PIK3CA‐related overgrowth spectrum (PROS): Diagnostic and testing eligibility criteria,differential diagnosis,and evaluation |
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| Authors: | Kim M. Keppler‐Noreuil Jonathan J. Rios Victoria E.R. Parker Robert K. Semple Marjorie J. Lindhurst Julie C. Sapp Ahmad Alomari Marybeth Ezaki William Dobyns Leslie G. Biesecker |
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| Affiliation: | 1. National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland;2. Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Department of Pediatrics, Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas;3. Department of Orthopaedic Surgery, UT Southwestern Medical Center, Dallas, Texas;4. Institute of Metabolic Science, University of Cambridge Metabolic Research Laboratories, Cambridge, Massachusetts;5. Division of Vascular and Interventional Radiology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts;6. University of Washington, Seattle, Washington |
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| Abstract: | Somatic activating mutations in the phosphatidylinositol‐3‐kinase/AKT/mTOR pathway underlie heterogeneous segmental overgrowth phenotypes. Because of the extreme differences among patients, we sought to characterize the phenotypic spectrum associated with different genotypes and mutation burdens, including a better understanding of associated complications and natural history. Historically, the clinical diagnoses in patients with PIK3CA activating mutations have included Fibroadipose hyperplasia or Overgrowth (FAO), Hemihyperplasia Multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal (CLOVES) syndrome, macrodactyly, Fibroadipose Infiltrating Lipomatosis, and the related megalencephaly syndromes, Megalencephaly‐Capillary Malformation (MCAP or M‐CM) and Dysplastic Megalencephaly (DMEG). A workshop was convened at the National Institutes of Health (NIH) to discuss and develop a consensus document regarding diagnosis and treatment of patients with PIK3CA‐associated somatic overgrowth disorders. Participants in the workshop included a group of researchers from several institutions who have been studying these disorders and have published their findings, as well as representatives from patient‐advocacy and support groups. The umbrella term of “PIK3CA‐Related Overgrowth Spectrum (PROS)” was agreed upon to encompass both the known and emerging clinical entities associated with somatic PIK3CA mutations including, macrodactyly, FAO, HHML, CLOVES, and related megalencephaly conditions. Key clinical diagnostic features and criteria for testing were proposed, and testing approaches summarized. Preliminary recommendations for a uniform approach to assessment of overgrowth and molecular diagnostic testing were determined. Future areas to address include the surgical management of overgrowth tissue and vascular anomalies, the optimal approach to thrombosis risk, and the testing of potential pharmacologic therapies. © 2014 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc. |
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| Keywords: | somatic mosaicism PIK3CA gene fibroadipose overgrowth segmental overgrowth macrodactyly CLOVES syndrome PIK3CA‐Related Overgrowth Spectrum (PROS) |
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