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 (PIP3) 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.

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The authors thank L. Ivey, J.J. Johnston, V. Tasic, M. Walters and E. Choolun for support and advice. The authors are especially grateful to the subjects who participated in this research study and to the Proteus Syndrome Foundations of the United States and United Kingdom, who have supported and encouraged these individuals and our research efforts. V.E.R.P., S.O., D.B.S., I.B. and R.K.S. were supported by the Wellcome Trust (grants 097721/Z/11/Z, 80952/Z/06/Z, 078986/Z/06/Z, 098051/Z/05/Z and 091551/Z/10/Z), the UK Medical Research Council Centre for Obesity and Related Disorders and the UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. L.G.B., M.J.L., J.C.S. and A.M.W. were supported by the Intramural Research Program of the National Human Genome Research Institute. S.R., Q.Z. and M.J.O.W. were supported by the Biotechnology and Biological Sciences Research Council (BBSRC). We are grateful for access to exome sequence data from the CoLaus cohort, which was sequenced as part of a partnership between the Wellcome Trust Sanger Institute, the CoLaus principal investigators and the Quantitative Sciences department of GlaxoSmithKline. S.M.H. is supported by the Manchester NIHR Biomedical Research Centre.

Author information

Author notes

    • Marjorie J Lindhurst
    •  & Victoria E R Parker

    These authors contributed equally to this work.


  1. The National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Marjorie J Lindhurst
    • , Julie C Sapp
    • , Alison M Witkowski
    •  & Leslie G Biesecker
  2. The University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge, UK.

    • Victoria E R Parker
    • , Julie Harris
    • , Matthijs P Groeneveld
    • , Stephen O'Rahilly
    • , David B Savage
    • , Inês Barroso
    •  & Robert K Semple
  3. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.

    • Felicity Payne
    • , Carol E Scott
    • , Allan Daly
    •  & Inês Barroso
  4. The Babraham Institute, Babraham Research Campus, Cambridge, UK.

    • Simon Rudge
    • , Qifeng Zhang
    •  & Michael J O Wakelam
  5. Genetics Unit, Manchester Academic Health Science Centre, Manchester, UK.

    • Susan M Huson
  6. Division of Orthopaedics, Children's National Medical Center, Washington, DC, USA.

    • Laura L Tosi
  7. Division of Craniofacial Medicine, University of Washington School of Medicine, Seattle, Washington, USA.

    • Michael L Cunningham
  8. Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.

    • Thomas N Darling
  9. Greenwood Genetics Center, Greenwood, South Carolina, USA.

    • Joseph Geer
  10. Department of Endocrinology and Genetics, Skopje Medical Faculty, Skopje, Macedonia.

    • Zoran Gucev
  11. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

    • V Reid Sutton
  12. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

    • Christos Tziotzios
  13. School of Clinical Medicine, University of Cambridge, Cambridge, UK.

    • Adrian K Dixon
  14. Liverpool Cancer Research UK Centre, University of Liverpool, Liverpool, UK.

    • Timothy Helliwell
  15. The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.

    • Stephen O'Rahilly
    • , David B Savage
    •  & Robert K Semple


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M.J.L., V.E.R.P., I.B., L.G.B. and R.K.S. designed the study and drafted the manuscript. M.J.L. and V.E.R.P. performed the research and analyzed the data. F.P., C.E.S., A.D. and I.B. performed analysis of whole-exome sequencing data and wrote the corresponding methods in the manuscript. J.C.S. provided clinical data and wrote the corresponding clinical descriptions. A.M.W. performed mutation assays and assisted with immunoblotting experiments. S.M.H., L.L.T., M.L.C., T.N.D., J.G., Z.G., V.R.S. and C.T. provided clinical data and/or fibroblast samples from affected individuals. S.R., Q.Z. and M.J.O.W. performed PIP3 quantification and data analysis. J.H. assisted with the collection of clinical data. M.P.G. assisted with immunoblotting experiments. T.H. performed histological analysis. A.K.D. interpreted imaging. S.O. and D.B.S. contributed to study design and reviewed the manuscript. L.G.B. and R.K.S. supervised the overall study.

Competing interests

I.B. and her spouse own stock in GlaxoSmithKline and the Incyte Corporation.

Corresponding authors

Correspondence to Inês Barroso or Leslie G Biesecker or Robert K Semple.

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