The exact mechanism by which oxidative stress can induce LVH in CRS-4 remains unclear but there is experimental evidence that nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity is increased, which subsequently activates the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and upregulates fibroblast growth factor‐2 (FGF2), a known promoter of cardiac fibrosis. This evidence concerns the gene MAPK3 and craniosynostosis 4.