Search Results (10)

von Hippel–Lindau syndrome (VHLS) is a hereditary cancer syndrome with CNS hemangioblastomas, clear cell renal carcinoma, pheochromocytoma, retinal angiomas, and a number of other manifestations. VHLS is caused by a mutation in the VHL gene and is inherited in an autosomal dominant manner. However, some cases of VHLS develop de novo, and among them, there are rare patients with a mosaic form of the disease. Genetic testing in mosaic patients is prone to false-negative results due to the low copy number of a mutant allele in DNA isolated from the blood. We describe a case of molecular genetic diagnostics of VHLS in a 39-year-old patient using various methods, including mutation analysis in asynchronous primary tumors and repeated DNA analysis from blood using NGS with high coverage for the mutant position. As a result, the patient was diagnosed with a mosaic form of VHLS caused by the variant c.481C>T (p.Arg161Ter), the proportion of which in the blood DNA was 2%. We also summarized the literature data on the mosaic form of VHLS: the severity of clinical manifestations, the features of differential diagnostics of VHLS with a negative result of routine molecular genetic VHL testing, and specific options of active surveillance and treatment for mutation carriers. Full article

Purpose: To delineate the genotype and phenotype of RH in a Chinese cohort. Methods: A group of 51 Chinese probands with RH across 76 eyes was assembled and underwent complete retinal imaging examinations. Sanger sequencing and universal primer quantitative fluorescent multiplex–polymerase chain reaction (UPQFM-PCR) were employed for mutation detection in the coding region of the Von Hippel–Lindal (VHL) gene. For frequency calculation, our series was combined with three large cohorts of East Asian descent through a literature review. Results: The Von Hippel–Lindal (VHL) syndrome was excluded in fifteen patients (median age: 32.00 years) with unilateral solitary RH. Thirty-six patients of younger ages (median: 22.00 years, p = 0.008, Mann–Whitney test) conformed to the diagnostic criteria of the VHL syndrome, and thirty-four patients were genetically confirmed. There were four novel variants identified in the VHL gene. Codons 167, 161 and 86 exhibited a mutation occurrence of more than 5% after pooling with literature data, and the large genomic deletion demonstrated a frequency of 17.65%. The RHs were classified as “extrapapillary”, “juxtapapillary” and “mixed” types in 53, 7 and 5 eyes, respectively. Almost all extrapapillary RH lesions were found in the peripheral retina. Hemangioblastomas in the central nervous system (CNS) were observed in 25 out of 31 kindreds (80.65%) with full systemic evaluation data. Conclusions: VHL-associated RH might exhibit earlier onset than non-VHL RH. Large genomic deletions were observed at a notably high frequency in the Chinese series with VHL-associated RH, which might be associated with East Asian ethnicity background. RH could potentially serve as an early indicator of CNS hemangioblastoma. Full article

(1) Background: Hemangiomas in Von Hippel-Lindau (VHL) syndrome patients are typically benign but pose threats due to their vital locations involving the central nervous system and the retina. An MRI is currently recommended as the gold standard for tumors associated with VHL in the head region. This narrative review aims to comprehensively outline current standards and recent findings related to imaging of retinal and CNS hemangiomas in Von Hippel-Lindau syndrome. (2) Material and Methods: A review in adherence to PRISMA guidelines using the search string “Von Hippel-Lindau hemangioblastoma imaging” was conducted on PUBMED and SCOPUS databases. (3) Results: After reviewing 455 titles and abstracts, 20 publications fulfilling the inclusion criteria were analyzed. The analysis included studies describing MRI, CT, optical coherence tomography, and PET/CT. (4) Conclusion: While MRI remains the gold standard for diagnosing head tumors in Von Hippel-Lindau syndrome, various PET/CT methods show promise as alternative imaging modalities. Full article

