scholarly journals New Insights Into Pheochromocytoma Surveillance of Young Patients With VHL Missense Mutations

2019 ◽  
Vol 3 (9) ◽  
pp. 1682-1692 ◽  
Author(s):  
Gustavo F C Fagundes ◽  
Janaina Petenuci ◽  
Delmar M Lourenco ◽  
Ericka B Trarbach ◽  
Maria Adelaide A Pereira ◽  
...  
Keyword(s):  
Stop Codon ◽  
Young Patients ◽  
Renal Cysts ◽  
Pancreatic Cysts ◽  
Missense Mutations ◽  
Biochemical Screening ◽  
Von Hippel Lindau ◽  
Large Gene ◽  
Vhl Disease ◽  
Splicing Site

Abstract Context Von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome caused by germline mutations in the VHL gene. Guidelines recommend pheochromocytoma (PHEO) biochemical screening should start at age 5 years. Objective Genotype–phenotype correlations in VHL, focusing on PHEO penetrance in children, were studied. Design We retrospectively evaluated 31 individuals (median age at diagnosis was 26 years) with diagnosed VHL disease. Results PHEO was diagnosed in six children with VHL. A large PHEO (5 cm) was detected in a 4-year-old boy with p.Gly114Ser mutation. PHEO penetrance was 55% starting at age 4 years. VHL missense mutations were identified in 11 of 22 families (50%), frameshift mutations in four (18.2%), stop codon in three (13.6%), splicing site in two (9.1%), and large gene deletion in two (9.1%). The codon 167 (n = 10) was a hotspot for VHL mutations and was significantly associated with PHEO (90% vs. 38%; P = 0.007). PHEOs and pancreatic neuroendocrine tumors (PNETs) were strongly associated with VHL missense mutations compared with other mutations (89.5% vs. 0% and 73.7% vs. 16.7%; P = 0.0001 and 0.002, respectively). In contrast, pancreatic cysts (91.7% vs. 26.3%; P = 0.0001), renal cysts (66.7% vs. 26.3%; P = 0.027), and central nervous system hemangioblastomas (91.7% vs. 47.3%; P = 0.012) were more frequent in VHL with nonmissense mutations. Conclusion VHL missense mutations were highly associated with PHEO and PNETs. Our data support that in children with VHL harboring missense mutations, biochemical screening for PHEO should be initiated at diagnosis.

scholarly journals Germline VHL gene mutations in Hungarian families with von Hippel–Lindau disease and patients with apparently sporadic unilateral pheochromocytomas

2009 ◽  
Vol 161 (3) ◽  
pp. 495-502 ◽  
Author(s):  
Peter Gergics ◽  
Attila Patocs ◽  
Miklos Toth ◽  
Peter Igaz ◽  
Nikolette Szucs ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Gene Mutations ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Missense Mutations ◽  
Gene Deletions ◽  
Von Hippel Lindau ◽  
Hereditary Tumor Syndrome ◽  
Large Gene ◽  
Vhl Disease

ObjectiveVon Hippel–Lindau (VHL) disease is a hereditary tumor syndrome caused by mutations or deletions of theVHLtumor-suppressor gene. GermlineVHLgene alterations may be also present in patients with apparently sporadic pheochromocytoma (ASP), although a wide variation in mutation frequencies has been reported in different patient cohorts.DesignHerein, we report the analysis of theVHLgene in Hungarian families with VHL disease and in those with ASP.MethodsSeven families (35 members) with VHL disease and 37 unrelated patients with unilateral ASP were analyzed. Patients were clinically evaluated and theVHLgene was analyzed using direct sequencing, multiplex ligation-dependent probe amplification, and real-time PCR with SYBR Green chemistry.ResultsDisease-causing genetic abnormalities were identified in each of the seven VHL families and in 3 out of the 37 patients with ASP (one nonsense and six missense mutations, two large gene deletions and one novel 2 bp deletion). Large gene deletions and other genetic alterations resulting in truncated VHL protein were found only in families with VHL type 1, whereas missense mutations were associated mainly, although not exclusively, with VHL type 2B and type 2C.ConclusionsThe spectrum ofVHLgene abnormalities in the Hungarian population is similar to that observed in Western, Japanese, or Chinese VHL kindreds. The presence ofVHLgene mutations in 3 out of the 37 patients with ASP suggests that genetic testing is useful not only in patients with VHL disease but also in those with ASP.

