Von Hipple-Lindau Research Articles

Von Hipple-Lindau disease complicated with central retinal vein occlusion: a case report

BackgroundCentral Retinal Vein Occlusion (CRVO) is a rare complication of von Hipple-Lindau (VHL) disease. This report presents the first case of VHL disease complicated with CRVO caused by VHL c.208G > A mutation.Case presentationA 20 s man whose left eye visual acuity gradually declined for half a year. The visual acuity of the left eye is counting fingers. Fundus examination revealed that retinal hemangioblastoma was also found in addition to typical CRVO signs such as tortuous expansion of retinal veins and flame-shaped hemorrhage of the retina. Liver tumor, cerebral infarction and erythrocytosis were found during systemic examination, and the diagnosis of polycythemia was confirmed by bone marrow smear. Furthermore, both family history and genetic analysis indicated that the patient had VHL disease caused by VHL c.208G > A. In this patient, a large number of bone marrow erythrocytes proliferated due to VHL disease, which led to the increase of blood viscosity and erythrocyte vascular adhesion, resulting in the obstruction of central retinal vein blood flow, and finally CRVO. For CRVO and its pathogenic factor polycythemia, patient received laser retinal photocoagulation and phlebotomies. After a 1-year follow-up, the vision in the left eye improved to 0.2 logMAR.ConclusionsThis is a rare case of polycythemia complicated by CRVO in patient with VHL disease. It reminds us that the systemic disease factors should be fully considered in the diagnosis of young patients with CRVO, and that treatment requires a coordinated effort of physicians.

MON-376 A Novel Mutation in VHL Gene as Posible Cause of Metastasic Pheocromocytoma

A 62-year-old woman with no family history of hereditary diseases presented to the ER department in 2008 with the diagnosis of a subarachnoid hemorrhage that required urgent decompressive craniotomy. On February 2011, due to resistant hypertension, an abdominal CT scan was performed, revealing a left adrenal gland-dependent tumor of 70x86 mm, with additional increased normetanephrine levels in a 24-hour urine sample. Laparoscopic left adrenalectomy was performed on June 3, 2011, with a histological report of pheochromocytoma. It was also documented an elevation of iPTH (301 pg/ml) with corrected calcium of 11 mg/dL and phosphorus of 2.7 mg/dL. Parathyroidectomy was performed with the report of parathyroid adenoma. On January 2015, an abdominal CT scan was performed, revealing recurrence of the pheochromocytoma at the surgical site. A MIBG PET-CT confirmed the recurrence and detected a left retroperitoneal lesion close to the tail of the pancreas. Metastasectomy of the retroperitoneal lesions, distal pancreatectomy, and dissection of tumor adjacent to left kidney were performed with a histopathologic report of pheochromocytoma with nest pattern and extensive necrosis, negative margins, and three positive lymph nodes. During follow-up a significant increase of normetanephrine in 24-hour urine sample was documented (3 months after surgery). A Ga-DOTATOC PET-CT revealed the presence of hepatic metastases. In the 131-MIBG SPECT-CT performed one year later, a decreased height of C3 vertebral body with an abnormal concentration of the radiopharmaceutical in relation to secondary deposit was also found. On August 2017 the patient was treated with a therapeutic dose of 131-MIBG, achieving complete biochemical remission during 14 months of follow-up. On March 2018 an Invitae Multi-Cancer Panel reported the germline variant C. 416C > G (P. Ser139Cys) related to VHL without mutations in other pathogenic genes related to pheochromocytoma. VHL c.416C>G (at the cDNA level ) is a germline variant of Von Hipple Lindau (VHL) disease, also known as p.Ser139Cys (S139C) at the protein level. It results in the change of a Serine to a Cysteine (TCT>TGT), located in 3p25.3. This variant has been reported in population databases (rs587780732, ExAC 0.06%) and related to familiar erythrocytosis, monogenic diabetes (likely benign) and a type of autosomal recessive A1 deafness (uncertain significance); however, to our knowledge it has not been previously published in the literature as a pathogenic nor benign form of the VHL disease. It was also not observed in the NHLBI Exome Sequencing Project that included 6,500 individuals of European and African American ancestry, indicating it is not a common benign variant in these populations. Because of the lack of evidence to determine its role in disease, to date, it is considered a variant of uncertain significance.

