{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T15:38:51Z","timestamp":1791041931544,"version":"4.1.0"},"reference-count":19,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T00:00:00Z","timestamp":1661212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Noonan syndrome (NS) is a multisystemic disorder caused by germline mutations in the Ras\/MAPK cascade, causing a broad spectrum of phenotypical abnormalities, including abnormal facies, developmental delay, bleeding diathesis, congenital heart disease (mainly pulmonary stenosis and hypertrophic cardiomyopathy), lymphatic disorders, and uro-genital abnormalities. Multifocal atrial tachycardia has been associated with NS, where it may occur independently of hypertrophic cardiomyopathy. Trametinib, a highly selective MEK1\/2 inhibitor currently approved for the treatment of cancer, has been shown to reverse left ventricular hypertrophy in two RIT1-mutated newborns with NS and severe hypertrophic cardiomyopathy. Severe lymphatic abnormalities may contribute to decreased pulmonary compliance in NS, and pulmonary lymphangiectasias should be included in the differential diagnosis of a newborn requiring prolonged oxygen administration. Herein we report the case of a pre-term newborn who was admitted to our unit for the occurrence of severe respiratory distress and subentrant MAT treated with trametinib.<\/jats:p>","DOI":"10.3390\/genes13091503","type":"journal-article","created":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T21:05:12Z","timestamp":1661288712000},"page":"1503","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Severe Lymphatic Disorder and Multifocal Atrial Tachycardia Treated with Trametinib in a Patient with Noonan Syndrome and SOS1 Mutation"],"prefix":"10.3390","volume":"13","author":[{"given":"Michele","family":"Lioncino","sequence":"first","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases Unit, Department of Translational Medical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital, 81031 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adelaide","family":"Fusco","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases Unit, Department of Translational Medical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital, 81031 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9304-988X","authenticated-orcid":false,"given":"Emanuele","family":"Monda","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases Unit, Department of Translational Medical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital, 81031 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6717-1953","authenticated-orcid":false,"given":"Diego","family":"Colonna","sequence":"additional","affiliation":[{"name":"Adult Congenital Heart Disease Unit, Monaldi Hospital, 81031 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelina","family":"Sibilio","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Santobono-Pausilipon Children\u2019s Hospital, 81031 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3805-4170","authenticated-orcid":false,"given":"Martina","family":"Caiazza","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases Unit, Department of Translational Medical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital, 81031 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Magri","sequence":"additional","affiliation":[{"name":"Department of Neonatal Intensive Care, Monaldi Hospital, 81031 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela Carla","family":"Borrelli","sequence":"additional","affiliation":[{"name":"Department of Neonatal Intensive Care, Monaldi Hospital, 81031 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"D\u2019Onofrio","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases Unit, Department of Translational Medical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital, 81031 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Luisa","family":"Mazzella","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases Unit, Department of Translational Medical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital, 81031 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Colantuono","sequence":"additional","affiliation":[{"name":"Department of Neonatal Intensive Care, Monaldi Hospital, 81031 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rosaria","family":"Arienzo","sequence":"additional","affiliation":[{"name":"Department of Neonatal Intensive Care, Monaldi Hospital, 81031 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9941-8500","authenticated-orcid":false,"given":"Berardo","family":"Sarubbi","sequence":"additional","affiliation":[{"name":"Adult Congenital Heart Disease Unit, Monaldi Hospital, 81031 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Giovanna","family":"Russo","sequence":"additional","affiliation":[{"name":"Paediatric Cardiology Unit, \u201cL.Vanvitelli\u201d University\u2014Monaldi Hospital, 81031 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Chello","sequence":"additional","affiliation":[{"name":"Department of Neonatal Intensive Care, Monaldi Hospital, 81031 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8291-9517","authenticated-orcid":false,"given":"Giuseppe","family":"Limongelli","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases Unit, Department of Translational Medical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital, 81031 Naples, Italy"},{"name":"Institute of Cardiovascular Sciences, University College of London and St. Bartholomew\u2019s Hospital, London WC1E 6DD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.hfc.2021.07.004","article-title":"Hypertrophic Cardiomyopathy in RASopathies","volume":"18","author":"Lioncino","year":"2021","journal-title":"Heart Fail. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0140-6736(12)61023-X","article-title":"Noonan syndrome","volume":"381","author":"Roberts","year":"2013","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"632293","DOI":"10.3389\/fped.2021.632293","article-title":"Hypertrophic Cardiomyopathy in Children: Pathophysiology, Diagnosis, and Treatment of Non-Sarcomeric Causes","volume":"9","author":"Monda","year":"2021","journal-title":"Front. Pediatr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/ng772","article-title":"Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome","volume":"29","author":"Tartaglia","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.beem.2010.09.002","article-title":"Noonan syndrome and clinically related disorders","volume":"25","author":"Tartaglia","year":"2011","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1002\/ajmg.a.38854","article-title":"Nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in RASopathy patients","volume":"176","author":"Levin","year":"2018","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1016\/j.jacc.2019.01.066","article-title":"Hypertrophic Cardiomyopathy in Noonan Syndrome Treated by MEK-Inhibition","volume":"73","author":"Andelfinger","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e003327","DOI":"10.1161\/CIRCGEN.121.003327","article-title":"Molecular Management of Multifocal Atrial Tachycardia in Noonan\u2019s Syndrome With MEK1\/2 Inhibitor Trametinib","volume":"14","author":"Meisner","year":"2021","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e20200167","DOI":"10.1542\/peds.2020-0167","article-title":"Severe Lymphatic Disorder Resolved With MEK Inhibition in a Patient With Noonan Syndrome and SOS1 Mutation","volume":"146","author":"Dori","year":"2020","journal-title":"Pediatrics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1007\/s00247-018-04337-6","article-title":"Imaging of central lymphatic abnormalities in Noonan syndrome","volume":"49","author":"Biko","year":"2019","journal-title":"Pediatr. Radiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1097\/00005382-200401000-00012","article-title":"Congenital Pulmonary Lymphangiectasia","volume":"19","author":"Nobre","year":"2004","journal-title":"J. Thorac. Imaging"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1124\/mol.114.094623","article-title":"Multiple modes of ryanodine receptor 2 inhibition by flecainide","volume":"86","author":"Mehra","year":"2014","journal-title":"Mol. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1378\/chest.113.1.203","article-title":"Multifocal Atrial Tachycardia","volume":"113","author":"McCord","year":"1998","journal-title":"Chest"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/0002-8703(89)90275-5","article-title":"Multifocal atrial tachycardia: Mechanisms, clinical correlates, and treatment","volume":"118","author":"Scher","year":"1989","journal-title":"Am. Heart J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1161\/CIRCRESAHA.115.306298","article-title":"The direct actions of flecainide on the human cardiac ryanodine receptor: Keeping open the debate on the mechanism of action of local anesthetics in CPVT","volume":"116","author":"Smith","year":"2015","journal-title":"Circ. Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Pabbidi, M.R., Ji, X., Maxwell, J.T., Mignery, G.A., Samarel, A.M., and Lipsius, S.L. (2016). Inhibition of cAMP-Dependent PKA Activates \u03b22-Adrenergic Receptor Stimulation of Cytosolic Phospholipase A2 via Raf-1\/MEK\/ERK and IP3-Dependent Ca2+ Signaling in Atrial Myocytes. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168505"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1007\/s10529-020-02843-y","article-title":"Crosstalk between PKC and MAPK pathway activation in cardiac fibroblasts in a rat model of atrial fibrillation","volume":"42","author":"Guo","year":"2020","journal-title":"Biotechnol. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1073\/pnas.0510113103","article-title":"Ryanodine receptor\/calcium release channel PKA phosphorylation: A critical mediator of heart failure progression","volume":"103","author":"Wehrens","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1002\/humu.21492","article-title":"SOS1 mutations in Noonan syndrome: Molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations","volume":"32","author":"Lepri","year":"2011","journal-title":"Hum. Mutat."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/9\/1503\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:14:09Z","timestamp":1760141649000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/9\/1503"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,23]]},"references-count":19,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["genes13091503"],"URL":"https:\/\/doi.org\/10.3390\/genes13091503","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,23]]}}}