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6. Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL

Author

Sánchez-Montalva, Adrian, Estevez, Ana Belén, Sánchez, Àlex, Sanjuan, Anna, Sena, Elena, Granados, Emma, Arévalo de Andrés, Esther, Nuñez, Fátima, Arteaga, Gara, Fuentes Ruiz, Gabriela Perez, Fernández, Guillermo, Rivera-Esteban, Jesus, Comella, Joan, Ramos-Quiroga, Josep Antoni, Genescà, Joan, Espinosa, Juan, Pericàs, Juan Manuel, Murcia, Lada, Cash-Gibson, Lucinda, de Valles Silvosa, Maria, Barroso de Sousa, María Fernanda, Sánchez-Maroto Carrizo, Olga, Ibañez-Jiménez, Pol, Augustin, Salvador, Perez-Hoyos, Santiago, Rodríguez-Navarro, Sarai, Muñoz-Martínez, Sergio, Serres, Silvia, Kalko, Susana, Michon, Amelie, Ussi, Anton, Lydall, Ben, van de Ketterij, Edwin, Quiles, Ignacio, Carapina, Tamara, Kumaus, Constantin, Ramazanova, Dariga, Meyer, Elias Laurin, Koenig, Franz, Roig, Marta Bofill, Brunner, Martin, Posch, Martin, Krotka, Pavla, Zehetmayer, Sonja, Carton, Charlotte, Legius, Eric, Begum, Amina, Pariante, Carmine, Worrell, Courtney, Lombardo, Giulia, Sforzini, Luca, Brown, Mollie, Gullet, Nancy, Amasi-Hartoonian, Nare, Ferner, Rosalie, Kose, Melisa, Spitaleri, Andrea, Ghodousi, Arash, Di Serio, Clelia, Cirillo, Daniela, Cugnata, Federica, Saluzzo, Francesca, Benedetti, Francesco, Scarale, Maria Giovanna, Zini, Michela, Rancoita, Paola Maria, Alagna, Riccardo, Poletti, Sara, Dhaenens, Britt, Van Der Lei, Johan, de Steenwinkel, Jurriaan, Moinat, Maxim, Oostenbrink, Rianne, Hoogendijk, Witte, Hölscher, Michael, Heinrich, Norbert, Otte, Christian, Potratz, Cornelia, Zocholl, Dario, Kulakova, Eugenia, Tacke, Frank, Brasanac, Jelena, Leubner, Jonas, Krajewska, Maja, Freitag, Michaela Maria, Gold, Stefan, Zoller, Thomas, Chae, Woo Ri, Daniel, Christel, Kara, Leila, Vaterkowski, Morgan, Griffon, Nicolas, Wolkenstein, Pierre, Pais, Raluca, Ratziu, Vlad, Voets, David, Maes, Christophe, Kalra, Dipak, Thienpoint, Geert, Deckerck, Jens, Lea, Nathan, Singleton, Peter, Viele, Kert, Jacko, Peter, Berry, Scott, Parke, Tom, Aydin, Burç, Kubiak, Christine, Demotes, Jacques, Ueda, Keiko, Matei, Mihaela, Contrino, Sergio, Röhl, Claas, Cordero, Estefania, Greenhalgh, Fiona, Jarke, Hannes, Angelova, Juliana, Boudes, Mathieu, Dressler, Stephan, Strammiello, Valentina, Anstee, Quentin, Gutierrez-Ibarluzea, Iñaki, Otte, Maximilian, Heimbach, Natalie, Hofner, Benjamin, Burgwinkel, Cora, Kaestel, Hue, Hees, Katharina, Nguyen, Quynh, Prieto-Alhambra, Daniel, Tan, Eng Hooi (Cheryl), Raviglione, Mario, de Colombani, Pierpaolo, Villa, Simone, Maron, Eduard, Evans, Gareth, Savitz, Adam J., Van Dessel, Ann, Duca, Anna, Kaminski, Anne, Wouters, Bie, Porter, Brandon, Charron, Catherine, Spiertz, Cecile, Zizzamia, Christopher, Millar, Daniel, Hasselbaink, Danny, Orr, David, Kesters, Divya, Hubin, Ellen, Davies, Emma, Didden, Eva-Maria, Guz, Gabriela, Verstraete, Evelyn, Mao, Gary, Capuano, George, Martynowicz, Heddie, De Smedt, Heidi, Larsson, Ingela, Bruegelmans, Ines, Coste, Isabelle, Gonzalez Moreno, Jesus Maria, Niewczas, Julia, Xu, Jiajun, Rombouts, Karin, Woo, Katherine, Wuyts, Kathleen, Hersh, Kathryn, Oldenburg, Khrista, Zhang, Lingjiao, Schmidt, Mark, Szuch, Mark, Todorovic, Marija, Mangelaars, Maartje, Grewal, Melissa, Sandor, Molli, Di Prospero, Nick, Van Houten, Pamela, Minnick, Pansy, Bastos, Polyana, Patrizi, Robert, Morello, Salvatore, De Wilde, Severijn, Sun, Tao, Kline, Timothy, de Marez, Tine, Mielke, Tobias, Reijns, Tom, Popova, Vanina, Flossbach, Yanina, Tymofyeyev, Yevgen, De Groote, Zeger, Sverdlov, Alex, Bobirca, Alexandra, Krause, Annekatrin, Bobrica, Catalin, Heintz, Daniela, Magirr, Dominic, Glimm, Ekkehard, Baffert, Fabienne, Castiglione, Federica, Caruso, Franca, Patalano, Francesco, Bretz, Frank, Heimann, Guenter, Carbarns, Ian, Rodríguez, Ignacio, Ratescu, Ioana, Hampson, Lisa, Pedrosa, Marcos, Hark, Mareile, Mesenbrink, Peter, Penna, Sabina Hernandez, Bergues-Lang, Sarah, Baltes-Engler, Susanne, Arsiwala, Tasneem, Mondragon, Valeria Jordan, Guo, Hua, Da Costa, Jose Leite, Burman, Carl-Fredrik, Kirk, George, Aaes-Jørgensen, Anders, Dirach, Jorgen, Kjær, Mette Skalshøi, Martin, Alexandra, Hristov, Diyan, Rousseaux, Florent, Hittel, Norbert, Dornheim, Robert, Evans, Daniel, Sykes, Nick, Couvert, Camille, Leuven, Catherine, Notelet, Loïc, Gidh-Jain, Madhavi, Jouannin, Mathieu, Ammour, Nadir, Pierre, Suzanne, Haufe, Volker, Dong, Yingwen, Dubanchet, Catherine, de Préville, Nathalie, Baltauss, Tania, Jian, Zhu, Shnider, Sara, Bar-El, Tal, Bakker, Annette, Nievo, Marco, Iloeje, Uche, Conradie, Almari, Auffarrth, Ece, Lombard, Leandra, Benhayoun, Majda, Olugbosi, Morounfolu, Seidel, Stephanie S., Gumí, Berta, Guzmán, Claudia García, Molero, Eva, Pairó, Gisela, Machin, Núria, Cardelús, Raimon, Ramasastry, Saira, Pelzer, Saskia, Kremer, Andreas, Lindfors, Erno, Lynch, Chris, Spiertz, Cécile, Machín, Núria, and Pericàs, Juan M.

