A Síndrome de Legius, também conhecida como síndrome parecida com a NF1, é uma doença genética rara que causa alterações na cor da pele. É caracterizada por múltiplas manchas cor de café com leite, que podem ou não vir acompanhadas de sardas nas axilas ou virilhas.
Introdução
O que você precisa saber de cara
A Síndrome de Legius, também conhecida como síndrome parecida com a NF1, é uma doença genética rara que causa alterações na cor da pele. É caracterizada por múltiplas manchas cor de café com leite, que podem ou não vir acompanhadas de sardas nas axilas ou virilhas.
Escala de raridade
<1/50kMuito rara
1/20kRara
1/10kPouco freq.
1/5kIncomum
1/2k
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Entender a doença
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Sinais e sintomas
O que aparece no corpo e com que frequência cada sintoma acontece
Partes do corpo afetadas
+ 23 sintomas em outras categorias
Características mais comuns
Os sintomas variam de pessoa para pessoa. Abaixo estão as 59 características clínicas mais associadas, ordenadas por frequência.
Linha do tempo da pesquisa
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Genética e causas
O que está alterado no DNA e como passa nas famílias
Genes associados
1 gene identificado com associação a esta condição. Padrão de herança: Autosomal dominant.
Tyrosine kinase substrate that inhibits growth-factor-mediated activation of MAP kinase (By similarity). Negatively regulates hematopoiesis of bone marrow (By similarity). Inhibits fibroblast growth factor (FGF)-induced retinal lens fiber differentiation, probably by inhibiting FGF-mediated phosphorylation of ERK1/2 (By similarity). Attenuates actin stress fiber formation via inhibition of TESK1-mediated phosphorylation of cofilin (PubMed:18216281). Inhibits TGFB-induced epithelial-to-mesenchyma
Cell membraneMembrane, caveolaNucleus
Legius syndrome
An autosomal dominant syndrome characterized mainly by cafe-au-lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1, axillary freckling, and macrocephaly. Additional clinical manifestations include Noonan-like facial dysmorphism, lipomas, learning disabilities, and features of attention deficit-hyperactivity disorder.
Variantes genéticas (ClinVar)
278 variantes patogênicas registradas no ClinVar.
Classificação de variantes (ClinVar)
Distribuição de 816 variantes classificadas pelo ClinVar.
Vias biológicas (Reactome)
3 vias biológicas associadas aos genes desta condição.
Diagnóstico
Os sinais que médicos procuram e os exames que confirmam
Tratamento e manejo
Remédios, cuidados de apoio e o que precisa acompanhar
Onde tratar no SUS
Hospitais de referência no Brasil e o protocolo oficial do SUS (PCDT)
🇧🇷 Atendimento SUS — Síndrome Legius
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Dados de DATASUS/CNES, SBGM, ABNeuro e Ministério da Saúde. Sempre confirme a disponibilidade diretamente com o estabelecimento.
Pesquisa ativa
Ensaios clínicos abertos e novidades científicas recentes
Ensaios em destaque
🟢 Recrutando agora
3 pesquisas recrutando participantes. Converse com seu médico sobre a possibilidade de participar.
Outros ensaios clínicos
6 ensaios clínicos encontrados, 4 ativos.
Publicações mais relevantes
Variant Resolution Through RNA Testing and Affected Tissue Analysis in the Neurofibromatoses: A Case Series.
