Primary Renal Paragangliomas and Renal Neoplasia Associated with Pheochromocytoma/Paraganglioma: Analysis of von Hippel–Lindau (VHL), Succinate Dehydrogenase (SDHX) and Transmembrane Protein 127 (TMEM127)

2017 ◽  
Vol 28 (3) ◽  
pp. 253-268 ◽  
Author(s):  
Sounak Gupta ◽  
Jun Zhang ◽  
Dragana Milosevic ◽  
John R. Mills ◽  
Stefan K. Grebe ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Transmembrane Protein ◽  
Von Hippel Lindau ◽  
Renal Neoplasia

von Hippel–Lindau disease and succinate dehydrogenase subunit (SDHB, SDHC, and SDHD) genes

2011 ◽  
pp. 954-959
Author(s):  
Eamonn R. Maher
Keyword(s):  
Succinate Dehydrogenase ◽  
Von Hippel Lindau ◽  
Clinical Phenotypes ◽  
Molecular Features ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease

This chapter considers the clinical and molecular features of von Hippel–Lindau (VHL) disease (OMIM 193300) and mutations in succinate dehydrogenase subunit genes (SDHB (OMIM 115310), SDHC (OMIM 605373), and SDHD (OMIM 168000)). Both disorders are important causes of phaeochromocytoma and, in addition to having overlapping clinical phenotypes, also share some similarities in mechanisms of tumourigenesis.

A New Polycythemia Syndrome: Congenital Polycythemia with High Erythropoietin and Propensity for Malignant Hypertension Due to Paraganglioma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4345-4345
Author(s):  
Yongli Guan ◽  
John K. Wu ◽  
Wasil Jastaniah ◽  
Larry G. Moss ◽  
Colleen Digman ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Germ Line ◽  
Hypoxia Inducible Factor ◽  
Malignant Hypertension ◽  
Compound Heterozygous ◽  
Molecular Defect ◽  
Erythroid Progenitors ◽  
Von Hippel Lindau ◽  
Normal Sensitivity ◽  
Endothelial Growth Factor

Abstract We report three patients, two females and one male, with congenital polycythemia and high erythropoietin. All were extensively investigated in childhood; no known polycythemic conditions were diagnosed nor were any tumors known to be associated with polycythemia uncovered. At the ages of 14, 16, and 32 years the patients developed malignant hypertension secondary to multiple paragangliomas. In addition, one of patients has also developed a malignant pancreatic carcinoid tumor that expressed somatostatin. After the surgical resection of paragangliomas, hypertension subsided, but polycythemia persisted in all three subjects. Comprehensive screening for germ-line mutations of von Hippel-Lindau (VHL) gene as well as genes known to be causing familial paragangliomas - catalytic succinate dehydrogenase subunits B (SDHB), and catalytic succinate dehydrogenase subunit D (SDHD), has not revealed any mutations. In one of these patients studied so far there was no abnormality of the any of the three hypoxia control associated proline hydroxylase genes expressions found. Unlike the erythroid progenitors of Chuvash Polycythemia, these patients had normal sensitivity of erythroid progenitors to erythropoietin. The search for somatic mutations of VHL, SDHB, and SDHD genes, as well as quantitative analysis of the expressions of hypoxia inducible factor 1 alpha subunit (HIF-1a), vascular endothelial growth factor (VEGF), VHL, SDHB, and SDHD mRNAs by real-time PCR is ongoing. In summary, we report a new polycythemic syndrome of congenital polycythemia with high erythropoietin and the normal sensitivity of erythroid progenitors to erythropoietin, which is not associated with VHL mutation. This is in contrast to our previous experience with about 200 patients, homozygous for Chuvash Polycythemia mutation or compound heterozygous for Chuvash Polycythemia R200W and other VHL mutations, who have not developed paraganglioma or any VHL syndrome tumors. This new polycythemic syndrome shares some clinical features with both von Hippel Lindau syndrome and with the Chuvash polycythemia. While its molecular defect is yet to be elucidated, it is a distinct clinical and genetic entity.

scholarly journals U tủy thượng thận ở trẻ em - kiều gen và kiểu hình

2021 ◽  
pp. 94-101
Author(s):  
Trọng Thành Nguyễn ◽  
Chí Dũng Vũ
Keyword(s):  
Succinate Dehydrogenase ◽  
Von Hippel Lindau ◽  
Iron Sulfur ◽  
Succinate Dehydrogenase Complex ◽  
Subunit B ◽  
Dehydrogenase Complex

