Clinical spectrum and outcomes in families with coronal synostosis and TCF12 mutations

Abstract

TCF12 mutations have been reported very recently in coronal synostosis. We report several cases of familial coronal synostosis among four families harbouring novel TCF12 mutations. We observed a broad interfamilial phenotypic spectrum with features overlapping with the Saethre-Chotzen syndrome. TCF12 molecular testing should be considered in patients with unilateral-or bilateral-coronal synostosis associated or not with syndactyly, after having excluded mutations in the TWIST1 gene and the p.Pro250Arg mutation in INTRODUCTIONThe aetiology of several cases of non-syndromic coronal craniosynostosis without abnormalities of the extremities remained genetically unexplained until fibroblast growth factor receptor 3 (FGFR3) and TWIST1 mutations were characterised. The p.Pro250Arg (c.749C4G) mutation in FGFR3, which is associated with Muenke syndrome [MIM#602849], 1 is identified in about 70% of familial non-syndromic coronal synostosis. 2 This syndrome, in its complete phenotype, includes unilateral (plagiocephaly) or bilateral (brachycephaly) premature closure of the coronal sutures, hearing loss, broad toes, and carpal and tarsal fusions. The phenotype is however, variable, including non-penetrance, isolated craniosynostosis and features which overlap with other craniosynostosis syndromes (eg Crouzon syndrome, Saethre-Chotzen syndrome (SCS) and cloverleaf skull). 3,4 TWIST1 mutations, which are typically associated with SCS syndrome may also be identified in up to 46% cases of brachycephaly. 3 SCS typically presents with coronal synostosis, small ear with prominent crus, ptosis, syndactyly, and broad thumb and/or broad hallux. However, SCS also displays phenotypic variability depending on the type of mutation involved. 5 The TCF12 gene, which encodes a basic helix-loop-helix (bHLH) transcription factor, was recently identified by exome sequencing in cases displaying premature fusion of the coronal sutures. 6 Therefore, we tried to detect TCF12 mutations in five families with coronal synostosis, after negative prior screening for FGFR3 or TWIST1 mutations, and found four positive families. We then reviewed the clinical manifestations and outcomes in these families, and further discussed their phenotype/genotype correlations.

Clinical genetics of craniosynostosis

“…The single largest contributor to these diagnoses is TCF12 , which encodes a partner protein of TWIST1 particularly critical for coronal suture development [27]. Two follow-up studies have confirmed the importance of TCF12 mutations in coronal craniosynostosis, both in the context of familial mutations [37], and in a more general screen of craniosynostosis [29]. Given the haploinsufficiency mechanism of TCF12 mutations, heterozygous deletions are also expected to be pathogenic and this has been confirmed in two reports [38, 39].…”

Genetic advances in craniosynostosis

“…Although 81% of the individuals with TCF12 mutations presented with apparent cNCS, some of the affected individuals had developmental delays and dysmorphic features overlapping with the Saethre-Chotzen syndrome [Sharma et al, 2013]. More recently, the phenotypic spectrum of TCF12 mutations has been extended to include possible facial and limb anomalies, and intellectual disability [Di Rocco et al, 2014; Le Tanno et al, 2014; Paumard-Hernandez et al, 2015; Piard et al, 2015]. Based on these observations, it is reasonable to recommend TCF12 testing for all patients with cCS, with or without associated anomalies.…”

Syndromic Craniosynostosis: Complexities of Clinical Care

“…Facial growth appears not greatly affected ( Fig. 10 ) [Di Rocco et al, 2014;Goos et al, 2016]. The phenotype is variable, including non-penetrance of the TCF12 gene, which encodes a basic helix-loop-helix transcription factor [Sharma et al, 2013].…”