{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:54:26Z","timestamp":1790391266646,"version":"4.1.0"},"reference-count":10,"publisher":"Georg Thieme Verlag KG","issue":"04","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":77,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["AJP Rep"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Noonan syndrome (Online Mendelian Inheritance in Man #163950) is a RASopathy caused by germline mutations in the RAS\/RAF\/mitogen-activated protein kinase signaling pathway and characterized by distinctive facial features, musculoskeletal abnormalities, and congenital heart defects. A subset of patients with RIT1 mutations present with hypertrophic cardiomyopathy and generalized lymphatic anomalies. While sirolimus, a mammalian target of rapamycin inhibitor (mTOR), has been shown to suppress lymphangiogenesis, its efficacy in Noonan syndrome remains unclear.<\/jats:p>\n                  <jats:p>We report the case of an infant with Noonan syndrome and RIT1 mutation who developed recurrent refractory chylothorax and edema. Despite multiple interventions, including corticosteroids, octreotide, thoracic duct ligation, and pleurodesis, the patient's condition remained critical and refractory. Skin biopsy revealed lymphatic malformations. Sirolimus (0.6\u2009mg\/day) was initiated at 220 days of age, but was discontinued due to a markedly elevated serum level (88.2\u2009ng\/mL) and a lack of therapeutic effect. The patient died of Escherichia coli sepsis at 235 days of age.<\/jats:p>\n                  <jats:p>Although sirolimus was ineffective in this case, initiation of treatment at a lower dose may be advisable for patients with compromised hepatic function or concurrent infections. Further studies are warranted to clarify the appropriate indications, dosage, and timing of sirolimus therapy for Noonan syndrome.<\/jats:p>","DOI":"10.1055\/a-2770-4952","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:41:12Z","timestamp":1766018472000},"page":"e186-e188","source":"Crossref","is-referenced-by-count":1,"title":["Sirolimus for Recurrent Chylothorax and Edema in an Infant with Noonan Syndrome after Resolved Hydrops Fetalis: A Case Report"],"prefix":"10.1055","volume":"15","author":[{"given":"Mariko","family":"Hattori","sequence":"additional","affiliation":[{"name":"Division of Neonatology, NHO Okayama Medical Center, Okayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3343-1590","authenticated-orcid":false,"given":"Kei","family":"Tamai","sequence":"additional","affiliation":[{"name":"Division of Neonatology, NHO Okayama Medical Center, Okayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirokazu","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Division of Neonatology, NHO Okayama Medical Center, Okayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihito","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Division of Neonatology, NHO Okayama Medical Center, Okayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Division of Neonatology, NHO Okayama Medical Center, Okayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michio","family":"Ozeki","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misao","family":"Kageyama","sequence":"additional","affiliation":[{"name":"Division of Neonatology, NHO Okayama Medical Center, Okayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"issue":"01","key":"ref1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000517605","article-title":"Lymphatic abnormalities in Noonan syndrome spectrum disorders: A systematic review","volume":"13","author":"J Sleutjes","year":"2022","journal-title":"Mol Syndromol"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.reth.2018.12.001","article-title":"Efficacy and safety of sirolimus treatment for intractable lymphatic anomalies: A study protocol for an open-label, single-arm, multicenter, prospective study (SILA)","volume":"10","author":"M Ozeki","year":"2019","journal-title":"Regen Ther"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"1335469","DOI":"10.3389\/fmed.2024.1335469","article-title":"Sirolimus treatment for intractable lymphatic anomalies: an open-label, single-arm, multicenter, prospective trial","volume":"11","author":"M Ozeki","year":"2024","journal-title":"Front Med (Lausanne)"},{"issue":"02","key":"ref4","doi-asserted-by":"crossref","first-page":"e20153257","DOI":"10.1542\/peds.2015-3257","article-title":"Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies","volume":"137","author":"D M Adams","year":"2016","journal-title":"Pediatrics"},{"issue":"09","key":"ref5","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1002\/lary.21927","article-title":"The successful management of diffuse lymphangiomatosis using sirolimus: A case report","volume":"121","author":"J Reinglas","year":"2011","journal-title":"Laryngoscope"},{"issue":"09","key":"ref6","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1007\/s00431-025-06376-2","article-title":"Molecular targeted treatment in infants with central conducting lymphatic anomalies","volume":"184","author":"V C van den Brink","year":"2025","journal-title":"Eur J Pediatr"},{"issue":"13","key":"ref7","doi-asserted-by":"crossref","first-page":"6126","DOI":"10.3390\/ijms26136126","article-title":"Targeted Therapy for complex lymphatic anomalies in patients with Noonan syndrome and related disorders","volume":"26","author":"E KSM Leenders","year":"2025","journal-title":"Int J Mol Sci"},{"issue":"12","key":"ref8","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1177\/0091270005281350","article-title":"Pharmacokinetics of sirolimus (rapamycin) in subjects with mild to moderate hepatic impairment","volume":"45","author":"J J Zimmerman","year":"2005","journal-title":"J Clin Pharmacol"},{"issue":"03","key":"ref9","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1177\/0091270007312902","article-title":"Pharmacokinetics of sirolimus (rapamycin) in subjects with severe hepatic impairment","volume":"48","author":"J J Zimmerman","year":"2008","journal-title":"J Clin Pharmacol"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.ejps.2018.12.004","article-title":"Significant effect of infection and food intake on sirolimus pharmacokinetics and exposure in pediatric patients with acute lymphoblastic leukemia","volume":"128","author":"T Mizuno","year":"2019","journal-title":"Eur J Pharm Sci"}],"container-title":["American Journal of Perinatology 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