Genetics versus environment in the pathophysiology of sagittal synostosis

Clinical Snapshot

Key Findings

• P Value: Not reported at review level

• Effect Size: No pooled effect sizes reported. Environmental risk factors identified include male sex, advanced maternal age, maternal smoking, thyroid dysfunction, fertility treatments, foetal constraint, prematurity, and abnormal birth weight — effect sizes described as variable across studies.

• Primary Outcome: Germline genetic variants potentially associated with craniosynostosis identified in 251 patients (12.6% of genetically tested sCS individuals), distributed across 125 genes with recurrent findings in 25 genes. Environmental/perinatal risk factors more consistently reported across large population-based and case-control studies.

• Nnt Or Sensitivity: Not applicable — no therapeutic intervention assessed. Genetic variant yield: 12.6% of genetically tested sCS patients carried potentially associated germline variants. No diagnostic sensitivity/specificity estimates provided for genetic testing.

• Confidence Interval: Not reported (no quantitative meta-analysis performed)

Clinical Application

The multifactorial model supports current clinical practice of individualised assessment rather than universal genetic testing. The 12.6% germline variant yield suggests selective genetic testing in patients with family history, dysmorphic features, or additional anomalies is clinically reasonable. Environmental risk factor data may inform preconception counselling regarding modifiable exposures (smoking cessation, thyroid optimisation, fertility treatment monitoring). In Australia, paediatric craniosynostosis is managed at specialist craniofacial units (e.g., Sydney Children's Hospitals Network, Royal Children's Hospital Melbourne, Women's and Children's Hospital Adelaide). Genetic testing for craniosynostosis-associated genes (FGFR1-3, TWIST1, EFNB1) is available through state-based clinical genetics services and Medicare-rebatable under specific clinical criteria. Whole-exome sequencing is increasingly accessible via the MBS (Item 73358 and related). The RACGP does not have specific craniosynostosis guidelines; management follows RACP/ANZCA paediatric surgical pathways. Maternal smoking cessation and thyroid screening during pregnancy align with existing RANZCOG antenatal care guidelines. The TGA has no specific regulatory implications from this review. PBS listing is not directly relevant as the review addresses aetiology rather than pharmacotherapy. Paediatric patients presenting with isolated or non-syndromic sagittal craniosynostosis, particularly those undergoing genetic counselling, surgical planning, or aetiological workup. Applicable to families seeking recurrence risk information.

Abstract

PURPOSE: This systematic review aims to provide an updated overview of the relative contribution of germline genetic and environmental factors to the pathophysiology of sagittal craniosynostosis (sCS). METHODS: Using the PubMed database in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, relevant studies addressing genetic and/or environmental determinants of sCS in paediatric patients were systematically reviewed. RESULTS: A total of 1238 records were identified, of which 97 studies met inclusion criteria after full-text review. Overall, 25,877 patients were included, with 11,086 diagnosed with sCS (42.8%). Germline genetic variants potentially associated with craniosynostosis were reported in 251 patients, accounting for 12.6% of genetically tested individuals with sCS. Identified variants were distributed across 125 genes, with recurrent findings in 25 genes. Environmental and perinatal factors were more consistently reported across large population-based and case-control studies. Frequently associated factors included male sex, advanced maternal age, maternal smoking, thyroid dysfunction, fertility treatments, foetal constraint, prematurity, and abnormal birth weight, although effect sizes varied across studies. CONCLUSION: Identifiable germline genetic causes appear to account for only a minority of sCS cases, whereas epidemiological evidence suggests that environmental and perinatal influences may also contribute to disease pathogenesis. Nevertheless, most cases lack identifiable germline mutations in key signalling pathways, and the available evidence does not support either genetic or environmental factors as individually deterministic drivers of disease development. Overall, the evidence synthesized in this review supports a multifactorial model for sCS, in which rare genetic susceptibility and non-genetic influences likely interact in the etiopathogenesis of the condition rather than reflecting a single dominant aetiology. However, heterogeneity across studies, differences in genetic testing methodologies, potential bias in exposure assessment, and the limited availability of integrative analyses restrict definitive conclusions regarding the relative contribution of these factors.

References

1. 1.De Gregorio, V., Tosi, D. D., Vita, A., Salvati, M., Massimi, L., Tamburrini, G., Tiberio, F., & Lattanzi, W. (2026). Genetics versus environment in the pathophysiology of sagittal synostosis. Child's Nervous System. Advance online publication. https://doi.org/10.1007/s00381-025-06789-x