{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T15:08:17Z","timestamp":1793372897847,"version":"4.5.0"},"reference-count":40,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T00:00:00Z","timestamp":1676246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and objectives: Otoferlin is a multi-C2 domain protein implicated in neurotransmitter-containing vesicle release and replenishment of the cochlear inner hair cell (IHC) synapses. Mutations in the OTOF gene have been associated with two different clinical phenotypes: a prelingual severe-to-profound sensorineural hearing loss (ANSD-DFNB9); and the peculiar temperature-sensitive auditory neuropathy (TS-ANSD), characterized by a baseline mild-to-moderate hearing threshold that worsens to severe-to-profound when the body temperature rises that returns to a baseline a few hours after the temperature has fallen again. The latter clinical phenotype has been described only with a few OTOF variants with an autosomal recessive biallelic pattern of inheritance. Case report: A 7-year-old boy presented a picture compatible with TS-ANSD exacerbated by febrile states or physical exercise with mild-to-moderate hearing loss at low and medium frequencies and a decrease in speech discrimination that worsened with an unfavorable speech-to-noise ratio. Otoacoustic emissions (OAEs) were present whereas auditory brainstem responses (ABRs) evoked by a click or tone-burst were generally absent. No inner ear malformations were described from the CT scan or MRI. Next-generation sequencing (NGS) of the known deafness genes and multi-phasic bioinformatic analyses of the data detected in OTOF a c.2521G&gt;A missense variant and the deletion of 7.4 Kb, which was confirmed by array-comparative genomic hybridization (array-CGH). The proband\u2019s parents, who were asymptomatic, were tested by Sanger sequencing and the father presented the c.2521G&gt;A missense variant. Conclusions: The picture presented by the patient was compatible with OTOF-induced TS-ANSD. OTOF has been generally associated with an autosomal recessive biallelic pattern of inheritance; in this clinical report, two pathogenic variants never previously associated with TS-ANSD were described.<\/jats:p>","DOI":"10.3390\/medicina59020352","type":"journal-article","created":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T03:28:46Z","timestamp":1676258926000},"page":"352","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Temperature-Sensitive Auditory Neuropathy: Report of a Novel Variant of OTOF Gene and Review of Current Literature"],"prefix":"10.3390","volume":"59","author":[{"given":"Francesca","family":"Forli","sequence":"first","affiliation":[{"name":"ENT, Audiology and Phoniatrics Unit, University of Pisa, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5466-584X","authenticated-orcid":false,"given":"Silvia","family":"Capobianco","sequence":"additional","affiliation":[{"name":"ENT, Audiology and Phoniatrics Unit, University of Pisa, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Berrettini","sequence":"additional","affiliation":[{"name":"ENT, Audiology and Phoniatrics Unit, University of Pisa, 56124 Pisa, Italy"},{"name":"Division of ENT Diseases, Karolinska Institutet, 171 77 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6900-1306","authenticated-orcid":false,"given":"Luca","family":"Bruschini","sequence":"additional","affiliation":[{"name":"ENT, Audiology and Phoniatrics Unit, University of Pisa, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Romano","sequence":"additional","affiliation":[{"name":"Department of Medical and Oncological Area, Section of Medical Genetics, Azienda Ospedaliero Universitaria Pisana, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Fogli","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Section of Molecular Genetics, Azienda Ospedaliero Universitaria Pisana, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Bertini","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Section of Cytogenetics, Azienda Ospedaliero Universitaria Pisana, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7142-4570","authenticated-orcid":false,"given":"Francesco","family":"Lazzerini","sequence":"additional","affiliation":[{"name":"ENT, Audiology and Phoniatrics Unit, University of Pisa, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1097\/00003446-199806000-00001","article-title":"Transient Deafness Due To Temperature-Sensitive Auditory Neuropathy","volume":"19","author":"Starr","year":"1998","journal-title":"Ear Hear."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/j.tins.2012.08.002","article-title":"Otoferlin: A multi-C2 domain protein essential for hearing","volume":"35","author":"Reisinger","year":"2012","journal-title":"Trends Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1038\/nn.2578","article-title":"Hearing requires otoferlin-dependent efficient replenishment of synaptic vesicles in hair cells","volume":"13","author":"Lasarow","year":"2010","journal-title":"Nat. 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