Published
2024
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7. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

Author

Legius, Eric, Messiaen, Ludwine, Wolkenstein, Pierre, Pancza, Patrice, Avery, Robert A, Berman, Yemima, Blakeley, Jaishri, Babovic-Vuksanovic, Dusica, Cunha, Karin Soares, Ferner, Rosalie, Fisher, Michael J, Friedman, Jan M, Gutmann, David H, Kehrer-Sawatzki, Hildegard, Korf, Bruce R, Mautner, Victor-Felix, Peltonen, Sirkku, Rauen, Katherine A, Riccardi, Vincent, Schorry, Elizabeth, Stemmer-Rachamimov, Anat, Stevenson, David A, Tadini, Gianluca, Ullrich, Nicole J, Viskochil, David, Wimmer, Katharina, Yohay, Kaleb, Huson, Susan M, Evans, D Gareth, and Plotkin, Scott R

Subjects
Biological Sciences, Genetics, Neurosciences, Rare Diseases, Clinical Research, Neurofibromatosis, Cafe-au-Lait Spots, Consensus, Genetic Testing, Humans, Neurofibromatosis 1, International Consensus Group on Neurofibromatosis Diagnostic Criteria, Clinical Sciences, Genetics & Heredity
Abstract

PurposeBy 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).MethodsWe used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups.ResultsWe 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.ConclusionThe 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.

Published
2021

8. The neurodevelopmental and facial phenotype in individuals with a TRIP12 variant

Author

Aerden, Mio, Denommé-Pichon, Anne-Sophie, Bonneau, Dominique, Bruel, Ange-Line, Delanne, Julian, Gérard, Bénédicte, Mazel, Benoît, Philippe, Christophe, Pinson, Lucile, Prouteau, Clément, Putoux, Audrey, Tran Mau-Them, Frédéric, Viora-Dupont, Éléonore, Vitobello, Antonio, Ziegler, Alban, Piton, Amélie, Isidor, Bertrand, Francannet, Christine, Maillard, Pierre-Yves, Julia, Sophie, Philippe, Anais, Schaefer, Elise, Koene, Saskia, Ruivenkamp, Claudia, Hoffer, Mariette, Legius, Eric, Theunis, Miel, Keren, Boris, Buratti, Julien, Charles, Perrine, Courtin, Thomas, Misra-Isrie, Mala, van Haelst, Mieke, Waisfisz, Quinten, Wieczorek, Dagmar, Schmetz, Ariane, Herget, Theresia, Kortüm, Fanny, Lisfeld, Jasmin, Debray, François-Guillaume, Bramswig, Nuria C., Atallah, Isis, Fodstad, Heidi, Jouret, Guillaume, Almoguera, Berta, Tahsin-Swafiri, Saoud, Santos-Simarro, Fernando, Palomares-Bralo, Maria, López-González, Vanesa, Kibaek, Maria, Tørring, Pernille M., Renieri, Alessandra, Bruno, Lucia Pia, Õunap, Katrin, Wojcik, Monica, Hsieh, Tzung-Chien, Krawitz, Peter, and Van Esch, Hilde

Published
2023
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9. Autism in neurofibromatosis type 1: misuse of covariance to dismiss autistic trait burden

Author

Morris, Stephanie M, Acosta, Maria T, Garg, Shruti, Green, Jonathan, Legius, Eric, North, Kathryn, Payne, Jonathan M, Weiss, Lauren A, Constantino, John N, and Gutmann, David H

Subjects
Biomedical and Clinical Sciences, Health Sciences, Psychology, Attention Deficit Disorder with Hyperactivity, Autism Spectrum Disorder, Autistic Disorder, Child, Humans, Neurofibromatosis 1, Phenotype, Medical and Health Sciences, Pediatrics, Biomedical and clinical sciences, Health sciences
Published
2021

10. Advancing RAS/RASopathy therapies: An NCI‐sponsored intramural and extramural collaboration for the study of RASopathies

Author

Gross, Andrea M, Frone, Megan, Gripp, Karen W, Gelb, Bruce D, Schoyer, Lisa, Schill, Lisa, Stronach, Beth, Biesecker, Leslie G, Esposito, Dominic, Hernandez, Edjay Ralph, Legius, Eric, Loh, Mignon L, Martin, Staci, Morrison, Deborah K, Rauen, Katherine A, Wolters, Pamela L, Zand, Dina, McCormick, Frank, Savage, Sharon A, Stewart, Douglas R, Widemann, Brigitte C, and Yohe, Marielle E

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Pediatric, Cardiovascular, Orphan Drug, Congenital Structural Anomalies, Pediatric Cancer, Clinical Research, Heart Disease, Neurosciences, Genetics, Neurofibromatosis, Cancer, Congenital Heart Disease, Rare Diseases, Prevention, 2.1 Biological and endogenous factors, Biomarkers, Tumor, Costello Syndrome, Ectodermal Dysplasia, Facies, Failure to Thrive, Heart Defects, Congenital, Humans, Intersectoral Collaboration, Molecular Targeted Therapy, Mutation, National Cancer Institute (U.S.), Neurofibromatosis 1, Noonan Syndrome, Research Report, Signal Transduction, United States, ras Proteins, cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome, Ras, MAP kinase pathway, RASopathies, Ras/MAP kinase pathway, Clinical sciences
Abstract

RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1-related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non-NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates.

Published
2020

11. YWHAE loss of function causes a rare neurodevelopmental disease with brain abnormalities in human and mouse

Author

Denommé-Pichon, Anne-Sophie, Collins, Stephan C., Bruel, Ange-Line, Mikhaleva, Anna, Wagner, Christel, Vancollie, Valerie E., Thomas, Quentin, Chevarin, Martin, Weber, Mathys, Prada, Carlos E., Overs, Alexis, Palomares-Bralo, María, Santos-Simarro, Fernando, Pacio-Míguez, Marta, Busa, Tiffany, Legius, Eric, Bacino, Carlos A., Rosenfeld, Jill A., Le Guyader, Gwenaël, Egloff, Matthieu, Le Guillou, Xavier, Mencarelli, Maria Antonietta, Renieri, Alessandra, Grosso, Salvatore, Levy, Jonathan, Dozières, Blandine, Desguerre, Isabelle, Vitobello, Antonio, Duffourd, Yannis, Lelliott, Christopher J., Thauvin-Robinet, Christel, Philippe, Christophe, Faivre, Laurence, and Yalcin, Binnaz

Published
2023
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14. Deep genomic analysis of malignant peripheral nerve sheath tumor cell lines challenges current malignant peripheral nerve sheath tumor diagnosis

Author

Magallón-Lorenz, Miriam, Terribas, Ernest, Ortega-Bertran, Sara, Creus-Bachiller, Edgar, Fernández, Marco, Requena, Gerard, Rosas, Inma, Mazuelas, Helena, Uriarte-Arrazola, Itziar, Negro, Alex, Lausová, Tereza, Castellanos, Elisabeth, Blanco, Ignacio, DeVries, George, Kawashima, Hiroyuki, Legius, Eric, Brems, Hilde, Mautner, Viktor, Kluwe, Lan, Ratner, Nancy, Wallace, Margaret, Fernández-Rodriguez, Juana, Lázaro, Conxi, Fletcher, Jonathan A., Reuss, David, Carrió, Meritxell, Gel, Bernat, and Serra, Eduard

Published
2023
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15. ERN GENTURIS tumour surveillance guidelines for individuals with neurofibromatosis type 1

