Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 Signaling Pathway

Dermatol Clin. 2017 Jan;35(1):51-60. doi: 10.1016/j.det.2016.07.001.


Somatic mutations in genes of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway cause segmental overgrowth, hamartomas, and malignant tumors. Mosaicism for activating mutations in AKT1 or PIK3CA cause Proteus syndrome and PIK3CA-Related Overgrowth Spectrum, respectively. Postzygotic mutations in PTEN or TSC1/TSC2 cause mosaic forms of PTEN hamartoma tumor syndrome or tuberous sclerosis complex, respectively. Distinct features observed in these mosaic conditions in part reflect differences in embryological timing or tissue type harboring the mutant cells. Deep sequencing of affected tissue is useful for diagnosis. Drugs targeting mTORC1 or other points along this signaling pathway are in clinical trials to treat these disorders.

Keywords: Mosaicism; Next-generation sequencing; PIK3CA-related overgrowth spectrum; PTEN hamartoma tumor syndrome; Proteus syndrome; Sirolimus; Tuberous sclerosis complex; mTORC1.

Publication types

  • Review

MeSH terms

  • Hamartoma Syndrome, Multiple / complications
  • Hamartoma Syndrome, Multiple / genetics*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mosaicism*
  • Multiprotein Complexes / genetics
  • PTEN Phosphohydrolase / genetics
  • Phenotype
  • Phosphatidylinositol 3-Kinase / genetics
  • Proteus Syndrome / complications
  • Proteus Syndrome / genetics*
  • Proto-Oncogene Proteins c-akt / genetics
  • Sequence Analysis, DNA
  • Signal Transduction / genetics
  • Skin Diseases / etiology
  • Skin Diseases / genetics*
  • TOR Serine-Threonine Kinases / genetics
  • Tuberous Sclerosis / complications
  • Tuberous Sclerosis / genetics*
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics


  • Multiprotein Complexes
  • TSC1 protein, human
  • TSC2 protein, human
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases
  • Phosphatidylinositol 3-Kinase
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase