EP07.04: Network medicine and biometric analysis facilitate the modern evolutionary theory of <i>in utero</i> phenotype/shape development in Chiari II malformation

To characterise the phenome of Chiari II malformation (CM II) in fetuses using a network medicine approach and identify variations of in utero evolutionary developmental shape patterns by biometric analysis. A single-centre retrospective review of fetal MRI scans obtained in fetuses with CM II (January 2004 to December 2022) was performed. Co-occurrence analysis was utilised to generate a phenotypic comorbidity matrix and visualised by Gephi software. Traditional univariate regression and geometric thin-plate spline methodology were used to further elucidate the mechanisms underlying the relationships between morphometric measurements and geometric landmarks of the spine, skull, and brain deformations. The CM II phenome comprises 35 nodes interconnected by 979 edges and exhibits a density of 0.828. Spinal bony defects, small posterior fossa dimensions, as well as vermis ectopia emerged as “hubs” and brain edema was identified as a noteworthy phenotype, associated with intracranial hemorrhage, epilepsy, worse motor level, and white matter volume loss. Traditional univariate regression revealed relationships between spinal defect size, posterior fossa dimension, and vermis ectopia. Geometric analysis-based principal component analysis (PCA) separated different morphometric patterns between cases with and without edema, and partial least-square analysis indicated that shape changes in the bone and brain are related. The CM II prenatal phenome is a multifaceted network centred around three key elements that demonstrate a strong interconnection. Biometric analysis revealed an in utero interrelated developmental patterns of spina bifida, skull, and brain geometric landmarks. Fetal brain edema emerged as a newly defined, apparently transient phenotype with prognostic relevance.