{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T11:38:50Z","timestamp":1788349130180,"version":"build-2803163510"},"reference-count":35,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T00:00:00Z","timestamp":1653955200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Dysregulation of the Ras\/Mitogen-activated protein kinase (MAPK) signaling pathway is suggested to play a pivotal role in the development of the lymphatic system in patients with Noonan Syndrome (NS). Pathogenic gene variants in the Ras\/MAPK pathway can therefore lead to various lymphatic diseases such as lymphedema, chylo-thorax and protein losing enteropathy. Diagnosis and treatment of the lymphatic phenotype in patients with NS remain difficult due to the variability of clinical presentation, severity and, probably, underlying unknown pathophysiologic mechanism. The objective of this article is to give an overview of the clinical presentation of lymphatic disease in relation to central conducting lymphatic anomalies (CCLA) in NS, including new diagnostic and therapeutic options. We visualized the central conducting lymphatic system using heavily T2-weighted MR imaging (T2 imaging) and Dynamic Contrast-enhanced MR Lymphangiography (DCMRL) and compared these results with the lymphatic clinical presentation in seven patients with NS. Our results show that most patients with NS and lymphatic disease have CCLA. Therefore, it is probable that CCLA is present in all patient with NS, presenting merely with lymphedema, or without sensing lymphatic symptoms at all. T2 imaging and DCMRL can be indicated when CCLA is suspected and this can help to adjust therapeutic interventions.<\/jats:p>","DOI":"10.3390\/jcm11113128","type":"journal-article","created":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T09:24:29Z","timestamp":1653989069000},"page":"3128","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Lymphatic Phenotype of Noonan Syndrome: Innovative Diagnosis and Possible Implications for Therapy"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0553-7064","authenticated-orcid":false,"given":"Lotte E. R.","family":"Kleimeier","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Radboudumc Amalia Children\u2019s Hospital, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"van Schaik","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Leenders","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxim","family":"Itkin","sequence":"additional","affiliation":[{"name":"Department of Radiology, Penn Center for Lymphatic Disorders, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4309-533X","authenticated-orcid":false,"given":"Willemijn M.","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos M. T.","family":"Draaisma","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Radboudumc Amalia Children\u2019s Hospital, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,31]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1038\/gim.2016.32","article-title":"Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation","volume":"18","author":"Kouz","year":"2016","journal-title":"Genet. 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