Search

von Hippel-Lindau (VHL) is an autosomal-dominant hereditary tumour susceptibility disease associated with pathogenic germline variants in the VHL tumour suppressor gene. VHL patients are at increased risk of developing multiple benign and malignant tumours. Current CLIA-based genetic tests demonstrate a very high detection rate of germline VHL variants in patients with clinical manifestations of VHL. In this report, we describe a large family with canonical VHL manifestations, for which no germline alteration had been detected by conventional germline testing. We identified a novel 291 kb chromosomal inversion involving chromosome 3p in affected family members. This inversion disrupts the VHL gene between exon 2 and exon 3 and is thereby responsible for the disease observed in this family., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Central nervous system hemangioblastomas are the most prevalent manifestation of von Hippel-Lindau (VHL) disease and remain the main cause of mortality. Surgical resection is the primary treatment strategy, but is not always possible, and should be used as restrictively as possible. There is an unmet need for less invasive treatment strategies, such as targeted therapy. Expression of somatostatin receptor 2A (SSTR2A) in VHL-related hemangioblastomas has been described earlier, but the extent of expression in a larger population has yet to be determined. The authors hypothesize that a substantial subset of VHL-related hemangioblastomas show SSTR2A expression, which may serve as a potential new treatment target., Methods: Patients who were surgically treated for a VHL-related hemangioblastoma from 1990 until 2021 at the UMC Utrecht were included. Clinical data was derived from a clinical database. Tissue samples were histopathologically examined with use of hematoxylin and eosin staining, and immunohistochemical analysis of SSTR2A expression was performed., Results: Forty-three tissue samples were obtained from 26 patients. Nine showed strong positivity for SSTR2A expression, whereas 13 showed moderate and 15 sparse expression. Three samples showed no expression of SSTR2A. The distribution showed right-skewedness favoring a strong expression. SSTR2A expression colocalized with endothelial markers and not with stromal cells. Additionally, within-patient variability for SSTR2A expression was described in 14 patients., Conclusion: SSTR2A is expressed in varying degrees in the majority of VHL-related hemangioblastomas. Future treatment with somatostatin analogues or even peptide receptor radionuclide treatment may be considered for SSTR2A-positive cases., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

This scientific report aims to investigate the genotype-phenotype correlations of retinal hemangioblastoma (RH) in von Hippel-Lindau (VHL) disease. The study included 77 patients with genetically confirmed VHL disease who visited an ophthalmology clinic for the evaluation of RH. The presence, location, and size of RH were evaluated, Patients were categorized into three groups based on variants: HIF-1α binding site missense (HM), non-HIF-1α binding site missense (nHM), and truncating (TR) mutations. Fifty-six patients (72.7%) had RH in either eye, and 24 had bilateral RH. Sixteen patients (20.8%) had juxtapapillary RH in either eye. Nine patients had RH ≥ 2.0 disc diameters in size. VHL c.208G>A variant was the most frequent single mutation. Compared with patients having nHM mutations (15 patients) in VHL gene, patients with HM mutations (33 patients) or TR mutations (26 patients) presented a greater number of eyes affected (p = 0.007 and 0.004, respectively), a greater number of RH (p = 0.012 and 0.003, respectively), and more frequent presentation of large RH ≥ 2.0 disc diameters (p = 0.012, and 0.013, respectively). In conclusion, this study provides a deeper understanding of the genetic spectrum of VHL disease in Korean VHL disease and highlights the importance of the location of missense mutations regarding the risk of RH., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hwang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Loss-of-function germline von Hippel-Lindau ( VHL ) tumor suppressor mutations cause VHL disease, which predisposes individuals to kidney cancer, hemangioblastomas, and paragangliomas. The risk that a given VHL disease family will manifest some or all these tumor types is profoundly influenced by the VHL allele it carries. For example, almost all VHL disease families that develop paraganglioma have missense VHL mutations. VHL families with null VHL alleles develop kidney cancer and hemangioblastomas without a high risk of paraganglioma. The latter is surprising because the VHL gene product, pVHL, suppresses the HIF2 transcription factor and gain-of-function HIF2 mutations are also linked to paraganglioma. Paragangliomas arise from the sympathetic or parasympathetic nervous system. Given the lack of human paraganglioma cell lines, we studied the effects of inactivating VHL in neuroblastoma cell lines, which also arise from the sympathetic nervous system. We found that total loss of pVHL function profoundly impairs the fitness of neuroblastoma cell lines in a HIF2-dependent manner both ex vivo and in vivo. This fitness defect can be rescued by pVHL variants linked to paraganglioma, but not by pVHL variants associated with a low risk of paraganglioma. These findings suggest that HIF2 activity above a critical threshold prevents the development of paraganglioma., Competing Interests: Competing interests statement:M.A.-R., N.S.P, and Y.L. declare no competing interests. D.E.R. receives research funding from members of the Functional Genomics Consortium (Abbvie, BMS, Jannsen, Merck), and is a director of Addgene, Inc. W.G.K. has financial interests in Lilly Pharmaceuticals, Fibrogen, Cedilla Therapeutics, Nextech Invest, Tango Therapeutics, Circle Pharma, IconOVir Bio, Casdin Capital, and LifeMine Therapeutics. He also has a royalty interest in the HIF2 inhibitor belzutifan, which is currently being commercialized by Merck.

Background: Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder that predisposes patients to develop multiple cysts and tumors, such as hemangioblastomas (HBs) and clear cell renal cell carcinoma (ccRCC), due to mutations in the VHL tumor suppressor gene. While treatment of HBs varies based on their characteristics and has improved patient survival, it still involves high morbidity and mortality, leading to ongoing debates and studies to refine therapy strategies. Recent developments include the emergence of Belzutifan, a novel inhibitor targeting hypoxia-inducible factor 2α (HIF-2α), which has shown promising results in ongoing trials, particularly for patients not immediately requiring surgery., Methods: This systematic review and meta-analysis aimed to comprehensively evaluate the efficacy and safety of Belzutifan for treating HBs associated with VHL disease. Search was conducted across Medline, Embase, Cochrane, and Web of Science databases. Statistical Analysis was performed, with proportions and 95 % confidence intervals. Statistical analyses were carried out using R Studio., Results: Ten studies were selected, comprising 553 patients. The population mean age was 40 (24-65), and 50 % of the population was formed by males. In terms of proportion, 6 analyses were performed: Disease Stability of 31 % [95 %CI:14 %-47 %; I2 = 2 %]; Disease Progression of 2 %[95 %CI:0 %-9 %; I2 = 0 %]; Partial Response of 75 % [95 %CI:54 %-96 %; I2 = 58 %]. Complete response of 1 % [95 %CI:0 %-7 %; I2 = 0 %];and Side effects, anemia 81 % rate [95 % CI:54 %-100 %; I2 = 94 %], and fatigue rate of 79 % [95 % CI:54 %-100 %;I2 = 94 %]., Conclusion: Results indicate that Belzutifan effectively stabilizes disease, reduces tumor progression, and achieves significant therapeutic responses, although side effects like anemia and fatigue were noted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

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.

Von-Hippel-Lindau (VHL) is a genetic multisystem disorder characterized by visceral cysts and benign and malignant tumors in various organs. Herein, we present the case of a 23-year-old woman with VHL presenting with multiple gastric neuroendocrine neoplasms (gNENs) type 1 in the context of chronic autoimmune gastritis (CAG). Although gNENs are not acknowledged as a typical entity in VHL patients, in the present case, gNENs were composed of neoplastic cells with clear cytoplasm usually seen in tumors related to VHL disease. We additionally performed a literature review on the presence of neuroendocrine clear cell tumors and report on further cases of clear cell NENs. The present case illustrates that clear-cell transformation in gNENs may be due to the dual genetic background of the patient; the real oncogenic stimulus may be more closely related to CAG than to VHL disease accompanied by an interplay between neoplastic and autoimmune processes. Therefore, close monitoring of patients with clear cell NENs appears to be important before excluding VHL disease, even in the context of phenotypically unrelated diseases., (© 2024. The Author(s).)

