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Eric Legius - One of the best experts on this subject based on the ideXlab platform.
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mek inhibition ameliorates social behavior phenotypes in a spred1 knockout mouse model for rasopathy disorders
2021Co-Authors: Sarah C Borrie, Eric Legius, Ype Elgersma, Akihiko Yoshimura, Ellen Plasschaert, Zsuzsanna Callaertsvegh, Rudi Dhooge, Steven A Kushner, Hilde BremsAbstract:Background RASopathies are a group of disorders that result from mutations in genes coding for proteins involved in regulating the Ras-MAPK signaling pathway, and have an increased incidence of autism spectrum disorder (ASD). Legius Syndrome is a rare RASopathy caused by loss-of-function mutations in the SPRED1 gene. The patient phenotype is similar to, but milder than, Neurofibromatosis type 1-another RASopathy caused by loss-of-function mutations in the NF1 gene. RASopathies exhibit increased activation of Ras-MAPK signaling and commonly manifest with cognitive impairments and ASD. Here, we investigated if a Spred1-/- mouse model for Legius Syndrome recapitulates ASD-like symptoms, and whether targeting the Ras-MAPK pathway has therapeutic potential in this RASopathy mouse model. Methods We investigated social and communicative behaviors in Spred1-/- mice and probed therapeutic mechanisms underlying the observed behavioral phenotypes by pharmacological targeting of the Ras-MAPK pathway with the MEK inhibitor PD325901. Results Spred1-/- mice have robust increases in social dominance in the automated tube test and reduced adult ultrasonic vocalizations during social communication. Neonatal ultrasonic vocalization was also altered, with significant differences in spectral properties. Spred1-/- mice also exhibit impaired nesting behavior. Acute MEK inhibitor treatment in adulthood with PD325901 reversed the enhanced social dominance in Spred1-/- mice to normal levels, and improved nesting behavior in adult Spred1-/- mice. Limitations This study used an acute treatment protocol to administer the drug. It is not known what the effects of longer-term treatment would be on behavior. Further studies titrating the lowest dose of this drug that is required to alter Spred1-/- social behavior are still required. Finally, our findings are in a homozygous mouse model, whereas patients carry heterozygous mutations. These factors should be considered before any translational conclusions are drawn. Conclusions These results demonstrate for the first time that social behavior phenotypes in a mouse model for RASopathies (Spred1-/-) can be acutely reversed. This highlights a key role for Ras-MAPK dysregulation in mediating social behavior phenotypes in mouse models for ASD, suggesting that proper regulation of Ras-MAPK signaling is important for social behavior.
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revised diagnostic criteria for neurofibromatosis type 1 and Legius Syndrome an international consensus recommendation
2021Co-Authors: Eric Legius, Yemima Berman, Jaishri O. Blakeley, Ludwine Messiaen, P Wolkenstein, Patrice Pancza, Robert A Avery, Dusica Babovicvuksanovic, Karin Soares Goncalves Cunha, Rosalie E FernerAbstract:By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius Syndrome (LGSS). We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.
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impaired instrumental learning in spred1 mice a model for a rare rasopathy
2021Co-Authors: Sarah C Borrie, Eric Legius, Akihiko Yoshimura, Alexa E Horner, Maksym V Kopanitsa, Hilde BremsAbstract:RASopathies are neuro-cardio-facio-cutaneous disorders stemming from mutations in genes regulating the RAS-MAPK pathway. Legius Syndrome is a rare RASopathy disorder caused by mutations in the SPRED1 gene. SPRED1 protein negatively regulates activation of Ras by inhibiting RAS/RAF and by its interaction with neurofibromin, a Ras GTPase-activating protein (RAS-GAP). Cognitive impairments have been reported in Legius Syndrome as well as in other RASopathy disorders. Modelling these cognitive deficits in a Spred1 mouse model for Legius Syndrome has demonstrated spatial learning and memory deficits, but other cognitive domains remained unexplored. Here, we attempted to utilize a cognitive touchscreen battery to investigate if Spred1-/- mice exhibit deficits in other cognitive domains. We show that Spred1-/- mice had heterogeneous performance in instrumental operant learning, with a large subgroup (n = 9/20) failing to reach the standard criterion on touchscreen operant pretraining, precluding further cognitive testing. To examine whether targeting the RAS-MAPK signalling pathway could rescue these cognitive impairments, Spred1-/- mice were acutely treated with the clinically relevant mitogen-activated protein kinase (MEK) inhibitor PD325901. However, MEK inhibition did not improve their instrumental learning. We conclude that Spred1-/- mice can model severe cognitive impairments that cannot be reversed in adulthood.
