Legius-syndrome Q85.0

Legius syndrome, also historically called neurofibromatosis type 1-like syndrome, is characterized by multiple café-au-lait spots with or without additional spatter-like axillary or ingunial pigment spots(freckles). In addition, macrocephaly, learning disabilities, and developmental delay may occur.

Other typical NF1-associated features(Lisch nodules, bone abnormalities, neurofibromas, visual pathway gliomas, and malignant peripheral nerve sheath tumors) are absent. In contrast, subcutaneous lipomas occur in adulthood in Legius syndrome.

Legius syndrome is caused by SPRED1 (Sprouty-Related EVH1 Domain Containing 1) loss-of-function mutations in the germline that lead to overactivation of the RAS-MAPK signal transduction cascade. SPRED1 is a member of the so-called Sprouty (SPRY) family of proteins that act as negative regulators within mitogen-activated protein kinase(MAPK) signal transduction.

All mutations have now been deposited in a database created with the Leiden Open Variation Database software and accessible at http://www.lovd.nl/SPRED1. Currently, the database contains 89 different mutations identified in 146 unrelated probands, including 16 new variants described for the first time. The database contains a spectrum of mutations: 29 missense, 28 frameshift, 19 nonsense, eight copy number changes, two splice, one silent, one in-frame deletion and one mutation affecting the initiation codon. Sixty-three mutations and deletions are definitely pathogenic or most likely pathogenic, eight SPRED1 mutations are likely benign rare variants, and 17 SPRED1 missense mutations are not yet classified and need further family and functional studies to classify them with confidence. Most pathogenic variants result in premature translational arrest in protein biosynthesis and loss of protein function upon inhibition of Raf1 kinase activation.

1. Tucci A et al (2017) The absence that makes the difference: choroidal abnormalities in Legius syndrome. J Hum Genet 62:1001-1004
2. Pasmant E et al. (2015) Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations? Eur J Hum Genet 23:596-601.
3. Brems H et al. (2012) Review and update of SPRED1 mutations causing Legius syndrome. Hum Mutat 33:1538-1546.