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Cowden syndrome


Other Names for this Disease
  • CD
  • Cowden disease
  • Cowden's disease
  • CS
  • MHAM
More Names
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Overview



What is Cowden syndrome?

What symptoms are associated with Cowden sydnrome?

What causes Cowden syndrome?

How is Cowden syndrome inherited?

How is Cowden syndrome diagnosed?

How might Cowden syndrome be treated?


What is Cowden syndrome?

Cowden syndrome is an inherited disorder characterized by multiple noncancerous, tumor-like growths called hamartomas on various areas of the body. Affected individuals are at an increased risk of developing certain cancers, especially cancer of the breast, thyroid or endometrium (lining the uterus). Cowden syndrome is caused by mutations in the PTEN, SDHB, SDHD, and KLLN  genes. This condition is inherited in an autosomal dominant pattern. In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene.[1][2][3]
Last updated: 11/15/2012

What symptoms are associated with Cowden sydnrome?

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 can also occur in the intestinal tract and other parts of the body. Abnormal growths on the skin and mucous membranes typically appear by a person's late twenties. [1]

People with Cowden syndrome also have an increased risk of developing several types of cancer, including cancers of the breast, thyroid, and the lining of the uterus (the endometrium). Noncancerous breast and thyroid diseases are also common. Other signs and symptoms of Cowden syndrome can include an enlarged head (macrocephaly); a rare, noncancerous brain tumor called Lhermitte-Duclos disease; and mental retardation. [1]
Last updated: 10/23/2012

What causes Cowden syndrome?

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.  PTEN is a tumor suppressor gene, which means that it normally prevents cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in the PTEN gene have been identified in about 85 percent of people with Cowden syndrome. These mutations, which affect all of the body's cells, prevent the PTEN protein from effectively regulating cell survival and division. Uncontrolled cell division can lead to the formation of hamartomas and cancerous tumors.

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. [1]

Last updated: 10/23/2012

How is Cowden syndrome inherited?

Cowden syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing noncancerous and cancerous tumors.  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. A person with Cowden syndrome has a 50% chance with each pregnancy of passing along the altered gene to his or her child. [1]
Last updated: 10/23/2012

How is Cowden syndrome diagnosed?

Diagnostic criteria for Cowden syndrome have been developed [2], and are grouped into three separate catagories:

Pathognomonic criteria:

  • Adult Lhermitte-Duclos disease (LDD), defined as the presence of a cerebellar dysplastic gangliocytoma
  • Mucocutaneous lesions:
    • Trichilemmomas (facial)
    • Acral keratoses (thickened area of skin that may be red, yellow, or brown)
    • Papillomatous lesions
    • Mucosal lesions

Major criteria:

  • Breast cancer
  • Thyroid cancer (non-medullary), especially follicular thyroid epithelial cancer
  • Macrocephaly (head circumference 97th percentile)
  • Endometrial carcinoma

Minor criteria:

A clinical diagnosis of Cowden syndrome is made if an individual meets any one of the following combinations:

  • Pathognomonic mucocutaneous lesions alone if there are:

    • Six or more facial papules, of which three or more must be trichilemmoma, or
    • Cutaneous facial papules and oral mucosal papillomatosis, or
    • Oral mucosal papillomatosis and acral keratoses, or
    • Six or more palmo-plantar keratoses

OR

  • Two or more major criteria
    OR
  • One major and at least three minor criteria
    OR
  • At least four minor criteria
Last updated: 10/23/2012

How might Cowden syndrome be treated?

The mucocutaneous manifestations of Cowden syndrome may be treated with topical agents, such as 5-fluorouracil, curettage, cryosurgery, or laser ablation.  Skin lesions may be excised if malignancy is suspected or symptoms (e.g., pain, deformity) are significant. [2]

Because people with Cowden syndrome have an increased risk of developing certain breast, thyroid, and endometrial cancers, an important aspect of management is increased cancer surveillance.  Specific surveillance for breast cancer in individuals with Cowden syndrome includes monthly self-examination beginning at age 18 years (for females and males), annual clinical breast examinations beginning at age 25 years, and annual mammography and breast MRI beginning at age 30-35 years; surveillance for thyroid cancer includes baseline thyroid ultrasound examination at age 18 years and annual thyroid ultrasound examinations; surveillance for endometrial cancer includes annual suction biopsies beginning at age 35-40 years for premenopausal women and annual transvaginal ultrasound examination for postmenopausal women.[2]

Last updated: 10/23/2012

References
  1. Cowden syndrome. Genetics Home Reference (GHR). March 2006; http://ghr.nlm.nih.gov/condition=cowdensyndrome. Accessed 5/18/2011.
  2. Eng C. PTEN Hamartoma Tumor Syndrome (PHTS). GeneReviews. May 5, 2009; http://www.ncbi.nlm.nih.gov/books/NBK1488/. Accessed 5/18/2011.
  3. Eng C. PTEN Hamartoma Tumor Syndrome. National Organization for Rare Disorders (NORD). 2007; http://www.rarediseases.org/rare-disease-information/rare-diseases/byID/1186/viewAbstract. Accessed 5/18/2011.