Cowden syndrome

If you have a positive result after genetic testing, other family members are at risk to have the same genetic change. First-degree relatives (siblings, children, and parents) have a 50% chance to have the same genetic change. Second-degree relatives (nieces/nephews, aunts/uncles, grandparents, grandchildren, and half siblings) have a 25% chance to have the same gene mutation. It is recommended that relatives be informed of their risk. Whether testing is right for them is a personal decision.

Hypothetical example: "John" has a PTEN mutation. His brother "Tom" then has testing for the PTEN mutation that returns negative. Tom’s children do not then need to receive genetic testing for John’s PTEN mutation. Tom could not have passed down the PTEN mutation, because he did not inherit it himself. You cannot pass on a gene mutation you do not have.

Other people with Cowden syndrome can be found through online support groups. These groups include:

People with Cowden syndrome should be managed by a multidisciplinary team with expertise in caring for people with this condition. Specialists may include oncologists, dermatologists, possibly surgeons, and other providers.

People with Cowden should see a genetic counselor. A genetic counselor can help to further explain Cowden syndrome and and answer any questions you have. A genetic counselor can also help to make any appropriate referrals to specialists. Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

In general, increased breast cancer screening may detect breast cancer at an earlier, more treatable stage. Increased breast cancer screening for women commonly involves clinical breast exams, starting at age 25, and an annual mammogram and breast MRI, starting at 30-35 years of age. Screening may be recommended earlier, depending on the family history. After age 75, breast screening should be considered on an individual basis.

There may also be options to lower the risk for breast cancer. More specifically, surgery may be an option to lower risk. But surgery is not for everyone. For women, a bilateral risk-reducing mastectomy (removal of both breasts) can greatly reduce the risk of developing breast cancer.

Families that have had multiple diagnoses of cancer, particularly breast, uterine, and thyroid cancer, may have a gene change in PTEN. Colorectal cancer, kidney cancer, and melanoma can also be found in families with Cowden syndrome. We expect to see these diagnoses at younger ages than usual as well. For breast cancer, a diagnosis before age 50 is younger than expected in the general population.

There are also non-cancer related findings that are commonly seen in families with Cowden syndrome. For example, most people with CS develop hamartomas (non-cancerous, tumor-like growths) on their skin and mucous membranes, such as the inside of their mouth. Macrocephaly (head circumference over 97th percentile) is also a common feature of this condition.

A genetic counselor can help you understand whether your family may have a PTEN gene change. Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

mTOR inhibitors are a class of drugs that inhibit the mammalian target of rapamycin (mTOR), which is a kind of protein in the body. mTOR inhibitors show promise for treatment of cancer in individuals with Cowden syndrome who have a germline PTEN mutation. However, use of mTOR is currently limited to clinical trials.

The Cleveland Clinic’s Genomic Medicine Institute created a risk assessment tool to help estimate the chance a person has a mutation in the PTEN gene. The risk calculator for estimation of PTEN mutation probability was designed to help healthcare providers determine the chance that a patient has a PTEN gene mutation. Patients are encouraged to share results with their healthcare provider. The risk calculator is not diagnostic, but can be used to help determine whether genetic testing is warranted.

If someone in your family has been diagnosed with Cowden syndrome, the chance that you also carry the same gene mutation can be determined by how that relative is related to you. For example, first-degree relatives (siblings, children, and parents) have a 50% chance to have the same genetic change. Second-degree relatives (nieces/nephews, aunts/uncles, grandparents, grandchildren, and half siblings) have a 25% chance to have the same gene mutation.

Genetic counselors can help individuals living with Cowden understand the risks to others in their family. Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

There are key differences between analyzing the DNA from a tumor and analyzing DNA from your blood. It is not uncommon to have DNA analysis (DNA sequencing) performed on a tumor sample. Outcomes can sometimes affect treatment options. Most of the genetic changes found in a tumor sample are new (somatic) changes. Somatic mutations are not present at birth, but rather they arise randomly later in life. Many somatic changes are made during the growth of a tumor. A PTEN gene mutation found in a tumor does not confirm that a person has Cowden syndrome.