Pheochromocytomas (PCC) và Pragangliomas (PLG) là những khối u thần kinh – nội tiết. Khối u tiết catecholamine xuất phát từ tủy thượng thận được gọi là Pheochromocytoma. Khối u có nguồn gốc ngoài thượng thận, có thể tiết catecholamine hoặc không có chức năng, bắt nguồn từ các hạch thần kinh giao cảm hoặc phó giao cảm được gọi là Paraganglioma. Vì biểu hiện lâm sàng của hai nhóm bệnh PCC và PLG có tiết catecholamine tương tự nhau, phương pháp điều trị như nhau, nên trên lâm sàng thuật ngữ PCC (u tủy thượng thận) được dùng để chỉ cả 2 loại khối u. U tủy thượng thận là một bệnh lý hiếm gặp ở trẻ em, ước tính tần suất gặp ở 1 trong 50.000 – 100.000 trẻ. Bệnh có thể xuất hiện đơn độc nhưng cũng có thể kèm theo trong một số hội chứng von Hippel – Lindau, bệnh u xơ thần kinh type 1 (NF1) hay hội chứng Pheochromocytoma – Paragangliomas di truyền. Ở trẻ em, khoảng 60% - 80% nguyên nhân u tủy thượng thận là do di truyền. Tăng huyết áp ác tính là một triệu chứng thường gặp và có thể gây những biến chứng nặng nề. Chúng tôi báo cáo 2 trường hợp trẻ nữ vào viện vì đau đầu dữ dội, nôn, đau bụng và co giật. Trẻ được phát hiện tình trạng cao huyết áp kèm theo có khối u ổ bụng. Chẩn đoán xác định của 2 bệnh nhân là u tủy thượng thận. Trong đó, một bệnh nhân tìm thấy nguyên nhân gây bệnh là do đột biết gen succinate dehydrogenase complex iron sulfur subunit B (SDHB).

scholarly journals Measurements of Plasma Methoxytyramine, Normetanephrine, and Metanephrine as Discriminators of Different Hereditary Forms of Pheochromocytoma

2011 ◽  
Vol 57 (3) ◽  
pp. 411-420 ◽  
Author(s):  
Graeme Eisenhofer ◽  
Jacques WM Lenders ◽  
Henri Timmers ◽  
Massimo Mannelli ◽  
Stefan K Grebe ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Plasma Concentrations ◽  
Neurofibromatosis Type ◽  
Underlying Disease ◽  
Plasma Catecholamine ◽  
Von Hippel Lindau ◽  
Men 2 ◽  
Succinate Dehydrogenase Complex ◽  
Succinate Dehydrogenase Complex Subunit ◽  
Dehydrogenase Complex

BACKGROUND Pheochromocytomas are rare catecholamine-producing tumors derived in more than 30% of cases from mutations in 9 tumor-susceptibility genes identified to date, including von Hippel-Lindau tumor suppressor (VHL); succinate dehydrogenase complex, subunit B, iron sulfur (Ip) (SDHB); and succinate dehydrogenase complex, subunit D, integral membrane protein (SDHD). Testing of multiple genes is often undertaken at considerable expense before a mutation is detected. This study assessed whether measurements of plasma metanephrine, normetanephrine, and methoxytyramine, the O-methylated metabolites of catecholamines, might help to distinguish different hereditary forms of the tumor. METHODS Plasma concentrations of O-methylated metabolites were measured by liquid chromatography with electrochemical detection in 173 patients with pheochromocytoma, including 38 with multiple endocrine neoplasia type 2 (MEN 2), 10 with neurofibromatosis type 1 (NF1), 66 with von Hippel-Lindau (VHL) syndrome, and 59 with mutations of SDHB or SDHD. RESULTS In contrast to patients with VHL, SDHB, and SDHD mutations, all patients with MEN 2 and NF1 presented with tumors characterized by increased plasma concentrations of metanephrine (indicating epinephrine production). VHL patients usually showed solitary increases in normetanephrine (indicating norepinephrine production), whereas additional or solitary increases in methoxytyramine (indicating dopamine production) characterized 70% of patients with SDHB and SDHD mutations. Patients with NF1 and MEN 2 could be discriminated from those with VHL, SDHB, and SDHD gene mutations in 99% of cases by the combination of normetanephrine and metanephrine. Measurements of plasma methoxytyramine discriminated patients with SDHB and SDHD mutations from those with VHL mutations in an additional 78% of cases. CONCLUSIONS The distinct patterns of plasma catecholamine O-methylated metabolites in patients with hereditary pheochromocytoma provide an easily used tool to guide cost-effective genotyping of underlying disease-causing mutations.

scholarly journals Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC–PGL syndromes: a clinicopathological and molecular analysis

