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

J Mol Diagn. 2017 Jul;19(4):487-497. doi: 10.1016/j.jmoldx.2017.04.001. Epub 2017 May 11.


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.

Publication types

  • Review

MeSH terms

  • Animals
  • Clinical Trials as Topic
  • Female
  • Fingers / abnormalities*
  • Genetic Testing / methods
  • Genetic Variation
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Hydrocephalus / diagnosis
  • Hydrocephalus / genetics*
  • Hypoglycemia / diagnosis
  • Hypoglycemia / genetics
  • Limb Deformities, Congenital / diagnosis
  • Limb Deformities, Congenital / genetics*
  • Lipoma / diagnosis
  • Lipoma / genetics*
  • Malformations of Cortical Development / diagnosis
  • Malformations of Cortical Development / genetics*
  • Mosaicism
  • Musculoskeletal Abnormalities / diagnosis
  • Musculoskeletal Abnormalities / genetics*
  • Nevus / diagnosis
  • Nevus / genetics*
  • Phosphatidylinositol 3-Kinase / genetics*
  • Polydactyly / diagnosis
  • Polydactyly / genetics*
  • Proto-Oncogene Proteins c-akt / genetics*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics*
  • Vascular Malformations / diagnosis
  • Vascular Malformations / genetics*


  • MTOR protein, human
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases

Supplementary concepts

  • Congenital Lipomatous Overgrowth, Vascular Malformations, and Epidermal Nevi
  • Megalancephaly Polymicrogyria-Polydactyly Hydrocephalus Syndrome
  • Megalodactyly