Clinical analysis of Noonan syndrome caused by RRAS2 mutations and literature review |
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| Institution: | 1. Department of Pediatric Rehabilitation Medicine, Children''s Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China;2. Henan Neurodevelopment Engineering Research Center for Children, Henan Key Laboratory of Children’s Genetics and Metabolic Diseases, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China;1. SIREDO Oncology Center of Care, Innovation and Research for Children, Adolescent and Young Adults with Cancer, Institut Curie, Paris, France;2. Université Paris-Cité, Paris, France;3. Department of Ophthalmology, Institut Curie, Paris, France;4. Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland;5. Institut de Recerca Sant Joan de Deu, Barcelona, Spain;6. SJD Pediatric Cancer Center Barcelona, Hospital Sant Joan de Deu, Barcelona, 08950, Spain;7. West Midlands Regional Genetics Service, Birmingham Women''s and Children''s NHS Foundation Trust, Birmingham, B15 2TG, UK;8. Department of Ophthalmology, VU University Medical Center, Amsterdam, the Netherlands;9. Department of Paediatric Oncology, Birmingham Women''s and Children''s NHS Foundation Trust, Birmingham, B4 6NH, UK;10. Department of Paediatrics III, University Hospital Essen, Essen, Germany;11. Department of Human Genetics, Amsterdam UMC location VUmc, Amsterdam, the Netherlands;12. Department of Pediatrics, Hematology-Oncology Unit, University Hospital, Lausanne, Switzerland;13. Unit of Pediatric Ocular Oncology, Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland;14. Department of Genetics, PSL Research University, Institut Curie, Paris, France;1. Centre de référence « Déficiences intellectuelles de causes rares », Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD), Hôpital d’Enfants, Centre Hospitalier Universitaire de Dijon, Dijon, France;2. Centre de Génétique et Centre de référence maladies rares « Anomalies du Développement et Syndromes Malformatifs », Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD), Hôpital d’Enfants, Centre Hospitalier Universitaire de Dijon, Dijon, France;3. UF Innovation en diagnostic génomique des maladies rares, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD), Centre Hospitalier Universitaire de Dijon, Dijon, France;4. UMR-Inserm 1231 GAD team, Génétique des Anomalies du développement, Université de Bourgogne Franche-Comté, F-21000, Dijon, France;5. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA;6. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA;7. Department of Health Sciences Research, Mayo Clinic, Mayo Clinic, Rochester, MN, 55905, USA;8. Department of Clinical Genomics, Mayo Clinic, Rochester, MN, 55905, USA;9. Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands;10. Assistance Publique-Hôpitaux de Paris, Département de Génétique, Hôpital Pitié-Salpêtrière, Paris, France;11. Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, 21205, USA;12. Department of Medical Genetics, Mayo Clinic, Rochester, MN, 55905, USA;13. University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands;14. Department of Clinical Genetics, Odense University Hospital, Denmark;15. H.C. Andersen Children Hospital, Odense University Hospital, Denmark;p. Division of Medical Genetics, McGill University Health Centre, Montreal, Canada;q. Department of Clinical Genetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands;r. Human Genetics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark;s. Greenwood Genetic Center, Greenwood, SC, 29646, USA;1. Service de Neurochirurgie Pédiatrique, Centre de Référence Craniosténoses-Lyon, HCL, Hôpital Femme Mère Enfant, Bron, France;2. Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d’Enfants, Dijon, France;3. Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU TRANSLAD, Hôpital d’Enfants, Dijon, France;4. Equipe GAD, INSERM UMR1231, Université de Bourgogne, Dijon, France;5. Service de Radiologie Pédiatrique, HCL, Hôpital Femme Mère Enfant, Bron, France;6. Centre de Référence des Maladies Rares de la Peau et des Muqueuses d''origine Génétique (MAGEC), FHU TRANSLAD, Service de Dermatologie, CHU Dijon, France;7. Oncobiologie Génétique Bioinformatique, CHU Besançon, F-25000, Besançon, France;1. Département de Génétique, CHU Robert Debré, Université de Paris Cité, Paris, France;2. Service de Rhumatologie, Hôpital Pierre-Paul Riquet, Toulouse, France;3. Service de Génétique Médicale, CHU de Nantes, Nantes, France;4. Inserm1132, CHU Lariboisière, Paris, France;5. Service de Dermatologie, CHU Saint-Louis, Université de Paris Cité, Paris, France;6. Service de Dermatologie, CHU Strasbourg, Strasbourg, France;7. Service de Médecine Interne, Centre Hospitalier Princesse Grâce, Monaco;8. Service de Rhumatologie, Hôpital Cochin, Université de Paris Cité, Paris, France;9. Service de Dermatologie, CHU de Nice, Nice, France;10. Service de Médecine Générale, GH Est Francilien, site Coulommiers, Coulommiers, France;11. Service de Cytogénétique, GH de l''Institut Catholique de Lille, Hopital Saint Vincent de Paul, Lille, France;12. Service de Rhumatologie, CHU Lariboisière, Université de Paris Cité, Paris, France;1. Department of Pediatric Hematology and Oncology, AP-HP, Armand Trousseau Hospital, Sorbonne University, Paris, France;2. Laboratory of Normal and Pathological Lymphoid Differentiation, Institut Necker Enfants Malades (INEM), INERM UMR1151, Paris, France;3. Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR1163, Imagine Institute, Paris, France;4. Université de Paris, Paris, France;5. Department of Hematology, Center Henri Becquerel, University of Rouen, INSERM UMR1245, Rouen, France;6. Department of Pediatric Hematology, AP-HP, Robert Debré Hospital, University Paris Diderot, Paris, France;1. Murdoch Children''s Research Institute, Parkville, 3052, Australia;2. The University of Melbourne, Parkville, 3052, Australia;3. Peter MacCallum Cancer Centre, Parkville, 3052, Australia;4. Victorian Comprehensive Cancer Centre, Parkville, 3052, Australia;5. Australian Genomics Health Alliance, Australia;6. Chen Su Lan Centennial Professor in Medical Ethics, Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore;7. Center for Biomedical Ethics and Law, Department of Public Health and Primary Care, Leuven, 3000, Belgium |
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| Abstract: | Noonan syndrome is a common developmental disorder characterized by distinctive facial dysmorphism, short stature, congenital heart defects, pectus deformity, and developmental delay. It is related to the abnormal activation of genes involved in the RAS-MAPK signaling pathway, more than a dozen of which can be affected. However, mutations of the RRAS2 gene are rare, with only 6 different RRAS2 variants in 13 patients reported to date. In this case report, whole-exome sequencing revealed a novel heterozygous variant in the RRAS2 gene NM_012250: c.212G > A, p.(Gly71Glu). Phenotypically, our patient had typical Noonan syndrome-related clinical manifestations consistent with published reports, such as short stature, facial dysmorphism, short neck, patent foramen ovale, moderate global developmental delay, and hearing impairment. In addition, our patient also had a distal middle finger deformity and hair defect, which have not been reported in previous cases. We analyzed the clinical characteristics of all patients with Noonan syndrome caused by RRAS2 variants and reviewed the literature. This discovery expands the genetic and phenotypic spectrum of Noonan syndrome. |
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| Keywords: | Noonan syndrome Whole exome sequencing Novel variant Literature review |
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