A Case of Type 1 von Hippel-Lindau (VHL) Disease associated with VHL Germline Mutation

2006 ◽  
Vol 21 (3) ◽  
pp. 239 ◽  
Author(s):  
Jeong Hoon Seo ◽  
Jae Hong Yang ◽  
Pyoung Lak Choi ◽  
Yu Lee Kim ◽  
Young Sik Choi ◽  
...  
Keyword(s):  
Germline Mutation ◽  
Von Hippel Lindau ◽  
Vhl Disease

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.

Familial tumour syndromes

2010 ◽  
pp. 482-493
Author(s):  
George Samandouras
Keyword(s):  
Tuberous Sclerosis ◽  
Giant Cell ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Subependymal Giant Cell Astrocytoma ◽  
Von Hippel Lindau ◽  
Vhl Disease ◽  
Giant Cell Astrocytoma

Chapter 8.18 covers familial tumour syndromes, including neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), von Hippel-Lindau (VHL) disease and capillary haemangioblastoma, tuberous sclerosis and subependymal giant cell astrocytoma (SEGA), and Lhermitte-Duclos disease.

scholarly journals Germline mutation of Glu70Lys is highly frequent in Korean patients with von Hippel–Lindau (VHL) disease

2014 ◽  
Vol 59 (9) ◽  
pp. 488-493 ◽  
Author(s):  
Sena Hwang ◽  
Cheol Ryong Ku ◽  
Ji In Lee ◽  
Kyu Yeon Hur ◽  
Myung-Shik Lee ◽  
...  
Keyword(s):  
Germline Mutation ◽  
Von Hippel Lindau ◽  
Korean Patients ◽  
Vhl Disease

scholarly journals EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance

2019 ◽  
Vol 116 (34) ◽  
pp. 16997-17006 ◽  
Author(s):  
Shuijie Li ◽  
Javier Rodriguez ◽  
Wenyu Li ◽  
Petra Bullova ◽  
Stuart M. Fell ◽  
...  
Keyword(s):  
Chemotherapy Resistance ◽  
Von Hippel Lindau ◽  
Extracellular Signal ◽  
Familial Pheochromocytoma ◽  
Oxygen Sensitive ◽  
Vhl Protein ◽  
Sensitive Function ◽  
Induced Apoptosis ◽  
Vhl Disease

Despite the discovery of the oxygen-sensitive regulation of HIFα by the von Hippel–Lindau (VHL) protein, the mechanisms underlying the complex genotype/phenotype correlations in VHL disease remain unknown. Some germline VHL mutations cause familial pheochromocytoma and encode proteins that preserve their ability to down-regulate HIFα. While type 1, 2A, and 2B VHL mutants are defective in regulating HIFα, type 2C mutants encode proteins that preserve their ability to down-regulate HIFα. Here, we identified an oxygen-sensitive function of VHL that is abolished by VHL type 2C mutations. We found that BIM-EL, a proapoptotic BH3-only protein, is hydroxylated by EglN3 and subsequently bound by VHL. VHL mutants fail to bind hydroxylated BIM-EL, regardless of whether they have the ability to bind hydroxylated HIFα or not. VHL binding inhibits BIM-EL phosphorylation by extracellular signal-related kinase (ERK) on serine 69. This causes BIM-EL to escape from proteasomal degradation, allowing it to enhance EglN3-induced apoptosis. BIM-EL was rapidly degraded in cells lacking wild-type VHL or in which EglN3 was inactivated genetically or by lack of oxygen, leading to enhanced cell survival and chemotherapy resistance. Combination therapy using ERK inhibitors, however, resensitizes VHL- and EglN3-deficient cells that are otherwise cisplatin-resistant.

scholarly journals Diagnostic Genetics at a Distance: Von Hippel-Lindau Disease and a Novel Mutation

2013 ◽  
Vol 2013 ◽  
pp. 1-5
Author(s):  
Clare Brookes ◽  
Debra O. Prosser ◽  
Jennifer M. Love ◽  
R. J. McKinlay Gardner ◽  
Donald R. Love
Keyword(s):  
At Risk ◽  
Genetic Testing ◽  
Germline Mutation ◽  
Health Professionals ◽  
Patient Involvement ◽  
Novel Mutation ◽  
Blood Samples ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease

Genetic testing at a distance is commonplace where members of a family with a segregating germline mutation are geographically separated. For the most part, this challenge is addressed through the intervention of health professionals in taking and/or processing blood samples for subsequent couriering of DNA to a referral laboratory. In some circumstances, however, the collecting of pivotal clinical material may involve direct patient involvement. We describe such a situation where noninvasive saliva samples were provided by members of a family manifesting Von Hippel-Lindau (VHL) disease. The analysis identified a novel mutation in the VHL gene that was used to exclude other family members as being at risk of VHL disease.

scholarly journals De novo VHL germline mutation detected in a patient with mild clinical phenotype of von Hippel-Lindau disease

