{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:09:16Z","timestamp":1787314156419,"version":"build-2736575974"},"reference-count":45,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Beijing Natural Science Foundation","award":["7242134"],"award-info":[{"award-number":["7242134"]}]},{"name":"Beijing Natural Science Foundation","award":["7244412"],"award-info":[{"award-number":["7244412"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Von Hippel\u2013Lindau disease-associated endolymphatic sac tumors (VHL-associated ELSTs) present diagnostic challenges due to their rarity and nonspecific symptoms. This study describes clinical, pathological and genotypic features to guide treatment. We retrospectively analyzed seven patients with VHL-associated ELSTs. The mean age of otologic symptom [hearing loss (100%) and facial nerve paralysis (85.71%)] onset was 22.43 \u00b1 8.68 years (range: 10\u201333). Surgical management included trans-labyrinthine and subtotal temporal bone resection approaches. Among three patients with severe preoperative facial nerve dysfunction, two underwent great auricular nerve grafting improved to House\u2013Brackmann grade IV, while one receiving hypoglossal\u2013facial nerve anastomosis reached grade V. Genetic testing identified pathogenic VHL gene missense mutations in three patients. Two female patients demonstrated disease progression during pregnancy. Literature analysis revealed exon-specific patterns: Exon 1 mutations correlated with cerebellar\/spinal hemangioblastomas in female patients, while Exon 3 mutations were associated with multisystem tumors. These findings support that VHL-associated ELSTs manifest early with otologic symptoms and demonstrate exon-specific phenotypic patterns. Optimal management requires complete surgical resection, genetic diagnosis, and a multidisciplinary approach to address these complex tumors and achieve favorable outcomes.<\/jats:p>","DOI":"10.3390\/curroncol32110633","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T02:37:54Z","timestamp":1762915074000},"page":"633","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Von Hippel\u2013Lindau Disease-Associated Endolymphatic Sac Tumours: Seven Cases and Genotype\u2013Phenotype Features"],"prefix":"10.3390","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7706-0525","authenticated-orcid":false,"given":"Qin","family":"Wang","sequence":"first","affiliation":[{"name":"Senior Department of Otorhinolaryngology Head and Neck Surgery, The 6th Medical Center of Chinese PLA General Hospital, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing and Balance Science, Beijing 100853, China"},{"name":"National Clinical Research Center for Otorhinolaryngologic Diseases, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing Science, Ministry of Education, Beijing 100853, China"},{"name":"Beijing Key Laboratory of Hearing Impairment for Prevention and Treatment, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhui","family":"Huang","sequence":"additional","affiliation":[{"name":"Senior Department of Otorhinolaryngology Head and Neck Surgery, The 6th Medical Center of Chinese PLA General Hospital, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing and Balance Science, Beijing 100853, China"},{"name":"National Clinical Research Center for Otorhinolaryngologic Diseases, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing Science, Ministry of Education, Beijing 100853, China"},{"name":"Beijing Key Laboratory of Hearing Impairment for Prevention and Treatment, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8238-026X","authenticated-orcid":false,"given":"Zhikai","family":"Zhao","sequence":"additional","affiliation":[{"name":"Senior Department of Otorhinolaryngology Head and Neck Surgery, The 6th Medical Center of Chinese PLA General Hospital, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing and Balance Science, Beijing 100853, China"},{"name":"National Clinical Research Center for Otorhinolaryngologic Diseases, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing Science, Ministry of Education, Beijing 100853, China"},{"name":"Beijing Key Laboratory of Hearing Impairment for Prevention and Treatment, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Su","sequence":"additional","affiliation":[{"name":"Senior Department of Otorhinolaryngology Head and Neck Surgery, The 6th Medical Center of Chinese PLA General Hospital, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing and Balance Science, Beijing 100853, China"},{"name":"National Clinical Research Center for Otorhinolaryngologic Diseases, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing Science, Ministry of Education, Beijing 100853, China"},{"name":"Beijing Key Laboratory of Hearing Impairment for Prevention and Treatment, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Wu","sequence":"additional","affiliation":[{"name":"Senior Department of Otorhinolaryngology Head and Neck Surgery, The 6th Medical Center of Chinese