This series reports 3 unrelated individuals with features of neurofibromatosis type 1 (NF1) and/or schwannomatosis (SWN) in whom variants of uncertain significance (VUSs) were resolved through RNA testing and tissue analysis, highlighting the clinical impact of these tests. Each patient's genetic testing identified a VUS that could have explained their clinical presentation. Because diagnostic criteria were not met, we performed VUS resolution. For patient 1, we conducted tissue analysis and RNA-based Sanger sequencing. For patients 2 and 3, RNA-based Sanger sequencing was pursued. Tissue analysis and RNA testing reclassified the NF1 c.8050 + 93A>T VUS in patient 1 as pathogenic, confirming diagnosis of NF1. RNA testing of the NF2 c.448-5T>C VUS in patient 2 reclassified the variant as likely benign, ruling out diagnosis of germline neurofibromatosis type 2 (NF2). RNA testing of the SPRED1 c.377-13T>A VUS in patient 3 reclassified the variant as likely benign, ruling out diagnosis of germline Legius syndrome. Because diagnostic criteria for NF1 and SWN include genetic testing, resolving VUSs in those who do not meet criteria is crucial for clinical care. In this article, we report 3 cases in which RNA testing and tissue analysis clarified pathogenicity of VUSs, thereby affecting clinical care, and in one case providing a definitive diagnosis. Legius syndrome is characterized by multiple café au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 (NF1). Additional clinical manifestations commonly reported include intertriginous freckling, lipomas, macrocephaly, and learning disabilities, attention-deficit/hyperactivity disorder (ADHD), and developmental delays. The diagnosis of Legius syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in SPRED1 identified by molecular genetic testing. Treatment of manifestations: Consideration of behavioral modification and/or pharmacologic therapy for those with ADHD; physical, speech, and occupational therapy for those with identified developmental delays; individualized education plans for those with learning disorders; referral to dermatologist as needed for lipoma management; treatment of pectus excavatum and scoliosis per orthopedist; standard treatment for seizures per experienced neurologist; referral to otolaryngologist for those with identified hearing loss. Surveillance: Monitor developmental progress, educational needs, and behavioral assessment at each visit; assess for pigmentary lesions, lipomas, scoliosis, and new-onset seizures at each visit; hearing evaluation as needed. Legius syndrome is inherited in an autosomal dominant manner. Many individuals diagnosed with Legius syndrome have an affected parent. Each child of an individual with Legius syndrome caused by a germline SPRED1 pathogenic variant has a 50% chance of inheriting the pathogenic variant. Once the SPRED1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Significance of the Absence of Focal Areas of Signal Intensity on Brain Magnetic Resonance Imaging Examinations in Legius Syndrome.
Legius syndrome (LGSS) is a rare neurocutaneous disorder that is differentiated from neurofibromatosis type I (NF1) based on pathogenic variants in the SPRED1 gene (15q14). Similar to NF1, LGSS also presents with café-au-lait macules on the skin and sometimes intertriginous freckling; however, the other diagnostic features of NF1 are absent in LGSS. Clinical contradistinction from NF1 is important for an LGSS diagnosis, but molecular genetic confirmation is necessary. Hypersignal areas on T2-weighted magnetic resonance imaging (MRI) (focal areas of signal intensity [FASI]) in specific brain locations are another common clinical finding in NF1. The aim of this study is to compare the incidence of FASI in LGSS and NF1 in an effort to further distinguish these two clinical entities and evaluate the clinical and diagnostic significance of an absence of FASI in LGSS. We have examined a group of 16 children with LGSS and a group of 130 children with NF1. All children had been clinically and molecularly diagnosed with LGSS or NF1 and had had MRI examinations of their brains. FASI findings on these scans were evaluated. The independence of FASI on diagnosis was evaluated using the Fischer exact test. FASI were found in 116 of 130 (89%) children with NF1, and no FASI was detected in children with LGSS (zero of 16, 0%). The presence of FASI was significantly dependent on the diagnosis. We suggest that the absence of FASI on brain MRI examinations of patients with LGSS is an important clinical and diagnostic feature of this disorder.
RASopathies. Part II: Cutaneous and extracutaneous manifestations.
Many RASopathies can be clinically diagnosed based on their cutaneous findings, thus it is essential for dermatologists to be comfortable differentiating RASopathies for accurate diagnosis and appropriate management. Employing the same framework to categorize as in Part I, the most common RASopathies include those principally caused by genetic variants in tumor suppressor genes (neurofibromatosis type 1, Noonan syndrome with multiple lentigines, Legius syndrome, capillary malformation-arteriovenous malformation syndrome), those principally due to variants in oncogenes (Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome), and mosaic conditions such as sebaceous nevus syndrome, neurocutaneous melanosis, McCune-Albright syndrome, phakomatosis pigmentokeratotica, epidermal nevus syndrome, and encephalocraniocutaneous lipomatosis. Germline variants cause systemic disease and must be managed in conjunction with a multidisciplinary team of specialists for holistic care. Common extracutaneous manifestations affect the neurologic, psychiatric, cardiac, ocular, musculoskeletal, genitourinary, and hematologic systems. The genetic basis of disease necessitates family counseling with a geneticist and patient support groups. It is also important to recognize risk of cancer in RASopathy patients for appropriate surveillance. Thus, dermatologists play a critical role in patients' healthcare through familiarity with and prompt diagnosis of RASopathies.
RASopathies. Part I: Genetics and therapeutic considerations.
