Legius syndrome nfls, neurofibromatosis type 1like syndrome omim 611431 background legius syndrome is found in some people who have mild nf1type symptoms, but have no mutation in the nf1 gene omim 61. Legius syndrome nfls, neurofibromatosis type 1like. Neurofibromatosis type 1 new york clients tests displaying the status new york approved. Investigating genetic counselors experiences with legius syndrome a thesis presented to the department of biological sciences graduate school of arts and sciences brandeis university waltham, massachusetts by sarah c. We described a first solitary case of legius syndrome identified by next. Investigating genetic counselors experiences with legius.
Legius syndrome is caused by heterozygous inactivating mutations in the. Nextgen rasopathy panel school of medicine genetics uab. The rasopathies are a group of syndromes characterized by dysregulation of signaling through the ras pathway and include neurofibromatosis type 1 nf1, noonan syndrome ns, ns with multiple lentigines, capillary malformationav malformation syndrome, legius syndrome, costello syndrome cs, and cardiofaciocutaneous syndrome cfc. Additional clinical manifestations reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities adhd developmental delays. It is caused by germline lossoffunction spred1 mutations and is a. Individuals frequently fulfill the nih diagnostic criteria for nf1 based on pigmentary manifestations of. Legius syndrome is an autosomal dominant condition characterized by cafe au lait spots. Spred1, a ras mapk pathway inhibitor that causes legius. The majority of the mutations identified in the rasopathies are point mutations which increase rasmapk pathway signaling. Indications for ordering confirm diagnosis of legius syndrome ls in symptomatic individuals for individuals being evaluated for neurofibromatosis type 1 nf1 who test negative for.
The ras opathies exhibit several overlapping phenotypic features due to their common underlying rasmapk pathway dysregulation. Each child of an individual with legius syndrome has a 50% chance of inheriting the pathogenic variant. Legius syndrome is an autosomal dominant disorder that shows some similarities to neurofibromatosis type i nf1. Lgss to ensure longterm funding for the omim project, we have diversified our revenue stream. We herein report the first instance of legius syndrome occurring in two female siblings in japan. Lisch nodules, neurofibromas, optic glioma, bone abnormalities. This pathway is involved in a signal transduction cascade that. Almost all affected individuals have multiple cafeaulait spots, which are flat patches on the skin that are darker than the surrounding area. The mgl provides testing for gnas given the overlap between segmentalmosaic nf1 legius syndrome and mccunealbright syndrome. Individuals with legius syndrome typically have multiple cafeaulait spots, sometimes associated with skin fold freckling, variable dysmorphic features such as hypertelorism or. The rasopathies are sometimes known to be associated with an increase in dysmorphic features. As a group, the rasopathies are one of the largest groups of malformation syndromes known, affecting 1. Nextgen gnas only for mccunealbright syndrome school of.
Legius syndrome is a condition characterized by changes in skin coloring pigmentation. The gnas gene codes for an alpha subunit of the stimulatory guanine nucleotidebinding protein g protein, which is responsible for transducing extracellular signals received by transmembrane receptors in a cascade to. The differential molecular diagnosis of these pathologies is a challenge that can now be met by combining next generation sequencing of target genes with concurrent secondlevel tests, such as multiplex ligationdependent. Legius syndrome is a rare genetic disorder caused by heterozygous germ line loss. The invitae legius syndrome test analyzes spred1, a gene that is associated with legius syndrome. Legius syndrome is inherited in an autosomal dominant manner. Yes are approved or conditionally approved by new york state and do not require an nys npl exemption. Constitutional dominant lossoffunction mutations in the spred1 gene cause a rare phenotype referred as neurofibromatosis type 1 nf1like syndrome or legius syndrome. Test neurofibromatosis type 1 and legius syndrome panel. Robart legius syndrome ls, caused by mutations in spred1, is a recently identified condition. Legius syndrome genetic and rare diseases information.