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

2018 ◽  
Vol 7 (7) ◽  
pp. 870-878 ◽  
Author(s):  
Qiuli Liu ◽  
Gang Yuan ◽  
Dali Tong ◽  
Gaolei Liu ◽  
Yuting Yi ◽  
...  
Keyword(s):  
Malignant Neoplasms ◽  
Missense Mutations ◽  
Chinese Families ◽  
Von Hippel Lindau ◽  
Disease Phenotypes ◽  
Mri Scans ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease

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

Hemangioblastomas of the central nervous system

1989 ◽  
Vol 70 (1) ◽  
pp. 24-30 ◽  
Author(s):  
Hartmut P. H. Neumann ◽  
Hans R. Eggert ◽  
Klaus Weigel ◽  
Hartmut Friedburg ◽  
Otmar D. Wiestler ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Screening Program ◽  
Family Background ◽  
Renal Cysts ◽  
Pancreatic Cysts ◽  
Content Type ◽  
Von Hippel Lindau ◽  
The Central Nervous System ◽  
Von Hippel Lindau Syndrome

✓ The findings of a 10-year study (1976 to 1986) conducted in southwest Germany on hemangioblastomas (HBL's) of the central nervous system (CNS) are presented. During that period, 47 HBL's were diagnosed and surgically removed in 44 patients, with a good postoperative survival rate and prognosis. The majority (83%) of these tumors were located in the cerebellum. By thorough clinical examination of the patients and careful evaluation of their family background, it was found that 23% of the HBL patients were afflicted with von Hippel-Lindau syndrome. In addition to the CNS tumors, 14 neoplastic or similar lesions were detected in other tissues. These included angiomatosis of the retinae, pheochromocytomas, pancreatic cysts, renal cysts, and renal carcinoma. The diagnosis of von Hippel-Lindau syndrome was thus established in seven families. The authors suggest the need for a screening program for patients with HBL of the CNS which is designed to confirm or exclude ocular or visceral lesions associated with von Hippel-Lindau syndrome.

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 Erratum: clinical and molecular characteristics of patients with 46,xy dsd due to nr5a1 gene mutations (Probl Endokrinol (Mosk). 2020 Sep 16;66(3):62-69. Russian. doi: 10.14341/probl12445)

2021 ◽  
Vol 67 (6) ◽  
pp. 124-126
Author(s):  
N. Yu. Kalinchenko ◽  
A. A. Kolodkina ◽  
N. Yu. Raygorodskaya ◽  
A. N. Tiulpakov
Keyword(s):  
Stop Codon ◽  
Premature Stop Codon ◽  
Gene Mutations ◽  
Synonymous Substitution ◽  
Molecular Characteristics ◽  
Missense Mutations ◽  
Reading Frame ◽  
Splicing Site

n the article some corrections were needed. Abstract: “Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described”. has been corrected to read “Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 22 were not previously described”. Results: “Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described”, has been corrected to read “Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 22 were not previously described”. Among the newly identified variants in the NR1A1 gene, two lead to the premature stop codon -p. Y197X and p. Y25X, two lead to a shift in the reading frame-p. N385fs and p. L245fs, which does not allow us to doubt their pathogenicityAmong the previously undescribed variant changes, 5 missense mutations (p. C283Y, p. C283B, p.H24Q, p.M126K, p.E81K) and 1  synonymous substitution affecting the splicing site (E330E) were evaluated as pathogenic, and 5 others as probably pathogenic.Has been corrected to read: Among the newly identified variants in the NR1A1 gene, two lead to the premature stop codon -p. Y197X and p. Y25X, two lead to a shift in the reading frame — p.N385SfsX10 and p.L245AfsX53, which does not allow us to doubt their pathogenicity Among the previously undescribed variants, 5 missense mutations (p.C283Y, p.С283F, p.H24Q, p.M126K, p.A82T) and 1 synonymous substitution affecting the splicing site (E330E) were predicted as pathogenic, and 5 others as probably pathogenic by calculating pathogenicity. The authors apologize for these errors. 