RASopathies are common developmental disorders caused by variants in RAS and RAS-related proteins that affect a biological signaling pathway regulating cell growth and development. Considering the genetic and biochemical basis, part I will discuss the RASopathies divided into germline and mosaic patterns. The germline RASopathies include neurofibromatosis type 1 (not discussed in detail in this review), Noonan syndrome, Noonan syndrome with multiple lentigines, Legius syndrome, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, and cardiofaciocutaneous syndrome. Mosaic RASopathies encompass a broad category including nevus sebaceus syndrome, neurocutaneous melanosis, melanocytic nevi, McCune-Albright syndrome, phacomatosis spilosebacea, epidermal nevus syndrome, and encephalocraniocutaneous lipomatosis. Due to the RAS pathway's downstream impact on cell growth, many RASopathies predispose to malignancy. Conversely, the RAS pathway is overactive in many cancers, and some oncologic therapies also benefit patients with RASopathies. Although RAS ubiquity and homology complicate the efficacy of direct inhibition, several candidate drugs carry potential for decreasing RAS activity. Continued investigation into RAS biochemistry and genetics may elucidate strategies for pharmacological targets and pathways in both RASopathies and cancers.
Legius Syndrome: A Clinical Observation of a Father-Son Pair.
Publicações recentes
Variant Resolution Through RNA Testing and Affected Tissue Analysis in the Neurofibromatoses: A Case Series.
Legius Syndrome: A Clinical Observation of a Father-Son Pair.
RASopathies. Part II: Cutaneous and extracutaneous manifestations.
RASopathies. Part I: Genetics and therapeutic considerations.
📚 EuropePMC48 artigos no totalmostrando 90
Variant Resolution Through RNA Testing and Affected Tissue Analysis in the Neurofibromatoses: A Case Series.
Neurology. GeneticsLegius Syndrome: A Clinical Observation of a Father-Son Pair.
Dermatology practical & conceptualRASopathies. Part II: Cutaneous and extracutaneous manifestations.
Journal of the American Academy of DermatologyRASopathies. Part I: Genetics and therapeutic considerations.
Journal of the American Academy of DermatologySignificance of the Absence of Focal Areas of Signal Intensity on Brain Magnetic Resonance Imaging Examinations in Legius Syndrome.
Pediatric neurologyPost-Axial Polydactyly and Postnatal Pulmonary Stenosis Observed With a SPRED1 Pathogenic Variant.
Prenatal diagnosisLegius Syndrome: the importance of molecular differential diagnosis with neurofibromatosis type 1.
Italian journal of dermatology and venereologyGenomic ascertainment to quantify prevalence and cancer risk in adults with pathogenic and likely pathogenic germline variants in RASopathy genes.
medRxiv : the preprint server for health sciencesClinical features and molecular genetics of patients with RASopathies: expanding the phenotype with rare genes and novel variants.
European journal of pediatricsLegius syndrome mutations in the Ras-regulator SPRED1 abolish its membrane localization and potentially cause neurodegeneration.
The Journal of biological chemistryCase report: MEK inhibitor as treatment for multi-lineage mosaic KRAS G12D-associated epidermal nevus syndrome in a pediatric patient.
Frontiers in neurology[Clinical and genetic analysis of three children with Legius syndrome due to variants of SPRED1 gene].
Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical geneticsNovel causative variants in Legius syndrome: SPRED1 Genotype spectrum expansion.
American journal of medical genetics. Part ARASopathies for Radiologists.
Radiographics : a review publication of the Radiological Society of North America, IncEpilepsy in Legius syndrome: Coincidence or causation?
American journal of medical genetics. Part AThe Cardiofaciocutaneous Syndrome: From Genetics to Prognostic-Therapeutic Implications.
GenesLegius Syndrome and Inflammatory Bowel Disease: A Pediatric Case Report.
CureusNovel mutation in SPRED1: a sporadic case of Legius syndrome in an infant.
European journal of dermatology : EJDFunctional Assays Combined with Pre-mRNA-Splicing Analysis Improve Variant Classification and Diagnostics for Individuals with Neurofibromatosis Type 1 and Legius Syndrome.
Human mutationHow common are ear, nose and throat disorders in children with Noonan syndrome and other RASopathies?
International journal of pediatric otorhinolaryngologyFamilial café-au-lait macules associated with in-frame deletion of NF1 p.Met992del mimicking Legius syndrome.
Congenital anomaliesDermatological manifestations, management, and care in RASopathies.
American journal of medical genetics. Part C, Seminars in medical geneticsNeurofibromatosis type 1: A comparison of the 1997 NIH and the 2021 revised diagnostic criteria in 75 children and adolescents.
Genetics in medicine : official journal of the American College of Medical GeneticsValue of a café-au-lait macules screening clinic: Experience from The Hospital for Sick Children in Toronto.
Pediatric dermatologyThe RASopathies: from pathogenetics to therapeutics.
Disease models & mechanismsRASopathies: Dermatologists' viewpoints.
Indian journal of dermatology, venereology and leprologyThe RASopathies: Biology, genetics and therapeutic options.
Advances in cancer researchChallenges in the diagnosis of neurofibromatosis type 1 (NF1) in young children facilitated by means of revised diagnostic criteria including genetic testing for pathogenic NF1 gene variants.
Human geneticsSPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype.
American journal of human geneticsMEK inhibition ameliorates social behavior phenotypes in a Spred1 knockout mouse model for RASopathy disorders.
Molecular autismRASopathies: The musculoskeletal consequences and their etiology and pathogenesis.
BoneRevised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation.
Genetics in medicine : official journal of the American College of Medical GeneticsRNF213 variant in a patient with Legius syndrome associated with moyamoya syndrome.
Molecular genetics & genomic medicineSPRED proteins and their roles in signal transduction, development, and malignancy.
Genes & developmentCentral precocious puberty in a girl with LEGIUS syndrome: an accidental association?
Italian journal of pediatricsImpaired instrumental learning in Spred1-/- mice, a model for a rare RASopathy.
Genes, brain, and behaviorNeurofibromatosis type 1 without cutaneous neurofibromas: a rare genotype-phenotype correlation?
European journal of dermatology : EJDLisch nodules and iris mammillations in two siblings with familial legius syndrome.
Clinical case reportsMoyamoya syndrome in a child with Legius syndrome: Introducing a cerebral vasculopathy to the SPRED1 phenotype?
American journal of medical genetics. Part ACafé au lait spots: When and how to pursue their genetic origins.
Clinics in dermatologyStructural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR.
Cell reportsGenetic basis of neurofibromatosis type 1 and related conditions, including mosaicism.
Child's nervous system : ChNS : official journal of the International Society for Pediatric NeurosurgerySimultaneous Detection of NF1, SPRED1, LZTR1, and NF2 Gene Mutations by Targeted NGS in an Italian Cohort of Suspected NF1 Patients.
GenesLegius Syndrome and its Relationship with Neurofibromatosis Type 1.
Acta dermato-venereologicaExpanding the Noonan spectrum/RASopathy NGS panel: Benefits of adding NF1 and SPRED1.
Molecular genetics & genomic medicineCafé au Lait Macules and Associated Genetic Syndromes.
Journal of pediatric health care : official publication of National Association of Pediatric Nurse Associates & PractitionersmiRNA Genetic Variants Alter Their Secondary Structure and Expression in Patients With RASopathies Syndromes.
Frontiers in geneticsOne NF1 Mutation may Conceal Another.
GenesPathogenic Mutations Associated with Legius Syndrome Modify the Spred1 Surface and Are Involved in Direct Binding to the Ras Inactivator Neurofibromin.
Journal of molecular biologyClinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders.
GenesAntenatal diagnosis of cardio-facio-cutaneous syndrome: Prenatal characteristics and contribution of fetal facial dysmorphic signs in utero. About a case and review of literature.
European journal of obstetrics, gynecology, and reproductive biologyRASopathy in Patients With Isolated Sagittal Synostosis.
Global pediatric healthPathogenesis of Growth Failure in Rasopathies.
Pediatric endocrinology reviews : PERFirst International Conference on RASopathies and Neurofibromatoses in Asia: Identification and advances of new therapeutics.
American journal of medical genetics. Part AConstitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy.
Journal of medical geneticsProceedings of the fifth international RASopathies symposium: When development and cancer intersect.
American journal of medical genetics. Part AThe RASopathy Family: Consequences of Germline Activation of the RAS/MAPK Pathway.
Endocrine reviewsRAS signalling in energy metabolism and rare human diseases.
Biochimica et biophysica acta. BioenergeticsNevus anemicus and RASopathies.
JAAD case reports2016 Children's Tumor Foundation conference on neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis.
American journal of medical genetics. Part ANeurocutaneous Disorders.
Continuum (Minneapolis, Minn.)NMR resonance assignments of the EVH1 domain of neurofibromin's recruitment factor Spred1.