PLA General Hospital, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing and Balance Science, Beijing 100853, China"},{"name":"National Clinical Research Center for Otorhinolaryngologic Diseases, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing Science, Ministry of Education, Beijing 100853, China"},{"name":"Beijing Key Laboratory of Hearing Impairment for Prevention and Treatment, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiming","family":"Yang","sequence":"additional","affiliation":[{"name":"Senior Department of Otorhinolaryngology Head and Neck Surgery, The 6th Medical Center of Chinese PLA General Hospital, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing and Balance Science, Beijing 100853, China"},{"name":"National Clinical Research Center for Otorhinolaryngologic Diseases, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing Science, Ministry of Education, Beijing 100853, China"},{"name":"Beijing Key Laboratory of Hearing Impairment for Prevention and Treatment, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Shen","sequence":"additional","affiliation":[{"name":"Senior Department of Otorhinolaryngology Head and Neck Surgery, The 6th Medical Center of Chinese PLA General Hospital, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing and Balance Science, Beijing 100853, China"},{"name":"National Clinical Research Center for Otorhinolaryngologic Diseases, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing Science, Ministry of Education, Beijing 100853, China"},{"name":"Beijing Key Laboratory of Hearing Impairment for Prevention and Treatment, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Sai","sequence":"additional","affiliation":[{"name":"Senior Department of Otorhinolaryngology Head and Neck Surgery, The 6th Medical Center of Chinese PLA General Hospital, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing and Balance Science, Beijing 100853, China"},{"name":"National Clinical Research Center for Otorhinolaryngologic Diseases, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing Science, Ministry of Education, Beijing 100853, China"},{"name":"Beijing Key Laboratory of Hearing Impairment for Prevention and Treatment, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiju","family":"Han","sequence":"additional","affiliation":[{"name":"Senior Department of Otorhinolaryngology Head and Neck Surgery, The 6th Medical Center of Chinese PLA General Hospital, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing and Balance Science, Beijing 100853, China"},{"name":"National Clinical Research Center for Otorhinolaryngologic Diseases, Beijing 100853, China"},{"name":"State Key Laboratory of Hearing Science, Ministry of Education, Beijing 100853, China"},{"name":"Beijing Key Laboratory of Hearing Impairment for Prevention and Treatment, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/0002-9343(64)90107-X","article-title":"Lindau\u2019s Disease. Review of the Literature and Study of a Large Kindred","volume":"36","author":"Melmon","year":"1964","journal-title":"Am. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1007\/s00405-021-07047-2","article-title":"Endolymphatic sac tumor: Single-institution series of seven cases with updated review of literature","volume":"279","author":"Talukdar","year":"2022","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nrc885","article-title":"Molecular basis of the VHL hereditary cancer syndrome","volume":"2","author":"Kaelin","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1186\/s12964-025-02366-x","article-title":"Lactylation modification of HIF-1\u03b1 enhances its stability by blocking VHL recognition","volume":"23","author":"Li","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"423","DOI":"10.14639\/0392-100X-1402","article-title":"Endolymphatic sac tumour in von Hippel-Lindau disease: Management strategies","volume":"37","author":"Zanoletti","year":"2017","journal-title":"Acta Otorhinolaryngol. Ital."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/B978-0-444-62702-5.00010-X","article-title":"Von Hippel-Lindau Disease","volume":"132","author":"Chittiboina","year":"2015","journal-title":"Handb. Clin. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1001\/jama.1997.03540420057030","article-title":"Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease","volume":"277","author":"Manski","year":"1997","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"242","DOI":"10.2471\/BLT.21.285643","article-title":"The world report on hearing, 2021","volume":"99","author":"Chadha","year":"2021","journal-title":"Bull. World Health Organ."