scholarly journals ISOLATED PARAGANGLIOMA IN A PATIENT WITH VHL P.L163F MUTATION

2020 ◽  
Vol 6 (4) ◽  
pp. e193-e196
Author(s):  
Michael Goldstein ◽  
Rebecca E. Neril ◽  
Gary D. Rothberger
Keyword(s):  
Genetic Testing ◽  
Reference Range ◽  
Disease Type ◽  
Surgical Pathology ◽  
Rare Mutation ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
The Many ◽  
Vhl Disease ◽  
Urinary Metanephrines

Objective: Paragangliomas (PGLs) are one of the many neoplasms associated with von Hippel-Lindau (VHL) disease. VHL disease type 2C is a unique subtype characterized by the presence of a PGL or pheochromocytoma without other VHL-associated neoplasms. This report describes a rare germline mutation in the VHL gene in a patient with isolated PGL. Methods: The clinical presentation, urinary metanephrines and normetanephrines, computed tomography scan, meta-iodobenzylguanidine scintiscan, surgical pathology, and genetic testing of a patient with PGL and a rare VHL gene mutation are described. A literature review is also presented. Results: A 23-year-old, Indian woman was incidentally found to have an indeterminate 4.2 × 3.6 × 3.2-cm mass adjacent to the liver. A 36-year-old first cousin was recently diagnosed with a PGL. Her 24-hour urinary metanephrines were 6,886 μg/g creatinine (reference range is 81 to 330 μg/g creatinine) and normetanephrines were 6,810 μg/g creatinine (reference range is 20 to 158 μg/g creatinine). Surgical pathology revealed a PGL adjacent to a normal adrenal gland. Genetic testing revealed a mutation in VHL p.L163F. Surveillance for other tumors associated with VHL disease has been negative thus far. Her cousin has not undergone genetic testing despite recommendations to do so. Conclusion: We present the first reported case of PGL in a patient with VHL disease caused by a missense mutation in VHL p.L163F. To date, reports of this rare mutation have only involved patients with pheochromocytoma and without other tumors associated with VHL disease, suggesting that VHL p.L163F mutation may cause a VHL disease type 2C phenotype.

scholarly journals Molecular analysis of the Von Hippel-Lindau (VHL) gene in a family with non-syndromic pheochromocytoma: the importance of genetic testing

2007 ◽  
Vol 51 (9) ◽  
pp. 1463-1467 ◽  
Author(s):  
Juliana B. Cruz ◽  
Leonardo P.S. Fernandes ◽  
Sueli A. Clara ◽  
Sandro J. Conde ◽  
Denise Perone ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Molecular Analysis ◽  
Adrenal Mass ◽  
Index Patient ◽  
Mibg Scintigraphy ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
The Family ◽  
Urinary Metanephrines

The two index patients of the family analyzed in this study had undergone bilateral adrenalectomy for pheochromocytomas. This prompted genetic analyses of the probands and seven first-degree relatives. The two pheochromocytoma patients and two additional asymptomatic family members were found to harbor a mutation c496G>T in exon 3 of the VHL gene. The family was then lost to systematic follow-up. Three years after performing the initial genetic evaluation, the sister of the probands, who was known to carry the same VHL germline mutation, was referred to our service after a pregnancy that was complicated by preeclampsia. She reported paroxysms suggestive for pheochromocytoma, but her urinary metanephrines were negative. However, computerized tomography of the abdomen showed an adrenal mass that was also positive on metaiodobenzylguanidine (MIBG) scintigraphy. This study illustrates that molecular analysis of the index patient(s) can lead to the identification of presymptomatic relatives carrying the mutation. Moreover, despite negative urinary metanephrines, the identification of a specific mutation has led to an increased suspicion and detection of a pheochromocytoma in the sister of the probands.

