Neurodevelopmental, Cognitive, and Psychosocial Outcomes for Individuals With Pathogenic Variants in the TCF12 Gene and Associated Craniosynostosis

Abstract Heterozygous mutations in the TCF12 gene were discovered in 2013 as a cause of craniosynostosis (CS). However, limited information regarding the behavioral phenotypic profile is available. Here the authors provide the first detailed study of the neurodevelopmental, cognitive, and psychosocial outcomes for patients with a pathogenic TCF12 variant and associated CS. A clinical casenote audit was conducted at the 4 UK highly specialized craniofacial centers. A total of 35 patients aged 18 months to 10 years with an identified TCF12 pathogenic variant and CS (bicoronal CS = 45.7%, unicoronal CS = 40.0%, multisuture = 14.3%) were included. Standardized screening and/or assessment of full-scale intelligence quotient, social communication, development, behavior, and self-concept were conducted. In the majority of cases, outcomes were consistent with age-related expectations. About 75% of patients demonstrated no delay across any early developmental domain, while 84.6% demonstrated full-scale intelligence quotient scores within 1 standard deviation of the population mean. Significant behavioral difficulties were demonstrated by parent reporters in 26.3% to 42.1% of cases (dependent upon domain). Clinically elevated social communication profiles were present in (41.7%) of parent-reported cases. Levels of self-concept (at age 10) were consistent with age-related normative data. Most patients with a TCF12 pathogenic variant had a mild behavioral and cognitive phenotype, although they may be at a slightly increased risk of social communication difficulties and psychosocial issues. Although not measured statistically, there were no clear associations between surgical history and cognitive, behavioral, or psychosocial outcomes. This paper highlights the need for robust integrated developmental assessment of all CS patients, particularly those with an identified syndrome.