TFE3-associated neurodevelopmental disorder: A distinct recognizable syndrome

The transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) gene encodes a transcription factor that regulates embryonic stem cell (ESC) differentiation. Its phosphorylation by the lysosomal Rag GTPase signaling pathway leads to cytoplasmic sequestration and inactivation promoting ESC differentiation and exit from pluripotency. Somatic translocations of this X-linked gene cause papillary renal cell carcinoma in which nuclear accumulation of the TFE3 oncoprotein is one of the most significant histopathologic characteristics. Early this year, Villegas et al. identified missense mutations in a TFE3 domain required for cytoplasmic inactivation as potentially causal for a mosaic human developmental disorder. They published five patients with de novo TFE3 nonsynonymous missense variants, four females and one male, with severe intellectual disability (5/5), coarse facial features (4/5), and Blaschkoid pigmentary mosaicism (4/5). The only male described has somatic mosaicism. All patients had normal brain Magnetic Resonance Imagings (MRIs). We present two unrelated females with this distinctive phenotype including the above triad along with other features not previously well described. Both were found to have de novo heterozygous variants in TFE3 on whole exome sequencing, one nonsynonymous missense, and one canonical splice site variant, thereby expanding the phenotypic and mutational spectrum for this disorder. Interestingly, due to significant coarsening of the facial features, both patients were initially thought to have a lysosomal storage disorder but enzyme screening and brain MRIs were negative.