Molecular Genetics of Saethre–Chotzen Syndrome


Saethre–Chotzen syndrome is caused by mutations and large deletions in the TWIST1 gene. It is a congenital disorder characterised by coronal suture synostosis, upper eyelid ptosis and mild anomalies of the hand and feet, amongst others. TWIST1 and other genes that can cause craniosynostosis closely interact during embryogenesis of the vault and in the establishment of the coronal sutures in particular. This involves a delicate process of progressive expansion of the frontal and parietal bones, inhibiting their osteogenic fronts when the cranial bones meet, and starting a balance between proliferation of mesenchymal cells within the sutural area and differentiation of osteoprogenitor cells towards the bony rims to allow expansion of the cranial bones. TWIST1 is particularly required for inhibition of the osteogenic fronts from the frontal and parietal bones when they get into close contact. The changes in TWIST1 that cause Saethre–Chotzen syndrome result in a loss of function and thus fusion of the bones, taking place at 16 weeks of gestation.

Key Concepts:

  • Saethre–Chotzen syndrome is caused by mutations and large deletions in the TWIST1 gene that result in a loss of function.

  • Coronal suture synostosis is a consistent feature of Saethre–Chotzen syndrome.

  • Mutations in FGFR2 are another frequent cause for syndromic craniosynostosis with coronal suture synostosis (Apert and Crouzon syndromes). The FGFR2 mutations result in a gain of function.

  • TWIST1 is required for establishment of the coronal sutures during embryogenesis.

  • TWIST1 inhibits the progression of the osteogenic fronts of the expanding frontal and parietal bones during embryogenesis and is mainly expressed by mesenchymal cells in the centre of the developing coronal suture.

  • TWIST1 interacts with MSX2, EPHNA4 and EphA4 in preventing osteoprogenitor cells from invading the coronal suture.

  • TWIST1 and TCF12 form heterodimers, whose dosage is critical for normal coronal suture development.

  • FGFR2 is particularly expressed at the osteogenic fronts of the frontal and parietal bones.

  • FGFR2 expression is regulated by TWIST1.

Keywords: Saethre–Chotzen; craniosynostosis; coronal suture; TWIST1; FGFR2; TCF12

Figure 1.

3D‐computed tomography scan of the skull of an infant with Saethre–Chotzen syndrome. (a) Normal, open, coronal suture in between the frontal and parietal bones at the left side. (b) Frontal view showing a slight elevation of the right orbit. (c) Closed coronal suture at the right side, causing a retrusion of the right supraorbital rim.



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Further Reading

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Morriss‐Kay GM and Wilkie AOM (2005) Growth of the normal skull vault and its alteration in craniosynostosis: insights from human genetics and experimental studies. Journal of Anatomy 207: 637–653.

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Mathijssen, Irene MJ(Dec 2013) Molecular Genetics of Saethre–Chotzen Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024347]