E198598 january 2011 with 500 reads how we measure reads. Pigmentary manifestations can represent an early clinical sign in children affected by neurofibromatosis type 1 nf1, legius syndrome, and other neurocutaneous disorders. She was born with these, but not until a recent pediatrician change were we aware that this could be a sign of nf1 or legius syndrome. Legius syndrome is differentiated from nf1 by the absence of the nonpigmentary clinical manifestations seen in this disorder i. When spred1 is dysfunctional then this in turn affects the aforementioned pathway, which in turn eventually leads to the physical symptoms created by this condition.
The disorder is quite similar to and may be misdiagnosed as neurofibromatosis type 1. Pdf legius syndrome in fourteen families hilde brems. To ascertain the frequency of spred1 mutations as a cause of this phenotype. We described a first solitary case of legius syndrome identified by next.
All doctors involved in the care, diagnosis, and treatment of. Lisch nodules, neurofibromas, optic glioma, bone abnormalities. 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. This pathway is involved in a signal transduction cascade that is necessary for the proper. A case report legius syndrome is a rare genetic disorder caused by heterozygous germ line lossoffunction spred1 mutation.
Individuals have multiple cafeaulait spots that are darker than the surrounding area. It was first described in 2007 and is often mistaken for neurofibromatosis type i nf1. Tests for a mutation previously identified in a family member. Legius syndrome is caused by mutations in the spred1 gene, while nf1 is caused by mutations in the gene encoding neurofibromin. The treatment of legius syndrome is primarily supportive and should be. Legius syndrome is characterized by multiple cafe au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 nf1.
We herein report the first instance of legius syndrome occurring in two female siblings in japan. In such patients, a correct diagnosis has important implications for prognosis, counseling, and potential prenatal genetic diagnosis. 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 is caused by spred1 mutations on chromosome 15q. Jan 02, 2016 legius syndrome, like nf, noonans, and leopard syndrome all involve a particular molecular pathway called ras, and are therefore, collectively known as rasopathies. Another pigmentation change, freckles in the armpits and groin, may occur in some affected individuals. Legius syndrome genetic and rare diseases information. Family with legius syndrome neurofibromatosis type 1. Legius syndrome is an autosomal dominant disorder that shows some similarities to neurofibromatosis type i nf1. Recently, missense mutations in the ptpn11 gene located in 12q24 were found to cause.
Almost all affected individuals have multiple cafeaulait spots, which are flat patches on the skin that are darker than the surrounding area. Cafe au lait spots, axillary and inguinal freckling, learning disability and macrocephaly. Legius syndrome is an autosomal dominant disorder caused by heterozygous inactivating mutations in the spred1 gene. Current knowledge of the natural history of legius syndrome is based. Legius syndrome follows an autosomal dominant pattern of inheritance. Legius syndrome is a condition characterized by changes in skin coloring pigmentation.
The spred1 gene provides instructions for making the spred1 protein. Abstractlegius syndrome ls is an autosomal dominant disorder caused by germline lossoffunction. A shared molecular mechanism underlies the human rasopathies. Other typical nf1 associated features lisch nodules, bone abnormalities, neurofibromas, optic pathway gliomas are. Legius syndrome, which is caused by pathogenic variants in the spred1 gene, has marked similarity to nf1. Legius syndrome has been characterized as a milder form of nf1, with individuals displaying multiple cafeaulait spots, axillary freckling, and macrocephaly, but lacking other common nf1 manifestations such as lisch nodules, neurofibromas, osseous lesions, or optic pathway gliomas. This protein controls regulates an important cell signaling pathway that is involved in the growth and division of cells proliferation, the process by which cells mature to carry out specific functions differentiation, cell movement, and the selfdestruction of cells apoptosis. She is 8 years old and has cafe au lait spots, and freckling in the armpit and groin. Legius syndrome is characterized by the presence of multiple cafeaulait spots and axillary and inguinal freckling. Genes free fulltext clinical and genetic findings in. Nov 18, 2009 the few reports of individuals with lossoffunction spred1 mutations have shown that the primary phenotype of legius syndrome is cafe au lait macules, sometimes associated with axillary freckling, inguinal freckling, or both. Jul 01, 2014 legius syndrome is differentiated from nf1 by the absence of the nonpigmentary clinical manifestations seen in this disorder i. Legius syndrome ls is characterized by multiple cafe au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 nf1. Legius syndrome, also known as neuro bromatosis nf.
