von Hippel-Lindau disease


Literature Analysis

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Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (24)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

VHL 3p25.3 RCA1, VHL1, pVHL, HRCA1 -VHL and von Hippel-Lindau Disease
CA9 9p13.3 MN, CAIX -CA9 and von Hippel-Lindau Disease
THRB 3p24.2 GRTH, PRTH, THR1, ERBA2, NR1A2, THRB1, THRB2, C-ERBA-2, C-ERBA-BETA -THRB and von Hippel-Lindau Disease
SDHAF2 11q12.2 PGL2, SDH5, C11orf79 -SDHAF2 and von Hippel-Lindau Disease
SDHA 5p15 FP, PGL5, SDH1, SDH2, SDHF, CMD1GG -SDHA and von Hippel-Lindau Disease
EPOR 19p13.3-p13.2 EPO-R -EPOR and von Hippel-Lindau Disease
FH 1q42.1 MCL, FMRD, LRCC, HLRCC, MCUL1 -FH and von Hippel-Lindau Disease
TMEM127 2q11.2 -TMEM127 and von Hippel-Lindau Disease
ATRX Xq21.1 JMS, SHS, XH2, XNP, ATR2, SFM1, MRX52, RAD54, MRXHF1, RAD54L, ZNF-HX -ATRX and von Hippel-Lindau Disease
DAXX 6p21.3 DAP6, EAP1, BING2 -DAXX and von Hippel-Lindau Disease
CHGA 14q32 CGA -CHGA and von Hippel-Lindau Disease
MAP2K1 15q22.1-q22.33 CFC3, MEK1, MKK1, MAPKK1, PRKMK1 -MAP2K1 and von Hippel-Lindau Disease
SKP1 5q31 OCP2, p19A, EMC19, SKP1A, OCP-II, TCEB1L -SKP1 and von Hippel-Lindau Disease
RBX1 22q13.2 ROC1, RNF75, BA554C12.1 -RBX1 and von Hippel-Lindau Disease
CBL 11q23.3 CBL2, NSLL, C-CBL, RNF55, FRA11B -Proto-Oncogene Proteins c-cbl and von Hippel-Lindau Disease
EGLN3 14q13.1 PHD3, HIFPH3, HIFP4H3 -EGLN3 and von Hippel-Lindau Disease
VIM 10p13 HEL113, CTRCT30 -VIM and von Hippel-Lindau Disease
HNRNPA2B1 7p15 RNPA2, HNRPA2, HNRPB1, SNRPB1, HNRNPA2, HNRNPB1, IBMPFD2, HNRPA2B1 -HNRNPA2B1 and von Hippel-Lindau Disease
ERCC6 10q11.23 CSB, CKN2, COFS, ARMD5, COFS1, RAD26, UVSS1 -ERCC6 and von Hippel-Lindau Disease
TFEB 6p21 TCFEB, BHLHE35, ALPHATFEB -TFEB and von Hippel-Lindau Disease
TNFRSF10D 8p21 DCR2, CD264, TRUNDD, TRAILR4, TRAIL-R4 -TNFRSF10D and von Hippel-Lindau Disease
CD70 19p13 CD27L, CD27LG, TNFSF7 -CD70 and von Hippel-Lindau Disease
TNFRSF10A 8p21 DR4, APO2, CD261, TRAILR1, TRAILR-1 -TNFRSF10A and von Hippel-Lindau Disease
GNAS 20q13.3 AHO, GSA, GSP, POH, GPSA, NESP, SCG6, SgVI, GNAS1, C20orf45 -GNAS and von Hippel-Lindau Disease

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest publications

Publications about von Hippel-Lindau Disease and cancer

Papadakis GZ, Millo C, Jassel IS, et al.
18F-FDG and 68Ga-DOTATATE PET/CT in von Hippel-Lindau Disease-Associated Retinal Hemangioblastoma.
Clin Nucl Med. 2017; 42(3):189-190 [PubMed] Related Publications
Retinal hemangioblastomas are highly vascular benign tumors that can be encountered either sporadically or within the von Hippel-Lindau (VHL) syndrome. We report a case of a VHL patient with retinal hemangioblastoma who underwent PET/CT scans using F-FDG and Ga-DOTATATE. The tumor showed low-level F-FDG and increased Ga-DOTATATE activity, suggesting cell-surface overexpression of somatostatin receptors. The presented case indicates the clinical applications of somatostatin receptor imaging with Ga-DOTA-conjugated peptides in detection and follow-up of VHL manifestations, screening of asymptomatic gene carriers, and in diagnosis of sporadic retinal hemangioblastomas, which may have similar features on MRI with other retinal tumors.