Von Hippel–Lindau (VHL) is a rare autosomal dominant hereditary cancer predisposition syndrome. Patients with VHL have a high risk for developing retinal and central nervous system hemangioblastoma, pheochromocytoma, renal cell carcinoma, and pancreatic neuroendocrine neoplasms (PNEN). About a fifth of patients with VHL will develop PNEN, and only a tenth of them will develop metastatic or unresectable (advanced) PNEN requiring medical intervention. In this review, we performed a literature search for studies, written in English, on the medical interventions for VHL-related localized and advanced PNENs and their clinical outcomes. We detail the various medical interventions for this rare group of patients, including their mode of action and potential efficacy and toxicity. Finally, based on the current literature, we delineate a possible management algorithm for patients with VHL and advanced PNEN. We can conclude that data on the efficacy of various vascular endothelial growth factor (VEGF) receptor inhibitors, and on the efficacy of belzutifan, a novel hypoxia-inducible factor 2 inhibitor, for the management of advanced PNEN in VHL, are scarce. Hence, deduction from the management of sporadic PNEN is required, and is implemented in the proposed management algorithm provided within this review. Full article

Von Hippel-Lindau disease (VHL disease or VHL syndrome) is a familial multisystem neoplastic syndrome stemming from germline disease-associated variants of the VHL tumor suppressor gene on chromosome 3. VHL is involved, through the EPO-VHL-HIF signaling axis, in oxygen sensing and adaptive response to hypoxia, as well as in numerous HIF-independent pathways. The diverse roles of VHL confirm its implication in several crucial cellular processes. VHL variations have been associated with the development of VHL disease and erythrocytosis. The association between genotypes and phenotypes still remains ambiguous for the majority of mutations. It appears that there is a distinction between erythrocytosis-causing VHL variations and VHL variations causing VHL disease with tumor development. Understanding the pathogenic effects of VHL variants might better predict the prognosis and optimize management of the patient. Full article

Von Hippel-Lindau (VHL) syndrome is a rare inherited cancer disease where the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HBs), CNS-HBs, and clear cell renal cell carcinoma (ccRCC). Since standard therapies in VHL have shown limited response, leaving surgery as the only possible treatment, targeting of the β2-adrenergic receptor (ADRB2) has shown therapeutic antitumor benefits on VHL-retinal HBs (clinical trial), VHL-CNS HBs, and VHL-ccRCC (in vitro and in vivo). In the present study, we wanted to look deep into the effects of the ADRB2 blockers propranolol and ICI-118,551 on two main aspects of cancer progression: (i) the changes on the inflammatory response of ccRCC cells; and (ii) the modulation on the Warburg effect (glycolytic metabolism), concretely, on the expression of genes involved in the cell reactive oxygen species (ROS) balance and levels. Accordingly, in vitro studies with primary VHL-ccRCC and 786-O cells measuring ROS levels, ROS-expression of detoxifying enzymes, and the expression of p65/NF-κB targets by RT-PCR were carried out. Furthermore, histological analyses of ccRCC samples from heterotopic mouse xenografts were performed. The obtained results show that ADRB2 blockade in ccRCC cells reduces the level of oxidative stress and stabilizes the inflammatory response. Thus, these data further support the idea of targeting ADRB2 as a promising strategy for the treatment of VHL and other non-VHL tumors. Full article

