Outcomes Associated With Isolated Agenesis of the Corpus Callosum: A Meta-Analysis

Objectives: The aims of this systematic review were to ascertain perinatal and neurodevelopmental outcomes in fetuses with a prenatal diagnosis of isolated complete (cACC) and partial (pACC) agenesis of the corpus callosum. Methods: Medline, Embase, Cinhal and Cochrane databases were searched using combinations of the medical subject heading terms “agenesis of the corpus callosum” and “outcome”. Two authors reviewed all abstracts independently. Quality assessment of the included studies was performed using the Newcastle-Ottawa Scale for cohort studies. The outcomes were: chromosomal abnormalities detected at standard karyotype analysis, pathogenic copy number variants (CNVs) detected at chromosomal microarray (CMA) analysis, additional anomalies detected only at prenatal magnetic resonance imaging (MRI), additional anomalies detected only at post-natal imaging or clinical evaluation, but missed at prenatal imaging, concordance between pre- and post- natal diagnosis. Neurodevelopmental outcome was assessed in terms of: gross and fine motor control, cognitive status, epilepsy, visual control, sensory status, language, coordination and intelligence. Meta-analyses of proportions were used to combine data; between-study heterogeneity was explored using the I2 statistic, and fixed or random effects models used accordingly. Results: 2296 articles were initially identified, and 27 studies were included in the systematic review. In cACC, the rate of chromosomal anomalies detected at standard karyotype was 4.8% (95% Confidence Interval - CI: 2.2%-8.4%) while pathogenic CNVs were found in 5.7% (95% CI: 1.3%-13.1%) of the cases. Additional anomalies not detected at prenatal ultrasound were diagnosed at fetal MRI in 7.8% (95% CI: 1.2%-19.6%) of the cases while the rate of additional structural anomalies diagnosed only after birth and missed at prenatal evaluation was 5.5% (95% CI: 2.4%-9.7%). Gross and fine motor control was affected in 4.4% (95% CI: 0.6%-11.3%) and 11.0% (95% CI: 4.1%-20.6%) of the cases, while 6.8% (95% CI: 1.7%-14.9%) of these children presented with epilepsy. Cognitive status and intelligence were affected in 19.5% (95% CI 10.1%-31.1%) and 21.3% (11.5%-33.2%) of the cases, whereas language impairment in 8.0% (2.1%-17.3%). Finally, abnormal ocular control and coordination occurred in 15.8% (95% CI: 4.3%-32.9%) and 9.5% (95% CI: 3.2%-18.7%) of the cases. In pACC, the rate of chromosomal anomalies was 7.5% (95% CI: 2.0%-15.9%). Additional anomalies not detected at prenatal ultrasound were diagnosed at fetal MRI in 11.9% (95% CI: 3.2%-24.9%) of the cases while the rate of additional structural anomalies diagnosed only after birth and missed at prenatal evaluation was 14.5% (95% CI: 6.7%-24.6%). Neurodevelopmental outcome was reported to be normal in 71.4% (95% CI: 53.1%-86.7%) of children. Fine motor control was affected in 11.7% (0.9%-32.1%) of the cases, 16.1% (95% CI: 2.5%-38.2%) presented with epilepsy. Cognitive status and intelligence were affected in 17.3% (95% CI: 3.0%-39.7%) and 12.4% (95% CI: 1.1%-33.1%) of the cases, whereas language impairment was noticed in 17.3% (95% CI: 3.0%-39.7%) of the cases. Finally, abnormal coordination occurred in 11.7% (95% CI 0.9%-32.1%) of the cases. Conclusions: Fetuses with isolated callosal agenesis are at high risk of chromosomal anomalies even when a standard karyotype is negative. Prenatal imaging is not able to completely rule out associated anomalies usually co-existing with this condition and the risk of ACC of being not truly isolated after birth is significant. In isolated callosal agenesis, about two third of children showed a normal neurodevelopmental outcome, although anomalies in fine and gross motor control, coordination, language, cognitive status and intelligence can be impaired in a significant proportion of children. Future large prospective studies aiming at assessing the neurodevelopmental and psychological performance of children with isolated callosal agenesis are needed in order to ascertain the actual neuropsychological and intellectual impairment of children with isolated ACC.