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Legius Syndrome and its relationship with neurofibromatosis type 1
2020Co-Authors: Ellen Denayer, Eric LegiusAbstract:Neurofibromatosis type 1 (NF1) is the most common disorder characterized by multiple cafe-au-lait macules. Most individuals with this autosomal dominant disorder also have other features, such as skinfold freckling, iris Lisch nodules and benign or malignant peripheral nerve sheath tumours. Legius Syndrome is a less frequent autosomal dominant disorder with similar multiple cafe-au-lait macules and skinfold freckling. Legius Syndrome is not characterized by an increased risk of tumours, and a correct diagnosis is important. In young children with a sporadic form of multiple cafe-au-lait macules with or without freckling and no other manifestations of NF1 these 2 conditions cannot be differentiated based on clinical examination. Molecular analysis of the NF1 and SPRED1 genes is usually needed to differentiate the 2 conditions. Other less frequent conditions with cafe-au-lait macules are Noonan Syndrome with multiple lentigines, constitutional mismatch repair deficiency and McCune-Albright Syndrome.
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Legius Syndrome other cafe au lait diseases and differential diagnosis of nf1
2020Co-Authors: Ellen Denayer, Eric Legius, Hilde BremsAbstract:Legius Syndrome is characterized by the presence of multiple cafe-au-lait macules (CALMs), axillary freckling, macrocephaly and clinically overlaps with neurofibromatosis type 1 (NF1). However, Legius Syndrome patients show a milder phenotype with tumoral complications systematically absent. Inactivating SPRED1 mutations were identified in Legius Syndrome. SPRED1 interacts with neurofibromin and both proteins are negative regulators of the RAS-MAPK pathway. Constitutive Mismatch Repair Deficiency (CMMRD) is a differential diagnosis of NF1. CMMRD patients show in addition to multiple CALMs supplementary clinical features of NF1. Similar NF1 Syndromes with CALMs are piebaldism, neurofibromatosis type 2, schwannomatosis, Noonan Syndrome with multiple lentigines, McCune-Albright Syndrome, and isolated cafe-au-lait spots. Differential diagnoses of NF1 are infantile myofibromatosis, Proteus Syndrome, orbital neurofibromas, hyaline fibromatosis Syndrome, and hybrid nerve sheath tumors.
Ludwine Messiaen - One of the best experts on this subject based on the ideXlab platform.
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revised diagnostic criteria for neurofibromatosis type 1 and Legius Syndrome an international consensus recommendation
2021Co-Authors: Eric Legius, Yemima Berman, Jaishri O. Blakeley, Ludwine Messiaen, P Wolkenstein, Patrice Pancza, Robert A Avery, Dusica Babovicvuksanovic, Karin Soares Goncalves Cunha, Rosalie E FernerAbstract:By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius Syndrome (LGSS). We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.
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Mosaicism for a SPRED1 deletion revealed in a patient with clinically suspected mosaic neurofibromatosis.
2017Co-Authors: Rebekah Jobling, Ludwine Messiaen, Andrea Shugar, Irene Lara-corrales, M-c Hsiao, S. Hedges, Peter KannuAbstract:Inactivating SPRED1 mutations cause Legius Syndrome, an autosomal dominant RASopathydescribed in 20071. Like Neurofibromatosis Type 1 (NF1), features include cafe-au-lait macules and skin fold freckling. Although neurofibromas, optic gliomas, Lisch nodules, tibial pseudarthrosis and nerve sheath tumors are not seen in Legius Syndrome, other symptoms and signs common to the RASopathies such as Noonan-like facial features, pulmonary stenosis, pectus deformity and learning disabilities are reported2,3. This article is protected by copyright. All rights reserved.
