If you have problems viewing pdf files, download the latest version of adobe reader. Pigmentary manifestations can represent an early clinical sign in children affected by neurofibromatosis type 1 nf1, legius syndrome, and other neurocutaneous disorders. Spred1 gene analysis in legius syndrome clinical features. Oct 14, 2010 legius syndrome in general lacks the tumor manifestations typically observed in nf1 i. The family had been already examined for nf 1, but no sign evocative of the disease was found. Cardiofaciocutaneous syndrome and the dermatologists. It was first described in 2007 and is often mistaken for neurofibromatosis type i nf1. These disorders, which include legius syndrome, noonan syndrome with. Pathogenic mutations associated with legius syndrome modify the spred1 surface and are involved in direct binding to the ras inactivator neurofibromin. Legius syndrome is a condition characterized by changes in skin coloring pigmentation.
Legius syndrome ls is an autosomal dominant disorder caused by germline lossoffunction mutations in the sproutyrelated, evh1 domain containing 1 spred1 gene. Germline lossoffunction variants in spred1, a negative regulator of the rasmapk pathway,germline lossoffunction variants in spred1, a negative regulator of the rasmapk pathway,cause a neurofibromatosis type 1like phenotype, first described in 2007 legius syndrome. Pathogenic mutations associated with legius syndrome. One group has suggested that individuals with legius syndrome are at an increased risk for. 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. Recently, missense mutations in the ptpn11 gene located in 12q24 were. 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. Hirecently my daughter was sent to a specialist to be evaluated for nf1legius syndrome. Cardiofaciocutaneous syndrome and the dermatologists contribution to diagnosis. 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. Cooperative regulation of rasmapk pathway signaling by.
Jul 01, 2014 legius syndrome is differentiated from nf1 by the absence of the nonpigmentary clinical manifestations seen in this disorder i. Additional clinical manifestations reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities adhd developmental delays. Current knowledge of the natural history of legius syndrome is based on the. Noonan syndrome ns, ns with multiple lentigines, capillary malformationav malformation syndrome, legius syndrome, costello syndrome cs, and. Legius syndrome, is a recently identified autosomal dominant disorder caused by loss of function mutations in the spred1 gene, with individuals mainly. Legius syndrome presents as an autosomal dominant condition characterized by cafeaulait macules with or without freckling and sometimes a noonanlike. Legius syndrome, which is caused by pathogenic variants in the spred1 gene, has marked similarity to nf1. Legius syndrome genetic and rare diseases information. Legius syndrome is an autosomal dominant disorder caused by heterozygous inactivating mutations in the spred1 gene. Understanding the interactions between the proteins implicated in legius syndrome and neurofibromatosis type 1 interaction between a domain of the negative regulator of the raserk pathway, spred1 protein, and the gtpaseactivating proteinrelated domain of neurofibromin is implicated in legius syndrome and neurofibromatosis type 1. Deafness and genital abnormalities are less frequently found. Legius syndrome is characterized by multiple cafe au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 nf1. 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.
Legius syndrome definition of legius syndrome by medical. Enable javascript to view the expandcollapse boxes. This pathway is involved in a signal transduction cascade that. The spred1 gene encodes a protein involved in the rasmapk mitogenactivated protein kinase signaling pathway. It is also known as neurofibromatosis type 1like syndrome nfls. Thus, we utilized tandem affinity purification of wildtype spred1 and evh1 domain mutants found in legius syndrome to identify novel binding partners of the nterminus. 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 is caused by spred1 mutations on chromosome 15q. One group has suggested that individuals with legius syndrome are at an increased risk for leukemia pasmant et al 2009, pasmant et al 2015. Individuals with legius syndrome typically have multiple cafeaulait spots, sometimes associated with skin fold freckling. One group has suggested that individuals with legius syndrome are at an increased risk for leukemia pasmant et al 2009, pasmant et al 2014.
Pdf legius syndrome in fourteen families researchgate. People with legius syndrome have multiple calms, intertriginous freckling fig 3, learning disabilities, and relative macrocephaly that is indistinguishable from. Legius syndrome is differentiated from nf1 by the absence of the nonpigmentary clinical manifestations seen in this disorder i. Genes free fulltext clinical and genetic findings in. To ascertain the frequency of spred1 mutations as a cause of this phenotype. The phenotype of ls is multiple cafe au lait macules calm with other commonly reported manifestations, including intertriginous freckling, lipomas, macrocephaly, and learning. Legius syndrome often mistaken for neurofibromatosis type 1. 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. 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. Genetic testing of spred1 is necessary to confirm the diagnosis of legius syndrome, a syndrome characterized by multiple pigmented skin lesions.
Pigmentary findings in neurofibromatosis type 1like syndrome. Ns with multiple lentigines, capillary malformationav malformation syndrome, legius syndrome, costello. A collection of disease information resources and questions answered by our genetic and rare diseases information specialists for legius syndrome. Understanding and developing treatment for syndromes of the ras pathway. Genetic testing of spred1 is necessary to confirm the diagnosis of legius syndrome, a.
Current knowledge of the natural history of legius syndrome is based on the clinical manifestations of fewer than 200 individuals with a molecularly confirmed diagnosis. The spred1 variants repository for legius syndrome. Other features include axillary freckling, macrocephaly, noonanlike facies, lipomas, learning disabilities and attention deficithyperactivity. Legius syndrome presents as an autosomal dominant condition characterized by cafeaulait macules with or without freckling and sometimes a noonanlike appearance andor learning difficulties. Lisch nodules, neurofibromas, optic glioma, bone abnormalities. Jan 02, 2016 legius syndrome hels1s avatar hels1 january 2, 2016 at 9.