Papadakis GZ, Millo C, Sadowski SM, et al.
Kidney Tumor in a von Hippel-Lindau (VHL) Patient With Intensely Increased Activity on 68Ga-DOTA-TATE PET/CT.
Clin Nucl Med. 2016; 41(12):970-971 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
Renal and pancreatic cysts and tumors are the most common visceral manifestations of von Hippel-Lindau (VHL) disease, a heritable multisystem cancer syndrome characterized by development of a variety of malignant and benign tumors. We report a case of a VHL patient with multiple renal cystic and complex cystic/solid lesions. The patient underwent Ga-DOTA-TATE-PET/CT showing intensely increased activity by a solid lesion which demonstrated enhancement on both CT and MRI scans, raising high suspicion for malignancy. The presented case indicates application of SSTR-imaging using Ga-DOTA-conjugated peptides in VHL-patients and emphasizes the need for cautious interpretation of renal parenchyma Ga-DOTATATE activity.

Panayi C, Antoun N, Sandford R
Bulbar dysfunction and aspiration pneumonia due to a brainstem haemangioblastoma: an unusual complication of von Hippel-Lindau disease.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
A 44-year-old woman with a history of von Hippel-Lindau (VHL) disease, a rare inherited neoplasia syndrome, presented acutely to hospital with a productive cough, symptoms of respiratory tract infection and odynophagia (painful swallowing). A chest X-ray confirmed right-sided pneumonia. Investigation of the persistent odynophagia using barium swallow revealed aspiration of the contrast into the lungs and suggested a neurological cause for her chest infection. Clinical assessment and speech and language therapy confirmed a pseudobulbar palsy. Subsequent neuroimaging identified a cystic haemangioblastoma, located at the cervicomedullary junction of the brainstem, as the cause of the pseudobulbar palsy. Urgent neurosurgical excision produced symptomatic relief and with continuing medical therapy, and clinical resolution of her pneumonia. In patients with VHL disease and other inherited cancer syndromes, a high index of suspicion should be maintained for new tumours presenting with common medical symptoms and signs.

Prokopienko M, Kunert P, Podgórska A, Marchel A
Surgical treatment of sporadic and von Hippel-Lindau syndrome-associated intramedullary hemangioblastomas.
Neurol Neurochir Pol. 2016; 50(5):349-55 [PubMed] Related Publications
OBJECT: Intramedullary hemangioblastomas are rare lesions. They can be related to von Hippel-Lindau syndrome or they may be sporadic. This study describes surgical treatment for this infrequent tumor.
METHODS: Twelve consecutive patients received surgery to remove sporadic or von Hippel-Lindau syndrome-associated intramedullary hemangioblastomas. Patients were evaluated at four time points: before treatment, on postoperative day one, on the day of discharge, and at a follow-up examination.
RESULTS: The patients showed good preoperative neurological status. The cohort had a slight female predominance. All tumors spanned at least one spinal segment. In all cases, total tumor removal was achieved, and a good outcome was obtained. None of the following factors had a significant effect on outcome: age, sex, tumor size, the presence of a syrinx, or the presence of von Hippel-Lindau syndrome.
CONCLUSIONS: The surgical removal of intramedullary hemangioblastomas resulted in satisfactory long-term functional outcomes. The best results were obtained before neurological symptoms occurred. Thus, we suggest that surgery should be considered for managing asymptomatic, surgically accessible, space-occupying lesions in sIH group, and isolated, space-occupying lesions in vHLS-IH group.

Hodgson TS, Nielsen SM, Lesniak MS, Lukas RV
Neurological Management of Von Hippel-Lindau Disease.
Neurologist. 2016; 21(5):73-8 [PubMed] Related Publications
Von Hippel-Lindau disease is a genetic condition due to mutation of the Von Hippel-Lindau gene, which leads to an increased risk in the development of hemangioblastomas of the brain and spinal cord. The pathophysiology of disease and its clinical manifestations, as they pertain to the general neurologist, are discussed. Therapeutic management of central nervous system hemangioblastomas ranging from neurosurgical resection, radiation therapy, and systemic therapies is reviewed.

