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Hartmut P. H. Neumann - One of the best experts on this subject based on the ideXlab platform.
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Pheochromocytoma and Paraganglioma.
The New England journal of medicine, 2019Co-Authors: Hartmut P. H. Neumann, William F Young, Charis EngAbstract:Pheochromocytoma and Paraganglioma Pheochromocytoma and paraganglioma are related tumors that differ mainly in location; Pheochromocytomas are adrenal, and paragangliomas can be anywhere else. The ...
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Pheochromocytoma and NF1
Neurofibromatosis Type 1, 2012Co-Authors: Birke Bausch, Hartmut P. H. NeumannAbstract:Pheochromocytoma and neurofibromatosis type 1 (NF1) are rarely observed in the same patient. However, Pheochromocytoma represents a substantial manifestation of NF1 and occurs in about 3 % of affected individuals. In general, Pheochromocytomas occur sporadically although they are a classic feature of numerous familial cancer syndromes. Neurofibromatosis type 1 is the oldest of the known inherited Pheochromocytoma-associated syndromes which also include multiple endocrine neoplasia type 2 (MEN2), von Hippel–Lindau disease (VHL), the Pheochromocytoma/paraganglioma syndromes type 1–4 (PGL1–4), and the familial Pheochromocytoma syndromes. Interestingly, NF1-associated Pheochromocytomas share many features with sporadic Pheochromocytomas such as the mean age at diagnosis, the frequency of malignant transformation, and the extra-adrenal and bilateral tumor growth. NF1 germline mutation analysis in patients with NF1 and Pheochromocytoma is time-consuming and remains a considerable challenge and hence has rarely been performed. More than 80 % of the mutations are either nonsense or frameshift mutations while 10 % are deletions or duplications affecting the length of one to >50 exons. A clustering within distinct areas of the NF1 gene is not evident. It is important to note that to date no case with Pheochromocytoma and a NF1 germline mutation has been reported that did not show typical lesions of NF1. Therefore, for clinical and scientific studies, mutation analysis of the NF1 gene is not indicated. Why Pheochromocytomas due to NF1 germline mutations grow only in selected NF1 patients has still to be elucidated.
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Familial Pheochromocytoma.
Hormones (Athens Greece), 2009Co-Authors: Zoran Erlic, Hartmut P. H. NeumannAbstract:Pheochromocytomas and Paragangliomas (PGL) form the group of paraganglial tumours which can occur in any paraganglia from the skull base to the pelvic floor. The terminology is not uniform. While the World Health Organization (WHO) applies Pheochromocytoma exclusively to adrenal tumours, many clinicians use the term Pheochromocytoma also for extra-adrenal abdominal and thoracic tumours, since by tradition Pheochromocytoma is a vasoactive tumour. In contrast, head and neck paraganglioma is mostly only a space-occupying mass. The diagnosis is confirmed by both biochemical testing and radiological imaging. One third of patients with Pheochromocytomas and paragangliomas are carriers of germline mutations in one of 6 genes and thus have a hereditary disorder. About 1% of Neurofibromatosis (NF) 1 patients have Pheochromocytomas. All Pheochromocytoma patients with NF 1 also show cutaneous lesions. About 50% of MEN2 patients harbour Pheochromocytoma. The dominant lesion in this entity is Medullary Thyroid Carcinoma (MTC) occurring in up to 100% of patients. Von Hippel-Lindau disease (VHL)is found in about 20% of patients in association with Pheochromocytoma. VHL is classified as type 1 predominantly without and type 2 predominantly with Pheochromocytoma. Other important components of VHL are hemangioblastomas of the eye and Central Nervous System (CNS), renal clear cell carcinoma, multiple pancreatic cysts and islet cell carcinoma. PGL syndromes have been genetically characterized as PGL 1, 3 and 4 and are caused by mutations in the succinate dehydrogenase (SDH) subunit D, C and B genes, respectively (SDHD, SDHC and SDHB). Paraganglioma syndromes include predisposition to paraganglial tumours in any location, whereas PGL 3 patients mostly show only head and neck paragangliomas. All syndromes associated with paraganglial tumours are autosomal dominantly transmitted, but patients with SDHD mutations develop tumours only if they inherit the mutation from the father. Familial paraganglial tumours are characterized by younger age at diagnosis and more frequently multifocal and extra-adrenal abdominal Pheochromocytomas. Patients with PGL 4 and less frequently VHL, are particularly predisposed to malignant Pheochromocytoma. Endoscopic surgery is the primary treatment for Pheochromocytoma. For malignant cases, chemotherapeutic as well as radionuclear approaches are available. No specific treatment has been proposed for prevention of the disease in inherited disorders. Thus, early diagnosis and regular follow-up are the only means for a better outcome.
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The genetic basis of Pheochromocytoma.
Frontiers of hormone research, 2004Co-Authors: Oliver Gimm, Christian A Koch, A. Januszewicz, Giuseppe Opocher, Hartmut P. H. NeumannAbstract:Until very recently, the majority of hereditary Pheochromocytomas were related to the MEN 2 and the VHL. In rare instances, hereditary Pheochromocytoma was reported in patients with NF1. In addition, nonsyndromic hereditary Pheochromocytomas have been reported. Recently, three more genes (SDHD, SDHB, and SDHC) which are all related subunits of the mitochondrial complex II have been identified to cause susceptibility to Pheochromocytoma and/or paraganglioma. Hence, mutation analysis of VHL, RET, SDHB, and SDHD is generally recommended in patients with Pheochromocytoma regardless of their family history or other features suggestive for a hereditary form. Mutation analysis should start with VHL and RET. However, in the presence of extra-adrenal Pheochromocytoma, it may be more useful to screen for VHL, SDHD and SDHB mutations. It is of interest that various different genes can lead to one type of tumor formation. A common pathway (i.e. oxygen sensing) has been shown for VHL and SDHX. However, although several genes that are involved in the pathogenesis of hereditary Pheochromocytoma are known, the precise molecular steps in tumorigenesis are widely unknown. In addition, recent data in MEN 2 Pheochromocytomas point to a 'second hit' mechanism as a trigger for tumor formation. The molecular pathogenesis of sporadic Pheochromocytomas remains obscure [114].
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germ line mutations in nonsyndromic Pheochromocytoma
The New England Journal of Medicine, 2002Co-Authors: Hartmut P. H. Neumann, Birke Bausch, Oliver Gimm, Sarah R Mcwhinney, Bernhard U Bender, Gerlind Franke, J Schipper, Joachim Klisch, Carsten Altehoefer, Klaus ZerresAbstract:Background The group of susceptibility genes for Pheochromocytoma that included the proto-oncogene RET (associated with multiple endocrine neoplasia type 2 [MEN-2]) and the tumor-suppressor gene VHL (associated with von Hippel–Lindau disease) now also encompasses the newly identified genes for succinate dehydrogenase subunit D (SDHD) and succinate dehydrogenase subunit B (SDHB), which predispose carriers to Pheochromocytomas and glomus tumors. We used molecular tools to classify a large cohort of patients with Pheochromocytoma with respect to the presence or absence of mutations of one of these four genes and to investigate the relevance of genetic analyses to clinical practice. Methods Peripheral blood from unrelated, consenting registry patients with Pheochromocytoma was tested for mutations of RET, VHL, SDHD, and SDHB. Clinical data at first presentation and follow-up were evaluated. Results Among 271 patients who presented with nonsyndromic Pheochromocytoma and without a family history of the disease,...
B Zbar - One of the best experts on this subject based on the ideXlab platform.
