Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria

J Natl Cancer Inst. 2013 Nov 6;105(21):1607-16. doi: 10.1093/jnci/djt277. Epub 2013 Oct 17.


Background: PTEN hamartoma tumor syndrome (PHTS) refers to a spectrum of disorders caused by mutations in the phosphatase and tensin homolog (PTEN) gene. Diagnostic criteria for Cowden syndrome, the principal PTEN-related disorder, were first established in 1996 before the identification of the PTEN gene and the ability to molecularly confirm a clinical diagnosis. These consortium criteria were based on clinical experience and case reports in the existing literature, with their inherent selection biases. Although it was initially reported that approximately 80% of patients with Cowden syndrome had an identifiable germline PTEN mutation, more recent work has shown these diagnostic criteria to be far less specific. In addition, increasing evidence has documented the association of a broader spectrum of clinical features with PTEN mutations. Our goal was to develop revised, evidence-based diagnostic criteria and to include features of the broader spectrum of PTEN-related clinical syndromes.

Methods: We performed a systematic search and review of the medical literature related to clinical features reported in individuals with a PTEN mutation and/or a related clinical diagnosis.

Results: We found no sufficient evidence to support inclusion of benign breast disease, uterine fibroids, or genitourinary malformations as diagnostic criteria. There was evidence to include autism spectrum disorders, colon cancer, esophageal glycogenic acanthosis, penile macules, renal cell carcinoma, testicular lipomatosis, and vascular anomalies.

Conclusions: We propose revised, evidence-based criteria covering the spectrum of PTEN-related clinical disorders. Additional research on clinical features associated with PTEN mutations is warranted.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Brain / pathology
  • Brain Neoplasms / diagnosis
  • Breast / pathology
  • Breast Neoplasms / diagnosis
  • Diagnosis, Differential
  • Evidence-Based Medicine
  • Gastrointestinal Neoplasms / diagnosis
  • Gastrointestinal Tract / pathology
  • Germ-Line Mutation*
  • Hamartoma Syndrome, Multiple / diagnosis*
  • Hamartoma Syndrome, Multiple / genetics
  • Hamartoma Syndrome, Multiple / pathology
  • Humans
  • PTEN Phosphohydrolase / genetics*
  • Skin / pathology
  • Skin Neoplasms / diagnosis
  • Thyroid Gland / pathology
  • Thyroid Neoplasms / diagnosis
  • Urogenital Neoplasms / diagnosis
  • Urogenital System / pathology


  • PTEN Phosphohydrolase
  • PTEN protein, human