S5A-07 SESSION 5A: GENERALITIES IN CRANIOSYNOSTOSIS – PART II SMAD6 GENOTYPE PREDICTS NEURODEVELOPMENT IN NON-SYNDROMIC CRANIOSYNOSTOSIS

Abstract

Introduction: De novo or rare transmitted mutations in the SMAD6 gene interact with common BMP2 variants to affect 7% of non-syndromic midline synostosis (NSC). In addition to cranial abnormalities and brain deformation, neurodevelopmental outcomes may be influenced by genetics. This study aimed to determine the cognitive sequelae of SMAD6 NSC in relation to non-SMAD6 NSC. Methods: Midline NSC patients ≥6 years of age, with SMAD6 mutations (identified in a national genetic study) and age/race/gender/synostosis type/operation matched non-SMAD6 NSC controls were recruited. All patients completed a double-blinded neurodevelopmental battery (Wechsler Fundamentals, Wechsler Abbreviated Scale of Intelligence, Beery-Buktenica Developmental Test) and parents/guardians completed behavioral surveys (Behavior Rating Inventory of Executive Function and Behavior Rating System for Children). Twenty demographic/patient factors, known to influence cognition, were collected. Results: Twenty subjects participated including all ten known SMAD6 patients nationwide (mean age at testing 10.1 years; 1 female; 8 metopic, 2 sagittal; 9 treated with cranial vault remodeling [CVR], 1 strip) and ten matched controls (mean age 9.8 years; 1 female; 8 metopic, 2 sagittal; 9 CVR, 1 strip). There was no significant difference between all 20 demographics. In head to head comparison, SMAD6 cases scored significantly worse on numerical operations (p=0.012), performance IQ (PIQ; p=0.004), full IQ (FIQ, p=0.007), and motor coordination (p=0.007). Individual correlations revealed age at testing, age at surgery, parental education, and household income significantly correlated with cognition. Multiple regressions were performed to control for these 4 variables. SMAD6 patients still performed worse on numerical operations(p=0.046), PIQ(p=0.018), FIQ(p=0.010), motor coordination(p=0.043). On behavioral surveys, SMAD6 scored worse on inhibition(p=0.003), behavior regulation(p=0.032), hyperactivity(p=0.007), aggression(p=0.008), conduct(p=0.029), social skills (p=0.039), and communication(p=0.018). Post-hoc power analysis yielded power between 84.4%>92.4%. Conclusion: This prospective double blind comparison revealed that genetic influences of NSC may play a role in functional neuropsychiatric development. Midline synostosis with SMAD6 mutations led to poorer non-adjusted and adjusted performance on mathematics, performance IQ, full IQ and motor coordination compared to non-SMAD6 NSC. SMAD6 patients had additional behavioral deficits in inhibition, hyperactivity, aggression, conduct, social skills, and communication. Moving forward, genetic testing may serve as a critical advocate for early adjunctive neuropsychiatric therapy in patients with NSC.