{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T06:15:23Z","timestamp":1783577723160,"version":"3.55.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To report a rare case of neonatal Noonan syndrome (NS) caused by a\n                      <jats:italic>RIT1<\/jats:italic>\n                      c.247A&amp;gt;C (p.Thr83Pro), and to expand the understanding of life-threatening presentations in neonatal\n                      <jats:italic>RIT1<\/jats:italic>\n                      associated NS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The clinical data of a neonate with NS admitted to the Neonatal Intensive Care Unit of Wuhan Children's Hospital were retrospectively analyzed, and\n                      <jats:italic>Vitro<\/jats:italic>\n                      functional studies were performed to investigate the pathogenic mechanism of the variant. A literature review of\n                      <jats:italic>RIT1<\/jats:italic>\n                      -NS cases reported between 2014 and 2025 was also performed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The proband was a term female neonate presenting with progressive acute kidney injury (AKI), systemic capillary leak syndrome (SCLS), refractory chylothorax, and a large patent ductus arteriosus. Whole-exome sequencing identified a\n                      <jats:italic>de novo<\/jats:italic>\n                      heterozygous\n                      <jats:italic>RIT1:<\/jats:italic>\n                      c.247A&amp;gt;C p.(Thr83Pro). Functional studies revealed that this variant significantly enhanced the phosphorylation of ERK, JNK, and p38, and markedly upregulated IL-1\u03b2, IL-6, and TNF-\u03b1 mRNA expression. Among 54 reported\n                      <jats:italic>RIT1<\/jats:italic>\n                      -NS cases, the p. Thr83Pro variant accounted for 3.7% (2\/54); our case was the only one presenting with AKI and SCLS. Among the reported neonatal cases, 4 of 10 died during the neonatal period.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>RIT1:<\/jats:italic>\n                      c.247A&amp;gt;C p.(Thr83Pro) might contribute to life-threatening NS in the neonatal period, and that early genetic testing may facilitate diagnosis and prognostic assessment.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fped.2026.1838907","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:34:47Z","timestamp":1783575287000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Neonatal Noonan syndrome with acute kidney injury and systemic capillary leak syndrome caused by a RIT1 variant: a case report and literature review"],"prefix":"10.3389","volume":"14","author":[{"given":"Chunfang","family":"Gao","sequence":"first","affiliation":[{"name":"Division of Neonatology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanli","family":"Kong","sequence":"additional","affiliation":[{"name":"Pain and Sleep Treatment Center, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuwei","family":"Tao","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1542\/peds.2009-3207","article-title":"Noonan syndrome: clinical features, diagnosis, and management guidelines","volume":"126","author":"Romano","year":"2010","journal-title":"Pediatrics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1002\/ajmg.c.32015","article-title":"Clinical overview on RASopathies","volume":"190","author":"Zenker","year":"2022","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"dmm049107","DOI":"10.1242\/dmm.049107","article-title":"The RASopathies: from pathogenetics to therapeutics","volume":"15","author":"Hebron","year":"2022","journal-title":"Dis Model Mech"},{"key":"B4","doi-asserted-by":"publisher","first-page":"61.e1","DOI":"10.1016\/j.anpedi.2020.04.008","article-title":"S\u00edndrome de Noonan: actualizaci\u00f3n gen\u00e9tica, cl\u00ednica y de opciones terap\u00e9uticas [Noonan syndrome: genetic and clinical update and treatment options]","volume":"93","author":"Carcavilla","year":"2020","journal-title":"An Pediatr (Engl Ed)"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1874","DOI":"10.1002\/ajmg.a.37657","article-title":"Two cases of RIT1 associated Noonan syndrome: further delineation of the clinical phenotype and review of the literature","volume":"170","author":"Milosavljevi\u0107","year":"2016","journal-title":"Am J Med Genet A"},{"key":"B6","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.ajhg.2013.05.021","article-title":"Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS\/MAPK