Papadakis GZ, Millo C, Sadowski SM, et al.
Epididymal Cystadenomas in von Hippel-Lindau Disease Showing Increased Activity on 68Ga DOTATATE PET/CT.
Clin Nucl Med. 2016; 41(10):781-2 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
von Hippel-Lindau (VHL) disease is a familial cancer syndrome characterized by the development of a variety of malignant and benign tumors, including epididymal cystadenomas. We report a case of a VHL patient with bilateral epididymal cystadenomas who was evaluated with Ga DOTATATE PET/CT, showing intensely increased activity (SUVmax, 21.6) associated with the epididymal cystadenomas, indicating cell-surface overexpression of somatostatin receptors. The presented case supports the usefulness of somatostatin receptor imaging using Ga DOTA-conjugated peptides for detection and follow-up of VHL manifestations, as well as surveillance of asymptomatic gene carriers.

Papadakis GZ, Millo C, Sadowski SM, et al.
Endolymphatic Sac Tumor Showing Increased Activity on 68Ga DOTATATE PET/CT.
Clin Nucl Med. 2016; 41(10):783-4 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
Endolymphatic sac tumors (ELSTs) are rare tumors arising from the epithelium of the endolymphatic sac and duct that can be either sporadic or associated with von Hippel-Lindau (VHL) disease. We report a case of a VHL patient with histologically proven residual ELST who underwent Ga DOTATATE PET/CT showing increased activity (SUVmax, 6.29) by the ELST. The presented case of a VHL-associated ELST with increased Ga DOTATATE uptake indicates cell-surface expression of somatostatin receptors by this tumor, suggesting the potential application of somatostatin receptor imaging using Ga DOTA-conjugated peptides in the workup and management of these patients.

Prasad V, Tiling N, Denecke T, et al.
Potential role of (68)Ga-DOTATOC PET/CT in screening for pancreatic neuroendocrine tumour in patients with von Hippel-Lindau disease.
Eur J Nucl Med Mol Imaging. 2016; 43(11):2014-20 [PubMed] Related Publications
PURPOSE: Neuroendocrine tumours of the pancreas (pNET) are observed in 8 - 17 % of patients with von Hippel-Lindau disease (vHLD), and 11 - 20 % of these patients develop metastatic disease. MRI and CT have a very high resolution; however, their sensitivity and specificity for the detection of pNET amongst cystic lesions in the pancreas of vHLD patients are generally considered insufficient. In contrast, (68)Ga-DOTATOC PET/CT demonstrates a high sensitivity for the diagnosis and staging of neuroendocrine tumours. In this study we investigated the potential role of (68)Ga-DOTATOC PET/CT in screening of patients with vHLD.
METHOD: (68)Ga-DOTATOC PET/three-phase contrast-enhanced CT was performed according to guidelines in all consecutive vHLD patients between January 2012 and November 2015. All patients underwent additional MRI imaging of the abdomen, spine, and head. Chromogranin A (CgA) was determined at the time of the PET/CT examination. A lesion seen on (68)Ga-DOTATOC PET in the pancreas was defined as positive if the uptake was visually higher than in the surrounding tissues. Lesions were quantified using maximum SUV.
RESULTS: Overall, 20 patients (8 men, 12 women; mean age 44.7 ± 11.1 years) were prospectively examined. Genetically, 12 patients had type 1 vHLD and 8 had type 2 vHLD. (68)Ga-DOTATOC PET/CT detected more pNET than morphological imaging (CT or MRI): 11 patients (55 %; 8 type 1, 3 type 2) vs. 9 patients (45 %; 6 type 1, 3 type 2). The concentration of CgA was mildly elevated in 2 of 11 patients with pNET. The mean SUVmax of the pancreatic lesions was 18.9 ± 21.9 (range 5.0 - 65.6). Four patients (36.4 %) had multiple pNETs. The mean size of the lesions on CT and/or MRI was 10.4 ± 8.3 mm (range 4 - 38 mm), and 41.1 % were larger than 10 mm. In addition, somatostatin receptor-positive cerebellar and spinal haemangioblastomas were detected in three patients (SUVmax 2.1 - 10.1). One patient presented with a solitary somatostatin receptor-positive lymph node metastasis. pNETs were observed more frequently in vHLD type 1 than type 2 (66.7 % vs. 37.5 %, p = 0.089). None of the patients showed progressive disease during follow-up.
CONCLUSION: In this study, (68)Ga-DOTATOC PET detected pNETs in a higher proportion of patients with vHLD than found in previous studies with (111)In-octreoscan, the imaging method recommended by the NCCN. We therefore suggest (68)Ga-DOTATOC PET/CT as the more sensible screening tool.

Crona J, Skogseid B
GEP- NETS UPDATE: Genetics of neuroendocrine tumors.
Eur J Endocrinol. 2016; 174(6):R275-90 [PubMed] Related Publications
Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel-Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.

