Phenotypic Signatures of CTNNB1 Syndrome: Longitudinal Neuropsychological Outcomes and Three-Dimensional Facial Morphology

Abstract CTNNB1 syndrome is a rare neurodevelopmental disorder caused by pathogenic variants in the CTNNB1 gene. Although its core clinical manifestations have been increasingly recognised, longitudinal data on cognitive, behavioural and motor trajectories remain limited, and the craniofacial phenotype has not previously been quantitatively characterised. This study provides longitudinal evidence on the cognitive, clinical and psychological profile of individuals with CTNNB1 syndrome, together with a detailed three-dimensional morphometric analysis of facial morphology. Cognitive, clinical, psychological and neuropsychological data were collected at two time points (T0 and T1), separated by a one-year interval, using a comprehensive and standardised assessment protocol. Longitudinal analyses indicated stability across most domains, with no evidence of systematic regression. A significant improvement in gross motor functioning was observed, particularly among younger participants. Linear mixed-effects models showed that age moderated developmental change, with younger individuals exhibiting greater gains over time in gross motor skills and adaptive behaviour compared to older participants. Three-dimensional facial morphometric analyses revealed a distinctive and statistically significant craniofacial pattern associated with CTNNB1 syndrome, independent of age and facial size. This phenotype was characterised by midfacial narrowing, reduced midface projection and mandibular retrusion. Importantly, facial shape variation was significantly associated with externalising behavioural problems and clinically relevant behavioural difficulties, suggesting a link between craniofacial morphology and behavioural severity. This study represents the first integrated longitudinal characterisation of CTNNB1 syndrome combining neurodevelopmental follow-up with quantitative craniofacial phenotyping. The findings indicate slow but progressive improvement in specific clinical domains during childhood and adolescence, alongside relative stability in global adaptive functioning, and highlight three-dimensional facial morphology as a sensitive structural biomarker for phenotypic stratification and clinical monitoring in CTNNB1 syndrome. Lay summary This study is the first to describe how children with CTNNB1 syndrome, a rare genetic condition that leads to global developmental delays, develop over time. We also performed advanced facial analysis to look for common facial features among patients.