pathway syndrome","volume":"93","author":"Aoki","year":"2013","journal-title":"Am J Hum Genet"},{"key":"B7","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.tjog.2022.03.025","article-title":"Prenatal case of RIT1 mutation associated Noonan syndrome by whole exome sequencing (WES) and review of the literature","volume":"61","author":"Qiu","year":"2022","journal-title":"Taiwan J Obstet Gynecol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"215","DOI":"10.5114\/aoms.2017.64720","article-title":"Noonan syndrome\u2014a new survey","volume":"13","author":"Tafazoli","year":"2017","journal-title":"Arch Med Sci"},{"key":"B9","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"B10","doi-asserted-by":"publisher","first-page":"2310","DOI":"10.1002\/ajmg.a.36646","article-title":"Contribution of RIT1 mutations to the pathogenesis of Noonan syndrome: four new cases and further evidence of heterogeneity","author":"Gos","year":"2014","journal-title":"Am J Med Genet A"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2952","DOI":"10.1002\/ajmg.a.36722","article-title":"Further evidence of the importance of RIT1 in Noonan syndrome","author":"Bertola","year":"2014","journal-title":"Am J Med Genet A"},{"key":"B12","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1111\/cge.12608","article-title":"Mutations in RIT1 cause Noonan syndrome\u2014additional functional evidence and expanding the clinical phenotype","volume":"89","author":"Koenighofer","year":"2016","journal-title":"Clin Genet"},{"key":"B13","doi-asserted-by":"publisher","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 Med"},{"key":"B14","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.ejmg.2017.03.009","article-title":"Expanding the cardiac spectrum of Noonan syndrome with RIT1 variant: left main coronary artery atresia causing sudden death","volume":"60","author":"Ramond","year":"2017","journal-title":"Eur J Med Genet"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e1253","DOI":"10.1002\/mgg3.1253","article-title":"Complicated ventricular arrhythmia and hematologic myeloproliferative disorder in RIT1-associated Noonan syndrome: expanding the phenotype and review of the literature","volume":"8","author":"Aly","year":"2020","journal-title":"Mol Genet Genomic Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s13023-019-1010-z","article-title":"Clinical and mutation profile of pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: results from a Chinese cohort","volume":"14","author":"Chen","year":"2019","journal-title":"Orphanet J Rare Dis"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e30780","DOI":"10.1002\/pbc.30780","article-title":"Myeloproliferative disorder in a patient with RIT1-associated Noonan syndrome: case report and literature review","volume":"71","author":"Suzuki","year":"2024","journal-title":"Pediatr Blood Cancer"},{"key":"B18","doi-asserted-by":"publisher","first-page":"934808","DOI":"10.3389\/fped.2022.934808","article-title":"Noonan syndrome caused by RIT1 gene mutation: a case report and literature review","volume":"10","author":"Zha","year":"2022","journal-title":"Front Pediatr"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12887-022-03818-w","article-title":"Dilated coronary arteries in a 2-month-old with RIT1-associated Noonan syndrome: a case report","volume":"23","author":"Aniol","year":"2023","journal-title":"BMC Pediatr"},{"key":"B20","doi-asserted-by":"publisher","first-page":"luaf088","DOI":"10.1210\/jcemcr\/luaf088","article-title":"Efficacy of sirolimus in treating refractory lymphatic malformation in Noonan syndrome: a case study","volume":"3","author":"Nakajima","year":"2025","journal-title":"JCEM Case Rep"},{"key":"B21","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1007\/s00439-015-1627-5","article-title":"Spectrum of mutations and genotype-phenotype analysis in Noonan syndrome patients with RIT1 mutations","volume":"135","author":"Yaoita","year":"2016","journal-title":"Hum Genet"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2755","DOI":"10.1042\/BCJ20200442","article-title":"The molecular functions of RIT1 and its contribution to human disease","volume":"477","author":"Van","year":"2020","journal-title":"Biochem J"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e51639","DOI":"10.1371\/journal.pone.0051639","article-title":"Ras\/MAPK signaling modulates VEGFR-3 expression through Ets-mediated p300 recruitment and histone acetylation on the Vegfr3 gene in lymphatic endothelial