Objective Evaluate speech, hearing, and neuropsychological correlates to reading among children, adolescents and young adults with non-syndromic cleft of the lip and/or palate (NSCL/P). Method All testing was completed in one visit at a Midwestern university hospital. Subjects in both the NSCL/P (n = 80) and control group (n = 62) ranged in age from 7 to 26 years (average age = 17.60 and 17.66, respectively). Subjects completed a battery of standardized tests evaluating intelligence, neuropsychological skills, and word reading. Subjects with NSCL/P also underwent speech assessment and past audiology records were evaluated. Results After controlling for age and SES, subjects with cleft performed significantly worse on a test of word reading. For subjects with cleft, word reading deficits were not associated with measures of speech or hearing, but were correlated with impairments in auditory memory. Conclusions These findings show poorer reading among subjects with NCL/P compared to those without. Further work needs to focus on correlates of reading among subjects with cleft to allow early identification and appropriate intervention/accommodation for those at risk.

Background Late preterm birth (34-36 weeks’ gestation) is a common occurrence with potential for altered brain development. Methods This observational cohort study compared children at age 6-13 years based on the presence or absence of the historical risk factor of late preterm birth. Children completed a battery of cognitive assessments and underwent magnetic resonance imaging of the brain. Results Late preterm children (n=52) demonstrated slower processing speed (p=0.035) and scored more poorly in visual-spatial perception (p=0.032) and memory (p=0.007) than full term children (n=74). Parents of late preterm children reported more behavioral difficulty (p=0.004). There were no group differences in cognitive ability or academic achievement. Imaging revealed similar intracranial volumes but less total tissue and more cerebrospinal fluid (p=0.004) for late preterm children compared to full term children. The tissue difference was driven by differences in the cerebrum (p=0.028) and distributed across cortical (p=0.051) and subcortical tissue (p=0.047). Late preterm children had a relatively smaller thalamus (p=0.012) than full term children. Only full term children demonstrated significant decreases in cortical tissue volume (p<0.001) and thickness (p<0.001) with age. Conclusion Late preterm birth may affect cognition, behavior, and brain structure well beyond infancy.

Isolated cleft lip and/or palate (ICLP) is one of the most common congenital birth defects in the USA, affecting roughly 1 in 600 births annually. Along with the facial deformity, this population has been found to have abnormal neurodevelopment and gross structural abnormalities in the brain, particularly within the cerebellum. The current study examined cerebellar structure within the two primary subtypes of ICLP: cleft lip with/without cleft palate (CL/P) and cleft palate alone (CPO). A large sample of 107 subjects aged 7 to 27 years with ICLP was compared to 127 healthy controls. Samples were separated by sex. Brain structure was obtained via magnetic resonance imaging. For males, after controlling for intracranial volume, cerebellum volume was significantly lower in the ICLP group (F= 12.351, p=0.001). Regionally in the cerebellum, males with ICLP had proportionally larger anterior lobes (F=4.022, p= 0.047) and smaller superior posterior lobes (F=5.686, p= 0.019). CL/P males showed only a reduction in overall cerebellum volume, with no regional changes. CPO males showed only regional changes, with no reduction in overall volume. Females with ICLP showed no overall or regional cerebellar abnormalities. However, females with CPO did have significantly lower cerebellum volumes than controls. The results reveal both global and regional cerebellar abnormalities within subjects with ICLP. They also establish the existence of abnormal cerebellar morphologies that are dependent on cleft subtype as well as sex. This lends further support to the claim that CL/P and CPO are distinct conditions.

Orofacial clefts are among the commonest birth defects. Among many genetic contributors to orofacial clefting, Interferon Regulatory Factor 6 (IRF6) is unique since mutations in this gene cause Van der Woude (VWS), the most common clefting syndrome. Furthermore, variants in IRF6 contribute to increased risk for non-syndromic cleft lip and/or palate (NSCL/P). Our previous work shows that individuals with either VWS or NSCL/P may have cerebral anomalies (larger anterior, smaller posterior regions), and a smaller cerebellum. The objective of this study was to test the hypothesis that disrupting Irf6 in the mouse will result in quantitative brain changes similar to those reported for humans with VWS and NSCL/P. Male mice heterozygous for Irf6 (Irf6gt1/+; n = 9) and wild type (Irf6+/+; n = 6) mice at comparable age underwent a 4.7T MRI scan to obtain quantitative measures of cortical and subcortical brain structures. There was no difference in total brain volume between groups. However, the frontal cortex was enlarged in the Irf6gt1/+ mice compared to that of wild types (p = 0.028) while the posterior cortex did not differ. In addition, the volume of the cerebellum of Irf6gt1/+ mice was decreased (p = 0.004). Mice that were heterozygous for Irf6 showed a similar pattern of brain anomalies previously reported in humans with VWS and NSCL/P. These structural differences were present in the absence of overt oral clefts. These results support a role for IRF6 in brain morphometry and provide evidence for a potential genetic link to abnormal brain development in orofacial clefting.