Three‐dimensional morphometric analysis of brain shape in nonsyndromic orofacial clefting

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Abstract
Previous studies report structural brain differences in individuals with nonsyndromic orofacial clefts (NSOFC) compared with healthy controls. These changes involve non‐uniform shifts in tissue volume within the cerebral cortex and cerebellum, suggesting that the shape of the brain may be altered in cleft‐affected individuals. To test this hypothesis, a landmark‐based morphometric approach was utilized to quantify and compare brain shape in a sample of 31 adult males with cleft lip with or without cleft palate (CL/P), 14 adult males with cleft palate only (CPO) and 41 matched healthy controls. Fifteen midline and surface landmarks were collected from MRI brain scans and the resulting 3D coordinates were subjected to statistical shape analysis. First, a geometric morphometric analysis was performed in three steps: Procrustes superimposition of raw landmark coordinates, omnibus testing for group difference in shape, followed by canonical variates analysis (CVA) of shape coordinates. Secondly, Euclidean distance matrix analysis (EDMA) was carried out on scaled inter‐landmark distances to identify localized shape differences throughout the brain. The geometric morphometric analysis revealed significant differences in brain shape among all three groups (P < 0.001). From CVA, the major brain shape changes associated with clefting included selective enlargement of the anterior cerebrum coupled with a relative reduction in posterior and/or inferior cerebral portions, changes in the medio‐lateral position of the cerebral poles, posterior displacement of the corpus callosum, and reorientation of the cerebellum. EDMA revealed largely similar brain shape changes. Thus, compared with controls, major brain shape differences were present in adult males with CL/P and CPO. These results both confirm and expand previous findings from traditional volumetric studies of the brain in clefting and provide further evidence that the neuroanatomical phenotype in individuals with NSOFC is a primary manifestation of the defect and not a secondarily acquired characteristic.