Legius syndrome

A hereditary autosomal dominant disorder that shows some similarities to NEUROFIBROMATOSIS 1 (OMIM: 162200) but is less severe. Affected individuals usually have multiple cafe-au-lait spots, sometimes associated with skin fold freckling, variable dysmorphic features such as HYPERTELORISM or MACROCEPHALY; LIPOMAS, and mild LEARNING DISORDERS or ATTENTION DEFICIT DISORDER. It is not associated with neurofibromas, optic gliomas, Lisch nodules, or tumor predisposition. Mutations in the SPRED1 gene have been identified. OMIM: 611431

Also Known As:

Networked: 19 relevant articles (0 outcomes, 1 trials/studies)

Disease Context: Research Results

Related Diseases

1.	Neurofibromatosis 1 (Neurofibromatosis Type I)
2.	Costello Syndrome
3.	Noonan Syndrome (Female Pseudo-Turner Syndrome)
4.	LEOPARD Syndrome (Syndrome, LEOPARD)
5.	Pulmonary Valve Stenosis (Pulmonary Stenosis)

Experts

1.	McCormick, Frank: 3 articles (01/2020 - 07/2012)
2.	Scheffzek, Klaus: 3 articles (01/2020 - 01/2016)
3.	Dunzendorfer-Matt, Theresia: 3 articles (01/2019 - 01/2016)
4.	Führer, Sebastian: 2 articles (01/2019 - 10/2017)
5.	Tollinger, Martin: 2 articles (01/2019 - 10/2017)
6.	Messiaen, Ludwine: 2 articles (02/2016 - 06/2011)
7.	Mercado, Ellen L: 2 articles (01/2016 - 07/2012)
8.	Carroll, Jennifer: 1 article (01/2021)
9.	Lo, Warren: 1 article (01/2021)
10.	Pabst, Lisa: 1 article (01/2021)

Drugs and Biologics

Drugs and Important Biological Agents (IBA) related to Legius syndrome:

