megalencephaly

Megalencephaly is a neurological condition defined by an abnormally large brain, typically resulting in a head circumference above the normal range for age and sex. It is defined by brain size rather than skull size and may be isolated or occur as part of broader overgrowth syndromes.

Most cases are linked to genetic disorders that increase brain growth, often via the PI3K-AKT-mTOR signaling pathway. The best described is the megalencephaly-capillary malformation (MCAP) syndrome, in which megalencephaly occurs with capillary malformations and a spectrum of brain malformations including ventriculomegaly and cortical malformations such as polymicrogyria. Other genetic etiologies include PTEN-related overgrowth syndromes and related megalencephalic disorders.

Diagnosis relies on clinical assessment and imaging. A markedly enlarged brain on MRI or CT supports the diagnosis of megalencephaly. Neuroimaging may reveal cortical malformations, ventriculomegaly, and other brain anomalies; genetic testing by sequencing panels or exome sequencing can identify pathogenic variants in genes such as PIK3CA, AKT3, CCND2, and other components of growth signaling pathways.

Management is individualized and multidisciplinary. Treatments address complications such as hydrocephalus, seizures, and developmental delay. Surveillance for associated vascular malformations and other organ anomalies may be indicated in specific syndromes. Early intervention and educational support improve outcomes, but prognosis depends on the underlying genetic condition and the extent of brain malformations.

Epidemiology is characterized by rarity and heterogeneity. Megalencephaly can be present at birth or develop in infancy, and outcomes range from normal development to significant impairment.