2014 ◽  
Vol 121 (2) ◽  
pp. 384-386 ◽  
Author(s):  
Xinghua Ding ◽  
Chao Zhang ◽  
Jason M. Frerich ◽  
Anand Germanwala ◽  
Chunzhang Yang ◽  
...  
Keyword(s):  
Germline Mutation ◽  
Autosomal Dominant ◽  
De Novo ◽  
Clinical Phenotype ◽  
Pancreatic Neuroendocrine Tumors ◽  
Renal Cell Carcinomas ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease ◽  
Mild Clinical Phenotype

Von Hippel-Lindau (VHL) disease is an autosomal dominant multiorgan tumor syndrome caused by a germline mutation in the VHL gene. Characteristic tumors include CNS hemangioblastomas (HBs), endolymphatic sac tumors, renal cell carcinomas, pheochromocytomas, and pancreatic neuroendocrine tumors. Sporadic VHL disease with a de novo germline mutation is rare. The authors describe a case of multiple CNS HBs in a patient with a heterozygous de novo germline mutation at c.239G>T [p.S80I] of VHL. This is the first known case of a sporadic de novo germline mutation of VHL at c.239G>T. Clinicians should continue to consider VHL disease in patients presenting with sporadic CNS HBs, including those without a family history, to confirm or exclude additional VHL-associated visceral lesions.

scholarly journals Biological and clinical impact of hemangioblastoma-associated peritumoral cysts in von Hippel-Lindau disease

2016 ◽  
Vol 124 (4) ◽  
pp. 971-976 ◽  
Author(s):  
Kristin Huntoon ◽  
Tianxia Wu ◽  
J. Bradley Elder ◽  
John A. Butman ◽  
Emily Y. Chew ◽  
...  
Keyword(s):  
Clinical Impact ◽  
Anatomical Location ◽  
Von Hippel Lindau ◽  
Study Enrollment ◽  
Common Location ◽  
Younger Age ◽  
The Mean ◽  
A Prospective Study ◽  
Vhl Disease

OBJECT Peritumoral cysts are frequently associated with CNS hemangioblastomas and often underlie neurological morbidity and mortality. To determine their natural history and clinical impact, the authors prospectively analyzed hemangioblastoma-associated peritumoral cysts in patients with von Hippel-Lindau (VHL) disease. METHODS Patients with VHL disease who had 2 or more years of follow-up and who were enrolled in a prospective study at the National Institutes of Health were included. Serial prospectively acquired laboratory, genetic, imaging, and clinical data were analyzed. RESULTS One hundred thirty-two patients (of 225 in the VHL study with at least 2 years of follow-up) had peritumoral cysts that were followed for more than 2 years (total of 292 CNS peritumoral cysts). The mean age at study entrance was 37.4 ± 13.1 years ([mean ± SD], median 37.9, range 12.3–65.1 years). The mean follow-up was 7.0 ± 1.7 years (median 7.3, range 2.1–9.0 years). Over the study period, 121 of the 292 peritumoral cysts (41.4%) became symptomatic. Development of new cysts was associated with a larger number cysts at study enrollment (p = 0.002) and younger age (p < 0.0001). Cyst growth rate was associated with anatomical location (cerebellum cysts grew faster than spine and brainstem cysts; p = 0.0002 and p = 0.0008), younger age (< 35 years of age; p = 0.0006), and development of new neurological symptoms (p < 0.0001). Cyst size at symptom production depended on anatomical location (p < 0.0001; largest to smallest were found, successively, in the cerebellum, spinal cord, and brainstem). The most common location for peritumoral cysts was the cerebellum (184 cysts [63%]; p < 0.0001). CONCLUSIONS Peritumoral cysts frequently underlie symptom formation that requires surgical intervention in patients with VHL disease. Development of new cysts was associated with a larger number of cysts at study enrollment and younger age. Total peritumoral cyst burden was associated with germline partial deletion of the VHL gene.

scholarly journals Inactivation of the Arylhydrocarbon Receptor Nuclear Translocator (Arnt) Suppresses von Hippel-Lindau Disease-Associated Vascular Tumors in Mice

2005 ◽  
Vol 25 (8) ◽  
pp. 3163-3172 ◽  
Author(s):  
Erinn B. Rankin ◽  
Debra F. Higgins ◽  
Jacqueline A. Walisser ◽  
Randall S. Johnson ◽  
Christopher A. Bradfield ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Germ Line ◽  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Vascular Tumors ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Arylhydrocarbon Receptor ◽  
Vhl Disease ◽  
Endothelial Growth Factor

