Cowden syndrome

Cowden syndrome (also known as "Cowden's disease," and "Multiple hamartoma syndrome") is a rare autosomal dominant inherited disorder characterized by multiple non-cancerous tumor-like growths called hamartomas, which typically are found in the skin, mucous membranes (mouth, nasal membranes, GI tract), thyroid gland, and breast tissue. While the hamartomas are benign, people with Cowden Syndrome are at increased risk of certain forms of cancer, including breast, thyroid, uterus (endometrial), and kidney cancers.

Cowden syndrome is associated with mutations in PTEN, a tumor suppressor gene, that cause the PTEN protein not to work properly leading to hyperactivity of the mTOR pathway. These mutations lead to characteristic features including macrocephaly, intestinal hamartomatous polyps, benign skin tumors (multiple trichilemmomas, papillomatous papules, and acral keratoses) and dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). In addition, there is a predisposition to breast carcinoma, follicular carcinoma of the thyroid, and endometrial carcinoma.^[1]

Signs and symptoms

People with Cowden syndrome develop characteristic lesions called hamartomas, which are small, noncancerous growths that are most commonly found on the skin and mucous membranes (such as the lining of the mouth, nose, and intestines), but can also occur other parts of the body, such as the thyroid and breast. The majority of affected individuals develop the characteristic skin lesions by 20 years of age.

Hamartomas are typically benign; however, people with Cowden syndrome are at increased risk of developing several types of cancer, including cancers of the breast, thyroid, uterus (endometrial), and kidney cancers.^[2][3] Two thirds of people have thyroid abnormalities, which usually consist of follicular adenomas (benign) or multinodular goiter of the thyroid.^[4] Up to 10 percent of people with Cowden Syndrome develop follicular thyroid cancer.^[2]

Skin abnormalities in people with Cowdens syndrome can include oral and skin papillomas and benign growths of the skin called trichilemmomas. Additional signs and symptoms of Cowden syndrome can include an enlarged head (macrocephaly), a rare noncancerous brain tumor called Lhermitte-Duclos disease, and glycogenic acanthosis of the esophagus.^[5] Up to 75% have benign breast conditions such as ductal hyperplasia, intraductal papillomatosis, adenosis, lobular atrophy, fibroadenomas, and fibrocystic changes.^[6]

Genetics

Mutations in the PTEN gene cause Cowden syndrome. PTEN is a tumor suppressor gene, which means it helps control the growth and division of cells. Inherited mutations in the PTEN gene have been found in about 80 percent of people with Cowden syndrome. These mutations prevent the PTEN protein from effectively regulating cell survival and division, which can lead to the formation of tumors. Cowden syndrome is one of several inherited diseases caused by mutations in the PTEN gene.

In the other 20 percent of Cowden syndrome cases, the cause is not yet known. Some of these cases may be caused by mutations in a region of DNA that regulates the activity of the PTEN gene. Others may have mutations in certain subunits of succinate dehydrogenase,^[7] a mitochondrial enzyme. Recently, methylation of the KILLIN gene has also been reported in patients with similar clinical features.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one 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. It is characterized by numerous hamartomas, among other symptoms.

Diagnosis

Diagnostic criteria have evolved over the years; the most recent is the Cleveland Clinic scoring system in 2011 derived from 3,042 probands.^[8] For an individual patient, these features may be evaluated by the Cleveland Clinic web calculator to derive an individual probability of a relevant gene mutation.

Treatment

Patients are usually managed by a multidisciplinary team including surgeons, gynecologists, and dermatologists because of the complex nature of this disorder. Follow-up for the increased risk of breast cancer risk includes monthly breast self-examination, annual breast examination, and mammography at age 30 or five years earlier than the youngest age of breast cancer in the family.^[2] The magnitude of the risk of breast cancer justifies routine screening with breast MRI as per published guidelines.^[9]

Epidemiology

Because Cowden syndrome can be difficult to diagnose, the exact prevalence is unknown; however, it probably occurs in at least 1 in 200,000 people.

A 2010 review of 211 patients (21 from one center, and the remaining 190 from the external literature) studied the risks for cancer and Lhermitte-Duclos disease in Cowden syndrome patients.^[10]

Cumulative risk of any cancer diagnosis in female (red) and male (blue) patients with Cowden syndrome from birth to age 70 (Kaplan-Meier).

The cumulative lifetime (age 70 years) risks were 89% for any cancer diagnosis (95% confidence interval (CI) = 80%,95%), breast cancer [female] 81% (CI = 66%,90%), LDD 32% (CI = 19%,49%), thyroid cancer 21% (CI = 14%,29%), endometrial cancer 19% (CI = 10%,32%) and renal cancer 15% (CI = 6%,32%). A previously unreported increased lifetime risk for colorectal cancer was identified (16%, CI = 8%,24%). Male CS patients had fewer cancers diagnosed than female patients and often had cancers not classically associated with CS.

History

Cowden syndrome was first described in 1963 by Lloyd & Dennis. They named the condition after the surname of the patient.^[11] The syndrome is also known as Multiple hamartoma syndrome.^[12])

See also

• List of cutaneous neoplasms associated with systemic syndromes

References

Notes

• de Jong MM, Nolte IM, te Meerman GJ, van der Graaf WT, Oosterwijk JC, Kleibeuker JH, Schaapveld M, de Vries EG (2002). "Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility". J Med Genet 39 (4): 225–42. doi:10.1136/jmg.39.4.225. PMC 1735082. PMID 11950848. 
• Eng C (2000). "Will the real Cowden syndrome please stand up: revised diagnostic criteria". J Med Genet 37 (11): 828–30. doi:10.1136/jmg.37.11.828. PMC 1734465. PMID 11073535. 
• Kelly P (2003). "Hereditary breast cancer considering Cowden syndrome: a case study". Cancer Nurs 26 (5): 370–5. doi:10.1097/00002820-200310000-00005. PMID 14710798. 
• Pilarski R, Eng C (2004). "Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome". J Med Genet 41 (5): 323–6. doi:10.1136/jmg.2004.018036. PMC 1735782. PMID 15121767. 
• Waite KA, Eng C (2002). "Protean PTEN: Form and Function". Am J Hum Genet 70 (4): 829–44. doi:10.1086/340026. PMC 379112. PMID 11875759. 
• Zhou XP, Waite KA, Pilarski R, Hampel H, Fernandez MJ, Bos C, Dasouki M, Feldman GL, Greenberg LA, Ivanovich J, Matloff E, Patterson A, Pierpont ME, Russo D, Nassif NT, Eng C (2003). "Germline PTEN Promoter Mutations and Deletions in Cowden/Bannayan-Riley-Ruvalcaba Syndrome Result in Aberrant PTEN Protein and Dysregulation of the Phosphoinositol-3-Kinase/Akt Pathway". Am J Hum Genet 73 (2): 404–11. doi:10.1086/377109. PMC 1180378. PMID 12844284. 

External links

Wikimedia Commons has media related to Cowden syndrome.

• GeneReviews/NCBI/NIH/UW entry on PTEN Hamartoma Tumor Syndrome (PHTS)
• Cancer.Net: Cowden Syndrome