Indexed: 02/07/2023]
Abstract
The last 10 years have produced an amazing number of significant discoveries in the field of adrenal endocrinology. The development of the adrenal gland was linked to specific molecules. Cortisol-producing lesions were associated mostly with defects of the cyclic AMP (cAMP) signaling pathway, whereas aldosterone-producing lesions were found to be the result of defects in aldosterone biosynthesis or the potassium channel KCNJ5 and related molecules. Macronodular adrenal hyperplasia was linked to ARMC5 defects and new genes were found to be involved in adrenocortical cancer (ACC). The succinate dehydrogenase (SDH) enzyme was proven to be the most important molecular pathway involved in pheochromocytomas, along with several other genes. Adrenomedullary tumors are now largely molecularly elucidated. Unfortunately, most of these important discoveries have yet to produce new therapeutic tools for our patients with adrenal diseases: ACC in its advanced stages remains largely an untreatable disorder and malignant pheochromocytomas are equally hard to treat. Thus, the challenge for the next 10 years is to translate the important discoveries of the previous decade into substantial advances in the treatment of adrenal disorders and tumors.
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Affiliation(s)
- Crystal D C Kamilaris
- Section on Endocrinology and Genetics & Inter-Institute Endocrinology Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, MD, 20892, USA
| | - Constantine A Stratakis
- Section on Endocrinology and Genetics & Inter-Institute Endocrinology Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, MD, 20892, USA.
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12
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Snezhkina AV, Lukyanova EN, Kalinin DV, Pokrovsky AV, Dmitriev AA, Koroban NV, Pudova EA, Fedorova MS, Volchenko NN, Stepanov OA, Zhevelyuk EA, Kharitonov SL, Lipatova AV, Abramov IS, Golovyuk AV, Yegorov YE, Vishnyakova KS, Moskalev AA, Krasnov GS, Melnikova NV, Shcherbo DS, Kiseleva MV, Kaprin AD, Alekseev BY, Zaretsky AR, Kudryavtseva AV. Exome analysis of carotid body tumor. BMC Med Genomics 2018; 11:17. [PMID: 29504908 PMCID: PMC5836820 DOI: 10.1186/s12920-018-0327-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background Carotid body tumor (CBT) is a form of head and neck paragangliomas (HNPGLs) arising at the bifurcation of carotid arteries. Paragangliomas are commonly associated with germline and somatic mutations involving at least one of more than thirty causative genes. However, the specific functionality of a number of these genes involved in the formation of paragangliomas has not yet been fully investigated. Methods Exome library preparation was carried out using Nextera® Rapid Capture Exome Kit (Illumina, USA). Sequencing was performed on NextSeq 500 System (Illumina). Results Exome analysis of 52 CBTs revealed potential driver mutations (PDMs) in 21 genes: ARNT, BAP1, BRAF, BRCA1, BRCA2, CDKN2A, CSDE1, FGFR3, IDH1, KIF1B, KMT2D, MEN1, RET, SDHA, SDHB, SDHC, SDHD, SETD2, TP53BP1, TP53BP2, and TP53I13. In many samples, more than one PDM was identified. There are also 41% of samples in which we did not identify any PDM; in these cases, the formation of CBT was probably caused by the cumulative effect of several not highly pathogenic mutations. Estimation of average mutation load demonstrated 6–8 mutations per megabase (Mb). Genes with the highest mutation rate were identified. Conclusions Exome analysis of 52 CBTs for the first time revealed the average mutation load for these tumors and also identified potential driver mutations as well as their frequencies and co-occurrence with the other PDMs. Electronic supplementary material The online version of this article (10.1186/s12920-018-0327-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | - Elena N Lukyanova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Dmitry V Kalinin
- Vishnevsky Institute of Surgery, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Anatoly V Pokrovsky
- Vishnevsky Institute of Surgery, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Alexey A Dmitriev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Nadezhda V Koroban
- National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Elena A Pudova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Maria S Fedorova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Nadezhda N Volchenko
- National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Oleg A Stepanov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.,National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Ekaterina A Zhevelyuk
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Sergey L Kharitonov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Anastasiya V Lipatova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Ivan S Abramov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Alexander V Golovyuk
- Vishnevsky Institute of Surgery, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Yegor E Yegorov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Khava S Vishnyakova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Alexey A Moskalev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - George S Krasnov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Nataliya V Melnikova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Dmitry S Shcherbo
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - Marina V Kiseleva
- National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Andrey D Kaprin
- National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Boris Y Alekseev
- National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Andrew R Zaretsky
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - Anna V Kudryavtseva
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia. .,National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia.
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13
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Affiliation(s)
- Anthony J Gill
- Department of Anatomical Pathology; Royal North Shore Hospital; St Leonards NSW Australia
- Cancer Diagnosis and Pathology Research Group; Kolling Institute of Medical Research; Royal North Shore Hospital; St Leonards NSW Australia
- University of Sydney; Sydney NSW Australia
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14
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Zhikrivetskaya SO, Snezhkina AV, Zaretsky AR, Alekseev BY, Pokrovsky AV, Golovyuk AL, Melnikova NV, Stepanov OA, Kalinin DV, Moskalev AA, Krasnov GS, Dmitriev AA, Kudryavtseva AV. Molecular markers of paragangliomas/pheochromocytomas. Oncotarget 2017; 8:25756-25782. [PMID: 28187001 PMCID: PMC5421967 DOI: 10.18632/oncotarget.15201] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 01/23/2017] [Indexed: 12/14/2022] Open
Abstract
Paragangliomas/pheochromocytomas comprise rare tumors that arise from the extra-adrenal paraganglia, with an incidence of about 2 to 8 per million people each year. Approximately 40% of cases are due to genetic mutations in at least one out of more than 30 causative genes. About 25-30% of pheochromocytomas/paragangliomas develop under the conditions of a hereditary tumor syndrome a third of which are caused by mutations in the VHL gene. Together, the gene mutations in this disorder have implicated multiple processes including signaling pathways, translation initiation, hypoxia regulation, protein synthesis, differentiation, survival, proliferation, and cell growth. The present review contemplates the mutations associated with the development of pheochromocytomas/paragangliomas and their potential to serve as specific markers of these tumors and their progression. These data will improve our understanding of the pathogenesis of these tumors and likely reveal certain features that may be useful for early diagnostics, malignancy prognostics, and the determination of new targets for disease therapeutics.
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Affiliation(s)
| | | | - Andrew R Zaretsky
- M.M. Shemyakin - Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - Boris Y Alekseev
- National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia
| | | | | | - Nataliya V Melnikova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Oleg A Stepanov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
- National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia
| | | | - Alexey A Moskalev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - George S Krasnov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Alexey A Dmitriev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Anna V Kudryavtseva
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
- National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia
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15
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Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Paragangliomas. Head Neck Pathol 2017; 11:88-95. [PMID: 28247224 PMCID: PMC5340727 DOI: 10.1007/s12105-017-0786-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 02/02/2017] [Indexed: 01/17/2023]
Abstract
Updated editions of The World Health Organization Classification of Tumours Pathology & Genetics for both Head and Neck Tumours and Tumours of Endocrine Organs took place in 2016 based on consensus conferences. These editions present unification of concepts in paragangliomas and highlight expanding knowledge of their etiology. There is a major emphasis in the new bluebooks on familial/syndromic paragangliomas, representing ~40% of all head and neck paragangliomas. Ancillary use of immunohistochemical evaluation, specifically of SDHB, allows the pathologist to screen for a large subset of these potentially hereditary cases. In addition, similarly to other neuroendocrine tumors, paragangliomas are now considered to represent a continuum of risk, and are assessed in terms of risk stratification. Tumors with SDHB mutations pose the highest risk for metastasis. There is currently no validated or endorsed histologic grading system. Paragangliomas remain tumors of undetermined biologic potential and should not be termed benign.
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16
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Murakami T, Usui T, Nakamoto Y, Nakajima A, Mochida Y, Saito S, Shibayama T, Yamazaki N, Hatoko T, Kato T, Yonemitsu S, Muro S, Oki S. Challenging Differential Diagnosis of Hypergastremia and Hyperglucagonemia with Chronic Renal Failure: Report of a Case with Multiple Endocrine Neoplasia Type 1. Intern Med 2017; 56:1375-1381. [PMID: 28566601 PMCID: PMC5498202 DOI: 10.2169/internalmedicine.56.7230] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
A 53-year-old woman developed end-stage renal failure during a 15-year clinical course of primary hyperparathyroidism and was referred to our hospital for evaluation of suspected multiple endocrine neoplasia type 1 (MEN1). Genetic testing revealed a novel deletion mutation at codon 467 in exon 10 of the MEN1 gene. Systemic and selective arterial calcium injection (SACI) testing revealed hyperglucagonemia and hypergastrinemia with positive gastrin responses. A pathological examination revealed glucagonoma and a lymph node gastrinoma. The findings in this case indicate the importance of early diagnosis of MEN1 and demonstrate the utility of systemic and SACI testing in renal failure cases.