Von Hipple-Lindau: Unusual case presentation with peripheral and juxtapapillary retinal hemangioma.

Von Hipple-Lindua (VHL) syndrome is an autosomal dominant neoplastic disorder in which multiple benign or malignant tumours and cysts develop in central nervous system and visceral organs. Retinal capillary hemangioma is the most frequent and often the earliest manifestation of VHL syndrome. We report a case with multisystemic involvement diagnosed as a case of multiple endocrine neoplasia (MEN) syndrome but the presence of multiple, unilateral peripheral and juxtapapillary retinal capillary hemangioma was able to clinche the definative diagnosis of VHL and thus helped in appropriate management of the patient.

882 - Shorter telomere length increases age-related risk of kidney cancer in von Hipple-Lindau disease

882 - Shorter telomere length increases age-related risk of kidney cancer in von Hipple-Lindau disease

VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma

Von Hipple-Lindau gene (VHL) inactivation represents the most frequent abnormality in clear cell renal cell carcinoma (ccRCC). Hypoxia-inducible factor-1α (HIF-1α) expression is regulated by O2 level. In normal O2 conditions, VHL binds HIF-1α and allows HIF-1α proteasomal degradation. A single-nucleotide polymorphism (SNP) has been found located in the oxygen-dependent degradation domain at codon 582 (C1772T, rs11549465, Pro582Ser). In hypoxia, VHL/HIF-1α interaction is abolished and HIF-1α activates target genes in the nucleus. This study analyzes the impact of genetic alterations and protein expression of VHL and the C1772T SNP of HIF-1α gene (HIF-1α) on prognosis in early-stage ccRCC (pT1a, pT1b, and pT2). Mutational analysis of the entire VHL sequence and the genotyping of HIF-1α C1772T SNP were performed together with VHL promoter methylation analysis and loss of heterozygosis (LOH) analysis at (3p25) locus. Data obtained were correlated with VHL and HIF-1α protein expression and with tumor-specific survival (TSS). VHL mutations, methylation status, and LOH were detected in 51, 11, and 12% of cases, respectively. Our results support the association between biallelic alterations and/or VHL silencing with a worse TSS. Moreover, we found a significant association between the HIF-1α C1772C genotype and a worse TSS. The same association was found when testing the presence of HIF-1α protein in the nucleus. Our results highlight the role of VHL/HIF-1α pathway in RCC and support the molecular heterogeneity of early-stage ccRCC. More important, we show the involvement of HIF-1α C1772T SNP in ccRCC progression.

Long-Term Follow-Up Clinical Courses of Cerebellar Hemangioblastoma in von Hippel-Lindau Disease : Two Case Reports and a Literature Review

Although cerebellar hemangioblastomas are histopathologically benign, they yield a degree of malignant clinical behavior in long-term follow-up. We present two cases of long-term progression of renal cell carcinoma, which had been diagnosed as renal cysts during treatment for cerebellar hemangioblastoma. A 14-year-old male with von Hippel-Lindau disease was admitted for a cerebellar hemangioblastoma with multiple spinal hemangioblastomas and a renal cyst. After primary total resection of the cerebellar hemangioblastoma, the patient required two further surgeries after 111 and 209 months for a recurrent cerebellar hemangioblastoma. Furthermore, he underwent radical nephrectomy as his renal cyst had progressed to renal cell carcinoma 209 months after initial diagnosis. A 26-year-old male presented with multiple cerebellar hemangioblastomas associated with von Hippel-Lindau disease and accompanied by multiple spinal hemangioblastomas and multiple cystic lesions in the liver, kidney, and pancreas. He underwent primary resection of the cerebellar hemangioblastoma in association with craniospinal radiation for multiple intracranial/spinal masses. Unexpectedly, a malignant glioma developed 83 months after discovery of the cerebellar hemangioblastoma. At the same time, renal cell carcinoma, which had developed from an initial renal cyst, was diagnosed, and a radical nephrectomy was performed. In the view of long term clinical course, cerebellar hemangioblastoma associated with von Hipple-Lindau disease may redevelop even after primary total resection. In addition, associated lesions such as renal cysts may also progress to malignancy after the passing of a sufficient length of time.

Mutation screening of VHL gene in a family with malignant bilateral pheochromocytoma: from isolated familial pheochromocytoma to von Hippel-Lindau disease

von Hippel-Lindau (vHL) disease is an inherited, autosomal dominant syndrome manifested by a variety of benign and malignant tumors. More than 300 germline VHL mutations have been identified that are involved in VHL disease. A large family (four generations) was evaluated. In this paper we report the presence of a single nucleotide mutation in exon 3 of VHL gene c499 C>T causing substitution of Arginine by Tryptophan at position 167 (R 167 W). It was detected in a family with bilateral malignant pheochromocytoma who has been followed for at least 9 years as RET negative isolated familial pheochromocytoma, finally diagnosed as von Hipple-Lindau disease according to retinal angioma and VHL gene mutation. VHL type 2 presenting with both pheochromocytoma and retinal angioma in this family found to be associated with the new missense mutation (c499 C>T) of VHL gene.

An unusual case of Von Hipple Lindau (VHL) syndrome with bilateral mutlicentric renal cell carcinoma with synchronous solitary urinary bladder metastasis

In VHL syndrome, renal cell carcinoma is distinctive for its early age of onset, for its bilateral and multifocal involvement. Synchronous solitary urinary bladder metastasis from renal cell carcinoma is extremely rare. We report an unusual case of VHL with bilateral multicentric renal cell carcinoma and synchronous solitary urinary bladder metastasis. To the best of our knowledge this is the first case reported in literature with this combination.

Point: Positive effects of intermittent hypoxia (live high:train low) on exercise performance are mediated primarily by augmented red cell volume

Point: Positive effects of intermittent hypoxia (live high:train low) on exercise performance are mediated primarily by augmented red cell volume

Juxtapapillary hemangioma: a case report and review of clinical features and management of von Hippel-Lindau disease

The phakomatose von Hipple-Lindau (VHL) disease is a multisystem disorder characterized by hemangioblastomas of the central nervous system (CNS), retinal angiomas, and multiple cysts and tumors of the viscera. Retinal capillary hemangiomas are the most common manifestation of VHL disease, which can occur in the optic nerve, where it may simulate disc edema, or in the retinal periphery, which is characterized by massive retinal exudation. Both locations can result in progressive accumulation of exudates leading to a decrease in visual acuity and potentially to a serous retinal detachment. A juxtapapillary hemangioma was observed in a 72-year-old man who presented for a routine examination. The patient was asymptomatic, despite the presence of a trace afferent papillary defect. This finding had to be carefully differentiated from sectoral disc edema. Blood tests, computed tomography (CT), and magnetic resonance imaging (MRI) all had normal results. Fluorescein angiography was a valuable secondary test showing early filling of the vascular network overlying the nerve head and characteristic late hyperfluorescence. There are 2 distinct forms of capillary hemangiomas--the juxtapapillary tumor or the peripheral capillary hemangioma. Although both types are similar histologically, they do vary in their appearance, differential diagnosis, and treatment. In both types, fluorescein angiography is an extremely helpful ancillary test in making the initial diagnosis. This case report reviews the ocular manifestations and systemic findings associated with VHL disease.

Vaccine therapy with tumor specific mutated VHL peptides in adult cancer patients with renal cell carcinoma

2589 Background: Chemotherapy in metastatic renal cell carcinoma is ineffective. Although Interferon α and IL-2 have been used with some success, there is a long way to go to achieve satisfactory results. Despite the success of local treatment in early disease, the overall survival is around 50%. Therefore, the development of another therapeutic approach is needed. Human cancers are commonly associated with mutations in oncogenes. These mutated genes produce proteins that are unique to cancer cells. The von Hipple-Lindau (VHL) gene was found to be mutated in 57% of sporadic renal cell carcinomas. 40 - 90% of these mutations are frame shift, 90% of the rest of the mutations are mis-sense point mutations, and very few are nonsense or stop mutations. Novel mutant proteins are processed and displayed as short peptides through HLA molecules on the tumor cell surface. Thus, mutant VHL protein can be an attractive vaccine therapy target. Methods: : In previous clinical trials, vaccination with peptide spanning the patient's mutations in Ras and P53 produced specific immunological responses. Specific lymphocytes, whetherCD4+ or CD8+, were generated that specifically recognized the mutant peptide with which the patient was vaccinated. On this trial, we treated 5 patients with advanced renal carcinoma with 1000 μg of the corresponding mutant VHL peptide mixed with Montanide ISA-51 adjuvant subcutaneously (SQ). Vaccine cycles were repeated every 4 weeks for a total of four vaccinations. Results: No grade 3 or grade 4 toxicities occurred. Grade I-II toxicities resolved spontaneously. Three of five patients showed evidence of lack of progression after four vaccinations (2 ms, 4 ms, 5.5 ms, 8.5ms+, 25ms+) and continued to receive additional vaccinations. Two patients started the vaccinations NED (no evidence of disease) and remained NED. For the first time, specific immunological responses for the mutant VHL peptides have been demonstrated by Elispot assay. Conclusions: We believe that this treatment may form a potentially promising approach in combination with other therapeutic modalities in metastatic renal cell carcinoma. No significant financial relationships to disclose.

Vaccine therapy with tumor specific mutated VHL peptides in adult cancer patients with renal cell carcinoma

2589 Background: Chemotherapy in metastatic renal cell carcinoma is ineffective. Although Interferon α and IL-2 have been used with some success, there is a long way to go to achieve satisfactory results. Despite the success of local treatment in early disease, the overall survival is around 50%. Therefore, the development of another therapeutic approach is needed. Human cancers are commonly associated with mutations in oncogenes. These mutated genes produce proteins that are unique to cancer cells. The von Hipple-Lindau (VHL) gene was found to be mutated in 57% of sporadic renal cell carcinomas. 40 - 90% of these mutations are frame shift, 90% of the rest of the mutations are mis-sense point mutations, and very few are nonsense or stop mutations. Novel mutant proteins are processed and displayed as short peptides through HLA molecules on the tumor cell surface. Thus, mutant VHL protein can be an attractive vaccine therapy target. Methods: : In previous clinical trials, vaccination with peptide spanning the patient's mutations in Ras and P53 produced specific immunological responses. Specific lymphocytes, whetherCD4+ or CD8+, were generated that specifically recognized the mutant peptide with which the patient was vaccinated. On this trial, we treated 5 patients with advanced renal carcinoma with 1000 μg of the corresponding mutant VHL peptide mixed with Montanide ISA-51 adjuvant subcutaneously (SQ). Vaccine cycles were repeated every 4 weeks for a total of four vaccinations. Results: No grade 3 or grade 4 toxicities occurred. Grade I-II toxicities resolved spontaneously. Three of five patients showed evidence of lack of progression after four vaccinations (2 ms, 4 ms, 5.5 ms, 8.5ms+, 25ms+) and continued to receive additional vaccinations. Two patients started the vaccinations NED (no evidence of disease) and remained NED. For the first time, specific immunological responses for the mutant VHL peptides have been demonstrated by Elispot assay. Conclusions: We believe that this treatment may form a potentially promising approach in combination with other therapeutic modalities in metastatic renal cell carcinoma. No significant financial relationships to disclose.

Pheochromocytoma.

Pheochromocytoma is a rare tumor, but it represents a potentially curable form of hypertension. In patients with inherited pheochromocytoma, benign and bilateral tumors are more common. The diagnosis of pheochromocytoma rests in biochemical confirmation of catecholamine excess. Plasma-free metanephrine levels are arguably the most sensitive and specific test for the biochemical diagnosis of pheochromocytoma in high-risk patient populations. A timed 24-hour urine collection for total catecholamines and metabolic products (eg, vanillylmandelic acid and metanephrines) is the favored confirmatory test. Localization is most commonly accomplished with high-resolution computed tomography imaging, but magnetic resonance imaging can also be used. If both of these imaging modalities are nonlocalizing or equivocal, then radiolabeled meta-iodobenzylguanidine or somatostatin can be used to identify an adrenal or extra-adrenal tumor (paraganglioma). These imaging modalities can be used in the evaluation of patients with suspected or confirmed recurrent or metastatic disease. Systemic therapies for the treatment of patients with recurrent or metastatic disease have been disappointing. Radiation therapy is best applied for palliative relief of pain associated with bony metastases. In the absence of radiographic evidence for local tumor invasion, laparoscopic resection of small- to medium-sized (< 6 cm) pheochromocytomas is indicated. Abundant evidence indicates that this approach is safe and well tolerated and results in more rapid recovery and less long-term wound morbidity compared to open anterior or posterior adrenalectomy. Open anterior adrenalectomy is appropriate for patients with large or recurrent tumors, suspected or documented locoregional invasion, or for those patients in whom a laparoscopic approach is technically contraindicated. For selected patients with pheochromocytoma in the von Hipple-Lindau syndrome or multiple endocrine neoplasia type 2 setting in which the cumulative incidence of clinical bilateral tumors is high, a cortical-sparing approach may minimize the risk of Addisonian complications.

Molecular epidemiology of VHL gene mutations in renal cell carcinoma patients: relation to dietary and other factors.

Carcinogenic chemicals act through DNA damage and mitogenic effects. No established mechanism explains the cancer preventive effects, if any, of food items, such as vegetables and fruit. If such data were available, preferably on tumor-initiating genes, the evidence for the protective effects would become stronger. The von Hipple-Lindau (VHL) gene is the tumor suppressor gene predisposing to both sporadic renal cell carcinoma (RCC) and von Hippel-Lindau disease. We have earlier analyzed VHL mutations in RCCs from 102 Swedish patients identified in a case-control study and here examine associations between patient characteristics, including dietary habits and mutations, considering the type of mutation. The results are given as odds ratios (OR), separately for smokers and all patients. In univariate analysis, consumption of vegetables and citrus fruit decreased the frequency of VHL mutations among smokers and citrus fruit among all patients. In multivariate analysis of smokers' characteristics, welding fumes showed a risk of 5.63 for multiple VHL mutations. In smokers, citrus fruit decreased the OR of GC to AT mutations to 0.13 and that of multiple mutations to 0.17; vegetables decreased the OR for single mutations to 0.22. Among all subjects, welding fumes were a risk factor and citrus fruit a protective factor. Additionally, an intake of selenium protected against multiple mutations. The present results provide evidence that the intake of vegetables, selenium and particularly of citrus fruit protects the renal VHL gene from mutational insults that may be endogenous or common in a population. Even though most of the associations are biologically plausible, and vegetables and fruit were an a priori hypothesis, fortuitous results cannot be ruled out in this relatively small study.

Stereotactic multiple arc radiotherapy. IV-haemangioblastoma

Our initial experience in the treatment of haemangioblastoma using conventional external beam radiotherapy and stereotactic radiotherapy (radiosurgery), by the linear accelerator method, is reported. Six haemangioblastomas in five patients were treated with a mean follow-up of 40 months (range 14-60). Five haemangioblastomas in four patients were treated with stereotactic radiotherapy, where four showed complete radiological response and the fifth was static. Neurological symptoms and signs improved in those patients. The sixth haemangioblastoma was situated close to the pituitary and optic chiasm, and was treated with conventionally fractionated external beam radiotherapy. The lesion showed partial response. No complications were noted in this patient group. This series complements and extends the relatively sparse published literature demonstrating that radiotherapy is an effective option for treating haemangioblastomas. Radiosurgery often lends itself particularly well to these discrete lesions allowing highly focused treatment. For patients with multiple and metachronous cerebellar haemangioblastomas as part of the von Hipple-Lindau syndrome, the data support a policy of conventionally fractionated external beam radiotherapy to the whole cerebellum of 50-55 Gy followed, after a period of time, by radiosurgery to persisting lesions (patients 3 and 4).

FAMILIAL PHEOCHROMOCYTOMA IN VON HIPPEL-LINDAU DISEASE

Pheochromocytoma developed in two members (a brother and sister) of a family inheriting von Hipple-Lindau disease is reported. The brother had multiple pheochromocytoma associated with reversible renal artery stenosis. His sister had malignant non-functioning pheochromocytoma with tumor embolus of the portal vein. She died of bleeding from gastric varix.The significance of regular screening including ultrasonography and computed tomography of the abdomen must be emphasized for family members of von Hippel-Lindau disease, because early detection of tumor is indispensable to improve the curability of malignant pheochromocytoma. In this sister' case we should reflect for delayed diagnosis of pheochromocytoma because of lacking screening.