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/s00405-022-07447-y","article-title":"Surgical management of endolymphatic sac tumor: Classification, outcomes and strategy. A single institution\u2019s experience","volume":"280","author":"Wu","year":"2023","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1038\/s41588-024-01800-z","article-title":"Saturation genome editing maps the functional spectrum of pathogenic VHL alleles","volume":"56","author":"Buckley","year":"2024","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.prp.2008.01.016","article-title":"Endolymphatic sac tumor (aggressive papillary tumor of middle ear and temporal bone): Report of two cases with analysis of the VHL gene","volume":"204","author":"Skalova","year":"2008","journal-title":"Pathol. Res. Pract."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.anndiagpath.2009.10.001","article-title":"Endolymphatic sac tumor with von Hippel-Lindau disease: Report of a case with analysis of von Hippel-Lindau gene and review","volume":"14","author":"Rao","year":"2010","journal-title":"Ann. Diagn. Pathol."},{"key":"ref_13","first-page":"2609","article-title":"Endolymphatic sac tumor with von Hippel-Lindau disease: Report of a case with atypical pathology of endolymphatic sac tumor","volume":"7","author":"Yang","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S0001-6519(02)78344-1","article-title":"Endolymphatic sac tumor and von Hippel-Lindau disease. Review of the literature","volume":"53","year":"2002","journal-title":"Acta Otorrinolaringol. Esp."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Lodi, M., Marrazzo, A., Cacchione, A., Macchiaiolo, M., Romanzo, A., Mastronardi, L., Diomedi-Camassei, F., Carboni, A., Carai, A., and Gandolfo, C. (2021). Synchronous Presentation of Rare Brain Tumors in Von Hippel-Lindau Syndrome. Diagnostics, 11.","DOI":"10.3390\/diagnostics11061005"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"488","DOI":"10.3171\/jns.2004.100.3.0488","article-title":"Endolymphatic sac tumors in patients with and without von Hippel-Lindau disease: The role of genetic mutation, von Hippel-Lindau protein, and hypoxia inducible factor-1alpha expression","volume":"100","author":"Jensen","year":"2004","journal-title":"J. Neurosurg."},{"key":"ref_17","first-page":"387","article-title":"Isolate vertigo crisis revealing an endolymphatic sac tumor","volume":"51","author":"Codreanu","year":"2010","journal-title":"Rom. J. Morphol. Embryol."},{"key":"ref_18","first-page":"1","article-title":"Benefits of screening in von Hippel-Lindau disease--comparison of morbidity associated with initial tumours in affected parents and children","volume":"66","author":"Priesemann","year":"2006","journal-title":"Horm. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1212\/WNL.53.1.208","article-title":"VHL gene inactivation in an endolymphatic sac tumor associated with von Hippel-Lindau disease","volume":"53","author":"Kawahara","year":"1999","journal-title":"Neurology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s11912-024-01631-5","article-title":"New Developments in VHL-Associated Neuroendocrine Neoplasms","volume":"27","author":"Tsoli","year":"2025","journal-title":"Curr. Oncol. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1001\/jama.298.1.41","article-title":"Mechanisms of morbid hearing loss associated with tumors of the endolymphatic sac in von Hippel-Lindau disease","volume":"298","author":"Butman","year":"2007","journal-title":"JAMA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1111\/nan.12741","article-title":"Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel-Lindau disease-related tumours","volume":"47","author":"Schweizer","year":"2021","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"E673","DOI":"10.1002\/hed.24067","article-title":"Characterization of endolymphatic sac tumors and von Hippel-Lindau disease in the International Endolymphatic Sac Tumor Registry","volume":"38","author":"Bausch","year":"2016","journal-title":"Head. Neck."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1002\/lary.23646","article-title":"Surgical resection of endolymphatic sac tumors in von Hippel-Lindau disease: Findings, results, and indications","volume":"123","author":"Kim","year":"2013","journal-title":"Laryngoscope"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5081","DOI":"10.1007\/s00405-022-07469-6","article-title":"Symptoms and clinical features in patients affected by endolymphatic sac tumor: A systematic review and meta-analysis","volume":"279","author":"Gioacchini","year":"2022","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_26","first-page":"913","article-title":"Endolymphatic sac tumor with von Hippel-Lindau disease: Report of two cases with testing of von Hippel-Lindau gene","volume":"48","author":"Su","year":"2013","journal-title":"Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"361","DOI":"10.5152\/iao.2021.0190","article-title":"Vestibular Function in Children with Von Hippel-Lindau Disease","volume":"17","author":"Crunkhorn","year":"2021","journal-title":"J. Int. Adv. Otol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e644","DOI":"10.1097\/MAO.0000000000004307","article-title":"Endolymphatic Sac Tumors Associated with von Hippel-Lindau: A Case Report Highlighting Opportunity for Novel Orphan Drug Therapy","volume":"45","author":"Tan","year":"2024","journal-title":"Otol. Neurotol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1097\/00129492-200409000-00021","article-title":"Differential grading of endolymphatic sac tumor extension by virtue of von Hippel-Lindau disease status","volume":"25","author":"Bambakidis","year":"2004","journal-title":"Otol. Neurotol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"387","DOI":"10.2310\/7070.2006.0082","article-title":"Endolymphatic sac tumours: Surgical management","volume":"35","author":"Schipper","year":"2006","journal-title":"J. Otolaryngol."