Cowden syndrome is caused by germline mutations. These are genetic changes that we have in our DNA from birth, and we expect to find them in every cell in our body. DNA sequencing on blood or saliva samples can detect these germline mutations.

A PTEN mutation can run in families and and when it does it will be inherited in an autosomal dominant pattern. This means that if a parent is found to have a mutation in that gene, each of their children have a 50% chance of inheriting it. The risk that a child will have the PTEN mutation if a half sibling is known to have the mutation is an good case study to explain how the autosomal dominant pattern of inheritance works. For purposes of this explanation, let’s assume that you have a donor-conceived child and you just learned that your child’s half sibling has a PTEN mutation with an associated developmental delay.

You would likely be concerned that the donor carries the PTEN mutation making it possible that your child also inherited the mutation but remember, there is also the possibility that your child’s half sibling inherited the PTEN mutation from the other parent. If that were the case, your child would not be at increased risk to have a mutation in the PTEN gene. Even if the donor DOES have the mutation, your child would have a 50% chance NOT to have the PTEN mutation.

Cowden syndrome (the syndrome associated with PTEN mutations) is likely under diagnosed because the symptoms aren’t always picked up by physicians because they can be so mild. Because of this, the actual number of isolated cases (individuals with no obvious family history) compared to familial cases (defined as two or more related affected individuals) isn’t well known. But, it is believed that most cases of Cowden syndrome (CS) are appearing for the first time in the family due to de novo mutations. Between 10%-50% of individuals with CS have an affected parent.

The most common sign of CS in both children and adults is having a head circumference that is bigger than 97% of people their age and of the same sex (macrocephaly). If you know that your child’s head is smaller than the 97th percentile for their age, that is one piece of information leaning towards them not having the PTEN mutation.

If the donor is found to carry the PTEN mutation, a genetic counselor would be a great person to talk to regarding ordering genetic testing for your child, the risks associated, and the appropriate management/surveillance. You can use the Find a Genetic Counselor’ tool to find a genetic nurse or counselor in your area.

Some people have some of the features of Cowden syndrome, such as the cancers associated with this condition, but do not meet the strict criteria for a diagnosis of Cowden syndrome. These individuals are often described as having Cowden-like syndrome.

Cowden syndrome (CS) is a genetic condition in which people have an increased risk for certain types of cancer, including breast, uterine, thyroid, and other cancers.

Cowden syndrome is characterized by multiple hamartomas, or non-cancerous tumor-like growths. There are certain skin findings associated with Cowden syndrome. These skin findings include both trichilemmomas (growths involving the hair follicle) and papillomatous papules (raised growths on the face). People with CS often have a larger head size (macrocephaly; head circumference over 97th percentile). A small number of people with this condition may have developmental delay or autism. Some people may also develop a hamartoma, or benign tumor, of the brain referred to as Lhermitte-Duclos disease.

Genes act as the instructions for the body. We all have two copies of the PTEN gene. We inherit one copy from our mom and one copy from our dad. PTEN is a tumor suppressor gene. When working properly, the PTEN genes help to reduce cancer risk. People with Cowden syndrome have a gene change (mutation) in one of their PTEN genes that causes the gene not to work properly. A nonworking copy of the PTEN leads to increased risk for cancer.

Genetic changes, or mutations, in the PTEN gene most often cause Cowden syndrome (CS). Rarely Cowden syndrome or Cowden-like syndrome can also result genetic changes involving the KLLN gene. This genetic change is called promoter hypermethylation. There are also other genes that should be considered for people who have a CS or Cowden-like syndrome and who had negative PTEN genetic testing. Some of these genes include: SDHB, SDHC, SDHD, PIK3CA and AKT1.

