Saethre–Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome

Kreß, Wolfram; Schropp, Christian; Lieb, Guillaume; Petersen, Birgit; Büsse-Ratzka, Maria; Kunz, Jürgen; Reinhart, E.; Schäfer, Wolf-Dieter; Sold, J.; Hoppe, Florian; Pahnke, J.; Trusen, Andreas; Sörensen, N.; Krauß, Jürgen; Collmann, H.

doi:10.1038/sj.ejhg.5201507

Cited by 135 publications

(124 citation statements)

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“…Nevertheless, because of the high heterogeneity of the phenotypes, the diseases of the patients in our cohort with this molecular defect had been classified on the basis of their clinical presentations. Consequently, the P250R FGFR3 mutant and other TWIST1 gene defects were associated with the SaethreChotzen, brachicephaly, and plagiocephaly syndromes (5,18,19 ).…”

Section: Discussionmentioning

confidence: 99%

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Integrated Strategy for Fast and Automated Molecular Characterization of Genes Involved in Craniosynostosis

et al. 2007

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Background: Craniosynostosis, the premature fusion of 1 or more sutures of the skull, is a common congenital defect, with a prevalence of 1 in 2500 live births. Untreated progressive craniosynostosis leads to inhibition of brain growth and increased intracranial and intraorbital pressure. The heterogeneity of clinical phenotypes and the overlap of the various associated syndromes render the correct diagnosis of the different craniosynostoses particularly difficult. Methods: To identify 10 common mutations in the genes for fibroblast growth factor receptors 2 and 3 (FGFR2 and FGFR3), we developed a microelectronic microchip assay that exploited the PCR multiplexing format and coupled it with serial addressing and probe hybridization on the same pad. For the molecular characterization of patients who tested negative in the microchip screening, we also developed conditions for denaturing HPLC (DHPLC) analysis of the most mutated regions of FGFR2 and FGFR3 and the entire coding region of the TWIST1 gene. Results: In our cohort of 159 patients with various craniosynostosis syndromes, mutations were found in

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Section: Discussionmentioning

confidence: 99%

“…Notably, the craniosynostosis associated with the P250R FGFR3 mutant has previously been referred to as Muenke syndrome (4,18,19 ). Nevertheless, because of the high heterogeneity of the phenotypes, the diseases of the patients in our cohort with this molecular defect had been classified on the basis of their clinical presentations.…”

Section: Discussionmentioning

confidence: 99%

Integrated Strategy for Fast and Automated Molecular Characterization of Genes Involved in Craniosynostosis

et al. 2007

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“…9,12 Mean FSIQs of patients who have Muenke and Saethre-Chotzen syndrome ranged from 50 to 120. [12][13][14][15][16] No published studies were found on intellectual functioning in children who have complex craniosynostosis.…”

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confidence: 99%

Intellectual, Behavioral, and Emotional Functioning in Children With Syndromic Craniosynostosis

Maliepaard

Mathijssen²,

Oosterlaan

et al. 2014

Pediatrics

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WHAT'S KNOWN ON THIS SUBJECT: Children who have syndromic craniosynostosis are at risk for developing intellectual disability, behavioral and emotional problems. Study results were often based on small samples and wide age-based variation, using nonvalidated instruments and describing no clear inclusion and exclusion criteria.WHAT THIS STUDY ADDS: Intellectual, behavioral, and emotional functioning is described in a national sample (N = 82) of schoolaged children with syndromic craniosynostosis. Using standardized instruments, this study indicates higher risks for intellectual disability and behavioral problems mainly in children having Apert and Muenke syndromes. abstract OBJECTIVES: To examine intellectual, behavioral, and emotional functioning of children who have syndromic craniosynostosis and to explore differences between diagnostic subgroups. METHODS:A national sample of children who have syndromic craniosynostosis participated in this study. Intellectual, behavioral, and emotional outcomes were assessed by using standardized measures: Wechsler Intelligence Scale for Children, Third Edition, Child Behavior Checklist (CBCL)/6-18, Disruptive Behavior Disorder rating scale (DBD), and the National Institute of Mental Health Diagnostic Interview Schedule for Children. RESULTS:We included 82 children (39 boys) aged 6 to 13 years who have syndromic craniosynostosis. Mean Full-Scale IQ (FSIQ) was in the normal range (M = 96.6; SD = 21.6). However, children who have syndromic craniosynostosis had a 1.9 times higher risk for developing intellectual disability (FSIQ ,85) compared with the normative population (P ,.001) and had more behavioral and emotional problems compared with the normative population, including higher scores on the CBCL/6-18, DBD Total Problems (P , .001), Internalizing (P , .01), social problems (P , .001), attention problems (P , .001), and the DBD Inattention (P , .001).Children who have Apert syndrome had lower FSIQs (M = 76.7; SD = 13.3) and children who have Muenke syndrome had more social problems (P , .01), attention problems (P , .05), and inattention problems (P , .01) than normative population and with other diagnostic subgroups. CONCLUSIONS: Although children who have syndromic craniosynostosishave FSIQs similar to the normative population, they are at increased risk for developing intellectual disability, internalizing, social, and attention problems. Higher levels of behavioral and emotional problems were related to lower levels of intellectual functioning. Pediatrics 2014;133:e1608-e1615 AUTHORS:

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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.

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Saethre–Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome

Cited by 135 publications

References 32 publications

Integrated Strategy for Fast and Automated Molecular Characterization of Genes Involved in Craniosynostosis

Integrated Strategy for Fast and Automated Molecular Characterization of Genes Involved in Craniosynostosis

Intellectual, Behavioral, and Emotional Functioning in Children With Syndromic Craniosynostosis

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

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