Review of the Molecular and Developmental Basis of Myhre Syndrome, Bench Research

Myhre syndrome (MS) is a connective-tissue disorder within the acromelic dysplasia spectrum. It is characterized by congenital craniofacial, skeletal, cutaneous anomalies, respiratory, cardiovascular along with intellectual disability, deafness, and progressive fibrosis. MS is caused by germline variants in the transcriptional co-regulator SMAD4 (mothers against DPP homolog 4). SMAD4 is a key intracellular mediator of signal transduction and participates in several pathways, notably canonical TGFβ and BMP signaling. These pathways play central roles in developmental and homeostatic processes. As the number of reported MS cases continues to grow, clarifying its pathophysiology is becoming increasingly important. Current evidence suggests that dysregulation of TGFβ/BMP signaling contributes to extracellular matrix (ECM) disorganization and fibrosis in MS, a relationship that remains under active investigation. Here, we review the literature and summarize current knowledge on the clinical features and pathogenic mechanisms of MS. We also discuss emerging biological roles of molecular actors that appear to be compromised, and outline therapeutic strategies that may lead to promising interventions to improve patients' quality of life.