Characterisation of Challenging Behaviours and Associated Genetic and Neurological Features in Cardiofaciocutaneous Syndrome.

Abstract

Background: Challenging behaviours such as self-injury and aggression are prevalent among individuals with intellectual disability (ID), significantly impacting quality of life. Cardiofaciocutaneous syndrome (CFCS), a rare multisystem genetic disorder caused by variants in the BRAF, MAP2K1, MAP2K2, or KRAS genes, commonly presents with ID and other neurobehavioural features. To inform effective clinical management, we aimed to characterise and quantify challenging and repetitive behaviours in CFCS, identify functions that may maintain the behaviours, and examine associations with genotype and neurological comorbidities.

Methods: In this cross-sectional cohort study, caregivers of 61 individuals with CFCS (mean age = 14.2 years; 61% female) completed an electronic survey to capture information regarding demographics, adaptive skills, and neurological history. Genotype was determined from molecular genetic testing results. The frequency, severity, topography, and function of challenging behaviours were assessed with behaviour questionnaires validated for children and adults with developmental disabilities. We evaluated trends using descriptive analyses and examined mean differences across age, genotype, and neurological variables.

Results: The cohort consisted primarily of individuals with BRAF variants (62%), followed by MAP2K1 (28%) and MAP2K2 (10%) variants. Prevalence of challenging behaviour was high (77%), and self-injurious and aggressive behaviours were most frequent and severe among adolescents with CFCS relative to younger children or adults. Escape (seeking to avoid an unwanted situation or task) was the most endorsed behavioural function to maintain self-injurious and aggressive/destructive behaviours. BRAF gene variants were associated with the most frequent and variable challenging behaviours, followed by MAP2K1, and then MAP2K2. Challenging and repetitive behaviours were most prevalent among individuals with moderate adaptive functioning, clinically significant sleep disturbance, higher levels of pain interference, and more substantial sensory modulation differences. Individuals with epilepsy also exhibited more frequent repetitive and self-injurious behaviours.

Conclusion: Caregivers reported a high prevalence of challenging behaviours among individuals with CFCS, especially in late childhood and adolescence. Therapeutic approaches to address challenging behaviours are needed to optimally support individuals with CFCS and their caregivers.