Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution.

The TWIST family is a group of highly conserved basic helix-loop-helix transcription factors. In humans, TWIST1 haploinsufficiency causes Saethre-Chotzen syndrome, which is characterized by craniosynostosis. Heterozygous localized TWIST1 and TWIST2 basic domain substitutions exert antimorphic effects to cause Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome, respectively. Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome share the facial features of ablepharon, hypertelorism, underdevelopment of the eyelids, and cheek pads adjacent to the corners of the mouth. Existence of phenotypic overlap between Saethre-Chotzen syndrome and Sweeney-Cox syndrome remains unknown. Herein, we document a male infant with the distinctive facial features of ablepharon, hypertelorism, cheek pads adjacent to the corners of the mouth, and bilateral coronal suture craniosynostosis who had a de novo heterozygous mutation in the basic domain of TWIST1, that is, c.351C>G p.Glu117Asp. The pathogenicity of this variant was supported by in silico and in vivo evidence. Our review showed that Sweeney-Cox syndrome appears to share many characteristics with Barber-Say syndrome and ablepharon-macrostomia syndrome except for craniosynostosis, which is a cardinal feature of Saethre-Chotzen syndrome. An amino acid substitution from Glu117 to Asp, both of which are the sole members of negatively charged amino acids, resulted in a prototypic Sweeney-Cox syndrome phenotype. This suggests that any amino acid substitutions at Glu117 would likely lead to the Sweeney-Cox syndrome phenotype or lethality. The present observation suggests that a localized TWIST1 basic domain substitution, that is, p.Glu117Asp, in TWIST1 may exert a mild antimorphic effect similar to that of haploinsufficiency, leading to craniosynostosis and ablepharon.