Biomolecular NMR assignmentsThe absence that makes the difference: choroidal abnormalities in Legius syndrome.
Journal of human geneticsAssociation of Piebaldism with Café-au-Lait Macules.
SkinmedCraniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype.
American journal of medical genetics. Part AA review of craniofacial and dental findings of the RASopathies.
Orthodontics & craniofacial research[Update on the treatment of RASopathies].
Revista de neurologiaConstitutional mismatch repair deficiency in a healthy child: On the spot diagnosis?
Clinical geneticsLegius syndrome: A case report.
The Journal of dermatologyThe first Slovak Legius syndrome patient carrying the SPRED1 gene mutation.
General physiology and biophysicsModeling RASopathies with Genetically Modified Mouse Models.
Methods in molecular biology (Clifton, N.J.)Molecular screening strategies for NF1-like syndromes with café-au-lait macules (Review).
Molecular medicine reportsChoroidal abnormalities in café-au-lait syndromes: a new differential diagnostic tool?
Clinical geneticsSPRED1 Interferes with K-ras but Not H-ras Membrane Anchorage and Signaling.
Molecular and cellular biologyIdentification of a PTPN11 hot spot mutation in a child with atypical LEOPARD syndrome.
Molecular medicine reportsMosaicism for a SPRED1 deletion revealed in a patient with clinically suspected mosaic neurofibromatosis.
The British journal of dermatologyComprehensive RNA Analysis of the NF1 Gene in Classically Affected NF1 Affected Individuals Meeting NIH Criteria has High Sensitivity and Mutation Negative Testing is Reassuring in Isolated Cases With Pigmentary Features Only.
EBioMedicineThe neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation.
Proceedings of the National Academy of Sciences of the United States of AmericaCell type-specific roles of RAS-MAPK signaling in learning and memory: Implications in neurodevelopmental disorders.
Neurobiology of learning and memoryCafé-au-lait Macules and Neurofibromatosis Type 1: A Review of the Literature.
Pediatric neurologyThe Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway.
American journal of medical genetics. Part AAn Update on Neurofibromatosis Type 1: Not Just Café-au-Lait Spots, Freckling, and Neurofibromas. An Update. Part I. Dermatological Clinical Criteria Diagnostic of the Disease.
Actas dermo-sifiliograficasMosaic Neurocutaneous Disorders and Their Causes.
Seminars in pediatric neurologyInteraction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1.
The Journal of biological chemistryRecent advances in RASopathies.
Journal of human geneticsHigh Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation.
Human mutationFamily with Legius syndrome (neurofibromatosis type 1-like syndrome).
The Journal of dermatologyPTPN11 mutation manifesting as LEOPARD syndrome associated with hypertrophic plexi and neuropathic pain.
BMC neurologyLegius syndrome: case report and review of literature.
Italian journal of pediatricsLegius Syndrome: two novel mutations in the SPRED1 gene.
Human genome variationAssociações
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Referências e fontes
Bases de dados externas citadas neste artigo
Publicações científicas
Artigos indexados no PubMed ligados a esta doença no grafo RarasNet — título, periódico e PMID direto da fonte, sem intermediação de IA.
- Variant Resolution Through RNA Testing and Affected Tissue Analysis in the Neurofibromatoses: A Case Series.
- Significance of the Absence of Focal Areas of Signal Intensity on Brain Magnetic Resonance Imaging Examinations in Legius Syndrome.
- RASopathies. Part II: Cutaneous and extracutaneous manifestations.
- RASopathies. Part I: Genetics and therapeutic considerations.
- Legius Syndrome: A Clinical Observation of a Father-Son Pair.
- Legius Syndrome.
Bases de dados e fontes oficiais
Identificadores e referências canônicas usadas para montar este verbete.
- ORPHA:137605(Orphanet)
- OMIM OMIM:611431(OMIM)
- MONDO:0012669(MONDO)
- GARD:10714(GARD (NIH))
- Variantes catalogadas(ClinVar)
- Busca completa no PubMed(PubMed)
- Q890470(Wikidata)
Dados compilados pelo RarasNet a partir de fontes abertas (Orphanet, OMIM, MONDO, PubMed/EuropePMC, ClinicalTrials.gov, DATASUS, PCDT/MS). Este conteúdo é informativo e não substitui avaliação médica.
Conteúdo mantido por Agente Raras · Médicos e pesquisadores podem colaborar