Author

Brunet, Joan, Van Calenbergh, Frank, Cassiman, Catherine, Czech, Thomas, Gavarrete de León, María José, Giele, Henk, Henley, Susie, Lazaro, Conxi, Lipkovskaya, Vera, Maher, Eamonn R., Martin, Vanessa, Mathijssen, Irene, Opocher, Enrico, Pires, Ana Elisabete, Pletschko, Thomas, Poupaki, Eirene, Ridola, Vita, Rietman, Andre, Rosenbaum, Thorsten, Santhouse, Alastair, Sehested, Astrid, Simmons, Ian, Taal, Walter, Wagner, Anja, Carton, Charlotte, Evans, D. Gareth, Blanco, Ignacio, Friedrich, Reinhard E., Ferner, Rosalie E., Farschtschi, Said, Salvador, Hector, Azizi, Amedeo A., Mautner, Victor, Röhl, Claas, Peltonen, Sirkku, Stivaros, Stavros, Legius, Eric, and Oostenbrink, Rianne

Published
2023
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16. Low mutation burden and frequent loss of CDKN2A/B and SMARCA2, but not PRC2, define pre-malignant neurofibromatosis type 1-associated atypical neurofibromas

Author

Pemov, Alexander, Hansen, Nancy F, Sindiri, Sivasish, Patidar, Rajesh, Higham, Christine S, Dombi, Eva, Miettinen, Markku M, Fetsch, Patricia, Brems, Hilde, Chandrasekharappa, Settara, Jones, Kristine, Zhu, Bin, Wei, Jun S, Mullikin, James C, Wallace, Margaret R, Khan, Javed, Legius, Eric, Widemann, Brigitte C, and Stewart, Douglas R

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Human Genome, Neurofibromatosis, Rare Diseases, Neurosciences, Genetics, Pediatric, Cancer, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p16, Humans, Mutation, Nerve Sheath Neoplasms, Neurofibroma, Neurofibroma, Plexiform, Neurofibromatosis 1, Neurofibrosarcoma, Transcription Factors, atypical neurofibromas, benign-to-malignant transformation, malignant peripheral nerve sheath tumor, neurofibromatosis type 1, plexiform neurofibromas, National Intramural Sequencing Center (NISC) Comparative Sequencing Program, National Cancer Institute (NCI) Division of Cancer Epidemiology and Genetics (DCEG) Cancer Genomics Research Laboratory, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundNeurofibromatosis type 1 (NF1) is a tumor-predisposition disorder caused by germline mutations in NF1. NF1 patients have an 8-16% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft-tissue sarcoma, often arising from preexisting benign plexiform neurofibromas (PNs) and atypical neurofibromas (ANFs). ANFs are distinct from both PN and MPNST, representing an intermediate step in malignant transformation.MethodsIn the first comprehensive genomic analysis of ANF originating from multiple patients, we performed tumor/normal whole-exome sequencing (WES) of 16 ANFs. In addition, we conducted WES of 3 MPNSTs, copy-number meta-analysis of 26 ANFs and 28 MPNSTs, and whole transcriptome sequencing analysis of 5 ANFs and 5 MPNSTs.ResultsWe identified a low number of mutations (median 1, range 0-5) in the exomes of ANFs (only NF1 somatic mutations were recurrent), and frequent deletions of CDKN2A/B (69%) and SMARCA2 (42%). We determined that polycomb repressor complex 2 (PRC2) genes EED and SUZ12 were frequently mutated, deleted, or downregulated in MPNSTs but not in ANFs. Our pilot gene expression study revealed upregulated NRAS, MDM2, CCND1/2/3, and CDK4/6 in ANFs and MPNSTs, and overexpression of EZH2 in MPNSTs only.ConclusionsThe PN-ANF transition is primarily driven by the deletion of CDKN2A/B. Further progression from ANF to MPNST likely involves broad chromosomal rearrangements and frequent inactivation of the PRC2 genes, loss of the DNA repair genes, and copy-number increase of signal transduction and cell-cycle and pluripotency self-renewal genes.

Published
2019

17. First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and advances of new therapeutics

Author

Rauen, Katherine A, Alsaegh, Abeer, Ben‐Shachar, Shay, Berman, Yemima, Blakeley, Jaishri, Cordeiro, Isabel, Elgersma, Ype, Evans, D Gareth, Fisher, Michael J, Frayling, Ian M, George, Joshi, Huson, Susan M, Kerr, Bronwyn, Khire, Uday, Korf, Bruce, Legius, Eric, Messiaen, Ludwine, van Minkelen, Rick, Nampoothiri, Sheela, Ngeow, Joanne, Parada, Luis F, Phadke, Shubha, Pillai, Ashok, Plotkin, Scott R, Puri, Ratna, Raji, Anup, Ramesh, Vijaya, Ratner, Nancy, Shankar, Suma P, Sharda, Sheetal, Tambe, Anant, Vikkula, Miikka, Widemann, Brigitte C, Wolkenstein, Pierre, and Upadhyaya, Meena

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Neurofibromatosis, Neurosciences, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Rare Diseases, Pediatric, Congenital, Biomarkers, Disease Management, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Mitogen-Activated Protein Kinases, Molecular Diagnostic Techniques, Molecular Targeted Therapy, Neurofibromatoses, Signal Transduction, Translational Research, Biomedical, ras Proteins, clinical trial, neurofibromatoses, RASopathy, signal transduction pathway, therapy, Clinical Sciences, Clinical sciences
Abstract

The neurofibromatoses, which include neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis, are a group of syndromes characterized by tumor growth in the nervous system. The RASopathies are a group of syndromes caused by germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. The RASopathies include NF1, Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardio-facio-cutaneous syndrome, Legius syndrome, capillary malformation arterio-venous malformation syndrome, and SYNGAP1 autism. Due to their common underlying pathogenetic etiology, all these syndromes have significant phenotypic overlap of which one common feature include a predisposition to tumors, which may be benign or malignant. Together as a group, they represent one of the most common multiple congenital anomaly syndromes estimating to affect approximately one in 1000 individuals worldwide. The subcontinent of India represents one of the largest populations in the world, yet remains underserved from an aspect of clinical genetics services. In an effort to bridge this gap, the First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and Advances of New Therapeutics was held in Kochi, Kerala, India. These proceedings chronicle this timely and topical international symposium directed at discussing the best practices and therapies for individuals with neurofibromatoses and RASopathies.

Published
2019

18. From process to progress—2017 International Conference on Neurofibromatosis 1, Neurofibromatosis 2 and Schwannomatosis

Author

Ferner, Rosalie E, Bakker, Annette, Elgersma, Ype, Evans, D Gareth R, Giovannini, Marco, Legius, Eric, Lloyd, Alison, Messiaen, Ludwine M, Plotkin, Scott, Reilly, Karlyne M, Schindeler, Aaron, Smith, Miriam J, Ullrich, Nicole J, Widemann, Brigitte, and Sherman, Larry S

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Cancer, Brain Disorders, Neurofibromatosis, Rare Diseases, Pediatric, Neurosciences, Animals, Disease Susceptibility, Humans, Neurilemmoma, Neurofibromatoses, Neurofibromatosis 1, Neurofibromatosis 2, Skin Neoplasms, neurofibromatosis 1, neurofibromatosis 2, schwannomatosis, Genetics, Clinical sciences
Abstract

The neurofibromatoses are inherited, tumor suppressor disorders that are characterized by multiple, benign peripheral nerve sheath tumors and other nervous system tumors. Each disease is associated with a distinct genetic mutation and with a different pathogenesis and clinical course. Neurofibromatosis 1 (NF1) is common and epitomized by multiple neurofibromas with widespread complications. NF2 and schwannomatosis are rare diseases that are typified by multiple schwannomas that are particularly painful in people with schwannomatosis. Since 1985, the Children's Tumor Foundation (formerly the National Neurofibromatosis Foundation) has hosted an international Neurofibromatosis Conference, bringing together international participants who are focused on NF research and clinical care. The 2017 Conference, held in Washington, DC, was among the largest gatherings of NF researchers to date and included presentations from clinicians and basic scientists, highlighting new data regarding the molecular and cellular mechanisms underlying each of these diseases as well as results from clinical studies and clinical trials. This article summarizes the findings presented at the meeting and represents the current state-of-the art for NF research.

