Excerpt from Cowden Disease (Multiple Hamartoma Syndrome)

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Background

Cowden disease (CD), also termed Cowden syndrome and multiple hamartoma syndrome, is an autosomal dominant condition with variable expression that results most commonly (80%) from a mutation in the PTEN gene on arm 10q, as reported by Liaw et al. A broader category, "PTEN (phosphatase and tensin homolog) hamartoma tumor syndrome," has been suggested as a name to combine multiple phenotypic presentations all due to PTEN genetic diseases. Rare cases of CD are due to a germline mutation in BMPR1A (bone morphogenetic proteins).

CD causes hamartomatous neoplasms of the skin and mucosa, GI tract, bones, CNS, eyes, and genitourinary tract. Skin is involved in 90-100% of cases, and the thyroid is involved in 66% of cases.

Mucocutaneous features of CD include trichilemmomas, oral mucosal papillomatosis, acral keratoses, and palmoplantar keratoses. CD is associated with the development of several types of malignancy, which is why recognition of individuals with the syndrome is important. In particular, a marked increase is seen in the incidence of breast carcinoma in women and of thyroid carcinoma in both men and women. Reports also exist of several other types of malignancies occurring in patients with CD.

Pathophysiology

CD is caused by a mutation in the PTEN tumor suppressor gene (also termed MMAC1 or TEP1) on band 10q23. The protein product of the gene is a phosphatase that regulates the function of other proteins by removing phosphate groups from those molecules. The PTEN protein product negatively controls the phosphoinositide 3-kinase–signaling pathway for regulating cell growth and survival by dephosphorylating the 3 position of phosphoinositide. The PTEN protein is believed to promote cell death. A mutation that causes loss of the protein's function may result in overproliferation of cells, resulting in hamartomatous growths. Part of this overproliferation may be due to some interaction between the PTEN tumor suppressor gene and a more widely known tumor suppressor gene, TP53.

Identical mutations in PTEN have been described by Tok Celebri et al in Bannayan-Zonana syndrome, and patients with either syndrome share some clinical features. Patients with Bannayan-Zonana syndrome have a much lower predisposition to cancer, which suggests that a mutation in the PTEN gene is not the only factor responsible for the clinical features of the disease.

A small percentage of patients with Proteus and Proteus-like syndromes have also demonstrated PTEN mutations.

Frequency

International

Internationally, over 300 cases have been published, including separate studies of several generations of affected family members, as reported by Tok Celebri et al.

Mortality/Morbidity

Morbidity and mortality from CD primarily is associated with increased frequency of malignant tumors. Benign tumors that develop in CD patients also can cause significant morbidity.

Sex

Males and females inherit the mutated gene in equal numbers as it is autosomal dominant. Cutaneous manifestations are similar in both sexes. However, the incidence of malignancies varies depending on the sex, eg, males are more likely to develop thyroid cancer, while females are at greater risk for breast cancer.

Age

Although the mutant gene is inherited, the onset of clinical manifestations of CD varies in age, ranging from birth to 46 years.

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