Myhre syndrome is a rare genetic connective tissue disorder with multisystem involvement. One of at least four known mutations in the SMAD4 gene replaces an amino acid at protein position 496 or 500 with a different amino acid. Studies suggest that these mutations result in an abnormally stable SMAD4 protein that remains active in the cell longer than needed, enhancing the activity of the SMAD4 protein, which may result in abnormal transforming growth factor beta (TGF-β) signaling in many cell types, affecting development of several parts of the body.

Associated restrictive cardiomyopathy can be rapidly progressive. Laryngotracheal stenosis can cause life-threatening complications. The risk appears to increase with age and usually presents in adolescence or young adulthood.