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J Med Genet 41:323-326 doi:10.1136/jmg.2004.018036
  • Commentary

Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome

  1. R Pilarski1,
  2. C Eng2,3
  1. 1Clinical Cancer Genetics Program, Comprehensive Cancer Center, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
  2. 2Clinical Cancer Genetics Program and Human Cancer Genetics Program, Comprehensive Cancer Center, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
  3. 3Cancer Research UK Human Cancer Genetics Research Group, University of Cambridge, UK
  1. Correspondence to:
 Professor C Eng
 Human Cancer Genetics Program, The Ohio State University, 420 W 12th Avenue, Ste 690 TMRF, Columbus, OH 43210, USA; eng-1medctr.osu.edu

    PTEN hamartoma tumour syndrome

    Since consensus operational diagnostic criteria for Cowden syndrome (MIM 158350) were first established in 1995, our understanding of this complex disease—and the spectrum of disorders related to it by virtue of also having germline mutations in the PTEN tumour suppressor gene—has continued to evolve. This was reflected in a commentary1 in this journal in 2000 in which it was proposed that endometrial cancer and renal cell carcinoma be added to the operational diagnostic criteria for Cowden syndrome (table 1). This updated commentary is intended to provide a review of significant changes in our understanding of the growing group of disorders, which are known to be caused by germline mutations in PTEN on 10q23.3, and which have been termed the PTEN hamartoma tumour syndrome.

    View this table:
    Table 1

    International Cowden Consortium operational criteria for the diagnosis of Cowden syndrome. Ver 2000

    THE CLINICAL SPECTRUM OF THE PTEN HAMARTOMA TUMOUR SYNDROME

    Cowden syndrome is a complex disorder with malignant and benign (hamartomatous) lesions affecting derivatives of all three germ cell layers. Major organs involved include the breast, thyroid, uterus, brain, and mucocutaneous tissues.2 It has been estimated to affect about 1 in 200 000 individuals,3,4 although this is probably an underestimate given the difficulty in diagnosis presented by this highly variable disease and the fact that many component features in and of themselves can occur in the general population. Penetrance is related to age, with most patients presenting by their late twenties with at least the mucocutaneous lesions of this disorder, which are reportedly seen in 99% of affected individuals. The lifetime risk for breast cancer in Cowden syndrome is estimated to be 25–50%, with an average age of diagnosis between 38 and 46 years old.2,5 The risk for thyroid cancer (typically follicular, but occasionally papillary) is approximately 10%, while the risk for endometrial cancer, …