scholarly journals Von Hippel-Lindau Tumor; Radiographic Images

2017 ◽  
Vol 2 (1) ◽  
pp. 30
Author(s):  
Reza Bidaki ◽  
Azam Ghanei ◽  
Seyed Mehdi Hosseinizade ◽  
Mohammad Ebrahim Ghanei
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Renal Cysts ◽  
Cell Renal Cell Carcinoma ◽  
Radiographic Images ◽  
Von Hippel Lindau ◽  
Malignant Lesions ◽  
Vhl Disease ◽  
Renal Computed Tomography

The patient is a 34-year-old patient with abdominal pain, gross hematuria with anxiety and worries about it from 5 months ago. The physician requested renal computed tomography (CT) without and then with contrast for rule out of renal stone. However, he found multiple lesions in kidneys. The laboratory tests were normal except hematuria. He was a candidate for surgery. The pathologist reported clear red cell renal cell carcinoma. He was referred to a radiologist for staging. Von Hippel – Lindau (VHL) disease is an inherited and rare disease that is characterized by a variety of benign and malignant lesions (1). It preval ence is 1 in 31,000 -53,000 (2,3). Previous studies shown 59 – 63% of patients have renal cysts and 24 - 45 % renal cell carcinoma (4), and in 75 % of cases ,the lesions are bilateral (4, 5). Involvement of pancreas includes simple cysts (50 – 91%), serous m icrocystic adenomas (12%) and adenocarcinoma (7%) (2, 4).

scholarly journals VHL-Associated Optic Nerve Hemangioblastoma Treated with Stereotactic Radiosurgery

2018 ◽  
Vol 5 (2) ◽  
pp. 1-6 ◽  
Author(s):  
Hiroshi Kanno ◽  
Seiki Osano ◽  
Masamichi Shinonaga
Keyword(s):  
Optic Nerve ◽  
Stereotactic Radiosurgery ◽  
Rare Case ◽  
Tumor Volume ◽  
Pancreatic Cysts ◽  
Von Hippel Lindau ◽  
First Case ◽  
History Of ◽  
Fractionated Stereotactic Radiosurgery ◽  
Vhl Disease

Central nervous system hemangioblastomas are generally restricted to the cerebellum, spinal cord, and brainstem. Supratentorial hemangioblastomas are uncommon, and optic nerve hemangioblastomas are extremely rare, with fewer than 25 reports including this case. In this report, we present the case of a 36-year-old woman with von Hippel-Lindau (VHL) disease who presented with progressive diminution of vison in the left eye due to a retrobulbar optic nerve hemangioblastoma. The patient had a history of cerebellar /spinal hemangioblastomas and pancreatic cysts, and her father and brother were patients with VHL disease. Gadolinium enhanced MRI showed intraorbital retrobulbar enhanced mass on the left optic nerve. The optic nerve hemangioblastoma was treated with fractionated stereotactic radiosurgery using Novalis. Eighteen months after the stereotactic radiosurgery, the tumor volume decreased although the patient lost vision. This report presents an extremely rare case of optic nerve hemangioblastoma, which is the first case treated with stereotactic radiosurgery.

