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Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum

Lookup NU author(s): Alexander Henderson

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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. © 2014 Wiley Periodicals, Inc.


Publication metadata

Author(s): Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, Parker VER, Blumhorst C, Darling T, Tosi LL, Huson SM, Whitehouse RW, Jakkula E, Grant I, Balasubramanian M, Chandler KE, Fraser JL, Gucev Z, Crow YJ, Brennan LM, Clark R, Sellars EA, Pena LD, Krishnamurty V, Shuen A, Braverman N, Cunningham ML, Sutton VR, Tasic V, Graham Jr JM, Geer Jr J, Henderson A, Semple RK, Biesecker LG

Publication type: Article

Publication status: Published

Journal: American Journal of Medical Genetics Part A

Year: 2014

Volume: 164

Issue: 7

Pages: 1713-1733

Print publication date: 01/07/2014

Online publication date: 29/04/2014

Acceptance date: 01/03/2014

Date deposited: 23/11/2017

ISSN (print): 1552-4825

ISSN (electronic): 1552-4833

Publisher: Wiley-Liss Inc.

URL: https://doi.org/10.1002/ajmg.a.36552

DOI: 10.1002/ajmg.a.36552

PubMed id: 24782230


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Funding

Funder referenceFunder name
097721/ Z/11/Z
098498/Z/12/Z

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