Von Hippel-Lindau Disease: The Importance of Retinal Hemangioblastomas in Diagnosis.
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ABSTRACT:
SUBMITTER: Sahin Atik S
PROVIDER: S-EPMC5468534 | biostudies-other | 2017 Jun
REPOSITORIES: biostudies-other
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Project description:A germline mutation in the Von-Hippel Lindau (VHL) gene predisposes carriers to development of abundantly vascularised tumours in the retina, cerebellum, spine, kidney, adrenal gland and pancreas. Most VHL patients die from the consequences of cerebellar haemangioblastoma or renal cell carcinoma. The VHL gene is a tumour suppressor gene and is involved in angiogenesis by regulation of the activity of hypoxia-inducible factor 1-alpha (HIF1-alpha). Clinical diagnosis of VHL can be confirmed by molecular genetic analysis of the VHL gene, which is informative in virtually all VHL families. A patient with (suspicion for) VHL is an indication for genetic counselling and periodical examination.
| S-EPMC2837060 | biostudies-literature
Project description:Von Hippel-Lindau disease is an autosomal dominant syndrome which occurs secondary to germline mutations in the VHL tumor suppressor gene, located on chromosome 3. Clinically von Hippel-Lindau disease is characterized by an increased risk of developing simple visceral cysts, most commonly in the pancreas and kidneys, in addition to an increased risk of developing neoplasms, often with clear cell features, in a multitude of organ systems. The most common neoplasms are cerebellar and retinal hemangioblastomas, adrenal pheochromocytomas, clear cell renal cell carcinomas, pancreatic neuroendocrine tumors, pancreatic serous cystadenomas, and endolymphatic sac tumors. These lesions most commonly present during adulthood; however, screening and surveillance for the development of these lesions should begin in the pediatric years for patients with von Hippel-Lindau disease. In this review article, the genetics and most common neoplasms of von Hippel-Lindau disease are reviewed, with an eye towards implications for the pediatric patient.
| S-EPMC4918695 | biostudies-literature
Project description:ObjectivesTo characterize the germline mutations found in a large population of persons having von Hippel-Lindau (VHL) disease mutations with the clinical characteristics of associated retinal capillary hemangioblastomas (RCHs), to measure the prevalence of RCHs among patients with VHL disease generally and specifically for each genotype category, to establish genotype-phenotype correlations between genotype category and phenotypic features of ocular VHL disease, and to establish genotype-phenotype correlations between genotype category and visual function.MethodsCross-sectional and molecular genetic study. Of 890 patients with VHL disease, 335 had ocular involvement in the form of RCHs. Statistical analysis was used to correlate the structure of the mutated VHL protein with the ocular phenotype.ResultsThree genotype categories (amino acid substitutions, protein-truncating mutations, and complete deletions of VHL protein) were defined in all patients. The prevalence of RCHs was lowest (14.5%) among patients with complete deletions; the overall prevalence of retinal angiomatosis was 37.2%. Genotype category had no correlation with the unilaterality or bilaterality of ocular disease or with the number or extent of peripheral RCHs. The prevalence of RCHs at the juxtapapillary location was lower among patients with protein-truncating mutations compared with those with amino acid substitutions. Complete deletions were associated with the highest mean visual acuity compared with the other 2 genotype categories.ConclusionPatients with complete deletions of VHL protein have the lowest prevalence of ocular disease and the most favorable visual outcome.Clinical relevanceThe VHL mutation genotype may be used to predict the prevalence and outcome of ocular VHL disease and to guide ophthalmic follow-up.
| S-EPMC3019103 | biostudies-literature
Project description:Retinal hemangioblastoma (also referred to as retinal capillary hemangioma) is a benign lesion originating from the endothelial and glial components of the neurosensory retina and optic nerve head. Historically known as a manifestation of the von Hippel-Lindau (VHL) disease, it can be seen as an isolated finding or in association with some rare ocular conditions. In addition to characteristic ophthalmoscopic features, results of numerous ancillary tests including angiography, ultrasound, optical coherence tomography, and genetic tests may support the diagnosis and differentiate it from similar conditions. Because of serious life-threatening complications of VHL disease, every ocular approach to retinal hemangioblastomas should be in relationship with additional multidisciplinary diagnostic and therapeutic efforts. In addition, any patient with actual or probable diagnosis of VHL disease should be screened for ocular involvement. Unfavorable visual loss can occur early, and ocular complications of VHL range from exudative retinopathy to tractional retinal detachment, neovascular glaucoma, and phthisis bulbi. Accordingly, various treatment methods have been tested with overall acceptable responses, including photocoagulation, cryotherapy, photodynamic therapy, plaque radiotherapy, vitrectomy, and more novel intravitreal injections of anti-vascular endothelial growth factors and propranolol.
| S-EPMC7001024 | biostudies-literature
Project description:BACKGROUND:To evaluate macular perfusion in patients with Von Hippel-Lindau (VHL) disease. METHODS:VHL patients with or without peripheral retinal hemangioblastomas (RHs) were consecutively enrolled. A group of healthy subjects served as controls. Macular perfusion was analyzed by means of OCT angiography (OCTA) in the superficial vascular plexus (SVP), and in the intermediate (ICP) and deep retinal capillary (DCP) plexuses. The following OCTA parameters were measured: Vessel Area Density (VAD), Vessel Length Fraction (VLF), Vessel Diameter Index (VDI) and Fractal Dimension (FD). RESULTS:Sixty-three VHL patients (113 eyes) and 28 healthy controls (56 eyes) were enrolled. All OCTA quantitative parameters were reduced in VHL patients vs. controls, reaching statistical significance for VAD of the SVP (0.348 ± 0.07 vs. 0.369 ± 0.06, p = 0.0368) and VDI of all plexuses (p < 0.03 for all). No significant differences were detected between eyes without or with peripheral RHs. CONCLUSIONS:Macular perfusion is reduced in VHL patients demonstrating retinal vessel changes that are independent of the presence of peripheral RHs. VHL gene mutations disrupt the hypoxia-induced (HIF)/vascular endothelium growth factors (VEGF) pathway and the Notch signaling, both essential for the normal retinal vasculogenesis and angiogenesis. Therefore, an anomalous generalized retinal vascular development may be hypothesized in VHL disease.
| S-EPMC7464479 | biostudies-literature
Project description:ObjectiveCharacterization of the structural and functional progression of ocular von Hippel-Lindau (VHL) disease and analysis of patient factors influencing disease progression.DesignRetrospective analysis of a case series from a longitudinal, observational study.ParticipantsTwo hundred forty-nine participants with clinically defined systemic VHL disease and more than 2 years of ophthalmic follow-up.MethodsStandardized scoring of ocular phenotype and systemic characteristics was performed at each study visit and was analyzed longitudinally to determine progression of ocular VHL disease.Main outcome measuresMeasures evaluated include: visual acuity, features of ocular VHL disease (presence, location, number, and extent of retinal capillary hemangioblastomas [RCHs]), germline mutation in the VHL gene, demographics (age, gender, age at onset of ocular disease), and patient characteristics (smoking status, body mass index).ResultsMost participants demonstrated relative anatomic and functional stability in ocular VHL disease status over a mean follow-up of 8.2 ± 4.0 years. Approximately three quarters (73%) of participants without ocular VHL disease at baseline remained disease free at the end of follow-up. Among eyes with ocular VHL disease at baseline, 88% did not demonstrate RCHs in a new retinal location, 70% remained stable in RCH number, and 79% remained stable in the extent of RCH involvement. Mean visual acuity for all study eyes (n = 498) decreased by 5.1 ± 0.6 letters across follow-up, with 16.1% of study eyes decreasing by more than 10 letters in visual acuity. Among eyes affected at baseline, greater vision loss was associated with the presence of juxtapapillary RCHs, development of RCH in a new location, and increase in peripheral RCH number and extent. Younger baseline age, younger age at onset of ocular VHL disease, involvement of the fellow eye with ocular VHL disease, and missense or protein-truncating germline mutations were associated significantly with increased anatomic involvement and functional deterioration.ConclusionsPatients with ocular VHL disease maintain relative anatomic and functional stability, with only a minority demonstrating marked anatomic progression and vision loss. Systemic and ocular risk factors for anatomic progression and vision loss can help practitioners identify patients with a higher risk profile for counseling, closer follow-up, and proactive treatment.Financial disclosure(s)The author(s) have no proprietary or commercial interest in any materials discussed in this article.