2014 ◽  
Vol 170 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Thomas G Papathomas ◽  
Jose Gaal ◽  
Eleonora P M Corssmit ◽  
Lindsey Oudijk ◽  
Esther Korpershoek ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Clear Cell ◽  
Renal Tumors ◽  
Papillary Thyroid ◽  
Partial Loss ◽  
Second Hit ◽  
Mutational Status ◽  
Neuroblastic Tumors ◽  
Design And Methods ◽  
Renal Neoplasia

ObjectiveAlthough the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated.Design and methodsThree unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC.ResultsOf the six index patients, all RCCs and one PA displayed SDHB immunonegativity in contrast to the other PA and PTC. All immunonegative tumors demonstrated loss of the WT allele, indicating bi-allelic inactivation of the germline mutated gene. Of 348 tumors, one clear cell RCC exhibited partial loss of SDHB expression.ConclusionsThese findings strengthen the etiological association of SDHx genes with pituitary neoplasia and provide evidence against a link between PTC and SDHx mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDHx alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.

scholarly journals Clinicopathological, immunophenotypic and genetic studies of mediastinal paragangliomas†

2019 ◽  
Vol 56 (5) ◽  
pp. 867-875 ◽  
Author(s):  
Ying-Han R Hsu ◽  
Jorge Torres-Mora ◽  
Benjamin R Kipp ◽  
William R Sukov ◽  
Sarah M Jenkins ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Succinate Dehydrogenase ◽  
Pathogenic Mutation ◽  
Next Generation ◽  
Von Hippel Lindau ◽  
Molecular Features ◽  
Programmed Death ◽  
Succinate Dehydrogenase Mutation ◽  
Mediastinal Paraganglioma ◽  
Generation Sequencing

Abstract OBJECTIVES Paragangliomas have unique features in the mediastinum, in part due to their location. Because of their paucity, they have not been thoroughly investigated. We studied the clinical, pathological, immunohistochemical and molecular features of mediastinal paragangliomas. METHODS Immunohistochemistry, next-generation sequencing mutation panel and the Oncoscan assay were performed. RESULTS Twenty-four patients with mediastinal paraganglioma (7 men, 29.2%) had a median age of 45.5 years (19.8–72.2). Twenty-one (87.5%) paragangliomas were completely resected. Six (of 24, 25.0%) tumours were considered metastatic. Mitotic activity occurred in 11 (of 24, 45.8%) paragangliomas. Programmed death-ligand 1 (PD-L1) (n = 23) was expressed in 6 (26%) patients in 10% (n = 2) and 1% (n = 4) of tumour cells, respectively. SDHB expression was lost in 19 (of 22, 86.4%) cases. ATRX expression was lost in 11 (of 23, 47.8%) cases. Next-generation sequencing revealed a single pathogenic mutation in 10 (of 19) specimens including SDHB (n = 4), SDHD (n = 6), SDHC (n = 1), ATRX (n = 1), and ≥2 mutations in 2 cases [SDHC and TERT (n = 1); SDHB, ATRX and TP53 (n = 1)]. Germline mutation analysis revealed the same succinate dehydrogenase mutation (or lack thereof) as identified in the paraganglioma in 11 (of 12) cases. During a median follow-up (n = 21) of 4.8 years (0.8–14.9), 3 patients developed metastases; 4 patients died, at least 1 of disease. CONCLUSIONS Mediastinal paragangliomas can be associated with morbidity and mortality. Many mediastinal paragangliomas have been reported to be associated with syndromes such as multiple endocrine neoplasia, von Hippel-Lindau or succinate dehydrogenase syndrome with mutation profiles dominated by alterations in genes associated with these syndromes.

TMEM161A, a transmembrane protein, regulates cells apoptosis

2010 ◽  
Vol 34 (8) ◽  
pp. S54-S54
Author(s):  
Jieshi Xie ◽  
Weiwei Deng ◽  
Jinhai Guo ◽  
Taiping Shi ◽  
Dalong Ma
Keyword(s):  
Transmembrane Protein

622: Von Hippel-Lindau Inactivation Downregulates the Cell-Cell Adhesion Molecule E Cadherin in Renal Cancer Cells

2005 ◽  
Vol 173 (4S) ◽  
pp. 170-170
Author(s):  
Maxine G. Tran ◽  
Miguel A. Esteban ◽  
Peter D. Hill ◽  
Ashish Chandra ◽  
Tim S. O'Brien ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cancer Cells ◽  
Renal Cancer ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Von Hippel Lindau ◽  
E Cadherin ◽  
Cell Cell
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