SPRED1 and Global developmental delay: Another noteworthy example is Legius syndrome, due to SPRED1 mutations (RAS-MAPK pathway), whose phenotype includes café-au-lait spots, freckling and lacks the non-pigmentary manifestations of NF1; additional clinical manifestations reported commonly include lipomas, macrocephaly, learning disabilities, attention deficit, hyperactivity disorder, developmental delays, Noonan syndrome-like facies and, less frequently, short stature, pectus anomalies, depigmented macules, vascular lesions, headaches, hearing loss, seizures, polydactyly, scoliosis.