It’s not uncommon to find a genetic difference in the PTEN gene that we don’t know much about. We call this a "variant of unknown significance" or a VUS. This means that a genetic change was found that we do not fully understand. In other words, this genetic change may cause Cowden syndrome or it may be a normal variation. We need more data to be sure. A genetic counselor or geneticist may be able to help explain what this result means in your particular situation. Over time, scientists may learn more about variants of unknown significance. It is important to check with your healthcare provider on an annual basis for updates on the VUS. Over time, scientists may learn enough about the VUS to determine if a variant is associated with an increased risk for cancer or if the finding is just a normal variation that is harmless.

A positive test result means that a genetic change was found in the PTEN gene that leads to increased risk for cancer. This result will likely change your medical management. Your doctor will discuss with you the recommendations for increased monitoring and cancer screening. It is also recommended that you inform your relatives if you receive a positive result. This information could affect their health as well.

A negative genetic test result means no genetic changes were identified in the gene(s) that were analyzed. A negative genetic testing result will mean different things to different people.

PTEN Hamartoma Tumor syndrome (PHTS) is the term used to describe the group of conditions caused by a genetic change in PTEN. These conditions include:

The main symptoms or features of Cowden syndrome (CS) include hamartomas, or non-cancerous tumor-like growths, and an increased risk to develop cancer.

People with CS have an increased risk for breast, uterine, and thyroid cancer. The risk for colorectal cancer, kidney cancer, and melanoma is also increased.

Hamartomas are most commonly found on the skin and mucous membranes, such as the inside of the mouth. These growths include both trichilemmomas (growths involving the hair follicle) and papillomatous papules (raised wart-like growths that can appear on the skin or inside the mouth). Acral keratoses (small, raised bumps on the upper surface of the hands or feet, nose, or ears), and palmoplantar keratoses (scaly spots on the palms and soles) are also common.

People with CS often have a larger head size (macrocephaly). A small number of people with this condition may have developmental delay or autism. Some people may also develop a hamartoma, or benign tumor, of the brain referred to as Lhermitte-Duclos disease.

Cancer screening recommendations for individuals with Cowden syndrome is slightly different between women and men. This may include:

Women beginning at age 30 years:

Women with Cowden syndrome (CS) have an increased risk for breast, uterine, and thyroid cancer. The lifetime risk for colorectal cancer, kidney cancer, and melanoma is also increased.

More specifically, women have up to an 85% risk to develop breast cancer and up to a 28% risk for uterine cancer by age 85. Women also have up to a 35% risk to develop thyroid cancer, typically follicular thyroid cancer, by age 85. While some people with CS develop papillary thyroid cancer, medullary thyroid cancer is not associated with Cowden syndrome. Women with CS have a 9-16% lifetime risk for colorectal cancer and up to a 34% risk for kidney cancer and up to a 6% risk for melanoma by age 85.

Men with Cowden syndrome have an increased for thyroid cancer, kidney cancer, colorecal cancer, and melanoma. More specifically, men have up to a 35% risk to develop thyroid cancer, typically follicular thyroid cancer, by age 85. While some people with CS develop papillary thyroid cancer, medullary thyroid cancer is not associated with Cowden syndrome. Men with CS have a 9-16% lifetime risk for colorectal cancer. Men also have up to a 34% risk for kidney cancer and up to a 6% risk for melanoma by age 85.

The penetrance of CS is approximately 80%, which means that most people with CS will develop some features of this condition over their lifetime. Most people with CS develop hamartomas (non-cancerous, tumor-like growths) on their skin and mucous membranes, such as the inside of their mouth, by their late 20’s. Macrocephaly (head circumference over 97th percentile) is also a common feature of this condition. It is estimated that 80-100% of people with CS will have macrocephaly.

Individuals with Cowden syndrome do not all develop the same symptoms. In other words, Cowden syndrome has variable expression. For example, only a small number of people have autism or developmental delay. Also, not every person with Cowden syndrome will develop cancer in his or her lifetime. The lifetime risk of developing breast cancer is 85%, with an average age of diagnosis between 38 and 46 years. The lifetime risk for thyroid cancer (usually follicular, rarely papillary, but never medullary thyroid cancer) is approximately 35%. The risk for endometrial cancer may approach 28%. Knowing about this increased risk for developing certain types of cancer will help healthcare providers offer appropriate screening and risk reduction options.

Some women at increased risk for breast cancer consider prophylactic mastectomy, where both breasts are removed surgically before being diagnosed with cancer. Prophylactic mastectomy reduces the risk of breast cancer by 90% in women at high risk. The recommendation of prophylactic mastectomy is a generalization for women at increased risk for breast cancer from a variety of causes, not just from Cowden syndrome. Discuss this information with your doctor. The best plan for you should be made on a case by case basis, for example, if breast tissue is dense or if repeated breast biopsies have been necessary.

Because symptoms of Cowden syndrome can onset before 18 years of age, it is not uncommon to test minors for this condition. There are not any guidelines for testing children for this condition nor is there a recommended age at which testing should be offered. The medical and psychological benefits and risks of testing a child for Cowden syndrome need to be carefully considered. Although there are medical benefits to learning if a child carries a PTEN mutation, testing during childhood takes away the child’s option to later choose not to be tested or when to have testing. Healthcare providers should help facilitate decision making by the parents and the child.

Certain features are suggestive of Cowden syndrome. Adult Lhermitte-Duclos disease (LDD), a rare, non-cancerous brain tumor, is strongly associated with CS. It has been reported that 32% of patients with CS will develop LDD. Furthermore, autism and macrocephaly (head circumference over 97th percentile) are also strongly associated with CS. Approximately 10-20% of people with autism spectrum disorder and macrocephaly have a PTEN gene mutation.

Hamartomas (benign growths) are not specific to Cowden syndrome, but can by suggestive of PTEN hamartoma tumor syndrome (PHTS), particularly if they are seen with early cancer diagnoses or other features associated with CS.

Newborn screening is performed soon after a baby is born. It ensures that all babies are screened for certain serious conditions at birth. Cowden syndrome is not one of the conditions included on newborn screening. Cowden syndrome is not included on the Recommended Uniform Screen Panel (RUSP). The RUSP is created by the Health Resources and Services Administration and lists the conditions every baby should be screened for. States use this list to guide what conditions they include on newborn screening.

There are multiple testing options for Cowden syndrome. If there is a known gene mutation in a family, targeted testing, also known as single site testing, can be ordered. With targeted testing, the laboratory will only look for one specific genetic change instead of scanning the entire gene. This is generally the least expensive option offered by testing companies. In order to have targeted testing, you must provide a copy of your relative’s positive genetic test result so the laboratory knows what genetic change to test for.

There are also testing options when a gene mutation has not been identified in the family. Many laboratories offer complete analysis of the PTEN gene. This analysis involves sequencing and deletion/duplication analysis of the PTEN gene.

Testing for the PTEN gene may also be included in a cancer panel test, which includes multiple genes that are associated with increased cancer risks.

There are numerous genes beyond PTEN that can be associated with hereditary breast and/or hereditary uterine cancer. In some situations, testing for multiple genes may be more efficient and/or cost-effective. This type of testing is often referred to as multi-gene testing or panel testing. Cancer panels often include PTEN and other genes that are associated with hereditary cancer.

Of note, there are other genes that should be considered for people who have a CS or Cowden-like syndrome and who had negative genetic testing for a PTEN gene mutation. Some of these genes include: KLLN, SDHB, SDHC, SDHD, PIK3CA and AKT1.

There are benefits, risks, and limitations to any type of genetic testing. It is important to have genetic counseling from a qualified healthcare provider to aid in this decision making process. Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

Current research being conducted on Cowden syndrome and for people with a mutation, or genetic change, in PTEN can be found at the following:

There may also options to lower the risk for uterine cancer. More specifically, surgery may be an option to lower risk. But surgery is not for everyone. A prophylactic hysterectomy (removal of the uterus) can be considered by women who are done having children.

For women who have not undergone this risk reducing surgery, screening may be considered at your doctor’s discretion. In general, screening involves a transvaginal ultrasound and random endometrial biopsies, which involves taking a small sample of the lining of the uterus. Screening should begin around 35 years of age.

In general, thyroid cancer screening may detect thyroid cancer at an earlier, more treatable stage. Both men and women should have an annual comprehensive physical exam, with particular attention to the thyroid exam. An annual thyroid ultrasound is also recommended from 7 years of age or from time of diagnosis.

A colonoscopy is recommended every 5 years, or more frequently if you are found to have colon polyps. Colonoscopy screening should begin at age 35, or possibly earlier, depending on the family history. A renal ultrasound is recommended every 1-2 years, starting at age 40. Some people may benefit from being managed by a dermatologist.

For children, a psychomotor assessment and brain MRI should be considered at diagnosis if the child is showing symptoms.

There is no treatment that can cure Cowden syndrome. That being said, there are options available to reduce your risk of developing cancer. These options include:

Currently, there is no cure for Cowden syndrome. Patients undergo lifelong surveillance to monitor for benign tumors and cancer. This helps detect any problems at the earliest, most treatable point in time.

Preimplantation genetic diagnosis (PGD) is available for Cowden syndrome if one of the parents is known to carry a PTEN mutation. PGD is performed on embryos produced through IVF. PGD allows for parents to only implant embryos into the mother’s uterus that do not have the gene mutation. PGD is still a very costly procedure though, and it is not guaranteed to lead to pregnancy every time.

Some labs may accept prenatal specimens for genetic testing if a parent is known to carry a PTEN mutation. With prenatal testing, the baby’s DNA is tested during the pregnancy to determine whether the baby has the gene mutation. The procedures (including amniocentesis and chorionic villi sampling) available to obtain the baby’s DNA during a pregnancy are associated with a risk of pregnancy loss. Prenatal testing is not commonly utilized or recommended for hereditary cancer conditions such as Cowden syndrome.

A genetic counselor can assist you as you decide what type of genetic testing is right for both you and your family. Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

The main symptoms or features of Cowden syndrome (CS) include hamartomas, or non-cancerous tumor-like growths, and an increased risk to develop breast, uterine, and thyroid cancer. The risk for colorectal cancer, kidney cancer, and melanoma is also increased.

If you have many of these symptoms it would make sense to talk to a genetic counselor/medical geneticist about Cowden syndrome and other genetic causes of multiple polyps. Those same healthcare providers would be able to do genetic testing and tell you about insurance coverage of the testing.

To find a genetics team member who focuses on genetic causes of cancer you can look one up here: https://ghr.nlm.nih.gov/primer/consult/findingprofessional

A PTEN mutation may or may not be inherited from a parent. It is possible for a genetic change to occur randomly during fetal development. This is a called a de novo mutation. About 50-90% of the time, Cowden syndrome occurs as the result of a de novo mutation in the PTEN gene, which means the genetic change was not inherited.

We all have two copies of every gene, including two PTEN genes. We inherit half of our genetic information from our mom and half from our dad, so one of our PTEN genes is inherited from our mother, and the other is inherited from our father. If a parent has Cowden syndrome, there is a 50% chance that each of his or her children will also have Cowden syndrome. This is called autosomal dominant inheritance. A person only needs to inherit one copy of a nonfunctioning, or mutated, PTEN gene to have Cowden syndrome.

There are multiple ways to help this community through financial contribution. You can donate to the PTEN Hamartoma Tumor Syndrome Foundation. Funds may be used to assist people with Cowden syndrome or donate to medical research.

Cancer Research UK allows you to choose what research project you fund. There may or may not be research related to Cowden syndrome or its associated cancer at any given time.

There are numerous laboratories that offer diagnostic testing for Cowden syndrome. There are multiple types of tests to choose from as well. A genetic counselor can assist you as you decide what type of genetic testing is right for both you and your family. Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

A genetic counselor can help to further explain Cowden syndrome and other hereditary cancer conditions and answer any questions you have. Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

[link url="ClinicalTrials.gov” target=”_blank”>ClinicalTrials.gov can provide up-to-date information on research being conducted. The Genomic Medicine Institute through the Cleveland Clinic also has information about how you can participate in research. Of note, if you are interested in participating in the PTEN Study through Cleveland Clinic, enrollment must be facilitated by a healthcare provider.

Cowden syndrome is a rare hereditary cancer condition. As of 2019,it is estimated that 1 in 200,000 people have Cowden syndrome. Because CS is difficult to diagnosis, this is likely an underestimate.

All genetic testing laboratories should accept blood samples, and many also accept saliva samples. Saliva sample tests are just as reliable as blood sample tests. All the cells in a person’s body have the same DNA, so it doesn’t matter if you test blood or saliva.

Most of the cancers and tumors associated with Cowden syndrome occur in adult years, after the age 18. Yearly thyroid ultrasound from the time of diagnosis and skin check with physical examination are recommended for individuals under 18 years of age, who carries the PTEN mutation.

A small number of people with Cowden syndrome may have autism or developmental delay. The American College of Medical Genetics and Genomics (ACMG) recommends PTEN testing for any child with an autism spectrum disorder and macrocephaly (head circumference over 97th percentile). Approximately 10-20% of people with autism spectrum disorder and macrocephaly have a PTEN gene mutation.

Skin lumps and bumps related to Cowden syndrome should be removed only if it is suspected to be cancerous or of there are other symptoms (e.g., pain, deformity, increased scarring). Otherwise, they can be monitored, because these lumps and bumps have a high tendency to grow back even after they are removed.

Women with Cowden syndrome can get pregnant and have children. Cowden syndrome does not affect one’s fertility. However, individuals with Cowden syndrome have a 50% chance of passing on the genetic mutation in the PTEN gene to each of their offspring. The optimal time to have a discussion about genetic risk and the availability of prenatal testing is before pregnancy.

Cowden syndrome (CS) may be also be referred to as Cowden disease (CD) or multiple hamartoma syndrome. Cowden syndrome was named after the first patient who was described to have this condition.

Cowden syndrome is one of four genetic conditions associated with genetic changes in the PTEN gene. PTEN Hamartoma Tumor syndrome (PHTS) is the term used to describe the group of conditions caused by a genetic change in PTEN. These syndromes include: Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome (PS), and Proteus-like syndrome.

Some people have some of the features of Cowden syndrome, such as the cancers associated with this condition, but do not meet the strict criteria for a diagnosis of Cowden syndrome. These individuals are often described as having Cowden-like syndrome.

There are good support groups for people with Cowden syndrome. These include:

The features of Cowden syndrome can manifest at any age. Children with CS may have macrocephaly, autism or developmental delay, characteristic skin findings, or gastrointestinal polyps. The cancer risk during childhood is low.

The penetrance of CS is high, which means that most people with CS will develop some features of this condition over their lifetime. The lifetime risk of developing breast cancer is 85%, with an average age of diagnosis between 38 and 50 years. The lifetime risk for thyroid cancer (usually follicular, rarely papillary, but never medullary thyroid cancer) is approximately 35%. The risk for endometrial cancer may approach 28%.

Most people with CS develop hamartomas (non-cancerous, tumor-like growths) on their skin and mucous membranes, such as the inside of their mouth, by their late 20’s. Macrocephaly (head circumference over percentile) is also a common feature of this condition. It is estimated that 80-100% of people with CS will have macrocephaly.

The PTEN Hamartoma Tumor Syndrome Foundation has information about how to request a scholarship for those who need financial assistance. Certain criteria must be met to qualify.

Cowden syndrome is characterized by multiple hamartomas, or non-cancerous tumor-like growths. Cowden syndrome is associated with mutations, or genetic changes, in the PTEN gene. There are also other hereditary cancer syndromes associated with hamartomous polyps of the digestive tract. For example: