{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:48:02Z","timestamp":1790837282748,"version":"4.1.0"},"reference-count":25,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T00:00:00Z","timestamp":1678838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Multiple synostoses syndrome (OMIM: #186500, #610017, #612961, #617898) is a genetically heterogeneous group of autosomal dominant diseases characterized by abnormal bone unions. The joint fusions frequently involve the hands, feet, elbows or vertebrae. Pathogenic variants in FGF9 have been associated with multiple synostoses syndrome type 3 (SYNS3). So far, only five different missense variants in FGF9 that cause SYNS3 have been reported in 18 affected individuals. Unlike other multiple synostoses syndromes, conductive hearing loss has not been reported in SYNS3. In this report, we describe the clinical and selected radiological findings in a large multigenerational family with a novel missense variant in FGF9: c.430T&gt;C, p.(Trp144Arg). We extend the phenotypic spectrum of SYNS3 by suggesting that cleft palate and conductive hearing loss are part of the syndrome and highlight the high degree of intrafamilial phenotypic variability. These findings should be considered when counseling affected individuals.<\/jats:p>","DOI":"10.3390\/genes14030724","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T03:50:45Z","timestamp":1678938645000},"page":"724","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["FGF9-Associated Multiple Synostoses Syndrome Type 3 in a Multigenerational Family"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8220-7854","authenticated-orcid":false,"given":"Ariane","family":"Schmetz","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Schaper","sequence":"additional","affiliation":[{"name":"Center for Rare Diseases, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Thelen","sequence":"additional","affiliation":[{"name":"Department of Orthopedic and Trauma Surgery, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majeed","family":"Rana","sequence":"additional","affiliation":[{"name":"Department of Oral, Maxillo- and Plastic Facial Surgery, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6883-0905","authenticated-orcid":false,"given":"Thomas","family":"Klenzner","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Schaumann","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin","family":"Beygo","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3595-9188","authenticated-orcid":false,"given":"Harald","family":"Surowy","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermann-Josef","family":"L\u00fcdecke","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"Wieczorek","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"},{"name":"Center for Rare Diseases, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1086\/301921","article-title":"Localization of a multiple synostoses-syndrome disease gene to chromosome 17q21-22","volume":"63","author":"Krakow","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1002\/ajmg.a.38503","article-title":"Further delineation of the GDF6 related multiple synostoses syndrome","volume":"176","author":"Terhal","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1097\/00019605-200504000-00004","article-title":"The facio-audio-symphalangism syndrome in a four generation family with a nonsense mutation in the NOG-gene","volume":"14","author":"Mattelaer","year":"2005","journal-title":"Clin. Dysmorphol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/wdev.176","article-title":"The Fibroblast Growth Factor signaling pathway","volume":"4","author":"Ornitz","year":"2015","journal-title":"Wiley Interdiscip. Rev. Dev. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/ng.316","article-title":"FGF9 monomer-dimer equilibrium regulates extracellular matrix affinity and tissue diffusion","volume":"41","author":"Harada","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00335-001-2143-6","article-title":"Elbow knee synostosis (Eks): A new mutation on mouse Chromosome 14","volume":"13","author":"Murakami","year":"2002","journal-title":"Mamm. Genome"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1002\/jbmr.4230","article-title":"Fgf9 Negatively Regulates Bone Mass by Inhibiting Osteogenesis and Promoting Osteoclastogenesis Via MAPK and PI3K\/AKT Signaling","volume":"36","author":"Tang","year":"2021","journal-title":"J. Bone Miner. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1002\/ajmg.a.36391","article-title":"Wide spectrum of congenital anomalies including choanal atresia, malformed extremities, and brain and spinal malformations in a girl with a de novo 5.6-Mb deletion of 13q12.11\u201313q12.13","volume":"164","author":"Pavone","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.ajhg.2009.06.007","article-title":"Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene","volume":"85","author":"Wu","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1002\/humu.23292","article-title":"FGF9 mutation causes craniosynostosis along with multiple synostoses","volume":"38","author":"Vallespin","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/humu.23912","article-title":"Multiplex targeted high-throughput sequencing in a series of 352 patients with congenital limb malformations","volume":"41","author":"Jourdain","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1111\/cge.13876","article-title":"Identification of the third FGF9 variant in a girl with multiple synostosis-comparison of the genotype:phenotype of FGF9 variants in humans and mice","volume":"99","author":"Heath","year":"2021","journal-title":"Clin. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1111\/cge.13880","article-title":"A novel heterozygous variant in FGF9 associated with previously unreported features of multiple synostosis syndrome 3","volume":"99","author":"Thuresson","year":"2021","journal-title":"Clin. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1002\/ajmg.a.62729","article-title":"Novel FGF9 variant contributes to multiple synostoses syndrome 3","volume":"188","author":"Dobson","year":"2022","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_16","unstructured":"Rehmann, I. (1973). Ein dominantes Syndrom multipler Gelenkaplasien in Verbindung mit Phalangenverk\u00fcrzungen und Humerusfehlbildungen. [Ph.D. Thesis, Westf\u00e4lischen Wilhelms-Universit\u00e4t zu M\u00fcnster]."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1107\/S0907444900020813","article-title":"Structure of fibroblast growth factor 9 shows a symmetric dimer with unique receptor- and heparin-binding interfaces","volume":"57","author":"Hecht","year":"2001","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.ajhg.2009.03.010","article-title":"DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources","volume":"84","author":"Firth","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Genome of the Netherlands Consortium (2014). Whole-genome sequence variation, population structure and demographic history of the Dutch population. Nat. Genet., 46, 818\u2013825.","DOI":"10.1038\/ng.3021"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: Improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"The UniProt Consortium (2023). UniProt: The Universal Protein Knowledgebase in 2023. Nucleic Acids Res., 51, D523\u2013D531.","DOI":"10.1093\/nar\/gkac1052"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"653040","DOI":"10.3389\/fphys.2021.653040","article-title":"The Fibroblast Growth Factor 9 (Fgf9) Participates in Palatogenesis by Promoting Palatal Growth and Elevation","volume":"12","author":"Li","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1097\/MAO.0000000000001234","article-title":"Long-term Incidence and Degree of Sensorineural Hearing Loss in Otosclerosis","volume":"37","author":"Ishai","year":"2016","journal-title":"Otol. Neurotol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e05921","DOI":"10.7554\/eLife.05921","article-title":"Cochlear progenitor number is controlled through mesenchymal FGF receptor signaling","volume":"4","author":"Huh","year":"2015","journal-title":"Elife"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/3\/724\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:56:07Z","timestamp":1760122567000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/3\/724"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,15]]},"references-count":25,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["genes14030724"],"URL":"https:\/\/doi.org\/10.3390\/genes14030724","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,15]]}}}