Shanbhogue KP, Hoch M, Fatterpaker G, Chandarana H
von Hippel-Lindau Disease: Review of Genetics and Imaging.
Radiol Clin North Am. 2016; 54(3):409-22 [PubMed] Related Publications
von Hippel-Lindau (VHL) disease is an autosomal-dominant, hereditary, multisystem neoplasia syndrome with increased susceptibility to several benign and malignant tumors. VHL occurs in about 1 in 36,000 live births and is associated with germline mutation of the VHL tumor suppressor gene on the short arm of chromosome 3. VHL disease exhibits diverse genotype and phenotype correlations, exhibits variable intrafamilial and interfamilial expressivity, and can manifest with benign and malignant tumors of the central nervous system, kidneys, adrenals, pancreas, and reproductive organs. Imaging and management of this entity are therefore multidisciplinary. An overview of VHL disease is presented.

Shaigany K, Vazquez A, Kwong KM, et al.
Endolymphatic sac tumor in association with von Hippel-Lindau syndrome.
Ear Nose Throat J. 2016; 95(3):96-8 [PubMed] Related Publications

Kobayashi A, Takahashi M, Imai H, et al.
Attainment of a Long-term Favorable Outcome by Sunitinib Treatment for Pancreatic Neuroendocrine Tumor and Renal Cell Carcinoma Associated with von Hippel-Lindau Disease.
Intern Med. 2016; 55(6):629-34 [PubMed] Related Publications
von Hippel-Lindau (VHL) disease, caused by germline mutations in the VHL gene, is a hereditary autosomal-dominant disorder which predisposes the individual to various malignant and benign tumors. VHL acts as a tumor suppressor, mainly through the negative regulation of hypoxia-inducible factors. Molecular-targeted drugs against vascular endothelial growth factor-signaling pathways, a target of hypoxia-inducible factors, have recently been introduced into clinical practice for the treatment of patients with sporadic renal cell carcinoma and pancreatic neuroendocrine tumors. However, whether such treatments are effective in patients with VHL disease remains to be elucidated. We herein report a Japanese patient with VHL disease who was successfully treated with sunitinib for approximately 5 years.

Agaimy A, Hartmann A
[Hereditary renal tumors: More common than expected?].
Pathologe. 2016; 37(2):134-43 [PubMed] Related Publications
Renal cell carcinomas are associated with hereditary tumor syndromes in approximately 5 % of cases. In patients with a hereditary predisposition, tumors show an earlier age of onset, often with a multicentric and bilateral manifestation. While some patients with renal cell carcinoma can be classified into well-characterized kidney cancer syndromes others have a genetic background which is still poorly understood. Most of the specific tumor syndromes are associated with a histopathologically distinct renal cell tumor phenotype. The recognition of patients with hereditary renal cell carcinoma and the identification of individual family members with a higher risk of development of renal tumors is important for early tumor detection and treatment. This manuscript reviews the clinical pathological and molecular findings of hereditary renal cell carcinoma syndromes.

Dolzhansky OV, Morozova MM, Korostelev SA, et al.
[Von Hippel-Lindau disease type 2-related pancreatic neuroendocrine tumor and adrenal myelolipoma].
Arkh Patol. 2016 Jan-Feb; 78(1):36-41 [PubMed] Related Publications
The paper describes a case of von Hippel--Lindau-related pancreatic neuroendocrine tumor and adrenal myelolipoma in a 44-year-old woman. The pancreatic tumor and a left retroperitoneal mass were removed in the women in July 2014 and May 2015. Histological examination of the pancreatic tumor revealed that the latter consisted of clear cells forming tubular and tubercular structures showing the expression of chromogranin A, synaptophysin, and cytokeratins 18 and 19 and a negative response to CD10 and RCC. The adrenal medullary mass presented as clear-cell alveolar structures with inclusions of adipose tissue mixed with erythroid, myeloid, and lymphoid cells. The clear-cell component of the adrenal gland expressed neuroendocrine markers with a negative response to cytokeratins, CD10, and RCC. Molecular genetic examination yielded a signal corresponding to two copies of the VHL gene. No deletions or amplifications of the gene were detected. Cases of von Hippel--Lindau disease concurrent with adrenal pheochromocytoma and myelolipoma and simultaneous pancreatic involvement were not found in the literature.

