Child Neurology: Multiple Genetic Etiologies Causing Dandy-Walker Variant With Microcephaly, Epilepsy, and Global...

Dandy-Walker syndrome is typically characterized by near-complete cerebellar vermis agenesis, enlarged posterior fossa, and dilated fourth ventricle. By contrast, Dandy-Walker variant (DWv) shows milder features, typically characterized by partial agenesis of the cerebellar vermis, mild enlargement of the posterior fossa, and variable dilation of the fourth ventricle. Both conditions are usually associated with normal or enlarged head circumference. We report a 16-month-old girl presenting with congenital microcephaly, frequent seizures, and severe global developmental delay. Brain MRI revealed findings consistent with DWv, which did not explain the severity of her clinical symptoms or her microcephaly. Chromosomal microarray analysis revealed multiple regions of homozygosity on chromosome 11, indicating potential recessive inheritance; karyotype analysis and mitochondrial testing showed no clear etiology. Trio-based whole-exome sequencing identified a heterozygous variant (NM_021096.4:c.4891T>A/p.Phe1631Ile) in CACNA1I and a homozygous variant (NM_002335.4:c.1310C>T/p.Thr437Met) in LRP5. Variants in CACNA1I are associated with neurodevelopmental disorders, including epilepsy and developmental delay, while variants in LRP5 are linked to osteoporosis and microcephaly. Based on the clinical presentation and molecular findings, we hypothesize that both variants contributed to the patient's complex phenotype. This case highlights that in patients with unusually severe or atypical manifestations, the possibility of multiple genetic pathogenic contributions should be considered, and comprehensive genomic evaluation is essential for accurate diagnosis and management.