Von Hippel-Lindau (VHL) disease is a rare genetic syndrome caused by a germline pathogenic variant in one VHL allele. Any somatic event disrupting the other allele induces VHL protein (pVHL) loss of function, ultimately leading to patients developing multiple tumours in multiple organs at multiple timepoints, and reducing life expectancy. Treatment of this complex, rare disease is often fragmented, as patients visit specialist clinicians in isolation at different medical centres. Consequently, patients can receive sub-optimal treatment that results in decreased quality of life and a poor experience of health care systems. In 2021, we established a comprehensive clinical centre at San Raffaele Hospital, Milan, devoted to VHL disease. The centre provides a structured programme for the diagnosis, surveillance and treatment of patients alongside research into VHL disease and involves a multidisciplinary team of dedicated physicians. This programme demonstrates the benefits of care centralization, including concentration of knowledge and services, synergy and multidisciplinary management, improved networking and patient resources, reducing health care costs, and fostering research and innovation. VHL disease provides an ideal model to assess the advantages of centralizing care for rare disease and represents an unparalleled opportunity to broaden our understanding of cancer biology in general., (© 2024. Springer Nature Limited.)

Introduction: Von Hippel-Lindau disease (e.g. VHL) is an autosomal dominant multi-organ cancer syndrome caused by a mutation in the VHL tumour suppressor gene. In this study, we introduce a novel genetic variant found in 11 family members diagnosed initially with isolated Pheochromocytoma. Subsequent findings revealed its association with VHL syndrome and corresponds to the Type 2 C phenotype., Methods: The VHL gene was amplified through the utilisation of the polymerase chain reaction (PCR). PCR fragments were sequenced using bidirectional Sanger sequencing, using BigDye™ Terminator v3.1 Cycle Sequencing Kit, running on the 3500 genetic analyser. Results were assembled and analysed Using Software SeqA and chromas pro., Results: A heterozygous in-frame duplication of three nucleotides, specifically ATG, c.377_379dup; p.Asp126dup in exon 2, was identified in all the patients tested within the pedigree., Conclusion: In this study, we disclose the identification of a novel genetic variant in a Jordanian family, affecting eleven family members with pheochromocytoma associated with VHL disease. This finding underscores the importance of screening family members and contemplating genetic testing for individuals newly diagnosed with pheochromocytoma and could enhance our comprehension of the potential adverse consequences associated with VHL germline mutations.

Background: Patients with von Hippel-Lindau (VHL) disease are at risk of developing tumors in the eye, brain, kidney, adrenal gland, and other organs based on their gene mutations. The VHL tumor suppressor gene contains pathogenic variants responsible for these events. This meta-analysis aims to investigate the genetic differences among the various types of VHL syndrome and their correlation with the location of mutations (exons and domains) in the VHL gene., Method: Papers eligible for publication until September 2023 were identified using the electronic databases of PubMed, Google Scholar, Scopus, and EMBASE. The Random Effect model was utilized to evaluate the genetic differences between type 1 and type 2 VHL syndromes., Results: The prevalence of missense mutations (MSs) was found to be 58.9% in type 1, while it was 88.1% in type 2. Interestingly, the probability of observing MSs in type 1 was 0.42 times lower compared to type 2. The mutation hotspots of the VHL gene were R167Q/W, Y98H, R238W, and S65L, respectively. Although type 2 had a high presentation of Y98H and R238W, it did not have a higher S65L than type 1. The analysis demonstrated a statistically significant higher prevalence of truncated mutations (PTMs) in type 1. Among type 1, large/complete deletions (L/C DELs) were found in 16.9% of cases, whereas in type 2 only 3.7%. This difference was statistically significant with a p-value < 0.001. Overall, the probability of identifying mutations in domain 2 compared to domain 1 was found to be 2.13 times higher in type 1 (p-value < 0.001). Furthermore, the probability of detecting exon 1 in comparison with observing exon 2 in type 1 was 2.11 times higher than type 2 and revealed a statistically significant result (p-value < 0.001). The detection of exon 2 was 2.18 times higher in type 1 (p-value < 0.001). In addition, the likelihood of discovering exon 2 compared with others was significantly lower in type 1 compared with type 2 VHL (OR = 0.63, p-value = 0.015)., Conclusions: We have revealed a comprehensive genetic difference between types 1 and 2 of VHL syndrome. The significant differences in MS, PTMs, L/C DELs, and the location of the mutations between type 1 and type 2 VHL patients in the Asian, European, and American populations emphasize the genetic heterogeneity of the syndrome. These findings may pave the way for the diagnosis, treatment, and further investigation of the mechanisms behind this complex genetic disorder., (© 2024. The Author(s).)

In a subset of patients with renal tumours, multiple primary lesions may occur. Predisposition to multiple primary renal tumours (MPRT) is a well-recognised feature of some inherited renal cancer syndromes. The diagnosis of MPRT should therefore provoke a thorough assessment for clinical and genetic evidence of disorders associated with predisposition to renal tumourigenesis. To better define the clinical and genetic characteristics of MPRT, a systematic literature review was performed for publications up to 3 April 2024. A total of 7689 patients from 467 articles were identified with MPRT. Compared to all patients with renal cell carcinoma (RCC), patients with MPRT were more likely to be male (71.8% versus 63%) and have an earlier age at diagnosis (<46 years, 32.4% versus 19%). In 61.1% of cases MPRT were synchronous. The proportion of cases with similar histology and the proportion of cases with multiple papillary renal cell carcinoma (RCC) (16.1%) were higher than expected. In total, 14.9% of patients with MPRT had a family history of cancer or were diagnosed with a hereditary RCC associated syndrome with von Hippel-Lindau (VHL) disease being the most common one (69.7%), followed by Birt-Hogg-Dubé (BHD) syndrome (14.2%). Individuals with a known or likely genetic cause were, on average, younger (43.9 years versus 57.1 years). In rare cases intrarenal metastatic RCC can phenocopy MPRT. We review potential genetic causes of MPRT and their implications for management, suggest an approach to genetic testing for individuals presenting with MPRT and considerations in cases in which routine germline genetic testing does not provide a diagnosis., (© 2024. The Author(s).)

Introduction: Renal cell carcinoma is one of the ten more common malignant tumors worldwide, with a high incidence and mortality rate. Kidney cancer frequently presents at an advanced stage, and it is almost invariably fatal. Much progress has been made in identifying molecular targets for therapy in the hope of improving survival rates, but still, we have no good markers for early detection or progression of the disease. Von Hippel Lindau syndrome (VHL) is an autosomal dominant cancer hereditary syndrome in which affected individuals are at risk of developing bilateral and multifocal renal cell carcinomas (RCC) as well as other tumors. These patients provide an ideal platform to investigate the potential of urinary exosomal miRNA biomarkers in the early development of ccRCC, as these patients are regularly imaged and tumors are actively monitored until the tumor reaches 3 cm before surgical excision. This allows for pre- and post-surgical urine collection and comparison to excised tumor tissues. Studying different biomarkers in urine can provide comprehensive molecular profiling available to patients and physicians and can be a great source of additional tumor genetic information., Methods: Pre- and postoperative urine samples were obtained from a cohort of VHL patients undergoing surveillance and surgical excision of ccRCCs, and exosomes were extracted. MicroRNA-Seq analysis was performed on miRNA extracted from both urine-derived exosomes and FFPE material from excised ccRCCs., Results: MicroRNA-Seq analysis highlighted a significant difference in the urinary exosome-derived miRNA expression profiles between VHL patients and normal control individuals. This included decreased expression of the miR-320 family, such as miR-320a, known to be decreased in sporadic ccRCC and suppressed by the HIF1α transcription factor activated by the loss of the VHL gene. MiR-542-5p represented a potential marker of VHL-associated ccRCC that was lowly expressed in normal control urinary exosomes, significantly increased in the preoperative urinary exosomes of tumor-bearing VHL patients, and subsequently reduced to normal levels of expression after tumor excision. In concordance with this, the expression of miR-542-5p was increased in the VHL-associated ccRCC in comparison to the normal kidney., Conclusions: This study shows the potential for miRNA profiling of exosomes from readily available biofluids to both distinguish VHL patient urine from normal control urine microRNAs and to provide biomarkers for the presence of VHL syndrome-associated ccRCC. Further validation studies are necessary to demonstrate the utility of urinary exosome-derived miRNAs as biomarkers in kidney cancer.

