Overgrowth Syndromes Caused by Somatic Variants in the Phosphatidylinositol 3-Kinase/AKT/Mammalian Target of Rapamycin Pathway

Abstract

Somatic variants have been well described in tumorigenesis; however, they are only recently appreciated in other human disorders, such as mosaic overgrowth syndromes. Although overgrowth is a manifestation in many genetic syndromes, not all overgrowth syndromes are inherited. Mosaic somatic variants have been lately described in several overgrowth disorders, such as Proteus syndrome, CLOVES (congenital, lipomatous, overgrowth, vascular malformations, epidermal nevi, and spinal/skeletal anomalies and/or scoliosis) syndrome, and megalencephalyepolymicrogyria-polydactyly-hydrocephalus syndrome. These syndromes are caused by somatic variants in the genes associated with the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway, resulting in a spectrum of overgrowth syndromes with overlapping features that could be difficult to distinguish based on phenotypic presentations alone. In addition, Sanger sequencing is ineffective for the detection of a causal variant because of the mosaic nature of these variants, whereas targeted next-generation sequencing technology offers a deeper sequencing coverage and allows the detection of low-level mosaicism. Recent studies have shown that the causal variants are only present in the affected tissues in most cases, and can be enriched by in vitro tissue culture. In this review, we describe several mosaic somatic overgrowth syndromes caused by variants in genes of the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin signaling pathway, their phenotypic and molecular spectrum, and the clinical utility of next-generation sequencing technology in the diagnosis of these disorders.

Molecular diagnosis of somatic overgrowth conditions: A single‐center experience

“…Molecular diagnosis of a somatic overgrowth condition can help guide patient management, aid in family planning, and may offer therapeutic opportunities. For individuals with a P/LP variant in the PIK3CA‐AKT‐mTOR pathway, mTOR inhibitors and small molecular inhibitors targeting AKT or PIK3CA, initially developed for oncological purposes, are now showing promise in off‐label trials and pre‐clinical models for management of somatic overgrowth conditions (e.g., sirolimus: NCT02428296; ARQ 092: NCT03094832) (Akgumus et al, ; Chang et al, ; Keppler‐Noreuil et al, ).…”

“…A heterogeneous group of overgrowth conditions are caused by post‐zygotic pathogenic variants, resulting in segmental mosaicism and give rise to neural, cutaneous and/or lipomatous overgrowth (Akgumus, Chang, & Li, ; Chang et al, ; Keppler‐Noreuil, Parker, Parker, Darling, & Martinez‐Agosto, ). Typically, these variants arise in growth‐promoting pathways, most commonly the PI3K‐AKT‐MTOR pathway, leading to cellular proliferation and enlargement of tissues arising from the affected cellular lineage.…”

The RNA helicase DDX3 induces neural crest by promoting AKT activity

“…Among the latter, the serine/threonine kinase AKT can inhibit GSK3b activity via direct phosphorylation of the Ser9 residue (Cross et al, 1995;Fukumoto et al, 2001;Naito et al, 2005;Sharma et al, 2002). Mutations that cause gain of AKT activity in humans and mice lead to overgrowth phenotypes in the CNS and NC (Akgumus et al, 2017;Butler et al, 2005;Rivière et al, 2012), which are opposite to those caused by loss of DDX3X function (Fig. 1).…”

PIK3CA c.3140A>G mutation in a patient with suspected Proteus Syndrome: a case report

“…All the mosaic overgrowth syndromes present overlapping features, but they can now be considered as distinct disorders classifiable on the bases of the molecular lesions that upregulate the activity of the PI3K/AKT/mTOR pathway 6. They include the Proteus Syndrome (PS), which is typically due to the AKT1 c.49G>A (p.Glu17Lys) activating mutation 2, the PIK3CA‐related overgrowth spectrum (PROS) and the PTEN hamartoma tumor syndrome (PHTS) 4.…”

“…Genomic analyses, conducted over the years in patients affected by a wide spectrum of focal growth abnormalities, have led to a more defined classification of all the syndromes and have identified in the activation of PI3K/ AKT/mTOR pathway the genomic background for their clinical expression [5]. All the mosaic overgrowth syndromes present overlapping features, but they can now be considered as distinct disorders classifiable on the bases of the molecular lesions that upregulate the activity of the PI3K/AKT/mTOR pathway [6]. They include the Proteus Syndrome (PS), which is typically due to the AKT1 c.49G>A (p.Glu17Lys) activating mutation [2], the PIK3CA-related overgrowth spectrum (PROS) and the PTEN hamartoma tumor syndrome (PHTS) [4].…”