Case report: A gain-of-function of hamartin may lead to a distinct inverse TSC1-hamartin phenotype characterized by reduced cell growth

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.

Automated summary

This article reports on a 5-year-old girl with a previously unreported clinical phenotype, including microcephaly, brain anomalies, intellectual disability, and growth retardation, without classical features of Tuberous Sclerosis Complex (TSC). The researchers hypothesize that this distinct phenotype may be related to a gain-of-function of the TSC1 protein product hamartin.