Purpose: Von Hippel-Lindau (VHL) disease is an autosomal-dominantly inherited tumor predisposition syndrome. One of the most common tumors are central nervous system (CNS) hemangioblastomas. Recommendations on the initiation and continuation of the screening and surveillance program for CNS tumors in pediatric VHL patients are based on small case series and thus low evidence level. To derive more robust screening recommendations, we report on the largest monocentric pediatric cohort of VHL patients., Methods: We performed a retrospective analysis on a pediatric cohort of 99 VHL patients consulted at our VHL center from 1992 to 2023. Clinical, surgical, genetic, and imaging data were collected and statistically analyzed., Results: 42 patients (50% male) developed CNS hemangioblastomas, of whom 18 patients (56% male) underwent hemangioblastoma surgery (mean age at first surgery: 14.9 ± 1.9 years; range 10.2-17). The first asymptomatic patient was operated on at the age of 13.2 years due to tumor progress. Truncating VHL mutation carriers had a significantly higher manifestation rate (HR = 3.7, 95% CI: 1.9-7.4, p < 0.0001) and surgery rate (HR = 3.3, 95% CI: 1.2-8.9, p = 0.02) compared with missense mutation carriers., Conclusion: We recommend starting MRI imaging at the age of 12 years with examination intervals every (1-) 2 years depending on CNS involvement. Special attention should be paid to patients with truncating variants. Affected families should be educated regularly on potential tumor-associated symptoms to enable timely MRI imaging and eventually intervention, as CNS hemangioblastoma may develop before screening begins., German Clinical Trials Register Registration Number: DRKS00029553, date of registration 08/16/2022, retrospectively registered., (© 2024. The Author(s).)

Purpose: To develop guidelines for ocular surveillance and early intervention for individuals with von Hippel-Lindau (VHL) disease., Design: Systematic review of the literature., Participants: Expert panel of retina specialists and ocular oncologists., Methods: A consortium of experts on clinical management of all-organ aspects of VHL disease was convened. Working groups with expertise in organ-specific features of VHL disease were tasked with development of evidence-based guidelines for each organ system. The ophthalmology subcommittee formulated questions for consideration and performed a systematic literature review. Evidence was graded for topic quality and relevance and the strength of each recommendation, and guideline recommendations were developed., Results: The quality of evidence was limited, and no controlled clinical trial data were available. Consensus guidelines included: (1) individuals with known or suspected VHL disease should undergo periodic ocular screening (evidence type, III; evidence strength, C; degree of consensus, 2A); (2) patients at risk of VHL disease, including first-degree relatives of patients with known VHL disease, or any patient with single or multifocal retinal hemangioblastomas (RHs), should undergo genetic testing for pathologic VHL disease gene variants as part of an appropriate medical evaluation (III/C/2A); (3) ocular screening should begin within 12 months after birth and continue throughout life (III/C/2A); (4) ocular screening should occur approximately every 6 to 12 months until 30 years of age and then at least yearly thereafter (III/C-D/2A); (5) ocular screening should be performed before a planned pregnancy and every 6 to 12 months during pregnancy (IV/D/2A); (6) ultra-widefield color fundus photography may be helpful in certain circumstances to monitor RHs, and ultra-widefield fluorescein angiography may be helpful in certain circumstances to detect small RHs (IV/D/2A); (7) patients should be managed, whenever possible, by those with subspecialty training, with experience with VHL disease or RHs, or with both and ideally within the context of a multidisciplinary center capable of providing multiorgan surveillance and access to genetic testing (IV/D/2A); (8) extramacular or extrapapillary RHs should be treated promptly (III/C/2A)., Conclusions: Based on available evidence from observational studies, broad agreement was reached for a strategy of lifelong surveillance and early treatment for ocular VHL disease. These guidelines were endorsed by the VHL Alliance and the International Society of Ocular Oncology and were approved by the American Academy of Ophthalmology Board of Trustees., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. All rights reserved.)

Background: The von Hippel-Lindau (VHL) disease is a hereditary tumour syndrome caused by germline mutations in VHL tumour suppressor gene. The identification of VHL variants requires accurate classification which has an impact on patient management and genetic counselling., Methods: The TENGEN (French oncogenetics network of neuroendocrine tumors) and PREDIR (French National Cancer Institute network for Inherited predispositions to kidney cancer) networks have collected VHL genetic variants and clinical characteristics of all VHL-suspected patients analysed from 2003 to 2021 by one of the nine laboratories performing VHL genetic testing in France. Identified variants were registered in a locus-specific database, the Universal Mutation Database-VHL database (http://www.umd.be/VHL/)., Results: Here we report the expert classification of 164 variants, including all missense variants (n=124), all difficult interpretation variants (n=40) and their associated phenotypes. After initial American College of Medical Genetics classification, first-round classification was performed by the VHL expert group followed by a second round for discordant and ambiguous cases. Overall, the VHL experts modified the classification of 87 variants including 30 variants of uncertain significance that were as (likely)pathogenic variants for 19, and as likely benign for 11., Conclusion: Consequently, this work has allowed the diagnosis and influenced the genetic counselling of 45 VHL-suspected families and can benefit to the worldwide VHL community, through this review., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The description of the child aged 5 months with the von Hippel-Lindau syndrome without any manifestations of this syndrome is presented. The reason for the molecular genetic examination was the presence of cases of this syndrome in the family (mother and sister). The heterozygous variant c.355T&gt;C p.F119L was found in the VHL gene. An objective examination revealed no pathology. A comprehensive laboratory and instrumental examination aimed at searching for components of the von Hippel-Lindau syndrome, including a blood test for metanephrines and normetanephrines, ultrasound of the abdominal organs, examination of the fundus, also did not reveal any abnormalities. Given the results of molecular genetic diagnosis, the child remains under observation and will undergo regular examinations to identify components of the von Hippel-Lindau syndrome, including blood/urine tests for normetanephrines.

Rationale: Hemangioblastomas occur both sporadically and as an important component of von Hippel-Lindau (VHL) disease. The typical MRI features of hemangioblastoma are cysts with enhanced cystic wall nodules in the cerebellum or lesions with uniform enhancement on the surface or inside the spinal cord. If there is edema around hemangioblastoma, it is easy to be misdiagnosed as brain metastasis on MRI., Patient Concerns: A 41-year-old male patient was found to have a lump in the pancreas during a health examination 3 months ago. Subsequently, the patient underwent surgical treatment. The postoperative pathology suggests that the pancreatic lesion is a neuroendocrine tumor. The patient subsequently came to our hospital for consultation on further treatment plans. Abnormal signals were found in the right cerebellum during pituitary magnetic resonance imaging (MRI) before the development of a treatment plan for neuroendocrine tumors. Subsequently, the patient underwent cerebellar mass resection surgery. The pathological result after the surgery was hemangioblastoma., Diagnosis: The patient underwent surgery to remove the tumor and was diagnosed with hemangioblastoma by pathological examination. Subsequently, the patient's genetic testing results confirmed the diagnosis of VHL syndrome., Interventions: The patient underwent cerebellar mass resection surgery., Outcomes: The patient recovered after surgical resection., Lessons: In this report, we emphasize the atypical MRI manifestations of hemangioblastoma. For patients with VHL syndrome-related hemangioblastoma, genetic testing is necessary for the patient and their family members., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Mutations within the Von Hippel-Lindau (VHL) tumor suppressor gene are known to cause VHL disease, which is characterized by the formation of cysts and tumors in multiple organs of the body, particularly clear cell renal cell carcinoma (ccRCC). A major challenge in clinical practice is determining tumor risk from a given mutation in the VHL gene. Previous efforts have been hindered by limited available clinical data and technological constraints., Methods: To overcome this, we initially manually curated the largest set of clinically validated VHL mutations to date, enabling a robust assessment of existing predictive tools on an independent test set. Additionally, we comprehensively characterized the effects of mutations within VHL using in silico biophysical tools describing changes in protein stability, dynamics and affinity to binding partners to provide insights into the structure-phenotype relationship. These descriptive properties were used as molecular features for the construction of a machine learning model, designed to predict the risk of ccRCC development as a result of a VHL missense mutation., Results: Analysis of our model showed an accuracy of 0.81 in the identification of ccRCC-causing missense mutations, and a Matthew's Correlation Coefficient of 0.44 on a non-redundant blind test, a significant improvement in comparison to the previous available approaches., Conclusion: This work highlights the power of using protein 3D structure to fully explore the range of molecular and functional consequences of genomic variants. We believe this optimized model will better enable its clinical implementation and assist guiding patient risk stratification and management., (© The Author(s) 2023. Published by Oxford University Press.)

