Genetic Syndromes Associated with Craniosynostosis

Abstract

Craniosynostosis is defined as the premature fusion of one or more of the cranial sutures. It leads not only to secondary distortion of skull shape but to various complications including neurologic, ophthalmic and respiratory dysfunction. Craniosynostosis is very heterogeneous in terms of its causes, presentation, and management. Both environmental factors and genetic factors are associated with development of craniosynostosis. Nonsyndromic craniosynostosis accounts for more than 70% of all cases. Syndromic craniosynostosis with a certain genetic cause is more likely to involve multiple sutures or bilateral coronal sutures. FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1 genes are major causative genes of genetic syndromes associated with craniosynostosis. Although most of syndromic craniosynostosis show autosomal dominant inheritance, approximately half of patients are de novo cases. Apert syndrome, Pfeiffer syndrome, Crouzon syndrome, and Antley-Bixler syndrome are related to mutations in FGFR family (especially in FGFR2), and mutations in FGFRs can be overlapped between different syndromes. Saethre-Chotzen syndrome, Muenke syndrome, and craniofrontonasal syndrome are representative disorders showing isolated coronal suture involvement. Compared to the other types of craniosynostosis, single gene mutations can be more frequently detected, in one-third of coronal synostosis patients. Molecular diagnosis can be helpful to provide adequate genetic counseling and guidance for patients with syndromic craniosynostosis.

Keywords: Antley-Bixler syndrome; Apert syndrome; Craniosynostosis; Crouzon syndrome; Pfeiffer syndrome; Saethre-Chotzen syndrome.

Fig. 1. A: Pre-operative 3D CT images show brachycephaly with premature fusion of bilateral coronal and lambdoid sutures, and skeletal radiographs show complex syndactyly of the hands and feet in Apert syndrome. B: Skeletal radiographs of the hands and feet show cutaneous syndactyly, broad radially-deviated thumbs, and broad big toes in Pfeiffer syndrome. C: Bilateral radio-humeral synostosis of the elbows joints was noted in Antley-Bixler syndrome.

Fig. 2. A: Pre-operative 3D CT images show asymmetric skull shape with unilateral (left) coronal synostosis in Saethre-Chotzen syndrome. B: Brachycephaly due to bilateral coronal synostosis, lateral displacement of orbits, and central defects between frontal bones are noted on the 3D CT images in craniofrontonasal syndrome.