Cowden Disease (Multiple Hamartoma Syndrome) 

Cowden disease, 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.^[1] Originally described in 1963 by Lloyd and Dennis, Cowden disease (multiple hamartoma syndrome) was named after the family in which it was first reported.^[2] A broader category, PTEN (phosphatase and tensin homolog) hamartoma tumor syndrome includes Cowden disease (multiple hamartoma syndrome), Bannayan-Riley-Ruvulcaba syndrome (BRRS), Proteus syndrome, and Proteuslike syndrome, which all have PTEN mutations. Rare cases of Cowden disease (multiple hamartoma syndrome) are due to a germline mutation in the BMPR1A (bone morphogenetic proteins) gene.

Cowden disease (multiple hamartoma syndrome) 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 Cowden disease (multiple hamartoma syndrome) include trichilemmomas, oral mucosal papillomatosis, acral keratoses, and palmoplantar keratoses. Cowden disease (multiple hamartoma syndrome) 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, such as colon cancer and renal cell carcinoma, in patients with Cowden disease (multiple hamartoma syndrome).

Note the clinical image below.

Cowden disease (multiple hamartoma syndrome) is caused by a mutation in the PTEN tumor suppressor gene (also termed MMAC1 or TEP1) on band 10q23.3. 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.PTEN mutations have been found to occur most frequently in association with endometrial cancer, glioblastomas, and prostate cancer.^[3]

Identical mutations in PTEN have been described in Bannayan-Ruvulcaba-Riley syndrome (BRRS). Alternate names for BRRS include Bannayan-Zonana syndrome, Riley-Smith syndrome, and Ruvulcaba-Myhre-Smith syndrome.^[4] Patients with BRRS 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 percentage of patients with Proteuslike syndromes, adult Lhermitte-Duclos disease (LDD), and autismlike disorders associated with macrocephaly have also demonstrated PTEN mutations.

Approximately 18% of Cowden disease (multiple hamartoma syndrome) patients are negative for PTEN mutations and have no identified genetic explanation for their clinical features. Various other possible mechanisms of PTEN inactivation have been explored, but no clear answer has been identified.^[5]

Frequency

International

Internationally, more than 300 cases have been published, including separate studies of several generations of affected family members, as reported by Tok Celebri et al.^[6] The prevalence of Cowden disease (multiple hamartoma syndrome) is estimated to be approximately 1 case per 200,000 population; however, it is likely more prevalent because many features of Cowden disease (multiple hamartoma syndrome) are found in the general population and the diagnosis may be overlooked, which leads to underdiagnosis. Penetrance is thought to be nearly complete; it approaches 90% by age 20 years.^[7]

Mortality/Morbidity

Morbidity and mortality from Cowden disease (multiple hamartoma syndrome) primarily is associated with increased frequency of malignant tumors. Benign tumors that develop in Cowden disease (multiple hamartoma syndrome) patients also can cause significant morbidity.

Sex

Males and females inherit the mutated gene in equal number; it is autosomal dominant. Cutaneous manifestations of Cowden disease (multiple hamartoma syndrome) are similar in both sexes. However, the incidence of malignancies varies depending on the sex. For example, 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 Cowden disease (multiple hamartoma syndrome) varies in age, ranging from birth to age 46 years.