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Skeletal abnormalities\u2014including postnatal short stature, brachydactyly, thickened calvarium, and craniofacial dysmorphism\u2014are cardinal features, often accompanied by joint contractures and progressive soft tissue fibrosis. Extensive cellular and genetic evidence supports a gain\u2010of\u2010function (GoF) mechanism wherein mutant SMAD4 displays increased protein stability and prolonged nuclear localization, enhancing canonical SMAD signaling and driving overexpression of profibrotic and extracellular matrix (ECM) genes. Although a dominant\u2010negative (DN) effect was recently proposed for some variants, GoF remains the prevailing and best\u2010supported model. The underlying skeletal pathophysiology likely reflects both primary disruption of mesenchymal differentiation affecting bone and cartilage, and secondary progressive fibrosis that amplifies contractures and skeletal rigidity over time, though direct mechanistic studies in bone tissue remain limited. Therapeutically, TGF\u2010\n                    <jats:italic>\u03b2<\/jats:italic>\n                    pathway inhibitors such as losartan exhibit promising in\u00a0vitro and early clinical benefits, while advanced strategies\u2014spanning targeted small molecules, anti\u2010fibrotic agents, and emerging gene\u2010editing approaches\u2014are prospective direction for therapies. The integration of patient\u2010derived iPSC models engineered animal systems, multi\u2010modal technologies, and artificial intelligence (AI) holds significant promise for precision medicine in Myhre syndrome.\n                  <\/jats:p>","DOI":"10.1002\/ajmgc.70004","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T05:23:16Z","timestamp":1770614596000},"page":"344-358","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Unraveling the Mechanistic Spectrum of Myhre Syndrome:\n                    <scp>SMAD4<\/scp>\n                    Signaling Disruption, Skeletal Phenotypes, and Translational Innovation"],"prefix":"10.1002","volume":"199","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0981-9296","authenticated-orcid":false,"given":"Min","family":"Zhu","sequence":"first","affiliation":[{"name":"School of Medicine Hunan University of Medicine  Huaihua Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanyuan","family":"Zeng","sequence":"additional","affiliation":[{"name":"Xiangya School of Medicine Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Loudi Central Hospital  Loudi Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,8]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm6010005"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diff.2022.09.002"},{"key":"e_1_2_14_4_1","unstructured":"Applications for Collaborative Research on Myhre Syndrome (MS) | Research Development. 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