{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:41:45Z","timestamp":1791229305343,"version":"4.1.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T00:00:00Z","timestamp":1756166400000},"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><jats:title>Objective<\/jats:title><jats:p>Mechanistic\/mammalian target of rapamycin (mTOR) inhibitors have been used successfully to reduce the size of cardiac rhabdomyomas. However, the number of published cases is small and thus there is no consensus about therapeutic approaches, especially regarding dosing regimens and safety profiles of mTOR inhibitors. Based on a systematic literature review and one new case report, we discuss in detail the indication and adverse effects of fetal and neonatal mTOR-inhibitor therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A comprehensive search was conducted on PubMed\/MEDLINE and Web of Science for studies using combinations of the relevant medical subject heading (MeSH) terms and keyword (rhabdomyoma AND fetal OR fetus OR prenatal AND cardiac AND sirolimus) from the first report in 2018 until July 2025. Studies were included if they reported on pregnancies with fetal cardiac tumor and rhabdomyoma entity suspicion treated with mTOR inhibitors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results of literature review and new case description<\/jats:title><jats:p>In total, 67 results were found. After excluding non-eligible publications, a total of 20 documented cases were identified from 15 reports, all presenting lifesaving effects of mTOR inhibitors in fetuses and neonates with cardiac rhabdomyomas. We report on a patient with a prenatally suspected cardiac rhabdomyoma, which, due to imminent bilateral outflow tract obstruction, was prenatally treated with sirolimus. Tumor regression could be achieved. For maternal medical reasons, prenatal sirolimus had to be stopped after 5 weeks. Postnatal incessant atrioventricular re-entrant tachycardia occurred, which was unresponsive to electric or medical cardioversion (amiodarone) and unresponsive to everolimus. The patient developed massive capillary leak syndrome within hours. In combination with restrictive ventricular filling properties, the tachycardia resulted in death on the seventh day of life.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Cardiac rhabdomyomas have the potential to become a life-threatening condition, not only by impairing myocardial function and cardiac outflow, but also by causing arrhythmia due to tumor muscle bundles as substrate for a pre-excitation syndrome resulting in intrauterine or postnatal atrioventricular re-entrant tachycardia, as observed in our patient. The pharmacological therapeutic approach is fetal and neonatal treatment with mTOR inhibitors. All previous reported cases present lifesaving effects of mTOR inhibitors in fetuses and neonates with cardiac rhabdomyomas; however, adverse effects cannot be disregarded.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fped.2025.1649341","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T05:28:20Z","timestamp":1756186100000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Drug review: mTOR-inhibitor therapy in fetal cardiac rhabdomyoma\u2014a tightrope walk"],"prefix":"10.3389","volume":"13","author":[{"given":"Nadine","family":"Muschel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"H\u00f6ck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke","family":"Griesmaier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samira Abdel","family":"Azim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Ralser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Schreiner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Schermer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Kiechl-Kohlendorfer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Mutz-Dehbalaie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Michel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1007\/s00246-003-0590-4","article-title":"Fetal and neonatal cardiac tumors","volume":"25","author":"Isaacs","year":"2004","journal-title":"Pediatr Cardiol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/1471-2261-14-66","article-title":"Rhabdomyomas and tuberous sclerosis complex: our experience in 33 cases","volume":"14","author":"Sciacca","year":"2014","journal-title":"BMC Cardiovasc Disord"},{"key":"B3","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/j.pedneo.2016.07.004","article-title":"Fetal primary cardiac tumors during perinatal period","volume":"58","author":"Yuan","year":"2017","journal-title":"Pediatr Neonatol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e1146","DOI":"10.1542\/peds.2006-0504","article-title":"Clinical and genotype studies of cardiac tumors in 154 patients with tuberous sclerosis complex","volume":"118","author":"Jozwiak","year":"2006","journal-title":"Pediatrics"},{"key":"B5","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1002\/uog.13434","article-title":"Prenatal diagnosis of giant cardiac rhabdomyoma in tuberous sclerosis