Published
2019

19. Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

Author

Koczkowska, Magdalena, Callens, Tom, Gomes, Alicia, Sharp, Angela, Chen, Yunjia, Hicks, Alesha D, Aylsworth, Arthur S, Azizi, Amedeo A, Basel, Donald G, Bellus, Gary, Bird, Lynne M, Blazo, Maria A, Burke, Leah W, Cannon, Ashley, Collins, Felicity, DeFilippo, Colette, Denayer, Ellen, Digilio, Maria C, Dills, Shelley K, Dosa, Laura, Greenwood, Robert S, Griffis, Cristin, Gupta, Punita, Hachen, Rachel K, Hernández-Chico, Concepción, Janssens, Sandra, Jones, Kristi J, Jordan, Justin T, Kannu, Peter, Korf, Bruce R, Lewis, Andrea M, Listernick, Robert H, Lonardo, Fortunato, Mahoney, Maurice J, Ojeda, Mayra Martinez, McDonald, Marie T, McDougall, Carey, Mendelsohn, Nancy, Miller, David T, Mori, Mari, Oostenbrink, Rianne, Perreault, Sebastién, Pierpont, Mary Ella, Piscopo, Carmelo, Pond, Dinel A, Randolph, Linda M, Rauen, Katherine A, Rednam, Surya, Rutledge, S Lane, Saletti, Veronica, Schaefer, G Bradley, Schorry, Elizabeth K, Scott, Daryl A, Shugar, Andrea, Siqveland, Elizabeth, Starr, Lois J, Syed, Ashraf, Trapane, Pamela L, Ullrich, Nicole J, Wakefield, Emily G, Walsh, Laurence E, Wangler, Michael F, Zackai, Elaine, Claes, Kathleen BM, Wimmer, Katharina, van Minkelen, Rick, De Luca, Alessandro, Martin, Yolanda, Legius, Eric, and Messiaen, Ludwine M

Subjects
Humans, Neurofibroma, Plexiform, Neurofibromatosis 1, Genetic Predisposition to Disease, Neurofibromin 1, Sequence Deletion, Heterozygote, Mutation, Missense, Adolescent, Adult, Child, Child, Preschool, Infant, Female, Male, Young Adult, Genetic Association Studies, Learning Disabilities, NF1, genotype–phenotype correlation, learning difficulties, neurofibroma, p.Met992del, genotype-phenotype correlation, Neurofibroma, Plexiform, Mutation, Missense, Preschool, Genetics, Clinical Sciences, Genetics & Heredity
Abstract

PurposeNeurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors.MethodsA total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study.ResultsNone of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del.ConclusionWe demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

Published
2019

20. Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

Author

Koczkowska, Magdalena, Callens, Tom, Gomes, Alicia, Sharp, Angela, Chen, Yunjia, Hicks, Alesha, Aylsworth, Arthur, Azizi, Amedeo, Basel, Donald, Bellus, Gary, Bird, Lynne, Blazo, Maria, Burke, Leah, Cannon, Ashley, Collins, Felicity, DeFilippo, Colette, Denayer, Ellen, Digilio, Maria, Dills, Shelley, Dosa, Laura, Greenwood, Robert, Griffis, Cristin, Gupta, Punita, Hachen, Rachel, Hernández-Chico, Concepción, Janssens, Sandra, Jones, Kristi, Jordan, Justin, Kannu, Peter, Korf, Bruce, Lewis, Andrea, Listernick, Robert, Lonardo, Fortunato, Mahoney, Maurice, Ojeda, Mayra, McDonald, Marie, McDougall, Carey, Mendelsohn, Nancy, Miller, David, Mori, Mari, Oostenbrink, Rianne, Perreault, Sebastién, Pierpont, Mary, Piscopo, Carmelo, Pond, Dinel, Randolph, Linda, Rauen, Katherine, Rednam, Surya, Rutledge, S, Saletti, Veronica, Schaefer, G, Schorry, Elizabeth, Scott, Daryl, Shugar, Andrea, Siqveland, Elizabeth, Starr, Lois, Syed, Ashraf, Trapane, Pamela, Ullrich, Nicole, Wakefield, Emily, Walsh, Laurence, Wangler, Michael, Zackai, Elaine, Claes, Kathleen, Wimmer, Katharina, van Minkelen, Rick, De Luca, Alessandro, Martin, Yolanda, Legius, Eric, and Messiaen, Ludwine

Abstract

A correction has been published to this Article. The PDF and HTML have been updated accordingly.

Published
2019

21. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

Author

Duijkers, Floor, Giltay, Jacques C., van Hest, Liselotte P., Kleefstra, Tjitske, Leter, Edward M., Nielsen, Maartje, Nijmeijer, Sebastiaan W.R., Olderode-Berends, Maran J.W., Hendricks, Linda A.J., Hoogerbrugge, Nicoline, Venselaar, Hanka, Aretz, Stefan, Spier, Isabel, Legius, Eric, Brems, Hilde, de Putter, Robin, Claes, Kathleen B.M., Evans, D. Gareth, Woodward, Emma R., Genuardi, Maurizio, Brugnoletti, Fulvia, van Ierland, Yvette, Dijke, Kim, Tham, Emma, Tesi, Bianca, Schuurs-Hoeijmakers, Janneke H.M., Branchaud, Maud, Salvador, Hector, Jahn, Arne, Schnaiter, Simon, Anastasiadou, Violetta Christophidou, Brunet, Joan, Oliveira, Carla, Roht, Laura, Blatnik, Ana, Irmejs, Arvids, Mensenkamp, Arjen R., and Vos, Janet R.

Published
2022
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22. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation

Author

Anten, Monique, Aylsworth, Arthur, Baralle, Diana, Barbarot, Sebastien, Barker, Fred, II, Ben-Shachar, Shay, Bergner, Amanda, Bessis, Didier, Blanco, Ignacio, Cassiman, Catherine, Ciavarelli, Patricia, Clementi, Maurizio, Frébourg, Thierry, Gomes, Alicia, Halliday, Dorothy, Helen Hanson Arvid Heiberg, Chris Hammond, Joly, Pascal, Jordan, Justin T., Karajannis, Matthias, Kroshinsky, Daniela, Larralde, Margarita, Lázaro, Conxi, Le, Lu, Link, Michael, Listernick, Robert, Mallucci, Conor, Merker, Vanessa L., Moertel, Christopher, Mueller, Amy, Ngeow, Joanne, Oostenbrink, Rianne, Packer, Roger, Parry, Allyson, Peltonen, Juha, Pichard, Dominique, Poppe, Bruce, Rezende, Nilton, Rodrigues, Luiz Oswaldo, Rosser, Tena, Ruggieri, Martino, Serra, Eduard, Steinke-Lange, Verena, Stivaros, Stavros Michael, Taylor, Amy, Toelen, Jaan, Tonsgard, James, Trevisson, Eva, Upadhyaya, Meena, Varan, Ali, Wilson, Meredith, Wu, Hao, Zadeh, Gelareh, Plotkin, Scott R., Messiaen, Ludwine, Legius, Eric, Pancza, Patrice, Avery, Robert A., Blakeley, Jaishri O., Babovic-Vuksanovic, Dusica, Ferner, Rosalie, Fisher, Michael J., Friedman, Jan M., Giovannini, Marco, Gutmann, David H., Hanemann, Clemens Oliver, Kalamarides, Michel, Kehrer-Sawatzki, Hildegard, Korf, Bruce R., Mautner, Victor-Felix, MacCollin, Mia, Papi, Laura, Rauen, Katherine A., Riccardi, Vincent, Schorry, Elizabeth, Smith, Miriam J., Stemmer-Rachamimov, Anat, Stevenson, David A., Ullrich, Nicole J., Viskochil, David, Wimmer, Katharina, Yohay, Kaleb, Huson, Susan M., Wolkenstein, Pierre, and Evans, D. Gareth

