Somatic activating PIK3CA mutations have been identified in peripheral nerve from patients with lipomatosis of nerve with type I macrodactyly, which is now classified as a PIK3CA-related overgrowth spectrum disorder.
A mosaic gain-of-function mutation in the catalytic domain of PIK3CA (c.3140 A > G; p.His1047Arg) was detected in the adipose tissue and in skin cultured fibroblasts from the macrodactyly but not in blood.
Affected tissue from individuals with facial infiltrating lipomatosis contains PIK3CA mutations that have previously been reported in cancers and in affected tissue from other nonheritable, overgrowth disorders, including congenital lipomatous overgrowth, vascular, epidermal, and skeletal anomalies syndrome, Klippel-Trenaunay syndrome, hemimegalencephaly, fibroadipose overgrowth, and macrodactyly.
Thus, isolated congenital macrodactyly is caused by somatic activation of the PI3K/AKT cell-signaling pathway and is genetically and biochemically related to other overgrowth syndromes.
Characterization of a distinct syndrome that associates complex truncal overgrowth, vascular, and acral anomalies: a descriptive study of 18 cases of CLOVES syndrome.