Irritability in Children with Rasopathies, Insights into Emotional Dysregulation and Social Skills Impairments

Rasopathies, including Noonan Syndrome (NS) and Neurofibromatosis type 1 (NF1), are developmental disorders caused by germline mutations in genes of the RAS/mitogen-activated protein kinase pathway (RAS-MAPK). This study investigates irritability, a highly prevalent transdiagnostic construct, in children with Rasopathies and the impact of Rasopathy status on the associations between irritability, emotional dysregulation-related disorders, and social skills impairments. The sample comprise 174 children aged 4-17 (age mean = 9.49; 98 females), including 113 children with Rasopathies (NS n = 85, NF1 n = 28) and 61 age-sex-matched typically developed (TD) children. We used parent questionnaires (CBCL, SRS) to assess irritability, symptoms of ADHD, defiance, anxiety/depression, and social skills impairments while controlling for cognitive measures (IQ). Children with Rasopathies exhibited higher irritability than TD children (mean difference = 1.09; p < 0.001). Children with NS showed a weaker association between irritability and ADHD symptoms compared to TD children (p = .032, η_p ² = .03) and a stronger association between irritability and social skills impairments compared to both TD (p = .033, η_p ² = .03), and NF1 groups (p = .009, η_p ² = .06). We present novel and clinically significant findings showing high irritability in children with Rasopathies. Our study provides syndrome-specific results, suggesting differences in the mechanisms involved in irritability, ADHD, and social processes in children with NS and NF1. In essence, children with Rasopathies showed a highly irritable profile associated with ADHD symptoms and social skills impairments, with a significantly stronger association between irritability and social processes in NS. Our results suggest that developing prevention and treatments targeting irritability can distinctly affect the trajectories of neurodevelopmental disorders in children with Rasopathies.