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Affiliation(s)
- Takaaki Murakami
- Department of Diabetes and Endocrinology, Osaka Red Cross Hospital, Japan
| | - Takeshi Usui
- Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan
| | - Yuji Nakamoto
- Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, Japan
| | - Akio Nakajima
- Department of Surgery, Osaka Red Cross Hospital, Japan
| | - Yuki Mochida
- Department of Surgery, Osaka Red Cross Hospital, Japan
| | - Sumio Saito
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Japan
| | | | | | - Tomonobu Hatoko
- Department of Diabetes and Endocrinology, Osaka Red Cross Hospital, Japan
| | - Tomoko Kato
- Department of Diabetes and Endocrinology, Osaka Red Cross Hospital, Japan
| | - Shin Yonemitsu
- Department of Diabetes and Endocrinology, Osaka Red Cross Hospital, Japan
| | - Seiji Muro
- Department of Diabetes and Endocrinology, Osaka Red Cross Hospital, Japan
| | - Shogo Oki
- Department of Diabetes and Endocrinology, Osaka Red Cross Hospital, Japan
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17
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Pillai S, Gopalan V, Smith RA, Lam AKY. Updates on the genetics and the clinical impacts on phaeochromocytoma and paraganglioma in the new era. Crit Rev Oncol Hematol 2016; 100:190-208. [DOI: 10.1016/j.critrevonc.2016.01.022] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Revised: 11/13/2015] [Accepted: 01/20/2016] [Indexed: 12/18/2022] Open
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Lips CJ, Valk GD, Dreijerink KM, Timmers M, van der Luijt RB, Links TP, van Nesselrooij BP, Vriens M, Höppener JW, Rinkes IB, van der Horst-Schrivers AN. Multiple Endocrine Neoplasia Type 1 (MEN1). GENETIC DIAGNOSIS OF ENDOCRINE DISORDERS 2016:343-359. [DOI: 10.1016/b978-0-12-800892-8.00024-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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19
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O'Toole SM, Dénes J, Robledo M, Stratakis CA, Korbonits M. 15 YEARS OF PARAGANGLIOMA: The association of pituitary adenomas and phaeochromocytomas or paragangliomas. Endocr Relat Cancer 2015; 22:T105-22. [PMID: 26113600 DOI: 10.1530/erc-15-0241] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/15/2015] [Indexed: 12/26/2022]
Abstract
The combination of pituitary adenomas (PA) and phaeochromocytomas (phaeo) or paragangliomas (PGL) is a rare event. Although these endocrine tumours may occur together by coincidence, there is mounting evidence that, in at least some cases, classical phaeo/PGL-predisposing genes may also play a role in pituitary tumorigenesis. A new condition that we termed '3Pas' for the association of PA with phaeo and/or PGL was recently described in patients with succinate dehydrogenase mutations and PAs. It should also be noted that the classical tumour suppressor gene, MEN1 that is the archetype of the PA-predisposing genes, is also rarely associated with phaeos in both mice and humans with MEN1 defects. In this report, we review the data leading to the discovery of 3PAs, other associations linking PAs with phaeos and/or PGLs, and the corresponding clinical and molecular genetics.