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CLINICAL AND GENETIC CHARACTERIZATION OF Pheochromocytoma IN VON HIPPEL-LINDAU FAMILIES: COMPARISON WITH SPORADIC Pheochromocytoma GIVES INSIGHT INTO NATURAL HISTORY OF Pheochromocytoma
The Journal of Urology, 1999Co-Authors: Mcclellan M. Walther, R Reiter, H R Keiser, P L Choyke, D Venzon, K Hurley, J R Gnarra, J C Reynolds, Gladys Glenn, B ZbarAbstract:AbstractPurpose: Families with von Hippel-Lindau disease have variable risk of Pheochromocytoma. Patients with von Hippel-Lindau disease and Pheochromocytoma identified by screening can have no characteristic signs or symptoms. Families with von Hippel-Lindau disease were screened and followed to describe the natural history of von Hippel-Lindau Pheochromocytoma, and to correlate these findings with von Hippel-Lindau germline mutation.Materials and Methods: Between 1988 and 1997, 246 individuals with von Hippel-Lindau disease were identified (von Hippel-Lindau group). Between August 1990 and June 1997, 26 consecutive patients with sporadic Pheochromocytoma were evaluated (sporadic group).Results: A total of 64 patients with von Hippel-Lindau disease had manifestations of Pheochromocytoma, including 33 newly diagnosed during screening at the National Institutes of Health and 31 previously treated (93 adrenal and 13 extra-adrenal Pheochromocytomas). Germline von Hippel-Lindau gene missense mutation was asso...
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Clinical and genetic characterization of Pheochromocytoma in von Hippel-Lindau families: comparison with sporadic Pheochromocytoma gives insight into natural history of Pheochromocytoma.
The Journal of urology, 1999Co-Authors: M M Walther, R Reiter, H R Keiser, P L Choyke, D Venzon, K Hurley, J R Gnarra, J C Reynolds, G M Glenn, B ZbarAbstract:Families with von Hippel-Lindau disease have variable risk of Pheochromocytoma. Patients with von Hippel-Lindau disease and Pheochromocytoma identified by screening can have no characteristic signs or symptoms. Families with von Hippel-Lindau disease were screened and followed to describe the natural history of von Hippel-Lindau Pheochromocytoma, and to correlate these findings with von Hippel-Lindau germline mutation. Between 1988 and 1997, 246 individuals with von Hippel-Lindau disease were identified (von Hippel-Lindau group). Between August 1990 and June 1997, 26 consecutive patients with sporadic Pheochromocytoma were evaluated (sporadic group). A total of 64 patients with von Hippel-Lindau disease had manifestations of Pheochromocytoma, including 33 newly diagnosed during screening at the National Institutes of Health and 31 previously treated (93 adrenal and 13 extra-adrenal Pheochromocytomas). Germline von Hippel-Lindau gene missense mutation was associated with extra-adrenal Pheochromocytoma, younger age at presentation and the only patient with metastases. Of the 33 newly diagnosed patients with von Hippel-Lindau disease 4 had Pheochromocytoma 2 times (37 Pheochromocytomas) during followup. Of these Pheochromocytomas 35% (13 of 37) were associated with no symptoms, normal blood pressure and normal catecholamine testing. Comparison of urinary catecholamines in the von Hippel-Lindau and sporadic groups demonstrated increased epinephrine, metanephrines and vanillylmandelic acid in the sporadic group. Analysis of urinary catecholamine excretion in the von Hippel-Lindau and sporadic groups together demonstrated a correlation between tumor size, and urinary metanephrines, vanillylmandelic acid, norepinephrine, epinephrine and dopamine. In 12 patients without signs or symptoms of Pheochromocytoma 17 newly diagnosed Pheochromocytomas were followed for a median of 34.5 months without morbidity. Median tumor doubling time was 17 months. Von Hippel-Lindau gene missense mutation correlated with the risk of Pheochromocytoma in patients with von Hippel-Lindau disease. These findings support a von Hippel-Lindau disease clinical classification, wherein some families are at high risk for manifestations of Pheochromocytoma. Von Hippel-Lindau disease Pheochromocytomas identified by screening were smaller and less functional than sporadic Pheochromocytomas.