Published
2022
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23. ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis

Author

Evans, D. Gareth, Mostaccioli, Stefania, Pang, David, Fadzil O Connor, Mary, Pittara, Melpo, Champollion, Nicolas, Wolkenstein, Pierre, Thomas, Nick, Ferner, Rosalie E., Kalamarides, Michel, Peyre, Matthieu, Papi, Laura, Legius, Eric, Becerra, Juan Luis, King, Andrew, Duff, Chris, Stivaros, Stavros, and Blanco, Ignacio

Published
2022
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24. The characteristics of 76 atypical neurofibromas as precursors to neurofibromatosis 1 associated malignant peripheral nerve sheath tumors.

Author

Higham, Christine S, Dombi, Eva, Rogiers, Aljosja, Bhaumik, Sucharita, Pans, Steven, Connor, Steve EJ, Miettinen, Markku, Sciot, Raf, Tirabosco, Roberto, Brems, Hilde, Baldwin, Andrea, Legius, Eric, Widemann, Brigitte C, and Ferner, Rosalie E

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Prevention, Neurosciences, Pain Research, Rare Diseases, Neurofibromatosis, Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Magnetic Resonance Imaging, Male, Middle Aged, Neurofibroma, Neurofibromatosis 1, Neurofibrosarcoma, Positron-Emission Tomography, Prognosis, Tomography, X-Ray Computed, Young Adult, atypical neurofibroma, neurofibromatosis 1, malignant peripheral nerve sheath tumor, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundNeurofibromatosis 1 (NF1) leads to the development of benign and malignant peripheral nerve sheath tumors (MPNST). MPNST have been described to develop in preexisting benign plexiform neurofibromas (PN) and have a poor prognosis. Atypical neurofibromas (ANF) were recently described as precursor lesions for MPNST, making early detection and management of ANF a possible strategy to prevent MPNST. We aimed to clinically characterize ANF and identify management approaches.MethodsWe analyzed clinical, imaging, and pathology findings of all patients with NF1 and ANF at 3 institutions.ResultsSixty-three patients had 76 ANF (32M/31F; median age 27.1 y). On MRI, most ANF appeared as distinct nodular lesions and were 18F-fluorodeoxyglucose (FDG) avid. Forty-six ANF were associated with pain, 19 with motor weakness, 45 were palpable or visible, and 13 had no clinical signs. Completely resected ANF (N = 57) have not recurred (median follow-up, 4.1 y; range, 0-14 y). Four ANF transformed into MPNST and 17 patients had a history of MPNST in a different location than was their ANF.ConclusionsGrowth of distinct nodular lesions, pain, and FDG-PET avidity should raise concern for ANF in NF1. Patients with ANF are at greater risk for development of MPNST. Complete resection of ANF may prevent development of MPNST.

Published
2018

28. TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila

Author

Goodman, Lindsey D., Cope, Heidi, Nil, Zelha, Ravenscroft, Thomas A., Charng, Wu-Lin, Lu, Shenzhao, Tien, An-Chi, Pfundt, Rolph, Koolen, David A., Haaxma, Charlotte A., Veenstra-Knol, Hermine E., Wassink-Ruiter, Jolien S. Klein, Wevers, Marijke R., Jones, Melissa, Walsh, Laurence E., Klee, Victoria H., Theunis, Miel, Legius, Eric, Steel, Dora, Barwick, Katy E.S., Kurian, Manju A., Mohammad, Shekeeb S., Dale, Russell C., Terhal, Paulien A., van Binsbergen, Ellen, Kirmse, Brian, Robinette, Bethany, Cogné, Benjamin, Isidor, Bertrand, Grebe, Theresa A., Kulch, Peggy, Hainline, Bryan E., Sapp, Katherine, Morava, Eva, Klee, Eric W., Macke, Erica L., Trapane, Pamela, Spencer, Christopher, Si, Yue, Begtrup, Amber, Moulton, Matthew J., Dutta, Debdeep, Kanca, Oguz, Wangler, Michael F., Yamamoto, Shinya, Bellen, Hugo J., and Tan, Queenie K.-G.

Published
2021
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30. Neurofibromatosis Type 1–Associated MPNST State of the Science: Outlining a Research Agenda for the Future

Author

Reilly, Karlyne M, Kim, AeRang, Blakely, Jaishri, Ferner, Rosalie E, Gutmann, David H, Legius, Eric, Miettinen, Markku M, Randall, R Lor, Ratner, Nancy, Jumbé, NL, Bakker, Annette, Viskochil, David, Widemann, Brigitte C, and Stewart, Douglas R

Subjects
Rare Diseases, Neurosciences, Biotechnology, Neurofibromatosis, Cancer, Pediatric, Biomedical Research, Consensus, Humans, Nerve Sheath Neoplasms, Neurilemmoma, Neurofibromatosis 1, Practice Guidelines as Topic, Therapies, Investigational, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma for which the only effective therapy is surgery. In 2016, an international meeting entitled "MPNST State of the Science: Outlining a Research Agenda for the Future" was convened to establish short- and long-term research priorities. Key recommendations included the: 1) development of standardized, cost-efficient fluorodeoxyglucose positron emission tomography and whole-body magnetic resonance imaging guidelines to evaluate masses concerning for MPNST; 2) development of better understanding and histologic criteria for the transformation of a plexiform neurofibroma to MPNST; 3) establishment of a centralized database to collect genetic, genomic, histologic, immunohistochemical, molecular, radiographic, treatment, and related clinical data from MPNST subspecialty centers in a standardized manner; 4) creation of accurate mouse models to study the plexiform neurofibroma-to-MPNST transition, MPNST metastasis, and drug resistance; 5) use of trial designs that minimize regulatory requirements, maximize availability to patients, consider novel secondary end points, and study patients with newly diagnosed disease. Lastly, in order to minimize delays in developing novel therapies and promote the most efficient use of research resources and patient samples, data sharing should be incentivized.

