{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:03:50Z","timestamp":1792782230955,"version":"4.5.0"},"reference-count":48,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2014,4,29]],"date-time":"2014-04-29T00:00:00Z","timestamp":1398729600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Intramural Research Program of the National Human Genome Research Institute","id":[{"id":"https:\/\/ror.org\/00baak391","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Wellcome Trust (Senior Research Fellowship in Clinical Science)","award":["098498\/Z\/12\/Z"],"award-info":[{"award-number":["098498\/Z\/12\/Z"]}],"id":[{"id":"https:\/\/ror.org\/029chgv08","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Clinical Research Training Fellowship","award":["097721\/Z\/11\/Z"],"award-info":[{"award-number":["097721\/Z\/11\/Z"]}]},{"name":"UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre","id":[{"id":"https:\/\/ror.org\/05m8dr349","id-type":"ROR","asserted-by":"crossref"}]},{"name":"UK Medical Research Council Centre for Obesity and Related Metabolic Diseases"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2014,7]]},"abstract":"<jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      Somatic mutations in the phosphatidylinositol\/AKT\/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      mutations include fibroadipose overgrowth (FAO), Hemihyperplasia multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis\/skeletal and spinal (CLOVES) syndrome, macrodactyly, and the megalencephaly syndrome, Megalencephaly\u2010Capillary malformation (MCAP) syndrome. We set out to refine the understanding of the clinical spectrum and natural history of these phenotypes, and now describe 35 patients with segmental overgrowth and somatic\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      mutations. The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum. While this spectrum overlaps with Proteus syndrome (sporadic, mosaic, and progressive) it can be distinguished by the absence of cerebriform connective tissue nevi and a distinct 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%) patients with\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      mutations had congenital overgrowth, and in 35\/35 patients this was asymmetric and disproportionate. Overgrowth was mild with little postnatal progression in most, while in others it was severe and progressive requiring multiple surgeries. Novel findings include: adipose dysregulation present in all patients, unilateral overgrowth that is predominantly left\u2010sided, overgrowth that affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern, and in the most severely affected patients is associated with marked paucity of adipose tissue in unaffected areas. While the current data are consistent with some genotype\u2013phenotype correlation, this cannot yet be confirmed. \u00a9 The Authors.\n                      <jats:italic>American Journal of Medical Genetics Part A<\/jats:italic>\n                      published by Wiley Periodicals, Inc.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ajmg.a.36552","type":"journal-article","created":{"date-parts":[[2014,4,29]],"date-time":"2014-04-29T13:35:20Z","timestamp":1398778520000},"page":"1713-1733","source":"Crossref","is-referenced-by-count":280,"title":["Clinical delineation and natural history of the\n                    <i>PIK3CA<\/i>\n                    \u2010related overgrowth spectrum"],"prefix":"10.1002","volume":"164","author":[{"given":"Kim M.","family":"Keppler\u2010Noreuil","sequence":"first","affiliation":[{"name":"National Human Genome Research Institute National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie C.","family":"Sapp","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjorie J.","family":"Lindhurst","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria E.R.","family":"Parker","sequence":"additional","affiliation":[{"name":"The University of Cambridge Metabolic Research Laboratories Institute of Metabolic Science Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Blumhorst","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Darling","sequence":"additional","affiliation":[{"name":"Department of Dermatology Uniformed Services University of the Health Sciences Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura L.","family":"Tosi","sequence":"additional","affiliation":[{"name":"Division of Orthopaedic Surgery and Sports Medicine Children's National Medical Center Washington District of Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Huson","sequence":"additional","affiliation":[{"name":"Manchester 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard W.","family":"Whitehouse","sequence":"additional","affiliation":[{"name":"Department of Radiology Central Manchester University Hospitals NHS Foundation Trust Manchester Royal Infirmary Oxford Road Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eveliina","family":"Jakkula","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Helsinki University Central Hospital Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Grant","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery Cambridge University Hospitals NHS Trust Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meena","family":"Balasubramanian","sequence":"additional","affiliation":[{"name":"Sheffield Clinical Genetics Service Sheffield Children's NHS Foundation Trust Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate E.","family":"Chandler","sequence":"additional","affiliation":[{"name":"Manchester 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie L.","family":"Fraser","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoran","family":"Gucev","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Genetics Medical Faculty Skopje Skopje Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanick J.","family":"Crow","sequence":"additional","affiliation":[{"name":"Manchester 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie Manace","family":"Brennan","sequence":"additional","affiliation":[{"name":"Medical Genetics Kaiser Permanente Oakland University of California San Francisco California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Clark","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Department of Pediatrics Loma Linda University Medical Center Loma Linda California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Sellars","sequence":"additional","affiliation":[{"name":"Section of Genetics and Metabolism Arkansas Children's Hospital Little Rock Arkansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loren 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Reid","family":"Sutton","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Velibor","family":"Tasic","sequence":"additional","affiliation":[{"name":"University Children's Hospital Medical School Skopje Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"John M.","family":"Graham","sequence":"additional","affiliation":[{"name":"Clinical Genetics and Dysmorphology Department of Pediatrics Harbor\u2010UCLA Medical Center Los Angeles California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Joseph","family":"Geer","sequence":"additional","affiliation":[{"name":"Greenwood Genetics Center Greenwood South Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Henderson","sequence":"additional","affiliation":[{"name":"Northern Genetics Service Newcastle Upon Tyne Hospitals Newcastle Upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert K.","family":"Semple","sequence":"additional","affiliation":[{"name":"The University of Cambridge Metabolic Research Laboratories Institute of Metabolic Science Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie G.","family":"Biesecker","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,4,29]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-0738"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/MCD.0b013e328317a716"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2010.04.023"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19981002)79:4<311::AID-AJMG14>3.0.CO;2-U"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201638"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2009.07.009"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-2933"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.913901"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2013.164"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/1096-8628(20000731)93:3<171::AID-AJMG1>3.0.CO;2-K"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1890"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0705218104"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1210878"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-4114"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408864102"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI59309"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.05.006"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2329"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208304"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-2142"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-5-29"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1104017"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2332"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2013.312"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.370809"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02172"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncponc1112"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-3827"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.34402"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31361"},{"key":"e_1_2_7_32_1","first-page":"1993","volume-title":"PIK3CA\u2010related segmental overgrowth. 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