{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T01:42:33Z","timestamp":1783820553256,"version":"3.55.0"},"reference-count":16,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T00:00:00Z","timestamp":1687824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Education, Culture, Sports, Science and Technology","award":["19H03616"],"award-info":[{"award-number":["19H03616"]}]},{"name":"Ministry of Education, Culture, Sports, Science and Technology","award":["21445007"],"award-info":[{"award-number":["21445007"]}]},{"name":"Ministry of Education, Culture, Sports, Science and Technology","award":["23810379"],"award-info":[{"award-number":["23810379"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["19H03616"],"award-info":[{"award-number":["19H03616"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["21445007"],"award-info":[{"award-number":["21445007"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["23810379"],"award-info":[{"award-number":["23810379"]}]},{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare, Japan","doi-asserted-by":"publisher","award":["19H03616"],"award-info":[{"award-number":["19H03616"]}],"id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare, Japan","doi-asserted-by":"publisher","award":["21445007"],"award-info":[{"award-number":["21445007"]}],"id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare, Japan","doi-asserted-by":"publisher","award":["23810379"],"award-info":[{"award-number":["23810379"]}],"id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Musculocontractural Ehlers\u2013Danlos syndrome (EDS) caused by pathogenic variants in CHST14 (mcEDS-CHST14) is a subtype of EDS characterized by multisystem malformations and progressive fragility-related manifestations. A recent international collaborative study showed that 55% of mcEDS-CHST14 patients had hearing loss (HL), more commonly of the high-frequency type. Here, we report the first systemic investigation of the otological features of patients with this disorder based on the world\u2019s largest cohort at Shinshu University Hospital. Nine patients [18 ears; four male and five female patients; mean age, 18 years old (range, 10\u201328)] underwent comprehensive otological evaluation: audiogram, distortion product otoacoustic emission (DPOAE) test, and tympanometry. The audiogram, available in all 18 ears, showed HL in eight patients (8\/9, 89%) and in 14 ears (14\/18, 78%): bilateral in six patients (6\/9, 67%) and unilateral in two (2\/9, 22%); mild in eight ears (8\/18, 44%) and moderate in six (6\/18, 33%); and high-frequency HL in five (5\/18, 28%) and low-frequency HL in five (5\/18, 28%). An air-bone gap was detected in one ear (1\/18, 6%). DPOAE was available in 13 ears, with the presence of a response in five (5\/13, 38%) and the absence in eight (8\/13, 62%), including in three ears of normal hearing. Tympanometry results were available in 12 ears: Ad type in nine (9\/12, 75%) and As type in one (1\/12, 8.3%). Patients with mcEDS-CHST14 had a high prevalence of HL, typically sensorineural and bilateral, with mild to moderate severity, of high-frequency or low-frequency type, and sometimes with no DPOAE response. The pathophysiology underlying HL might be complex, presumably related to alterations of the tectorial membrane and\/or the basilar membrane of Corti associated with disorganized collagen fibril networks. Regular and careful check-ups of hearing using multiple modalities are recommended for mcEDS-CHST14 patients.<\/jats:p>","DOI":"10.3390\/genes14071350","type":"journal-article","created":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T00:25:21Z","timestamp":1687911921000},"page":"1350","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Otological Features of Patients with Musculocontractural Ehlers\u2013Danlos Syndrome Caused by Pathogenic Variants in CHST14 (mcEDS-CHST14)"],"prefix":"10.3390","volume":"14","author":[{"given":"Masayuki","family":"Kawakita","sequence":"first","affiliation":[{"name":"Asama General Hospital, Saku 385-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"},{"name":"Department of Otolaryngology, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Moteki","sequence":"additional","affiliation":[{"name":"Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"},{"name":"Department of Otolaryngology, Aizawa Hospital, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6640-2297","authenticated-orcid":false,"given":"Shin-ya","family":"Nishio","sequence":"additional","affiliation":[{"name":"Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8344-7507","authenticated-orcid":false,"given":"Tomoki","family":"Kosho","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"},{"name":"Center for Medical Genetics, Shinshu University Hospital, Matsumoto 390-8621, Japan"},{"name":"Division of Clinical Sequencing, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"},{"name":"Research Center for Supports to Advanced Science, Shinshu University, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5068-6122","authenticated-orcid":false,"given":"Shin-ichi","family":"Usami","sequence":"additional","affiliation":[{"name":"Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/ajmg.c.31552","article-title":"The 2017 international classification of the Ehlers-Danlos syndromes","volume":"175","author":"Malfait","year":"2017","journal-title":"Am. J. Med. Genet. Part C Semin. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/s41572-020-0194-9","article-title":"The Ehlers-Danlos syndromes","volume":"6","author":"Malfait","year":"2020","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/ajmg.c.31550","article-title":"The Ehlers-Danlos syndromes, rare types","volume":"175","author":"Brady","year":"2017","journal-title":"Am. J. Med. Genet. Part C Semin. Med. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.ajhg.2009.11.010","article-title":"Loss of dermatan-4-sulfotransferase 1 function results in adducted thumb-clubfoot syndrome","volume":"85","author":"Zhang","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1002\/humu.21300","article-title":"Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome","volume":"31","author":"Miyake","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1002\/humu.21355","article-title":"Musculocontractural Ehlers-Danlos Syndrome (former EDS type VIB) and adducted thumb clubfoot syndrome (ATCS) represent a single clinical entity caused by mutations in the dermatan-4-sulfotransferase 1 encoding CHST14 gene","volume":"31","author":"Malfait","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3761","DOI":"10.1093\/hmg\/ddt227","article-title":"Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers-Danlos syndrome","volume":"22","author":"Mizumoto","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1111\/ped.12878","article-title":"CHST14\/D4ST1 deficiency: New form of Ehlers-Danlos syndrome","volume":"58","author":"Kosho","year":"2016","journal-title":"Pediatr. Int."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kosho, T., Mizumoto, S., Watanabe, T., Yoshizawa, T., Miyake, N., and Yamada, S. (2019). Recent advances in the pathophysiology of musculocontractural Ehlers-Danlos syndrome. Genes, 11.","DOI":"10.3390\/genes11010043"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1136\/jmedgenet-2020-107623","article-title":"Clinical and molecular features of 66 patients with musculocontractural Ehlers-Danlos syndrome caused by pathogenic variants in CHST14 (mcEDS-CHST14)","volume":"59","author":"Minatogawa","year":"2022","journal-title":"J. Med. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.bbagen.2018.12.006","article-title":"Structural alteration of glycosaminoglycan side chains and spatial disorganization of collagen networks in the skin of patients with mcEDS-CHST14","volume":"1863","author":"Hirose","year":"2019","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1097\/MAO.0000000000001082","article-title":"Audiologic outcomes in Ehlers-Danlos syndrome","volume":"37","author":"Weir","year":"2016","journal-title":"Otol. Neurotol."},{"key":"ref_13","unstructured":"Young, A., and Ng, M. (2023). StatPearls, StatPearls Publishing."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1001\/archotol.132.3.293","article-title":"The collagen structure of the tympanic membrane: Collagen types I, II, and III in the healthy tympanic membrane, during healing of a perforation, and during infection","volume":"132","author":"Stenfeldt","year":"2006","journal-title":"Arch. Otolaryngol. Head Neck Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1093\/glycob\/cwaa058","article-title":"Systematic investigation of the skin in Chst14-\/- mice: A model for skin fragility in musculocontractural Ehlers-Danlos syndrome caused by CHST14 variants (mcEDS-CHST14)","volume":"31","author":"Hirose","year":"2021","journal-title":"Glycobiology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1159\/000275855","article-title":"Collagen\u2014The predominant protein of the tectorial membrane","volume":"48","author":"Thalmann","year":"1986","journal-title":"ORL"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/7\/1350\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:01:36Z","timestamp":1760126496000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/7\/1350"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,27]]},"references-count":16,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["genes14071350"],"URL":"https:\/\/doi.org\/10.3390\/genes14071350","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,27]]}}}