Cowden syndrome

Synonyms

2

Overview

Cowden 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.

Cowden syndrome is associated with mutations in PTEN, a tumor suppressor gene, that cause the PTEN protein not to work properly leading to hyperactivity of the mTOR pathway. These mutations lead to characteristic features including macrocephaly, intestinal hamartomatous polyps, benign skin tumors (multiple trichilemmomas, papillomatous papules, and acral keratoses) and dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). In addition, there is a predisposition to breast carcinoma, follicular carcinoma of the thyroid, and endometrial carcinoma.

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 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 esophagus.The majority of affected individuals develop the characteristic skin lesions by age 20.

Causes

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.

Diagnosis

The diagnostic criteria for CS are complex and reviewed by geneticists (health professionals with specialized training in medical genetics) frequently as new information becomes available. Sometimes CS is difficult to diagnosis. That’s why teams of hereditary cancer risk specialists including oncologists (cancer doctors), geneticists, genetic counselors, and nurses certified in hereditary cancer have worked together to create diagnostic categories (termed major and minor criteria) summarized in the National Comprehensive Cancer Network (NCCN) guidelines.

Below are the current major and minor criteria as well as the testing criteria for Cowden syndrome:

Major criteria:

  • Breast cancer
  • Endometrial cancer
  • Follicular thyroid cancer
  • Multiple gastrointestinal hamartomas or ganglioneuromas
  • Macrocephaly 
  • Macular pigmentation of glans penis (a discolored area on the skin)
  • Mucocutaneous lesions
  • One biopsy proven trichilemmoma
  • Multiple palmoplantar keratosis (abnormal thickening of the hands and feet)
  • Multifocal or extensive oral mucosal papillomatosis
  • Multiple cutaneous facial papules (often verrucous)

Minor Criteria:

  • Colon cancer
  • Esophageal glycogenic acanthosis (3)
  • Autism spectrum disorder
  • Mental retardation
  • Papillary or follicular variant of papillary thyroid cancer
  • Thyroid structural lesions (such as, adenoma, nodule(s), goiter)
  • Renal cell kidney carcinoma
  • Vascular anomalies (including multiple intracranial developmental venous anomalies)
  • Lipomas (benign soft tissue tumor)
  • Single gastrointestinal hamartoma or ganglioneuroma
  • Testicular lipomatosis

Cowden Syndrome PTEN Gene Testing Criteria

  • Individuals with a personal history of:
  • A family with a known PTEN gene mutation
  • Meeting clinical diagnostic criteria for CS
  • Bannayan-Riley-Ruvalcaba syndrome (BRR)
  • Adult Lhermitte-Duclos disease (cerebellar tumors)
  • Autism spectrum disorder and macrocephaly
  • Two or more biopsy-proben trichilemmomas
  • Two or more major criteria (one must be macrocephaly)

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.