Unraveling the Mechanistic Spectrum of Myhre Syndrome: <scp>SMAD4</scp> Signaling Disruption, Skeletal Phenotypes, and Translational Innovation

ABSTRACT Myhre syndrome (MYHRS) is an ultra‐rare, progressive multisystem disorder caused by recurrent heterozygous missense variants in the SMAD4 gene, a central mediator of TGF‐ β and BMP signaling. Skeletal abnormalities—including postnatal short stature, brachydactyly, thickened calvarium, and craniofacial dysmorphism—are cardinal features, often accompanied by joint contractures and progressive soft tissue fibrosis. Extensive cellular and genetic evidence supports a gain‐of‐function (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‐negative (DN) effect was recently proposed for some variants, GoF remains the prevailing and best‐supported 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 studi