Cowden syndrome (CS) or multiple hamartoma syndrome (MIM 158350) is an autosomal 
dominant disorder with an increased risk for breast and thyroid carcinoma. The 
diagnosis of CS, as operationally defined by the International Cowden 
Consortium, is made when a patient, or family, has a combination of 
pathognomonic major and/or minor criteria. The CS gene has recently been 
identified as PTEN, which maps at 10q23.3 and encodes a dual specificity 
phosphatase. PTEN appears to function as a tumour suppressor in CS, with between 
13-80% of CS families harbouring germline nonsense, missense, and frameshift 
mutations predicted to disrupt normal PTEN function. To date, only a small 
number of tumour suppressor genes, including BRCA1, BRCA2, and p53, have been 
associated with familial breast or breast/ovarian cancer families. Given the 
involvement of PTEN in CS, we postulated that PTEN was a likely candidate to 
play a role in families with a "CS-like" phenotype, but not classical CS. To 
answer these questions, we gathered a series of patients from families who had 
features reminiscent of CS but did not meet the Consortium Criteria. Using a 
combination of denaturing gradient gel electrophoresis (DGGE), temporal 
temperature gel electrophoresis (TTGE), and sequence analysis, we screened 64 
unrelated CS-like subjects for germline mutations in PTEN. A single male with 
follicular thyroid carcinoma from one of these 64 (2%) CS-like families 
harboured a germline point mutation, c.209T-->C. This mutation occurred at the 
last nucleotide of exon 3 and within a region homologous to the cytoskeletal 
proteins tensin and auxilin. We conclude that germline PTEN mutations play a 
relatively minor role in CS-like families. In addition, our data would suggest 
that, for the most part, the strict International Cowden Consortium operational 
diagnostic criteria for CS are quite robust and should remain in place.