Cowden Syndrome

ABSTRACT

• Cowden syndrome (CS) is an autosomal dominant disorder characterized by multiple hamartomas and a risk of breast and thyroid cancers.

• The great majority of tumors, including those of the thyroid and breast, are benign. Up to 10 percent of affected individuals develop nonmedullary thyroid carcinoma, and up to 50 percent of affected females develop breast cancer.

• The pathognomonic hamartoma is the trichilemmoma, a benign tumor of the infundibulum of the hair follicle.

• The susceptibility gene for CS is a tumor-suppressor gene as evidenced by loss of heterozygosity in the PTEN region of 10q23 in various tumors and by transfection.

• The CS gene PTEN was isolated by a combination of genetic mapping analyses, somatic genetics, and a candidate gene approach. PTEN, located on 10q23.3, encodes a 403-amino acid protein, which contains a phosphatase signature motif and has sequences homologous to tensin.

• PTEN is a dual-specificity lipid phosphatase. PTEN is the 3-phosphatase for phosphotidylinositol-3,4,5-triphosphate and, hence, coordinately regulates the cell survival factor PKB/Akt via the PI3 kinase signaling pathway.

• Germ line mutations in PTEN have been found in CS families as well as in the related but distinct hamartoma disorder Bannayan-Ruvalcaba-Riley syndrome. These mutations result in predicted protein truncation or likely loss of function, hence supporting its predicted function as a tumor suppressor.

• Somatic mutations of PTEN occur in a broad spectrum of sporadic tumors, which is almost always biallelic. However, alternate mechanisms of PTEN inactivation do occur.

INTRODUCTION

Cowden syndrome (CS) [MIM 158350], named after Rachel Cowden, is an autosomal dominant inherited cancer syndrome characterized by multiple hamartomas, which are benign hyperplastic disorganized growths, involving organ systems derived from all three germ cell layers and a risk of breast and thyroid cancers.¹ Females with CS have been reported to have as high as a 67 percent risk of fibrocystic disease of the breasts and a 25 to 50 percent lifetime risk of developing adenocarcinoma of the breast.^2,3 This maximum lifetime risk exceeds that of the general population in the United States (11 percent). Furthermore, affected individuals are said to have a 3 to 10 percent lifetime risk of developing epithelial thyroid carcinoma:^3–5 this, too, exceeds that of the general population (1 percent).

The CS susceptibility gene, PTEN, is located on chromosome sub-band 10q23.3.^6,7

CLINICAL ASPECTS

Incidence

CS has not been well recognized; as of 1993, there were approximately 160 reported cases in the world literature.⁸ From an informal population-based study, the estimated gene frequency is one in one million.⁶ Because of frequencies such as this, CS is often listed as rare, but exponents of the field suspect that it is much more common than believed. Because of the variable, protean and often subtle external manifestations of CS, many cases remain undiagnosed^9,10 (Eng, unpublished). Indeed, between two centers in the ...