title: Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria.
abstract: 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.
authors.affiliation: Affiliations of authors: Division of Human Genetics, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH (RP); Huntsman Cancer Institute, Salt Lake City, UT (RB, WK, LP); University of Utah School of Medicine, Salt Lake City, UT (RB, WK); Department of Dermatology, University of Utah, Salt Lake City, UT (LP); Massachusetts General Hospital Cancer Center, Center for Cancer Risk Assessment, Boston, MA (KMS); University of Washington Medical Center/Seattle Cancer Care Alliance, Seattle, WA (ES).
authors.forename: Robert
authors.initials: R
authors.lastname: Pilarski
authors.forename: Randall
authors.initials: R
authors.lastname: Burt
authors.forename: Wendy
authors.initials: W
authors.lastname: Kohlman
authors.forename: Lana
authors.initials: L
authors.lastname: Pho
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Shannon
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Swisher
mesh_terms: D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000175:diagnosis; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000175:diagnosis; D003937:Diagnosis, Differential; D019317:Evidence-Based Medicine; D005770:Gastrointestinal Neoplasms / Q000175:diagnosis; D041981:Gastrointestinal Tract / Q000473:pathology; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000175:diagnosis; D013961:Thyroid Gland / Q000473:pathology; D013964:Thyroid Neoplasms / Q000175:diagnosis; D014565:Urogenital Neoplasms / Q000175:diagnosis; D014566:Urogenital System / Q000473:pathology
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human