megalencephalypolymicrogyriapolydactylyhydrocephalus

Megalencephaly is a neurological condition defined by an abnormally large brain, typically reflected by a head circumference well above age norms. It denotes brain enlargement rather than simply an enlarged skull and can be present at birth or develop in infancy. In many cases, megalencephaly occurs as part of broader syndromes that include cortical malformations and vascular or limb anomalies.

Most reported cases arise from mosaic activating mutations that disrupt the PI3K–AKT–mTOR signaling pathway. Genes such as PIK3CA, PIK3R2, AKT3, and CCND2 have been implicated in various megalencephaly-related syndromes. The genetic changes promote increased cellular growth and abnormal brain development, leading to features such as megalencephaly with polymicrogyria, hydrocephalus, capillary malformations, and, in some syndromes, limb malformations like polysyndactyly.

Clinical features are heterogeneous. Key signs include a markedly large head circumference and potential developmental delay or intellectual disability. Seizures, hypotonia in infancy, and movement disorders can occur. Many patients exhibit skin findings such as capillary malformations, and some may have vascular or limb anomalies depending on the specific syndrome. Brain imaging often shows megalencephaly with cortical malformations (e.g., polymicrogyria), ventriculomegaly, or hydrocephalus.

Diagnosis relies on clinical examination, measurements of head size, and MRI findings, with genetic testing supporting a mosaic PI3K–AKT–mTOR pathway involvement. Because mosaic mutations may be present at low levels, testing may require samples from affected tissue or deep sequencing.

Management is multidisciplinary, focusing on seizure control, monitoring and treating hydrocephalus or vascular issues, and providing developmental and educational support. Prognosis varies widely, reflecting the degree of brain involvement and the mosaic nature of the condition.