Cowden syndrome (CS, MIM 158350) is an autosomal dominant disorder with age related penetrance characterised by multiple hamartomas and a high risk of breast, thyroid, and perhaps other cancers. These hamartomas can arise in tissues derived from all three embryonic germ cell layers, in accordance with the prominent expression of the susceptibility gene throughout human embryonic and fetal development. 1 The cardinal features of CS include trichilemmomas, which are hamartomas of the infundibulum of the hair follicle, and mucocutaneous papillomatous papules, which occur in the great majority (> 90%) of aVected subjects. 2 3 Lesions in the breast or thyroid occur in at least two thirds of CS cases. The incidence of CS before gene identification was estimated to be 1 in a million in a population based Dutch clinical epidemiological study. 2 4 However, after gene identification, this figure was revised to 1 in 200 000, 5 which is almost certainly an underestimate. This is because CS has variable expression and often can have nothing but subtle skin signs, and so this condition is diY-cult to recognise and remains underdiagnosed.

Before 1996, little was known about the molecular aetiology of the inherited hamartoma syndromes, including CS. For purposes of localising the CS gene, the International Cowden Consortium proposed a set of operational diagnostic criteria to ascertain CS families and to assign aVected status within families (table 1). 4 6 These criteria have been adopted by the US based National Comprehensive Cancer Network (NCCN) Genetics/High Risk Cancer Surveillance Panel, whose task is to present evidence based or expert consensus practice guidelines. 7