Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations

Cowden disease (CD) is characterised by multiple hamartomas in a variety of tissues. The pathological hallmark is the presence of a number of trichile mmomas. Several neurological symptoms are also part of CD with megalencepha ly and Lhermitte-Duclos disease (LDD) as the most important features. Early recognition of CD patients is important because of the increased risk of d eveloping malignancies. Breast cancer is the most frequent malignancy, but also urogenital, digestive tract, and thyroid cancers are found,vith higher frequencies. CD was localised to chromosome 10q23 and the PTEN gene (also known as MMAC1 or TEP1) was shown to be involved. Germline mutations were i dentified in both familial and sporadic CD patients. We identified eight PT EN mutations, of which seven were novel, in 13 CD patients. Combined with p revious data we have identified 17 independent CD mutations. Gross DNA alte rations in CD patients were not detected. Genotype-phenotype relations are discussed. The only correlation suggested to exist is that missense mutatio ns are not detected in LDD patients. However, larger numbers are needed to confirm this. Association of PTEN mutations and the occurrence of malignant breast disease found in an earlier study cannot be confirmed. Clinical fea tures of five CD patients without a PTEN mutation in the coding sequence do not differ from CD patients with a PTEN mutation. Furthermore, if is likel y that we have identified the majority of CD patients in the Netherlands. F rom this we estimate that CD has a prevalence of about 1 in 250 000 in the Dutch population with a low mutation frequency.