Dysfunction in the PI3K pathway causes a spectrum of related megalencephaly syndromes.

A number of overgrowth syndromes affecting tissues of multiple lineages have been linked to specific mutations that can occur postzygotically and involve only diseased tissue. Investigators of two recent studies examined the overgrowth syndromes that affect the brain. Megalencephaly-capillary malformation (MCAP) is associated with skeletal overgrowth and vascular malformations that meet criteria for Klippel-Trenaunay syndrome; hemimegalencephaly (HME) is associated with hypomelanosis of Ito and Proteus syndrome.

Rivière and colleagues performed whole exome sequencing of germline and affected tissue DNA in families with MCAP or megalencephaly-polydactyly -polymicrogyria-hydrocephalus. They found that 74% of affected individuals had mutations, either in the germline or in affected somatic tissues that activate AKT3, PIK3R2, and PIK3CA. Lee and colleagues identified de novo mutations in affected somatic tissues in AKT3, PIK3CA, and mTOR in 30% of 20 patients with HME. These genes are all in the same pathway with a well-established role in the regulation of cell growth and survival; the identified mutations are known to lead to persistent proliferation.

CITATION(S):

Rivière J-B et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet 2012 Aug; 44:934.