ABSTRACT Patients with germ line mutations in the VHL tumor suppressor gene are predisposed to the development of highly vascularized tumors within multiple tissues. Loss of pVHL results in constitutive activation of the transcription factors HIF-1 and HIF-2, whose relative contributions to the pathogenesis of the VHL phenotype have yet to be defined. In order to examine the role of HIF in von Hippel-Lindau (VHL)-associated vascular tumorigenesis, we utilized Cre-loxP-mediated recombination to inactivate hypoxia-inducible factor-1α (Hif-1α) and arylhydrocarbon receptor nuclear translocator (Arnt) genes in a VHL mouse model of cavernous liver hemangiomas and polycythemia. Deletion of Hif-1α did not affect the development of vascular tumors and polycythemia, nor did it suppress the increased expression of vascular endothelial growth factor (Vegf) and erythropoietin (Epo). In contrast, phosphoglycerokinase (Pgk) expression was substantially decreased, providing evidence for target gene-dependent functional redundancy between different Hif transcription factors. Inactivation of Arnt completely suppressed the development of hemangiomas, polycythemia, and Hif-induced gene expression. Here, we demonstrate genetically that the development of VHL-associated vascular tumors in the liver depends on functional ARNT. Furthermore, we provide evidence that individual HIF transcription factors may play distinct roles in the development of specific VHL disease manifestations.

scholarly journals Adrenal Cortex-Sparing Surgery for Bilateral Multiple Pheochromocytomas in a Patient with Von Hippel-Lindau Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Tarık Esen ◽  
Ömer Acar ◽  
Ahmet Tefekli ◽  
Ahmet Musaoğlu ◽  
İzzet Rozanes ◽  
...  
Keyword(s):  
Adrenal Cortex ◽  
Adrenocortical Function ◽  
Renal Masses ◽  
Von Hippel Lindau ◽  
Pancreatic Masses ◽  
Adrenal Pheochromocytoma ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease

Pheochromocytomas can be a part of familial neoplastic syndromes, in which case they tend to be multiple and involve both adrenal glands. Therefore, sparing adrenocortical function represents a major concern while dealing with these hereditary lesions. Herein, we describe the clinical characteristics and the management strategy of a patient with von Hippel-Lindau (VHL) disease who had multiple, bilateral pheochromocytomas as well as bilateral renal masses, pancreatic masses, and a paracaval mass. Only a portion of the left adrenal gland has remained in situ after two consecutive open surgeries and a percutaneous radiofrequency ablation which have been performed to treat the various components of this syndrome. No adrenal or extra-adrenal pheochromocytoma recurrences have been detected during a follow-up period of more than 2 years. Pancreatic and adrenal functions were normal throughout the postoperative period and never necessitated any replacement therapy. Adrenal cortex-sparing surgery is a valid option for VHL disease patients who present with synchronous bilateral adrenal pheochromocytomas.

Surgical management of spinal cord hemangioblastomas in patients with von Hippel—Lindau disease

2003 ◽  
Vol 98 (1) ◽  
pp. 106-116 ◽  
Author(s):  
Russell R. Lonser ◽  
Robert J. Weil ◽  
John E. Wanebo ◽  
Hetty L. Devroom ◽  
Edward H. Oldfield
Keyword(s):  
Spinal Cord ◽  
Surgical Management ◽  
Postoperative Outcome ◽  
Tumor Location ◽  
Neurological Dysfunction ◽  
Autosomal Dominant Disorder ◽  
Content Type ◽  
Von Hippel Lindau ◽  
Vhl Disease ◽  
Fine Print

Object. Von Hippel—Lindau (VHL) disease is an autosomal-dominant disorder frequently associated with hemangioblastomas of the spinal cord. Because of the slow progression, protean nature, and high frequency of multiple spinal hemangioblastomas associated with VHL disease, the surgical management of these lesions is complex. Because prior reports have not identified the factors that predict which patients with spinal cord hemangioblastomas need surgery or what outcomes of this procedure should be expected, the authors have reviewed a series of patients with VHL disease who underwent resection of spinal hemangioblastomas at a single institution to identify features that might guide surgical management of these patients. Methods. Forty-four consecutive patients with VHL disease (26 men and 18 women) who underwent 55 operations with resection of 86 spinal cord hemangioblastomas (mean age at surgery 34 years; range 20–58 years) at the National Institutes of Health were included in this study (mean clinical follow up 44 months). Patient examination, review of hospital charts, operative findings, and magnetic resonance imaging studies were used to analyze surgical management and its outcome. To evaluate the clinical course, clinical grades were assigned to patients before and after surgery. Preoperative neurological status, tumor size, and tumor location were predictive of postoperative outcome. Patients with no or minimal preoperative neurological dysfunction, with lesions smaller than 500 mm3, and with dorsal lesions were more likely to have no or minimal neurological impairment. Syrinx resolution was the result of tumor removal and was not influenced by whether the syrinx cavity was entered. Conclusions. Spinal cord hemangioblastomas can be safely removed in the majority of patients with VHL disease. Generally in these patients, hemangioblastomas of the spinal cord should be removed when they produce symptoms or signs.

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