Keppler-Noreuil, K.M., Sapp, J.C., Lindhurst, M.J. et al. (28 more authors) (2014) Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet A, 164A (7). pp. 1713-1733. ISSN 1552-4825
Abstract
Somatic mutations in the phosphatidylinositol/AKT/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with PIK3CA 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-Capillary 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 PIK3CA 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 PIK3CA 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-sided, 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-phenotype correlation, this cannot yet be confirmed.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2014 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), 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 |
Keywords: | CLOVES syndrome; PIK3CA gene; fibroadipose overgrowth; macrodactyly; segmental overgrowth; somatic mosaicism; Adipose Tissue; Adolescent; Adult; Age of Onset; Child; Child, Preschool; Female; Genetic Association Studies; Genotype; Humans; Hyperplasia; Infant; Infant, Newborn; Lipoma; Male; Middle Aged; Musculoskeletal Abnormalities; Mutation; Nevus; Organ Specificity; Phenotype; Phosphatidylinositol 3-Kinases; Vascular Malformations; Young Adult |
Dates: |
|
Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 14 Jul 2016 14:04 |
Last Modified: | 14 Jul 2016 14:04 |
Published Version: | http://dx.doi.org/10.1002/ajmg.a.36552 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1002/ajmg.a.36552 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:101550 |
Download
Filename: Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum.pdf
Licence: CC-BY-NC-ND 4.0