Variability, asymmetry and sexual dimorphism in craniofacial anomalies in Loeys-Dietz syndrome 2: geometric morphometric analysis in mice

Abstract Loeys-Dietz syndrome is a rare connective tissue disorder characterized by life-threatening aortic aneurysm and distinctive craniofacial anomalies. It is caused by mutations along the transforming growth factor beta (TGF-β) signaling pathway (LDS1-6). We previously showed that craniofacial anomalies varied among LDS subtypes and that LDS2, caused by mutations in the TGFBR2 gene, exhibited the most severe and variable phenotype. In this study, we performed a thorough qualitative and quantitative analysis of craniofacial anomalies in a mouse model for LDS2, through micro computed tomography and 3D geometric morphometric analysis at multiple postnatal stages. We show that craniofacial shape in Tgfbr2 G357W/ + mice strongly deviates from their WT littermates from an early age and exhibit high variability and evidence of left–right asymmetry despite the pure genetic background. Cranial doming, shortening of the anterior part of the skull, widening of the space between orbits, reduction of mandibular size, suture fusion in the cranial vault and palate, and abnormal condylar shape were among features that were consistent with the phenotype seen in patients with LDS. Interestingly, several of these features were more prevalent and severe in females than in males, indicating potential sexual dimorphism, further supported by the trend observed in our revisited clinical data.