scholarly journals Macular Perfusion Impairment in Von Hippel-Lindau Disease Suggests a Generalized Retinal Vessel Alteration

2020 ◽  
Vol 9 (8) ◽  
pp. 2677 ◽  
Author(s):  
Elisabetta Pilotto ◽  
Elisabetta Beatrice Nacci ◽  
Alfonso Massimiliano Ferrara ◽  
Gilda De Mojà ◽  
Stefania Zovato ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Gene Mutations ◽  
Retinal Vessel ◽  
Vessel Diameter ◽  
Von Hippel Lindau ◽  
Length Fraction ◽  
Retinal Capillary ◽  
Von Hippel Lindau Disease ◽  
Vasculogenesis And Angiogenesis ◽  
Vhl Disease

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.

scholarly journals Von Hippel-Lindau Disease and the Eye

2020 ◽  
Author(s):  
Saeed Karimi ◽  
Amir Arabi ◽  
Toktam Shahraki ◽  
Sare Safi
Keyword(s):  
Benign Lesion ◽  
Neovascular Glaucoma ◽  
Capillary Hemangioma ◽  
Ocular Involvement ◽  
Von Hippel Lindau ◽  
Retinal Capillary ◽  
Life Threatening ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease ◽  
Endothelial Growth Factors

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 intra-vitreal injections of anti-vascular endothelial growth factors and propranolol.

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.

von Hippel–Lindau disease and succinate dehydrogenase subunit (SDHB, SDHC, and SDHD) genes

2011 ◽  
pp. 954-959
Author(s):  
Eamonn R. Maher
Keyword(s):  
Succinate Dehydrogenase ◽  
Von Hippel Lindau ◽  
Clinical Phenotypes ◽  
Molecular Features ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease

This chapter considers the clinical and molecular features of von Hippel–Lindau (VHL) disease (OMIM 193300) and mutations in succinate dehydrogenase subunit genes (SDHB (OMIM 115310), SDHC (OMIM 605373), and SDHD (OMIM 168000)). Both disorders are important causes of phaeochromocytoma and, in addition to having overlapping clinical phenotypes, also share some similarities in mechanisms of tumourigenesis.

Endocrine Manifestations of von Hippel–Lindau Disease

2015 ◽  
Vol 139 (2) ◽  
pp. 263-268 ◽  
Author(s):  
Clarissa Cassol ◽  
Ozgur Mete
Keyword(s):  
Neuroendocrine Tumors ◽  
Autosomal Dominant ◽  
Suppressor Gene ◽  
Autosomal Dominant Disorder ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Sporadic Cases ◽  
Vhl Disease

von Hippel–Lindau (VHL) disease is an autosomal dominant disorder caused by heterozygous mutations in the VHL tumor suppressor gene that is characterized by the occurrence of multiple endocrine and nonendocrine lesions. This review focuses on the endocrine manifestations of VHL disease. Pancreatic neuroendocrine proliferations (ductuloinsular complexes, islet dysplasia, endocrine microadenoma, and neuroendocrine tumors), pheochromocytomas, and extra-adrenal paragangliomas are important endocrine manifestations of VHL disease. They frequently display characteristic clinical, biochemical, and histopathologic features that, although not pathognomonic, can be helpful in suggesting VHL disease as the underlying etiology and distinguishing these tumors from sporadic cases. Recent improvements in treatment and outcomes of renal cell carcinomas have allowed pancreatic neuroendocrine tumors to emerge as a significant source of metastatic disease, making the accurate recognition and classification of these neoplasms by the pathologist of utmost importance to determine prognosis, treatment, and follow-up strategies for affected patients.

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.

scholarly journals von Hippel-Lindau Disease: an Update

2019 ◽  
Vol 7 (4) ◽  
pp. 227-235 ◽  
Author(s):  
Eamonn R Maher ◽  
Richard N Sandford
Keyword(s):  
Natural History ◽  
Patient Outcomes ◽  
Molecular Characterisation ◽  
Von Hippel Lindau ◽  
Functional Characterisation ◽  
History Of ◽  
Vhl Protein ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease ◽  
Improve Patient

Abstract Purpose of Review In this review, we discuss the key molecular and clinical developments in VHL disease that have the potential to impact on the natural history of the disease and improve patient outcomes. Recent Findings Identifiable mutations in VHL underlie most cases of VHL and define clear genotype-phenotype correlations. Detailed clinical and molecular characterisation has allowed the implementation of lifelong screening programmes that have improved clinical outcomes. Functional characterisation of the VHL protein complex has revealed its role in oxygen sensing and the mechanisms of tumourigenesis that are now being exploited to develop novel therapies for VHL and renal cancer. Summary The molecular and cellular landscape of VHL-associated tumours is revealing new opportunities to modify the natural history of the disease and develop therapies. Drugs are now entering clinical trials and combined with improved clinical and molecular diagnosis, and lifelong surveillance programmes, further progress towards reducing the morbidity and mortality associated with VHL disease is anticipated.

