Cowden syndrome

Cowden syndrome (CS), also known as Cowden’s disease and multiple hamartoma syndrome, is a rare inherited disorder that causes benign, or noncancerous, growths in various places on the body. The growths, called hamartomas, typically start to appear when patients reach their late 20s. However, they may appear at any time between birth and your mid-40s.

The growths are most likely to develop on the outer sheath of hair follicles and in the mouth. Hamartomas also may be found along the inner lining of the gastrointestinal tract.

While some tumors are benign, this syndrome increases the risk of developing certain types of cancer, including:

• Breast cancer
• Colorectal cancer
• Endometrial (in the lining of the uterus)
• Kidney cancer
• Melanoma
• Thyroid cancer

Women with CS are at greatest risk of developing breast cancer. The risk may be as high as 85 percent, according to the American Society of Clinical Oncology (ASCO). Women with CS may develop breast cancer at a younger age compared with other women. Women also are at risk of developing cancer in a second breast if they have cancer in the other. Men with CS are at some risk for developing breast cancer as well.

According to ASCO, other risks for people with CS include:

• Thyroid cancer: 30-40 percent
• Kidney cancer: 30-35 percent
• Endometrial cancer in women: 25-30 percent
• Colorectal cancer: 5-10 percent
• Melanoma: 6 percent

People with CS also may be at risk for other cancers, but more research is needed to determine whether the risks are increased.

Signs and symptoms

People with CS may have:

• Skin tags
• Flesh-colored growths or papules around the eyes, nose and mouth
• Wart-like papules on the back of the hands and feet

Other signs and symptoms of CS include:

• Enlarged head (macrocephaly)
• Autism spectrum disorder
• Abnormalities of the blood vessels     
• Benign diseases of the breast, thyroid and endometrium
• Lhermitte-Duclos (rare, benign brain tumor)

Causes of CS

Cowden syndrome is a genetic disorder, meaning that it’s caused by a gene mutation. Most often, the mutation occurs in the PTEN (phosphatase and tensin homolog) gene that regulates cell growth. When mutated, PTEN is unable to suppress tumor growth, which increases risks for benign and cancerous tumors.

Cowden syndrome is an autosomal dominantly inherited condition, meaning the inheritance of a single gene mutation causes the condition. There is a 50 percent chance that each child of someone with CS will inherit the condition, according to the Genetic and Rare Diseases Information Center.

In rare instances, CS may result from mutations in other genes, including:

• KLLN
• SDHB
• SDHC
• SDHD
• PIK3CA
• AKT1

Some people may have CS and not know which gene, if any, caused it. Some may develop CS because of a new mutation that was not inherited from a parent, but that can be passed down to their children.

How common is CS?

Men and women inherit this disorder in equal numbers. Although rare, CS is estimated to affect one in every 200,000 people, according to ASCO.

How is CS diagnosed?

Cowden syndrome may be difficult to diagnose. It is typically detected based on a combination of factors, including physical exams or imaging studies such as CT or MRI. Cowden syndrome can also be diagnosed based on genetic test results.

The criteria are divided into three groups:

1. Mucosal and skin lesions
2. Cancers
3. Other malformations

The major criteria include:

• Breast, endometrial and/or follicular thyroid cancer
• Macrocephaly
• Multiple benign tumors of the gastrointestinal tract, or ganglioneuromas
• Discolored area on the skin of the head of the penis
• Multiple wart-like projections on the face
• Abnormal thickening of the hands and feet
• Extensive mucosal papillomatosis in the oral cavity
• Biopsy-confirmed benign tumor of the outer sheath of the hair follicle
• Mucocutaneous lesions

The minor criteria include:

• Colon cancer
• Autism spectrum disorder
• Mental retardation
• A variant of thyroid cancer
• Thyroid lesions, such as adenoma or goiter
• Kidney cancer
• Vascular anomalies
• Benign soft-tissue tumors (lipomas)
• Glycogenic acanthosis (benign thickening of the esophageal squamous epithelium
• A gastrointestinal hamartoma or ganglioneuroma
• A testicular disorder known as lipomatosis

The number of major and minor criteria patients exhibit determines a diagnosis. For example, adult patients who have two or more major criteria, one major and three or more minor criteria, or four or more minor criteria are likely to be diagnosed with CS.

Cancer screening

Because Cowden syndrome greatly increases the risk of developing different cancers, cancer screening for early detection is important.

It’s recommended women with CS undergo:

• Breast self-exam starting at age 18
• Clinician-performed breast exams every six to 12 months, starting at age 25 or five to10 years before the earliest diagnosed breast cancer in the family (whichever is the younger age)
• Annual mammograms, perhaps with annual magnetic resonance imaging (MRI) screening starting at age 35 or five to10 years before the earliest diagnosed breast cancer in the family (whichever is the younger age)

Some women may opt to have prophylactic surgery (removing healthy organs) to reduce the risk of developing cancer of the breast and/or uterus.

Men and women with Cowden syndrome in the family should have:

• Annual physical exam starting at age 18, or five years before the earliest diagnosis of a Cowden syndrome-related cancer in the family (whichever is the younger age)
• Annual thyroid ultrasound starting at age 7
• Baseline colonoscopy starting at age 35, or five to 10 years before the earliest diagnosis of colon cancer in the family (whichever is the younger age).
• Possible kidney ultrasound every one to two years starting at age 40
• Annual dermatology exams and regular sunscreen use and protective clothing to reduce risks for melanoma

Children in families with Cowden syndrome should have:

• Yearly skin checks as part of physical exams
• Neurological exams with brain MRI if there are concerning symptoms

Treating skin lesions

Not much may be done to control skin lesions that are common in Cowden syndrome. Some doctors prescribe topical treatments, though these haven’t been shown to provide much improvement. Some patients have seen improvements with systemic retinoids.

Facial lesions may be treated with:

• Chemical peels
• Dermabrasion
• Laser resurfacing

Surgery to remove the benign tumors is possible, but it must be done with care because scarring may occur, and the lesions may return.

Because people with CS are at increased risk for melanoma, it’s important to take preventive measures, such as wearing sunscreen and protective clothing, when in the sun starting as a child. It’s also critical to avoid blistering burns, especially before age 20.

Clinical trials are underway to look at new treatments, including Sirolimus (rapamycin), a type of immunosuppressant and antibiotic.

Cancer screenings and follow-ups are key for those with CS. Patients should look for providers who specialize inCowden syndrome and can help sort out the challenges and options for detecting cancer early.