External hydrocephalus (EH) is associated with subsequent neurodevelopmental delays, potentially resulting from the excessive cerebrospinal fluid-disrupted cortical development. This study aims to investigate early alterations in the morphometric similarity network (MSN) and corresponding regional transcriptional expression patterns in relation to subsequent motor and speech delays in EH infants. This retrospective study recruited 127 EH infants, identified through routine MRI within 1 year after birth, whose neurodevelopmental outcomes were assessed at 1 to 4 years of age. Early alterations in morphometric similarity (MS) were identified using multiple linear regression. MS alterations-related genes were examined by partial least squares regression. We found that MS significantly increased in the left inferior parietal region and decreased in the right banks of the superior temporal sulcus in EH infants with subsequent motor delay. MS alterations-related genes were enriched in immune pathways. These genes were primarily involved in microglial cells. Notably, these genes showed a significant overlap with those associated with autism spectrum disorder (ASD) and schizophrenia (all p FDR <0.05). Early MS alterations in EH infants may serve as predictors of subsequent motor and speech delays, and are associated with genes enriched in immune pathways, overlapping with those implicated in ASD and schizophrenia. • Although external hydrocephalus (EH) is often regarded as a benign finding in infancy, accumulating evidence suggests its association with later neurodevelopmental delays. Our study is among the first to characterize the whole-brain morphometric and transcriptional alterations in EH infants in relation to subsequent motor and speech delays, offering insights that are both clinically meaningful and mechanistically informative. • We identified specific morphometric changes—namely, increased morphometric similarity in the left inferior parietal cortex and decreased similarity in the right banks of the superior temporal sulcus—that were significantly associated with subsequent motor delays. • We found that these MSN alterations corresponded to transcriptional signatures enriched in immune-related pathways and synaptic pruning processes. • Genes associated with these alterations were predominantly expressed in microglial cells, with additional enrichment of astrocyte-related genes observed in the speech delay group. • Notably, these gene sets showed significant overlap and correlations with those implicated in autism spectrum disorder and schizophrenia, suggesting broader relevance to neurodevelopmental disorders.
Sun et al. (Sun,) studied this question.