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Affiliation(s)
- Samuel M O'Toole
- Department of EndocrinologyBarts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UKHereditary Endocrine Cancer GroupSpanish National Cancer Center, Madrid and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainSection on Endocrinology and Genetics Eunice Kennedy Shriver Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
| | - Judit Dénes
- Department of EndocrinologyBarts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UKHereditary Endocrine Cancer GroupSpanish National Cancer Center, Madrid and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainSection on Endocrinology and Genetics Eunice Kennedy Shriver Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
| | - Mercedes Robledo
- Department of EndocrinologyBarts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UKHereditary Endocrine Cancer GroupSpanish National Cancer Center, Madrid and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainSection on Endocrinology and Genetics Eunice Kennedy Shriver Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
| | - Constantine A Stratakis
- Department of EndocrinologyBarts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UKHereditary Endocrine Cancer GroupSpanish National Cancer Center, Madrid and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainSection on Endocrinology and Genetics Eunice Kennedy Shriver Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
| | - Márta Korbonits
- Department of EndocrinologyBarts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UKHereditary Endocrine Cancer GroupSpanish National Cancer Center, Madrid and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainSection on Endocrinology and Genetics Eunice Kennedy Shriver Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
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20
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Hernandez KG, Ezzat S, Morel CF, Swallow C, Otremba M, Dickson BC, Asa SL, Mete O. Familial pheochromocytoma and renal cell carcinoma syndrome: TMEM127 as a novel candidate gene for the association. Virchows Arch 2015; 466:727-32. [DOI: 10.1007/s00428-015-1755-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Revised: 02/21/2015] [Accepted: 03/09/2015] [Indexed: 12/30/2022]
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Dénes J, Swords F, Rattenberry E, Stals K, Owens M, Cranston T, Xekouki P, Moran L, Kumar A, Wassif C, Fersht N, Baldeweg SE, Morris D, Lightman S, Agha A, Rees A, Grieve J, Powell M, Boguszewski CL, Dutta P, Thakker RV, Srirangalingam U, Thompson CJ, Druce M, Higham C, Davis J, Eeles R, Stevenson M, O'Sullivan B, Taniere P, Skordilis K, Gabrovska P, Barlier A, Webb SM, Aulinas A, Drake WM, Bevan JS, Preda C, Dalantaeva N, Ribeiro-Oliveira A, Garcia IT, Yordanova G, Iotova V, Evanson J, Grossman AB, Trouillas J, Ellard S, Stratakis CA, Maher ER, Roncaroli F, Korbonits M. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort. J Clin Endocrinol Metab 2015; 100:E531-41. [PMID: 25494863 PMCID: PMC4333031 DOI: 10.1210/jc.2014-3399] [Citation(s) in RCA: 114] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
CONTEXT Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence. OBJECTIVE The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL. DESIGN Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples. SETTING The study was conducted at university hospitals. PATIENTS Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study. OUTCOME Outcomes included genetic screening and clinical characteristics. RESULTS Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context. CONCLUSIONS Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.
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Affiliation(s)
- Judit Dénes
- Department of Endocrinology (J.D., U.S., M.D., P.G., W.M.D., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Semmelweis University, School of PhD studies, Doctoral School of Clinical Medicine, Budapest, Hungary (J.D.), Endocrinology Directorate (F.S.), Norfolk and Norwich University Hospital, Norwich NR4 7UZ, United Kingdom; Department of Medical and Molecular Genetics (E.R., E.R.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Molecular Genetics (K.S., M.O., S.E.), Royal Devon and Exeter National Health Service Foundation Trust, Exeter EX2 5DW, United Kingdom; University of Exeter Medical School (S.E.), Exeter EX4 4PY, United Kingdom; Oxford Medical Genetics Laboratories (T.C.), Oxford University Hospitals National Health Service Trust, The Churchill Hospital, Oxford OX3 7LJ, United Kingdom; Section on Endocrinology and Genetics (P.X., C.A.S.) and Section on Molecular Dysmorphology (C.W.), Eunice Kennedy Shriver Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Electron Microscopy Unit (L.M.), Department Histopathology, Charing Cross Hospital, Imperial College Healthcare National Health Service Trust, London W6 8RF, United Kingdom; Department of Clinical Genetics (A.K.), Great Ormond Street Hospital, London WC1N 1LE, United Kingdom; Departments of Oncology (N.F.) and Endocrinology (S.E.B.), University College London Hospitals, London WC1E 6BT, United Kingdom; Department of Diabetes and Endocrinology (D.M.), The Ipswich Hospital National Health Service Trust, Ipswich IP4 5PD, United Kingdom; Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (S.L.), University of Bristol, Bristol BS1 3NY, United Kingdom; Department of Endocrinology (A.Ag., C.J.T.), Beaumont Hospital, Dublin 9, Ireland; Institute of Molecular and Experimental Medicine (A.R.), Cardiff University, Cardiff CF10 3US, United Kingd
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Meng L, Wang J, Fang SH. Primary pancreatic paraganglioma: A report of two cases and literature review. World J Gastroenterol 2015; 21:1036-1039. [PMID: 25624744 PMCID: PMC4299323 DOI: 10.3748/wjg.v21.i3.1036] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Revised: 06/23/2014] [Accepted: 07/25/2014] [Indexed: 02/07/2023] Open
Abstract
Paraganglioma is a rare tumor of paraganglia, derived from neural crest cells in sympathetic or parasympathetic ganglions. Primary paraganglioma originating from the pancreas is rare. We report two patients with paraganglioma in the head of the pancreas, in whom computed tomography showed a sharply marginated, hypervascular tumor with cystic areas. Significant intratumoral vessels and early contrast filling of the draining veins from the mass were not found. Although the pancreatic paraganglioma was located at the pancreatic head, the bile ducts often revealed no dilation, and sometimes the main pancreatic duct was mildly dilated. These findings are helpful in differentiating pancreatic paraganglioma from other pancreatic neoplasms. It is often difficult to distinguish between nonfunctional pancreatic paragangliomas and pancreatic endocrine tumors. In many reports,pancreatic paragangliomas show the retroperitoneal extension of a paraganglioma into the pancreas rather than a true pancreatic neoplasm. In surgical treatment, we could select simple excision of the tumor rather than radical surgery.