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CLINICAL AND GENETIC CHARACTERIZATION OF COMPARISON WITH SPORADIC Pheochromocytoma GIVES INSIGHT INTO NATURAL HISTORY OF Pheochromocytoma Pheochromocytoma IN VON HIPPEL-LINDAU FAMILIES:
1999Co-Authors: M M Walther, R Reiter, H R Keiser, P L Choyke, D Venzon, K Hurley, J R Gnarra, J C Reynolds, Gladys Glenn, B ZbarAbstract:Purpose: Families with von Hippel-Lindau disease have variable risk of Pheochromocytoma. Patients with von Hippel-Lindau disease and Pheochromocytoma identified by screening can have no characteristic signs or symptoms. Families with von Hippel-Lindau disease were screened and followed to describe the natural history of von Hippel-Lindau Pheochromocytoma, and to correlate these findings with von Hippel-Lindau germline mutation. Materials and Methods: Between 1988 and 1997, 246 individuals with von Hippel-Lindau disease were identified (von Hippel-Lindau group). Between August 1990 and June 1997, 26 consecutive patients with sporadic Pheochromocytoma were evaluated (sporadic group). Results: A total of 64 patients with von Hippel-Lindau disease had manifestations of Pheochromocytoma, including 33 newly diagnosed during screening at the National Institutes of Health and 3 1 previously treated (93 adrenal and 13 extra-adrenal Pheochromocytomas). Germline von Hippel-Lindau gene missense mutation was associated with extra-adrenal Pheochromocytoma, younger age at presentation and the only patient with metastases. Of the 33 newly diagnosed patients with von Hippel-Lindau disease 4 had Pheochromocytoma 2 times (37 Pheochromocytomas) during followup. Of these Pheochromocytomas 35% (13 of 37) were associated with no symptoms, normal blood pressure and normal catecholamine testing. Comparison of urinary catecholamines in the von Hippel-Lindau and sporadic groups demonstrated increased epinephrine, metanephrines and vanillylmandelic acid in the sporadic group. Analysis of urinary catecholamine excretion in the von Hippel-Lindau and sporadic groups together demonstrated a correlation between tumor size, and urinary metanephrines, vanillylmandelic acid, norepinephrine, epinephrine and dopamine. In 12 patients without signs or symptoms of Pheochromocytoma 17 newly diagnosed Pheochromocytomas were followed for a median of 34.5 months without morbidity. Median tumor doubling time was 17 months. Conclusions: Von Hippel-Lindau gene missense mutation correlated with the risk of Pheochromocytoma in patients with von Hippel-Lindau disease. These findings support a von HippelLindau disease clinical classification, wherein some families are at high risk for manifestations of Pheochromocytoma. Von Hippel-Lindau disease Pheochromocytomas identified by screening
Itaru Kimura - One of the best experts on this subject based on the ideXlab platform.
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Neurofibromin and NF1 Gene Analysis in Composite Pheochromocytoma and Tumors Associated with von Recklinghausen’s Disease
Modern Pathology, 2002Co-Authors: Noriko Kimura, Toshiya Watanabe, Masayuki Fukase, Atsushi Wakita, Takao Noshiro, Itaru KimuraAbstract:Composite tumor of Pheochromocytoma and neuroblastoma, or ganglioneuroma, or ganglioneuroblastoma (composite Pheochromocytoma), also known as mixed neuroendocrine and neural tumor, are sometimes combined with neurofibromatosis type 1 (NF1). To better understand the relationship between NF1 and composite Pheochromocytoma, an immunohistochemical study using anti-neuro-fibromin that is an NF1 gene product and DNA sequence of NF1 Exon 31 were carried out in five cases of composite Pheochromocytoma and in various tumors from five patients with NF1. Neurofibromin was not expressed in Schwann cells and sustentacular cells of composite Pheochromocytomas and was very weakly or negatively expressed in neurofibroma of NF1 patients. However, it was strongly expressed in ganglionic cells and Pheochromocytoma cells of the composite Pheochromocytomas and also in mucosal ganglioneuromas, a gangliocytic paraganglioma, and in Pheochromocytomas from the patients with NF1. Although there was no mutation in NF1 Exon 31, it could not be ruled out that there were mutations in other sites of the NF1 gene. Neurofibromin insufficiency may induce abnormal proliferation of Schwann cells in composite Pheochromocytomas as well as in neurofibromatosis.
