Germline PTEN mutations are rare and highly penetrant

In 1963 Lloyd and Dennis described a patient named Rachel Cowden who died of bilateral breast cancer in her thirties [1]. Cowden syndrome is now recognized as an autosomal dominant syndrome characterized by multiple hamartomas originating from all three germ-cell layers. Mucocutaneous lesions including trichilemmomas are seen in 90-100% of patients [2]. There is increased risk of early breast cancer from 14 years of age, and lifetime risk is estimated to 25-50% [3-5]. Goitre and thyroid adenomas are frequently seen and the estimated prevalence of thyroid cancer is 3-7% [3,6,7]. We have previously reported endometrial cancer in one Norwegian family with Cowden syndrome [8].In 1995 the International Cowden Syndrome Consortium was formed and a set of clinical diagnostic criteria were suggested; see Table 1[2,9,10]. In 1997 the susceptibility gene for Cowden syndrome was identified on chromosome 10q23.3 and was found to be PTEN [11,12]. Germline mutations are found throughout the PTEN gene, the majority in exons 5, 7 and 8 [2,13]. The frequency of germline PTEN mutations, including mutations in the promoter region, in Cowden syndrome have been reported to approach 85-90% [14]. Genotype/phenotype correlations have been suggested, but have not been confirmed [15-17].Nelen has estimated the incidence to be between 1 per 200,000 and 1 per 250,000 in the Dutch population [16].As for all inherited cancer syndromes, the penetrance of the underlying genetic defects and the full clinical spectrum of their expressions have been difficult to assess without access to genetic testing.Fifty to sixty percent of patients with Bannayan-Riley-Ruvalcaba syndrome (BRRS, MIM 153480) have been shown to have germline mutations in the PTEN gene [14,18]. An association between germline PTEN mutations and Proteus syndrome (MIM 176920) has been disputed [19-22].Our aim was to validate strategies to identify families with PTEN mutations and to estimate prevalences and penetrances of PTEN mutations