The von Hippel-Lindau protein (pVHL) is a tumor suppressor involved in oxygen regulation via dynamic nucleocytoplasmic shuttling. It plays a crucial role in cell survival by degrading hypoxia-inducible factors (HIFs). Mutations in the VHL gene cause angiogenic tumors, characterized as VHL syndrome. However, aggressive tumors involving wild-type pVHL have also been described but the underlying mechanism remains to be revealed. We have previously shown that pVHL possesses several short amyloid-forming motifs, making it aggregation-prone. In this study, using a series of biophysical assays, we demonstrated that a pVHL-derived fragment (pVHL104-140) that harbors the nuclear export motif and HIF binding site, forms amyloid-like fibrillar structures in vitro by following secondary-nucleation-based kinetics. The peptide also formed amyloids at acidic pH that mimics the tumor microenvironment. We, subsequently, validated the amyloid formation by pVHL in vitro. Using the Curli-dependent amyloid generator (C-DAG) expression system, we confirmed the amyloidogenesis of pVHL in bacterial cells. The pVHL amyloids are an attractive target for therapeutics of the VHL syndrome. Accordingly, we demonstrated in vitro that Purpurin is a potent inhibitor of pVHL fibrillation. The amyloidogenic behavior of wild-type pVHL and its inhibition provide novel insights into the molecular underpinning of the VHL syndrome and its possible treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Daniel Segal reports financial support was provided by United States-Israel Binational Science Foundation., (Copyright © 2023 Elsevier Inc. All rights reserved.)

von Hippel-Lindau (VHL) disease is characterized by biallelic inactivation of the VHL gene leading to abnormal or absent VHL protein function, and constitutive activation of hypoxia-inducible factors (HIF) that leads to pro-tumorigenic signaling. Individuals with VHL disease develop numerous cysts and tumors involving multiple organs including the kidneys, central nervous system, endolymphatic sac, lungs, pancreatobiliary system, adrenal glands, epididymis, and/or broad ligament. On histologic examination, these lesions show morphologic overlap as they are frequently characterized by cells with clear cytoplasm and prominent vascularity. In addition to distinguishing non-renal tumors from metastatic clear cell renal cell carcinoma, understanding site-specific histopathologic and immunophenotypic features of these tumors has several applications. This includes distinguishing VHL-related tumors from those that arise sporadically and lack VHL gene alterations, guiding further genetic workup, and helping distinguish between different genetic predisposition syndromes. In this context, immunohistochemical studies for markers such as paired box 8 (PAX-8), carbonic anhydrase 9 (CA9), and glucose transporter 1 (GLUT-1) have an important role in routine clinical practice and represent cost-effective diagnostic tools. The recent development of targeted therapeutics directed against HIF-mediated signaling represents a significant milestone in the management of VHL disease and highlights the importance of accurately diagnosing and characterizing the wide spectrum of VHL disease-associated lesions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Von Hippel-Lindau (VHL) is a rare inherited disease mainly characterized by the growth of tumours, predominantly hemangioblastomas (Hbs) in the CNS and retina, and renal carcinomas. The natural history of VHL disease is variable, differing in the age of onset and its penetrance, even among relatives. Unfortunately, sometimes VHL shows more severe than average: the onset starts in adolescence, and surgeries are required almost every year. In these cases, the factor that triggers the appearance and growth of Hbs usually remains unknown, although additional mutations are suspected., Methods: We present the case of a VHL patient whose first surgery was at 13 years of age. Then, along his next 8 years, he has undergone 5 surgeries for resection of 10 CNS Hbs. To clarify this severe VHL condition, DNA from a CNS Hb and white blood cells (WBC) was sequenced using next-generation sequencing technology., Results: Massive DNA sequencing of the WBC (germ line) revealed a pathogenic mutation in CHEK2 and the complete loss of a VHL allele (both tumour suppressors). Moreover, in the tumour sample, several mutations, in BRAF1 and PTPN11 were found. Familiar segregation studies showed that CHEK2 mutation was in the maternal lineage, while VHL was inherited by paternal lineage., Conclusions: Finally, clinical history correlated to the different genotypes in the family, concluding that the severity of these VHL manifestations are due to both, VHL-and-CHEK2 mutations. This case report aims to notice the importance of deeper genetic analyses, in inherited rare diseases, to uncover non-expected mutations., (© 2023. The Author(s).)

Background: Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary tumor syndrome with an incidence of approximately 1/36,000. VHL disease-associated clear cell renal cell carcinoma (ccRCC) is the most common congenital RCC. Although recent advances in treating RCC have improved the long-term prognosis of patients with VHL disease, kidney cancer is still the leading cause of death in these patients. Therefore, finding new targets for diagnosing and treating VHL disease-associated ccRCC is still essential., Methods: In this study, we collected matched tumor tissues and normal samples from 25 patients with VHL disease-associated ccRCC, diagnosed and surgically treated in the Department of Urology, Peking University First Hospital. After screening, we performed whole genome bisulfite sequencing (WGBS) on 23 pairs of tissues and RNA-seq on 6 pairs of tissues. And we also compared the VHL disease-associated ccRCC transcriptome data with the sporadic ccRCC transcriptome data from the The Cancer Genome Atlas (TCGA) public database RESULTS: We found that the methylation level of VHL disease-associated ccRCC tumor tissues was significantly lower than that of normal tissues. The tumor tissues showed a difference in the copy number of 3p loss and 5q and 7q gain compared with normal tissues. We integrated RNA-seq and WGBS data to reveal methylation candidate genes associated with VHL disease-associated ccRCC; our results showed 124 hypermethylated and downregulated genes, and 245 hypomethylated and upregulated genes. By comparing the VHL disease-associated ccRCC transcriptome data with the sporadic ccRCC transcriptome data from the TCGA public database, we found that the major pathways of differential gene enrichment differed between them., Conclusions: Our study mapped the multiomics of copy number variation, methylation and mRNA level changes in tumor and normal tissues of clear cell renal cell carcinoma with VHL syndrome, which provides a solid foundation for the mechanistic study, biomarker screening, and therapeutic target discovery of clear cell renal cell carcinoma., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Neurocutaneous syndromes (also known as phakomatoses) are heterogenous group of disorders that involve derivatives of the neuroectoderm. Each disease has diagnostic and pathognomonic criteria, once identified, thorough clinical examination to the patient and the family members should be done. Magnetic resonance imaging (MRI) is used to study the pathognomonic findings withing the CNS (Evans et al. in Am J Med Genet A 152A:327-332, 2010). This chapter includes the 4 most common syndromes faced by neurosurgeons and neurologists; neurofibromatosis types 1 and 2, tuberous sclerosis and Von Hippel-Lindau disease. Each syndrome has specific genetic anomaly that involves a tumor suppressor gene and the loss of inhibition of specific pathways. The result is a spectrum of cutaneous manifestations and neoplasms., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Patients with von Hippel-Lindau disease (vHL) are at risk of developing spatially and temporally multiple clear cell renal cell carcinomas (ccRCCs), which offers a valuable opportunity to analyze inter- and intra-tumor heterogeneity of genetic and immune profiles within the same patient. Here, we perform whole-exome and RNA sequencing, digital gene expression, and immunohistochemical analyses for 81 samples from 51 ccRCCs of 10 patients with vHL. Inherited ccRCCs are clonally independent and have less genomic alterations than sporadic ccRCCs. Hierarchical clustering of transcriptome profiles shows two clusters with distinct immune signatures: immune hot and cold clusters. Interestingly, not only samples from the same tumors but also different tumors from the same patients tend to show a similar immune signature, whereas samples from different patients frequently exhibit different signatures. Our findings reveal the genetic and immune landscape of inherited ccRCCs, demonstrating the relevance of host factors in shaping anti-tumor immunity., Competing Interests: Declaration of interests K.K. holds individual stocks in Asahi Genomics; has a patent for genetic alterations as a biomarker in T cell lymphomas and a patent for PD-L1 abnormalities as a predictive biomarker for immune checkpoint blockade therapy; has received research funding from Otsuka Pharmaceutical, Chordia Therapeutics, Chugai Pharmaceutical, and Takeda Pharmaceutical; has received scholarships from Asahi Kasei Pharma, Eisai, Otsuka Pharmaceutical, Ono Pharmaceutical, Kyowa Kirin, Shionogi, Takeda Pharmaceutical, Sumitomo Pharma, Chugai Pharmaceutical, Teijin Pharma, Japan Blood Products Organization, Mochida Pharmaceutical, JCR Pharmaceuticals, and Nippon Shinyaku; has received honoraria from Ono Pharmaceutical, Celgene, Eisai, Astellas Pharma, Novartis, Chugai Pharmaceutical, AstraZeneca, Sumitomo Pharma, Kyowa Kirin, Janssen Pharmaceutical, Takeda Pharmaceutical, Otsuka Pharmaceutical, SymBio Pharmaceuticals, Bristol Myers Squibb, Pfizer, Nippon Shinyaku, Daiichi Sankyo, Alexion Pharmaceuticals, AbbVie, Meiji Seika Pharma, and Sanofi. Y.O.-K. is an employee of Otsuka Pharmaceutical Co., Ltd. The spouse of Y.O.-K. is an employee of Taiho Pharmaceutical Co., Ltd. S.O. holds stocks in RegCell, Ashahi Genomics, and Chordia Therapeutics; has received research funding from Sumitomo Pharma. and Chordia Therapeutics; has received consultancy from Kan Research Laboratory and Chordia Therapeutics; and is a speaker’s bureau for Novartis Pharmaceutical and Astellas Pharma., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Von Hippel-Lindau (VHL) loss is the hallmark event characterizing the clear cell renal cancer subtype (ccRCC). Carriers of germinal VHL mutations have an increased prevalence of kidney cysts and ccRCC as well as hemangioblastoma, pheochromocytoma and pancreatic neuroendocrine tumors. In both sporadic and inherited ccRCC, the primary mechanism of VHL-mediated carcinogenesis is the abnormal stabilization of hypoxia-inducible factors (HIF1A and HIF2A). While HIF1A acts as a tumor suppressor and is frequently lost through inactivating mutations/14q chromosome deletions, HIF2A acts as an oncogene promoting the expression of its target genes (VEGF, PDGF, CAIX Oct4, among others). Selective HIF2a inhibitors block the heterodimerization between HIF2A and ARNT, stopping HIF2A-induced transcription. Several HIF2A inhibitors have entered clinical trials, where they have shown a favorable toxicity profile, characterized by anemia, fatigue and edema and promising activity in heavily pretreated ccRCC patients. Belzutifan, a second-generation HIF2a inhibitor, was the first to receive FDA approval for the treatment of unresectable ccRCC in VHL syndrome. In this review, we recapitulate the rationale for HIF2a blockade in ccRCC, summarize the development of HIF2a inhibitors from preclinical models up to its introduction to the clinic with emphasis on Belzutifan, and discuss their role in VHL disease management.

Purpose: Missense mutated von Hippel Lindau (VHL) protein (pVHL) maintains intrinsic function but undergoes proteasomal degradation and tumor initiation and/or progression in VHL disease. Vorinostat can rescue missense mutated pVHL and arrest tumor growth in preclinical models. We asked whether short-term oral vorinostat could rescue pVHL in central nervous system hemangioblastomas in patients with germline missense VHL., Patients and Methods: We administered oral vorinostat to 7 subjects (ages 46.0 ± 14.5 years) and then removed symptomatic hemangioblastomas surgically (ClinicalTrials.gov identifier NCT02108002)., Results: Vorinostat was tolerated without serious adverse events by all patients. pVHL expression was elevated in neoplastic stromal cells compared with untreated hemangioblastomas from same patients. We found transcriptional suppression of downstream hypoxia-inducible factor (HIF) effectors. Mechanistically, vorinostat prevented Hsp90 recruitment to mutated pVHL in vitro. The effects of vorinostat on the Hsp90-pVHL interaction, pVHL rescue, and transcriptional repression of downstream HIF effectors was independent of the location of the missense mutation on the VHL locus. We confirmed a neoplastic stromal cell-specific effect in suppression of protumorigenic pathways with single-nucleus transcriptomic profiling., Conclusions: We found that oral vorinostat treatment in patients with germline missense VHL mutations has a potent biologic effect that warrants further clinical study. These results provide biologic evidence to support the use of proteostasis modulation for the treatment of syndromic solid tumors involving protein misfolding. Proteostasis modulation with vorinostat rescues missense mutated VHL protein. Further clinical trials are needed to demonstrate tumor growth arrest., (©2023 American Association for Cancer Research.)

Von Hippel-Lindau (VHL) disease is an autosomal dominant, inherited syndrome with variants in the VHL gene, causing predisposition to multi-organ neoplasms with vessel abnormality. Germline variants in VHL can be detected in 80-90% of patients clinically diagnosed with VHL disease. Here, we summarize the results of genetic tests for 206 Japanese VHL families, and elucidate the molecular mechanisms of VHL disease, especially in variant-negative unsolved cases. Of the 206 families, genetic diagnosis was positive in 175 families (85%), including 134 families (65%) diagnosed by exon sequencing (15 novel variants) and 41 (20%) diagnosed by multiplex ligation-dependent probe amplification (MLPA) (one novel variant). The deleterious variants were significantly enriched in VHL disease Type 1. Interestingly, five synonymous or non-synonymous variants within exon 2 caused exon 2 skipping, which is the first report of exon 2 skipping caused by several missense variants. Whole genome and target deep sequencing analysis were performed for 22 unsolved cases with no variant identified and found three cases with VHL mosaicism (variant allele frequency: 2.5-22%), one with mobile element insertion in the VHL promoter region, and two with a pathogenic variant of BAP1 or SDHB. The variants associated with VHL disease are heterogeneous, and for more accuracy of the genetic diagnosis of VHL disease, comprehensive genome and DNA/RNA analyses are required to detect VHL mosaicism, complicated structure variants and other related gene variants., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Hemangioblastoma, one of the characteristic tumors associated with Von Hippel-Lindau (VHL) disease, most often presents in the central nervous system (CNS) but can uncommonly arise in extraneuraxial, or previously referred to as peripheral, locations. Without the clinical context of known VHL disease, hemangioblastoma may not enter the differential for a soft tissue mass outside the CNS. Here, we present two patients with diagnostically challenging extraneuraxial hemangioblastoma to highlight the importance of considering this entity within the differential diagnosis of soft tissue neoplasms containing clear cells and delicate vasculature. We review the relevant diagnostic features, including a suggested immunohistochemical panel, along with the potential associated clinical implications of making this diagnosis. It is recommended that affected patients be offered genetic counseling to assess for underlying VHL disease.