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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
2016Co-Authors: Yasuko Hirata, Hilde Brems, Ludwine Messiaen, Mayu Suzuki, Mitsuhiro Kanamori, Masahiro Okada, Rimpei Morita, Isabel Llanorivas, Toyoyuki Ose, Eric LegiusAbstract:Constitutional heterozygous loss-of-function mutations in the SPRED1 gene cause a phenotype known as Legius Syndrome, which consists of symptoms of multiple cafe-au-lait macules, axillary freckling, learning disabilities, and macrocephaly. Legius Syndrome resembles a mild neurofibromatosis type 1 (NF1) phenotype. It has been demonstrated that SPRED1 functions as a negative regulator of the Ras-ERK pathway and interacts with neurofibromin, the NF1 gene product. However, the molecular details of this interaction and the effects of the mutations identified in Legius Syndrome and NF1 on this interaction have not yet been investigated. In this study, using a yeast two-hybrid system and an immunoprecipitation assay in HEK293 cells, we found that the SPRED1 EVH1 domain interacts with the N-terminal 16 amino acids and the C-terminal 20 amino acids of the GTPase-activating protein (GAP)-related domain (GRD) of neurofibromin, which form two crossing α-helix coils outside the GAP domain. These regions have been shown to be dispensable for GAP activity and are not present in p120(GAP). Several mutations in these N- and C-terminal regions of the GRD in NF1 patients and pathogenic missense mutations in the EVH1 domain of SPRED1 in Legius Syndrome reduced the binding affinity between the EVH1 domain and the GRD. EVH1 domain mutations with reduced binding to the GRD also disrupted the ERK suppression activity of SPRED1. 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.
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review and update of spred1 mutations causing Legius Syndrome
2012Co-Authors: Hilde Brems, Eric Legius, Ludwine Messiaen, Meena Upadhyaya, Eric Pasmant, Rick Van Minkelen, Katharina WimmerAbstract:Legius Syndrome presents as a mild neurofibromatosis type 1 (NF1) phenotype. Multiple cafe-au-lait spots and macrocephaly are present with or without axillary or inguinal freckling. Other typical NF1-associated features (Lisch nodules, bone abnormalities, neurofibromas, optic pathway gliomas, and malignant peripheral nerve sheath tumors) are systematically absent. Legius Syndrome is caused by germline loss-of-function SPRED1 mutations, resulting in overactivation of the RAS-MAPK signal transduction cascade. The first families were identified in 2007. Here, we review all identified SPRED1 mutations and summarize molecular, clinical, and functional data. All mutations have been deposited in a database created using the Leiden Open Variation Database software and accessible at http://www.lovd.nl/SPRED1. At present, the database contains 89 different mutations identified in 146 unrelated probands, including 16 new variants described for the first time. The database contains a spectrum of mutations: 29 missense, 28 frameshift, 19 nonsense, eight copy number changes, two splicing, one silent, one in-frame deletion and a mutation affecting the initiation codon. Sixty-three mutations and deletions are definitely pathogenic or most likely pathogenic, eight SPRED1 mutations are probably benign rare variants, and 17 SPRED1 missense mutations are still unclassified and need further family and functional studies to help with the interpretation.
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cafe au lait macules and intertriginous freckling in piebaldism clinical overlap with neurofibromatosis type 1 and Legius Syndrome
2012Co-Authors: Cathy A. Stevens, Pei Wen Chiang, Ludwine MessiaenAbstract:Piebaldism is an autosomal dominant disorder characterized by congenital hypopigmented patches of skin and hair and has been found to be associated with mutations in the KIT or SLUG genes. Caf e-au-lait macules (CALM) may occasionally be seen in piebaldism. There are four reports describing six patients who were said to have both piebaldism and neurofibromatosis type 1 (NF1) due to the presence of multiple CALM and intertriginous freckling, but none of these patients had undergone comprehensive NF1 mutation analysis. We describe a large family with piebaldism in which two members meet diagnostic criteria for NF1 based on the presence of >5 CALM and intertriginous freckling. Interestingly, only these two family members are of mixed race, which could be of importance. A novel complex mutation in the KIT gene was identified in several family members affected with piebaldism; the proband meeting diagnostic criteria for NF1 also underwent comprehensive NF1 and SPRED1 testing with no mutations detected. These findings suggest that piebaldism may occasionally include CALM and intertriginous freckling, which may create diagnostic confusion especially in the absence of a family history of piebaldism. However, careful clinical evaluation and molecular testing if necessary should distinguish these two disorders. � 2012 Wiley Periodicals, Inc.
Hilde Brems - One of the best experts on this subject based on the ideXlab platform.