Phase II study of pazopanib in patients with von Hippel-Lindau disease.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4516-4516 ◽  
Author(s):  
Eric Jonasch ◽  
Dan S. Gombos ◽  
Steven G. Waguespack ◽  
Valerie Marcott ◽  
Diane D Liu ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Clinical Features ◽  
Surgical Intervention ◽  
Standards Of Care ◽  
Common Side Effect ◽  
Drug Discontinuation ◽  
Best Interest ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease

4516 Background: Von Hippel-Lindau disease (VHL) is an autosomal dominant inherited disorder. Affected individuals develop vascular neoplastic lesions in multiple sites including eye, brain, pancreas, adrenal and kidney. Standards of care include surveillance imaging and surgical intervention. We hypothesized that treatment of VHL related lesions with an antiangiogenic agent would result in shrinkage of all lesion types. We chose the multikinase inhibitor pazopanib to test this hypothesis. Methods: After obtaining IRB approval, patients with clinical features or genetic confirmation of VHL disease and with measurable lesions were treated with pazopanib 800mg PO daily for two 12-week cycles. Efficacy was determined by RECIST after two cycles. Patients had the option to continue therapy if considered in patient’s best interest. Continuous monitoring for any lesion progression and drug discontinuation due to toxicity during the whole period of the treatment was planned. Results: Patients were enrolled (N=32) and treated (N=31) between 1/2012 and 6/2016. Median age was 37 (range 19-67). 23 patients had genomically confirmed VHL disease; four had family and personal history but had not undergone genetic testing, and five patients had clinical features of VHL disease and negative genetic testing. A median of two cycles (range 1-12) of therapy was administered. Of 31 evaluable patients, 13 (42%) showed a response, 18 patients had stable disease and no patients had PD as best response. Responses were seen in renal (2 CR and 29 PR/59 total), pancreatic (9 PR/17 total) and CNS 2 PR/49 total) target lesions. The most common side effect was diarrhea (grades 1 and 2) experienced in 14 patients. Twelve patients dose reduced to 600 mg and 6 to 400 mg pazopanib PO daily. Eight patients discontinued therapy due to adverse events of whom 4 experienced transaminitis. One patient experienced a grade V CNS hemorrhage. Conclusions: This is the largest prospective VHL disease specific therapeutic study performed to date. Pazopanib resulted in significant and sustained disease control for the majority of VHL patients enrolled on the study, with an acceptable safety profile. This agent may be considered as an alternative to surgical intervention in patients with VHL disease. Clinical trial information: NCT01436227.

scholarly journals Identification of a VHL gene mutation in atypical Von Hippel-Lindau syndrome: genotype–phenotype correlation and gene therapy perspective

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Dali Tong ◽  
Yao Zhang ◽  
Jun Jiang ◽  
Gang Bi
Keyword(s):  
Gene Therapy ◽  
Gene Mutation ◽  
Suppressor Gene ◽  
Pancreatic Cysts ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
Genetic Examination ◽  
Examination Methods ◽  
Vhl Disease ◽  
Von Hippel Lindau Syndrome

Abstract Background Classical von Hippel Lindau (VHL) disease/syndrome includes CNS hemangioblastoma, renal or pancreatic cysts, pheochromocytoma, renal carcinoma and exodermic cystadenoma. The syndrome is caused by mutation of VHL tumor suppressor gene. The most prevalent mutations are present in VHL syndrome. To date, > 500 mutations of gene related to the progression of VHL syndrome have been reported. VHL gene mutation presented in single lung or pancreatic tumor has been reported occasionally, but there is no report of both. Methods In this paper, we used CT scan, pathological and genetic examination methods to diagnose a rare atypical VHL syndrome. Results We reported a rare case of atypical VHL syndrome with authenticated VHL mutation at p.Arg167Gln, that was associated with not only bilateral pheochromocytoma but also lung carcinoid and neuroendocrine tumor of pancreas. Based on literature reviews, the patient was recommended to be further subjected to octreotide-based radionuclide therapy. Conclusions Combined with gene detection and clinical diagnosis, we found the inherent relationship between VHL genotype and phenotype, and constructed the standard diagnosis and treatment process of disease with rare VHL mutation from the perspective of gene therapy.

