RESEARCH ARTICLE Clinical Delineation and Natural History of the PIK3CA-Related Overgrowth SpectrumÃÃ Kim M. Keppler-Noreuil,1* Julie C. Sapp,1 Marjorie J. Lindhurst,1 Victoria E.R. Parker,2 Cathy Blumhorst,1 Thomas Darling,3 Laura L. Tosi,4 Susan M. Huson,5 Richard W. Whitehouse,6 Eveliina Jakkula,7 Ian Grant,8 Meena Balasubramanian,9 Kate E. Chandler,5 Jamie L. Fraser,1 Zoran Gucev,10 Yanick J. Crow,5 Leslie Manace Brennan,11 Robin Clark,12 Elizabeth A. Sellars,13 Loren DM Pena,14 Vidya Krishnamurty,15 Andrew Shuen,16 Nancy Braverman,17 Michael L. Cunningham,18 V. Reid Sutton,19 Velibor Tasic,20 John M. Graham Jr.,21 Joseph Geer Jr.,22 Alex Henderson,23 Robert K. Semple,2 and Leslie G. Biesecker1 1National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 2The University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge, UK 3Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 4Division of Orthopaedic Surgery and Sports Medicine, Children’s National Medical Center, Washington, District of Columbia 5Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK 6Department of Radiology, Central Manchester University Hospitals NHS Foundation Trust Manchester Royal Infirmary Oxford Road Manchester, Manchester, UK 7Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland 8Department of Plastic Surgery, Cambridge University Hospitals NHS Trust, Cambridge, UK 9Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK 10Department of Endocrinology and Genetics, Medical Faculty Skopje, Skopje, Macedonia 11Medical Genetics, Kaiser Permanente Oakland, University of California, San Francisco, California 12Division of Medical Genetics, Department of Pediatrics, Loma Linda University Medical Center, Loma Linda, California 13Section of Genetics and Metabolism, Arkansas Children’s Hospital, Little Rock, Arkansas 14Division of Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 15Pediatrics and Genetics Clinics, Alpharetta, Georgia 16Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada 17Department of Human Genetics and Pediatrics, McGill University, Montreal Children’s Hospital Research Institute, Montreal, Canada 18Division of Craniofacial Medicine, University of Washington School of Medicine, Seattle, Washington This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. There are no conflicts of interest declared by the co-authors; L.G.B. and M.J.L. declare receipt of royalties from Genentech, and L.G.B. declares receipt of royalties from Amgen and an honorarium from Wiley-Blackwell. ÃÃThe copyright line for this article was changed on 19 November 2014 after original online publication. Grant sponsor: Intramural Research Program of the National Human Genome Research Institute; Grant sponsor: Wellcome Trust (Senior Research Fellowship in Clinical Science); Grant number: 098498/Z/12/Z; Grant sponsor: Clinical Research Training Fellowship; Grant number: 097721/Z/11/Z; Grant sponsor: UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre; Grant sponsor: UK Medical Research Council Centre for Obesity and Related Metabolic Diseases. ÃCorrespondence to: Kim M. Keppler-Noreuil, M.D., National Human Genome Research Institute/NIH, 49 Convent Drive 4A83, Bethesda, MD 20892. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 29 April 2014 DOI 10.1002/ajmg.a.36552 Ó 2014 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc. 1713 1714 AMERICAN JOURNAL OF MEDICAL GENETICS PART A 19Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 20University Children’s Hospital, Medical School, Skopje, Macedonia 21Clinical Genetics and Dysmorphology, Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles, California 22Greenwood Genetics Center, Greenwood, South Carolina 23Northern Genetics Service, Newcastle Upon Tyne Hospitals, Newcastle Upon Tyne, UK Manuscript Received: 2 December 2013; Manuscript Accepted: 1 March 2014 Somaticmutationsinthephosphatidylinositol/AKT/mTORpath- way cause segmental overgrowth disorders. Diagnostic descrip- How to Cite this Article: tors associated with PIK3CA mutations include fibroadipose Keppler-Noreuil KM, Sapp JC, Lindhurst overgrowth (FAO), Hemihyperplasia multiple Lipomatosis MJ, Parker VER, Blumhorst C, Darling T, (HHML), Congenital Lipomatous Overgrowth, Vascular malfor- Tosi LL, Huson SM, Whitehouse RW, mations, Epidermal nevi, Scoliosis/skeletal