},{"key":"ref_31","first-page":"12","article-title":"Surgical management of endolymphatic sac tumors","volume":"74","author":"Friedman","year":"2013","journal-title":"J. Neurol. Surg. B Skull Base"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"18","DOI":"10.4103\/sni.sni_312_17","article-title":"Gamma knife radiosurgery in the management of endolymphatic sac tumors","volume":"9","author":"Sinclair","year":"2018","journal-title":"Surg. Neurol. Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1093\/neuonc\/nor085","article-title":"Infratentorial craniospinal irradiation for von Hippel-Lindau: A retrospective study supporting a new treatment for patients with CNS hemangioblastomas","volume":"13","author":"Simone","year":"2011","journal-title":"Neuro Oncol."},{"key":"ref_34","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_35","first-page":"1228","article-title":"Expression of VHL, VEGF and HIF-1\u03b1 in endolymphatic sac tumors","volume":"50","author":"Mao","year":"2021","journal-title":"Zhonghua Bing Li Xue Za Zhi"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e009963","DOI":"10.1136\/jitc-2024-009963","article-title":"VHL missense mutation delineate aggressive clear cell renal cell carcinoma subtype with favorable immunotherapeutic response","volume":"12","author":"Xu","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_37","first-page":"B4763","article-title":"Von Hippel-Lindau disease (vHL). National clinical guideline for diagnosis and surveillance in Denmark. 3rd edition","volume":"60","author":"Binderup","year":"2013","journal-title":"Dan. Med. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1136\/jmedgenet-2016-104058","article-title":"Survival and causes of death in patients with von Hippel-Lindau disease","volume":"54","author":"Binderup","year":"2017","journal-title":"J. Med. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1136\/jmedgenet-2017-104995","article-title":"Risk factors for survival in patients with von Hippel-Lindau disease","volume":"55","author":"Wang","year":"2018","journal-title":"J. Med. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"818","DOI":"10.3171\/2012.7.JNS12367","article-title":"Effect of pregnancy on hemangioblastoma development and progression in von Hippel-Lindau disease","volume":"117","author":"Ye","year":"2012","journal-title":"J. Neurosurg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1212\/WNL.0000000000002064","article-title":"New von Hippel-Lindau manifestations develop at the same or decreased rates in pregnancy","volume":"85","author":"Binderup","year":"2015","journal-title":"Neurology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1212\/WNL.0b013e3182661f3c","article-title":"Pregnancy-related hemangioblastoma progression and complications in von Hippel-Lindau disease","volume":"79","author":"Frantzen","year":"2012","journal-title":"Neurology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"325","DOI":"10.2147\/IJWH.S166216","article-title":"Pregnancy-induced growth of a spinal hemangioblastoma: Presumed mechanisms and their implications for therapeutic approaches","volume":"10","author":"Farage","year":"2018","journal-title":"Int. J. Womens Health"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s10143-017-0910-4","article-title":"Accelerated growth of hemangioblastoma in pregnancy: The role of proangiogenic factors and upregulation of hypoxia-inducible factor (HIF) in a non-oxygen-dependent pathway","volume":"42","author":"Laviv","year":"2019","journal-title":"Neurosurg. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.placenta.2007.11.015","article-title":"Proteasomal activity in placentas from women with preeclampsia and intrauterine growth restriction: Implications for expression of HIF-alpha proteins","volume":"29","author":"Rajakumar","year":"2008","journal-title":"Placenta"}],"container-title":["Current Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1718-7729\/32\/11\/633\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T05:15:15Z","timestamp":1763097315000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1718-7729\/32\/11\/633"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,12]]},"references-count":45,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["curroncol32110633"],"URL":"https:\/\/doi.org\/10.3390\/curroncol32110633","relation":{},"ISSN":["1718-7729"],"issn-type":[{"value":"1718-7729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,12]]}}}