Figure 1. Dysregulation of ERBB2 and ERBB3 signaling as the molecular basis of a diverse array of developmental disorders.

Le et al. (18) described patients with neurocristopathies, developmental disorders arising from the neural crest; the most prominent included congenital aganglionosis of the terminal bowel (HSCR) and CIPO or PIPO. Some individuals had arthrogryposis, possibly due to disordered development of skeletal muscle myotubes. The authors identified variants in ERBB2/ERBB3 genes, which encode transmembrane epidermal growth factor receptors and bind NRG1. ERBB3/ERBB2 was expressed in enteric neuronal progenitor cells, which derive from the neural crest. The loss-of-function ERBB3/ERBB2 variants resulted in reduced expression and altered signaling. The figure was adapted with permission from Rao et al., Hicks et al., and Choi et al. (4, 24, 25).