Impact of SMAD6 Variants on Neurodevelopment in Craniosynostosis

Some pathogenic variants in Smad6 are implicated in midline craniosynostosis, particularly in metopic synostosis. These variants increase the risk of both nonsyndromic and syndromic presentations. Craniosynostosis, whether treated surgically or not, can be associated with developmental delays.

The authors aimed to assess developmental outcomes in children with craniosynostosis carrying a Smad6 variant. A cohort of children who underwent craniosynostosis surgery at the national reference center for craniosynostosis at Lyon University Hospital (2018-2023) was studied. Children with Smad6 variants were followed postsurgery to evaluate their neuropsychological development. Evaluations were conducted by a multidisciplinary team comprising neurosurgeons, clinical geneticists, and neuropsychologists.

Among 249 patients with craniosynostosis, 11 were identified with Smad6 variants. Of these, 7 presented with trigonocephaly, 2 with scaphocephaly, and 2 with oxycephaly. Patients with SMAD6 gene variants followed by the department were between 18 and 121 months, with a sex ratio of 6 girls to 5 boys. None of these children exhibited cardiac abnormalities. Mild walking and/or language acquisition delays are observed in 8 children, 5 of them benefit from ambulatory-specific care, and only one cannot benefit from a normal schooling.

Neuropsychological follow-up is crucial for children with craniosynostosis. Most patients with SMAD6 variants show mild to moderate effects, with developmental scores normalizing with appropriate therapies. However, the impact of Smad6, especially in cases with additional variants, requires further study. Early intervention remains key to optimizing cognitive and behavioral outcomes.