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neurofibromin and nf1 gene analysis in composite Pheochromocytoma and tumors associated with von recklinghausen s disease
Modern Pathology, 2002Co-Authors: Noriko Kimura, Toshiya Watanabe, Masayuki Fukase, Atsushi Wakita, Takao Noshiro, Itaru KimuraAbstract:Composite tumor of Pheochromocytoma and neuroblastoma, or ganglioneuroma, or ganglioneuroblastoma (composite Pheochromocytoma), also known as mixed neuroendocrine and neural tumor, are sometimes combined with neurofibromatosis type 1 (NF1). To better understand the relationship between NF1 and composite Pheochromocytoma, an immunohistochemical study using anti-neuro-fibromin that is an NF1 gene product and DNA sequence of NF1 Exon 31 were carried out in five cases of composite Pheochromocytoma and in various tumors from five patients with NF1. Neurofibromin was not expressed in Schwann cells and sustentacular cells of composite Pheochromocytomas and was very weakly or negatively expressed in neurofibroma of NF1 patients. However, it was strongly expressed in ganglionic cells and Pheochromocytoma cells of the composite Pheochromocytomas and also in mucosal ganglioneuromas, a gangliocytic paraganglioma, and in Pheochromocytomas from the patients with NF1. Although there was no mutation in NF1 Exon 31, it could not be ruled out that there were mutations in other sites of the NF1 gene. Neurofibromin insufficiency may induce abnormal proliferation of Schwann cells in composite Pheochromocytomas as well as in neurofibromatosis.
H R Keiser - One of the best experts on this subject based on the ideXlab platform.
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Plasma metanephrines: a novel and cost-effective test for Pheochromocytoma
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, 2000Co-Authors: Graeme Eisenhofer, H R Keiser, Mcclellan M. Walther, Jacques W.m. Lenders, Peter Friberg, Karel PacakAbstract:Pheochromocytomas are rare chromaffin cell tumors that nevertheless must be excluded in large numbers of patients who develop sustained or episodic hypertension as well as in many others with suggestive symptoms or with a familial history of Pheochromocytoma. Diagnosis of Pheochromocytoma depends importantly on biochemical evidence of excess catecholamine production by a tumor. Imperfect sensitivity and specificity of commonly available biochemical tests and the low incidence of the tumor among the tested population mean that considerable time and effort can be expended in confirming or ruling out Pheochromocytoma in patients where the tumor is suspected. Measurements of plasma free metanephrines provide a superior test compared to other available tests for diagnosis of Pheochromocytoma. In particular, the high sensitivity of plasma free metanephrines means that a normal test result reliably excludes all but the smallest of Pheochromocytomas so that no other tests are necessary. Measurements of plasma free metanephrines, when systematically combined with other diagnostic procedures outlined in this review, provide a more efficient, reliable and cost-effective approach for diagnosis of Pheochromocytoma than offered by previously available approaches.
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CLINICAL AND GENETIC CHARACTERIZATION OF Pheochromocytoma IN VON HIPPEL-LINDAU FAMILIES: COMPARISON WITH SPORADIC Pheochromocytoma GIVES INSIGHT INTO NATURAL HISTORY OF Pheochromocytoma
The Journal of Urology, 1999Co-Authors: Mcclellan M. Walther, R Reiter, H R Keiser, P L Choyke, D Venzon, K Hurley, J R Gnarra, J C Reynolds, Gladys Glenn, B ZbarAbstract:AbstractPurpose: Families with von Hippel-Lindau disease have variable risk of Pheochromocytoma. Patients with von Hippel-Lindau disease and Pheochromocytoma identified by screening can have no characteristic signs or symptoms. Families with von Hippel-Lindau disease were screened and followed to describe the natural history of von Hippel-Lindau Pheochromocytoma, and to correlate these findings with von Hippel-Lindau germline mutation.Materials and Methods: Between 1988 and 1997, 246 individuals with von Hippel-Lindau disease were identified (von Hippel-Lindau group). Between August 1990 and June 1997, 26 consecutive patients with sporadic Pheochromocytoma were evaluated (sporadic group).Results: A total of 64 patients with von Hippel-Lindau disease had manifestations of Pheochromocytoma, including 33 newly diagnosed during screening at the National Institutes of Health and 31 previously treated (93 adrenal and 13 extra-adrenal Pheochromocytomas). Germline von Hippel-Lindau gene missense mutation was asso...