Von Hippel-Lindau disease (VHL) is a rare autosomal dominant disease characterized by progressive development of cysts and tumors. Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disorder and the most common arthritis in children. Although the mechanism of pathogenesis is not fully understood, JIA is thought to be a polygenic, autoimmune-mediated disease. Inherited or acquired disorders resulting in immune dysregulation can lead to neoplastic and autoimmune disease, but very few cases of patients with VHL and concomitant autoimmune disease are reported in the literature. Herein, we describe, to the best of our knowledge, the first reported case of a child with VHL and inflammatory arthritis, and we discuss three possible pathophysiologic mechanisms that could link VHL and JIA. Understanding the shared pathophysiology and genetics of both diseases may help guide future direction of targeted therapies and lead to improved clinical outcomes.

Background: Retinal capillary hemangioblastoma (RCH), while sporadic in some cases, is the most common and earliest manifestation of von Hippel-Lindau disease (VHL). This is the first report on different types of VHL variants and genotype-phenotype correlations in Iranian families with RCH., Materials and Methods: In this prospective observational case series study, 17 families with RCH were included. PCR was performed to amplify 3 exons of VHL gene. Afterward, Sanger sequencing was performed on all PCR products. For the detection of VHL copy number variations, MLPA was used., Results: Our study identified 10 different types of VHL variants. Missense mutations were the most common variants found and affected the structure of α domain of the VHL protein (pVHL). The majority of mutations (72.7%) in the patients with RCH and central nervous system hemangioblastoma (CNS-HB) were located on α domain., Conclusion: α domain of VHL may play a potential role in the pathogenesis of RCH. Our findings suggest that genotype-phenotype characteristics in those variants in α- domain may predispose patients to RCH with CNS-HB.

Von Hippel-Lindau (VHL) disease is a tumor predisposition syndrome caused by mutations in the VHL gene that presents with visceral neoplasms and growths, including clear cell renal cell carcinoma, and central nervous system manifestations, such as hemangioblastomas of the brain and spine. The pathophysiology involves dysregulation of oxygen sensing caused by the inability to degrade HIFα, leading to the overactivation of hypoxic pathways. Hemangioblastomas are the most common tumors in patients with VHL and cause significant morbidity. Until recently, there were no systemic therapies available for patients that could effectively reduce the size of these lesions. Belzutifan, the first approved HIF-2α inhibitor, has demonstrated benefit in VHL-associated tumors, with a 30% response rate in hemangioblastomas and ~30%-50% reduction in their sizes over the course of treatment. Anemia is the most prominent adverse effect, affecting 76%-90% of participants and sometimes requiring dose reduction or transfusion. Other significant adverse events include hypoxia and fatigue. Overall, belzutifan is well tolerated; however, long-term data on dosing regimens, safety, and fertility are not yet available. Belzutifan holds promise for the treatment of neurological manifestations of VHL and its utility may influence the clinical management paradigms for this patient population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Approximately 20%-40% of patients with von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary disease, exhibit large deletions (LDs). Few studies have focused on this population. Hence, we aimed to elucidate the genotype-phenotype correlations and clinical outcomes in VHL patients with LDs., Methods: In this retrospective study, we included 119 patients with VHL disease from 50 unrelated families in whom LDs were detected using traditional and next-generation sequencing methods. Other germline mutations were confirmed by Sanger sequencing. Genotype-phenotype correlations and survival were analysed in different groups using Kaplan-Meier and Cox regression. We also evaluated therapeutic response to tyrosine kinase inhibitor (TKI) therapy., Results: The overall penetrance of patients aged <60 was 95.2%. Two VHL patients with LDs also carried CHEK2 and FLCN germline mutations. An earlier age of onset of retinal haemangioblastoma was observed in the next generation. Patients with exon 2 deletion of VHL had an earlier onset age of renal cell carcinoma and pancreatic lesions. The risk of renal cell carcinoma was lower in VHL patients with LDs and a BRK1 deletion. The group with earlier age of onset received poorer prognosis. Four of eight (50%) patients showed partial response to TKI therapy., Conclusion: The number of generations and the status of exon 2 could affect age of onset of VHL-related manifestations. Onset age was an independent risk factor for overall survival. TKI therapy was effective in VHL patients with LDs. Our findings would further support clinical surveillance and decision-making processes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Hemangioblastomas are benign vascular tumors that can occur throughout the central nervous system (CNS) sporadically or in association with von Hippel-Lindau (VHL) disease. We present a case of an 11-year-old girl with a hemangioblastoma that tested negative for germline mutation of VHL disease at the time of diagnosis. Our patient went on to have multiple recurrences and further areas of concern for disease within the CNS. Repeat VHL testing was pursued many years later and remained negative for germline mutations. However, next-generation sequencing (NGS) testing on prior tumor tissue returned positive for VHL somatic mutations. The diagnosis of VHL mosaicism has important implications on management and risk of recurrence of hemangioblastoma, along with the need for close follow-up with surveillance imaging., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder caused by pathogenic variants in VHL gene. The common manifestations include hemangioblastomas (HB) of the central nervous system (CNS) and retina (RH); pheochromocytoma (PHEO); clear cell renal cell carcinoma (ccRCC); pancreatic and renal cysts (PRC) and pancreatic neuroendocrine neoplasm (PNEN)., Methods: The first characterization of VHL in Brazil was published in 2003 and included 20 families with a history of VHL. The aim of this study was to expand the previous Brazilian cohort to include more families, as well as to collect prospectively both clinical and molecular characteristics of patients with VHL to build the VHL Brazilian Registry (VHLBR). Patients with VHL were selected through review of data from medical records of experts and from social networks of support for families with VHL in Brazil., Results: A total of 142 subjects representing 62 unrelated Brazilian families with VHL were registered. The mean age of VHL onset was 28.78 years old and 128 individuals (90.1%) had at least one VHL-related lesion. CNS HB was the most common manifestation occurring in 91 (71%) patients, followed by multiple PRC (48.4%), RH (39.8%), ccRCC (28.9%), PHEO (12.5%) and PNEN (7.8%). Of the 97 subjects whose presence of VHL variants was confirmed, 51 (52.6%) had missense variants, 22 (22.7%) large deletions, 10 (10.3%) frameshift, 7 (7.2%) splice site, 4 (4.1%) nonsense and 3 (3.1%) in-frame deletions. Regarding surveillance, 115 (81%) participants had at least one physician responsible for their outpatient follow-up; however, 69 (60%) of them did not report a regular frequency of tests., Conclusion: We built the largest prospective VHLBR with organized collections of clinical and genetic data from families with VHL, which will be helpful to guide policies for VHL care and oncogenetics in Brazil. Although there have been improvements in diagnosis and clinical screening methods, VHL care in Brazil is still deficient, especially regarding surveillance and regular medical appointments with experts., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Intratumoral hypoxia is associated with tumor progression and therapeutic resistance. The VHL tumor suppressor gene was identified in 1993, and later studies revealed that the gene product pVHL interacts with other proteins to form the VBC complex. The VBC complex functions as an E3 ubiquitin ligase and regulates the abundance of the α-subunit of the transcription factor hypoxia-inducible factor (HIF). Hypoxia-inducible factor regulates thousands of genes required for cells to adapt and survive in hypoxic conditions, and thus pVHL plays a major role in oxygen-sensing pathways. Patients with von Hippel-Lindau (VHL) disease, harboring a germline mutation of the VHL gene, develop renal cell carcinomas and a series of tumors showing hypervascular phenotypes. The extensive findings that have clarified the function of VHL have contributed to the development of novel first-in-human drugs, including belzutifan, a HIF-2α inhibitor. The 2019 Nobel Prize in Physiology or Medicine was awarded to Dr. William G. Kaelin Jr., Dr. Peter J. Ratcliffe, and Dr. Gregg L. Semenza as researchers contributing to clarifying the mechanism of the oxygen-sensing pathway of cells. The first report of VHL disease was in 1894, meaning the development of a specific drug for this disease took almost 125 years. In this article, we describe how researchers and clinician scientists successfully clarified the function of VHL and achieved a preclinical proof of concept to apply for clinical trials, key requirements for drug development., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Kidney tumors may develop in association with hereditary tumor syndromes. The clinical presentation of these disorders is various, and in some cases, the renal tumor is the first manifestation of the syndrome. Thus, pathologists need to be aware of the gross and histological signs that may suggest the possibility of a tumor syndrome. In this paper, we summarize and illustrate the characteristics of kidney tumors, genetic background along with the extrarenal manifestations in the following diseases: Von Hippel-Lindau syndrome, hereditary papillary renal cell carcinoma syndrome, hereditary leiomyomatosis and renal cell carcinoma syndrome, Birt-Hogg-Dubé syndrome, tuberous sclerosis, hereditary paraganglioma and pheochromocytoma syndrome, and inherited BAP1 tumor syndrome. At the end of the manuscript, we discuss the tumor syndromes with increased risk of Wilms tumors. Such patients require a holistic approach and multidisciplinary care. Our work aims to make those involved in the diagnosis and treatment of kidney tumors aware of these rare diseases that require life-long surveillance. Orv Hetil. 2023; 164(10): 363-375.

Pathogenic germline mutations in VHL gene cause von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary cancer syndrome associated with high penetrance of benign and malignant neoplasms, including clear cell renal cell carcinoma (ccRCC), central nervous system haemangioblastomas (CNS-HB), retinal angiomas, phaeochromocytomas and pancreatic neuroendocrine tumours (pNET). Management of VHL disease involves lifelong radiological and biochemical surveillance, often leading to repeat surgical intervention causing significant morbidity and mortality. Systemic therapy that prevents or reduces the need for surgical intervention could improve clinical outcomes and quality of life for affected individuals. Belzutifan is a second-generation small molecule hypoxia-inducible factor 2α (HIF-2α) inhibitor recently approved by US and UK regulators for the treatment of VHL (disease)-associated ccRCC, CNS-HB and pNET. While this is a welcome step forward, it is vital that we consider in what circumstances these drugs are recommended and how they fit into the overall management of VHL disease. In this personal view article, we reflect on the history of the use of systemic therapy in localised VHL disease and consider open questions relating to the use of HIF-2α inhibitors, including the need to involve medical oncologists in the multidisciplinary team moving forward. Indeed, VHL disease is the perfect paradigm for similar settings in the future., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Neuroendocrine neoplasms can occur as part of inherited disorders, usually in the form of well-differentiated, slow-growing tumors (NET). The main predisposing syndromes include: multiple endocrine neoplasias type 1 (MEN1), associated with a large spectrum of gastroenteropancreatic and thoracic NETs, and type 4 (MEN4), associated with a wide tumour spectrum similar to that of MEN1; von Hippel-Lindau syndrome (VHL), tuberous sclerosis (TSC), and neurofibromatosis 1 (NF-1), associated with pancreatic NETs. In the present review, we propose a reappraisal of the genetic basis and clinical features of gastroenteropancreatic and thoracic NETs in the setting of inherited syndromes with a special focus on molecularly targeted therapies for these lesions., Methods: Literature search was systematically performed through online databases, including MEDLINE (via PubMed), and Scopus using multiple keywords' combinations up to June 2022., Results: Somatostatin analogues (SSAs) remain the mainstay of systemic treatment for NETs, and radiolabelled SSAs can be used for peptide-receptor radionuclide therapy for somatostatin receptor (SSTR)-positive NETs. Apart of these SSTR-targeted therapies, other targeted agents have been approved for NETs: the mTOR inhibitor everolimus for lung, gastroenteropatic and unknown origin NET, and sunitinib, an antiangiogenic tyrosine kinase inhibitor, for pancreatic NET. Novel targeted therapies with other antiangiogenic agents and immunotherapies have been also under evaluation., Conclusions: Major advances in the understanding of genetic and epigenetic mechanisms of NET development in the context of inherited endocrine disorders have led to the recognition of molecular targetable alterations, providing a rationale for the implementation of treatments and development of novel targeted therapies., (© 2022. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

A Surgically Treated Depression Abstract. We present a 64-year-old patient with an unclear deterioration of her general condition due to a suspected depression. Despite antidepressive treatment, her condition further deteriorated. The CT/MRI of the skull showed a cerebellar tumor as well as a hydrocephalus obstructivus. Together with tumor staging, the histology, which revealed a hemangioblastoma, led to the diagnosis of VHL syndrome. Patients with VHL syndrome and their families should be included in a screening program, unless molecular genetic testing has ruled out the disease.

Hemangioblastoma is a benign tumor of the central nervous system arising sporadically or as a component of Von Hippel-Lindau disease. Von Hippel-Lindau disease is a rare autosomal dominant hereditary syndrome with various phenotypes caused by VHL gene variants. To date, only about 40 cases of optic nerve hemangioblastoma have been described in the literature. Stereotactic irradiation may be effective for supratentorial hemangioblastomas including lesions of optic nerves. The authors describe a rare case of stereotactic irradiation of intraorbital hemangioblastoma of the optic nerve in a patient with Von Hippel-Lindau disease.

Hemangioblastomas (HBs) are highly vascularized, slow-growing, rare benign tumors (WHO grade I). They account for about 2% of intracranial neoplasms; however, they are the most common primary cerebellar tumors in adults. Another frequent seat is the spinal cord (2-10% of primary spinal cord tumors). HBs are constituted by stromal and capillary vascular cells; macroscopically, HBs appear as nodular tumors, with or without cystic components. Although most of the HBs are sporadic (57-75%), they represent a particular component of von Hippel-Lindau disease (VHL), an autosomal dominant syndrome with high penetrance, due to a germline pathogenic mutation in the VHL gene, which is a tumor suppressor with chromosomal location on the short arm of chromosome three. VHL disease determines a variety of malignant and benign tumors, most frequently HBs, renal cell carcinomas, pheochromocytomas/paragangliomas, pancreatic neuroendocrine tumors, and endolymphatic sac tumors. Up to 20% of cases are due to de novo pathogenic variants without a family history. Many epidemiologic details of these tumors, especially the sporadic forms, are not well known. The median age of patients with sporadic HBS is about 40 years. More than two-third of VHL patients develop one or more central nervous system HBs during their lifetime; in case of VHL, patients at first diagnosis are usually younger than the patients with sporadic tumors. The most common presenting signs and symptoms are related to increased intracranial pressure, cerebellar signs, or spinal cord alterations in case of spinal involvement. Magnetic resonance imaging is the gold standard for the diagnosis, assessment, and follow-up of HBs, both sporadic and syndrome-related; angiography is rarely performed because the diagnosis is easily obtained with magnetic resonance. However, the diagnosis of an asymptomatic lesion does not automatically result in therapeutic actions, as the risks of treatment and the onset of possible neurological deficit need to be balanced, considering that HBs may remain asymptomatic and have a static or slow-growing behavior. In such cases, regular follow-up can represent a valid therapeutic option until the patients remain asymptomatic. There are no actual pharmacological therapies that are demonstrated to be effective for HBs. Surgery represents the primary therapeutic approach for these tumors. Observation or radiotherapy also plays a role in the long-term management of patients harboring HBs, especially in VHL; in few selected cases, endovascular treatment has been suggested before surgical removal. This chapter presents a systematic overview of epidemiology, clinical appearance, histopathological and neuroradiological characteristics of central nervous system HBs. Moreover, the genetic and molecular biology of sporadic and VHL HBS deserves special attention. Furthermore, we will describe all the available therapeutic options, along with the follow-up management. Finally, we will briefly report other vascular originating tumors as hemangioendotheliomas, hemangiomas, or angiosarcomas., (© 2023. Springer Nature Switzerland AG.)

