Abstract
BACKGROUND: Craniosynostosis (CS), a heterogeneous craniofacial disorder caused by premature fusion of cranial sutures, is sub-classified anatomically by suture involvement (sagittal, metopic, coronal, lambdoid) and phenotypically into isolated/non-syndromic forms or syndromic (CS with extracranial anomalies). Pathogenic variants in multiple genetic loci have been implicated in CS, with particular significance attributed to allelic variants in IL11RA (interleukin-11 receptor alpha subunit; OMIM#600939). Clinical observations of individuals with IL11RA mutations indicate syndromic CS, characterized by dental anomalies and Crouzon-like facial features. METHODS: Genetic analyses were carried out utilizing whole-exome sequencing, with subsequent validation through direct Sanger sequencing. IL11RA biallelic pathogenic variants were detected and further analyzed by multiple in silico prediction tools, including 3D protein modeling. RESULTS: Our cohort comprises six pediatric patients presenting with CS linked to biallelic pathogenic mutations in IL11RA, including two previously unreported variants (p.Pro218Argfs*140, p.Trp132Ter). Three-dimensional protein structure modeling and molecular docking simulations demonstrated that four missense variants (p.Pro116Leu, p.Glu126Gly, p.Gly231Val, p.Leu236Pro) disrupt hydrogen bond networks critical for maintaining the IL-11 receptor alpha subunit's tertiary structure, significantly reducing ligand-binding affinity to both interleukin-11 (IL-11) and gp130. CONCLUSION: This study describes the clinical phenotype of six children with craniosynostosis and reveals novel variants in the IL11RA gene, thereby broadening the genotypic spectrum associated with this gene. Given the scarcity of patients reported in the literature, a detailed examination of the specific clinical and molecular characteristics will benefit our understanding of craniosynostosis caused by IL11RA variants.