Cowden syndrome

Other Names: Cowden disease; CD; Cowden's disease; CS; Multiple hamartoma syndrome; MHAM

Cowden syndrome is a disorder characterized by multiple noncancerous, tumor-like growths called hamartomas and an increased risk of developing certain cancers. Almost everyone with Cowden syndrome develops hamartomas. These growths are most commonly found on the skin and mucous membranes (such as the lining of the mouth and nose), but they can also occur in the intestine and other parts of the body. The growth of hamartomas on the skin and mucous membranes typically becomes apparent by a person's late twenties.

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Epidemiology

Although the exact prevalence of Cowden syndrome is unknown, researchers estimate that it affects about 1 in 200,000 people.

Cause

Changes involving at least four genes, PTEN, SDHB, SDHD, and KLLN, have been identified in people with Cowden syndrome or Cowden-like syndrome.

Most cases of Cowden syndrome and a small percentage of cases of Cowden-like syndrome result from mutations in the PTEN gene. The protein produced from the PTEN gene is a tumor suppressor, which means that it normally prevents cells from growing and dividing (proliferating) too rapidly or in an uncontrolled way. Mutations in the PTEN gene prevent the protein from regulating cell proliferation effectively, leading to uncontrolled cell division and the formation of hamartomas and cancerous tumors. The PTEN gene likely has other important functions within cells; however, it is unclear how mutations in this gene cause the other features of Cowden syndrome, such as macrocephaly and intellectual disability.

Other cases of Cowden syndrome and Cowden-like syndrome result from changes involving the KLLN gene. This gene provides instructions for making a protein called killin. Like the protein produced from the PTEN gene, killin probably acts as a tumor suppressor. The genetic change that causes Cowden syndrome and Cowden-like syndrome is known as promoter hypermethylation. The promoter is a region of DNA near the gene that controls gene activity (expression). Hypermethylation occurs when too many small molecules called methyl groups are attached to the promoter region. The extra methyl groups reduce the expression of the KLLN gene, which means that less killin is produced. A reduced amount of killin may allow abnormal cells to survive and proliferate inappropriately, which can lead to the formation of tumors.

A small percentage of people with Cowden syndrome or Cowden-like syndrome have variations in the SDHB or SDHD gene. These genes provide instructions for making parts of an enzyme called succinate dehydrogenase (SDH), which is important for energy production in the cell. This enzyme also plays a role in signaling pathways that regulate cell survival and proliferation. Variations in the SDHB or SDHD gene alter the function of the SDH enzyme. Studies suggest that the defective enzyme may allow cells to grow and divide unchecked, leading to the formation of hamartomas and cancerous tumors. However, researchers are uncertain whether the identified SDHB and SDHD gene variants are directly associated with Cowden syndrome and Cowden-like syndrome. Some of the variants described above have also been identified in people without the features of these conditions.

When Cowden syndrome and Cowden-like syndrome are not related to changes in the PTEN, SDHB, SDHD, or KLLN genes, the cause of the conditions is unknown.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

Cowden syndrome and Cowden-like syndrome are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the condition and increase the risk of developing cancer. In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.

Signs and symptoms

Cowden syndrome is characterized primarily by multiple, noncancerous growths (called hamartomas) on various parts of the body. Approximately 99% of people who have Cowden syndrome will have benign growths on the skin and/or in the mouth by the end of their 20s. A majority of people with Cowden syndrome will also develop growths (called hamartomatous polyps) along the inner lining of the gastrointestinal tract.

People affected by Cowden syndrome also have an increased risk of developing certain types of cancer. Breast, thyroid, and endometrial (the lining of the uterus) cancers are among the most commonly reported tumors. The lifetime risk of developing breast cancer is 85%; for thyroid cancer the risk is approximately 35%; and the risk for endometrial cancer is about 28%. Other associated cancers include colorectal cancer, kidney cancer, and melanoma. People with Cowden syndrome often develop cancers at earlier ages (before age 50) than people without a hereditary predisposition to cancer.

