Cowden syndrome is a genetic disorder distinguished by tumour-like multiple, noncancerous growth called hamartomas. There is an increased risk of other benign and cancerous tumours, such as breast, endometrium, thyroid, colorectal, kidney, and skin. Therefore, compared with the general population, people having this syndrome develop these cancers at young ages, often starting in their thirties or forties. People having Cowden syndrome are also more likely to develop more than one cancer during their lifetimes compared to the general population.
Almost everyone having this syndrome generally develops hamartomas. These growths are common on the skin and mucous membranes (like the lining of the nose and mouth), but they can also happen in the intestine and other parts of the body. In addition to this, the growth of hamartomas on the skin and mucous membranes usually becomes apparent by a person’s late twenties.
Signs and Symptoms
Approximately 99% of people with this syndrome will have benign growths on the skin or in the mouth by the end of their twenties.
Signs and symptoms of Cowden syndrome can also include benign diseases of the breast, endometrium and thyroid; a rare, noncancerous brain tumour called Lhermitte-Duclos disease; an enlarged head (macrocephaly); intellectual disability; autism spectrum disorder; and vascular (the body’s network of blood vessels) abnormalities.
Mutations in the PTEN gene cause most cases of Cowden syndrome. PTEN is a tumour suppressor gene. PTEN mutation generally results in a defective protein that cannot carry out its typical role. Hence, this leads to the development of the different tumours and cancers linked with this syndrome.
Rarely, Cowden syndrome may be caused by mutations in other genes such as KLN, SDHC, SDHB, SDHD, AKT1 or PIK3CA. Some affected families may have no identifiable mutation in any of the genes associated with Cowden syndrome; the exact underlying cause is unknown in these families.
How is Cowden Syndrome inherited?
Cowden syndrome is an autosomal dominant syndrome that means that a person only needs a change or mutation in one copy of the gene responsible for each cell to be affected. Moreover, in a few cases, an affected person inherits the mutation from an affected parent.
Typically, every cell has two copies of the same gene: 1 inherited from the mother and one inherited from the father. While this syndrome follows an autosomal dominant inheritance pattern in which a mutation in only one copy of the gene can cause the Cowden syndrome. This means that a parent with a mutation in a gene can pass along a copy of the normal gene or the mutated gene. And so, it takes one copy of the gene with the mutation to have the disease. Therefore, a parent who has a mutation in the PTEN gene has a 50% chance of passing the mutation to their child each pregnancy.
A brother, sister, or parent of a person who has the mutation also has a 50% chance of inheriting the same gene mutation. However, suppose the parents test negative for the mutation (meaning each person’s test results found no mutation). In that case, the risk to the siblings significantly decreases, but their risk may still be higher than the average risk.
Cowden Syndrome and Genetics
Options exist for people desiring to have a child when a prospective parent has a gene mutation that increases the risk for this hereditary cancer syndrome. Preimplantation genetic diagnosis (PGD), a medical procedure with in-vitro fertilization, allows people who have a particular known genetic mutation to decrease the likelihood that their children will inherit the mutation. A woman’s eggs undergo fertilization in a laboratory. When the embryos reach a specific size (approximately eight cells), one cell is removed and is tested for the hereditary condition in question. The parents can then transfer embryos that don’t have the mutation. PGD has been prevalent for over two decades and for various hereditary cancer predisposition syndromes. But, it is a complex procedure with financial, emotional, and physical factors to consider before starting.
How common is Cowden syndrome?
Cowden syndrome is thought to be rare. And so, is estimated that this syndrome affects about 1 in every 200,000 people.
Hence, the classical definition of syndromes like Cowden syndrome may change as testing for hereditary cancer expands to include multi-gene panels. Some individuals may have a mutation in the PTEN gene but may not meet any of the criteria listed above for this syndrome. However, it is unknown if these people will have similar risks for developing cancer.
Cancer risks associated with Cowden syndrome
- The most significant cancer risk for women with this syndrome is breast cancer. However, the lifetime risk for a woman with Cowden syndrome to develop breast cancer is about 50% to 85%. Breast cancer can develop earlier in women with this syndrome than in general. There is also an increased risk for second breast cancer in the opposite breast and a few increased risks of breast cancer in men with Cowden syndrome, but the specific risk is unknown.
- The risk of thyroid cancer in women and men with Cowden syndrome is about the range of 30% to 40%. Thyroid cancer in Cowden syndrome is most commonly the follicular type but may also be the papillary type.
- The risk for kidney cancer is around 30% to 35%, and it is amongst the highest cancer risks for those with a mutation in PTEN.
- Risk of endometrial cancer in women with Cowden syndrome is in the range of 25% to 30%.
- The risk for colorectal cancer is about 5% to 10% and often occurs at a younger age than the general population.
- The risk for melanoma is about 6%. It is essential to be aware of the risk as prevention can start in childhood by using sunscreen and protective clothing to decrease the number of blistering burns before age 20. Melanoma is cancer has multiple contributing factors, including skin colour, eye and hair colour, sun exposure, and, in a few cases, inherited gene mutations. If a person tests negative for a PTEN gene mutation previously identified in their family, they can still have risk factors that increase their risk of melanoma.