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Clinical and genetic characterization of Pheochromocytoma in von Hippel-Lindau families: comparison with sporadic Pheochromocytoma gives insight into natural history of Pheochromocytoma.
The Journal of urology, 1999Co-Authors: M M Walther, R Reiter, H R Keiser, P L Choyke, D Venzon, K Hurley, J R Gnarra, J C Reynolds, G M Glenn, B ZbarAbstract:Families with von Hippel-Lindau disease have variable risk of Pheochromocytoma. Patients with von Hippel-Lindau disease and Pheochromocytoma identified by screening can have no characteristic signs or symptoms. Families with von Hippel-Lindau disease were screened and followed to describe the natural history of von Hippel-Lindau Pheochromocytoma, and to correlate these findings with von Hippel-Lindau germline mutation. Between 1988 and 1997, 246 individuals with von Hippel-Lindau disease were identified (von Hippel-Lindau group). Between August 1990 and June 1997, 26 consecutive patients with sporadic Pheochromocytoma were evaluated (sporadic group). A total of 64 patients with von Hippel-Lindau disease had manifestations of Pheochromocytoma, including 33 newly diagnosed during screening at the National Institutes of Health and 31 previously treated (93 adrenal and 13 extra-adrenal Pheochromocytomas). Germline von Hippel-Lindau gene missense mutation was associated with extra-adrenal Pheochromocytoma, younger age at presentation and the only patient with metastases. Of the 33 newly diagnosed patients with von Hippel-Lindau disease 4 had Pheochromocytoma 2 times (37 Pheochromocytomas) during followup. Of these Pheochromocytomas 35% (13 of 37) were associated with no symptoms, normal blood pressure and normal catecholamine testing. Comparison of urinary catecholamines in the von Hippel-Lindau and sporadic groups demonstrated increased epinephrine, metanephrines and vanillylmandelic acid in the sporadic group. Analysis of urinary catecholamine excretion in the von Hippel-Lindau and sporadic groups together demonstrated a correlation between tumor size, and urinary metanephrines, vanillylmandelic acid, norepinephrine, epinephrine and dopamine. In 12 patients without signs or symptoms of Pheochromocytoma 17 newly diagnosed Pheochromocytomas were followed for a median of 34.5 months without morbidity. Median tumor doubling time was 17 months. Von Hippel-Lindau gene missense mutation correlated with the risk of Pheochromocytoma in patients with von Hippel-Lindau disease. These findings support a von Hippel-Lindau disease clinical classification, wherein some families are at high risk for manifestations of Pheochromocytoma. Von Hippel-Lindau disease Pheochromocytomas identified by screening were smaller and less functional than sporadic Pheochromocytomas.
