{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T01:56:32Z","timestamp":1790042192610,"version":"4.0.1"},"reference-count":42,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2013,4,16]],"date-time":"2013-04-16T00:00:00Z","timestamp":1366070400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt C"],"published-print":{"date-parts":[[2013,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>The megalencephaly\u2010polymicrogyria\u2010polydactyly\u2010hydrocephalus (MPPH) and megalencephaly\u2010capillary 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 <jats:italic>PIK3R2<\/jats:italic> and <jats:italic>AKT3<\/jats:italic> in individuals with MPPH, and both postzygotic, mosaic and rare germline mutations in <jats:italic>PIK3CA<\/jats:italic> in individuals with MCAP. <jats:italic>PIK3R2<\/jats:italic>, <jats:italic>AKT3<\/jats:italic>, and <jats:italic>PIK3CA<\/jats:italic> are members of the critical phosphatidylinositol\u20103\u2010kinase (PI3K)\u2010vakt murine thymoma viral oncogene homolog (AKT) pathway that is well implicated in cell growth, proliferation, survival, apoptosis, among other diverse cellular functions. The identified mutations in these three genes have been shown to lead to gain of function and activation of the PI3K\u2010AKT pathway. Germline and postzygotic mutations of <jats:italic>PIK3CA<\/jats:italic> and other PI3K\u2010AKT\u2010mTOR 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. \u00a9 2013 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.c.31361","type":"journal-article","created":{"date-parts":[[2013,4,16]],"date-time":"2013-04-16T20:07:42Z","timestamp":1366142862000},"page":"122-130","source":"Crossref","is-referenced-by-count":151,"title":["Megalencephaly Syndromes and Activating Mutations in the PI3K\u2010AKT Pathway: MPPH and MCAP"],"prefix":"10.1002","volume":"163","author":[{"given":"GHAYDA 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