Legius Syndrome and SPRED 1

Abstract

Abstract Legius syndrome, initially reported as neurofibromatosis type 1‐like syndrome, is an autosomal dominant disorder caused by heterozygous inactivating SPRED1 mutations. The disease is characterised by multiple café‐au‐lait spots (CALs), sometimes associated with axillary or inguinal freckling and macrocephaly as seen in neurofibromatosis type 1 ( NF1 ). Other typical NF1 associated features (Lisch nodules, bone abnormalities, neurofibromas, optic pathway gliomas and malignant peripheral nerve sheath tumours) are lacking. Some degree of learning disability and/or speech problems in infancy are frequently observed and are usually milder than in NF1 . The SPRED1 protein is a negative regulator of the RAS (rat sarcoma viral oncogene homolog)‐MAPK ( mitogen‐activated protein kinase ) pathway. CALs in Legius syndrome result from bi‐allelic SPRED1 inactivation in melanocytes. SPRED1 loss‐of‐function results in overactivation of the RAS‐MAPK signalling pathway. This is similar to what is seen in a group of disorders caused by mutations in other genes coding for key proteins of the RAS‐MAPK pathway (referred as RASopathies). Key Concepts: Legius syndrome is an autosomal dominant disorder. It is caused by heterozygous mutations in the SPRED1 gene. The phenotype consists of café‐au‐lait spots, sometimes with axillary or inguinal freckling and a variable degree of macrocephaly. Learning disabilities and speech problems in infants are frequently reported. SPRED1 is a negative regulator of the RAS‐MAPK pathway at the level of activation of RAF by RAS‐GTP. Legius syndrome is a RASopathy (RAS‐MAPK syndrome).