Other signs and symptoms of Cowden syndrome may include benign diseases of the breast, thyroid, and endometrium; a rare, noncancerous brain tumor called Lhermitte-Duclos disease; an enlarged head (macrocephaly); autism spectrum disorder; intellectual disability; and vascular (the body's network of blood vessels) abnormalities.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 

80%-99% of people have these symptoms

• Breast carcinoma(Breast cancer)
• Colorectal polyposis
• Conjunctival hamartoma
• Generalized hyperkeratosis
• Goiter(Enlarged thyroid gland in neck)
• Macule(Flat, discolored area of skin)
• Palmoplantar keratoderma(Thickening of palms and soles)
• Papilloma
• Papule

30%-79% of people have these symptoms

• Abnormality of the penis
• Adenoma sebaceum
• Ataxia
• Cavernous hemangioma(Collection of dilated blood vessels that forms mass)
• Cognitive impairment(Abnormality of cognition)
• Furrowed tongue(Grooved tongue)
• Global developmental delay
• Hamartomatous polyposis
• Intellectual disability(Mental deficiency)
• Lipoma(Fatty lump)
• Macrocephaly(Increased size of skull)
• Macroglossia(Abnormally large tongue)
• Melanocytic nevus(Beauty mark)
• Meningioma
• Mucosal telangiectasiae
• Subcutaneous nodule(Firm lump under the skin)

Diagnosis

A diagnosis of Cowden syndrome is based on the presence of characteristic signs and symptoms. Genetic testing for a mutation in the PTEN gene can then be ordered to confirm the diagnosis. If a mutation in PTEN is not found, genetic testing for the other genes known to cause Cowden syndrome can be considered.

The National Comprehensive Cancer Network [NCCN 2015] consensus clinical diagnostic criteria have been divided into three categories:

Pathognomonic criteria (criteria that is characteristic for a particular disease): mucosal and skin lesions Major criteria: breast cancer, macrocephaly, thyroid cancer and endometrial cancer Minor criteria: thyroid lesions, intellectual disability, hamartomatous intestinal polyps, fibrocystic disease of the breast, lipomas, fibromas, genital and urinary tumors or malformations, uterine fibroids

A diagnosis is given if a patient has the "pathognomonic" skin lesions, two or more major criteria, one major and 3 or more minor criteria, or 4 or more minor criteria. The diagnostic criteria for adults and children have some differences. The PTEN Cleveland Clinic Risk Calculator can be used to estimate the chance of finding a PTEN mutation in children and adults with signs and symptoms of Cowden syndrome.

Finding mutations in the PTEN gene or other causal genes confirms diagnosis.

Treatment

Because Cowden syndrome is associated with an increased risk for certain types of cancer, management is typically focused on high-risk cancer screening. According to the National Comprehensive Cancer Network 2014, the recommended screening protocol for Cowden syndrome includes: Cancer Screening for Women

• Breast self exams beginning at age 18
• Clinical breast exams every 6-12 months beginning at age 25
• Annual mammogram and breast MRI beginning at age 30-35
• Annual screening for endometrial cancer with ultrasound and/or random biopsy may be considered beginning at age 30-35
• Prophylactic surgeries may be considered as a preventative option for some forms of cancer
• Cancer Screening for Men and Women
• Annual physical examination beginning at age 18
• Annual thyroid ultrasound beginning at age 18
• Baseline colonoscopy at age 35 with follow-up every 5 years (more frequent if polyps identified)
• Consider renal (kidney) ultrasound every 1-2 years beginning at age 40
• or individualized based on the earliest diagnosis of cancer in the family.

Pediatric (age <18 years)

• Yearly thyroid ultrasound examination** (on identification of a PTEN pathogenic variant)
• Yearly skin check with physical examination
• Neurodevelopmental evaluation

If there are not any symptoms, observation alone is prudent. Cutaneous lesions should be removed only if malignancy is suspected or symptoms (e.g., pain, deformity, increased scarring) are serious. When symptomatic, topical agents (e.g., 5-fluorouracil), curettage, cryosurgery, or laser ablation may offer temporary relief.

NIH genetic and rare disease info

• NIH info on Cowden syndrome

Cowden syndrome is a rare disease.

Cowden syndrome Resources
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