Multiple café-au-lait macules (CALMs) are the hallmark of Von Recklinghausen disease, or neurofibromatosis type 1 (NF1). In 2007 we reported that some individuals with multiple CALMs have a heterozygous mutation in the SPRED1 gene and have NF1-like syndrome, or Legius syndrome. Individuals with Legius syndrome have multiple CALMs with or without freckling, but they do not show the typical NF1-associated tumors such as neurofibromas or optic pathway gliomas. NF1-associated bone abnormalities and Lisch nodules are also not reported in patients with Legius syndrome. Consequently, individuals with Legius syndrome require less intense medical surveillance than those with NF1. The SPRED1 gene was identified in 2001 and codes for a protein that downregulates the RAS-mitogen activated protein kinase (RAS-MAPK) pathway; as does neurofibromin, the protein encoded by the NF1 gene. It is estimated that about 1-4% of individuals with multiple CALMs have a heterozygous SPRED1 mutation. Mutational and clinical data on 209 patients with Legius syndrome are tabulated in an online database (http://www.lovd.nl/SPRED1). Mice with homozygous knockout of the Spred1 gene show learning deficits and decreased synaptic plasticity in hippocampal neurons similar to those seen in Nf1 heterozygous mice, underlining the importance of the RAS-MAPK pathway for learning and memory. Recently, specific binding between neurofibromin and SPRED1 was demonstrated. SPRED1 seems to play an important role in recruiting neurofibromin to the plasma membrane.