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Cowden Syndrome - PTEN

PTEN Harmatoma Tumor Syndrome (PHTS)

Clinical Features

Cowden Syndrome (CS) is an autosomal dominant inherited disease characterised by the occurrence of multiple harmatomatous polyps in the gastrointestinal tract, tumor diseases and, in some cases, mucocutaneous lesions (especially trichilemmoma and papillomatous papules) of the face and mouth. The characteristic features of Cowden Syndrome normally appear in a person's twenties. Cowden Syndrome is associated with a markedly increased risk of developing breast, thyroid, endometrium, and renal cell kidney cancer. This association between harmatomatous polyps and increased risk of developing tumors is described in the literature as PTEN Harmatoma Tumor Syndrome (PHTS).

Additionally, benign conditions such as fibrocystic diseases of the breast, lipoma and fibroma have been observed. The histology of CS polyps is comparable to that of Juvenile Polyposis Syndrome (JPS), in that they demonstrate a cystic spreading of crypts, inflammations and regenerative mutations. Other histologies, particularly adenomas, may also be present.

Germline mutations in the PTEN gene are responsible for CS. Mutations in the same gene can also cause the rare Bannayan-Zonana Syndrome (Bannayan-Riley-Ruvalcaba Syndrome), which is associated with intestinal polyps of the harmatomatous type and further symptoms such as macrocephaly, lipoma, mental retardation, among others. The literature also discusses a relation between PTEN mutations and Proteus Syndrome, but this connection has yet to be proven.

The following clinical syndromes belong to PHTS:

• Cowden Syndrome (CS)
• Bannayan-Riley-Ruvalcaba Syndrome (BRRS)
• Proteus Syndrome (PS) (not proven)
• Proteus-like Syndrome
• Lhermitte-Duclos Syndrome

Risk of Tumors with Cowden Syndrome:

• Women have a 25-50% lifelong risk of developing breast cancer (the average age of diagnosis is between 38-46 years of age).
• Approximately two-thirds of women develop benign breast tumors.
• The lifelong risk of developing thyroid carcinoma (often follicular, rarely papillary, never medullary) is approx. 10%. Up to 75% of patients with CS have a benign, tuberous, multi-nodular struma (goiter); adenomatous and follicular adenomas have also been described.
• The risk of developing endometrium carcinoma is estimated to be about 5-10%.
• Benign uterine fibroids are common.
• Occasionally, skin cancer, renal cell carcinoma and brain tumors are found.
• Patients with CS are also occasionally shown to have cerebellar dysplastic ganglioglioma (one speaks of Lhermitte-Duclos Syndrome in such cases).
• Many patients show no signs of the skin mutations indicated as being typical of the disease.

Early Detection for Affected Patients and their Families
Due to the heightened risk to women with CS of developing breast cancer and to both women and men with CS of developing thyroid cancer, it is wise to continually monitor patients in regards to these tumor diseases. The following examinations are recommended for all patients with Cowden Syndrome and their close relatives (parents, siblings, children):

• Physical exam: An annual thorough physical examination for both men and women with CS beginning at 18 years of age (or 5 years earlier than the age of diagnosis of the most recently diagnosed tumor in the family), with special attention paid to skin changes and the throat area.
• Thyroid: An annual examination (touch, ultrasound, if appropriate puncture or nuclear medicine) beginning at puberty.
• Breast cancer: For women with CS, a monthly self-exam and annual clinical breast exam beginning at age 25 as well as an annual mammography and ultrasound beginning at 30 years of age (or 5 years earlier than the age of diagnosis of the most recently diagnosed case of breast cancer in the family).
• Endometrium: Women should consider a regular ultrasound exam beginning at age 35.
• Gastrointestinal tract: Although harmatomous polyps can occur in the gastrointestinal tract, they do not seem to present an increased risk of intestinal cancer and seldom cause any symptoms. For asymptomatic patients, a basic colonoscopy is recommended beginning at age 50. As long as only harmatoma of the fine tissue are found, patients should follow the general guidelines for monitoring colon cancer (e.g., the Guidelines of the German Association for Digestive and Metabolic Diseases 2004)

Genetic Information

Cowden Syndrome is caused by germline mutations in the tumor suppressor gene PTEN (Phosphatase and Tensin homolog; 10q23.31); approximately 80% of all clinical CS patients are shown to have a mutation in this gene. The PTEN gene is comprised of 10 exons; the mRNA has a length of 1212 bp and codes a protein tyrosinphosphatase of 403 amino acids.

Prevalence

approx. 1 : 200 000

Diagnostic