and spinal (CLOVES) Jakkula E, Grant I, Balasubramanian M, syndrome, macrodactyly, and the megalencephaly syndrome, Chandler KE, Fraser JL, Gucev Z, Crow YJ, Megalencephaly-Capillary malformation (MCAP) syndrome. Brennan LM, Clark R, Sellars EA, Pena We set out to refine the understanding of the clinical spectrum LDM, Krishnamurty V, Shuen A, and natural history of these phenotypes, and now describe 35 Braverman N, Cunningham ML, Sutton patients with segmental overgrowth and somatic PIK3CA muta- VR, Tasic V, Graham JM, Geer J, tions. The phenotypic data show that these previously described Henderson A, Semple RK, Biesecker LG. disease entities have considerable overlap, and represent a spec- 2014. Clinical delineation and natural trum. While this spectrum overlaps with Proteus syndrome (spo- history of the PIK3CA-related overgrowth radic, mosaic, and progressive) it can be distinguished by the spectrum. absence of cerebriform connective tissue nevi and a distinct Am J Med Genet Part A 164A:1713–1733. natural history. Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. Unlike Proteus syndrome, 31/35 (89%) sequent reports have described activating mutations in other patients with PIK3CA mutations had congenital overgrowth, signaling proteins in the same RTK/PI3K/AKT/mTOR growth and in 35/35 patients this was asymmetric and disproportionate. pathway in several different segmental overgrowth syndromes. Overgrowth was mild with little postnatal progression in most, The mutated genes include PIK3CA, PIK3R2, AKT3 and mTOR while in others it was severe and progressive requiring multiple [Lindhurst et al., 2012; Kurek et al., 2012; Lee et al., 2012; Poduri surgeries. Novel findings include: adipose dysregulation present et al., 2012; Rivie`re et al., 2012; Rios et al., 2013]. Some mutations in all patients, unilateral overgrowth that is predominantly left- have been found in more than one phenotypically distinct disor- sided, overgrowth that affects the lower extremities more than the der, and this overlap raises the important question of the relative upper extremities and progresses in a distal to proximal pattern, contributions of underlying genotype, of timing of the mutation and in the most severely affected patients is associated with and of the precise cell of origin of the founder mutation during marked paucity of adipose tissue in unaffected areas. While the development to the ultimate clinical phenotype. A particularly current data are consistent with some genotype–phenotype cor- encouraging aspect of recent genetic findings is that the pharma- relation, this cannot yet be confirmed. ceutical industry is engaged in a major effort to develop drugs Ó The Authors. American Journal of Medical Genetics Part A published by Wiley targeting this pathway for use in cancer. This means that these Periodicals, Inc. genetic discoveries have brought the prospect of targeted drug trials in segmental overgrowth dramatically closer. Critical to the planning of effective trials will be an understanding of the natural Key words: somatic mosaicism; PIK3CA gene; fibroadipose history of the different RTK/PI3K/AKT/MTOR-related over- overgrowth; segmental overgrowth; macrodactyly; CLOVES growth disorders. syndrome One of the recently described segmental overgrowth phenotypes caused by mutations in the PIK3CA gene is fibroadipose over- INTRODUCTION growth (FAO) [Lindhurst et al., 2012]. The major manifestation of this disorder is segmental and progressive overgrowth of subcuta- Next generation sequencing has resulted in major advances in neous, muscular, and visceral fibroadipose tissue, sometimes asso- understanding the molecular etiology of somatic overgrowth ciated with skeletal overgrowth. We now provide further details of syndromes [Lindhurst et al., 2011; Lindhurst et al., 2012; Kurek eight of the patients with this disorder previously described in an et al., 2012; Lee et al., 2012; Raffan and Semple, 2011; Rivie`re et al., abbreviated form [Lindhurst et al., 2012] (a ninth patient from that 2012; Shirley et al., 2013]. Since the finding in 2011 that Proteus report was not included because she was the subject of a recent syndrome is caused by somatic activating mutations in the clinical report [Tziotzios et al., 2011]) and present 27 additional growth-promoting serine/threonine