Fan Y, Li H, Ma X, et al.
Dicer suppresses the malignant phenotype in VHL-deficient clear cell renal cell carcinoma by inhibiting HIF-2α.
Oncotarget. 2016; 7(14):18280-94 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
Both the von Hippel-Lindau (VHL)/hypoxia-inducible factor (HIF) pathway and microRNA (miRNA) regulation are important mechanisms underlying the development and progression of clear cell renal cell carcinoma (ccRCC). Here we demonstrate that VHL deficiency leads to downregulation of Dicer and, in turn, defects in the miRNA biogenesis machinery in ccRCCs. Dicer inhibited expression of HIF-2α, which was a direct target of Dicer-dependent miR-182-5p in VHL-deficient ccRCCs. Ectopic Dicer expression in VHL-deficient ccRCCs suppressed tumor growth and angiogenesis by inhibiting HIF-2α both in vitro and in vivo. Reduced Dicer mRNA levels served as an independent prognostic factor for poor survival in patients with VHL-deficient ccRCC. Our results indicate that downregulation of Dicer in VHL-deficient ccRCCs contributes to high levels of HIF-2α and a malignant phenotype, which suggests Dicer could be a useful therapeutic target for managing this disease.

Amin S, Kim MK
Islet Cell Tumors of the Pancreas.
Gastroenterol Clin North Am. 2016; 45(1):83-100 [PubMed] Related Publications
Islet cell tumors of the pancreas, also known as pancreatic neuroendocrine tumors, constitute less than 5% of pancreatic tumors, and 7% of all neuroendocrine tumors. Most are non-functional, and patients often present with metastatic disease. Functional tumors present with distinct clinical syndromes. Accurate staging is critical as surgery is both the cornerstone of treatment, and the only hope for cure. Medical management involves treating the manifestations of hormonal excess, and using somatastatin analogues when appropriate. Systemic chemotherapy, targeted molecular therapy, and peptide receptor radiotherapy may be used for refractory disease in lieu of or as an adjunct to surgery.

van Asselt SJ, Brouwers AH, van Dullemen HM, et al.
Potential value of EUS in pancreatic surveillance of VHL patients.
Eur J Endocrinol. 2016; 174(5):611-20 [PubMed] Related Publications
BACKGROUND: Patients with von Hippel-Lindau (VHL) disease are prone to develop pancreatic neuroendocrine tumors (pNETs). However, the best imaging technique for early detection of pNETs in VHL is currently unknown. In a head-to-head comparison, we evaluated endoscopic ultrasound (EUS) and (11)C-5-hydroxytryptophan positron emission tomography ((11)C-5-HTP PET) compared with conventional screening techniques for early detection of pancreatic solid lesions in VHL patients.
METHODS: We conducted a cross-sectional, prospective study in 22 patients at a tertiary care university medical center. Patients with VHL mutation or with one VHL manifestation and a mutation carrier as first-degree family member, with recent screening by abdominal computed tomography (CT) or magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS), were eligible. Patients underwent EUS by linear Pentax echoendoscope and Hitachi EUB-525, and (11)C-5-HTP PET. Patient-based and lesion-based positivity for pancreatic solid lesions were calculated for all imaging techniques with a composite reference standard.
RESULTS: In 10 of the 22 patients, 20 pancreatic solid lesions were detected: 17 with EUS (P < 0.05 vs CT/MRI+ SRS), 3 with (11)C-5-HTP PET, 3 with SRS, 9 with CT/MRI, and 9 with CT/MRI + SRS. EUS evaluations showed solid lesions with a median size of 9.7 mm (range 2.9-55 mm) and most of them were homogeneous, hypoechoic, isoelastic, and hypervascular. Moreover, EUS detected multiple pancreatic cysts in 18 patients with a median of 4 cysts (range 1-30).
CONCLUSIONS: EUS is superior to CT/MRI + SRS for detecting pancreatic solid lesions in VHL disease.(11)C-5-HTP PET has no value as a screening method in this setting. EUS performs well in early detection of pNETs, but its role in VHL surveillance is unclear.

Tsimafeyeu I
Sunitinib treatment of metastatic renal cell carcinoma in von Hippel-Lindau disease.
J Cancer Res Ther. 2015 Oct-Dec; 11(4):920-2 [PubMed] Related Publications
Von Hippel-Lindau disease (VHL) is a major heritable renal cell cancer (RCC) syndrome. 24-45% of VHL patients have a cumulative risk to develop RCC. The management of VHL has changed significantly as clinicians have learned how to best balance the risk of cancer dissemination while minimizing renal morbidity. Despite the improving management of this disease, there are no evidence-based guidelines of the treatment of localized and advanced RCC in VHL. Here, we describe a 39-year-old patient with VHL disease who developed metastatic RCC and received sunitinib with complete remission.