The invitae legius syndrome test analyzes spred1, a gene that is associated with legius syndrome. Family with legius syndrome neurofibromatosis type 1. Patients present with multiple cafeaulait spots with or without skinfold freckling. Legius syndrome in general lacks the tumor manifestations typically observed in nf1 i. Legius syndrome is an autosomal dominant disorder that shows some similarities to neurofibromatosis type i nf1. 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 formerly termed nf1like syndrome nfls. Spred1, a ras mapk pathway inhibitor that causes legius syndrome, is a tumour suppressor downregulated in paediatric acute myeloblastic leukaemia. Genetic testing of this gene may establish or confirm a diagnosis and help guide treatment and management decisions. Correct diagnosis is essential because of the differences in prognosis and longterm monitoring between legius syndrome and nf1.
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. Pigmentary findings in neurofibromatosis type 1like syndrome legius syndrome. Her family history was remarkable for the presence of multiple cafeaulait spots in the mother, the grandfather and two aunts. January 20 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. 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. Test description polymerase chain reaction followed by bidirectional sequencing of. Genetic counseling should be provided to affected families.
Mutations in the spred1 gene have been found in patients with legius syndrome, originally termed neurofibromatosis type 1like syndrome. Genetic test for legius syndrome by ambry genetics ambry. Almost all affected individuals have multiple cafeaulait spots, which are flat patches on the skin that are darker than the surrounding area. We then suspected legius syndrome, a dominant disease characterized by a mild neurofibromatosis 1 phenotype. Noonanlike, costello, neurofibromatosis, leopard, cardiofaciocutaneous cfc and legius syndromes. Other typical nf1 associated features lisch nodules, bone abnormalities, neurofibromas, optic pathway gliomas are. Mar 01, 2011 hirecently my daughter was sent to a specialist to be evaluated for nf1 legius syndrome. 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 follows an autosomal dominant pattern of inheritance.
Download pdf 1608k download meta ris compatible with endnote, reference manager, procite, refworks. To ascertain the frequency of spred1 mutations as a cause of this. 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. Pathogenic mutations associated with legius syndrome modify. Clinical and mutational spectrum of neurofibromatosis type. We described a first solitary case of legius syndrome identified by next. In japan, a family with legius syndrome was first described in 2015 by sakai et al.
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. Pdf legius syndrome in fourteen families hilde brems. Freckling typically found in the armpit andor the groin areas, and varying degrees of macrocephaly i. Pdf legius syndrome presents as an autosomal dominant condition. Similar to nf1, individuals with legius syndrome have multiple cafeaulait macules. Clinical features in 14 families with legius syndrome. A genetic test for legius syndrome using next generation sequencing. Legius syndrome online mendelian inheritance in man no. Understanding the interactions between the proteins.
Analysis of protein complexes by mass spectrometry revealed neurofibromin, the nf1 gene product, as a novel spred1 interacting protein. Jan 27, 2014 spred1, a ras mapk pathway inhibitor that causes legius syndrome, is a tumour suppressor downregulated in paediatric acute myeloblastic leukaemia. Molecular screening strategies for nf1like syndromes with cafeau. Legius syndrome is a rare genetic disorder caused by heterozygous germ line loss. Individuals frequently fulfill the nih diagnostic criteria for nf1 based on pigmentary manifestations of. It is caused by germline lossoffunction spred1 mutations and is a member of the rasmapk pathway syndromes. Legius syndrome ls is an autosomal dominant condition characterized by cafe au lait spots. It is caused by germline lossoffunction spred1 mutations and is a. Spred1, a ras mapk pathway inhibitor that causes legius. Mutations in spred1 have been reported to cause legius syndrome, a rare. Individuals with legius syndrome typically have multiple cafeaulait spots, sometimes associated with skin fold freckling, variable dysmorphic features such as hypertelorism. Nextgen spred1 only school of medicine genetics uab. We report a father and daughter and a third, unrelated patient with leopard syndrome.
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. Germline lossoffunction variants in spred1, a negative regulator of the rasmapk pathway, cause a neurofibromatosis type 1like phenotype, first described in 2007 legius syndrome. She is 8 years old and has cafe au lait spots, and freckling in the armpit and groin. However unlike nf1, there is notable absence of neurofibromas, lisch nodules, bony lesions, or optic. Ptpn11 mutations in leopard syndrome journal of medical. Pigmentary findings in neurofibromatosis type 1like. Clinical and mutational spectrum of neurofibromatosis type 1. Pathogenic mutations associated with legius syndrome modify the spred1 surface and are involved in direct binding to the ras. Am trying to find somebody else like my lovely 2 year old who has been recently diagnosed. We herein report the first instance of legius syndrome occurring in two female siblings in japan. Further studies will be needed to determine the roles of these mutations in the mechanisms of legius syndrome. The spred1 variants repository for legius syndrome g3. Legius syndrome is a genetic condition characterized by multiple cafeaulait i. It is characterised by multiple cafeaulait macules calm with or without axillary or inguinal freckling and mild macrocephaly.
1431 29 600 1093 4 763 743 18 1166 962 1375 9 571 194 1052 1174 747 1485 735 1523 912 14 665 926 916 519 152 560 423 274 630 487 645 1349 654 164 1053 1126 1459 819