PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation

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.

Keywords: CLOVES syndrome; PIK3CA gene; PIK3CA-Related Overgrowth Spectrum (PROS); fibroadipose overgrowth; macrodactyly; segmental overgrowth; somatic mosaicism.

Figure 1

PI3K-AKT Pathway and associated clinical overgrowth disorders.

Figure 2

PIK3CA-Related Overgrowth Spectrum (PROS). PIK3CA predicted protein mutations and associated clinical overgrowth disorders discovered to date. Oncogenic potency: *Hot spot mutations, **Strong mutations, and ⁺Intermediate [Gymnopoulos et al., 2007]

Figure 3

Phenotypic Spectrum of PROS: disorders have overlapping clinical features, some with tissue-specific, localized effects, some with pleiotropic and more severe manifestations; FAO/HHML, Fibroadipose Overgrowth/Hemihyperplasia-Multiple Lipomatosis; ILM, Isolated Large Lymphatic Malformation; CLOVES, Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal; EN, Epidermal Nevi; SK, Seborrheic Keratoses; BLK, Benign Lichenoid Keratoses; MCAP, Megalencephaly-Capillary Malformation; HMEG, Hemimegalencephaly; DMEG, Dysplastic Megalencephaly