Cowden syndrome is a genetic 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.

Cowden syndrome is associated with an increased risk of developing several types of cancer, particularly cancers of the breast, a gland in the lower neck called the thyroid, and the lining of the uterus (the endometrium). Other cancers that have been identified in people with Cowden syndrome include kidney cancer, colorectal cancer, and an agressive form of skin cancer called melanoma. Compared with the general population, people with Cowden syndrome develop these cancers at younger ages, often beginning in their thirties or forties. People with Cowden syndrome are also more likely to develop more than one cancer during their lifetimes compared to the general population. Other diseases of the breast, thyroid, and endometrium are also common in Cowden syndrome. Additional signs and symptoms can include an enlarged head (macrocephaly) and a rare, noncancerous brain tumor called Lhermitte-Duclos disease. A small percentage of affected individuals have delayed development, intellectual disability, or autism spectrum disorder, which can affect communication and social interaction.

Some people do not meet the strict criteria for a clinical diagnosis of Cowden syndrome, but they have some of the characteristic features of the condition, particularly the cancers. These individuals are often described as having Cowden-like syndrome. Both Cowden syndrome and Cowden-like syndrome are caused by mutations in the same genes.

The features of Cowden syndrome overlap with those of another disorder called Bannayan-Riley-Ruvalcaba syndrome. People with Bannayan-Riley-Ruvalcaba syndrome also develop hamartomas and other noncancerous tumors. Some people with Cowden syndrome have relatives diagnosed with Bannayan-Riley-Ruvalcaba syndrome, and other affected individuals have the characteristic features of both conditions. Based on these similarities, researchers have proposed that Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome represent a spectrum of overlapping features known as PTEN hamartoma tumor syndrome (named for the genetic cause of the conditions) instead of two distinct conditions.

Changes in the PTEN, KLLN, or WWP1gene are most commonly identified in people with Cowden syndrome or Cowden-like syndrome.

About 25 percent 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 PTEN 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, research is needed to determine what role mutations in this gene play in causing the other features of Cowden syndrome, such as macrocephaly and intellectual disability.

Rarely, Cowden syndrome and Cowden-like syndrome result from a change 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 leads to reduced production of the killin protein. 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 Cowden syndrome and Cowden-like syndrome are associated with variants in the WWP1 gene. The WWP1 gene provides instructions for making a protein that is involved in the process that targets other proteins to be broken down (degraded) within cells. During this process, the WWP1 protein attaches (binds) to the PTEN protein, which impairs PTEN's function. WWP1 gene variants are described as "gain-of-function" because they appear to enhance the activity of the WWP1 protein. Studies suggest that the altered protein binds to the PTEN protein more readily than normal. Excessive binding impairs PTEN's tumor suppressor activity, allowing cells to proliferate unchecked and, leading to the formation of tumors.

Mutations in a few other genes are each responsible for a very small percentage of cases of Cowden syndrome and Cowden-like syndrome. In the remaining cases, the genetic cause is unknown.

Normal Function

The PTEN gene provides instructions for making an enzyme that is found in almost all tissues in the body. The enzyme acts as a tumor suppressor, which means that it helps regulate cell division by keeping cells from growing and dividing (proliferating) too rapidly or in an uncontrolled way. To function, the PTEN enzyme attaches (binds) to another PTEN enzyme (dimerizes) then binds to the cell membrane. The PTEN enzyme modifies other proteins and fats (lipids) by removing phosphate groups, each of which consists of a cluster of oxygen and phosphorus atoms. Enzymes with this function are called phosphatases.

The PTEN enzyme is part of a chemical pathway that signals cells to stop dividing and triggers cells to self-destruct through a process called apoptosis. Evidence suggests that this enzyme also helps control cell movement (migration), the sticking (adhesion) of cells to surrounding tissues, and the formation of new blood vessels (angiogenesis). Additionally, it likely plays a role in maintaining the stability of a cell's genetic information. All of these functions help prevent uncontrolled cell proliferation that can lead to the formation of tumors.

Health Conditions Related to Genetic Changes

Bannayan-Riley-Ruvalcaba syndrome

More than 30 mutations in the PTEN gene have been found to cause Bannayan-Riley-Ruvalcaba syndrome. Common features of this condition include a large head size (macrocephaly), multiple noncancerous tumors and tumor-like growths called hamartomas, and dark freckles on the penis in males. Bannayan-Riley-Ruvalcaba syndrome is one of several related conditions that are often considered together as PTEN hamartoma tumor syndrome (described below).

Some of the mutations that cause Bannayan-Riley-Ruvalcaba syndrome change single DNA building blocks (base pairs) in the PTEN gene or insert or delete a small number of base pairs. Other mutations result in an abnormally short enzyme or reduce the amount of enzyme that is produced. In about 10 percent of cases, Bannayan-Riley-Ruvalcaba syndrome results from the deletion of a large amount of genetic material that includes part or all of the PTEN gene. All of these genetic changes prevent the PTEN enzyme from regulating cell proliferation effectively, which can lead to uncontrolled cell growth and the formation of hamartomas and other types of tumors. Research is needed to determine what role PTEN gene mutations play in causing macrocephaly and the other features of Bannayan-Riley-Ruvalcaba syndrome.

