Genotype–phenotype correlation in von Hippel‐Lindau disease

Reich, Michael; Jaegle, Sabine; Neumann-Haefelin, Elke; Klingler, Jan-Helge; Evers, Charlotte; Daniel, Moritz Claudius; Bucher, Felicitas; Ludwig, Franziska; Nuessle, Simone; Köpp, Julia; Boehringer, Daniel; Reinhard, Thomas; Lagrèze, Wolf A.; Lange, Clemens; Agostini, Hansjuergen; Lang, Stefan J.

doi:10.1111/aos.14843

Cited by 20 publications

(19 citation statements)

References 34 publications

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“…The onset age of CHB was also earlier than RCC, which is consistent with recent research. 25 In the previous study, the mean onset age was 31.2±12.8 years. We could conclude that the mean onset age was slightly earlier in affected offspring when compared with the whole VHL patients.…”

Section: Discussionmentioning

confidence: 85%

Clinical characteristics and risk factors for survival in affected offspring of von Hippel-Lindau disease patients

et al. 2021

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BackgroundVon Hippel-Lindau (VHL) disease is an autosomal dominant genetic tumour syndrome with poor prognosis. The clinical manifestation was found to be more serious in affected offspring of patients with VHL disease, but the risk factors and survival for them have never been reported before. We aimed to explore how these patients were influenced by genetic and clinical factors.MethodsIn this retrospective study, we collected 372 affected offspring of VHL patients from 118 unrelated VHL families. Patients were stratified into different groups based on sets of variables. The age-related risk, overall survival and central nervous systemhaemangioblastoma (CHB)-specific survival were analysed between different groups using Kaplan-Meier survival analysis and Cox regression analysis.ResultsThe estimated median life expectancy and median age of onset for affected offspring of VHL patients were 66 years and 28 years, respectively. The later generation and patients with mutations in exon 3 had an earlier onset age. The first presenting symptom was the only independent risk factor influencing overall survival and CHB-specific survival. Patients that the first presenting symptom is central nervous system (CNS) significantly had a lower life expectancy both in overall survival and CHB-specific survival analysis than abdominal lesions group.ConclusionThis study indicated that affected offspring of VHL patients with CNS as the first presenting symptom was an independent risk factor for overall survival and CHB-specific survival. Generation and mutation region only had an effect on the onset age, which is helpful to clinical decision-making and generate a more precise surveillance protocol.

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Section: Discussionmentioning

confidence: 85%

Clinical characteristics and risk factors for survival in affected offspring of von Hippel-Lindau disease patients

et al. 2021

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“…Another limitation is represented by the lack of genotype-phenotype correlations. Therefore, we cannot exclude that the genotype of VHL germline mutation may differently influence the microglia behavior in the retina [34][35][36].…”

Section: Discussionmentioning

confidence: 99%

Hyper-reflective retinal foci as possible in vivo imaging biomarker of microglia activation in von Hippel-Lindau disease

et al. 2022

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Purpose von Hippel-Lindau (VHL) disease is caused by a mutation of the VHL gene and characterized by the development of retinal hemangioblastomas (RH). Current pathophysiologic mechanisms of RH development and progression are still insufficient to predict RH behavior. VHL gene is involved in the cellular response to hypoxia and in many intracellular signaling pathways expressed both in angiogenesis and inflammation. Optical coherence tomography (OCT) allows to identify hyper-reflective retinal foci (HRF) known as aggregates of activated microglial cells as possible in vivo biomarker of local inflammation. The aim of the present study was to investigate the presence of HRF in patients with genetically confirmed VHL disease. Methods In this cross-sectional study, patients with VHL underwent complete ophthalmological examination and OCT with HRA + OCT Spectralis. HRF were manually identified and calculated in inner (IR), outer (OR) and full retina. Age-matched healthy subjects were enrolled as controls. Results 113 eyes of 63 VHL patients and 56 eyes of 28 healthy subjects were evaluated. HRF number was significantly higher in VHL than in controls in IR (28.06 ± 7.50 vs 25.25 ± 6.64, p = 0.042). No difference was observed in OR and in full retina (OR: 7.73 ± 2.59 vs 7.95 ± 2.51, p = 0.599; full retina: 35.79 ± 8.77 vs 33.20 ± 7.47, p = 0.093). Conclusion The increase of HRF, which mirror retinal microglial activation, characterizes VHL eyes. The role of activated microglia in the retina of VHL eyes needs to be better investigated, mainly considering local VHL disease manifestations.

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“…In recent reviews, Michael Reich et al concluded the data from single-centre cohort study of Germany including 216 patients with clinically expected VHL disease due to positive family history or the presence of VHL typical tumors [ 44 ]. In total, 42 different rare VHL gene variants were detected, including truncating (Deletion, VHL gene deletion, Deletion Exon 1 and 2, Deletion Exon 2 and 3, Deletion Exon 1, Deletion Exon 2, Deletion Exon 3), Splice (c.464-2A > G), Frameshift (c.220del, c.408del, c.493del), Nonsense (c.394C > T, c.481C > T, c.490C > T, c.548C > A, c.555C > A), In frame (c.227_229del), Missense (c.233A > G, c.235C > G, c.238A > C, c.239G > T, c.254T > C, c.256C > G, c.257C > A, c.262T > A, c.266 T > C, c.269A > T, c.292 T > C, c.319C > G, c.320G > A, c.335A > G, c.386T > C, c.388G > A, c.395A > C, c.407T > C, c.461C > T, c.463G > C, c.475A > G, c.486C > G, c.491A > T, c.499C > T, c.562C > G), Synonymous (c.93G > A).…”

Section: Discussionmentioning

confidence: 99%

Identification of a VHL gene mutation in atypical Von Hippel-Lindau syndrome: genotype–phenotype correlation and gene therapy perspective

et al. 2021

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Background Classical von Hippel Lindau (VHL) disease/syndrome includes CNS hemangioblastoma, renal or pancreatic cysts, pheochromocytoma, renal carcinoma and exodermic cystadenoma. The syndrome is caused by mutation of VHL tumor suppressor gene. The most prevalent mutations are present in VHL syndrome. To date, > 500 mutations of gene related to the progression of VHL syndrome have been reported. VHL gene mutation presented in single lung or pancreatic tumor has been reported occasionally, but there is no report of both. Methods In this paper, we used CT scan, pathological and genetic examination methods to diagnose a rare atypical VHL syndrome. Results We reported a rare case of atypical VHL syndrome with authenticated VHL mutation at p.Arg167Gln, that was associated with not only bilateral pheochromocytoma but also lung carcinoid and neuroendocrine tumor of pancreas. Based on literature reviews, the patient was recommended to be further subjected to octreotide-based radionuclide therapy. Conclusions Combined with gene detection and clinical diagnosis, we found the inherent relationship between VHL genotype and phenotype, and constructed the standard diagnosis and treatment process of disease with rare VHL mutation from the perspective of gene therapy.

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Genotype–phenotype correlation in von Hippel‐Lindau disease

Cited by 20 publications

References 34 publications

Clinical characteristics and risk factors for survival in affected offspring of von Hippel-Lindau disease patients

Clinical characteristics and risk factors for survival in affected offspring of von Hippel-Lindau disease patients

Hyper-reflective retinal foci as possible in vivo imaging biomarker of microglia activation in von Hippel-Lindau disease

Identification of a VHL gene mutation in atypical Von Hippel-Lindau syndrome: genotype–phenotype correlation and gene therapy perspective

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