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 Von Hippel-Lindau disease and endocrine tumour susceptibility

2006 ◽  
Vol 13 (2) ◽  
pp. 415-425 ◽  
Author(s):  
Emma R Woodward ◽  
Eamonn R Maher
Keyword(s):  
Target Genes ◽  
Phenotypic Variability ◽  
Familial Cancer ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Cancer Syndrome ◽  
Pancreatic Islet Cell ◽  
Cell Renal Cell Carcinoma ◽  
Von Hippel Lindau ◽  
Vhl Disease

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome caused by mutations in the VHL tumour suppressor gene. VHL disease is characterised by marked phenotypic variability and the most common tumours are haemangioblastomas of the retina and central nervous system and clear cell renal cell carcinoma. However, endocrine tumours, most commonly phaeochromocytoma and non-secretory pancreatic islet cell cancers, demonstrate marked interfamilial variations in frequency and are significant causes of morbidity and, sometimes, mortality. Genotype–phenotype correlations have revealed that certain missense mutations are associated with a high risk of phaeochromocytoma but total loss of function mutations are associated with a low risk. Furthermore, rare mutations may predispose to a phaeochromocytoma-only phenotype. Germline VHL mutations may be detected in 5–11% of all phaeochromocytoma cases and mutation analysis of VHL and other phaeochromocytoma susceptibility genes (SDHB, SDHD and RET) should be performed in all cases of familial, multiple or early onset phaeochromocytomas, and considered in other cases. The VHL gene product has a key role in regulating the stability of hypoxia-inducible factors (HIF-1 and HIF-2) such that inactivation of VHL leads to up-regulation of HIF-1 and HIF-2 protein expression and activation of hypoxic gene response pathways. Germline SDHB and SDHD mutations also lead to increased expression of HIF target genes, but it appears that phaeochromocytoma susceptibility in VHL disease cannot be attributed to HIF activation alone. Recently, it has been suggested that an HIF-independent failure of developmental apoptosis is a common feature of all inherited phaeochromocytoma susceptibility syndromes.

Molecular pathology of von Hippel–Lindau disease and the VHL tumour suppressor gene

2001 ◽  
Vol 3 (8) ◽  
pp. 1-27 ◽  
Author(s):  
Frances M. Richards
Keyword(s):  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Missense Mutations ◽  
Cancer Syndrome ◽  
Inherited Cancer ◽  
Von Hippel Lindau ◽  
Adrenal Chromaffin ◽  
Vhl Disease

von Hippel–Lindau (VHL) disease is a dominantly inherited cancer syndrome characterised by predisposition to multiple tumours of the eyes and central nervous system (haemangioblastomas), kidneys (renal cell carcinoma; RCC), adrenal chromaffin cells (phaeochromocytoma), and other organs. The VHL gene was isolated in 1993 and mutations or deletions in the VHL gene have been identified in the germline of nearly all tested individuals with VHL disease. Genotype–phenotype correlations have been observed: individuals with missense mutations are more likely to develop phaeochromocytoma than those with deletions or protein-truncating mutations are, and specific missense mutations at certain codons might not predispose to RCC. In accordance with its role as a tumour suppressor gene, the normal allele of the VHL gene is deleted, mutated or silenced by promoter methylation in the tumours from VHL patients, and in a large proportion of sporadic tumours of the same histological types as observed in VHL disease. Thus, the VHL gene is of major importance in the development of RCC in the general population. Recent advances in understanding the structure and function of the VHL protein (pVHL) have revealed insights into the different phenotypes, with indications that some retention of function might be required for predisposition to phaeochromocytoma. pVHL interacts with many cellular proteins, mainly via one of two protein-binding domains (α and β). The best-characterised interaction is that of pVHL with elongin C, which forms a complex with elongin B and Cullin 2 proteins. This complex has E3 ubiquitin ligase activity and promotes ubiquitin-mediated proteasomal degradation of the hypoxia-inducible factor 1α (HIF-1α) transcription factor under normal oxygen (normoxic) conditions. Loss of pVHL function leads to stabilisation of HIF-1 and expression under normoxic conditions of hypoxia-inducible genes including vascular endothelial growth factor (VEGF), which might explain the hypervascular phenotype of VHL tumours. Several other genes implicated in intra- and intercellular signalling and control of tumour growth are overexpressed in the absence of pVHL, but it is not yet clear which features of pVHL function are most significant for tumour suppression in different tissues. Further advances in understanding pVHL function might eventually enable development of specific therapies for prevention or treatment of VHL tumours and RCC.

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