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mek inhibition ameliorates social behavior phenotypes in a spred1 knockout mouse model for rasopathy disorders
2021Co-Authors: Sarah C Borrie, Eric Legius, Ype Elgersma, Akihiko Yoshimura, Ellen Plasschaert, Zsuzsanna Callaertsvegh, Rudi Dhooge, Steven A Kushner, Hilde BremsAbstract:Background RASopathies are a group of disorders that result from mutations in genes coding for proteins involved in regulating the Ras-MAPK signaling pathway, and have an increased incidence of autism spectrum disorder (ASD). Legius Syndrome is a rare RASopathy caused by loss-of-function mutations in the SPRED1 gene. The patient phenotype is similar to, but milder than, Neurofibromatosis type 1-another RASopathy caused by loss-of-function mutations in the NF1 gene. RASopathies exhibit increased activation of Ras-MAPK signaling and commonly manifest with cognitive impairments and ASD. Here, we investigated if a Spred1-/- mouse model for Legius Syndrome recapitulates ASD-like symptoms, and whether targeting the Ras-MAPK pathway has therapeutic potential in this RASopathy mouse model. Methods We investigated social and communicative behaviors in Spred1-/- mice and probed therapeutic mechanisms underlying the observed behavioral phenotypes by pharmacological targeting of the Ras-MAPK pathway with the MEK inhibitor PD325901. Results Spred1-/- mice have robust increases in social dominance in the automated tube test and reduced adult ultrasonic vocalizations during social communication. Neonatal ultrasonic vocalization was also altered, with significant differences in spectral properties. Spred1-/- mice also exhibit impaired nesting behavior. Acute MEK inhibitor treatment in adulthood with PD325901 reversed the enhanced social dominance in Spred1-/- mice to normal levels, and improved nesting behavior in adult Spred1-/- mice. Limitations This study used an acute treatment protocol to administer the drug. It is not known what the effects of longer-term treatment would be on behavior. Further studies titrating the lowest dose of this drug that is required to alter Spred1-/- social behavior are still required. Finally, our findings are in a homozygous mouse model, whereas patients carry heterozygous mutations. These factors should be considered before any translational conclusions are drawn. Conclusions These results demonstrate for the first time that social behavior phenotypes in a mouse model for RASopathies (Spred1-/-) can be acutely reversed. This highlights a key role for Ras-MAPK dysregulation in mediating social behavior phenotypes in mouse models for ASD, suggesting that proper regulation of Ras-MAPK signaling is important for social behavior.
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impaired instrumental learning in spred1 mice a model for a rare rasopathy
2021Co-Authors: Sarah C Borrie, Eric Legius, Akihiko Yoshimura, Alexa E Horner, Maksym V Kopanitsa, Hilde BremsAbstract:RASopathies are neuro-cardio-facio-cutaneous disorders stemming from mutations in genes regulating the RAS-MAPK pathway. Legius Syndrome is a rare RASopathy disorder caused by mutations in the SPRED1 gene. SPRED1 protein negatively regulates activation of Ras by inhibiting RAS/RAF and by its interaction with neurofibromin, a Ras GTPase-activating protein (RAS-GAP). Cognitive impairments have been reported in Legius Syndrome as well as in other RASopathy disorders. Modelling these cognitive deficits in a Spred1 mouse model for Legius Syndrome has demonstrated spatial learning and memory deficits, but other cognitive domains remained unexplored. Here, we attempted to utilize a cognitive touchscreen battery to investigate if Spred1-/- mice exhibit deficits in other cognitive domains. We show that Spred1-/- mice had heterogeneous performance in instrumental operant learning, with a large subgroup (n = 9/20) failing to reach the standard criterion on touchscreen operant pretraining, precluding further cognitive testing. To examine whether targeting the RAS-MAPK signalling pathway could rescue these cognitive impairments, Spred1-/- mice were acutely treated with the clinically relevant mitogen-activated protein kinase (MEK) inhibitor PD325901. However, MEK inhibition did not improve their instrumental learning. We conclude that Spred1-/- mice can model severe cognitive impairments that cannot be reversed in adulthood.