Published
2017

31. The path forward: 2015 International Children's Tumor Foundation conference on neurofibromatosis type 1, type 2, and schwannomatosis

Author

Blakeley, Jaishri O, Bakker, Annette, Barker, Anne, Clapp, Wade, Ferner, Rosalie, Fisher, Michael J, Giovannini, Marco, Gutmann, David H, Karajannis, Matthias A, Kissil, Joseph L, Legius, Eric, Lloyd, Alison C, Packer, Roger J, Ramesh, Vijaya, Riccardi, Vincent M, Stevenson, David A, Ullrich, Nicole J, Upadhyaya, Meena, and Stemmer‐Rachamimov, Anat

Subjects
Biomedical and Clinical Sciences, Immunology, Brain Disorders, Neurofibromatosis, Pediatric, Rare Diseases, Orphan Drug, Cancer, Pediatric Cancer, Pediatric Research Initiative, Neurosciences, Brain Cancer, Child, Humans, Neurilemmoma, Neurofibromatoses, Neurofibromatosis 1, Neurofibromatosis 2, Pediatrics, Skin Neoplasms, neurofibromatosis type 1, neurofibromatosis type 2, pediatric tumors, rare disease, schwannomatosis, therapeutic discovery, Genetics, Clinical Sciences, Clinical sciences
Abstract

The Annual Children's Tumor Foundation International Neurofibromatosis Meeting is the premier venue for connecting discovery, translational and clinical scientists who are focused on neurofibromatosis types 1 and 2 (NF1 and NF2) and schwannomatosis (SWN). The meeting also features rare tumors such as glioma, meningioma, sarcoma, and neuroblastoma that occur both within these syndromes and spontaneously; associated with somatic mutations in NF1, NF2, and SWN. The meeting addresses both state of the field for current clinical care as well as emerging preclinical models fueling discovery of new therapeutic targets and discovery science initiatives investigating mechanisms of tumorigenesis. Importantly, this conference is a forum for presenting work in progress and bringing together all stakeholders in the scientific community. A highlight of the conference was the involvement of scientists from the pharmaceutical industry who presented growing efforts for rare disease therapeutic development in general and specifically, in pediatric patients with rare tumor syndromes. Another highlight was the focus on new investigators who presented new data about biomarker discovery, tumor pathogenesis, and diagnostic tools for NF1, NF2, and SWN. This report summarizes the themes of the meeting and a synthesis of the scientific discoveries presented at the conference in order to make the larger research community aware of progress in the neurofibromatoses.

Published
2017

33. Comprehensive genome-wide analysis of routine non-invasive test data allows cancer prediction: A single-center retrospective analysis of over 85,000 pregnancies

Author

Lenaerts, Liesbeth, Brison, Nathalie, Maggen, Charlotte, Vancoillie, Leen, Che, Huiwen, Vandenberghe, Peter, Dierickx, Daan, Michaux, Lucienne, Dewaele, Barbara, Neven, Patrick, Floris, Giuseppe, Tousseyn, Thomas, Lannoo, Lore, Jatsenko, Tatjana, Bempt, Isabelle Vanden, Van Calsteren, Kristel, Vandecaveye, Vincent, Dehaspe, Luc, Devriendt, Koenraad, Legius, Eric, Bogaert, Kris Van Den, Vermeesch, Joris Robert, and Amant, Frédéric

Published
2021
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34. The phenotypic and genotypic spectrum of individuals with mono‐ or biallelic ANK3 variants.

Author

Furia, Francesca, Levy, Amanda M., Theunis, Miel, Bamshad, Michael J., Bartos, Meghan N., Bijlsma, Emilia K., Brancati, Francesco, Cejudo, Lucile, Chong, Jessica X., De Luca, Chiara, Dean, Sarah Joy, Egense, Alena, Goel, Himanshu, Guenzel, Adam J., Hüffmeier, Ulrike, Legius, Eric, Mancini, Grazia M. S., Marcos‐Alcalde, Iñigo, Niclass, Tanguy, and Planes, Marc

Subjects
SLEEP disorders, SLEEP interruptions, ALTERNATIVE RNA splicing, ATTENTION-deficit hyperactivity disorder, AUTISM spectrum disorders
Abstract

ANK3 encodes ankyrin‐G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin‐G isoforms comprising different domains with distinct expression patterns. Mono‐ or biallelic ANK3 variants are associated with non‐specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self‐injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono‐ and biallelic variants appear to be localized differently across the three different ankyrin‐G isoforms, suggesting isoform‐specific pathological mechanisms. [ABSTRACT FROM AUTHOR]

Published
2024
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35. Pigment epithelium derived factor drives melanocyte proliferation and migration in neurofibromatosis café au lait macules.

Author

Lovatt, Charlotte, Williams, Megan, Gibbs, Alex, Mukhtar, Abdullahi, Morgan, Huw J., Lanfredini, Simone, Olivero, Carlotta, Spurlock, Gill, Davies, Sally, Philpott, Charlotte, Tovell, Hannah, Turnpenny, Peter, Baban, Dilair, Knight, Sam, Brems, Hilde, Sampson, Julian R., Legius, Eric, Upadhyaya, Meena, and Patel, Girish K.

Published
2024
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36. Encephalocraniocutaneous lipomatosis phenotype associated with mosaic biallelic pathogenic variants in the NF1 gene.

Author

Smeijers, Steven, Brems, Hilde, Verhaeghe, Alexander, van Paesschen, Wim, van Loon, Johannes, Van der Auweraer, Seppe, Sciot, Raf, Thal, Dietmar Rudolf, Lagae, Lieven, Legius, Eric, and Theys, Tom

Abstract

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic congenital condition characterised by ocular, cutaneous and central nervous system involvement. Mosaic activating variants in FGFR1 and KRAS have been reported in several individuals with this syndrome. We report on a patient with neurofibromatosis type 1 (NF1) with a germline pathogenic variant in the NF1 gene and an ECCL phenotype, suggesting ECCL to be part of a spectrum of malformations associated with NF1 pathogenic variants. An anatomical hemispherectomy was performed for intractable epilepsy. Through genetic analysis of blood, cerebral tissue and giant cell lesions in both jaws, we identified the germline NF1 pathogenic variant in all samples and a second- hit pathogenic NF1 variant in cerebral tissue and both giant cell lesions. Both NF1 variants were located on different alleles resulting in somatic mosaicism for a biallelic NF1 inactivation originating in early embryogenesis (second- hit mosaicism or Happle type 2 mosaicism). The biallelic deficit in NF1 in the left hemicranium explains the severe localised, congenital abnormality in this patient. Identical first and second- hit variants in a giant cell lesion of both upper and lower jaws provide confirmatory evidence for an early embryonic second hit involving at least the neural crest. We suggest that the ECCL phenotype may be part of a spectrum of congenital problems associated with mosaic NF1 nullisomy originating during early embryogenesis. The biallelic NF1 inactivation during early embryogenesis mimics the severe activation of the RAS- MAPK pathway seen in ECCL caused by embryonic mosaic activating FGFR1 and KRAS variants in the cranial region. We propose that distinct mechanisms of mosaicism can cause the ECCL phenotype through convergence on the RAS- MAPK pathway. [ABSTRACT FROM AUTHOR]

Published
2024

37. Examination of the genetic factors underlying the cognitive variability associated with neurofibromatosis type 1

Author

Ottenhoff, Myrthe J., Rietman, André B., Mous, Sabine E., Plasschaert, Ellen, Gawehns, Daniela, Brems, Hilde, Oostenbrink, Rianne, van Minkelen, Rick, Nellist, Mark, Schorry, Elizabeth, Legius, Eric, Moll, Henriette A., Elgersma, Ype, de Wit, Marie-Claire Y., de Nijs, Pieter F.A., Legerstee, Jeroen S., Dieleman, Gwendolyn C., and ten Hoopen, Leontine W.

