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Saethre-Chotzen syndrome is a common autosomal dominant form of craniosynostosis, the premature fusion of the sutures of the calvarial bones of the skull. Most Saethre-Chotzen syndrome cases are caused by haploinsufficiency for the TWIST gene. Mice heterozygous for a null mutation of the Twist gene replicate certain features of Saethre-Chotzen syndrome, but have not been reported to exhibit craniosynostosis. We demonstrate that Twist heterozygous mice exhibit fusions of the coronal suture and other cranial suture abnormalities, indicating that Twist heterozygous mice constitute a better animal model for Saethre-Chotzen syndrome than was previously appreciated.
Anat Rec 2002 Oct 01
PMID:Craniosynostosis in Twist heterozygous mice: a model for Saethre-Chotzen syndrome. 1222 14

Craniosynostosis results in cranial deformities and increased intracranial pressure, which pose extensive and recurrent surgical management problems. Developmental studies in rodents have shown that low levels of transforming growth factor-beta 3 (Tgf-beta 3) are associated with normal fusion of the interfrontal (IF) suture, and that Tgf-beta 3 prevents IF suture fusion in a dose-dependent fashion. The present study was designed to test the hypothesis that Tgf-beta 3 can also prevent or "rescue" fusing sutures in a rabbit model with familial craniosynostosis. One hundred coronal sutures from 50 rabbits with delayed-onset, coronal suture synostosis were examined in the present study. The rabbits were divided into five groups of 10 rabbits each: 1) sham controls, 2) bovine serum albumin (BSA, 500 ng) low-dose protein controls, 3) low-dose Tgf-beta 3 (500 ng), 4) high-dose BSA (1,000 ng) controls, and 5) high-dose Tgf-beta 3 (1,000 ng). At 10 days of age, radiopaque amalgam markers were implanted in all of the rabbits on either side of the coronal suture to monitor sutural growth. At 25 days of age, the BSA or Tgf-beta 3 was combined with a slow-absorbing collagen vehicle and injected subperiosteally above the coronal suture. Radiographic results revealed that high-dose Tgf-beta 3 rabbits had significantly greater (P < 0.05) coronal suture marker separation than the other groups. Histomorphometric analysis revealed that high-dose Tgf-beta 3 rabbits also had patent coronal sutures and significantly (P < 0.01) greater sutural widths and areas than the other groups. The results suggest that there is a dose-dependent effect of TGF-beta 3 on suture morphology and area in these rabbits, and that the manipulation of such growth factors may have clinical applications in the treatment of craniosynostosis.
Anat Rec A Discov Mol Cell Evol Biol 2003 Oct
PMID:Rescue of coronal suture fusion using transforming growth factor-beta 3 (Tgf-beta 3) in rabbits with delayed-onset craniosynostosis. 1297 20

Studies of isolated craniosynostosis have shown biomechanical and biochemical influences on the craniofacial phenotype, resulting from both genetic and epigenetic factors. Much less attention has been directed toward the morphology of the brain, despite the interactive nature of the developing skull and developing brain. The aim of this study is to define the morphology of the brain in nonsyndromic unilateral coronal synostosis (UCS) in order to form more complete hypotheses about the cause of craniosynostosis. Landmark coordinate data were collected from 3D magnetic resonance image reconstructions of the brain in a sample of UCS patients and an age-matched morphologically normal cohort. These data were analyzed using Euclidean distance matrix analysis. The results of our study demonstrate that despite the basic similarity of overall shape of the brain and skull in UCS, the effects of craniosynostosis on the brain are not localized to structures immediately adjacent to the fused suture or to the endocranial surface of the skull. Rather, alterations are observed throughout the volume of the brain, with subcortical structures altered in conjunction with cortical changes. These results indicate that the morphological correlates are different for brain and skull and suggest that there is a large degree of independence in the developmental trajectories of the brain and skull.
Anat Rec A Discov Mol Cell Evol Biol 2005 Aug
PMID:Brain morphology in nonsyndromic unicoronal craniosynostosis. 1597 20

Craniosynostosis (CS) is a relatively common birth defect resulting from the premature fusion of one or more cranial sutures. Human genetic studies have identified several genes in association with CS. One such gene that has been implicated in both syndromic (Saethre-Chotzen syndrome) and nonsyndromic forms of CS in humans is TWIST1. In this study, a heterozygous Twist1 knock out (Twist1(+/-) ) mouse model was used to study the craniofacial shape changes associated with the partial loss of function. A geometric morphometric approach was used to analyze landmark data derived from microcomputed tomography scans to compare craniofacial shape between 17 Twist1(+/-) mice and 26 of their Twist1(+/+) (wild type) littermate controls at 15 days of age. The results show that despite the purported wide variation in synostotic severity, Twist1(+/-) mice have a consistent pattern of craniofacial dysmorphology affecting all major regions of the skull. Similar to Saethre-Chotzen, the calvarium is acrocephalic and wide with an overall brachycephalic shape. Mutant mice also exhibited a shortened cranial base and a wider and shorted face, consistent with coronal CS associated phenotypes. The results suggest that these differences are at least partially the direct result of the Twist1 haploinsufficiency on the developing craniofacial skeleton. This study provides a quantitative phenotype complement to the developmental and molecular genetic research previously done on Twist1. These results can be used to generate further hypotheses about the effect of Twist1 and premature suture fusion on the entire craniofacial skeleton.
Anat Rec (Hoboken) 2014 May
PMID:Craniofacial shape variation in Twist1+/- mutant mice. 2458 49