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Legius Syndrome other cafe au lait diseases and differential diagnosis of nf1
2020Co-Authors: Ellen Denayer, Eric Legius, Hilde BremsAbstract:Legius Syndrome is characterized by the presence of multiple cafe-au-lait macules (CALMs), axillary freckling, macrocephaly and clinically overlaps with neurofibromatosis type 1 (NF1). However, Legius Syndrome patients show a milder phenotype with tumoral complications systematically absent. Inactivating SPRED1 mutations were identified in Legius Syndrome. SPRED1 interacts with neurofibromin and both proteins are negative regulators of the RAS-MAPK pathway. Constitutive Mismatch Repair Deficiency (CMMRD) is a differential diagnosis of NF1. CMMRD patients show in addition to multiple CALMs supplementary clinical features of NF1. Similar NF1 Syndromes with CALMs are piebaldism, neurofibromatosis type 2, schwannomatosis, Noonan Syndrome with multiple lentigines, McCune-Albright Syndrome, and isolated cafe-au-lait spots. Differential diagnoses of NF1 are infantile myofibromatosis, Proteus Syndrome, orbital neurofibromas, hyaline fibromatosis Syndrome, and hybrid nerve sheath tumors.
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Nevus anemicus and RASopathies
2018Co-Authors: Charlotte Bulteel, Petra De Haes, Ellen Denayer, Eric Legius, Marie-anne Morren, Hilde BremsAbstract:Tadini and colleagues were the first to report the correlation between anemic nevi and RASopathies.1 A retrospective study in their genodermatosis center identified anemic nevi at different anatomic sites in a cohort of neurofibromatosis type 1 (NF1) (50/565). In 2013, Marque et al published the frequent occurrence of anemic nevi in 77 of 151 patients clinically diagnosed with NF1, but not in 7 patients with SPRED1 (sprouty-related, EVH1 domain–containing protein 1), 2 with PTPN11 (protein tyrosine phosphatase nonreceptor type 11), and 1 with RAF1 (rapidly accelerated fibrosarcoma-1) mutations.2 In a later study in 100 genetically confirmed NF1 patients, anemic nevi were found in 28 children with NF1,3 much higher than the estimated 1%-5% in the general population.2 Anemic nevi were suggested as an additional diagnostic marker of NF1, facilitating differentiation from other genodermatoses with cafe au lait macules (CALMs) and lentigines.1, 2, 3 Anemic nevi are congenital pale macules or patches, which become more prominent by warming or rubbing of the skin and disappear with diascopy or wood lamp examination.1, 2 In a review of the clinical features of 159 patients with Legius Syndrome (LS), anemic nevi were not reported4; however, they can easily be overlooked if not specifically searched for. We report 2 patients with nonNF1 RASopathies and anemic nevi.
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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
2016Co-Authors: Yasuko Hirata, Hilde Brems, Ludwine Messiaen, Mayu Suzuki, Mitsuhiro Kanamori, Masahiro Okada, Rimpei Morita, Isabel Llanorivas, Toyoyuki Ose, Eric LegiusAbstract:Constitutional heterozygous loss-of-function mutations in the SPRED1 gene cause a phenotype known as Legius Syndrome, which consists of symptoms of multiple cafe-au-lait macules, axillary freckling, learning disabilities, and macrocephaly. Legius Syndrome resembles a mild neurofibromatosis type 1 (NF1) phenotype. It has been demonstrated that SPRED1 functions as a negative regulator of the Ras-ERK pathway and interacts with neurofibromin, the NF1 gene product. However, the molecular details of this interaction and the effects of the mutations identified in Legius Syndrome and NF1 on this interaction have not yet been investigated. In this study, using a yeast two-hybrid system and an immunoprecipitation assay in HEK293 cells, we found that the SPRED1 EVH1 domain interacts with the N-terminal 16 amino acids and the C-terminal 20 amino acids of the GTPase-activating protein (GAP)-related domain (GRD) of neurofibromin, which form two crossing α-helix coils outside the GAP domain. These regions have been shown to be dispensable for GAP activity and are not present in p120(GAP). Several mutations in these N- and C-terminal regions of the GRD in NF1 patients and pathogenic missense mutations in the EVH1 domain of SPRED1 in Legius Syndrome reduced the binding affinity between the EVH1 domain and the GRD. EVH1 domain mutations with reduced binding to the GRD also disrupted the ERK suppression activity of SPRED1. 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.
Legius Eric - One of the best experts on this subject based on the ideXlab platform.
