Will the real Cowden syndrome please stand up: revised diagnostic criteria.

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. 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. 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. 4 However, after gene identification, this figure was revised to 1 in 200 000, 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 diYcult 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). 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. The susceptibility gene for CS was mapped to 10q22-23 and identified a year later as PTEN. 8 PTEN is an almost ubiquitously expressed dual specificity phosphatase which acts as a tumour suppressor by mediating cell cycle arrest or apoptosis or both, among other as yet unelucidated functions. When CS families and cases are ascertained strictly by the Consortium criteria (table 1), the PTEN mutation frequency is approximately 80%. 15 However, when these criteria are not used, the mutation frequency ranges from 10-50%. Bannayan-Riley-Ruvalcaba syndrome (BRR, MIM 153480), an autosomal dominant developmental disorder characterised by macrocephaly, developmental delay, lipomatosis, haemangiomatosis, and speckled penis, is allelic to CS, with a mutation frequency of 50-60%. The highest PTEN mutation frequencies (>92%) are consistently obtained in CS-BRR overlap families (Eng and Hampel, 2000, unpublished observations). Recently, a Proteus syndrome-like subject was found to have a germline PTEN mutation and a germline mosaic PTEN mutation. This Proteus-like patient presented at birth with marked hypertrophy of the right lower extremity in girth and length, pink verrucoid epidermoid naevi in whirls and plaques on the right side of his body, and macrocephaly. The hemihypertrophy progressed such that massive arteriovenous malformations involving the muscles and bones of the entire right lower extremity and pelvis were noted at the age of 6 years. This patient does not meet the diagnostic criteria for Proteus syndrome nor BRR. A de novo germline PTEN R335X was found in this case, and nongermline R130X was found in three diVerent non-contiguous aVected tissues from the hypertrophied lower extremity. Whether Table 1 International Cowden Consortium operational criteria for the diagnosis of CS, Ver 1995