The Genotype-Phenotype Association of Von Hipple Lindau Disease Based on Mutation Locations: A Retrospective Study of 577 Cases in a Chinese Population

Qiu, Jianhui; Zhang, Kenan; Ma, Kaifang; Zhou, Jingcheng; Gong, Yanqing; Cai, Lin; Gong, Kan

doi:10.3389/fgene.2020.532588

Cited by 10 publications

(12 citation statements)

References 31 publications

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“…Type 1 patients have a higher lifetime risk of HGBs and a lower risk of phaeochromocytoma development; in turn, the risk of phaeochromocytoma in type 2 patients is estimated at approximately 40–60% ( 10 , 16 ). Type 2 patients are subsequently subdivided into 3 subtypes based on the risk of RCC development: Type 2A (susceptibility to HGBs and pheochromocytoma but rarely RCC), Type 2B (susceptibility to HGBs, RCC, and pheochromocytoma), and Type 2C (susceptibility to pheochromocytoma only) ( 10 , 11 , 17 ).…”

Section: Discussionmentioning

confidence: 99%

“…Missense mutations and truncating mutations are the most common pathogenic variants in the VHL gene. Deletions and truncating mutations are more highly associated with VHL type 1 disease, while missense mutation carriers seem to have a higher risk of VHL type 2 disease ( 11 , 18 , 19 ). This association also leads to a higher risk of pheochromocytomas in patients with missense germline variants compared to those with truncating variants, a trend that is reversed for CNS HGBs, RCC and pancreatic cysts ( 11 , 19 – 21 ).…”

Section: Discussionmentioning

confidence: 99%

“…Deletions and truncating mutations are more highly associated with VHL type 1 disease, while missense mutation carriers seem to have a higher risk of VHL type 2 disease (11,18,19). This association also leads to a higher risk of pheochromocytomas in patients with missense germline variants compared to those with truncating variants, a trend that is reversed for CNS HGBs, RCC and pancreatic cysts (11,(19)(20)(21). Notably, missense mutations appear to result in a milder phenotype than deletions or truncating mutations because the residual VHL protein can maintain intrinsic function (22)(23)(24).…”

Section: The Genotype-phenotype Association Of Vhl Diseasementioning

confidence: 99%

“…VHL disease is a rare autosomal dominantly inherited cancer syndrome. It is associated with a mutation in the VHL tumor suppressor gene, which is located on chromosome band 3p25-26 ( 10 , 11 ). Once pathogenic variants occur, patients can exhibit a series of clinical manifestations: CNS HGBs, pheochromocytomas, clear cell renal cell carcinomas (RCCs), renal cysts, pancreatic cysts, pancreatic neuroendocrine tumors, endolymphatic sac tumors and so on ( 10 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

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Central Nervous System Hemangioblastoma in a Pediatric Patient Associated With Von Hippel-Lindau Disease: A Case Report and Literature Review

Yang

Wang

et al. 2021

Front. Oncol.

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BackgroundHemangioblastoma is a benign tumor of the central nervous system and may appear as a component of von Hippel-Lindau (VHL) disease. At present, approximately 40 cases of optic nerve HGBs have been reported in the literature. VHL disease is a rare autosomal-dominant inherited cancer syndrome with different phenotypes caused by variants in the VHL gene. Herein, the authors describe a case of a pediatric patient with VHL disease and with optic nerve HGB, a rare phenotypic expression. The purpose of this study was to explore the genotype-phenotype, clinical features, treatment and follow-up of VHL-associated hemangioblastomas in pediatric patients.Case DescriptionA 12-year-old boy presented with vision loss, headache and dizziness at our hospital. Magnetic resonance imaging (MRI) revealed a large (19.8 mm*18.5 mm*23.5 mm) irregular mass located in the suprasellar region. The mass was successfully removed after craniotomy and microsurgical treatment. The pathological diagnosis was left optic nerve HGB. Genetic analyses showed p.Pro86Leu (c. 257C>T) heterozygous missense mutations in the VHL gene.ConclusionThis is the first reported pediatric case of VHL-associated optic nerve HGB. The genotype-phenotype correlation of VHL disease may provide new evidences for predicting tumor penetrance and survival. Gross tumor resection combined with stereotactic radiosurgery might be the most beneficial treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: The Genotype-phenotype Association Of Vhl Diseasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Central Nervous System Hemangioblastoma in a Pediatric Patient Associated With Von Hippel-Lindau Disease: A Case Report and Literature Review

Yang

Wang

et al. 2021

Front. Oncol.

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“…The effects of TKIs may differ between VHL patients with LDs and overall patients with VHL disease due to differences in mutation patterns. There have been plenty of studies focused on the genotype–phenotype correlations and survival of overall patients with VHL disease 21 22. However, there are few studies on VHL patients with LDs, especially those involving the Chinese population.…”

Section: Introductionmentioning

confidence: 99%

Genotype–phenotype correlations and clinical outcomes of patients with von Hippel-Lindau disease with large deletions

Zhang

Yang

et al. 2022

J Med Genet

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BackgroundApproximately 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.MethodsIn 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.ResultsThe 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.ConclusionThe 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.

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Large scale genotype‐ and phenotype‐driven machine learning in Von Hippel‐Lindau disease

et al. 2022

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Von Hippel‐Lindau (VHL) disease is a hereditary cancer syndrome where individuals are predisposed to tumor development in the brain, adrenal gland, kidney, and other organs. It is caused by pathogenic variants in the VHL tumor suppressor gene. Standardized disease information has been difficult to collect due to the rarity and diversity of VHL patients. Over 4100 unique articles published until October 2019 were screened for germline genotype–phenotype data. Patient data were translated into standardized descriptions using Human Genome Variation Society gene variant nomenclature and Human Phenotype Ontology terms and has been manually curated into an open‐access knowledgebase called Clinical Interpretation of Variants in Cancer. In total, 634 unique VHL variants, 2882 patients, and 1991 families from 427 papers were captured. We identified relationship trends between phenotype and genotype data using classic statistical methods and spectral clustering unsupervised learning. Our analyses reveal earlier onset of pheochromocytoma/paraganglioma and retinal angiomas, phenotype co‐occurrences and genotype–phenotype correlations including hotspots. It confirms existing VHL associations and can be used to identify new patterns and associations in VHL disease. Our database serves as an aggregate knowledge translation tool to facilitate sharing information about the pathogenicity of VHL variants.

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The Genotype-Phenotype Association of Von Hipple Lindau Disease Based on Mutation Locations: A Retrospective Study of 577 Cases in a Chinese Population

Cited by 10 publications

References 31 publications

Central Nervous System Hemangioblastoma in a Pediatric Patient Associated With Von Hippel-Lindau Disease: A Case Report and Literature Review

Central Nervous System Hemangioblastoma in a Pediatric Patient Associated With Von Hippel-Lindau Disease: A Case Report and Literature Review

Genotype–phenotype correlations and clinical outcomes of patients with von Hippel-Lindau disease with large deletions

Large scale genotype‐ and phenotype‐driven machine learning in Von Hippel‐Lindau disease

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