Multiple primary malignancies and subtle mucocutaneous lesions associated with a novel PTEN gene mutation in a patient with Cowden syndrome: Case report

Here we report on a 58-year-old woman with multiple primary malignancies and subtle mucocutaneous lesions such as small polyps and wart-like papulas. Over a period of 23 years, she developed various malignant neoplasms including thyroid, ovarian, stomach, and colon carcinomas, and a benign meningioma. Direct sequencing analysis of the PTEN gene revealed a novel germline mutation (c.438delT, p.Leu146X).This case demonstrates that Cowden syndrome is a multi-system disease that can result in the development of multiple malignant and benign tumors.Cowden syndrome (CS, OMIM 158350) is an autosomal dominant disorder characterized by multiple hamartomas, which develop in the skin, thyroid gland, breast, gastrointestinal tract, and brain[1]. Germline mutations in the PTEN (phosphatase and tensin homolog deleted on chromosome ten) gene have been found in 80% of patients with CS[2]. The PTEN gene encodes a dual-specificity protein and lipid phosphatase that regulates the phosphoinositol-3-kinase/Akt signal pathway which can result in cell cycle arrest in the G1-phase and apoptosis[3]. PTEN can directly or indirectly dephosphorylate focal adhesion kinase (FAK), resulting in inhibition of cell migration and cell spreading[3-5].Diagnosing CS remains a challenge due to the variations in its clinical presentation. A recent molecular-genetic study estimated that the incidence of CS was 1/200 000, although the actual incidence is likely to be higher[6]. The pathognomonic features of CS include mucocutaneous wart-like lesions, which are present in 99% of affected individuals before the age of 30 years[3]. The other most commonly reported manifestations are breast carcinomas, thyroid abnormalities, macrocephaly, hamartomatous polyps and mental retardation [7,8]. In women with CS, the lifetime risk of breast cancer is estimated to be 25-50%, compared to the general female population risk of approximately 11%. The lifetime risk of epithelial thyroid cancer can be as high as 10% in both