Cowden syndrome, also known as multiple hamartoma syndrome, is a rare, inherited disorder that affects multiple body systems. The condition is characterized primarily by the development of multiple benign growths called hamartomas. These growths can occur in various organs, including the skin, thyroid, breast, and gastrointestinal tract. While the hamartomas themselves are not malignant, the syndrome significantly increases a person’s lifetime risk for developing several types of cancer and requires specialized medical management due to its varied presentation and cancer risk.
The Genetic Basis
Cowden syndrome is caused by a mutation in the PTEN gene, which stands for Phosphatase and Tensin Homolog. This PTEN gene is located on chromosome 10 and acts as a tumor suppressor, regulating cell growth and division and preventing the formation of tumors.
When the PTEN gene is mutated, its ability to control cell proliferation is lost or severely impaired. This loss of function allows cells to grow and divide in an uncontrolled manner, which causes both the benign hamartomas and the increased cancer risk seen in the syndrome.
The inheritance pattern for Cowden syndrome is autosomal dominant. This means that a person only needs to inherit one copy of the altered PTEN gene from either parent to have the condition. An affected parent has a 50% chance of passing the mutation on to each of their children.
In some individuals, the gene mutation occurs spontaneously and is not inherited from a parent, known as a de novo mutation. The mechanisms of tumor development often require a second, “acquired” mutation in the remaining healthy copy of the gene, a process sometimes referred to as the “two-hit hypothesis.”
Characteristic Non-Cancerous Symptoms
Many of the physical manifestations of Cowden syndrome are benign, yet they serve as important clues for diagnosis, often appearing earlier than the malignant tumors. Over 90% of affected individuals develop mucocutaneous lesions (growths on the skin and mucous membranes), typically by their late twenties.
Specific skin growths include trichilemmomas, which are small, flesh-colored or yellow-brown, wart-like papules, commonly found clustered around the nose, eyes, and mouth. The mouth often shows papillomatous papules, which are numerous small, raised bumps that give the tongue and oral lining a cobblestone appearance.
Other common skin findings are acral keratoses, which are small, translucent papules found on the palms of the hands and soles of the feet. Lipomas, which are benign fatty tumors located just under the skin, and fibromas, which are benign tumors of fibrous connective tissue, can also be present throughout the body.
Macrocephaly, or an abnormally large head circumference, is another highly characteristic feature of the syndrome. This physical sign is present in a large percentage of individuals with the PTEN mutation. Benign growths are also common in the thyroid, such as goiter or multiple thyroid adenomas, and in the breast tissue, manifesting as fibrocystic changes and fibroadenomas.
Elevated Cancer Risk
The most serious consequence of Cowden syndrome is the significantly increased lifetime risk for developing specific cancers, which often manifest at a younger age than in the general population. Breast cancer represents the highest risk, with estimates suggesting a lifetime risk of up to 85% for women with the syndrome. These cancers tend to be diagnosed much earlier, often before age 50, and there is also an increased risk for a second primary breast cancer.
Thyroid cancer is the second most common malignancy, with a lifetime risk estimated to range from 3% to 38%. The follicular type of thyroid cancer is disproportionately seen in individuals with Cowden syndrome compared to the general population. For women, there is also an elevated risk of endometrial cancer (cancer of the lining of the uterus), with a reported lifetime risk between 5% and 30%. This risk is particularly high for women diagnosed before the age of 50.
Kidney cancer, specifically renal cell carcinoma, is another associated malignancy, with lifetime risk estimates as high as 34% in some studies. Colorectal cancer and melanoma are also associated with the syndrome, though at lower estimated frequencies than breast, thyroid, and endometrial cancers.
Screening and Management Strategies
Once Cowden syndrome is diagnosed, management shifts toward rigorous, lifelong cancer surveillance. The goal is to detect any potential malignancy at the earliest, most treatable stage.
Cancer Surveillance Guidelines
- For women, breast cancer screening begins significantly earlier than the general population, with annual mammograms and breast magnetic resonance imaging (MRI) recommended starting between the ages of 30 and 35, or even earlier if there is a strong family history. Clinical breast exams are also advised every six to twelve months, starting at age 25.
- Thyroid surveillance involves an annual ultrasound of the thyroid gland, often recommended to begin in childhood, as early as age seven. This early and frequent monitoring is necessary due to the increased risk of follicular thyroid cancer.
- Screening for colorectal cancer typically involves a colonoscopy starting at age 35, with subsequent screenings every five years or more frequently if polyps are found. Similarly, screening for renal cell carcinoma is generally recommended to begin around age 40 with a renal ultrasound performed every one to two years.
For endometrial cancer, symptom awareness is emphasized, and women are encouraged to report any abnormal bleeding immediately. Risk-reducing surgeries, such as prophylactic mastectomy or hysterectomy, are also options that can be discussed with a specialist, particularly after childbearing is complete.