Background: Von Hippel–Lindau (VHL) disease is a neoplastic syndrome caused by a mutation of the VHL tumor suppressor gene. Retinal hemangioblastoma (RH) is a vascularized tumor and represents the most common ocular manifestation of this disease. At the retinal level, VHL protein is able to regulate tumor growth, angiogenic factors, and neuroinflammation, probably stimulating retinal glial cells. The aim of the present study was to analyze in vivo the optical coherence tomography (OCT) biomarkers of retinal macroglia and microglia in a cohort of VHL patients. Methods: The mean thicknesses of macular retinal nerve fiber layer (mRNFL), ganglion cell layer (GCL), and peripapillary retinal nerve fiber layer (pRNFL) were measured with OCT as biomarkers of retinal macroglia. OCT images were also analyzed to detect and quantify hyperreflective retinal foci (HRF), a biomarker of retinal activated microglia. Results: 61 eyes of 61 VHL patients (22 eyes (36.07%) with peripheral RH and 39 eyes (63.93%) without RH) and 28 eyes of 28 controls were evaluated. pRNFL was thinner in VHL patients (p < 0.05) and in VHL without RH (p < 0.01) compared to controls, and thicker in VHL patients with RH than in those without RH (p < 0.05). The thickness of mRNFL (p < 0.0001) and GCL (p < 0.05) was reduced in VHL patients and in VHL without RH compared to controls, whereas mRNFL (p < 0.0001) and GCL (p < 0.05) were increased in VHL patients with RH compared to those without RH. HRF were significantly higher in number in VHL patients and in VHL without RH, than in controls, and significantly lower (p < 0.05) in the eyes of VHL patients with RH, than in those without RH. Conclusions: The OCT analysis, which detects and allows to quantify the biomarkers of retinal microglia (HRF) and macroglia (pRNFL, mRNFL and GCL), showed a different behavior of these two retinal glial cells populations in VHL patients, related to the presence or absence of peripheral RH. These data allow to hypothesize a novel pathophysiologic pathway of retinal hemangioblastoma in VHL disease. Full article

Von Hippel–Lindau (VHL), is a rare autosomal dominant inherited cancer in which the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HB), CNS-HB, and clear cell renal cell carcinoma (ccRCC). ccRCC ranks third in terms of incidence and first in cause of death. Standard systemic therapies for VHL-ccRCC have shown limited response, with recurrent surgeries being the only effective treatment. Targeting of β2-adrenergic receptor (ADRB) has shown therapeutic antitumor benefits on VHL-retinal HB (clinical trial) and VHL-CNS HB (in vitro). Therefore, the in vitro and in vivo antitumor benefits of propranolol (ADRB-1,2 antagonist) and ICI-118,551 (ADRB-2 antagonist) on VHL^−/− ccRCC primary cultures and 786-O tumor cell lines have been addressed. Propranolol and ICI-118,551 activated apoptosis inhibited gene and protein expression of HIF-2α, CAIX, and VEGF, and impaired partially the nuclear internalization of HIF-2α and NFĸB/p65. Moreover, propranolol and ICI-118,551 reduced tumor growth on two in vivo xenografts. Finally, ccRCC patients receiving propranolol as off-label treatment have shown a positive therapeutic response for two years on average. In summary, propranolol and ICI-118,551 have shown antitumor benefits in VHL-derived ccRCC, and since ccRCCs comprise 63% of the total RCCs, targeting ADRB2 becomes a promising drug for VHL and other non-VHL tumors. Full article

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. Full article

We report the case of a 21-year old woman presenting with high blood pressure and raised normetanephrine levels. Indium-111-pentetreotide single photon-emission computed tomography with computed tomography (SPECT/CT) and 2-deoxy-2-[fluorine-18]fluoro-d-glucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging showing isolated tracer-uptake by a 2 cm tumor close to the costovertebral angle of the third thoracic vertebra. Thoracic surgery led to normalization of normetanephrine levels. Histological findings were consistent with the presence of a paraganglioma. Mutations in SDHA, SDHB, SDHC, SDHD, RET, SDHAF2, TMEM127, MAX, NF1, FH, MDH2, and EPAS1 were absent, but a heterozygous missense mutation, c.311G > T, was found in exon 1 of the von Hippel-Lindau gene, VHL, resulting in a glycine to valine substitution in the VHL protein at position 104, p.Gly104Val. This same mutation was found in both the mother and the 17-year old sister in whom a small retinal hemangioblastoma was also found. We diagnose an unusual functional mediastinal paraganglioma in this young patient with a germline VHL gene mutation, a mutation previously described as inducing polycythemia and/or pheochromocytoma but not paraganglioma or retinal hemangioblastoma. Full article