scholarly journals Pathology of the Nervous System in Von Hippel-Lindau Disease

2015 ◽  
Vol 2 (3) ◽  
pp. 114-129 ◽  
Author(s):  
Alexander O. Vortmeyer ◽  
Ahmed K. Alomari
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Hypoxia Inducible Factors ◽  
Metastatic Renal Cancer ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
The Central Nervous System ◽  
Vhl Disease ◽  
Common Manifestation

Von Hippel-Lindau (VHL) disease is a tumor syndrome that frequently involves the central nervous system (CNS). It is caused by germline mutation of the VHL gene. Subsequent VHL inactivation in selected cells is followed by numerous well-characterized molecular consequences, in particular, activation and stabilization of hypoxia-inducible factors HIF1 and HIF2. The link between VHL gene inactivation and tumorigenesis remains poorly understood. Hemangioblastomas are the most common manifestation in the CNS; however, CNS invasion by VHL disease-associated endolymphatic sac tumors or metastatic renal cancer also occur, and their differentiation from primary hemangioblastoma may be challenging. Finally, in this review, we present recent morphologic insights on the developmental concept of VHL tumorigenesis which is best explained by pathologic persistence of temporary embryonic progenitor cells. 

Von Hippel–Lindau disease germline mutations in Mexican patients with cerebellar hemangioblastoma

2006 ◽  
Vol 104 (3) ◽  
pp. 389-394 ◽  
Author(s):  
Astrid Rasmussen ◽  
Sonia Nava-Salazar ◽  
Petra Yescas ◽  
Elisa Alonso ◽  
Rogelio Revuelta ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Novel Mutation ◽  
Germline Mutations ◽  
Vascular Tumors ◽  
Hereditary Cancer Syndrome ◽  
Cancer Syndrome ◽  
Genetic Sequencing ◽  
Von Hippel Lindau ◽  
Screening Protocol ◽  
Vhl Disease

Object Central nervous system (CNS) hemangioblastomas are benign vascular tumors arising either sporadically or as a manifestation of von Hippel–Lindau (VHL) disease, a hereditary cancer syndrome. The authors studied a series of patients with CNS hemangioblastomas and their families to identify germline mutations in the VHL tumor suppressor gene and to establish a predictive testing and screening protocol. Methods Patients admitted between 2002 and 2004 to the Instituto Nacional de Neurología y Neurocirugía for hemangioblastoma were prospectively enrolled, together with their at-risk family members. The authors performed the molecular analysis of the VHL gene by using polymerase chain reaction and direct genetic sequencing. All asymptomatic mutation carriers underwent genetic counseling and tumor surveillance. Ninety-eight individuals were tested for VHL mutations—23 symptomatic and 75 asymptomatic individuals belonging to 16 families. Seven of the families had definite clinical criteria of VHL disease, five had sporadic hemangioblastoma, and four had CNS hemangioblastoma combined with minor visceral signs. Molecular genetic testing identified five germline mutations in six of the definite VHL families (sensitivity 85%), but none in the possible VHL and sporadic hemangioblastoma cases; four of these mutations had been previously described and one is a novel mutation present in two unrelated families. After patients carrying the mutation were identified, they underwent clinical screening and asymptomatic VHL-related lesions were identified in 43%. Conclusions Genetic testing for mutations in the VHL gene is crucial in patients with CNS hemangioblastoma. The prompt identification of patients carrying the genetic mutation allows for a multidisciplinary screening protocol to decrease morbidity and mortality rates in these patients, while avoiding costly and invasive procedures for noncarriers.

scholarly journals Extraneural hemangioblastoma of the kidney: the challenge for clinicopathological diagnosis

