{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T15:20:56Z","timestamp":1788016856513,"version":"build-2784847793"},"reference-count":39,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:00:00Z","timestamp":1750896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Orphan disease centre million dollar bike ride","award":["MDBR-23-022-RAS"],"award-info":[{"award-number":["MDBR-23-022-RAS"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recent diagnostic advances reveal that lymphatic disease in Noonan syndrome (NS) and other NS-like RASopathies often stems from central conducting lymphatic anomalies (CCLAs). The RAS\/MAPK-ERK pathway plays a central role in lymphangiogenesis. Targeting this pathway with MEK-inhibitor trametinib has emerged as a promising therapeutic strategy for managing CCLAs in patients with NS-like RASopathies. This case series assessed the clinical outcomes of trametinib therapy in eight patients with NS-like RASopathies and CCLA, each offering unique insights into the therapeutic efficacy of MEK inhibition. In infants, a lower dose of 0.01 mg\/kg\/day and earlier discontinuation of trametinib therapy effectively alleviated the symptoms of congenital chylothorax and rescued the lymphatic phenotype, compared to similar published cases. Moreover, four patients aged &gt;11 y showed a slower response and did not achieve complete symptomatic recovery. In conclusion, it is advised to consider trametinib therapy for patients with severe, therapy-refractory CCLA in patients with NS-like RASopathies. However, individual responses to trametinib therapy may vary, with some patients demonstrating more favorable outcomes than others. Further investigation into potential enhancers and suppressors of the lymphatic phenotype is necessary for more accurate treatment predictions. While these factors are likely genetic, we cannot rule out other intrinsic or physiological factors.<\/jats:p>","DOI":"10.3390\/ijms26136126","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T06:55:13Z","timestamp":1750920913000},"page":"6126","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeted Therapy for Complex Lymphatic Anomalies in Patients with Noonan Syndrome and Related Disorders"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7311-6862","authenticated-orcid":false,"given":"Erika K. S. M.","family":"Leenders","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"},{"name":"Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9697-2940","authenticated-orcid":false,"given":"Vera C.","family":"van den Brink","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"},{"name":"Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0553-7064","authenticated-orcid":false,"given":"Lotte E. R.","family":"Kleimeier","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"},{"name":"Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8688-2045","authenticated-orcid":false,"given":"Danielle T. J.","family":"Woutersen","sequence":"additional","affiliation":[{"name":"Hubrecht Institute-KNAW, University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catelijne H.","family":"Coppens","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8642-8088","authenticated-orcid":false,"given":"Jeroen","family":"den Hertog","sequence":"additional","affiliation":[{"name":"Hubrecht Institute-KNAW, University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands"},{"name":"Institute Biology Leiden, Leiden University, 2333 BE Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4350-8106","authenticated-orcid":false,"given":"Tuula","family":"Rinne","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"},{"name":"Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2390-1864","authenticated-orcid":false,"given":"Sabine L.","family":"Vrancken","sequence":"additional","affiliation":[{"name":"Department of Perinatology (Neonatology), Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0502-0647","authenticated-orcid":false,"given":"Saskia N.","family":"de Wildt","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmacology and Toxicology, 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, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joris","family":"Fuijkschot","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1002\/ajmg.c.32012","article-title":"The molecular genetics of RASopathies: An update on novel disease genes and new disorders","volume":"190","author":"Tartaglia","year":"2022","journal-title":"Am. J. Med. Genet. C Semin. Med. 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