Cowden syndrome

Cowden syndrome (also known as "Cowden's disease," and "Multiple hamartoma syndrome" ) is a rare autosomal dominant inherited disorder characterized by multiple tumor-like growths called hamartomas and an increased risk of certain forms of cancer.

Signs and symptoms
Clinical features of Cowden syndrome are diverse, including breast, endometrial, thyroid, kidney and colorectal cancers, dermatologic features such as oral and skin papillomas, trichilemmomas, gastrointestinal features such as mixed polyposis including hamartomas, and neurologic features such as autism and Lhermitte Duclos disease. Diagnostic criteria have evolved over the years; the most recent is the Cleveland Clinic scoring system in 2011 derived from 3,042 probands. For an individual patient, these features may be evaluated by the Cleveland Clinic web calculator to derive an individual probability of a relevant gene mutation.

The characteristic hamartomas of Cowden syndrome are small, noncancerous growths that are most commonly found on the skin and mucous membranes (such as the lining of the mouth and nose), but can also occur in the intestinal tract and other parts of the body. They are largely benign. However, people with Cowden syndrome have an increased risk of developing several types of cancer, including cancers of the breast, thyroid, and uterus.

Up to 75% have benign breast conditions such as ductal hyperplasia, intraductal papillomatosis, adenosis, lobular atrophy, fibroadenomas, and fibrocystic changes. Nonmedullary thyroid cancer develops in up to 10 percent of affected individuals. In addition, over one-half of those affected have follicular adenomas or multinodular goiter of the thyroid. Other malignancies that appear to be associated with Cowden and Cowden-like syndrome include endometrial and renal cancers. Other signs and symptoms of Cowden syndrome can include an enlarged head, a rare noncancerous brain tumor called Lhermitte-Duclos disease, and glycogenic acanthosis of the oesophagus. The majority of affected individuals develop the characteristic skin lesions by age 20.

A 2010 review of 211 patients (21 from one center, and the remaining 190 from the external literature) studied the risks for cancer and Lhermitte-Duclos disease in Cowden syndrome patients.

The cumulative lifetime (age 70 years) risks were 89% for any cancer diagnosis (95% confidence interval (CI) = 80%,95%), breast cancer [female] 81% (CI = 66%,90%), LDD 32% (CI = 19%,49%), thyroid cancer 21% (CI = 14%,29%), endometrial cancer 19% (CI = 10%,32%) and renal cancer 15% (CI = 6%,32%). A previously unreported increased lifetime risk for colorectal cancer was identified (16%, CI = 8%,24%). Male CS patients had fewer cancers diagnosed than female patients and often had cancers not classically associated with CS.

History
Cowden syndrome was first described in 1963 by Lloyd & Dennis. They named the condition after the surname of the patient.

Epidemiology
Because Cowden syndrome can be difficult to diagnose, the exact prevalence is unknown; however, it probably occurs in at least 1 in 200,000 people.

Genetics
Mutations in the PTEN gene cause Cowden syndrome. PTEN is a tumor suppressor gene, which means it helps control the growth and division of cells. Inherited mutations in the PTEN gene have been found in about 80 percent of people with Cowden syndrome. These mutations prevent the PTEN protein from effectively regulating cell survival and division, which can lead to the formation of tumors. Cowden syndrome is one of several inherited diseases caused by mutations in the PTEN gene.

In the other 20 percent of Cowden syndrome cases, the cause is not yet known. Some of these cases may be caused by mutations in a region of DNA that regulates the activity of the PTEN gene. Others may have mutations in certain subunits of succinate dehydrogenase, a mitochondrial enzyme. Recently, methylation of the KILLIN gene has also been reported in patients with similar clinical features.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new ("de novo") mutations in the gene. These cases occur in people with no history of the disorder in their family. It is characterized by numerous hamartomas, among other symptoms.

Treatment
Patients are usually managed by a multidisciplinary team including surgeons, gynecologists, and dermatologists because of the complex nature of this disorder. Follow-up for the increased risk of breast cancer risk includes monthly breast self-examination, annual breast examination, and mammography at age 30 or five years earlier than the youngest age of breast cancer in the family. The magnitude of the risk of breast cancer justifies routine screening with breast MRI as per published guidelines.