| S-EPMC3504630 | biostudies-literature
Project description:PURPOSE:Von Hippel-Lindau (VHL) disease is a hereditary disorder that can lead to ophthalmic manifestations, including retinal capillary hemangioma (RCH). The diagnosis of RCH is often guided by wide-field fluorescein angiography. In some cases, optical coherence tomography angiography (OCT-A) serves as a non-invasive alternative to FA. Herein, we used OCT-A to examine the macular microvasculature in patients with VHL disease. SUBJECTS:Subjects were selected from patients with a diagnosis of VHL. The control group included eyes without retinal diagnosis from patients with an episode of unilateral retinal detachment or trauma and age ≤ 50 years old. METHODS:Subjects were scanned on the Optovue RTVue-XR device to acquire 3mm x 3mm OCT-A images of the superficial (SCP) and deep capillary plexus (DCP). SCP and DCP vessel density (VD) were calculated after the images were binarized. Furthermore, for subjects with RCH, each OCT-A image was divided equally into four quadrants. SCP and DCP VD of quadrants with RCH were compared to those without RCH. T-tests were performed for statistical analysis. RESULTS:67 eyes with a history of VHL disease were included as study subjects, while 16 eyes were included as controls. Significant increases in VD were found in patients with VHL disease for both the SCP (p = 0.0441) and DCP (p = 0.0344). When comparing quadrants with associated RCH development to those without, we found no significant difference in SCP VD (p = 0.160) or DCP VD (p = 0.484). CONCLUSIONS:OCT-A can detect changes in the retinal microvasculature in the macula of patients with VHL disease. OCT-A imaging may be an additional tool for screening and early detection of patients at risk of developing ocular complications of VHL disease. Future studies should explore subtle progression on OCT-A associated with the pathogenesis and development of RCH, particularly with larger scan patterns.
| S-EPMC7032707 | biostudies-literature
Project description:PurposeTo describe the clinical course of advanced juxtapapillary retinal capillary hemangioblastomas (RCH) associated with von Hippel-Lindau (VHL) disease treated with systemic sunitinib malate, an agent that inhibits both anti-vascular endothelial growth factor and anti-platelet-derived growth factor signaling.DesignObservational case review.ParticipantsThree patients with advanced VHL-related juxtapapillary RCH treated with systemic sunitinib malate.MethodsPatient 1 was followed routinely every 4 months while on systemic sunitinib prescribed by her oncologist for metastatic pancreatic neuroendocrine and kidney tumors. Patients 2 and 3 were part of a prospective clinical trial evaluating the use of systemic sunitinib for ocular VHL lesions during a period of 9 months. Visual acuity, size of RCH, and degree of exudation were recorded at each visit. Optical coherence tomography (OCT) and fluorescein angiography were also obtained at some visits.Main outcome measuresVisual acuity, size of RCH, and degree of exudation.ResultsThree patients with advanced VHL-associated juxtapapillary RCH were treated with systemic sunitinib malate. While none of the patients lost vision during therapy, treatment with sunitinib malate did not improve visual acuity or reduce the size of RCH. Improvements in RCH-associated retinal edema were observed in two patients. All patients experienced multiple adverse effects, including thyroid toxicity, thrombocytopenia, nausea, fatigue, jaundice, and muscle aches. Two of the three patients had to discontinue treatment prematurely and the third required dose reduction.ConclusionsSystemic sunitinib malate may be useful in slowing progression of ocular disease from VHL-associated RCH. However, significant systemic adverse effects limited its use in this small series, and systemic sunitinib malate may not be safe for treatment of RCH when used at the doses described in this report. Further studies are required to determine if this medication used at lower doses with different treatment strategies, other medications in the same class or drugs directed at multiple targets in the tumor, may be safer and more effective for the treatment of advanced VHL-associated RCH.
| S-EPMC5490440 | biostudies-literature
Project description:Pancreatic cysts are a heterogeneous group of lesions, which can be benign or malignant. Due to improved imaging techniques, physicians are more often confronted with pancreatic cysts. Little is known about the origin of pancreatic cysts in general. Von Hippel-Lindau (VHL) disease is an atypical ciliopathy and inherited tumor syndrome, caused by a mutation in the VHL tumor suppressor gene encoding the VHL protein (pVHL). VHL patients are prone to develop cysts and neuroendocrine tumors in the pancreas in addition to several other benign and malignant neoplasms. Remarkably, pancreatic cysts occur in approximately 70% of VHL patients, making it the only hereditary tumor syndrome with such a discernible expression of pancreatic cysts. Cellular loss of pVHL due to biallelic mutation can model pancreatic cystogenesis in other organisms, suggesting a causal relationship. Here, we give a comprehensive overview of various pVHL functions, focusing on those that can potentially explain pancreatic cyst development in VHL disease. Based on preclinical studies, cilia loss in ductal cells is probably an important early event in pancreatic cyst development.
| S-EPMC3579754 | biostudies-literature
Project description:The autosomal dominantly inherited disorder von Hippel-Lindau disease (VHL) is caused by germline mutations in the VHL tumour suppressor gene (TSG). VHL mutations predispose to the development of a variety of tumours (most commonly retinal and central nervous system haemangioblastomas, clear cell renal carcinoma and phaeochromocytomas). Here, we review the clinical and genetic features of VHL disease, briefly review the molecular pathogenesis and outline clinical management and tumour surveillance strategies.
| S-EPMC3110036 | biostudies-literature