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

Abstract

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.

TWIST1 interacts with adherens junction proteins during neural tube development and regulates fate transition in cranial neural crest cells

“…Previous findings, including the data from this study, demonstrated that Twist1 cko/mice have severe craniofacial deformities, including exencephaly, severe mandibular hypoplasia, and a lack of frontonasal and maxillary bone (Bildsoe et al, 2009;Firulli et al, 2007;Vincentz et al, 2008). In humans, haploinsufficiency of TWIST1 leads to the syndromic form of craniosynostosis and cleft palate (Kunz and Fritz, 1999;Seto et al, 2007;Takenouchi et al, 2018). It has been shown that Twist1-deficient mesenchymal cells do not have mesenchymal characteristics as observed in mouse chimeras created from wild type embryos injected with Mtwist deficient embryonic stem cells (Chen and Behringer, 1995), and that Twist1 is essential for CNCC survival to give rise to CNCC-derived craniofacial formation as shown by an increased level of mesenchymal apoptosis in Twist1 cko/- (Bildsoe et al, 2013;Chen et al, 2007;Zhang et al, 2012).…”

“…Twist1 expression is maintained in the cranial neural crest-derived mesenchyme of the frontonasal and pharyngeal processes (Bildsoe et al, 2009;Fuchtbauer, 1995). In humans, mutations in TWIST1 cause Saethre-Chotzen syndrome, characterized by craniosynostosis and cleft palate, Sweeney-Cox syndrome, and Robinow-Sorauf syndrome (Kunz and Fritz, 1999;Takenouchi et al, 2018;Seto et al, 2007). In mice, Twist1 is crucial for neural tube closure and CNCC-derived craniofacial bone and cartilage formation as reported in the phenotypes of Twist1 null and conditional knockout (CKO) in CNCCs (Chen et al, 2007;Bildsoe et al, 2013;Zhang et al, 2012).…”

The growth and expansion of meningeal lymphatic networks are affected in craniosynostosis

“…Our results show that changes to the local meningeal environment are sufficient to disrupt the growth and remodeling of mLVs in craniosynostosis. The model we have chosen for our current analysis is overall more affected than what is typically observed in humans, and shows similarities with Sweeney-Cox syndrome, a severe craniofacial disorder caused by dominant-negative mutations in TWIST1 (Kim et al, 2017; Takenouchi et al, 2018). However, homozygous Twist1 FLX/FLX :Sm22a-Cre animals model venous malformations that are absent in heterozygous Twist1 FLX/WT :Sm22a-Cre animals, the latter of which more closely mimic skull phenotypes found in humans (Tischfield et al, 2017).…”

Progressive hemifacial atrophy in a Chinese patient: A case report

“…Human phenotypes related to Sweeney-Cox syndrome involve the facial nerves of the central nervous system. [ 18 ] We thus further posit that CFAP47 may act in a particular region of the nervous system such that CFAP47 mutations can cause abnormal facial development, thereby promoting hemifacial atrophy.…”