Phase II study of pazopanib in patients with von Hippel-Lindau disease.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4516-4516 ◽  
Author(s):  
Eric Jonasch ◽  
Dan S. Gombos ◽  
Steven G. Waguespack ◽  
Valerie Marcott ◽  
Diane D Liu ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Clinical Features ◽  
Surgical Intervention ◽  
Standards Of Care ◽  
Common Side Effect ◽  
Drug Discontinuation ◽  
Best Interest ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease

4516 Background: Von Hippel-Lindau disease (VHL) is an autosomal dominant inherited disorder. Affected individuals develop vascular neoplastic lesions in multiple sites including eye, brain, pancreas, adrenal and kidney. Standards of care include surveillance imaging and surgical intervention. We hypothesized that treatment of VHL related lesions with an antiangiogenic agent would result in shrinkage of all lesion types. We chose the multikinase inhibitor pazopanib to test this hypothesis. Methods: After obtaining IRB approval, patients with clinical features or genetic confirmation of VHL disease and with measurable lesions were treated with pazopanib 800mg PO daily for two 12-week cycles. Efficacy was determined by RECIST after two cycles. Patients had the option to continue therapy if considered in patient’s best interest. Continuous monitoring for any lesion progression and drug discontinuation due to toxicity during the whole period of the treatment was planned. Results: Patients were enrolled (N=32) and treated (N=31) between 1/2012 and 6/2016. Median age was 37 (range 19-67). 23 patients had genomically confirmed VHL disease; four had family and personal history but had not undergone genetic testing, and five patients had clinical features of VHL disease and negative genetic testing. A median of two cycles (range 1-12) of therapy was administered. Of 31 evaluable patients, 13 (42%) showed a response, 18 patients had stable disease and no patients had PD as best response. Responses were seen in renal (2 CR and 29 PR/59 total), pancreatic (9 PR/17 total) and CNS 2 PR/49 total) target lesions. The most common side effect was diarrhea (grades 1 and 2) experienced in 14 patients. Twelve patients dose reduced to 600 mg and 6 to 400 mg pazopanib PO daily. Eight patients discontinued therapy due to adverse events of whom 4 experienced transaminitis. One patient experienced a grade V CNS hemorrhage. Conclusions: This is the largest prospective VHL disease specific therapeutic study performed to date. Pazopanib resulted in significant and sustained disease control for the majority of VHL patients enrolled on the study, with an acceptable safety profile. This agent may be considered as an alternative to surgical intervention in patients with VHL disease. Clinical trial information: NCT01436227.

scholarly journals Oral Propranolol in Von Hippel Lindau Ocular Affection

2021 ◽  
Author(s):  
BEATRIZ GONZÁLEZ-RODRÍGUEZ ◽  
MARIA GONZÁLEZ-RODRÍGUEZ ◽  
NATALIA BEJARANO RAMÍREZ ◽  
ROSA MARÍA JIMÉNEZ ESCRIBANO ◽  
FRANCISCO JAVIER REDONDO CALVO
Keyword(s):  
Visual Acuity ◽  
Malignant Tumors ◽  
Anterior Segment ◽  
First Year ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Promising Treatment ◽  
Vhl Disease ◽  
Oral Propranolol

Abstract Purpose. von Hippel Lindau (VHL) disease is a familiar syndrome associated with benign and malignant tumors. These tumors appear in the retina, cerebellum, spinal cord, and kidney. Retinal hemangioblastomas are one of the earliest and most frequent manifestations of this entity, and they can lead to blindness at a young age. Propranolol could be a promising treatment for retinal hemangioblastomas in von Hippel Lindau disease. Methods. Prospective cohort study. Seven patients with VHL disease and ocular affection that had rejected conventional treatment were included. Prospective analysis of seven patients was performed. We evaluated them for three years, with a complete ophthalmic evaluation that included: visual acuity, intraocular pressure, an examination of the anterior segment of the eye, fundoscopy, retinography, and optical coherence tomography (OCT). Heart rate and blood pressure on each patient were also measured. During the follow-up evaluation, two patients discontinued the treatment with propranolol after the first year and rejected any further treatment for their ocular affection; the rest continued therapy for the three years. Results: Visual acuity and tumor areas remained stable in 4 patients. Increased and new retinal exudation area was found in the two patients that discontinued the treatment with oral propranolol. Conclusions: Oral propranolol has shown a role in the reabsorption of retinal exudates in patients with von Hippel Lindau affection. It could delay or stabilize the ocular disease, maintaining visual acuity, and avoiding further complications in these patients. It is a well-known and available drug, without so many secondary effects, that could also have a role in other ocular diseases that course with exudation.

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