What are the screening options for Cowden syndrome?
It is essential to discuss the following screening options with your doctor, as each person is different.
At the time of diagnosis:
- People with this syndrome of all ages: an annual thyroid ultrasound scan and a yearly skin exam.
Starting at age 30:
- Women with Cowden syndrome: an annual mammogram; a yearly breast MRI; and an annual endometrial biopsy or transvaginal ultrasound (or from 5 years before the age of earliest uterine cancer in the family.)
Starting at age 40:
- All adults with Cowden syndrome: a colonoscopy every two years and a kidney ultrasound scan or MRI every two years.
- Women with Cowden syndrome: The preventive removal of the breasts before cancer develops through a prophylactic mastectomy surgery can be considered. The preventive removal of the woman’s uterus can also be called a prophylactic hysterectomy.
Screening Protocol for Cowden Syndrome
According to the National Comprehensive Cancer Network (NCCN) 2014, the suggested screening protocol for Cowden syndrome includes:
Cancer Screening for Women
- Breast self-exams beginning at age 18
- Clinical breast exams every 6-12 months starting at age 25*
- Annual mammogram and breast MRI starting at age 30-35*
- Prophylactic surgeries can be considered as a preventative option for some forms of cancer
- Yearly screening for endometrial cancer with ultrasound or random biopsy may be considered beginning at age 30-35
Cancer Screening for Men and Women
- Annual physical examination beginning at age 18*
- Yearly thyroid ultrasound starting at age 18*
- Baseline colonoscopy at age 35 with follow-up every five years (more frequent if polyps identified)
- Consider renal ultrasound every 1-2 years beginning at age 40
- or individualized based on the earliest diagnosis of cancer in the family.
Pediatric (age less than 18 years)
- Yearly thyroid ultrasound examination*(on the identification of a PTEN pathogenic variant)
- Annual skin check with physical examination
- Neurodevelopmental evaluation
How is Cowden syndrome diagnosed?
As new information becomes available, the diagnostic criteria for this syndrome are complex and frequently reviewed by geneticists (health professionals specializing in medical genetics). Sometimes this syndrome is challenging to diagnose.
Few people don’t meet the strict criteria for a clinical diagnosis of this syndrome, but they have some characteristic features, specifically cancers. Hence ,these individuals are mostly described as having Cowden-like syndrome. Mutations in the same genes cause both the syndrome and Cowden-like syndrome.
Below are the major and minor criteria and the genetic testing criteria for Cowden syndrome.
- Breast cancer
- Endometrial cancer
- Follicular thyroid cancer
- Multiple gastrointestinal hamartomas or ganglioneuromas
- Macular pigmentation of the glans penis, meaning a discoloured area on the skin
- Mucocutaneous lesions
- One biopsy-proven trichilemmoma
- Multiple palmoplantar keratosis, meaning abnormal thickening of the hands and feet
- Multiple cutaneous facial papules that are most often verrucous, meaning wart like projections
- Multifocal or extensive oral mucosal papillomatosis
- Colon cancer
- Esophageal glycogenic acanthosis
- Mental retardation
- Autism-spectrum disorder
- Renal cell carcinoma
- Papillary or follicular variant of papillary thyroid cancer
- Vascular anomalies, consisting (kidney cancer) multiple intracranial developmental venous anomalies
- Thyroid structural lesions, like adenoma, nodule(s), or goitre
- Lipomas, meaning benign soft-tissue tumour
- Testicular lipomatosis
- Single gastrointestinal hamartoma or ganglioneuroma
Cowden Syndrome PTEN Gene Testing
People having a personal history of –
- Bannayan-Riley-Ruvalcaba syndrome (BRR)
- A family with a known PTEN gene mutation
- Meeting clinical diagnostic criteria for CS
- Adult Lhermitte-Duclos disease (cerebellar tumours)
- Autism spectrum disorder and macrocephaly
- Two or more major criteria (one must be macrocephaly)
- Two or more biopsy-proven trichilemmomas
Additionally research is ongoing to understand the Cowden syndrome better. And so, about 80% of the people who meet the current clinical diagnosis of the syndrome have a mutation in the PTEN gene. A blood test can check if someone has the PTEN gene mutation. Hence, if a person has the PTEN gene mutation, they have this syndrome.
Questions to ask the health care team
If you are concerned about the cancer risk, talk to the health care team. Consider asking the health care team the following questions:
- What are the chances of developing cancer?
- How can I decrease the risk of cancer?
- What are my alternatives for cancer screening and prevention?
If you are tensed about your family history and think your family may have Cowden syndrome, you can also ask the below-mentioned questions:
- Does my family history increase my chances of cancer?
- Could my family have Cowden syndrome?
- Will you refer me to a genetic counselor for a cancer risk assessment?
- Should I meet with a genetic counselor?