The Clinical Spectrum of PTEN Mutations

Annu Rev Med. 2020 Jan 27:71:103-116. doi: 10.1146/annurev-med-052218-125823. Epub 2019 Aug 21.


PTEN is a tumor suppressor gene that classically dampens the PI3K/AKT/mTOR growth-promoting signaling cascade. PTEN dysfunction causes dysregulation of this and other pathways, resulting in overgrowth. Cowden syndrome, a hereditary cancer predisposition and overgrowth disorder, was the first Mendelian condition associated with germline PTEN mutations. Since then, significant advances by the research and medical communities have elucidated how clinical phenotypic manifestations result from the underlying germline PTEN mutations. With time, it became evident that PTEN mutations can result in a broad phenotypic spectrum, causing seemingly disparate disorders from cancer to autism. Hence, the umbrella term of PTEN hamartoma tumor syndrome (PHTS) was coined. Timely diagnosis and understanding the natural history of PHTS are vital because early recognition enables gene-informed management, particularly as related to high-risk cancer surveillance and addressing the neurodevelopmental symptoms.

Keywords: Bannayan-Riley-Ruvalcaba syndrome; Cowden syndrome; PTEN hamartoma tumor syndrome; autism spectrum disorder; cancer; overgrowth.

Publication types

  • Review

MeSH terms

  • Early Detection of Cancer / methods*
  • Female
  • Genetic Predisposition to Disease / epidemiology
  • Genetic Predisposition to Disease / genetics*
  • Germ-Line Mutation / genetics*
  • Humans
  • Incidence
  • Male
  • Mutation / genetics
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • PTEN Phosphohydrolase
  • Phenotype
  • Prognosis
  • Risk Assessment


  • PTEN Phosphohydrolase
  • PTEN protein, human