{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T10:27:31Z","timestamp":1781260051150,"version":"3.54.1"},"reference-count":23,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T00:00:00Z","timestamp":1759536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Audiology Research"],"abstract":"<jats:p>Introduction: Noggin encoding (NOG) gene plays a critical role in early embryogenesis and development of bones, joints, cartilage, eyes, and neural tissue. The NOG gene encodes the noggin protein. Noggin is the only secreted inhibitor of bone morphogenetic protein (BMP) that is associated with abnormal phenotypes in humans. The most commonly observed manifestations of NOG gene mutations include bilateral conductive hearing loss, proximal symphalangism, broad thumbs, hyperopia, and a distinct facial appearance. This genetic disorder was first reported in 1990 by Teunissen and Cremers. Since then, various phenotypic presentations of NOG mutation have been reported, leading to the introduction of the term NOG-related symphalangism spectrum disorder (NOG-SSD). Case report: In this report, we describe a family (mother and daughter) with bilateral mixed hearing loss. Both patients had hyperopia, distinct facial appearance with hemicylindrical nose, broad thumbs, and syndactyly of the second and third toes. Genetic testing confirmed a NOG gene mutation. Bilateral stapedotomy was successfully performed, resulting in significant hearing improvement. However, due to sensorineural component of hearing loss, complete hearing recovery was only achieved with the use of hearing aids. Discussion: The etiology of the sensorineural component of hearing loss in NOG-SSD remains unclear. In animal models, the NOG gene is essential for inner ear development, while in humans, only middle ear malformations have been reported. The phenotypic variability observed in individuals with NOG mutations is very wide, suggesting that the sensorineural component of hearing loss could represent one of the possible manifestations. Conclusions: Conductive hearing loss is the primary manifestation of the NOG-SSD, and all previously reported cases of NOG gene mutations have presented exclusively with conductive hearing loss. It is possible that additional genetic factors, not necessarily directly related to the NOG gene but present in this family, contribute to the development of the sensorineural component of hearing loss, although thorough genetic testing did not reveal any additional mutation. This is, to our knowledge, the first report of mixed hearing loss associated with a NOG mutation confirmed preoperatively. Further studies are needed to determine whether the sensorineural component represents a primary manifestation or arises from secondary mechanisms.<\/jats:p>","DOI":"10.3390\/audiolres15050130","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T08:10:51Z","timestamp":1759738251000},"page":"130","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Novel Clinical Feature in NOG Gene Mutation-Associated Syndrome"],"prefix":"10.3390","volume":"15","author":[{"given":"Matea","family":"Zrno","sequence":"first","affiliation":[{"name":"Ministry of Defense of the Republic of Croatia, 10000 Zagreb, Croatia"},{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Sveti Duh, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6988-5896","authenticated-orcid":false,"given":"Tena","family":"Simunjak","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Sveti Duh, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filip","family":"Bacan","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Lakus Ivancek","sequence":"additional","affiliation":[{"name":"SUVAG, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakov","family":"Ajduk","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Otolaryngology and Head and Neck Surgery, University Hospital Center Sestre Milosrdnice, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1126\/science.280.5368.1455","article-title":"Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton","volume":"280","author":"Brunet","year":"1998","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.ymgme.2012.03.008","article-title":"Molecular analysis of the Noggin (NOG) gene in holoprosencephaly patients","volume":"106","author":"Srivastava","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s43042-025-00672-0","article-title":"Unraveling the role of NOG gene in hereditary sensory neuropathy type 1F through CRISPR\/Cas9-mediated ATL3 knockout","volume":"26","author":"Saffar","year":"2025","journal-title":"Egypt. J. Med. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1038\/nature01245","article-title":"Structural basis of BMP signalling inhibition by the cystine knot protein Noggin","volume":"420","author":"Groppe","year":"2002","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/6821","article-title":"Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis","volume":"21","author":"Gong","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1288\/00005537-199004000-00009","article-title":"An autosomal dominant inherited syndrome with congenital stapes ankylosis","volume":"100","author":"Teunissen","year":"1990","journal-title":"Laryngoscope"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/0165-5876(91)90097-U","article-title":"The impact of a syndromal diagnosis on surgery for congenital minor ear anomalies","volume":"22","author":"Cremers","year":"1991","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1097\/00129492-200501000-00008","article-title":"Teunissen-Cremers syndrome: A clinical, surgical, and genetic report","volume":"26","author":"Weekamp","year":"2005","journal-title":"Otol. Neurotol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1002\/humu.21515","article-title":"A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD)","volume":"32","author":"Potti","year":"2011","journal-title":"Hum. Mutat."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.bjorl.2013.10.002","article-title":"Congenital defects of the middle ear\u2014Uncommon cause of pediatric hearing loss","volume":"80","author":"Esteves","year":"2014","journal-title":"Braz. J. Otorhinolaryngol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1111\/j.1399-0004.2011.01831.x","article-title":"Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis","volume":"82","author":"Usami","year":"2012","journal-title":"Clin. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1001\/archoto.2011.137","article-title":"Congenital stapes ankylosis associated with another ossicular chain anomaly: Surgical results in 30 ears","volume":"137","author":"Thomeer","year":"2011","journal-title":"Arch. Otolaryngol. Head Neck Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1097\/00129492-200109000-00006","article-title":"Prevalence of otosclerosis in an unselected series of temporal bones","volume":"22","author":"Declau","year":"2001","journal-title":"Otol. Neurotol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1002\/dvdy.22200","article-title":"Role of bone morphogenetic proteins on cochlear hair cell formation: Analyses of Noggin and Bmp2 mutant mice","volume":"239","author":"Hwang","year":"2010","journal-title":"Dev. Dyn."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ydbio.2007.08.013","article-title":"Role of hindbrain in inner ear morphogenesis: Analysis of Noggin knockout mice","volume":"311","author":"Bok","year":"2007","journal-title":"Dev. Biol."},{"key":"ref_16","first-page":"344","article-title":"Proximal symphalangism and congenital conductive hearing loss: Otologic aspects","volume":"20","author":"Ensink","year":"1999","journal-title":"Am. J. Otol."},{"key":"ref_17","first-page":"50","article-title":"A case of Teunissen-Cremers syndrome","volume":"143","author":"Yasuda","year":"2015","journal-title":"Pract. Oto-Rhino-Laryngol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.ejmg.2015.06.005","article-title":"Novel NOG mutation in Japanese patients with stapes ankylosis with broad thumbs and toes","volume":"58","author":"Ishino","year":"2015","journal-title":"Eur. J. Med. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"16023","DOI":"10.1038\/hgv.2016.23","article-title":"A novel nonsense mutation in the NOG gene causes familial NOG-related symphalangism spectrum disorder","volume":"3","author":"Takano","year":"2016","journal-title":"Hum. Genome Var."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s40246-022-00407-x","article-title":"Expanding ACMG variant classification guidelines into a general framework","volume":"16","author":"Masson","year":"2022","journal-title":"Hum. Genom."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1097\/00129492-200303000-00014","article-title":"Characterization of a stapes ankylosis family with a NOG mutation","volume":"24","author":"Brown","year":"2003","journal-title":"Otol. Neurotol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1097\/MAO.0000000000000861","article-title":"Temporal Bone Histopathology in NOG-Symphalangism Spectrum Disorder","volume":"36","author":"Quesnel","year":"2015","journal-title":"Otol. Neurotol."}],"container-title":["Audiology Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2039-4349\/15\/5\/130\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T08:56:21Z","timestamp":1759740981000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2039-4349\/15\/5\/130"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,4]]},"references-count":23,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["audiolres15050130"],"URL":"https:\/\/doi.org\/10.3390\/audiolres15050130","relation":{},"ISSN":["2039-4349"],"issn-type":[{"value":"2039-4349","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,4]]}}}