2015 ◽  
Vol 68 (12) ◽  
pp. 1020-1025 ◽  
Author(s):  
Yong Wu ◽  
Tao Wang ◽  
Pei-Pei Zhang ◽  
Xiaoqun Yang ◽  
Jian Wang ◽  
...  
Keyword(s):  
The Other ◽  
Pathological Examination ◽  
Cancer Center ◽  
Tumour Resection ◽  
Sequencing Analysis ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
Sporadic Disease ◽  
Mitotic Figures ◽  
Vhl Disease

BackgroundHemangioblastoma is a benign cerebellar tumour which may occur as a sporadic entity or in association with von Hippel-Lindau (VHL) disease in approximately 25% of cases. Renal hemangioblastoma (RH) is an extremely rare and newly recognised tumour. Here, we describe five cases of RH, one discovered by CT in an accident and the other four detected during routine examinations.MethodsFive cases of renal hemangioblastoma retrieved from the Department of Pathology, Fudan University Shanghai Cancer Center were studied and the literatures were reviewed. Immunohistochemistry was used to differentiate and confirm this tumour.ResultsPathological examination following tumour resection revealed RH in all cases, the first patient was also diagnosed with renal cell carcinoma (RCC), suggesting the possibility of VHL syndrome, but PCR sequencing analysis of the VHL gene confirmed no mutation in any of the three exons, implying sporadic disease .Histologically, the tumours were circumscribed, composed of sheets of oval or polygonal cells and a prominent vascular network. Tumour cells had pleomorphic nuclei, but mitotic figures were rare. The diagnosis of hemangioblastoma was confirmed by immunohistochemistry.ConclusionsRH is very rare and is challenging to differentially diagnose. Distinguishing RCC and RH is difficult and each has a different prognosis, so differentiating between them is essential for avoiding over-diagnosis and unnecessary treatment.

scholarly journals Protective Function of von Hippel-Lindau Protein against Impaired Protein Processing in Renal Carcinoma Cells

1999 ◽  
Vol 19 (2) ◽  
pp. 1289-1300 ◽  
Author(s):  
Myriam Gorospe ◽  
Josephine M. Egan ◽  
Berton Zbar ◽  
Michael Lerman ◽  
Laura Geil ◽  
...  
Keyword(s):  
Gene Function ◽  
Brefeldin A ◽  
Glucose Deprivation ◽  
Suppressor Gene ◽  
Protein Processing ◽  
Protective Function ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
Gene Status ◽  
Vhl Disease

ABSTRACT The absence of functional von Hippel-Lindau (VHL) tumor suppressor gene leads to the development of neoplasias characteristic of VHL disease, including renal cell carcinoma (RCC). Here, we compared the sensitivity of RCC cells lacking VHL gene function with that of RCC cells expressing the wild-type VHL gene (wtVHL) after exposure to various stresses. While the response to most treatments was not affected by the VHL gene status, glucose deprivation was found to be much more cytotoxic for RCC cells lacking VHL gene function than for wtVHL-expressing cells. The heightened sensitivity of VHL-deficient cells was not attributed to dissimilar energy requirements or to differences in glucose uptake, but more likely reflects a lesser ability of VHL-deficient cells to handle abnormally processed proteins arising from impaired glycosylation. In support of this hypothesis, other treatments which act through different mechanisms to interfere with protein processing (i.e., tunicamycin, brefeldin A, and azetidine) were also found to be much more toxic for VHL-deficient cells. Furthermore, ubiquitination of cellular proteins was elevated in VHL-deficient cells, particularly after glucose deprivation, supporting a role for the VHL gene in ubiquitin-mediated proteolysis. Accordingly, the rate of elimination of abnormal proteins was lower in cells lacking a functional VHL gene than in wtVHL-expressing cells. Thus, pVHL appears to participate in the elimination of misprocessed proteins, such as those arising in the cell due to the unavailability of glucose or to other stresses.

scholarly journals In silico VHL Gene Mutation Analysis and Prognosis of Pancreatic Neuroendocrine Tumors in von Hippel–Lindau Disease