Published
2020
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40. Disease Burden and Symptom Structure of Autism in Neurofibromatosis Type 1: A Study of the International NF1-ASD Consortium Team (INFACT)

Author

Morris, Stephanie M, Acosta, Maria T, Garg, Shruti, Green, Jonathan, Huson, Susan, Legius, Eric, North, Kathryn N, Payne, Jonathan M, Plasschaert, Ellen, Frazier, Thomas W, Weiss, Lauren A, Zhang, Yi, Gutmann, David H, and Constantino, John N

Subjects
Autism, Behavioral and Social Science, Rare Diseases, Neurofibromatosis, Intellectual and Developmental Disabilities (IDD), Mental Health, Brain Disorders, Clinical Research, Neurosciences, Pediatric, Adolescent, Adult, Aged, Aged, 80 and over, Autism Spectrum Disorder, Child, Child, Preschool, Comorbidity, Cost of Illness, Female, Genetic Predisposition to Disease, Humans, Internationality, Male, Middle Aged, Neurofibromatoses, Quantitative Trait Loci, Young Adult, Other Medical and Health Sciences, Psychology, Cognitive Sciences
Abstract

ImportanceRecent reports have demonstrated a higher incidence of autism spectrum disorder (ASD) and substantially elevated autistic trait burden in individuals with neurofibromatosis type 1 (NF1). However, important discrepancies regarding the distribution of autistic traits, sex predominance, and association between ASD symptoms and attentional problems have emerged, and critical features of the ASD phenotype within NF1 have never been adequately explored. Establishing NF1 as a monogenic cause for ASD has important implications for affected patients and for future research focused on establishing convergent pathogenic mechanisms relevant to the potential treatment targets for ASD.ObjectiveTo characterize the quantitative autistic trait (QAT) burden in a pooled NF1 data set.Design, setting, and participantsAnonymized, individual-level primary data were accumulated from 6 tertiary referral centers in the United States, Belgium, United Kingdom, and Australia. A total of 531 individuals recruited from NF1 clinical centers were included in the study.Main outcomes and measuresDistribution of ASD traits (Social Responsiveness Scale, second edition [SRS-2], with T scores of ≥75 associated with a categorical ASD diagnosis); attention-deficit/hyperactivity disorder (ADHD) traits (4 versions of Conners Rating Scale, with T scores of ≥65 indicating clinically significant ADHD symptoms); ASD symptom structure, latent structure, base rate derived from mixture modeling; and familiality.ResultsOf the 531 patients included in the analysis, 247 were male (46.5%); median age was 11 years (range, 2.5-83.9 years). QAT scores were continuously distributed and pathologically shifted; 13.2% (95% CI, 10.3%-16.1%) of individuals scored within the most severe range (ie, above the first percentile of the general population distribution) in which the male to female ratio was markedly attenuated (1.6:1) relative to idiopathic ASD. Autistic symptoms in this NF1 cohort demonstrated a robust unitary factor structure, with the first principal component explaining 30.9% of the variance in SRS-2 scores, and a strong association with ADHD symptoms (r = 0.61). Within-family correlation for QAT burden (intraclass correlation coefficient, 0.73 in NF1-affected first-degree relatives) exceeded that observed in the general population and ASD family samples.Conclusions and relevanceThis study provides confirmation that the diversity of mutations that give rise to NF1 function as quantitative trait loci for ASD. Moreover, the within-family correlation implicates a high degree of mutational specificity for this associated phenotype. Clinicians should be alerted to the increased frequency of this disabling comorbidity, and the scientific community should be aware of the potential for this monogenic disorder to help elucidate the biological features of idiopathic autism.

Published
2016

41. Platform trial design for neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis:A potential model for rare diseases

Author

Dhaenens, Britt A. E., Heimann, Guenter, Bakker, Annette, Nievo, Marco, Ferner, Rosalie E., Evans, D. Gareth, Wolkenstein, Pierre, Leubner, Jonas, Potratz, Cornelia, Carton, Charlotte, Iloeje, Uchenna, Kirk, George, Blakeley, Jaishri O., Plotkin, Scott, Fisher, Michael J., Kim, Aerang, Driever, Pablo Hernaiz, Azizi, Amedeo A., Widemann, Brigitte C., Gross, Andrea, Parke, Tom, Legius, Eric, Oostenbrink, Rianne, Dhaenens, Britt A. E., Heimann, Guenter, Bakker, Annette, Nievo, Marco, Ferner, Rosalie E., Evans, D. Gareth, Wolkenstein, Pierre, Leubner, Jonas, Potratz, Cornelia, Carton, Charlotte, Iloeje, Uchenna, Kirk, George, Blakeley, Jaishri O., Plotkin, Scott, Fisher, Michael J., Kim, Aerang, Driever, Pablo Hernaiz, Azizi, Amedeo A., Widemann, Brigitte C., Gross, Andrea, Parke, Tom, Legius, Eric, and Oostenbrink, Rianne

Abstract

Background Neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis (grouped under the abbreviation "NF") are rare hereditary tumor predisposition syndromes. Due to the low prevalence, variability in the range, and severity of manifestations, as well as limited treatment options, these conditions require innovative trial designs to accelerate the development of new treatments.Methods Within European Patient-Centric Clinical Trial Platforms (EU-PEARL), we designed 2 platform-basket trials in NF. The trials were designed by a team of multidisciplinary NF experts and trial methodology experts.Results The trial will consist of an observational and a treatment period. The observational period will serve as a longitudinal natural history study. The platform trial design and randomization to a sequence of available interventions allow for the addition of interventions during the trial. If a drug does not meet the predetermined efficacy endpoint or reveals unacceptable toxicities, participants may stop treatment on that arm and re-enter the observational period, where they can be re-randomized to a different treatment arm if eligible. Intervention-specific eligibility criteria and endpoints are listed in intervention-specific-appendices, allowing the flexibility and adaptability needed for highly variable and rare conditions like NF.Conclusions These innovative platform-basket trials for NF may serve as a model for other rare diseases, as they will enhance the chance of identifying beneficial treatments through optimal learning from a small number of patients. The goal of these trials is to identify beneficial treatments for NF more rapidly and at a lower cost than traditional, single-agent clinical trials.

Published
2024

44. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author

Konrad, Enrico D.H., Nardini, Niels, Caliebe, Almuth, Nagel, Inga, Young, Dana, Horvath, Gabriella, Santoro, Stephanie L., Shuss, Christine, Ziegler, Alban, Bonneau, Dominique, Kempers, Marlies, Pfundt, Rolph, Legius, Eric, Bouman, Arjan, Stuurman, Kyra E., Õunap, Katrin, Pajusalu, Sander, Wojcik, Monica H., Vasileiou, Georgia, Le Guyader, Gwenaël, Schnelle, Hege M., Berland, Siren, Zonneveld-Huijssoon, Evelien, Kersten, Simone, Gupta, Aditi, Blackburn, Patrick R., Ellingson, Marissa S., Ferber, Matthew J., Dhamija, Radhika, Klee, Eric W., McEntagart, Meriel, Lichtenbelt, Klaske D., Kenney, Amy, Vergano, Samantha A., Abou Jamra, Rami, Platzer, Konrad, Ella Pierpont, Mary, Khattar, Divya, Hopkin, Robert J., Martin, Richard J., Jongmans, Marjolijn C.J., Chang, Vivian Y., Martinez-Agosto, Julian A., Kuismin, Outi, Kurki, Mitja I., Pietiläinen, Olli, Palotie, Aarno, Maarup, Timothy J., Johnson, Diana S., Venborg Pedersen, Katja, Laulund, Lone W., Lynch, Sally A., Blyth, Moira, Prescott, Katrina, Canham, Natalie, Ibitoye, Rita, Brilstra, Eva H., Shinawi, Marwan, Fassi, Emily, Sticht, Heinrich, Gregor, Anne, Van Esch, Hilde, and Zweier, Christiane

Published
2019
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46. Gonadal and gonadosomatic mosaicism in NF1: report of two families