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Revised diagnostic criteria for neurofibromatosis type 1 and Legius Syndrome: an international consensus recommendation
2021Co-Authors: Legius Eric, Berman Yemima, Blakeley Jaishri, Messiaen Ludwine, Wolkenstein Pierre, Pancza Patrice, Avery, Robert A., Babovic-vuksanovic Dusica, Cunha, Karin Soares, Ferner RosalieAbstract:Funder: Children’s Tumor Foundation; doi: https://doi.org/10.13039/http://dx.doi.org/10.13039/100001545Abstract: Purpose: By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius Syndrome (LGSS). Methods: We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. Results: We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. Conclusion: The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS
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Legius Syndrome and its Relationship with Neurofibromatosis Type 1
2020Co-Authors: Denayer Ellen, Legius EricAbstract:Neurofibromatosis type 1 (NF1) is the most common disorder characterized by multiple café-au-lait macules. Most individuals with this autosomal dominant disorder also have other features, such as skinfold freckling, iris Lisch nodules and benign or malignant peripheral nerve sheath tumours. Legius Syndrome is a less frequent autosomal dominant disorder with similar multiple café-au-lait macules and skinfold freckling. Legius Syndrome is not characterized by an increased risk of tumours, and a correct diagnosis is important. In young children with a sporadic form of multiple café-au-lait macules with or without freckling and no other manifestations of NF1 these 2 conditions cannot be differentiated based on clinical examination. Molecular analysis of the NF1 and SPRED1 genes is usually needed to differentiate the 2 conditions. Other less frequent conditions with café-au-lait macules are Noonan Syndrome with multiple lentigines, constitutional mismatch repair deficiency and McCune-Albright Syndrome.status: publishe
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Genetic basis of neurofibromatosis type 1 and related conditions, including mosaicism
2020Co-Authors: Legius Eric, Brems HildeAbstract:INTRODUCTION: Neurofibromatosis type 1 (NF1) is a frequent autosomal dominant disorder characterised by café-au-lait maculae (CALM), skinfold freckling, iris Lisch nodules and benign peripheral nerve sheath tumours (neurofibromas). MECHANISM: The NF1 gene is a tumour suppressor gene and NF1 individuals have an increased risk for a long list of tumours, all resulting from a second hit in the normal copy of the NF1 gene. Remarkably, some non-tumour phenotypes such as CALM and pseudarthrosis are also caused by a "second hit". Germline mutations inactivating the NF1 gene show a large variability in genetic mechanisms ranging from single-nucleotide substitutions and somatic mosaicism to large deletions affecting neighbouring genes. Molecular confirmation of the clinical diagnosis is becoming increasingly more important to differentiate NF1 from other Syndromes such as Legius Syndrome, to investigate genotype-phenotype correlations relevant in 10% of cases and to detect somatic mosaicism. SURVEILLANCE AND THERAPY: Some degree of learning difficulties, attention deficit and social problems are observed in most children and affect quality of life. There is a large individual variability in complications and the evolution of the disease is difficult to predict. Specialised outpatient clinics for children have been widely established and are important for surveillance and guidance. Regular surveillance is also important for adolescents and adults because many tumour complications can be detected by whole-body MRI and treated even before symptoms develop and irreversible damage occurs. Recent data on nodular plexiform neurofibromas with continued growth in adolescents and young adults show that many of these tumours are premalignant lesions called atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP). Specific surveillance and timely local resection of these benign peripheral nerve sheath tumours might be important to prevent malignant degeneration. In the last years, targeted therapy with MEK inhibitors has shown promise to treat unresectable and symptomatic plexiform neurofibromas. Many more challenges remain to find the best way to monitor children and adults for potential complications and to find a satisfying cure for many complications in this disorder.status: publishe
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Choroidal abnormalities in café-au-lait Syndromes: A new differential diagnostic tool ?