2017 ◽  
Vol 103 (4) ◽  
pp. 1631-1638 ◽  
Author(s):  
Amit Tirosh ◽  
Mustapha el Lakis ◽  
Patience Green ◽  
Pavel Nockel ◽  
Dhaval Patel ◽  
...  
Keyword(s):  
Disease Progression ◽  
In Silico ◽  
Prediction Models ◽  
Gene Mutations ◽  
Pancreatic Cysts ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
Vhl Disease ◽  
The Impact ◽  
Predicted Risk

Abstract Context Patients with von Hippel–Lindau (vHL) disease caused by a missense VHL mutation have a more severe phenotype compared with other VHL mutation types. Objective To define pancreatic neuroendocrine tumor (PNET) aggressiveness according to VHL genotype. Design A prospective natural history study. Setting The National Institutes of Health clinical center. Patients Patients with vHL disease, pancreatic manifestations, and germline missense VHL gene mutations. Intervention In-silico prediction of VHL mutation via five computational prediction models. Patients with >80% prediction for disease-causing mutations in all models [high predicted risk (HPR)] were compared with others [low predicted risk (LPR)]. Main Outcome Measure Rates of metastases, surgical intervention, and disease progression. Results Sixty-nine patients were included: 2 developed metastases, 12 needed surgery, and 31 had disease progression during a median follow-up of 60 months (range 13 to 84 months). Thirteen patients were excluded for low prediction reliability. In the remaining 56 patients (45 with PNETs, 11 with pancreatic cysts), the HPR group (n = 13) had a higher rate of disease progression than the LPR group (n = 43) in multivariable analysis (hazard ratio 3.6; 95% confidence interval, 1.1 to 11.9; P = 0.037). The HPR group also had a higher risk of developing metastases (P = 0.015). Among patients with codon 167 hotspot mutations (n = 26), those in the HPR group had a higher risk for disease progression (P = 0.03) than other patients. Conclusions Computational models for predicting the impact of missense VHL gene mutations may be used as a prognostic factor in patients with PNETs in the context of vHL disease.

scholarly journals Central Nervous System Hemangioblastoma in a Pediatric Patient Associated With Von Hippel-Lindau Disease: A Case Report and Literature Review

2021 ◽  
Vol 11 ◽  
Author(s):  
Bo Yang ◽  
Zhenyu Li ◽  
Yubo Wang ◽  
Chaoling Zhang ◽  
Zhen Zhang ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Optic Nerve ◽  
Pediatric Patient ◽  
Tumor Resection ◽  
Phenotypic Expression ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
Suprasellar Region ◽  
Vhl Disease

BackgroundHemangioblastoma is a benign tumor of the central nervous system and may appear as a component of von Hippel-Lindau (VHL) disease. At present, approximately 40 cases of optic nerve HGBs have been reported in the literature. VHL disease is a rare autosomal-dominant inherited cancer syndrome with different phenotypes caused by variants in the VHL gene. Herein, the authors describe a case of a pediatric patient with VHL disease and with optic nerve HGB, a rare phenotypic expression. The purpose of this study was to explore the genotype-phenotype, clinical features, treatment and follow-up of VHL-associated hemangioblastomas in pediatric patients.Case DescriptionA 12-year-old boy presented with vision loss, headache and dizziness at our hospital. Magnetic resonance imaging (MRI) revealed a large (19.8 mm*18.5 mm*23.5 mm) irregular mass located in the suprasellar region. The mass was successfully removed after craniotomy and microsurgical treatment. The pathological diagnosis was left optic nerve HGB. Genetic analyses showed p.Pro86Leu (c. 257C>T) heterozygous missense mutations in the VHL gene.ConclusionThis is the first reported pediatric case of VHL-associated optic nerve HGB. The genotype-phenotype correlation of VHL disease may provide new evidences for predicting tumor penetrance and survival. Gross tumor resection combined with stereotactic radiosurgery might be the most beneficial treatment.

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