Author

Seidl‐Philipp, Magdalena, primary, Veyt, Nathalie, additional, Schnaiter, Simon, additional, Krogsdam, Anne, additional, Schwendinger, Simon, additional, Maertens, Ophélia, additional, Fauth, Christine, additional, Schmuth, Matthias, additional, Legius, Eric, additional, Wimmer, Katharina, additional, and Brems, Hilde, additional

Published
2024
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47. Platform trial design for Neurofibromatosis type 1, NF2-related Schwannomatosis and non-NF2-related Schwannomatosis: a potential model for rare diseases

Author

Dhaenens, Britt A E, primary, Heimann, Günter, additional, Bakker, Annette, additional, Nievo, Marco, additional, Ferner, Rosalie E, additional, Evans, D Gareth, additional, Wolkenstein, Pierre, additional, Leubner, Jonas, additional, Potratz, Cornelia, additional, Carton, Charlotte, additional, Iloeje, Uchenna, additional, Kirk, George, additional, Blakeley, Jaishri O, additional, Plotkin, Scott, additional, Fisher, Michael J, additional, Kim, Ae Rang, additional, Driever, Pablo Hernáiz, additional, Azizi, Amedeo A, additional, Widemann, Brigitte C, additional, Gross, Andrea, additional, Parke, Tom, additional, Legius, Eric, additional, and Oostenbrink, Rianne, additional

Published
2024
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48. Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL

Author

Koenig, Franz, primary, Spiertz, Cécile, additional, Millar, Daniel, additional, Rodríguez-Navarro, Sarai, additional, Machín, Núria, additional, Van Dessel, Ann, additional, Genescà, Joan, additional, Pericàs, Juan M., additional, Posch, Martin, additional, Sánchez-Montalva, Adrian, additional, Estevez, Ana Belén, additional, Sánchez, Àlex, additional, Sanjuan, Anna, additional, Sena, Elena, additional, Granados, Emma, additional, Arévalo de Andrés, Esther, additional, Nuñez, Fátima, additional, Arteaga, Gara, additional, Fuentes Ruiz, Gabriela Perez, additional, Fernández, Guillermo, additional, Rivera-Esteban, Jesus, additional, Comella, Joan, additional, Ramos-Quiroga, Josep Antoni, additional, Espinosa, Juan, additional, Pericàs, Juan Manuel, additional, Murcia, Lada, additional, Cash-Gibson, Lucinda, additional, de Valles Silvosa, Maria, additional, Barroso de Sousa, María Fernanda, additional, Sánchez-Maroto Carrizo, Olga, additional, Ibañez-Jiménez, Pol, additional, Augustin, Salvador, additional, Perez-Hoyos, Santiago, additional, Muñoz-Martínez, Sergio, additional, Serres, Silvia, additional, Kalko, Susana, additional, Michon, Amelie, additional, Ussi, Anton, additional, Lydall, Ben, additional, van de Ketterij, Edwin, additional, Quiles, Ignacio, additional, Carapina, Tamara, additional, Kumaus, Constantin, additional, Ramazanova, Dariga, additional, Meyer, Elias Laurin, additional, Koenig, Franz, additional, Roig, Marta Bofill, additional, Brunner, Martin, additional, Krotka, Pavla, additional, Zehetmayer, Sonja, additional, Carton, Charlotte, additional, Legius, Eric, additional, Begum, Amina, additional, Pariante, Carmine, additional, Worrell, Courtney, additional, Lombardo, Giulia, additional, Sforzini, Luca, additional, Brown, Mollie, additional, Gullet, Nancy, additional, Amasi-Hartoonian, Nare, additional, Ferner, Rosalie, additional, Kose, Melisa, additional, Spitaleri, Andrea, additional, Ghodousi, Arash, additional, Di Serio, Clelia, additional, Cirillo, Daniela, additional, Cugnata, Federica, additional, Saluzzo, Francesca, additional, Benedetti, Francesco, additional, Scarale, Maria Giovanna, additional, Zini, Michela, additional, Rancoita, Paola Maria, additional, Alagna, Riccardo, additional, Poletti, Sara, additional, Dhaenens, Britt, additional, Van Der Lei, Johan, additional, de Steenwinkel, Jurriaan, additional, Moinat, Maxim, additional, Oostenbrink, Rianne, additional, Hoogendijk, Witte, additional, Hölscher, Michael, additional, Heinrich, Norbert, additional, Otte, Christian, additional, Potratz, Cornelia, additional, Zocholl, Dario, additional, Kulakova, Eugenia, additional, Tacke, Frank, additional, Brasanac, Jelena, additional, Leubner, Jonas, additional, Krajewska, Maja, additional, Freitag, Michaela Maria, additional, Gold, Stefan, additional, Zoller, Thomas, additional, Chae, Woo Ri, additional, Daniel, Christel, additional, Kara, Leila, additional, Vaterkowski, Morgan, additional, Griffon, 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2024
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49. CTF meeting 2012: Translation of the basic understanding of the biology and genetics of NF1, NF2, and schwannomatosis toward the development of effective therapies

Author

Widemann, Brigitte C, Acosta, Maria T, Ammoun, Sylvia, Belzberg, Allan J, Bernards, Andre, Blakeley, Jaishri, Bretscher, Antony, Cichowski, Karen, Clapp, D Wade, Dombi, Eva, Evans, Gareth D, Ferner, Rosalie, Fernandez‐Valle, Cristina, Fisher, Michael J, Giovannini, Marco, Gutmann, David H, Hanemann, C Oliver, Hennigan, Robert, Huson, Susan, Ingram, David, Kissil, Joe, Korf, Bruce R, Legius, Eric, Packer, Roger J, McClatchey, Andrea I, McCormick, Frank, North, Kathryn, Pehrsson, Minja, Plotkin, Scott R, Ramesh, Vijaya, Ratner, Nancy, Schirmer, Susann, Sherman, Larry, Schorry, Elizabeth, Stevenson, David, Stewart, Douglas R, Ullrich, Nicole, Bakker, Annette C, and Morrison, Helen

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Pediatric, Neurosciences, Orphan Drug, Genetics, Neurofibromatosis, Rare Diseases, Brain Disorders, 5.1 Pharmaceuticals, Humans, Neurilemmoma, Neurofibromatoses, Neurofibromatosis 1, Neurofibromatosis 2, Skin Neoplasms, neurofibromatosis type 1, neurofibromatosis type 2, NF1, NF2, schwannomatosis, tumor suppressor, SMARCB1, merlin neurofibromin, preclinical models, Clinical sciences
Abstract

The neurofibromatoses (NF) are autosomal dominant genetic disorders that encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect more people worldwide than Duchenne muscular dystrophy and Huntington's disease combined. NF1 and NF2 are caused by mutations of known tumor suppressor genes (NF1 and NF2, respectively). For schwannomatosis, although mutations in SMARCB1 were identified in a subpopulation of schwannomatosis patients, additional causative gene mutations are still to be discovered. Individuals with NF1 may demonstrate manifestations in multiple organ systems, including tumors of the nervous system, learning disabilities, and physical disfigurement. NF2 ultimately can cause deafness, cranial nerve deficits, and additional severe morbidities caused by tumors of the nervous system. Unmanageable pain is a key finding in patients with schwannomatosis. Although today there is no marketed treatment for NF-related tumors, a significant number of clinical trials have become available. In addition, significant preclinical efforts have led to a more rational selection of potential drug candidates for NF trials. An important element in fueling this progress is the sharing of knowledge. For over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share novel findings, ideas, and build collaborations. The 2012 NF Conference held in New Orleans hosted over 350 NF researchers and clinicians. This article provides a synthesis of the highlights presented at the conference and as such, is a "state-of-the-field" for NF research in 2012.

Published
2014

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