{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T12:17:22Z","timestamp":1761653842784,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Von Hippel-Lindau (VHL) is a rare genetic disorder caused by mutations in the VHL gene on chromosome 3. The disease is associated with increased incidence of neoplasia. The most common manifestations of the disease are hemangioblastomas of the CNS and spinal cord, followed by renal cell carcinomas (RCC), pancreatic tumors, pheocromocytomas, endolymphatic sac tumors, and broad ligament or epididymal cystadenomas. Due to low incidence of the disease, information about its manifestation and genetic makeup has been slow to be gathered. Herein, we present three patients suffering from VHL, all part of the same family: patient one is the father; patient two is the daughter; and patient three is the nephew of the father, cousin to the daughter. Patients and their samples were investigated by magnetic resonance imaging, immunohistochemistry and genetic testing. Results show a tumor process in the left cerebellar hemisphere of the first patient which was successfully removed. The second patient presents with cervical medullary hemangioblastoma which was also successfully removed. The third patient had a tumor formation located at the craniospinal junction, at the level of the posterior bulb which was also treated. Genetic analysis showed patients one and two presented mutations in the VHL gene, confirming the VHL diagnosis. While the cases presented here follow the general lines for VHL disease, patients are related to each other, present tumors of the nervous system and mutations in the VHL gene, their particularities of presentation and manifestation bring new insights into this rare genetic disease.<\/jats:p>","DOI":"10.3390\/life15111649","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T01:14:02Z","timestamp":1761182042000},"page":"1649","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Familial Von Hippel\u2013Lindau Disease: A Case Series of Cerebral Hemangioblastomas with MRI, Histopathological, and Genetic Correlations"],"prefix":"10.3390","volume":"15","author":[{"given":"Claudiu","family":"Matei","sequence":"first","affiliation":[{"name":"Department of Clinical Surgical, Faculty of Medicine, \u201cLucian Blaga\u201d University of Sibiu, 550024 Sibiu, Romania"},{"name":"Medlife Polisano Hospital Sibiu, 550024 Sibiu, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioana","family":"Boeras","sequence":"additional","affiliation":[{"name":"Biology and Ecology Research Center, Faculty of Sciences, \u201cLucian Blaga\u201d University of Sibiu, 550012 Sibiu, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Orga Dumitriu","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Faculty of Medicine, \u201cLucian Blaga\u201d University of Sibiu, 550024 Sibiu, Romania"},{"name":"County Emergency Clinical Hospital Sibiu, 550025 Sibiu, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cosmin","family":"Mutu","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Faculty of Medicine, \u201cLucian Blaga\u201d University of Sibiu, 550024 Sibiu, Romania"},{"name":"County Emergency Clinical Hospital Sibiu, 550025 Sibiu, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriana","family":"Popescu","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Faculty of Medicine, \u201cLucian Blaga\u201d University of Sibiu, 550024 Sibiu, Romania"},{"name":"County Emergency Clinical Hospital Sibiu, 550025 Sibiu, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5847-6480","authenticated-orcid":false,"given":"Mihai Gabriel","family":"Cucu","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genomics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania"},{"name":"Regional Centre of Medical Genetics, Emergency Clinical County Hospital Craiova, 200642 Craiova, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandru","family":"Calot\u0103-Dobrescu","sequence":"additional","affiliation":[{"name":"Regional Centre of Medical Genetics, Emergency Clinical County Hospital Craiova, 200642 Craiova, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8640-7546","authenticated-orcid":false,"given":"Bogdan","family":"Fetica","sequence":"additional","affiliation":[{"name":"PATHOS Molecular Pathology Laboratory, Oncological Institute \u201cProf. Dr. Ion Chiricuta\u201d Cluj-Napoca, 400015 Cluj-Napoca, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diter","family":"Atasie","sequence":"additional","affiliation":[{"name":"Medlife Polisano Hospital Sibiu, 550024 Sibiu, Romania"},{"name":"Department of Clinical Medicine, Faculty of Medicine, \u201cLucian Blaga\u201d University of Sibiu, 550024 Sibiu, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"78","DOI":"10.18502\/jovr.v15i1.5950","article-title":"Von Hippel-Lindau disease and the eye","volume":"15","author":"Karimi","year":"2020","journal-title":"J. Ophthalmic Vis. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"115","DOI":"10.4132\/jptm.2022.04.13","article-title":"Neuropathologic features of central nervous system hemangioblastoma","volume":"56","author":"Yoda","year":"2022","journal-title":"J. Pathol. Transl. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.3171\/2014.1.JNS131431","article-title":"Prospective natural history study of central nervous system hemangioblastomas in von Hippel-Lindau disease","volume":"120","author":"Lonser","year":"2014","journal-title":"J. Neurosurg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1001\/archopht.117.3.371","article-title":"Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation","volume":"117","author":"Webster","year":"1999","journal-title":"Arch. Ophthalmol."},{"key":"ref_5","first-page":"3067","article-title":"Retinal hemangioblastoma in von Hippel-Lindau disease: A clinical and molecular study","volume":"43","author":"Dollfus","year":"2002","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"82","DOI":"10.3171\/jns.2003.98.1.0082","article-title":"The natural history of hemangioblastomas of the central nervous system in patients with von Hippel\u2014Lindau disease","volume":"98","author":"Wanebo","year":"2003","journal-title":"J. Neurosurg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"248","DOI":"10.3171\/jns.2006.105.2.248","article-title":"Long-term natural history of hemangioblastomas in patients with von Hippel\u2013Lindau disease: Implications for treatment","volume":"105","author":"Ammerman","year":"2006","journal-title":"J. Neurosurg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1016\/S0140-6736(03)13643-4","article-title":"von Hippel-Lindau disease","volume":"361","author":"Lonser","year":"2003","journal-title":"Lancet"},{"key":"ref_9","first-page":"521","article-title":"Genetic analysis of von Hippel-Lindau disease","volume":"31","author":"Lolkema","year":"2010","journal-title":"Human Mutat."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1136\/jmg.30.2.104","article-title":"Detailed genetic mapping of the von Hippel-Lindau disease tumour suppressor gene","volume":"30","author":"Richards","year":"1993","journal-title":"J. Med. Genet."},{"key":"ref_11","first-page":"861","article-title":"Von Hippel-Lindau syndrome: Cloning and identification of the plasma membrane Ca++-transporting ATPase isoform 2 gene that resides in the von Hippel-Lindau gene region","volume":"53","author":"Latif","year":"1993","journal-title":"Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1126\/science.8493574","article-title":"Identification of the von Hippel-Lindau disease tumor suppressor gene","volume":"260","author":"Latif","year":"1993","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1038\/sj.onc.1202473","article-title":"Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity","volume":"18","author":"Blankenship","year":"1999","journal-title":"Oncogene"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1038\/nm0895-822","article-title":"Tumour suppression by the human von Hippel-Lindau gene product","volume":"1","author":"Iliopoulos","year":"1995","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8817","DOI":"10.1073\/pnas.95.15.8817","article-title":"A second major native von Hippel\u2013Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor","volume":"95","author":"Schoenfeld","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1158\/0008-5472.CAN-05-2560","article-title":"Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis","volume":"66","author":"Kurban","year":"2006","journal-title":"Cancer Res."},{"key":"ref_17","unstructured":"(2025, April 07). PedigreeXP; PC PAL. Available online: https:\/\/www.pedigreexp.com\/."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1093\/qjmed\/77.2.1151","article-title":"Clinical features and natural history of von Hippel-Lindau disease","volume":"77","author":"Maher","year":"1990","journal-title":"QJM Int. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1136\/jmg.28.7.443","article-title":"Von Hippel-Lindau disease: A genetic study","volume":"28","author":"Maher","year":"1991","journal-title":"J. Med. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/nrc3844","article-title":"VHL, the story of a tumour suppressor gene","volume":"15","author":"Gossage","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1002\/humu.20496","article-title":"Loss of the actin regulator HSPC300 results in clear cell renal cell carcinoma protection in Von Hippel-Lindau patients","volume":"28","author":"Escobar","year":"2007","journal-title":"Human Mutat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.4065\/82.10.1271","article-title":"Central nervous system tumors","volume":"Volume 82","author":"Buckner","year":"2007","journal-title":"Mayo Clinic Proceedings"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1210\/er.2014-1003","article-title":"Inhibin at 90: From discovery to clinical application, a historical review","volume":"35","author":"Makanji","year":"2014","journal-title":"Endocr. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Weidemann, S., Noori, N.A., Lennartz, M., Reiswich, V., Dum, D., Menz, A., Chirico, V., Hube-Magg, C., Fraune, C., and Bawahab, A.A. (2022). Inhibin alpha expression in human tumors: A tissue microarray study on 12,212 tumors. Biomedicines, 10.","DOI":"10.3390\/biomedicines10102507"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Listik, E., Horst, B., Choi, A.S., Lee, N.Y., Gy\u0151rffy, B., and Mythreye, K. (2021). A bioinformatic analysis of the inhibin-betaglycan-endoglin\/CD105 network reveals prognostic value in multiple solid tumors. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0249558"},{"key":"ref_26","first-page":"11","article-title":"Supratentorial dural-based haemangioblastoma in a Native American patient without Von Hippel Lindau Syndrome","volume":"2012","author":"Kaloostian","year":"2012","journal-title":"J. Surg. Case Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1016\/j.jcjo.2013.01.014","article-title":"Scleral penetration of an unusually aggressive case of a retinal hemangioblastoma","volume":"48","author":"Rodrigues","year":"2013","journal-title":"Can. J. Ophthalmol. J. Can. D\u2019ophtalmologie"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"14","DOI":"10.4081\/rt.2015.5679","article-title":"Primary gastric hemangioblastoma: Report of a case","volume":"7","author":"Basave","year":"2015","journal-title":"Rare Tumors"},{"key":"ref_29","first-page":"e9107","article-title":"Sporadic pituitary stalk hemangioblastoma: A rare case report and review of the literature","volume":"12","author":"Kasapas","year":"2020","journal-title":"Cureus"},{"key":"ref_30","first-page":"CASE2059","article-title":"Spinal intramedullary hemangioblastoma and schwannoma collision tumor: Illustrative case","volume":"18","author":"Neal","year":"2021","journal-title":"J. Neurosurg. Case Lessons"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Yang, B., Li, Z., Wang, Y., Zhang, C., Zhang, Z., and Zhang, X. (2021). Central nervous system hemangioblastoma in a pediatric patient associated with Von Hippel-Lindau disease: A case report and literature review. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.683021"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e28665","DOI":"10.1097\/MD.0000000000028665","article-title":"Hemangioblastoma masquerading as a ring enhancing lesion in the cerebellum: A case report","volume":"101","author":"Li","year":"2022","journal-title":"Medicine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"161","DOI":"10.4132\/jptm.2021.12.28","article-title":"Adrenal hemangioblastoma","volume":"56","author":"Koo","year":"2022","journal-title":"J. Pathol. Transl. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"9518","DOI":"10.12998\/wjcc.v10.i26.9518","article-title":"Supratentorial hemangioblastoma at the anterior skull base: A case report","volume":"10","author":"Xu","year":"2022","journal-title":"World J. Clin. Cases"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4178","DOI":"10.21037\/tcr-22-851","article-title":"Usefulness of neuroimaging and immunohistochemical study for accurate diagnosis of parasagittal hemangioblastoma arising in the supratentorial region: A case report and review of the literature","volume":"11","author":"Kanehisa","year":"2022","journal-title":"Transl. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1097\/PAS.0b013e3181609d7d","article-title":"Immunohistochemical markers to distinguish between hemangioblastoma and metastatic clear-cell renal cell carcinoma in the brain: Utility of aquaporin1 combined with cytokeratin AE1\/AE3 immunostaining","volume":"32","author":"Weinbreck","year":"2008","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"24","DOI":"10.25259\/SNI_477_2020","article-title":"Spinal cord hemangioblastomas with a focus on clinical presentation, diagnosis, and treatment at a tertiary care hospital of Karachi, Pakistan: A retrospective chart review","volume":"12","author":"Bukhari","year":"2021","journal-title":"Surg. Neurol. Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1097\/PAS.0b013e3182a266c1","article-title":"Peripheral hemangioblastoma: Clinicopathologic characterization in a series of 22 cases","volume":"38","author":"Doyle","year":"2014","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1016\/j.prp.2018.05.007","article-title":"Extraneuraxial hemangioblastoma: A clinicopathologic study of 10 cases with molecular analysis of the VHL gene","volume":"214","author":"Muscarella","year":"2018","journal-title":"Pathol. Res. Pract."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1097\/00000478-200308000-00014","article-title":"Inhibin alpha distinguishes hemangioblastoma from clear cell renal cell carcinoma","volume":"27","author":"Hoang","year":"2003","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1093\/jnen\/nlx008","article-title":"Immunohistochemical approach to the differential diagnosis of meningiomas and their mimics","volume":"76","author":"Fleury","year":"2017","journal-title":"J. Neuropatholgy Exp. Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1111\/j.1399-0004.2007.00827.x","article-title":"Frequency of Von Hippel-Lindau germline mutations in classic and non-classic Von Hippel-Lindau disease identified by DNA sequencing, Southern blot analysis and multiplex ligation-dependent probe amplification","volume":"72","author":"Hes","year":"2007","journal-title":"Clin. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1136\/jmg-2022-108633","article-title":"Genotype\u2013phenotype correlations and clinical outcomes of patients with von Hippel-Lindau disease with large deletions","volume":"60","author":"Zhang","year":"2023","journal-title":"J. Med. Genet."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/11\/1649\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T12:12:12Z","timestamp":1761653532000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/11\/1649"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,22]]},"references-count":43,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["life15111649"],"URL":"https:\/\/doi.org\/10.3390\/life15111649","relation":{},"ISSN":["2075-1729"],"issn-type":[{"type":"electronic","value":"2075-1729"}],"subject":[],"published":{"date-parts":[[2025,10,22]]}}}