Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA.


The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.

DOI: 10.1038/ng.2332

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@article{Lindhurst2012MosaicOW, title={Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA.}, author={Marjorie J. Lindhurst and Victoria E R Parker and Felicity Payne and Julie Chevalier Sapp and Simon A . Rudge and Julie M. Harris and Alison M. Witkowski and Qifeng Zhang and Matthijs P Groeneveld and Carol E Scott and Allan Daly and Susan Mary Huson and Laura Lowe Tosi and Michael L. Cunningham and Thomas N Darling and Joseph S Geer and Zoran S. Gucev and Vernon Reid Sutton and Christos Tziotzios and A. Dixon and Timothy R Helliwell and Stephen O'Rahilly and David B. Savage and Michael J O Wakelam and In{\^e}s Barroso and Leslie G. Biesecker and Robert K Semple}, journal={Nature genetics}, year={2012}, volume={44 8}, pages={928-33} }