Therapy for Myhre Syndrome: Goals, Misconceptions, and Current Agents.

Myhre Syndrome (MYHRS, MIM #139210) is a rare, multisystem connective tissue disorder caused by recurrent heterozygous gain-of-function pathogenic variants in the SMAD4 gene, a key player in TGF-β signaling and a regulator of extracellular matrix homeostasis. MYHRS is characterized by a progressive fibrotic phenotype affecting multiple organ systems, including the skeletal, cardiovascular, respiratory, and integumentary systems. MYHRS individuals often present with short stature, joint contractures, cardiac valve defects, subglottic stenosis, and skin thickening. Neurodevelopmental disorders, including autism spectrum disorder, may also occur. Despite the recurrent mutations, MYHRS individuals have significant phenotypic variability. Treatment for MYHRS is symptomatic, and no disease-modifying therapies are currently available. In this article, we discuss potential future therapies in MYHRS, such as TGF-β inhibitors, anti-fibrotic drugs, and gene editing approaches. Furthermore, we discuss unmet needs on clinical and biochemical endpoints that are critical for the investigation of new therapies.