SPRED1 and Legius syndrome: Germline loss-of-function mutations of SPRED1 were found in neurofibromatosis-1 (NF1)-like disease.74,75) This disease is caused by the haplo-insufficiency of SPRED1, which is dominantly inherited, and causes café au lait macules, axillary freckling, macrocephaly, learning disabilities, and leukemia at low rates,76) and is now called Legius syndrome.77) The NF1 gene encodes neurofibromin, a GAP that deactivates Ras.