cells","volume":"7","author":"Ichise","year":"2012","journal-title":"PLoS One"},{"key":"B24","doi-asserted-by":"publisher","first-page":"eadf4766","DOI":"10.1126\/sciadv.adf4766","article-title":"RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy","volume":"9","author":"Cuevas-Navarro","year":"2023","journal-title":"Sci Adv"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e1007370","DOI":"10.1371\/journal.pgen.1007370","article-title":"RIT1 Controls actin dynamics via complex formation with RAC1\/CDC42 and PAK1","volume":"14","author":"Meyer Zum B\u00fcschenfelde","year":"2018","journal-title":"PLoS Genet"},{"key":"B26","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1038\/75997","article-title":"Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema","volume":"25","author":"Karkkainen","year":"2000","journal-title":"Nat Genet"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000517605","article-title":"Lymphatic abnormalities in noonan syndrome Spectrum disorders: a systematic review","volume":"13","author":"Sleutjes","year":"2022","journal-title":"Mol Syndromol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1002\/ajmg.c.32024","article-title":"New prospectives on treatment opportunities in RASopathies","volume":"190","author":"Gelb","year":"2022","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"B29","doi-asserted-by":"publisher","first-page":"C21","DOI":"10.1152\/ajpcell.2000.279.1.C21","article-title":"H(2)O(2)-mediated permeability: role of MAPK and occludin","volume":"279","author":"Kevil","year":"2000","journal-title":"Am J Physiol Cell Physiol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"90","DOI":"10.7326\/0003-4819-153-2-201007200-00005","article-title":"Narrative review: the systemic capillary leak syndrome","volume":"153","author":"Druey","year":"2010","journal-title":"Ann Intern Med"},{"key":"B31","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1016\/j.jaci.2016.10.042","article-title":"Idiopathic systemic capillary leak syndrome (clarkson disease)","volume":"140","author":"Druey","year":"2017","journal-title":"J Allergy Clin Immunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"3000605241301863","DOI":"10.1177\/03000605241301863","article-title":"A case of frequent of prerenal acute kidney injury attacks: importance of recognizing systemic capillary leak syndrome: a case report","volume":"52","author":"Miyazawa","year":"2024","journal-title":"J Int Med Res"},{"key":"B33","doi-asserted-by":"publisher","first-page":"2024-vol5","DOI":"10.69097\/41-05-2024-07","article-title":"[Hypotension and generalized edema due to plasma leakage: a case report]","volume":"41","author":"Gatto","year":"2024","journal-title":"G Ital Nefrol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1093\/abbs\/gmy071","article-title":"Effect of lentiviral vector-mediated KSR1 gene silencing on the proliferation of renal tubular epithelial cells and expression of inflammatory factors in a rat model of ischemia\/reperfusion injury","volume":"50","author":"Bai","year":"2018","journal-title":"Acta Biochim Biophys Sin (Shanghai)"},{"key":"B35","doi-asserted-by":"publisher","first-page":"e196119","DOI":"10.1172\/JCI196119","article-title":"Cooperative ETS transcription factors are required for lymphatic endothelial cell integrity and resilience","volume":"136","author":"Yang","year":"2025","journal-title":"J Clin Invest"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.1016\/j.resinv.2024.10.006","article-title":"Refractory bilateral chylothorax and chylous ascites in a patient with systemic lupus erythematosus treated by pleuro-peritoneal and peritoneal-venous shunts along with cell-free and concentrated ascites re-infusion therapy","volume":"62","author":"Kuwahara","year":"2024","journal-title":"Respir Investig"},{"key":"B37","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1002\/ccd.24639","article-title":"Ischemic changes associated with a large patent arterial duct in small infants","volume":"83","author":"Crystal","year":"2014","journal-title":"Catheter Cardiovasc Interv"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2026.1838907\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:34:48Z","timestamp":1783575288000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2026.1838907\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":37,"alternative-id":["10.3389\/fped.2026.1838907"],"URL":"https:\/\/doi.org\/10.3389\/fped.2026.1838907","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,9]]},"article-number":"1838907"}}