Craniosynostosis is the premature ossification of cranial sutures. Depending on which cranial sutures are affected by synostosis, this results in altered skull growth and characteristic head shapes. Most primary craniosynostoses are congenital and can occur in isolation or as a symptom of various complex syndromes. The total frequency is 1:2,000-3,000. Besides exogenous causes (e.g., extreme preterm birth, valproate embryopathy, etc.) monogenic causes are found in about 25% of all craniosynostoses.
The complex forms show one or more synostoses and sometimes further symptoms of pathological development of bony structures such as syndactylia. The classic craniosynostosis syndromes include:
These syndromes are inherited in an autosomal dominant manner and, except for Saethre‑Chotzen syndrome, are caused by changes in the fibroblast growth factor receptor (FGFR) 1, 2 and 3 genes. Saethre-Chotzen syndrome is usually caused by pathogenic changes in the TWIST1 gene. There is clinical overlap between the syndromes.
Among the isolated forms, sagittal synostosis or metopic synostosis are the most common with a proportion of about 50%; however, genetic causes are detectable in less than 1% and are usually variants in TWIST1. In unilateral coronal synostoses, causative variants are found in approximately 13%, in bilateral coronal synostoses in approximately 60%, and in multiple suture synostoses, in approximately 15%. The most frequent cause of isolated coronal synostoses are variants in TCF12 that lead to haploinsufficiency.
The molecular cause of premature suture ossification is not yet understood in detail. The fibroblast growth factor receptors involved are tyrosine kinase receptors, which play an important role in ossification. TWIST interacts with FGFR.
Complications include increased intracranial pressure, impaired vision and hearing, and in some syndromes also a delay in development. The treatment is surgical.
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