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. Hirecently my daughter was sent to a specialist to be evaluated for nf1 legius syndrome. The trip database provides clinical publications about evidence. Her family history was remarkable for the presence of multiple cafeaulait spots in the mother, the grandfather and two aunts. Legius syndrome definition of legius syndrome by medical. Oct 14, 2010 legius syndrome is characterized by multiple cafe au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 nf1. It is also known as neurofibromatosis type 1like syndrome nfls. It is characterised by multiple cafeaulait macules calm with or without axillary or inguinal freckling and mild macrocephaly. In japan, a family with legius syndrome was first described in 2015 by sakai et al. Each child of an individual with legius syndrome has a 50% chance of inheriting the pathogenic variant. Legius syndrome is a rare genetic disorder caused by heterozygous germ line loss.
Legius syndrome is a rare genetic disorder characterized by multiple cafe au lait macules and other clinical manifestations like freckling, lipomas, macrocephaly, learning disabilities, developmental delays. Mutations in the spred1 gene cause legius syndrome. While multiple cafeaulait spots, axillary and inguinal freckling are features common to both conditions, nf1 has additional features that are typically absent in legius syndrome, such as lisch nodules i. Legius syndrome is genetically distinct but similar to. Spred1 gene analysis in legius syndrome clinical features. Deafness and genital abnormalities are less frequently found. The phenotype of ls is multiple cafe au lait macules calm with other commonly reported manifestations, including intertriginous freckling, lipomas, macrocephaly, and learning disabilities including adhd and developmental delays. Lossoffunction mutations in one feedback regulator of rasmapk signaling, spred1 sproutyrelated protein with an evh1 domain, cause legius syndrome, an autosomal dominant human disorder that resembles neurofibromatosis1 nf1. Spred1 functions as a negative regulator of the rasmapk pathway. Pdf legius syndrome in fourteen families yolande van. Legius syndrome online mendelian inheritance in man no. Individuals with legius syndrome typically have multiple cafeaulait spots, sometimes associated with skin fold freckling, variable dysmorphic features such as hypertelorism. 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. To ascertain the frequency of spred1 mutations as a cause of this.
This protein controls regulates an important cell signaling pathway that is involved in the growth and division of cells proliferation, the process by which cells mature to carry out specific functions differentiation, cell movement, and the selfdestruction of cells. Neurofibromatosis type 1 nf1 and legius syndrome ls often confuse. Mar 01, 2011 hirecently my daughter was sent to a specialist to be evaluated for nf1 legius syndrome. However unlike nf1, there is notable absence of neurofibromas, lisch nodules, bony lesions, or optic. We report a father and daughter and a third, unrelated patient with leopard syndrome. Individuals frequently fulfill the nih diagnostic criteria for nf1 based on pigmentary manifestations of. Mutations in the spred1 gene have been implicated in legius syndrome. Clinical and mutational spectrum of neurofibromatosis type 1. Genetic test for legius syndrome by ambry genetics ambry. Many legius syndrome signs and symptoms also occur in a similar disorder called neurofibromatosis type 1 nf1. Legius syndrome often mistaken for neurofibromatosis type 1. 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.
Individuals with legius syndrome have multiple calms with or without freckling, but they do not show the typical nf1. Additional clinical manifestations reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities. In terms of the mechanism of legius syndrome, the rasmapk signaling, which is a chain of proteins in a cell that sends signals to the nucleus of a cell from the surface receptors, can be regulated adversely by spred1 protein. Enable javascript to view the expandcollapse boxes. 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.
Similar to nf1, individuals with legius syndrome have multiple cafeaulait macules. Mutations in the spred1 gene have been found in patients with legius syndrome, originally termed neurofibromatosis type 1like syndrome. Leopard syndrome is an autosomal dominant disorder with multiple lentigines, congenital cardiac abnormalities, ocular hypertelorism, and retardation of growth. Legius syndrome is characterized by multiple cafe au lait macules without neurofibromas or. Pigmentary findings in neurofibromatosis type 1like syndrome. Understanding the interactions between the proteins. 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.
Consider the possibility of legius syndrome, which can be confirmed by molecular genetic analysis, in patients with six or more cafe au lait macules and axillary freckling but none of the other classic features of nf1. Legius syndrome is a condition where skin coloring changes in patches. In individuals with calms with or without freckling and no other specific distinguishing features, the nih criteria cannot reliably distinguish nf1 from legius syndrome. Legius syndrome is a rare genetic disorder that was first described in 2007 1. 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. Legius syndrome spred1 sequencing arup lab test directory.
