{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:14:03Z","timestamp":1792005243339,"version":"4.4.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"For Wis(h)dom Foundation","award":["FWF\/2022\/1330"],"award-info":[{"award-number":["FWF\/2022\/1330"]}]},{"name":"For Wis(h)dom Foundation","award":["FWF\/2022\/1330"],"award-info":[{"award-number":["FWF\/2022\/1330"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Pediatr"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Central conducting lymphatic anomaly (CCLA) is a rare and potentially life-threatening vascular malformation characterized by impaired central lymphatic flow. Hydrops fetalis and congenital hydro-\/chylothorax are common neonatal presentations; however, diagnosing CCLA poses challenges and requires advanced imaging. Management typically includes supportive therapies with limited effect, such as medium-chain triglyceride (MCT) diet, octreotide or propranolol, and thoracic drainage. Upcoming treatment options with mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MEK) inhibitors have shown promising results in vascular anomalies driven by dysregulated PI3K\/AKT\/mTOR and RAS\/RAF\/MAPK signalling pathways. However, data on neonatal use remain scarce. This series describes infants (gestational age 29\u2009+\u20093\u201340\u2009+\u20094\u00a0weeks) with neonatal-onset CCLA treated with mTOR and\/or MEK inhibitors (age IQR: 27\u201357\u00a0days), detailing clinical presentations, imaging, genetic findings, and outcomes. Genetic testing included germline and somatic variant analysis. Most patients underwent dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) for diagnosis and to guide management. Pathogenic germline variants were identified in four patients; three had no genetic diagnosis. DCMRL revealed heterogeneous phenotypes; follow-up imaging showed improved lymphatic flow. Substantial clinical improvement occurred following mTOR and\/or MEK inhibitor treatment (sirolimus and\/or trametinib). In most cases, therapy was tapered within weeks; no relapses occurred (mean follow-up 10.3\u00a0months). No deaths or other severe adverse events occurred during inhibitor treatment.<\/jats:p>\n                  <jats:p>\n                    <jats:italic>Conclusion<\/jats:italic>\n                    : This series describes infants with CCLA, treated with mTOR and\/or MEK inhibitors early after birth, with rapid improvement possibly reflecting treatment response leading to functional recovery during a critical developmental phase of the lymphatic system.\n                    <jats:table-wrap>\n                      <jats:table>\n                        <jats:tbody>\n                          <jats:tr>\n                            <jats:td colspan=\"2\">\n                              <jats:bold>What is Known:<\/jats:bold>\n                              <jats:italic>\u2022 Central conducting lymphatic anomalies are rare conditions associated with high morbidity and mortality, especially in neonates.<\/jats:italic>\n                              <jats:italic>\u2022 Molecular targeted therapies such as MEK inhibitors and mTOR inhibitors show promise in vascular anomalies driven by upregulated PI3K\/AKT\/mTOR and RAS\/RAF\/MAPK signalling pathways.<\/jats:italic>\n                              <jats:bold>What is New:<\/jats:bold>\n                              <jats:italic>\u2022 This series offers a detailed description of the early disease course, clinical variation, and management in infants with congenital chylothorax\/hydrops fetalis due to CCLA, contributing to a better understanding of this rare condition in the neonatal period.<\/jats:italic>\n                              <jats:italic>\u2022 Early treatment with low-dose mTOR and\/or MEK inhibitors seems effective in infants with CCLA, potentially reducing morbidity and mortality.<\/jats:italic>\n                            <\/jats:td>\n                          <\/jats:tr>\n                        <\/jats:tbody>\n                      <\/jats:table>\n                    <\/jats:table-wrap>\n                  <\/jats:p>","DOI":"10.1007\/s00431-025-06376-2","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:45:04Z","timestamp":1755737104000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Molecular targeted treatment in infants with central conducting lymphatic anomalies"],"prefix":"10.1007","volume":"184","author":[{"given":"Vera C.","family":"van den Brink","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lotte E. R.","family":"Kleimeier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika K. S. M.","family":"Leenders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willemijn M.","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willem P.","family":"de Boode","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joris","family":"Fuijkschot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine L. A. G.","family":"Vrancken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"6376_CR1","unstructured":"ISSVA classification of vascular anomalies. 