What are the other Names for this Condition? (Also known as/Synonyms)

• Cowden's Disease
• CS (Cowden Syndrome)
• Multiple Hamartoma Syndrome

What is Cowden Syndrome? (Definition/Background Information)

• Cowden Syndrome is an inherited condition that is characterized primarily by multiple, noncancerous growths (called hamartomas) on various parts of the body
• People with the syndrome usually have large head (macrocephaly), benign tumors of the hair follicle (trichilemmomas), and white papules with a smooth surface in the mouth (papillomatous papules), starting by the late 20s
• It is considered part of the PTEN hamartoma tumor syndrome spectrum which also includes Bannayan-Riley-Ruvalcaba syndrome and Proteus syndrome
• People who have Cowden Syndrome are at an increased risk of developing certain types of cancer, such as breast, thyroid, and endometrial (lining of the uterus) cancer
• Most cases are caused by mutations in the PTEN gene and are inherited in an autosomal dominant manner
• Management typically includes screening for associated tumors and/or prophylactic surgeries

(Source: Cowden Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Cowden Syndrome? (Age and Sex Distribution)

• Cowden Syndrome is a rare disorder that is known to present symptoms during early adulthood (age before or around 30 years)
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Cowden Syndrome? (Predisposing Factors)

• A positive family history may be an important risk factor, since Cowden Syndrome is an inherited condition
• Currently, no other risk factors have been clearly identified for the syndrome

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Cowden Syndrome? (Etiology)

Most cases of Cowden Syndrome are caused by mutations in the PTEN gene

• PTEN is a tumor suppressor gene. Mutations in PTEN result in a defective protein that is unable to carry out its normal role
• This leads to the development of the various tumors and cancers associated with Cowden syndrome
• Rarely, Cowden syndrome is caused by mutations in another gene like KLLN, SDHB, SDHC, SDHD, PIK3CA or AKT1
• Some affected families have no identifiable mutation in any of the genes associated with Cowden syndrome; in these families, the exact underlying cause is unknown
• Cowden Syndrome is inherited in an autosomal dominant manner. This means that to be affected, a person only needs a change (mutation) in one copy of the responsible gene in each cell

In some cases, an affected person inherits the mutation from an affected parent. Other cases may result from new (de novo) mutations in the gene. These cases occur in people with no history of the disorder in their family.

(Source: Cowden Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of Cowden Syndrome?

Cowden Syndrome is characterized primarily by multiple, noncancerous growths (called hamartomas) on various parts of the body. Approximately 99% of people who have Cowden Syndrome will have benign growths on the skin and/or in the mouth by the end of their 20s. A majority of people with Cowden Syndrome will also develop growths (called hamartomatous polyps) along the inner lining of the gastrointestinal tract. 

People affected by Cowden syndrome also have an increased risk of developing certain types of cancer. Breast, thyroid, and endometrial (the lining of the uterus) cancers are among the most commonly reported tumors. The lifetime risk of developing breast cancer is 85%; for thyroid cancer the risk is approximately 35%; and the risk for endometrial cancer is about 28%. Other associated cancers include: 

• Colorectal cancer
• Kidney cancer
• Melanoma

People with Cowden Syndrome often develop cancers at earlier ages (before age 50) than people without a hereditary predisposition to cancer.

Other signs and symptoms of Cowden Syndrome may include: 

• Benign diseases of the breast, thyroid, and endometrium
• A rare, non-cancerous brain tumor called Lhermitte-Duclos disease
• An enlarged head (macrocephaly)
• Autism spectrum disorder
• Intellectual disability
• Vascular (the body's network of blood vessels) abnormalities
• Abnormality of the vasculature
• Acrokeratosis
• Adult onset
• Angioid streaks of the retina
• Colonic diverticula
• Fibroadenoma of the breast
• Hydrocele testis
• Hyperthyroidism
• Hypoplasia of the maxilla
• Hypothyroidism
• Intellectual disability, mild
• Intention tremor
• Micrognathia
• Narrow mouth
• Ovarian cyst
• Palmoplantar hyperkeratosis
• Progressive macrocephaly
• Skin tags
• Subcutaneous lipoma
• Thyroid adenoma
• Thyroiditis
• Transitional cell carcinoma of the bladder
• Varicocele

Based on the frequency of symptoms observed, the following information may be noted:

Very frequently present symptoms in 80-99% of the cases:

• Breast carcinoma
• Colorectal polyposis
• Conjunctival hamartoma
• Generalized hyperkeratosis
• Goiter
• Macule                   
• Palmoplantar keratoderma
• Papilloma
• Papule

Frequently present symptoms in 30-79% of the cases:

• Abnormality of the penis
• Adenoma sebaceum 
• Ataxia 
• Cavernous hemangioma
• Cognitive impairment 
• Furrowed tongue 
• Hamartomatous polyposis 
• Intellectual disability 
• Lipoma 
• Macrocephaly
• Melanocytic nevus 
• Meningioma 
• Mucosal telangiectasiae 
• Subcutaneous nodule 

Occasionally present symptoms in 5-29% of the cases:

• Autism  
• Bone cyst
• Brachydactyly
• Cataract
• Cellular immunodeficiency 
• Endometrial carcinoma
• Enlarged polycystic ovaries
• Failure to thrive
• Follicular thyroid carcinoma
• Gynecomastia 
• Hearing impairment
• High palate 
• Hypopigmented skin patches
• Increased intracranial pressure
• Kyphosis
• Melanoma 
• Multiple cafe-au-lait spots 
• Myopia 
• Pectus excavatum
• Renal cell carcinoma
• Scoliosis 
• Seizures

(Source: Cowden Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Cowden Syndrome Diagnosed?

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.

(Source: Cowden Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Cowden Syndrome?

The complications of Cowden Syndrome may include:

• Increased risk for cancer formation
• Organ dysfunction due to the presence of benign or malignant lesions

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Cowden Syndrome Treated?

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 (or individualized based on the earliest diagnosis of cancer in the family)
• Annual mammogram and breast MRI beginning at age 30-35 (or individualized based on the earliest diagnosis of cancer in the family)
• 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 (or individualized based on the earliest diagnosis of cancer in the family)
• Annual thyroid ultrasound beginning at age 18 (or individualized based on the earliest diagnosis of cancer in the family)
• 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

Pediatric (age <18 years):

• Yearly thyroid ultrasound examination (on identification of a PTEN pathogenic variant); or individualized based on the earliest diagnosis of cancer in the family
• 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.

(Source: Cowden Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How can Cowden Syndrome be Prevented?

• Currently, Cowden Syndrome may not be preventable, since it is a genetic disorder
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders
• Regular medical screening at periodic intervals with tests and physical examinations are recommended

What is the Prognosis of Cowden Syndrome? (Outcomes/Resolutions)

• The prognosis of Cowden Syndrome is dependent upon the severity of the signs and symptoms and associated complications, if any
• Individuals with mild conditions have better prognosis than those with severe symptoms and complications
• Typically, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for Cowden Syndrome:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/