Cowden syndrome

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.

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.

GeneReviews offers more detailed information regarding the diagnosis of Cowden syndrome including the clinical diagnostic criteria.

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. A person with Cowden syndrome has a 50% chance with each pregnancy of passing along the mutated gene to his or her child.

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].

GeneReviews offers more specific information on the treatment and management of Cowden syndrome.

PTEN World is an online discussion forum where members dealing with Cowden syndrome can share advice and support with other patients and caregivers.