Synchondrosis fusion contributes to the progression of postnatal craniofacial dysmorphology in syndromic craniosynostosis

Abstract

Syndromic craniosynostosis (CS) patients exhibit early, bony fusion of calvarial sutures and cranial synchondroses, resulting in craniofacial dysmorphology. In this study, we chronologically evaluated skull morphology change after abnormal fusion of the sutures and synchondroses in mouse models of syndromic CS for further understanding of the disease. We found fusion of the inter-sphenoid synchondrosis (ISS) in Apert syndrome model mice (Fgfr2 S252W/+ ) around 3 weeks old as seen in Crouzon syndrome model mice (Fgfr2c C342Y/+ ). We then examined ontogenic trajectories of CS mouse models after 3 weeks of age using geometric morphometrics analyses. Antero-ventral growth of the face was affected in Fgfr2 S252W/+ and Fgfr2c C342Y/+ mice, while Saethre-Chotzen syndrome model mice (Twist1 +/− ) did not show the ISS fusion and exhibited a similar growth pattern to that of control littermates. Further analysis revealed that the coronal suture synostosis in the CS mouse models induces only the brachycephalic phenotype as a shared morphological feature. Although previous studies suggest that the fusion of the facial sutures during neonatal period is associated with midface hypoplasia, the present study suggests that the progressive postnatal fusion of the cranial synchondrosis also contributes to craniofacial dysmorphology in mouse models of syndromic CS. These morphological trajectories increase our understanding of the progression of syndromic CS skull growth.

Sphenoid Bone Determines the Curvature of the Cranial Vault in Postnatal Skull Development in C57BL/6 Mice

“…[3] Furthermore, it has been suggested in previous studies that the ISS and SOS in the cranial base contribute significantly to the growth of the cranial vault. [2,4] Similar to this, in the present study, it is suggested that the sphenoid bone contributes to the cranial vault curvature.…”

“…ISS and SOS contribute significantly to the growth of the cranial vault and upper face as well as the skull base. [ 2 , 4 ] The cranial vault consists of frontal bones, parietal bones, the squamous parts of the temporal bone, and the interparietal part of occipital bone.…”

Evolution, conservatism and overlooked homologies of the mammalian skull

“…A computer simulation study suggests that cranial sutures are positioned in the skull where higher patterns of strain are experienced [122]. The premature fusion of one suture, which occurs in craniosynostosis, may result in increased irregular loading on other parts of the skull, possibly causing abnormal bone growth and malformations [124]. Developmentally, open cranial sutures are the major sites of bone growth and behave as signalling centres for regulating the balance between the proliferation of osteoblast precursors and osteogenic differentiation [125,126].…”

“…Suture closure and bone fusion occur when the fibrous borders between bones become ossified and closed owing to the activity of the Hedgehog, Fgf , Wnt and Pthlh signalling pathways [127,128]. To maintain their function as bone growth sites, sutures are required to remain patent, whereas the premature closure of sutures leads to growth abnormalities in the skull [124,126,129]. Evolutionarily, extra suture closures induce bone fusions, resulting in the apparent decrease of skull bone elements, as observed in the origin of the mammalian interparietal.…”

“…In a hypothetical scenario, encephalization may have driven the selection of genes such as Dlx5 and Lmx1b , which also pleiotropically promote bone fusion in various skull regions. Furthermore, we can postulate that genes such as Twist1 [124], which acts in the maintenance of patent calvarial sutures, have been selected in mammalian taxa that acquired especially enlarged brains. Future studies involving gene knockouts and gain-of-function experiments will allow these tentative hypotheses to be tested.…”