Pires DE, Chen J, Blundell TL, Ascher DB
In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity.
Sci Rep. 2016; 6:19848 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
Despite interest in associating polymorphisms with clinical or experimental phenotypes, functional interpretation of mutation data has lagged behind generation of data from modern high-throughput techniques and the accurate prediction of the molecular impact of a mutation remains a non-trivial task. We present here an integrated knowledge-driven computational workflow designed to evaluate the effects of experimental and disease missense mutations on protein structure and interactions. We exemplify its application with analyses of saturation mutagenesis of DBR1 and Gal4 and show that the experimental phenotypes for over 80% of the mutations correlate well with predicted effects of mutations on protein stability and RNA binding affinity. We also show that analysis of mutations in VHL using our workflow provides valuable insights into the effects of mutations, and their links to the risk of developing renal carcinoma. Taken together the analyses of the three examples demonstrate that structural bioinformatics tools, when applied in a systematic, integrated way, can rapidly analyse a given system to provide a powerful approach for predicting structural and functional effects of thousands of mutations in order to reveal molecular mechanisms leading to a phenotype. Missense or non-synonymous mutations are nucleotide substitutions that alter the amino acid sequence of a protein. Their effects can range from modifying transcription, translation, processing and splicing, localization, changing stability of the protein, altering its dynamics or interactions with other proteins, nucleic acids and ligands, including small molecules and metal ions. The advent of high-throughput techniques including sequencing and saturation mutagenesis has provided large amounts of phenotypic data linked to mutations. However, one of the hurdles has been understanding and quantifying the effects of a particular mutation, and how they translate into a given phenotype. One approach to overcome this is to use robust, accurate and scalable computational methods to understand and correlate structural effects of mutations with disease.

Wofford J, Fenves AZ, Jackson JM, et al.
The spectrum of nephrocutaneous diseases and associations: Genetic causes of nephrocutaneous disease.
J Am Acad Dermatol. 2016; 74(2):231-44; quiz 245-6 [PubMed] Related Publications
There are a significant number of diseases and treatment considerations of considerable importance relating to the skin and renal systems. This emphasizes the need for dermatologists in practice or in clinical training to be aware of these associations. Part I of this 2-part continuing medical education article reviews the genetic syndromes with both renal and cutaneous involvement that are most important for the dermatologist to be able to identify, manage, and appropriately refer to nephrology colleagues. Part II reviews the inflammatory syndromes with relevant renal manifestations and therapeutic agents commonly used by dermatologists that have drug-induced effects on or require close consideration of renal function. In addition, we will likewise review therapeutic agents commonly used by nephrologists that have drug-induced effects on the skin that dermatologists are likely to encounter in clinical practice. In both parts of this continuing medical education article, we discuss diagnosis, management, and appropriate referral to our nephrology colleagues in the context of each nephrocutaneous association. There are a significant number of dermatoses associated with renal abnormalities and disease, emphasizing the need for dermatologists to be keenly aware of their presence in order to avoid overlooking important skin conditions with potentially devastating renal complications. This review discusses important nephrocutaneous disease associations with recommendations for the appropriate urgency of referral to nephrology colleagues for diagnosis, surveillance, and early management of potential renal sequelae.

Johansson G, Andersson U, Melin B
Recent developments in brain tumor predisposing syndromes.
Acta Oncol. 2016; 55(4):401-11 [PubMed] Related Publications
The etiologies of brain tumors are in the most cases unknown, but improvements in genetics and DNA screening have helped to identify a wide range of brain tumor predisposition disorders. In this review we are discussing some of the most common predisposition disorders, namely: neurofibromatosis type 1 and 2, schwannomatosis, rhabdoid tumor predisposition disorder, nevoid basal cell carcinoma syndrome (Gorlin), tuberous sclerosis complex, von Hippel-Lindau, Li-Fraumeni and Turcot syndromes. Recent findings from the GLIOGENE collaboration and the newly identified glioma causing gene POT1, will also be discussed. Genetics. We will describe these disorders from a genetic and clinical standpoint, focusing on the difference in clinical symptoms depending on the underlying gene or germline mutation. Central nervous system (CNS) tumors. Most of these disorders predispose the carriers to a wide range of symptoms. Herein, we will focus particularly on tumors affecting the CNS and discuss improvements of targeted therapy for the particular disorders.

Sekkouri KA, Alaoui SR, Batta F, et al.
Dizziness and renal failure revealing the Von Hippel Lindau disease.
Saudi J Kidney Dis Transpl. 2015; 26(6):1266-9 [PubMed] Related Publications
The germinal mutation of the Von Hippel Lindeau (VHL) tumor suppressor gene predisposes to the development of benign or malignant richly vascularized tumors. VHL disease is an autosomal-dominant disorder with complete penetrance at the age of 60 years. Screening for people at risk is strongly recommended, and careful monitoring allows treatment of the tumor lesions as early as possible. A 42-year-old man sought medical consult for hematuria, disabling dizziness and balance disorders lasting for two months. The neurological examination revealed the presence of a kinetic cerebellar syndrome. The cerebro-spinal magnetic resonance imaging revealed multiple hemangioblastomas, both encephalic and medullar. Abdominal computed tomography revealed a big solid mass in the left kidney and multiple intra-parenchymal cystic lesions in the right kidney and the pancreas. The diagnosis of VHL disease was strongly suspected. The operative indication of brain damage and renal mass have been submitted. The pathological study of the renal surgical specimen revealed a clear cell carcinoma. The post-operative course was uneventful and all the symptoms have disappeared. Genetic study and close follow-up are recommended for this disease.

Valero E, Rumiz E, Pellicer M
Cardiac Involvement in Von Hippel-Lindau Disease.
Med Princ Pract. 2016; 25(2):196-8 [PubMed] Related Publications
OBJECTIVE: The aim of this case report was to highlight the importance of ruling out pheochromocytoma in a patient with Von Hippel-Lindau disease (VHL) and cardiovascular manifestations.
CLINICAL PRESENTATION AND INTERVENTION: A 22-year-old woman with type IIb VHL presented with signs and symptoms of acute decompensated heart failure. Transthoracic echocardiography showed a dilated left ventricle with severely depressed ejection fraction, confirmed by MRI. Urinary catecholamine and metanephrine tests had elevated levels and an abdominal MRI showed the presence of two cystic masses at the left hypochondrium. Surgical resection of both masses was performed, confirming the diagnosis of pheochromocytoma and clear cell renal carcinoma on histology. Six-month echocardiography showed a left ventricle with normal diameters and preserved ejection fraction. Genetic analysis revealed a germline mutation (exon 3 deletion of VHL). As there was no family history of VHL, it was determined to be a de novo mutation.
CONCLUSION: This case report showed an atypical manifestation in a patient with VHL and underlines the importance of screening for pheochromocytoma in such patients.

Chittiboina P, Lonser RR
Von Hippel-Lindau disease.
Handb Clin Neurol. 2015; 132:139-56 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
von Hippel-Lindau (VHL) disease is an inheritable condition with an incidence of 1 in 36000 live births. Individuals with VHL develop benign and malignant tumors including retinal and central nervous system hemangioblastomas, clear cell renal cell carcinomas (RCC), pheochromocytomas, pancreatic neuroendocrine tumors and endolymphatic sac tumors (ELSTs). VHL is caused by germline loss of function of the VHL gene on one allele at chromosome 3p25-26. A somatic "second hit" event leads to the loss of the other allele and tumor formation. Loss of VHL function in cells leads to increased expression and stabilization of hypoxia inducible factor (HIF). VHL protein/HIF pathway has been implicated in tumorigenesis for hemangioblastomas, RCC and other VHL tumors. Clinical examination, imaging, and genetic testing for VHL mutations confirm VHL disease. Management of VHL disease largely consists of surgical resection of symptomatic tumors (hemangioblastomas), tumors prone to metastasize (RCC larger than 3cm), or tumors causing hormonal symptoms (pheochromocytomas). Despite advances in early diagnosis and management of VHL disease, life expectancy for VHL patients remains low at 40-52 years. Secondary effects from VHL manifestations are mitigated by routine surveillance and early detection. In this chapter, we summarize the current state of knowledge in VHL disease.

Yu F, Das N, Singh AK
Cerebellar Hemangioblastoma and Pancreatic Cysts in a Case of von Hippel-Lindau Disease.
J Pediatr. 2016; 168:251-e1 [PubMed] Related Publications

Huntoon K, Wu T, Elder JB, et al.
Biological and clinical impact of hemangioblastoma-associated peritumoral cysts in von Hippel-Lindau disease.
J Neurosurg. 2016; 124(4):971-6 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
OBJECTIVE: 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.

