TGF-β-opathies: Craniofacial anomalies in two syndromes associated with TGF-β misregulation.

Objectives: Elevated transforming growth factor (TGF)-β signaling has been implicated in the pathogenesis of syndromic presentations of Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). Shprintzen-Goldberg syndrome (SGS), which has considerable phenotypic overlap with MFS and LDS, is also characterized by a defect in the (TGF)-β signaling path. We thoroughly describe in detail for the first time the craniofacial phenotype of a group of different types of LDS and SGS patients.
Methods: Extensive clinical craniofacial examination and CBCT scan qualitative and cephalometric analyses of n=40 LDS and n=4 SGS genetically diagnosed patients.
Results: The most characteristic findings were the presence of bitemporal narrowing, mandibular retrognathism, flat midface projection, anti-mongoloid slant, ptosis, abnormal lip morphology, skin translucency and low set ears, while the most distinguishing cephalometric findings were mandibular retrognathism, short midface length, short cranial base length and platybasia. Upon comparison of the severity of craniofacial anomalies, the patients with TGF Beta Receptor 2 mutations and the SGS patients were the most severe.
Conclusions: Based on the results of this study, both the facial structures as well as the cranial base were affected by misregulations in the TGF-β pathway. We do not currently have a clear knowledge of the TGF-β signaling mechanism and its functional impact on craniofacial development. Further research is required to understand the genetic and molecular variations resulting in the specific clinical phenotype. This detailed phenotypic description could become a valuable tool in the future research and differential clinical diagnosis of these conditions.