2017Co-Authors: Cassiman Catherine, Brems Hilde, Plasschaert Ellen, Casteels Ingele, Jacob Julie, Dubron Kathia, Van Keer Karel, Legius EricAbstract:The best known café-au-lait Syndrome is neurofibromatosis type 1 (NF1). Legius Syndrome (LS) is another, rarer Syndrome with café-au-lait macules (CALMs). In young patients their clinical picture is often indistinguishable. We investigated the presence of choroidal abnormalities in Syndromes with CALMs as a candidate tool for a more efficient diagnosis. 34 patients with NF1 (14 with a truncating mutation, 14 with a non-truncating mutation and 6 with unknown mutation) and 11 patients with LS. All patients underwent an ophthalmological examination. Infrared images were performed. Choroidal nodules were diagnosed in 65% of the NF1 group. 71% of NF1 patients with a truncating mutation and 50% of patients with a non-truncating mutation were found to have nodules. Choroidal nodules were seen in 18% of the LS patients, never more than one nodule/eye was detected in this group. Choroidal nodules are more abundantly present in NF1 genotypes with truncating mutations. In contrast, the number of choroidal nodules in LS is comparable with their presence in healthy individuals. Especially at an early age, when the clinical picture is incomplete, the detection of choroidal nodules are of diagnostic value, and help in an appropriate genetic counselling and follow up. These results support the suggestion to include choroidal nodules to the diagnostic criteria for NF1.status: publishe
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Poster session: The sterol synthesis inhibitor lovastatin rescues impaired hippocampal synaptic plasticity in a mouse model of Legius Syndrome, a novel NF1-like-Syndrome
2010Co-Authors: Ahmed Tariq, Legius Eric, Denayer Ellen, Sabanov Victor, D'hooge Rudi, Balschun DetlefAbstract:Spred proteins belong to a novel family of evolutionary conserved, negative regulators of the Ras/mitogen-activated protein kinase (MAPK) signal transduction pathway. Germline mutations in SPRED1 were recently shown to cause a neurofibromatosis type 1 (NF1) -like Syndrome (Legius Syndrome) in children that included learning difficulties, the inference being that SPRED1 is involved in neural and behavioural plasticity. We investigated hippocampus-dependent synaptic plasticity in Spred1 knock-out mice, an animal model of this newly described human Syndrome. Spred1 knockout mice when examined for synaptic plasticity in the hippocampal CA1 region in vitro, displayed decremental long-term potentiation (LTP) after theta-burst stimulation (TBS). In contrast, LTP in WT littermates was robust and maintained for at least 4 h (Denayer et al., 2008). A similar result was reported for the NF1+/- mouse model. Furthermore, treatment of NF1+/- mice with: (1) picrotoxin, a GABAA antagonist rescued the phenotype and; (2) with a sterol synthesis inhibitor (statin) resulted in amelioration of synaptic plasticity (Costa et al 2002; Li et al 2005). When a similar strategy was applied for Spred1 KO mice, picrotoxin normalized their smaller input/output values which are most likely caused by a higher tonic inhibition, but did not abolish the impairment of LTP. However, chronic treatment of Spred1 KO mice with the sterol synthesis inhibitor lovastatin rescued the LTP-deficit. Thus, delineating this pathway in cognition and synaptic plasticity may open up new therapeutic approaches for this and other NF1-like human disorders.status: publishe
Ellen Denayer - One of the best experts on this subject based on the ideXlab platform.
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Legius Syndrome and its relationship with neurofibromatosis type 1
2020Co-Authors: Ellen Denayer, Eric LegiusAbstract:Neurofibromatosis type 1 (NF1) is the most common disorder characterized by multiple cafe-au-lait macules. Most individuals with this autosomal dominant disorder also have other features, such as skinfold freckling, iris Lisch nodules and benign or malignant peripheral nerve sheath tumours. Legius Syndrome is a less frequent autosomal dominant disorder with similar multiple cafe-au-lait macules and skinfold freckling. Legius Syndrome is not characterized by an increased risk of tumours, and a correct diagnosis is important. In young children with a sporadic form of multiple cafe-au-lait macules with or without freckling and no other manifestations of NF1 these 2 conditions cannot be differentiated based on clinical examination. Molecular analysis of the NF1 and SPRED1 genes is usually needed to differentiate the 2 conditions. Other less frequent conditions with cafe-au-lait macules are Noonan Syndrome with multiple lentigines, constitutional mismatch repair deficiency and McCune-Albright Syndrome.
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Legius Syndrome other cafe au lait diseases and differential diagnosis of nf1
2020Co-Authors: Ellen Denayer, Eric Legius, Hilde BremsAbstract:Legius Syndrome is characterized by the presence of multiple cafe-au-lait macules (CALMs), axillary freckling, macrocephaly and clinically overlaps with neurofibromatosis type 1 (NF1). However, Legius Syndrome patients show a milder phenotype with tumoral complications systematically absent. Inactivating SPRED1 mutations were identified in Legius Syndrome. SPRED1 interacts with neurofibromin and both proteins are negative regulators of the RAS-MAPK pathway. Constitutive Mismatch Repair Deficiency (CMMRD) is a differential diagnosis of NF1. CMMRD patients show in addition to multiple CALMs supplementary clinical features of NF1. Similar NF1 Syndromes with CALMs are piebaldism, neurofibromatosis type 2, schwannomatosis, Noonan Syndrome with multiple lentigines, McCune-Albright Syndrome, and isolated cafe-au-lait spots. Differential diagnoses of NF1 are infantile myofibromatosis, Proteus Syndrome, orbital neurofibromas, hyaline fibromatosis Syndrome, and hybrid nerve sheath tumors.
