Loeys-Dietz and Shprintzen-Goldberg syndromes: analysis of TGF-β-opathies with craniofacial manifestations using an innovative multimodality method

Background Elevated transforming growth factor-beta (TGF-beta) signalling has been implicated in the pathogenesis of Loeys-Dietz syndrome (LDS) and Shprintzen-Goldberg syndrome (SGS). In this study, we provide a qualitative and quantitative analysis of the craniofacial and functional features among the LDS subtypes and SGS. Methods We explore the variability within and across a cohort of 44 patients through deep clinical phenotyping, three-dimensional (3D) facial photo surface analysis, cephalometric and geometric morphometric analyses of cone-beam CT scans. Results The most common craniofacial features detected in this cohort include mandibular retrognathism (84%), flat midface projection (84%), abnormal eye shape (73%), low-set ears (73%), abnormal nose (66%) and lip shape (64%), hypertelorism (41%) and a relatively high prevalence of nystagmus/strabismus (43%), temporomandibular joint disorders (38%) and obstructive sleep apnoea (23%). 3D cephalometric analysis demonstrated an increased cranial base angle with shortened anterior cranial base and underdevelopment of the maxilla and mandible, with evidence of a reduced pharyngeal airway in 55% of those analysed. Geometric morphometric analysis confirmed that the greatest craniofacial shape variation was among patients with LDS type 2, with distinct clustering of patients with SGS. Conclusions This comprehensive phenotypic approach identifies developmental abnormalities that segregate to mutation variants along the TGF-beta signalling pathway, with a particularly severe phenotype associated with TGFBR2 and SKI mutations. Multimodality assessment of craniofacial anomalies objectively reveals the impact of mutations of the TGF-beta pathway with perturbations associated with the cranium and cranial base with severe downstream effects on the orbit, maxilla and mandible with the resultant clinical phenotypes.

Automated summary

The study provides a comprehensive analysis of craniofacial and functional features among LDS subtypes and SGS, revealing developmental abnormalities associated with mutation variants along the TGF-beta signalling pathway. Results show that LDS type 2 patients exhibit the greatest craniofacial shape variation, while SGS patients cluster distinctly. The study highlights the impact of mutations on the TGF-beta pathway on craniofacial anomalies with severe downstream effects on cranial base structures and clinical phenotypes.