complex: a new therapeutic option with everolimus","volume":"45","author":"Mlczoch","year":"2015","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"bcr2015212946","DOI":"10.1136\/bcr-2015-212946","article-title":"Rapid resolution of cardiac rhabdomyomas following everolimus therapy","volume":"2015","author":"Choudhry","year":"2015","journal-title":"BMJ Case Rep"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1844","DOI":"10.1056\/NEJMc1800352","article-title":"Maternal sirolimus therapy for fetal cardiac rhabdomyomas","volume":"378","author":"Barnes","year":"2018","journal-title":"N Engl J Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e1199","DOI":"10.1542\/peds.2013-3293","article-title":"Rapid regression of left ventricular outflow tract rhabdomyoma after sirolimus therapy","volume":"134","author":"Breathnach","year":"2014","journal-title":"Pediatrics"},{"key":"B9","doi-asserted-by":"publisher","first-page":"280","DOI":"10.5468\/ogs.2019.62.4.280","article-title":"Sirolimus therapy for fetal cardiac rhabdomyoma in a pregnant woman with tuberous sclerosis","volume":"62","author":"Park","year":"2019","journal-title":"Obstet Gynecol Sci"},{"key":"B10","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.pediatrneurol.2021.09.014","article-title":"Prenatal sirolimus treatment for rhabdomyomas in tuberous sclerosis","volume":"125","author":"Ebrahimi-Fakhari","year":"2021","journal-title":"Pediatr Neurol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1002\/uog.20196","article-title":"In-utero treatment of large symptomatic rhabdomyoma with sirolimus","volume":"53","author":"Vachon-Marceau","year":"2019","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1002\/pd.5613","article-title":"Fetal cardiac rhabdomyomas treated with maternal sirolimus","volume":"40","author":"Pluym","year":"2020","journal-title":"Prenat Diagn"},{"key":"B13","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1080\/15513815.2021.1948646","article-title":"Fetal tuberous sclerosis: sirolimus for the treatment of fetal rhabdomyoma","volume":"41","author":"Dagge","year":"2022","journal-title":"Fetal Pediatr Pathol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"48","DOI":"10.5114\/pcard.2022.127365","article-title":"Massive fetal cardiac rhabdomyoma treated with transplacental sirolimus","volume":"12","author":"McLoughlin","year":"2022","journal-title":"Prenat Cardiol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"245","DOI":"10.3390\/pediatric15010020","article-title":"Successful prenatal treatment of cardiac rhabdomyoma in a fetus with tuberous sclerosis","volume":"15","author":"Will","year":"2023","journal-title":"Pediatr Rep"},{"key":"B16","doi-asserted-by":"publisher","first-page":"12886","DOI":"10.3390\/ijms241612886","article-title":"Three-year follow-up after intrauterine mTOR inhibitor administration for fetus with TSC-associated rhabdomyoma","volume":"24","author":"Maasz","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B17","doi-asserted-by":"publisher","first-page":"3897","DOI":"10.1007\/s00381-021-05218-4","article-title":"Everolimus as a possible prenatal treatment of in utero diagnosed subependymal lesions in tuberous sclerosis complex: a case report","volume":"37","author":"Cavalheiro","year":"2021","journal-title":"Childs Nerv Syst"},{"key":"B18","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1002\/uog.29103","article-title":"Transplacental therapy with sirolimus for non-tuberous sclerosis rhabdomyoma in fetus","volume":"64","author":"Griesman","year":"2024","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B19","first-page":"195","article-title":"Neoplasms metastatic to the heart: review of 3314 consecutive autopsies","volume":"3","author":"Abraham","year":"1990","journal-title":"Am J Cardiovasc Pathol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1055\/a-2408-1068","article-title":"Prenatal initiation of therapy with mTOR inhibitors for giant cardiac rhabdomyoma","volume":"45","author":"Schenk","year":"2024","journal-title":"Ultraschall Med"},{"key":"B21","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1186\/s13023-025-03780-7","article-title":"Transplacental sirolimus: a new treatment strategy for life-threatening fetal cardiac rhabdomyomas\u2014a case report","volume":"20","author":"Uno","year":"2025","journal-title":"Orphanet J Rare Dis"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e64175","DOI":"10.1002\/ajmg.a.64175","article-title":"Maternal sirolimus treatment reverses cardiac rhabdomyoma-induced hydrops fetalis in a twin gestation with tuberous sclerosis complex","author":"Ritter","year":"2025","journal-title":"Am J Med Genet A"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1002\/pd.6640","article-title":"Characteristics and outcomes of fetal cardiac rhabdomyoma with or without mTOR inhibitors, a systematic review and meta-analysis","volume":"44","author":"Mustafa","year":"2024","journal-title":"Prenat Diagn"},{"key":"B24","doi-asserted-by":"publisher","first-page":"94","DOI":"10.3390\/children12010094","article-title":"Prenatally diagnosed cardiac tumors and tuberous sclerosis complex: a single-center experience","volume":"12","author":"Bakos","year":"2025","journal-title":"Children (Basel)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1002\/uog.12472","article-title":"Pulmonary artery blood flow patterns in fetuses with pulmonary outflow tract obstruction","volume":"43","author":"Peyvandi","year":"2014","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1002\/j.1552-4604.1997.tb04318.x","article-title":"Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration","volume":"37","author":"Zimmerman","year":"1997","journal-title":"J Clin Pharmacol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1001\/archpedi.1993.02160300075027","article-title":"Rhabdomyoma and ventricular preexcitation syndrome. A report of two cases and review of literature","volume":"147","author":"Mehta","year":"1993","journal-title":"Am J Dis Child"},{"key":"B28","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1046\/j.1440-1754.2000.00443.x","article-title":"Pre-excitation syndrome secondary to cardiac rhabdomyomas in tuberous sclerosis","volume":"36","author":"Mas","year":"2000","journal-title":"J Paediatr Child Health"},{"key":"B29","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1017\/S1047951119003147","article-title":"Everolimus for cardiac rhabdomyomas in children with tuberous sclerosis. The ORACLE study protocol (everOlimus for caRdiac rhAbdomyomas in tuberous sCLErosis): a randomised, multicentre, placebo-controlled, double-blind phase II trial","volume":"30","author":"Stelmaszewski","year":"2020","journal-title":"Cardiol Young"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1478","DOI":"10.1007\/s00246-017-1688-4","article-title":"Regression of neonatal cardiac rhabdomyoma in two months through low-dose everolimus therapy: a report of three cases","volume":"38","author":"Chang","year":"2017","journal-title":"Pediatr Cardiol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1109646","DOI":"10.3389\/fped.2023.1109646","article-title":"Case report: accelerated regression of giant cardiac rhabdomyomas in neonates with low dose everolimus","volume":"11","author":"Hurtado-Sierra","year":"2023","journal-title":"Front Pediatr"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e213","DOI":"10.1055\/s-0039-1692198","article-title":"Effect and complications of everolimus use for giant cardiac rhabdomyomas with neonatal tuberous sclerosis","volume":"9","author":"Shibata","year":"2019","journal-title":"AJP Rep"},{"key":"B33","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1007\/s40264-019-00810-9","article-title":"Sirolimus and mTOR inhibitors: a review of side effects and specific management in solid organ transplantation","volume":"42","author":"Nguyen","year":"2019","journal-title":"Drug Saf"},{"key":"B34","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/ki.2009.231","article-title":"Posttransplant anemia: the role of sirolimus","volume":"76","author":"Fishbane","year":"2009","journal-title":"Kidney Int"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1681\/ASN.2007111202","article-title":"Sirolimus is associated with new-onset diabetes in kidney transplant recipients","volume":"19","author":"Johnston","year":"2008","journal-title":"J Am Soc Nephrol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"721","DOI":"10.7164\/antibiotics.28.721","article-title":"Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle","volume":"28","author":"Vezina","year":"1975","journal-title":"J Antibiot (Tokyo)"},{"key":"B37","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1111\/tri.12275","article-title":"Interstitial pneumonitis caused by everolimus: a case-cohort study in renal transplant recipients","volume":"27","author":"Baas","year":"2014","journal-title":"Transpl Int"},{"key":"B38","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1016\/j.healun.2010.05.034","article-title":"The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients","volume":"29","author":"Costanzo","year":"2010","journal-title":"J Heart Lung Transplant"},{"key":"B39","doi-asserted-by":"publisher","first-page":"2681","DOI":"10.1016\/j.transproceed.2021.07.053","article-title":"Edema associated with everolimus de novo","volume":"53","author":"Gago","year":"2021","journal-title":"Transplant Proc"}],"updated-by":[{"DOI":"10.3389\/fped.2025.1694368","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T00:00:00Z","timestamp":1757376000000}}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2025.1649341\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T08:24:12Z","timestamp":1757406252000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2025.1649341\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,26]]},"references-count":39,"alternative-id":["10.3389\/fped.2025.1649341"],"URL":"https:\/\/doi.org\/10.3389\/fped.2025.1649341","relation":{"correction":[{"id-type":"doi","id":"10.3389\/fped.2025.1694368","asserted-by":"object"}]},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,26]]},"article-number":"1649341"}}