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Nevus anemicus and RASopathies
2018Co-Authors: Charlotte Bulteel, Petra De Haes, Ellen Denayer, Eric Legius, Marie-anne Morren, Hilde BremsAbstract:Tadini and colleagues were the first to report the correlation between anemic nevi and RASopathies.1 A retrospective study in their genodermatosis center identified anemic nevi at different anatomic sites in a cohort of neurofibromatosis type 1 (NF1) (50/565). In 2013, Marque et al published the frequent occurrence of anemic nevi in 77 of 151 patients clinically diagnosed with NF1, but not in 7 patients with SPRED1 (sprouty-related, EVH1 domain–containing protein 1), 2 with PTPN11 (protein tyrosine phosphatase nonreceptor type 11), and 1 with RAF1 (rapidly accelerated fibrosarcoma-1) mutations.2 In a later study in 100 genetically confirmed NF1 patients, anemic nevi were found in 28 children with NF1,3 much higher than the estimated 1%-5% in the general population.2 Anemic nevi were suggested as an additional diagnostic marker of NF1, facilitating differentiation from other genodermatoses with cafe au lait macules (CALMs) and lentigines.1, 2, 3 Anemic nevi are congenital pale macules or patches, which become more prominent by warming or rubbing of the skin and disappear with diascopy or wood lamp examination.1, 2 In a review of the clinical features of 159 patients with Legius Syndrome (LS), anemic nevi were not reported4; however, they can easily be overlooked if not specifically searched for. We report 2 patients with nonNF1 RASopathies and anemic nevi.
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observations on intelligence and behavior in 15 patients with Legius Syndrome
2011Co-Authors: Ellen Denayer, Ellen Plasschaert, Miejef Descheemaeker, Douglas R Stewart, Kathelijn Keymolen, Sarah L Ruppert, Joseph Snow, Audrey Thurm, Lisa Joseph, Jeanpierre FrynsAbstract:Legius Syndrome is a RAS-MAPK Syndrome characterized by pigmentary findings similar to neurofibromatosis type 1 (NF1), but without tumor complications. Learning difficulties and behavioral problems have been reported to be associated with Legius Syndrome, but have not been studied systematically. We investigated intelligence and behavior in 15 patients with Legius Syndrome and 7 unaffected family members. We report a mean full scale IQ of 101.57 in patients with Legius Syndrome, which does not differ from the control group. We find a significantly lower performance IQ in children with Legius Syndrome compared to their unaffected family members. Few behavioral problems are present as assessed by the Child Behavior Checklist (CBCL) questionnaire. Our observations suggest that, akin to the milder somatic phenotype, the cognitive phenotype in Legius Syndrome is less severe than that of NF1.
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Legius Syndrome in fourteen families
2011Co-Authors: Ellen Denayer, Hilde Brems, Rick Van Minkelen, Magdalena Chmara, Anneke Kievit, Yolande Van Bever, Ans M W Van Den Ouweland, Arja De Goedebolder, Rianne OostenbrinkAbstract:Legius Syndrome presents as an autosomal dominant condition characterized by cafe-au-lait macules with or without freckling and sometimes a Noonan-like appearance and/or learning difficulties. It is caused by germline loss-of-function SPRED1 mutations and is a member of the RAS-MAPK pathway Syndromes. Most mutations result in a truncated protein and only a few inactivating missense mutations have been reported. Since only a limited number of patients has been reported up until now, the full clinical and mutational spectrum is still unknown. We report mutation data and clinical details in fourteen new families with Legius Syndrome. Six novel germline mutations are described. The Trp31Cys mutation is a new pathogenic SPRED1 missense mutation. Clinical details in the 14 families confirmed the absence of neurofibromas, and Lisch nodules, and the absence of a high prevalence of central nervous system tumors. We report white matter T2 hyperintensities on brain MRI scans in 2 patients and a potential association between postaxial polydactyly and Legius Syndrome. © 2010 Wiley-Liss, Inc.