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RESEARCH PRODUCT

Megalencephaly Syndromes and Activating Mutations in the PI3K-AKT Pathway: MPPH and MCAP

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The megalencephaly‐polymicrogyria‐polydactyly‐hydrocephalus (MPPH) and megalencephaly‐capillary malformation (MCAP) syndromes are highly recognizable and partly overlapping disorders of brain overgrowth (megalencephaly). Both syndromes are characterized by congenital or early postnatal megalencephaly, with a high risk for progressive ventriculomegaly leading to hydrocephalus and cerebellar tonsillar ectopia leading to Chiari malformation, and cortical brain abnormalities, specifically polymicrogyria. MCAP is further characterized by distinct cutaneous capillary malformations, finger or toe syndactyly, postaxial polydactyly, variable connective tissue dysplasia and mild focal or segmental body overgrowth, among other features. MPPH, on the other hand, lacks consistent vascular or somatic manifestations besides postaxial polydactyly in almost half of reported individuals. We identified de novo germline mutations in PIK3R2 and AKT3 in individuals with MPPH, and both postzygotic, mosaic and rare germline mutations inPIK3CAin individuals with MCAP.PIK3R2,AKT3, andPIK3CA are members of the critical phosphatidylinositol‐3‐kinase (PI3K)‐vakt murine thymoma viral oncogene homolog (AKT)pathwaythatiswellimplicatedincellgrowth,proliferation,survival,apoptosis,amongotherdiversecellular functions. The identified mutations in these three genes have been shown to lead to gain of function and activation of the PI3K‐AKT pathway. Germline and postzygotic mutations of PIK3CA and other PI3K‐AKT‐mTOR pathway genes have also been identified in several other overgrowth syndromes, highlighting the key role of this signaling pathway in normal development and pathophysiology of a large group of congenital anomalies. © 2013 Wiley Periodicals, Inc.