Breast cancer

Inherited mutations in the PTEN gene increase the risk of developing breast cancer. In many cases, this increased risk occurs as part of Cowden syndrome (described below). Inherited mutations in the PTEN gene are thought to account for only a small fraction of all breast cancer cases.

Noninherited (somatic) PTEN gene mutations occur in some breast cancers in women without a family history of the disease. Somatic mutations are not inherited and do not occur as part of a familial cancer syndrome. They are acquired during a person's lifetime and occur only in certain cells in the breast. These mutations impair the tumor suppressor function of the PTEN enzyme, allowing cells to grow and divide without control or order. This uncontrolled cell growth contributes to the formation of a cancerous tumor. Studies suggest that a loss of functional PTEN enzyme is also related to poor responsiveness to a drug called trastuzumab (Herceptin), which is used to treat breast cancer.

Cowden syndrome

Researchers have identified more than 300 mutations in the PTEN gene that can cause Cowden syndrome or a similar disorder called Cowden-like syndrome. These conditions are characterized by the growth of multiple hamartomas and an increased risk of developing certain cancers, particularly breast cancer (described above), thyroid cancer, and cancer of the uterine lining (endometrial cancer). Cowden syndrome and Cowden-like syndrome are considered to be part of PTEN hamartoma tumor syndrome (described below).

Mutations that cause Cowden syndrome and Cowden-like syndrome include changes in a small number of base pairs and, in some cases, deletions of a larger amount of genetic material from the PTEN gene. These mutations lead to the production of a PTEN enzyme that does not function properly or does not work at all. The altered enzyme is unable to restrain cell division or signal abnormal cells to die, which contributes to the development of hamartomas and cancerous tumors.

Autism spectrum disorder

PTEN gene mutations have been identified in several people who have both an unusually large head size and the characteristic features of autism spectrum disorder, which affects communication and social interaction. Many of these mutations change single protein building blocks (amino acids) in the PTEN enzyme or lead to the production of an abnormally short version of the enzyme. Researchers are studying how changes in the PTEN gene are related to the risk of developing autism spectrum disorder. Some of these mutations have also been reported in families with PTEN hamartoma tumor syndrome (described below), and it is unclear how these mutations can cause different disorders.

Prostate cancer

Studies suggest that somatic mutations in the PTEN gene may be the most frequent genetic changes in prostate cancer. Mutations in the PTEN gene reduce or eliminate the tumor suppressor function of the PTEN enzyme. The loss of this enzyme's function likely permits certain cells to divide uncontrollably, contributing to the growth of cancerous tumors. In some cases, the presence of PTEN gene mutations is associated with more advanced stages of tumor growth.

Bladder cancer

MedlinePlus Genetics provides information about Bladder cancer

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Head and neck squamous cell carcinoma

MedlinePlus Genetics provides information about Head and neck squamous cell carcinoma

Lung cancer

MedlinePlus Genetics provides information about Lung cancer

Other disorders

Several related conditions caused by mutations in the PTEN gene, including Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome (described above), are often considered together as PTEN hamartoma tumor syndrome. The mutations that cause these conditions are present in cells throughout the body and are often inherited from a parent. Some of the mutations that cause PTEN hamartoma tumor syndrome lead to a defective version of the PTEN enzyme that cannot perform its function as a tumor suppressor. Other mutations prevent the PTEN gene from producing any enzyme at all. Without functional PTEN enzyme, cell division is not controlled effectively and damaged cells continue to divide inappropriately, leading to the development of hamartomas and other tumors.

In some published case reports, mutations in the PTEN gene have been associated with Proteus syndrome, a rare condition characterized by asymmetric overgrowth of the bones, skin, and other tissues. However, many researchers now believe that individuals with PTEN gene mutations and asymmetric overgrowth do not meet the strict guidelines for a clinical diagnosis of Proteus syndrome. Instead, these individuals have a condition that is considered part of PTEN hamartoma tumor syndrome. One name that has been proposed for the condition is segmental overgrowth, lipomatosis, arteriovenous malformations, and epidermal nevus (SOLAMEN) syndrome; another is type 2 segmental Cowden syndrome. However, some scientific articles still refer to PTEN-related Proteus syndrome.

Other cancers

Somatic mutations in the PTEN gene are among the most common genetic changes found in human cancers. The cancers associated with somatic mutations are not inherited and do not occur as part of a cancer syndrome. Somatic mutations in the PTEN gene have been reported in many types of cancer, and studies suggest that PTEN may be the most frequently mutated gene in endometrial cancer. PTEN gene mutations are also commonly found in brain tumors called glioblastomas and astrocytomas, and in an aggressive form of skin cancer called melanoma. Mutations in the PTEN gene reduce or eliminate the tumor suppressor function of the PTEN enzyme. The loss of this enzyme's function likely permits certain cells to divide uncontrollably, contributing to the growth of cancerous tumors. In some cases, the presence of PTEN gene mutations is associated with more advanced stages of tumor growth.