Leong KG, Kanellis J, Mulley WR
Transplant considerations in a man with von Hippel-Lindau disease with bilateral renal cell carcinoma and a pancreatic neuroendocrine tumour.
Nephrology (Carlton). 2015; 20(12):956-7 [PubMed] Related Publications

Migliorini D, Haller S, Merkler D, et al.
Recurrent multiple CNS hemangioblastomas with VHL disease treated with pazopanib: a case report and literature review.
CNS Oncol. 2015; 4(6):387-92 [PubMed] Related Publications
Hemangioblastoma is a rare benign neoplasm, accounting for less than 2% of all primitive brain tumors. It may arise sporadically in a solitary form, or associated with Von Hippel-Lindau (VHL) disease with multiple tumors. Surgery is the mainstay treatment, but management is challenging in case of recurrent and/or multiple tumors. VHL protein is defective in both forms of hemangioblastoma, leading to the accumulation of hypoxia-inducible factor, stimulating angiogenesis via VEGF and PDGF mainly. Here, we report a 37-year-old woman's case with recurrent and rapidly progressive VHL-associated hemangioblastomas, causing severe disability. She was treated 24 months with pazopanib, a multityrosine kinase inhibitor (TKI) targeting VEGF and PDGF-β pathways. Despite moderate radiological changes, progressive improvement in her clinical condition persisting over 3 years was observed. Inhibiting angiogenesis is a therapeutic option that may improve the quality of life and the autonomy of VHL patients disabled with multiple hemangioblastomas.

Umehara Y, Umehara M, Tokura T, et al.
[A Case of Von Hippel-Lindau Disease with Nonfunctioning Pancreatic Neuroendocrine Tumors Treated by Duodenum-Preserving Resection of the Head of the Pancreas and Spleen-Preserving Resection of the Tail of the Pancreas].
Gan To Kagaku Ryoho. 2015; 42(10):1325-7 [PubMed] Related Publications
A 26-year-old woman presented to our department with a diagnosis of multiple nonfunctioning pancreatic neuroendocrine tumors. She had a family history of pheochromocytoma and a medical history of bilateral adrenalectomy for pheochromocytoma at the age of 25 years. During follow-up treatment for adrenal insufficiency after the surgery, highly enhanced tumors in the pancreas were detected on contrast-enhanced CT. Other examinations found that the patient did not satisfy the clinical criteria for von Hippel-Lindau (VHL) disease. Considering her age and risk of developing multiple heterotopic and heterochronous tumors, we performed a duodenum-preserving resection of the head of the pancreas and spleen-preserving resection of the tail of the pancreas with informed consent. The histopathological findings revealed that all of the tumors were NET G1. She underwent genetic testing postoperatively and was diagnosed with VHL disease. This diagnosis meant that we were able to create an optimal treatment plan for the patient. If a tumor predisposition syndrome is suspected, VHL disease should be borne in mind and genetic testing after genetic counseling should be duly considered.

Aufforth RD, Ramakant P, Sadowski SM, et al.
Pheochromocytoma Screening Initiation and Frequency in von Hippel-Lindau Syndrome.
J Clin Endocrinol Metab. 2015; 100(12):4498-504 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
CONTEXT: Patients with von Hippel-Lindau (VHL) syndrome have a 25-30% chance of developing pheochromocytoma. Although practice guidelines recommend biochemical and radiological screening every 1-2 years for pheochromocytoma in patients with VHL, there are limited data on the optimal age and frequency for screening.
OBJECTIVE: Our objective was to determine the earliest age of onset and frequency of contralateral and recurrent pheochromocytomas in patients with VHL syndrome.
METHODS: This is a retrospective analysis of a prospective cohort of patients with VHL enrolled in a natural history study.
RESULTS: A total of 273 patients diagnosed with VHL were enrolled in a natural history clinical study. Thirty-one percent (84) were diagnosed with pheochromocytoma. The mean age of diagnosis was 28.8 ± 13.9 years. The earliest age at diagnosis was 5.5 years. Median follow-up for the cohort was 116.6 months (range, 0.1-613.2). Ninety-nine percent (83) of patients underwent adrenalectomy. Fifty-eight and 32% of patients had metanephrines and/or catecholamines elevated more than two times and more than four times the upper limit of normal, respectively. Twenty-five percent (21) of pheochromocytomas were diagnosed in pediatric patients younger than 19 years of age, and 86% and 57% of pediatric patients had an elevation more than two times and more than four times upper limit of normal, respectively. Eight patients had a total of nine recurrences. The median age at recurrence was 33.5 years (range, 8.8-51.9). Recurrences occurred as short as 0.5 years and as long as 39.7 years after the initial operation.
CONCLUSIONS: Our findings among VHL pediatric patients supports the need for biochemical screening starting at age 5 with annual lifelong screening.

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