2025 [cited 2025 04\u201304\u20132025]; Available from:\u00a0https:\/\/www.issva.org\/classification."},{"issue":"3","key":"6376_CR2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sempedsurg.2024.151424","volume":"33","author":"BM Dulmovits","year":"2024","unstructured":"Dulmovits BM, Taha DK (2024) Neonatal perspective on central lymphatic disorders. Semin Pediatr Surg 33(3):151424","journal-title":"Semin Pediatr Surg"},{"issue":"1","key":"6376_CR3","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1159\/000518217","volume":"101","author":"B Resch","year":"2022","unstructured":"Resch B, Sever Yildiz G, Reiterer F (2022) Congenital chylothorax of the newborn: a systematic analysis of published cases between 1990 and 2018. Respiration 101(1):84\u201396","journal-title":"Respiration"},{"issue":"9","key":"6376_CR4","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1038\/s41431-022-01123-9","volume":"30","author":"M Liu","year":"2022","unstructured":"Liu M et al (2022) Genetics etiologies and genotype phenotype correlations in a cohort of individuals with central conducting lymphatic anomaly. Eur J Hum Genet 30(9):1022\u20131028","journal-title":"Eur J Hum Genet"},{"issue":"2","key":"6376_CR5","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.jpedsurg.2019.10.029","volume":"55","author":"B Reisen","year":"2020","unstructured":"Reisen B et al (2020) Thoracic duct-to-vein anastomosis for the management of thoracic duct outflow obstruction in newborns and infants: a case series. J Pediatr Surg 55(2):234\u2013239","journal-title":"J Pediatr Surg"},{"issue":"3","key":"6376_CR6","doi-asserted-by":"publisher","first-page":"e220231","DOI":"10.1148\/radiol.220231","volume":"307","author":"J Benjamin","year":"2023","unstructured":"Benjamin J et al (2023) Imaging and interventions for lymphatic and lymphatic-related disorders. Radiology 307(3):e220231","journal-title":"Radiology"},{"issue":"8","key":"6376_CR7","doi-asserted-by":"publisher","DOI":"10.1172\/JCI172839","volume":"134","author":"LD Garlisi Torales","year":"2024","unstructured":"Garlisi Torales LD et al (2024) Central conducting lymphatic anomaly: from bench to bedside. J Clin Invest 134(8):e172839","journal-title":"J Clin Invest"},{"issue":"3","key":"6376_CR8","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/j.hoc.2019.01.011","volume":"33","author":"DM Adams","year":"2019","unstructured":"Adams DM, Ricci KW (2019) Vascular anomalies: diagnosis of complicated anomalies and new medical treatment options. Hematol Oncol Clin North Am 33(3):455\u2013470","journal-title":"Hematol Oncol Clin North Am"},{"issue":"2","key":"6376_CR9","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.29510","volume":"69","author":"S Agarwal","year":"2022","unstructured":"Agarwal S et al (2022) Sirolimus efficacy in the treatment of critically ill infants with congenital primary chylous effusions. Pediatr Blood Cancer 69(2):e29510","journal-title":"Pediatr Blood Cancer"},{"key":"6376_CR10","doi-asserted-by":"publisher","first-page":"1304133","DOI":"10.3389\/fped.2023.1304133","volume":"11","author":"M Kim","year":"2023","unstructured":"Kim M et al (2023) Clinical effectiveness and safety of sirolimus in pediatric patients with complex vascular anomalies: necessitating personalized and comprehensive approaches. Front Pediatr 11:1304133","journal-title":"Front Pediatr"},{"key":"6376_CR11","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.jpeds.2022.05.030","volume":"248","author":"TA Nakano","year":"2022","unstructured":"Nakano TA et al (2022) Trametinib for refractory chylous effusions and systemic complications in children with Noonan syndrome. J Pediatr 248:81-88 e1","journal-title":"J Pediatr"},{"issue":"9","key":"6376_CR12","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.155888","volume":"8","author":"SE Sheppard","year":"2023","unstructured":"Sheppard SE et al (2023) Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition. JCI Insight 8(9):e155888","journal-title":"JCI Insight"},{"issue":"13","key":"6376_CR13","doi-asserted-by":"publisher","first-page":"6126","DOI":"10.3390\/ijms26136126","volume":"26","author":"E Leenders","year":"2025","unstructured":"Leenders E et al (2025) Targeted therapy for complex lymphatic anomalies in patients with noonan syndrome and related disorders. Int J Mol Sci 26(13):6126","journal-title":"Int J Mol Sci"},{"issue":"5","key":"6376_CR14","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1111\/cts.13488","volume":"16","author":"VEM Harbers","year":"2023","unstructured":"Harbers VEM et al (2023) Clinical differences in sirolimus treatment with low target levels between children and adults with vascular malformations - a nationwide trial. Clin Transl Sci 16(5):781\u2013796","journal-title":"Clin Transl Sci"},{"issue":"2","key":"6376_CR15","doi-asserted-by":"publisher","first-page":"e20153257","DOI":"10.1542\/peds.2015-3257","volume":"137","author":"DM Adams","year":"2016","unstructured":"Adams DM et al (2016) Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies. Pediatrics 137(2):e20153257","journal-title":"Pediatrics"},{"key":"6376_CR16","doi-asserted-by":"publisher","first-page":"1475143","DOI":"10.3389\/fped.2025.1475143","volume":"13","author":"I De Brouchoven","year":"2025","unstructured":"De Brouchoven I et al (2025) Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome. Front Pediatr 13:1475143","journal-title":"Front Pediatr"},{"issue":"3","key":"6376_CR17","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1002\/ped4.12397","volume":"7","author":"S Dong","year":"2023","unstructured":"Dong S et al (2023) Rapid response with good toleration of sirolimus for life-threatening neonatal lymphatic malformations. Pediatr Investig 7(3):206\u2013211","journal-title":"Pediatr Investig"},{"issue":"7","key":"6376_CR18","doi-asserted-by":"publisher","first-page":"e9164","DOI":"10.1002\/ccr3.9164","volume":"12","author":"E Leenders","year":"2024","unstructured":"Leenders E et al (2024) Trametinib restores the central conducting lymphatic flow in a premature infant with Noonan syndrome. Clin Case Rep 12(7):e9164","journal-title":"Clin Case Rep"},{"issue":"1","key":"6376_CR19","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1002\/pd.6492","volume":"44","author":"S Qaderi","year":"2024","unstructured":"Qaderi S et al (2024) Mammalian target of rapamycin inhibitors: a new-possible approach for in-utero medication therapy. Prenat Diagn 44(1):88\u201398","journal-title":"Prenat Diagn"},{"issue":"6","key":"6376_CR20","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1038\/s44161-023-00280-4","volume":"2","author":"E Seront","year":"2023","unstructured":"Seront E et al (2023) A case report of sirolimus use in early fetal management of lymphatic malformation. Nat Cardiovasc Res 2(6):595\u2013599","journal-title":"Nat Cardiovasc Res"},{"issue":"1","key":"6376_CR21","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1161\/CIRCRESAHA.121.319587","volume":"129","author":"HP Janardhan","year":"2021","unstructured":"Janardhan HP et al (2021) Vascular and lymphatic malformations: perspectives from human and vertebrate studies. Circ Res 129(1):131\u2013135","journal-title":"Circ Res"},{"issue":"6","key":"6376_CR22","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1016\/j.cell.2017.02.004","volume":"168","author":"RA Saxton","year":"2017","unstructured":"Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168(6):960\u2013976","journal-title":"Cell"},{"key":"6376_CR23","doi-asserted-by":"publisher","first-page":"1276333","DOI":"10.3389\/fcell.2023.1276333","volume":"11","author":"LM Fernandes","year":"2023","unstructured":"Fernandes LM et al (2023) Hyperactive KRAS\/MAPK signaling disrupts normal lymphatic vessel architecture and function. Front Cell Dev Biol 11:1276333","journal-title":"Front Cell Dev Biol"},{"issue":"1","key":"6376_CR24","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/s41392-023-01723-x","volume":"9","author":"Z Hu","year":"2024","unstructured":"Hu Z et al (2024) Lymphatic vessel: origin, heterogeneity, biological functions, and therapeutic targets. Signal Transduct Target Ther 9(1):9","journal-title":"Signal Transduct Target Ther"},{"issue":"1","key":"6376_CR25","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1186\/s13023-024-03211-z","volume":"19","author":"E Seront","year":"2024","unstructured":"Seront E et al (2024) Targeted treatment in complex lymphatic anomaly: a case of synergistic efficacy of trametinib and sirolimus. Orphanet J Rare Dis 19(1):199","journal-title":"Orphanet J Rare Dis"},{"issue":"4","key":"6376_CR26","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1016\/j.jpeds.2014.12.069","volume":"166","author":"VL Luks","year":"2015","unstructured":"Luks VL et