Overgrowth Syndromes Caused by Somatic Variants in the Phosphatidylinositol 3- Kinase/AKT/Mammalian Target of Rapamycin Pathway  Gozde Akgumus, Fengqi Chang, Marilyn M. Li  The Journal of Molecular Diagnostics  Volume 19, Issue 4, Pages 487-497 (July 2017) DOI: 10.1016/j.jmoldx.2017.04.001 Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions

Figure 1 Diagram of the PI3K/AKT/mTOR pathway and associated overgrowth syndromes. 1, Pathogenic variants in PIK3CA or PIK3R2 lead to PI3K-associated overgrowth syndromes, including CLOVES, macrodactyly, MCAP, and FAO. 2, Pathogenic variants in AKT genes lead to AKT-associated overgrowth syndromes, including Proteus syndrome (AKT1), hypoinsulinemic hypoglycemia and hemihypertrophy (AKT2), and MPPH (AKT3). 3, Pathogenic variants in MTOR lead to MTOR-associated overgrowth syndrome, such as MPPH. Ras homolog enriched in brain (RHEB) activates the protein kinase activity of mTORC1; FK506 binding protein 1A (FKBP12; 12kD) forms a complex with rapamycin and suppresses the protein kinase activity of mTORC1; regulatory associated protein of MTOR complex 1 (RAPTOR) functions as a scaffold for recruiting mTORC1 substrates; RPTOR-independent companion of MTOR complex 2 (RICTOR) is a subunit of mTORC2 that regulates cell growth and survival; insulin-like growth factor 1 receptor (IGF1R) phosphorylates insulin-receptor substrates and leads to the activation of the PI3K/AKT pathway; p70S6K, a member of the ribosomal S6 kinase family encoded by ribosomal protein S6 kinase B1 (RPS6KB1), is a serine/threonine kinase, and when phosphorylated promotes cell proliferation and cell cycle progression; eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) is a repressor of mRNA translation, phosphorylation of which inactivates the repressor, leading to cell proliferation and cell cycle progression. FAO, fibroadenomatous overgrowth; PDK1, 3-phosphoinositide–dependent protein kinase 1; PTEN, phosphatase and tensin homolog; TSC, tuberous sclerosis; VEGF, vascular endothelial growth factor. The Journal of Molecular Diagnostics 2017 19, 487-497DOI: (10.1016/j.jmoldx.2017.04.001) Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions

Figure 2 Prenatal diagnosis identified a PIK3CA c.1624G>A (p.E542K) in a fetus with CLOVES syndrome. A: Next-generation sequencing (NGS) shows a PIK3CA c.1624G>A (p.E542K) at <1% (7 of 1195 reads) in uncultured amniotic fluid; closed red arrow indicates the G>A change identified by NGS and visualized by Integrative Genomics Viewer (IGV), and open red arrow shows no G>A change at this location by Sanger sequencing. B: NGS shows the same PIK3CA c.1624G>A (p.E542K) at 38.4% (1132 of 2951 reads) in cultured amniotic fluid; closed red arrow indicates the G>A change identified by NGS and visualized using IGV, and open red arrow indicates the G>A change identified by Sanger sequencing. The Journal of Molecular Diagnostics 2017 19, 487-497DOI: (10.1016/j.jmoldx.2017.04.001) Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions