Legius syndrome (LGSS; OMIM 611431) is the RASopathy with the most overlap to NF1.13 LGSS, inherited in an autosomal dominant pattern, is characterized by multiple CALMs similar to NF1 with or without skinfold freckling, caused by heterozygous PVs in SPRED1, located on chromosome 15.13,14 Further studies have shown that SPRED1 PVs account for 1% of sporadic cases and 19% of familial cases with pigmentary features of NF1 (CALMs and freckling) only.14 No individuals with LGSS have developed Lisch nodules, neurofibromas, or other complications of NF1. This evidence concerns the gene NF1 and Legius syndrome.