{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:12:38Z","timestamp":1753891958027,"version":"3.41.2"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T00:00:00Z","timestamp":1708473600000},"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:p>Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by a mutation in either of the two tumor suppressor genes, <jats:italic>TSC1<\/jats:italic> and <jats:italic>TSC2<\/jats:italic>. Due to dysregulated activity of the mammalian target of rapamycin (mTOR) pathway, hamartomas or benign tumors frequently occur in many organs and are often treated with mTOR inhibitors. Hemihypertrophy is a rare complication of TSC. Although not being a tumor, progressive overgrowth of the affected limb may cause cosmetic and functional problems, for which the efficacy of mTOR inhibitors has not been reported previously. We herein report a case of TSC-associated hemihypertrophy. In this case, genetic studies revealed <jats:italic>TS<\/jats:italic>C<jats:italic>1<\/jats:italic> loss of heterozygosity as the cause of hemihypertrophy. Clinically, pharmacological treatment with an mTOR inhibitor sirolimus successfully ameliorated cosmetic and functional problems with no intolerable adverse effects.<\/jats:p>","DOI":"10.3389\/fped.2024.1333064","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T05:49:56Z","timestamp":1708494596000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Tuberous sclerosis complex-associated hemihypertrophy successfully treated with mTOR inhibitor sirolimus"],"prefix":"10.3389","volume":"12","author":[{"given":"Konomi","family":"Shimoda","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Iwasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoko","family":"Mizuno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masafumi","family":"Seki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masakazu","family":"Mimaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motohiro","family":"Kato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aya","family":"Shinozaki-Ushiku","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harushi","family":"Mori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seishi","family":"Ogawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masashi","family":"Mizuguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,2,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1086\/302381","article-title":"Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis","volume":"64","author":"Jones","year":"1999","journal-title":"Am J Hum Genet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"16035","DOI":"10.1038\/nrdp.2016.35","article-title":"Tuberous sclerosis complex","volume":"2","author":"Henske","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"B3","doi-asserted-by":"publisher","first-page":"6677","DOI":"10.3390\/ijms22136677","article-title":"Brain symptoms of tuberous sclerosis complex: pathogenesis and treatment","volume":"22","author":"Mizuguchi","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B4","doi-asserted-by":"publisher","first-page":"962","DOI":"10.1136\/jmg.33.11.962","article-title":"Loss of heterozygosity in tuberous sclerosis hamartomas","volume":"33","author":"Sepp","year":"1996","journal-title":"J Med Genet"},{"key":"B5","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.jdermsci.2015.04.005","article-title":"Mammalian target of rapamycin and tuberous sclerosis complex","volume":"79","author":"Wataya-Kaneda","year":"2015","journal-title":"J Dermatol Sci"},{"key":"B6","doi-asserted-by":"publisher","first-page":"9820181","DOI":"10.1155\/2017\/9820181","article-title":"Recent advances and challenges of mTOR inhibitors use in the treatment of patients with tuberous sclerosis complex","volume":"2017","author":"Palavra","year":"2017","journal-title":"Oxid Med Cell Longev"},{"key":"B7","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1186\/s13023-021-01917-y","article-title":"Rare manifestations and malignancies in tuberous sclerosis complex: findings from the TuberOus SClerosis registry to increAse disease awareness (TOSCA)","volume":"16","author":"Sauter","year":"2021","journal-title":"Orphanet J Rare Dis"},{"key":"B8","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1111\/j.1365-2133.1996.tb01161.x","article-title":"Widespread angiokeratomas and tuberous sclerosis","volume":"135","author":"Gil-Mateo","year":"1996","journal-title":"Br J Dermatol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e32663","DOI":"10.7759\/cureus.32663","article-title":"Periodontoid pseudotumor in tuberous sclerosis associated with neck diffuse lipomatosis","volume":"14","author":"Pinto","year":"2022","journal-title":"Cureus"},{"key":"B10","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1186\/s12920-022-01362-1","article-title":"Clinical and genetic analyses of patients with lateralized overgrowth","volume":"15","author":"Kim","year":"2022","journal-title":"BMC Med Genomics"},{"key":"B11","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1086\/518809","article-title":"Highly sensitive method for genomewide detection of allelic composition in nonpaired, primary tumor specimens by use of affymetrix single-nucleotide-polymorphism genotyping microarrays","volume":"81","author":"Yamamoto","year":"2007","journal-title":"Am