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CLINICAL AND GENETIC CHARACTERIZATION OF COMPARISON WITH SPORADIC Pheochromocytoma GIVES INSIGHT INTO NATURAL HISTORY OF Pheochromocytoma Pheochromocytoma IN VON HIPPEL-LINDAU FAMILIES:
1999Co-Authors: M M Walther, R Reiter, H R Keiser, P L Choyke, D Venzon, K Hurley, J R Gnarra, J C Reynolds, Gladys Glenn, B ZbarAbstract:Purpose: Families with von Hippel-Lindau disease have variable risk of Pheochromocytoma. Patients with von Hippel-Lindau disease and Pheochromocytoma identified by screening can have no characteristic signs or symptoms. Families with von Hippel-Lindau disease were screened and followed to describe the natural history of von Hippel-Lindau Pheochromocytoma, and to correlate these findings with von Hippel-Lindau germline mutation. Materials and Methods: Between 1988 and 1997, 246 individuals with von Hippel-Lindau disease were identified (von Hippel-Lindau group). Between August 1990 and June 1997, 26 consecutive patients with sporadic Pheochromocytoma were evaluated (sporadic group). Results: A total of 64 patients with von Hippel-Lindau disease had manifestations of Pheochromocytoma, including 33 newly diagnosed during screening at the National Institutes of Health and 3 1 previously treated (93 adrenal and 13 extra-adrenal Pheochromocytomas). Germline von Hippel-Lindau gene missense mutation was associated with extra-adrenal Pheochromocytoma, younger age at presentation and the only patient with metastases. Of the 33 newly diagnosed patients with von Hippel-Lindau disease 4 had Pheochromocytoma 2 times (37 Pheochromocytomas) during followup. Of these Pheochromocytomas 35% (13 of 37) were associated with no symptoms, normal blood pressure and normal catecholamine testing. Comparison of urinary catecholamines in the von Hippel-Lindau and sporadic groups demonstrated increased epinephrine, metanephrines and vanillylmandelic acid in the sporadic group. Analysis of urinary catecholamine excretion in the von Hippel-Lindau and sporadic groups together demonstrated a correlation between tumor size, and urinary metanephrines, vanillylmandelic acid, norepinephrine, epinephrine and dopamine. In 12 patients without signs or symptoms of Pheochromocytoma 17 newly diagnosed Pheochromocytomas were followed for a median of 34.5 months without morbidity. Median tumor doubling time was 17 months. Conclusions: Von Hippel-Lindau gene missense mutation correlated with the risk of Pheochromocytoma in patients with von Hippel-Lindau disease. These findings support a von HippelLindau disease clinical classification, wherein some families are at high risk for manifestations of Pheochromocytoma. Von Hippel-Lindau disease Pheochromocytomas identified by screening
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Plasma Metanephrines Are Markers of Pheochromocytoma Produced by Catechol-O-Methyltransferase Within Tumors
The Journal of clinical endocrinology and metabolism, 1998Co-Authors: Graeme Eisenhofer, H R Keiser, Peter Friberg, Eva Mezey, Thanh-truc Huynh, Bhargava Hiremagalur, Todd Ellingson, Sushil Duddempudi, Agnes Eijsbouts, Jacques W.m. LendersAbstract:This study examined whether the high sensitivity of plasma free metanephrines for diagnosis of Pheochromocytoma may result from production of free metanephrines within tumors. Presence in Pheochromocytomas of catechol-O-methyltransferase (COMT), the enzyme responsible for conversion of catecholamines to metanephrines, was confirmed by Western blot analysis, enzyme assay, and immunohistochemistry. Western blot analysis and enzyme assay indicated that membrane-bound and not soluble COMT was the predominant form of the enzyme in Pheochromocytoma. Immunohistochemistry revealed colocalization of COMT in the same chromaffin cells where catecholamines are translocated into storage vesicles by the vesicular monoamine transporter. Levels of free metanephrines in Pheochromocytoma over 10,000 times higher than plasma concentrations in the same patients before removal of tumors indicated production of metanephrines within tumors. Comparisons of the production of metanephrines in patients with Pheochromocytoma with production from catecholamines released or infused into the circulation indicated that more than 93% of the consistently elevated levels of circulating free metanephrines in patients with Pheochromocytoma are derived from metabolism before and not after release of catecholamines into the circulation. The data indicate that the elevated plasma levels of free metanephrines in patients with Pheochromocytoma are derived from catecholamines produced and metabolized within tumors. Some tumors do not secrete catecholamines, but all appear to metabolize catecholamines to free metanephrines, thus explaining the better sensitivity of plasma free metanephrines over other tests for diagnosis of Pheochromocytoma.