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Murakami T, Usui T, Nakajima A, Mochida Y, Saito S, Nambu T, Kato T, Matsuda Y, Yonemitsu S, Muro S, Oki S. A Novel Missense Mutation of the MEN1 Gene in a Patient with Multiple Endocrine Neoplasia Type 1 with Glucagonoma and Obesity. Intern Med 2015; 54:2475-81. [PMID: 26424307 DOI: 10.2169/internalmedicine.54.4886] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
A 35-year-old obese diabetic man presented with recurrent primary hyperparathyroidism during a three-year outpatient follow-up. He was clinically diagnosed with multiple endocrine neoplasia type 1 (MEN1) due to the presence of a pituitary adenoma and multiple glucagonomas. The glucagonomas may have affected his glycemic control. However, he did not demonstrate weight loss, suggesting that the patient's obesity could have obscured the early diagnosis of a glucagonoma. Genetic testing revealed a novel missense mutation at codon 561 in exon 10, resulting in an amino acid substitution from methionine to arginine (M561R) in the MEN1 gene. This mutation appeared to be responsible for the MEN1 pathogenicity.
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Affiliation(s)
- Takaaki Murakami
- Department of Diabetes and Endocrinology, Osaka Red Cross Hospital, Japan
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Welander J, Andreasson A, Juhlin CC, Wiseman RW, Bäckdahl M, Höög A, Larsson C, Gimm O, Söderkvist P. Rare germline mutations identified by targeted next-generation sequencing of susceptibility genes in pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 2014; 99:E1352-60. [PMID: 24694336 PMCID: PMC5393486 DOI: 10.1210/jc.2013-4375] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Accepted: 03/26/2014] [Indexed: 02/08/2023]
Abstract
CONTEXT Pheochromocytomas and paragangliomas have a highly diverse genetic background, with a third of the cases carrying a germline mutation in 1 of 14 identified genes. OBJECTIVE This study aimed to evaluate next-generation sequencing for more efficient genetic testing of pheochromocytoma and paraganglioma and to establish germline and somatic mutation frequencies for all known susceptibility genes. DESIGN A targeted next-generation sequencing approach on an Illumina MiSeq instrument was used for a mutation analysis in 86 unselected pheochromocytoma and paraganglioma tumor samples. The study included the genes EGLN1, EPAS1, KIF1Bβ, MAX, MEN1, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL. RESULTS were verified in tumor and constitutional DNA with Sanger sequencing. RESULTS In all cases with clinical syndromes or known germline mutations, a mutation was detected in the expected gene. Among 68 nonfamilial tumors, 32 mutations were identified in 28 of the samples (41%), including germline mutations in EGLN1, KIF1Bβ, SDHA, SDHB, and TMEM127 and somatic mutations in EPAS1, KIF1Bβ, MAX, NF1, RET, and VHL, including one double monoallelic EPAS1 mutation. CONCLUSIONS Targeted next-generation sequencing proved to be fast and cost effective for the genetic analysis of pheochromocytoma and paraganglioma. More than half of the tumors harbored mutations in the investigated genes. Notably, 7% of the apparently sporadic cases carried germline mutations, highlighting the importance of comprehensive genetic testing. KIF1Bβ, which previously has not been investigated in a large cohort, appears to be an equally important tumor suppressor as MAX and TMEM127 and could be considered for genetic testing of these patients.