al (2015) Lymphatic and other vascular malformative\/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr 166(4):1048\u201354 e1-5","journal-title":"J Pediatr"},{"issue":"1","key":"6376_CR27","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-024-03196-9","volume":"19","author":"N Revencu","year":"2024","unstructured":"Revencu N et al (2024) Assessment of gene-disease associations and recommendations for genetic testing for somatic variants in vascular anomalies by VASCERN-VASCA. Orphanet J Rare Dis 19(1):213","journal-title":"Orphanet J Rare Dis"},{"issue":"1","key":"6376_CR28","doi-asserted-by":"publisher","first-page":"11","DOI":"10.3390\/jdb10010011","volume":"10","author":"SY Lee","year":"2022","unstructured":"Lee SY et al (2022) Genetic and molecular determinants of lymphatic malformations: potential targets for therapy. J Dev Biol 10(1):11","journal-title":"J Dev Biol"},{"issue":"6","key":"6376_CR29","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1038\/s41591-023-02364-x","volume":"29","author":"D Li","year":"2023","unstructured":"Li D et al (2023) Genomic profiling informs diagnoses and treatment in vascular anomalies. Nat Med 29(6):1530\u20131539","journal-title":"Nat Med"},{"issue":"3","key":"6376_CR30","doi-asserted-by":"publisher","first-page":"466","DOI":"10.14366\/usg.22218","volume":"42","author":"JJJ Vullings","year":"2023","unstructured":"Vullings JJJ et al (2023) Visualizing the lymphatic vessels and flow with high-resolution ultrasonography and microvascular flow imaging. Ultrasonography 42(3):466\u2013473","journal-title":"Ultrasonography"},{"issue":"2","key":"6376_CR31","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2022-058555","volume":"151","author":"R Handal-Orefice","year":"2023","unstructured":"Handal-Orefice R et al (2023) Propranolol therapy for congenital chylothorax. Pediatrics 151(2):e2022058555","journal-title":"Pediatrics"},{"issue":"1","key":"6376_CR32","doi-asserted-by":"publisher","first-page":"68","DOI":"10.3390\/cells13010068","volume":"13","author":"K Kuonqui","year":"2023","unstructured":"Kuonqui K et al (2023) Dysregulation of lymphatic endothelial VEGFR3 signaling in disease. Cells 13(1):68","journal-title":"Cells"}],"container-title":["European Journal of Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00431-025-06376-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00431-025-06376-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00431-025-06376-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T15:10:16Z","timestamp":1774624216000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00431-025-06376-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,21]]},"references-count":32,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["6376"],"URL":"https:\/\/doi.org\/10.1007\/s00431-025-06376-2","relation":{},"ISSN":["1432-1076"],"issn-type":[{"value":"1432-1076","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,21]]},"assertion":[{"value":"17 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 July 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 July 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 August 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This series was conducted in accordance with the principles of the Declaration of Helsinki, Dutch ethical standards, and applicable regulatory requirements. It forms part of a prospective observational study for which the Dutch Medical Ethical Commission granted a waiver under the Dutch Medical Research Involving Human Subjects Act (WMO; case number 2023\u201316807).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Written informed consent was obtained from the parents or legal guardians. The authors affirm that human research participants provided informed consent for publication of the images in Figs.\u00a0\n                      \n                      and\n                      \n                      .","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate and publish"}},{"value":"All authors have no relevant financial interests to disclose. W. P. de Boode is president of the European Society of Pediatric Research (ESPR). All other authors have no non-financial interests to disclose.J. Fuijkschot and W.M. Klein are part of the European Reference Network for Rare Multisystemic Vascular Disease. E.K.S.M. Leenders is member of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA. W. P. de Boode is president of the European Society of Pediatric Research (ESPR).All other authors have no non-financial interests to disclose.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"567"}}