Charis Eng - One of the best experts on this subject based on the ideXlab platform.
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Pheochromocytoma and Paraganglioma.
The New England journal of medicine, 2019Co-Authors: Hartmut P. H. Neumann, William F Young, Charis EngAbstract:Pheochromocytoma and Paraganglioma Pheochromocytoma and paraganglioma are related tumors that differ mainly in location; Pheochromocytomas are adrenal, and paragangliomas can be anywhere else. The ...
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gene mutations in the succinate dehydrogenase subunit sdhb cause susceptibility to familial Pheochromocytoma and to familial paraganglioma
American Journal of Human Genetics, 2001Co-Authors: Dewi Astuti, Charis Eng, Farida Latif, Ashraf Dallol, Patricia L M Dahia, Fiona Douglas, Emad George, Filip Skoldberg, Eystein S Husebye, Eamonn R MaherAbstract:The Pheochromocytomas are an important cause of secondary hypertension. Although Pheochromocytoma susceptibility may be associated with germline mutations in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RET, the genetic basis for most cases of nonsyndromic familial Pheochromocytoma is unknown. Recently, Pheochromocytoma susceptibility has been associated with germline SDHD mutations. Germline SDHD mutations were originally described in hereditary paraganglioma, a dominantly inherited disorder characterized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane. Although mutations in SDHC and in SDHD may cause hereditary paraganglioma, germline SDHA mutations are associated with juvenile encephalopathy, and the phenotypic consequences of SDHB mutations have not been defined. To investigate the genetic causes of Pheochromocytoma, we analyzed SDHB and SDHC, in familial and in sporadic cases. Inactivating SDHB mutations were detected in two of the five kindreds with familial Pheochromocytoma, two of the three kindreds with Pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic Pheochromocytoma. These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of Pheochromocytoma susceptibility.
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somatic and occult germ line mutations in sdhd a mitochondrial complex ii gene in nonfamilial Pheochromocytoma
Cancer Research, 2000Co-Authors: Oliver Gimm, Hartmut P. H. Neumann, Charis Eng, Mary Armanios, Heather DziemaAbstract:Most Pheochromocytomas are sporadic but about 10% are though to be hereditary. Although the etiology of most inherited Pheochromocytoma is well known, little is known about the etiology of the more common sporadic tumor. Recently, germ-line mutations of SDHD, a mitochondria complex II gene, were found in patients with hereditary paraganglioma. We sought to determine whether SDHD plays a role in the development of sporadic Pheochromocytomas and performed a mutation and deletion analysis of SDHD. Among 18 samples, we identified 4 heterozygous sequence variants (3 germ-line, 1 somatic). One germ-line SDHD mutation IVS1+2T>G (absent among 78 control alleles) is predicted to cause aberrant splicing. On reinvestigation, this patient was found to have a tumor of the carotid body, which was likely a paraganglioma. Another patient with malignant, extra-adrenal Pheochromocytoma was found to have germ-line c.34G> A (G12S). However, this sequence variant was also found in 1 of 78 control alleles. The third, germ-line nonsense mutation R38X was found in a patient with extra-adrenal Pheochromocytoma. The only somatic heterozygous mutation, c.242C>T (P81L), has been found in the germ line of two families with hereditary paraganglioma and is conserved among four eukaryotic multicellular organisms. Hence, this mutation is most likely of functional significance too. Overall, loss of heterozygosity in at least one of the two markers flanking SDHD was found in 13 tumors (72%). All of the tumors that already harbored intragenic SDHD mutations, whether germ-line or somatic, also had loss of heterozygosity. Our results indicate that SDHD plays a role in the pathogenesis of Pheochromocytoma. Given the minimum estimated germline SDHD mutation frequency of 11% (maximum estimate up to 17%) in this set of apparently sporadic Pheochromocytoma cases and if these data can be replicated in other populations, our observations might suggest that all such patients be considered for SDHD mutation analysis.