1.	Neurofibromin 1 (Neurofibromin)IBA 02/12/2016 - "These data clearly demonstrate that SPRED1 inhibits the Ras-ERK pathway by recruiting neurofibromin to Ras through the EVH1-GRD interaction, and this study also provides molecular basis for the pathogenic mutations of NF1 and Legius syndrome. " 01/01/2020 - "Analysis of the neurofibromin-SPRED1 interface provides a rationale for mutations observed in Legius syndrome and suggests why SPRED1 can bind to neurofibromin but no other RasGAPs. " 01/01/2019 - "Taken together, our data provide structural insight into the interaction of Spred1 and neurofibromin and characterize the structural or functional consequence of selected patient-derived mutations associated with Legius syndrome." 01/01/2019 - "Pathogenic Mutations Associated with Legius Syndrome Modify the Spred1 Surface and Are Involved in Direct Binding to the Ras Inactivator Neurofibromin." 01/01/2018 - "The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. "
2.	Proteins (Proteins, Gene)FDA Link 07/01/2012 - "Loss-of-function mutations in one feedback regulator of Ras/MAPK signaling, SPRED1 (Sprouty-related protein with an EVH1 domain), cause Legius syndrome, an autosomal dominant human disorder that resembles Neurofibromatosis-1 (NF1). " 01/01/2019 - "NF1 and Legius syndrome are caused by alterations in the NF1 and SPRED1 genes encoding the Ras inhibitors neurofibromin and Spred1 (sprouty related EVH1 domain-containing protein), respectively. " 01/01/2016 - "Neurofibromatosis type 1 (NF1) and Legius syndrome are related diseases with partially overlapping symptoms caused by alterations of the tumor suppressor genes NF1 (encoding the protein neurofibromin) and SPRED1 (encoding sprouty-related, EVH1 domain-containing protein 1, Spred1), respectively. " 05/01/2013 - "Patients with similar cutaneous findings have been previously reported, and their disorder has been attributed to an overlap of piebaldism and neurofibromatosis type 1. Legius syndrome is a recently described syndrome caused by Sprouty-related, Ena/vasodilator-stimulated phosphoprotein homology-1 domain containing protein 1 (SPRED1) mutations that also has multiple café-au-lait macules and intertriginous freckling. " 07/01/2009 - "Mutations of the SPRED1 gene, one of a family of Sprouty (Spry)/Spred 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).To ascertain the frequency of SPRED1 mutations as a cause of this phenotype and to investigate whether other SPRED/SPRY genes may be causal, a panel of unrelated mild NF1 patients were screened for mutations of the SPRED1-3 and the SPRY1-4 genes. "
3.	Mitogen-Activated Protein KinasesIBA 01/01/2021 - "Legius syndrome is a disorder of the RAS and mitogen-activated protein kinase (MAPK) pathway first described in 2007 by Eric Legius, et al., that has been considered a milder phenotype than reported in the RASopathy neurofibromatosis type 1 (NF1). " 07/01/2009 - "Mutations of the SPRED1 gene, one of a family of Sprouty (Spry)/Spred 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).To ascertain the frequency of SPRED1 mutations as a cause of this phenotype and to investigate whether other SPRED/SPRY genes may be causal, a panel of unrelated mild NF1 patients were screened for mutations of the SPRED1-3 and the SPRY1-4 genes. " 10/01/2017 - "Neurofibromin and Sprouty-related EVH1 domain-containing protein 1 (Spred1) both act as negative regulators of the mitogen-activated protein kinase pathway and are associated with the rare diseases Neurofibromatosis type 1 and Legius syndrome, respectively. "
4.	MicroRNAs (MicroRNA)IBA 01/01/2019 - "The pathways, biological processes, and diseases that were over-represented among the target genes of the mature miRNAs harboring variants included the RAS, MAPK, RAP1, and PIK3-Akt signaling pathways, neuronal differentiation, neurogenesis and nervous system development, congenital cardiac defects (hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy), and the phenotypes and syndromes of RASopathies (Noonan syndrome, Legius syndrome, Costello syndrome, Cafe au lait spots multiple, subaortic stenosis, pulmonary valve stenosis, and LEOPARD syndrome). "
5.	Mitogen-Activated Protein Kinase Kinases (MEKs)IBA 09/01/2010 - "We conclude that germline CBL mutations have developmental, tumorigenic and functional consequences that resemble disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome and Legius syndrome."
6.	GTPase-Activating Proteins (GTPase-Activating Protein)IBA 02/12/2016 - "Interaction 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."
7.	Nonsense Codon (Nonsense Mutation)IBA 04/01/2017 - "In one case we identified a nonsense mutation c.46C>T (p.Arg16*) in exon 2 of SPRED1 gene, confirming diagnosis of Legius syndrome. "
8.	Phosphotransferases (Kinase)IBA 06/01/2011 - "The concept of neuro-cardio-facio-cutaneous (NCFC) syndrome has recently been formulated in order to bring together a number of hereditary diseases that include a number of shared phenotypic features to differing degrees: (i) craniofacial dysmorphia; (ii) delayed growth; (iii) mental retardation or learning difficulties; (iv) cardiac malformations (most commonly pulmonary valve stenosis and hypertrophic cardiomyopathy); (v) cutaneous anomalies, and in some cases, predisposition to certain forms of malignant solid tumors and blood diseases, associated at the physiopathological level with deregulation of the Ras-MAP kinase cellular signaling pathways 1. NCFC subsumes neurofibromatosis type1, Legius syndrome, LEOPARD syndrome, Noonan syndrome, Costello syndrome and cardiofaciocutaneous (CFC) syndrome. "
9.	vasodilator-stimulated phosphoproteinIBA 05/01/2013 - "Patients with similar cutaneous findings have been previously reported, and their disorder has been attributed to an overlap of piebaldism and neurofibromatosis type 1. Legius syndrome is a recently described syndrome caused by Sprouty-related, Ena/vasodilator-stimulated phosphoprotein homology-1 domain containing protein 1 (SPRED1) mutations that also has multiple café-au-lait macules and intertriginous freckling. "
10.	1-nitrohydroxyphenyl-N-benzoylalanine (GAL 1)IBA 10/15/2016 - "The physiological significance of these novel interactions is supported by two Legius syndrome-associated mutations that show diminished binding to both Gal-1 and B-Raf. "

Therapies and Procedures

1.	Ligation 06/01/2011 - "To determine if copy number changes (CNCs) are a cause of Legius syndrome, we have used a Multiplex Ligation-dependent Probe Amplification (MLPA) assay covering all SPRED1 exons in a cohort of 510 NF1-negative patients presenting with multiple CALMs with or without freckling, but no other NF1 diagnostic signs. "
2.	Lasers (Laser) 11/01/2017 - "We examined the fundus of 16 eyes by confocal scanning laser ophthalmoscopy with infrared monochromatic light in eight patients with molecularly confirmed Legius syndrome. "