AUTHOR=Praticò Andrea D. , Falsaperla Raffaele , Comella Mattia , Belfiore Giuseppe , Polizzi Agata , Ruggieri Martino TITLE=Case report: A gain-of-function of hamartin may lead to a distinct “inverse TSC1-hamartin” phenotype characterized by reduced cell growth JOURNAL=Frontiers in Pediatrics VOLUME=11 YEAR=2023 URL=https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2023.1101026 DOI=10.3389/fped.2023.1101026 ISSN=2296-2360 ABSTRACT=

Mutations of TSC1 and TSC2 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 = 40 cm, −5.6 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 < 3rd centiles). No classical features of TSC were recorded; the girl harbored a novel missense variant in TSC1 (c.611G > A). We hypothesize that her clinical phenotype could be related to a “gain-of-function” of the TSC1 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 “inverse TSC1-hamartin” phenotype characterized by reduced growth of cells instead of the more classical predisposition to increased cell growth.