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Affiliation(s)
| | | | - C. Christofer Juhlin
- Department of Clinical and Experimental Medicine (J.W., O.G., P.S.), Faculty of Health Sciences, Linköping University, Departments of Surgery (O.G.) and Clinical Genetics (P.S.), County Council of Östergötland, Linköping SE-58185, Sweden; Department of Oncology-Pathology (A.A., C.C.J., A.H., C.L.), Karolinska Institutet, Cancer Center Karolinska (A.A., C.C.J., A.H., C.L.), Karolinska University Hospital Solna, and Department of Molecular Medicine and Surgery (A.A., C.C.J., M.B., C.L.), Karolinska Institutet, Karolinska University Hospital, Stockholm SE-17176, Sweden; and Wisconsin National Primate Research Center (R.W.W.), University of Wisconsin-Madison, Madison, Wisconsin 53715
| | - Roger W. Wiseman
- Department of Clinical and Experimental Medicine (J.W., O.G., P.S.), Faculty of Health Sciences, Linköping University, Departments of Surgery (O.G.) and Clinical Genetics (P.S.), County Council of Östergötland, Linköping SE-58185, Sweden; Department of Oncology-Pathology (A.A., C.C.J., A.H., C.L.), Karolinska Institutet, Cancer Center Karolinska (A.A., C.C.J., A.H., C.L.), Karolinska University Hospital Solna, and Department of Molecular Medicine and Surgery (A.A., C.C.J., M.B., C.L.), Karolinska Institutet, Karolinska University Hospital, Stockholm SE-17176, Sweden; and Wisconsin National Primate Research Center (R.W.W.), University of Wisconsin-Madison, Madison, Wisconsin 53715
| | - Martin Bäckdahl
- Department of Clinical and Experimental Medicine (J.W., O.G., P.S.), Faculty of Health Sciences, Linköping University, Departments of Surgery (O.G.) and Clinical Genetics (P.S.), County Council of Östergötland, Linköping SE-58185, Sweden; Department of Oncology-Pathology (A.A., C.C.J., A.H., C.L.), Karolinska Institutet, Cancer Center Karolinska (A.A., C.C.J., A.H., C.L.), Karolinska University Hospital Solna, and Department of Molecular Medicine and Surgery (A.A., C.C.J., M.B., C.L.), Karolinska Institutet, Karolinska University Hospital, Stockholm SE-17176, Sweden; and Wisconsin National Primate Research Center (R.W.W.), University of Wisconsin-Madison, Madison, Wisconsin 53715
| | - Anders Höög
- Department of Clinical and Experimental Medicine (J.W., O.G., P.S.), Faculty of Health Sciences, Linköping University, Departments of Surgery (O.G.) and Clinical Genetics (P.S.), County Council of Östergötland, Linköping SE-58185, Sweden; Department of Oncology-Pathology (A.A., C.C.J., A.H., C.L.), Karolinska Institutet, Cancer Center Karolinska (A.A., C.C.J., A.H., C.L.), Karolinska University Hospital Solna, and Department of Molecular Medicine and Surgery (A.A., C.C.J., M.B., C.L.), Karolinska Institutet, Karolinska University Hospital, Stockholm SE-17176, Sweden; and Wisconsin National Primate Research Center (R.W.W.), University of Wisconsin-Madison, Madison, Wisconsin 53715
| | - Catharina Larsson
- Department of Clinical and Experimental Medicine (J.W., O.G., P.S.), Faculty of Health Sciences, Linköping University, Departments of Surgery (O.G.) and Clinical Genetics (P.S.), County Council of Östergötland, Linköping SE-58185, Sweden; Department of Oncology-Pathology (A.A., C.C.J., A.H., C.L.), Karolinska Institutet, Cancer Center Karolinska (A.A., C.C.J., A.H., C.L.), Karolinska University Hospital Solna, and Department of Molecular Medicine and Surgery (A.A., C.C.J., M.B., C.L.), Karolinska Institutet, Karolinska University Hospital, Stockholm SE-17176, Sweden; and Wisconsin National Primate Research Center (R.W.W.), University of Wisconsin-Madison, Madison, Wisconsin 53715
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