J Hum Genet"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1097\/01.pas.0000126859.70814.6d","article-title":"Lymphangiogenesis in lymphangioleiomyomatosis: its implication in the progression of lymphangioleiomyomatosis","volume":"28","author":"Kumasaka","year":"2004","journal-title":"Am J Surg Pathol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1619","DOI":"10.1182\/blood.2021014027","article-title":"Sirolimus plus prednisolone vs sirolimus monotherapy for kaposiform hemangioendothelioma: a randomized clinical trial","volume":"139","author":"Ji","year":"2022","journal-title":"Blood"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2023","DOI":"10.1093\/hmg\/ddt597","article-title":"Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex","volume":"23","author":"Tyburczy","year":"2014","journal-title":"Hum Mol Genet"},{"key":"B15","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/S0140-6736(12)61134-9","article-title":"Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial","volume":"381","author":"Franz","year":"2013","journal-title":"Lancet"},{"key":"B16","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1016\/S0140-6736(12)61767-X","article-title":"Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial","volume":"381","author":"Bissler","year":"2013","journal-title":"Lancet"},{"key":"B17","doi-asserted-by":"publisher","first-page":"4071","DOI":"10.1158\/1078-0432.CCR-11-0445","article-title":"Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial","volume":"17","author":"Davies","year":"2011","journal-title":"Clin Cancer Res"},{"key":"B18","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1001\/jamadermatol.2016.3545","article-title":"Efficacy and safety of topical sirolimus therapy for facial angiofibromas in the tuberous sclerosis complex: a randomized clinical trial","volume":"153","author":"Wataya-Kaneda","year":"2017","journal-title":"JAMA Dermatol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1136\/jnnp.38.5.500","article-title":"Tuberous sclerosis and klippel-trenaunay-weber syndromes. Association of two complete phakomatoses in a single individual","volume":"38","author":"Troost","year":"1975","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"B20","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1001\/archderm.118.11.877","article-title":"Primary localized gigantism and tuberous sclerosis","volume":"118","author":"Ortonne","year":"1982","journal-title":"Arch Dermatol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1111\/j.1346-8138.1992.tb03741.x","article-title":"A rare association of localized gigantism with tuberous sclerosis","volume":"19","author":"Reddy","year":"1992","journal-title":"J Dermatol"},{"key":"B22","first-page":"315","article-title":"Tuberous sclerosis complex (TSC) and Klippel\u2013Trenaunay\u2013Weber (KTW) syndromes association of two complete phakomatoses in a single individual","volume":"48","author":"Assefa","year":"2010","journal-title":"Ethiop Med J"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e27","DOI":"10.1097\/BPO.0000000000000240","article-title":"Lymphoedema in tuberous sclerosis: case report and review of the literature","volume":"34","author":"Navarre","year":"2014","journal-title":"J Pediatr Orthop"},{"key":"B24","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1111\/pde.12946","article-title":"Tuberous sclerosis complex associated with vascular anomalies or overgrowth","volume":"33","author":"Jenkins","year":"2016","journal-title":"Pediatr Dermatol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2803","DOI":"10.1002\/ajmg.a.61811","article-title":"Limb overgrowth associated with a mosaic TSC2\u2005s-hit in tuberous sclerosis complex","volume":"182","author":"Tessarech","year":"2020","journal-title":"Am J Med Genet A"},{"key":"B26","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1016\/j.jaad.2015.07.018","article-title":"Improvement of tuberous sclerosis complex (TSC) skin tumors during long-term treatment with oral sirolimus","volume":"73","author":"Nathan","year":"2015","journal-title":"J Am Acad Dermatol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1007\/s10147-017-1224-9","article-title":"Effect of everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex: an evaluation based on tumor density","volume":"23","author":"Hatano","year":"2018","journal-title":"Int J Clin Oncol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e30215","DOI":"10.1002\/pbc.30215","article-title":"Response to sirolimus in capillary lymphatic venous malformations and associated syndromes: impact on symptomatology, quality of life, and radiographic response","volume":"70","author":"Engel","year":"2023","journal-title":"Pediatr Blood Cancer"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2024.1333064\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T05:49:58Z","timestamp":1708494598000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2024.1333064\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,21]]},"references-count":28,"alternative-id":["10.3389\/fped.2024.1333064"],"URL":"https:\/\/doi.org\/10.3389\/fped.2024.1333064","relation":{},"ISSN":["2296-2360"],"issn-type":[{"type":"electronic","value":"2296-2360"}],"subject":[],"published":{"date-parts":[[2024,2,21]]},"article-number":"1333064"}}