Legius syndrome online mendelian inheritance in man no. Legius syndrome, is a recently identified autosomal dominant disorder caused by loss of function mutations in the spred1 gene, with individuals mainly presenting with multiple cafeaulait. Individuals with legius syndrome have multiple calms with or without freckling, but they do not show the typical. Legius syndrome is a genetic condition inherited in an autosomal dominant manner that involves a spred1 gene mutation on chromosome 15q14. Legius syndrome, like nf, noonans, and leopard syndrome all involve a particular molecular pathway called ras, and are therefore, collectively known as rasopathies. Family with legius syndrome neurofibromatosis type 1. Although uncommonly requested, prenatal diagnosis for pregnancies at increased risk is possible if the spred1 pathogenic variant has been identified in an affected family member. This mutation results in the abnormal function of the spred1 protein, which is responsible for regulating specific cellsignalling pathways involved in cell proliferation, differentiation, and apoptosis. It is also known as neurofibromatosis type 1like syndrome.
Legius syndrome is characterized by multiple cafe au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 nf1. The spred1 gene encodes a protein involved in the rasmapk mitogenactivated protein kinase signaling pathway. Another pigmentation change, freckles in the armpits and groin, may occur in some affected. January 20 mutations in the spred1 gene have been found in patients with legius syndrome, originally termed neurofibromatosis type 1like syndrome. In 2007 we reported that some individuals with multiple calms have a heterozygous mutation in the spred1 gene and have nf1like syndrome, or legius syndrome. Neurologists should be aware that legius syndrome can resemble neurofibromatosis type 1, report investigators led by ludwine messiaen, phd, from the university of alabama at birmingham.
The rasopathies are a genetically heterogeneous group of disorders caused by variants in the genes involved in the rasmapk pathway. Legius syndrome is one of the ras opathies, which are a class of pediatric disorders associated with genes that are members of the mitogenactivated protein kinase rasmapk pathway. Nearly 100 different mutations in this gene have been identified. Pigmentary manifestations can represent an early clinical sign in children affected by neurofibromatosis type 1 nf1, legius syndrome, and other neurocutaneous disorders.
Neurofibromatosis 1like syndrome, or legius syndrome, is an autosomal dominant disorder resembling neurofibromatosis 1 with cafeaulait spots, axillary freckling, macrocephaly, learning disabilities, adhd, developmental delays, and dysmorphic facial features similar to noonan syndrome denayer et al. Legius syndrome is differentiated from nf1 by the absence of the nonpigmentary clinical manifestations seen in this disorder i. However unlike nf1, there is notable absence of neurofibromas, lisch nodules, bony lesions, or optic. Legius syndrome is caused by spred1 mutations on chromosome 15q. The condition is a rasopathy, a group of developmental syndromes due to germline mutations in genes. Freckling typically found in the armpit andor the groin areas, and varying degrees of macrocephaly i. Legius syndrome, which is caused by pathogenic variants in the spred1 gene, has marked similarity to nf1. Legius syndrome is not characterized by an increased risk of tumours, and a correct diagnosis is important. Legius syndrome sharma mk, kumar r, gupta s, jain sk. Activating mutations of the stimulatory g protein in the mccunealbright syndrome. Rasmapk pathway germline mutations were described in rasopathies, a class of rare genetic syndromes combining facial abnormalities, heart defects, short stature, skin and genital abnormalities, and mental retardation. In japan, a family with legius syndrome was first described in 2015 by sakai et al. Legius syndrome often mistaken for neurofibromatosis type 1.
Legius syndrome in a 16 year old child, vol 1, issue 1, 2019 page 17 legius syndrome in a 16 year old kumar p. View edit human view edit mouse sproutyrelated, evh1 domaincontaining protein 1 spread1 is a protein that in humans is encoded by the spred1 gene located on. Mutations in spred1 have been reported to cause legius syndrome, a rare developmental disorder that shares some clinical features with neurofibromatosis1. Individuals with legius syndrome typically have multiple cafeaulait spots, sometimes associated with skin fold freckling, variable dysmorphic features such as hypertelorism or macrocephaly, lipomas, and mild learning disabilities or attention problems. Correct diagnosis is essential because of the differences in prognosis and longterm monitoring between legius syndrome and nf1.
Legius syndrome is caused by heterozygous inactivating mutations in the spred1 gene 15q14, involved in regulation of the rasmapk signal transduction pathway. Genes free fulltext clinical and genetic findings in. Tests for a mutation previously identified in a family member. Test description polymerase chain reaction followed by bidirectional sequencing of.