Renal clear cell carcinoma commonly occurs in patients with von Hippel‑Lindau disease (VHL). Kidneys of VHL disease patients (VHL kidneys) contain an abundance of independent clear cell proliferation events that have been hypothesized to represent precursor structures of clear cell carcinoma. In the present study, it was tried to identify the site of origin of clear cell proliferation, and the immunophenotype of clear cells. Using 3D histological tracking, the topographic origin of microscopic clear cell proliferation was investigated by identification of informative structures of interest and immunohistochemical staining for cluster of differentiation 10 (CD10) and cytokeratin 7 (CK7) in consecutive serial sections. In addition, the CD10/CK7 immunophenotype of proliferating clear cells was evaluated. Clear cell proliferation uniformly occurred in the distal tubular system. Some clear cell proliferation, however, revealed proximal tubule immunophenotype. It was concluded that early proliferation of VHL‑deficient clear cells occurs in the distal tubular system. Despite the association with the distal tubular system, the immunohistochemical profile of early clear cell proliferation may be inconsistent with its distal tubular origin.

Von Hippel-Lindau disease (VHL) is frequently associated with pancreatic neuroendocrine tumors (PNETs). Here, we report a case of tumor-to-tumor metastasis in a VHL patient in whom colon cancer metastasized to the interior of a PNET. A 65-year-old man had undergone bilateral adrenalectomy for pheochromocytomas in both adrenal glands in his 50 s. Genetic screening was performed considering his family history of pheochromocytoma, and he was diagnosed with VHL. PNET was detected, for which the patient was regularly monitored by follow-up imaging. One year ago, the patient underwent right hemicolectomy to remove a tumor in the ascending colon (pT3N0M0, pStage IIA). He was admitted to our department for detailed examination because the pancreatic tumor had grown, and thus, pancreaticoduodenectomy was performed. Diagnostic imaging and histological findings indicated tumor-to-tumor metastasis, in which the patient's previous colon cancer had metastasized to and proliferated within the PNET. Colon cancer metastasizing to a PNET is extraordinarily rare and has never been reported in the literature. Thus, practitioners should be vigilant for tumor-to-tumor metastasis when performing imaging surveillance of PNETs., (© 2022. The Author(s).)

Purpose: We investigated the clinical features of Korean patients with retinal capillary hemangioblastoma (RCH) and genetic variants of the von Hippel-Lindau (VHL) gene., Methods: A retrospective analysis was performed on patients with RCH from 2003 to 2021 at Seoul National University Bundang Hospital. Sporadic and hereditary RCH associated with VHL disease were classified based on the specific tumors and family history. Clinical features, including the location and number of RCH and bilateral involvement, were investigated. Multiplex ligation-dependent probe amplification and direct sequencing targeting the VHL gene were performed for six RCH cases associated with VHL disease., Results: A total of 18 patients (23 eyes) were enrolled in this study. The mean age at diagnosis was 37 ± 15 years. Twelve patients had hereditary RCH associated with VHL disease, and six patients had sporadic RCH. All five patients with bilateral RCH were clinically diagnosed with VHL disease, and 13 patients had unilateral RCH. Juxtapapillary RCH was only observed in patients with VHL. The most common complication of RCH was the epiretinal membrane, followed by the subretinal fluid. Pathogenic variants were identified in four patients. All three patients with type 1 VHL had the well-known missense mutation p.Glu70Lys, and one patient with type 2 VHL had the nonsense mutation p.Trp88Ter., Conclusions: In Korean patients with RCH, bilateral involvement and juxtapapillary RCH are highly likely to be associated with VHL disease. Because RCH may be the first clinical manifestation in patients with VHL, active genetic testing of the VHL gene and systemic evaluation are required.

von Hippel-Lindau (VHL) disease is a rare autosomal-dominant hereditary disease characterized by mutation of the VHL gene. This gene encodes for the VHL protein, which regulates the activity of HIF-α, a transcription factor involved in the cellular response to hypoxia. Mutations in VHL lead to the accumulation of HIF-α and, consequently, the engagement of hypoxia-sensitive genes with tumorigenic effects. VHL disease is associated with the development of tumors in multiple organs, including pancreatic neuroendocrine tumors (pNETs). Belzutifan is an HIF-α inhibitor; however, it has not been previously evaluated in patients with metastatic or treatment-refractory pNETs. This report presents a 43-year-old woman with VHL-associated metastatic pNET treated with belzutifan after progression on multiple systemic therapies. She began treatment with belzutifan and experienced partial radiographic response within 1 month of treatment. Other than asymptomatic anemia, no adverse effects developed during 5 months of ongoing therapy. Belzutifan is an inhibitor of HIF-2α that targets the underlying pathophysiology of VHL-associated pNETs. Our case report describes exceptional activity in a metastatic pNET arising from VHL.

Background: The von Hippel-Lindau disease is a highly penetrant autosomal dominant syndrome characterized by tumor predisposition in different organs., Aim: This study aimed to describe a case of a pancreatoduodenectomy for a 30-year-old male patient with von Hippel-Lindau disease., Methods: We present a case study and the literature review aiming at the state-of-the-art management of a patient with pheochromocytoma, capillary hemangioblastoma in the peripheral retina, and two neuroendocrine tumors in the pancreas., Results: A larger pancreatic lesion was located in the uncinate process, measuring 31 mm. The smaller lesion was located in the proximal pancreas and was detected only on the positron emission tomography-computed tomography scan with DOTATOC-68Ga. Genetic investigation revealed a mutation in the locus NM&#95;000551.3 c.482G>A (p.Arg161Gln) of the Von Hippel-Lindau Human Suppressor gene. The uncinate process tumor was larger than 30 mm and the patient had a mutation on exon 3; therefore, we indicated a pancreatoduodenectomy involving the proximal pancreas to resect both tumors en bloc. During the postoperative period, the patient presented a peripancreatic fluid collection, which was treated as a grade B pancreatic fistula with clinical resolution of the complication. On postoperative day 21, he was discharged home., Conclusion: The management of patients with von Hippel-Lindau disease and pancreatic neuroendocrine tumors is complex and must be centered on tertiary institutions with a large volume of pancreatic surgery. Although the current literature assists in decision-making in most situations, each step of the treatment requires analysis and discussion between different medical specialties, including surgeons, clinicians, radiologists, and anesthesiologists.

Background: Von Hippel-Lindau (VHL) syndrome is an autosomal dominant hereditary disease affecting multiple organs, with pheochromocytoma in 26% of cases. However, VHL syndrome with congestive heart failure and dilated cardiomyopathy as the primary clinical manifestations has been rarely reported., Case Presentation: A 35-year-old male patient was admitted to the hospital with dyspnea. The patient had a history of cerebellar hemangioblastoma that had been resected, and a one-year history of hypertension. Echocardiography and cardiac magnetic resonance imaging demonstrated a dilated left ventricle, decreased systolic function, and nonischemic myocardial changes. Contrast-enhanced abdominal computed tomography showed pheochromocytoma, neoplastic lesions, and multiple cysts in the kidneys and pancreas. Genetic analysis revealed a missense mutation of the VHL gene, c.269 A > T (p.Asn90Ile), which was identified as the cause of the disease. Dilated cardiomyopathy and VHL syndrome type 2 were diagnosed. The patient was administered a diuretic, α-blocker, β-blocker, and an angiotensin receptor neprilysin inhibitor (ARNI), but refused pheochromocytoma resection. At the six-month follow-up, the patient was asymptomatic with improved cardiac function., Conclusion: Cardiac involvement is an atypical manifestation in VHL syndrome. Early diagnosis with genetic screening is essential for avoiding life-threatening complications associated with VHL. The management of this rare manifestation of VHL syndrome requires further investigation., (© 2022. The Author(s).)