Other Names for This Gene

• MMAC1
• mutated in multiple advanced cancers 1
• phosphatase and tensin homolog (mutated in multiple advanced cancers 1)
• phosphatase and tensin homolog deleted on chromosome 10
• protein-tyrosine phosphatase PTEN
• PTEN-MMAC1 protein
• PTEN1
• PTEN_HUMAN
• TEP1
• TEP1 phosphatase

Genomic Location

Normal Function

The KLLN gene provides instructions for making a protein called killin. The activity of the KLLN gene is controlled by a protein called p53 (which is produced from the TP53 gene). Little is known about the function of killin, although it is thought to trigger cells to self-destruct (undergo apoptosis) when they are damaged or no longer needed. In this way, killin helps to prevent abnormal cells from growing and dividing unchecked to form tumors. Through its role in regulating cell division, killin helps maintain the stability of a cell's genetic information. Based on these roles, killin is thought to be a tumor suppressor.

Health Conditions Related to Genetic Changes

Cowden syndrome

Some cases of Cowden syndrome and a similar condition called Cowden-like syndrome result from a change involving the KLLN gene. These conditions are characterized by multiple tumor-like growths called hamartomas and an increased risk of developing certain cancers. When Cowden syndrome and Cowden-like syndrome are caused by KLLN gene mutations, the conditions are associated with a particularly high risk of developing breast and kidney cancers.

The genetic change associated with these conditions 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.

The promoter region of the KLLN gene is shared with another gene, PTEN. The single promoter controls the expression of both genes. However, specific hypermethylation of the KLLN gene promoter only affects the expression of the KLLN gene; people with this type of genetic change have normal expression of the PTEN gene. Other types of mutations in the PTEN gene can cause Cowden syndrome and Cowden-like syndrome.

Other Names for This Gene

• KILIN_HUMAN
• KILLIN
• killin
• killin, p53-regulated DNA replication inhibitor

Genomic Location

Normal Function

The WWP1 gene provides instructions for making a protein that is found is many tissues. This protein has activity known as E3 ubiquitin ligase. Proteins with this activity are involved in the process that targets other proteins to be broken down (degraded) within cells. Protein degradation is a normal process that removes damaged or unnecessary proteins and helps maintain the normal functions of cells.

The WWP1 protein can attach (bind) to various other proteins and mark them for degradation or alteration. In particular, the WWP1 protein binds to an enzyme called PTEN. The PTEN enzyme acts as a tumor suppressor, which means that it helps regulate cell division by keeping cells from growing and dividing (proliferating) too rapidly or in an uncontrolled way. To function, the PTEN enzyme has to bind to another PTEN enzyme (dimerize). Binding of the WWP1 protein to the PTEN enzyme impairs the PTEN enzyme's ability to dimerize, impairing the enzyme's activity.

Health Conditions Related to Genetic Changes

Cowden syndrome

At least 7 variants in the WWP1 gene have been identified in people with Cowden syndrome or a similar disorder called Cowden-like syndrome. These conditions are characterized by multiple tumor-like growths called hamartomas and an increased risk of developing certain cancers, particularly breast cancer, thyroid cancer, colorectal cancer, and cancer of the uterine lining (endometrial cancer). Other features of Cowden syndrome can include an enlarged head (macrocephaly) and a rare, noncancerous brain tumor called Lhermitte-Duclos disease. People with Cowden syndrome or Cowden-like syndrome and WWP1 gene variants are more likely to develop colorectal cancer than individuals with Cowden syndrome associated with other genes.

The WWP1 gene variants associated with Cowden syndrome and Cowden-like syndrome change single amino acids in the WWP1 protein. Researchers describe these variants as "gain-of-function" because they appear to enhance the activity of the WWP1 protein. Studies suggest that the altered protein binds to the PTEN enzyme more often than normal. Excessive binding impairs PTEN enzyme tumor suppressor activity, allowing cells to proliferate unchecked, leading to the formation of tumors.

Cancers

Mutations in the WWP1 gene are also associated with several types of cancers without the additional features of Cowden syndrome (described above). These include cancers of the prostate, breast, liver as well as other cancers that often occur in Cowden syndrome. Unlike the WWP1 gene changes in Cowden syndrome, these mutations are somatic, which means they arise during a person's lifetime and are not inherited. These mutations are found only in cells that give rise to cancer.

Similar to those in Cowden syndrome, the WWP1 gene changes are also known "gain-of-function" mutations as they enhance the activity of the WWP1 protein. As a result, the altered protein is thought to bind to the PTEN enzyme more often than normal. Excessive binding impairs PTEN enzyme tumor suppressor activity, allowing cells to proliferate unchecked, leading to cancer development in affected cells.

Other Names for This Gene

• TGIF-interacting ubiquitin ligase 1
• TIUL1
• WW domain-containing E3 ubiquitin protein ligase 1

Genomic Location

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.

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.

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. [Hildenbrand et al 2001].

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