Introduction

Cowden disease (CD; MIM158350) is a rare disorder, with an incidence of 1 in 400 000 in the Netherlands. Easily recognizable in its classic form, it is often overlooked in its common presentation unless one is attentive to its harmless-looking skin features or to a family history of multiple and different malignancies. Not described as an independent disease entity before 1962, the authors named the disease after their first patient (Lloyd & Dennis, 1963). Undoubtedly, similar patients had been reported before, but the dermatological features which came to define the disease had not been recognized (Ambler et al., 1969). Subsequent studies characterized the disease as a genodermatosis with autosomal dominant inheritance. The mesodermal and endodermal hamartomatous lesions were soon recognized as part of CD, leading to the name multiple hamartoma syndrome (Weary et al., 1972).

Gradually attention shifted to the malignant tendency of some of these tumors. The high incidence of macrocephaly had been mentioned before, but the frequent presence of mild neurological signs, the megalencephaly, and the recognition of the dysplastic cerebellar gangliocytoma as a characteristic central nervous system lesion led us to redefine CD as a phakomatosis (Padberg et al., 1991). By analogy, its gene was expected to be a tumor-suppressor gene involved in apoptosis and cellular growth regulation pathways, and its possible significance was compared to the Li–Fraumeni gene p53. The discovery of PTEN as the CD-gene in 1998 and the subsequent flood of papers on the function of PTEN proved this prediction to be correct.