Legius syndrome ls is an autosomal dominant condition characterized by cafe au lait spots. The spred1 variants repository for legius syndrome europe. The phenotype of ls is multiple cafe au lait macules calm with other commonly reported manifestations, including intertriginous freckling, lipomas, macrocephaly, and learning disabilities including adhd and developmental. Legius syndrome in fourteen families article pdf available in human mutation 321. Background information for legius syndrome spred1 sequencingcharacteristics. 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 an autosomal dominant disorder caused by the mutation in the spred1 gene involving a negative regulator of the rasmapk pathway, similar to neurofibromin and therefore shows some clinical similarities to neurofibromatosis type i. 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.
Legius syndrome sharma mk, kumar r, gupta s, jain sk indian j. Legius syndrome is a newly described genetic condition characterized primarily by multiple cafeaulait cal macules with or without skin fold freckling. Because of the presence of isolated calms in many family members, we hypothesized a legius syndrome, an autosomal dominant disease characterized by a mild nf 1 phenotype. The spred1 variants repository for legius syndrome. The features seen in legius syndrome may resemble another genetic condition called neurofibromatosis type 1 nf1. The spred1 variants repository for legius syndrome g3. Legius syndrome is inherited in an autosomal dominant manner.
Germline lossoffunction variants in spred1, a negative regulator of the rasmapk pathway, cause a neurofibromatosis type 1like phenotype, first described in 2007 legius syndrome. Prior to the discovery of the gene for legius syndrome in 2007, many individuals with these two benign skin findings were thought to. 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. Legius syndrome, also known as neurofibromatosis nf type 1like syndrome, is a rare, genetic skin pigmentation disorder characterized by. Nov 01, 2011 legius syndrome ls is an autosomal dominant disorder caused by germline lossoffunction mutations in the sproutyrelated, evh1 domain containing 1 spred1 gene. Legius syndrome ls is an autosomal dominant disorder caused by germline lossoffunction mutations in the sproutyrelated, evh1 domain containing 1 spred1 gene. Individuals with legius syndrome typically have multiple cafeaulait spots, sometimes associated with skin fold freckling.
The invitae legius syndrome test analyzes spred1, a gene that is associated with legius syndrome. Given the absence of neurofibromas in any patient described so far, 68 it has been proposed to refer to this new syndrome as legius syndrome as named in omim 611431 7,8 and discontinue referring to it as neurofibromatosis type 1like syndrome nfls. Additional clinical manifestations reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities adhd developmental delays. Pdf on jan 1, 2017, manojkumar sharma and others published legius syndrome. Legius syndrome, like nf, noonans, and leopard syndrome all involve a particular molecular pathway called ras, and are therefore, collectively known as rasopathies. Prior to the discovery of the gene for legius syndrome in 2007, many individuals with these two benign skin findings were thought to have neurofibromatosis type 1 nf1. Mutations of the spred1 gene, one of a family of sprouty spryspred proteins known to downregulate mitogen activated protein kinase mapk signalling, have been identified in patients with a mild neurofibromatosis type 1 nf1 phenotype with pigmentary changes but no neurofibromas legius syndrome. The rasopathies are sometimes known to be associated with an increase in dysmorphic features. January 20 mutations in the spred1 gene have been found in patients with legius syndrome, originally termed neurofibromatosis type 1like syndrome. Genedx 207 perry parkway gaithersburg, md 20877 toll free.
Genetic testing of spred1 is necessary to confirm the diagnosis of legius syndrome, a syndrome characterized by multiple pigmented skin lesions. Investigating genetic counselors experiences with legius. Ptpn11 mutations in leopard syndrome journal of medical. Genetic counseling should be provided to affected families. Legius syndrome presents as an autosomal dominant condition characterized by cafeaulait macules with or without freckling and sometimes a noonanlike appearance andor learning difficulties. Other features include axillary freckling, macrocephaly, noonanlike facies, lipomas, learning disabilities and attention deficithyperactivity. Current knowledge of the natural history of legius syndrome is based on the. A genetic test for legius syndrome using next generation sequencing. Here are links to possibly useful sources of information about legius syndrome. Owing to the many similarities with neurofibromatosis type 1 nf1, legius syndrome was initially identified as nf1like syndrome. New research may help differentiate similar diagnoses levenson. Correct diagnosis is essential because of the differences in prognosis and longterm monitoring between legius syndrome and nf1.