{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T12:34:38Z","timestamp":1764333278468,"version":"3.41.2"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"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>Mutations of <jats:italic>TSC1<\/jats:italic> and <jats:italic>TSC2<\/jats:italic> genes cause classical Tuberous Sclerosis Complex (TSC), a neurocutaneous disorder characterized by a tendency to develop hamartias, hamartomas, and other tumors. We herein report on a girl, now aged 5 years, who presented a previously unreported, distinct clinical phenotype consisting of primary microcephaly (head circumference\u2009=\u200940\u2005cm, \u22125.6 standard deviations), brain anomalies including hypoplasia of the corpus callosum (with a residual draft of the genu), simplified parieto-temporal gyral pattern, colpocephaly with ectasia of the temporal ventricular horns, intellectual disability, and a general pattern of reduced growth (with weight and height\u2009&amp;lt;\u20093rd centiles). No classical features of TSC were recorded; the girl harbored a novel missense variant in <jats:italic>TSC1<\/jats:italic> (c.611G\u2009&amp;gt;\u2009A). We hypothesize that her clinical phenotype could be related to a \u201cgain-of-function\u201d of the <jats:italic>TSC1<\/jats:italic> protein product hamartin, causing an increase in the effects of the protein on inhibition of its intracellular targets (i.e., mTORC or RAC1 pathways), resulting in a distinct \u201cinverse <jats:italic>TSC1<\/jats:italic>-hamartin\u201d phenotype characterized by reduced growth of cells instead of the more classical predisposition to increased cell growth.<\/jats:p>","DOI":"10.3389\/fped.2023.1101026","type":"journal-article","created":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T06:36:52Z","timestamp":1680158212000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Case report: A gain-of-function of hamartin may lead to a distinct \u201cinverse TSC1-hamartin\u201d phenotype characterized by reduced cell growth"],"prefix":"10.3389","volume":"11","author":[{"given":"Andrea D.","family":"Pratic\u00f2","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raffaele","family":"Falsaperla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mattia","family":"Comella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Belfiore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agata","family":"Polizzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martino","family":"Ruggieri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.pediatrneurol.2021.07.011","article-title":"Updated international 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