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

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.

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

Cancer Cell International ◽

10.1186/s12935-021-02386-w ◽

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.

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rs779805 Von Hippel-Lindau Gene Polymorphism Induced/Related Polycythemia Entity, Clinical Features, Cancer Association, and Familiar Characteristics

Pathology & Oncology Research ◽

10.3389/pore.2021.1609987 ◽

2021 ◽

Vol 27 ◽

Author(s):

Gyula Remenyi ◽

Zsuzsanna Bereczky ◽

Réka Gindele ◽

Aniko Ujfalusi ◽

Arpad Illes ◽

...

Keyword(s):

Risk Factors ◽

Colon Cancer ◽

Gene Mutations ◽

Tissue Oxygen ◽

Blood Cell Count ◽

Von Hippel Lindau ◽

The Family ◽

Red Blood Cell Count ◽

Vhl Disease ◽

Secondary Causes

Increased red blood cell count may result from primary erythrocytosis (polycythemia vera), but it is often due to secondary causes with increased erythropoietin levels. Secondary erythrocytosis may also be congenital due to different gene mutations of hemoglobin, hemoglobin stabilization proteins, EPO receptors, or oxygen sensing pathways. Von Hippel- Lindau gene mutation causes altered tissue oxygen sensation in VHL disease, usually with normal hemoglobin. Germline VHL mutations associate with classical VHL disease and represent genetic susceptibility for pheochromocytoma. VHL polymorphisms are mostly considered an innocent phenomenon. Still, some data indicate that these polymorphisms are not always harmless and can occur with prostate, renal, and colon cancer or even with isolated erythrocytosis. Seventy-eight patients referred to our department with elevated hemoglobin were screened for VHL mutations. There were no classical somatic VHL mutations. However, we found heterozygous (GA) or homozygous (AA) rs779805 VHL c.-195G>A polymorphism accompanied by erythrocytosis. These patients are Jak-2 negative, with normal or elevated EPO levels, sometimes with family accumulations and often phlebotomy needs, and in some cases with malignancies in the family. No other cause of erythrocytosis was found. We use phlebotomy regularly, and for those with cardiovascular risk factors, we recommend aspirin.

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Pathology of the Nervous System in Von Hippel-Lindau Disease

Journal of Kidney Cancer and VHL ◽

10.15586/jkcvhl.2015.35 ◽

2015 ◽

Vol 2 (3) ◽

pp. 114-129 ◽

Cited By ~ 5

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.

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

Journal of the Endocrine Society ◽

10.1210/js.2019-00225 ◽

2019 ◽

Vol 3 (9) ◽

pp. 1682-1692 ◽

Cited By ~ 2

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.

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p.Arg82Leu von Hippel-Lindau (VHL) Gene Mutation among Three Members of a Family with Familial Bilateral Pheochromocytoma in India: Molecular Analysis and In Silico Characterization

PLoS ONE ◽

10.1371/journal.pone.0061908 ◽

2013 ◽

Vol 8 (4) ◽

pp. e61908 ◽

Cited By ~ 7

Author(s):

Anulekha Mary John ◽

George Priya Doss C ◽

Andrew Ebenazer ◽

Mandalam Subramaniam Seshadri ◽

Aravindan Nair ◽

...

Keyword(s):

Gene Mutation ◽

Molecular Analysis ◽

In Silico ◽

Vhl Gene ◽

Von Hippel Lindau ◽

Bilateral Pheochromocytoma ◽

In Silico Characterization

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Von Hippel-Lindau disease associated with myasthenia gravis not related to thymoma

Italian Journal of Medicine ◽

10.4081/itjm.2009.44 ◽

2013 ◽

pp. 44-46

Author(s):

Paolo Pozzato ◽

Giovanni Sorrenti ◽

Fabrizio Salvi ◽

Maurizio Ventrucci

Keyword(s):

Myasthenia Gravis ◽

Acetylcholine Receptor ◽

Tumour Suppressor Gene ◽

The Body ◽

Pancreatic Cysts ◽

Vhl Gene ◽

Von Hippel Lindau ◽

Increased Risk ◽

Von Hippel Lindau Disease ◽

Receptor Antibodies

BACKGROUND Von Hippel-Lindau disease (VHL) is a rare autosomal dominant inherited disorder characterized by an increased risk of tumours in a number of locations (eyes, brain, adrenal gland, pancreas, liver, kidneys, or other areas of the body). It is caused by germline mutation in the VHL gene. The VHL gene is a tumour suppressor gene that has been identified on the short arm of chromosome 3. CASE REPORT We report a case of a 60 year-old female with the clinical diagnosis of VHL type 1 (cerebellar haemangioblastoma, pancreatic cysts with subsequent steatorrhoea, and bilateral renal carcinoma) who developed weakness and fatigability of skeletal muscles, left lid ptosis, snarling expression and nasal timbre speech. Acetylcholine receptor antibodies were negative in serum, while the electrodiagnostic test demonstrated an alteration of neuromuscolar junction which was consistent with the diagnosis of myasthenia gravis. Contrast-enhanced TC scan of the anterior mediastinum was performed, which excluded thymus enlargement. VHL gene evaluation in this patient identified a new mutation (c279delC9) and polymorphism c291C>G. At present the patient still suffers from ataxia and dysmetria due to cerebellar involvement in VHL, while fatigue and lid ptosis improved after the treatment with oral pyridostigmine 60 mg tid. DISCUSSION AND CONCLUSIONS To our knowledge this is the first report of a case of VHL associated with myasthenia gravis without thymoma. A case of VHL associated with a form of myasthenia gravis related to thymoma has been recently reported. In our case the absence of acetylcholine receptor antibodies may suggest a genetic origin also for the myasthenia gravis.

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Extraneural hemangioblastoma of the kidney: the challenge for clinicopathological diagnosis

Journal of Clinical Pathology ◽

10.1136/jclinpath-2015-202900 ◽

2015 ◽

Vol 68 (12) ◽

pp. 1020-1025 ◽

Cited By ~ 8

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.

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VHL-Associated Optic Nerve Hemangioblastoma Treated with Stereotactic Radiosurgery

Journal of Kidney Cancer and VHL ◽

10.15586/jkcvhl.2018.104 ◽

2018 ◽

Vol 5 (2) ◽

pp. 1-6 ◽

Cited By ~ 2

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.

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