RSPO2 and tetra-amelia: Rspos could as well activate Wnt/β-catenin signaling via interacting with HSPGs independent of Lgrs.117 Interestingly, Rspo2 mutations were unraveled to associate with tetra-amelia syndrome, contributing to the destruction of Rspo2-Lgr binding.118 Current evidence depicted the crucial roles of somatic mutations of Rspos in cancers.