35. Comprehensive Clinical and Genetic Outcomes of Craniosynostosis: A 16-year Study

PURPOSE: Craniosynostosis is a multifaceted craniofacial disorder involving early fusion of cranial sutures, resulting in diverse clinical presentations and complications. While most cases are labeled as ‘non-syndromic,’ this classification is debated due to associated comorbidities and diagnostic challenges. This study aims to profile patients with craniosynostosis, assess comorbidity prevalence, and analyze genetic referral and testing patterns to provide a clearer understanding of this complex condition. METHODS: We conducted a retrospective review of 719 patients diagnosed with craniosynostosis over a 16-year period at our institution. Comprehensive data on patient history, family medical background, clinical features, and genetic evaluations were gathered. Craniosynostosis was classified into isolated, variable, or syndromic categories based on clinical examination, genetic test outcomes, and medical history. Data sources included genetic panels, annotated with ClinGen, gnomAD, GTEx, and linked with disease data from OMIM and Orphanet. Outcome measures included the type and frequency of interventions, surgical complications, and follow-up duration. Statistical analysis employed t-tests for continuous variables and χ² tests for categorical variables, with logistic regression used to identify predictors of genetic findings. RESULTS: Among the cohort, 81.25% were asymptomatic at initial presentation, with comorbidities present in 78.47% of cases, including 68.75% exhibiting additional congenital anomalies. Common symptoms included obstructive sleep apnea (OSA) in 10.42%, headaches in 5.9%, and emesis in 3.82%. Craniosynostosis subtypes were predominantly sagittal (55.9%), metopic (25.35%), multi-suture (19.4%), and lambdoid (11.11%). Of the patients, 80.7% were classified as non-syndromic, but genetic testing identified pathogenic variants in 52.7% of those tested (288 patients). The most frequently implicated genes were FGFR2, FGFR3, TWIST1, and TCF12. Notably, patients with pathogenic variants presented with more symptoms and comorbidities and had a higher maternal history of miscarriage, although surgical outcomes and complication rates were similar between groups. A total of 42 of the variants identified to likely be pathogenic were novel, expanding the known genetic landscape of craniosynostosis. CONCLUSION: The discovery of novel pathogenic variants underscores the necessity of genetic testing to improve diagnostic accuracy and guide early intervention. Furthermore, the genetic findings suggest a strong correlation between certain variants and increased clinical burden, advocating for routine genetic evaluation in craniosynostosis patients to optimize treatment strategies.