Cowden Syndrome

What is Cowden Syndrome?

Cowden syndrome is an autosomal genetic condition refer to multiple benign tumor growth in the skin and mucous membrane. The name of the Cowden’s syndrome was derived after the first expressed patient, Rachael Cowden, in the year 1963. The outer growth of the tissue is termed as hamartomas. The hamartomas growth is usually noticeable, as they developed internal body parts, mainly with mucous membrane lining organs. Cowden syndrome is not cancerous, but increase the risk of development of the cancer.

In comparing with the general population, people with Cowden syndrome have a tendency to develop cancer is more, especially in breast, thyroid and uterus cancer at their early age. The cancerous development starts at 30 to 40 years of age. Cowden syndrome is also cause cancer in kidney and skin.

Some typical health related risk factors, like a specific brain tumor clinically termed as Lhermitte-Duclos disease is associated with Cowden syndrome. Lhermitte-Duclos disease is non-cancerous in nature. The additional distinct indication may come across like larger sized head (macrocephaly) with Cowden syndrome. Rarely, Cowden syndrome is interfered with cognitive impairment which is often due to delayed metal development.

Cowden’s disease is an autosomal prevailing turmoil. the genetic mapping of the Cowden’s disease has ben indicated that gene locus, and positive influence obtained from the chromosome 10q22-23 in which the PTEN gene is sited. Encoding of PTEN is a lipid phosphatase.

PTEN is a depressive controller of the phosphatidylinositol 3-kinase (PI3K) pathway, as it is altering phosphatidylinositol 3,4,5-triphosphate (PIP3) into phosphatidylinositol 4,5-biphosphate (PIP2). Emphasizing the significance of PTEN as a tumor suppressor gene. The numerous autosomal regulating hamartoma syndromes together with Cowden’s disease is resultant of the association of the germline mutations of PTEN.

With Cowden’s disease, the involvement of the PTEN germline mutations has been found in maximum cases, and almost 80% of the patients have linked up with PTEN germline mutations in either of the PTEN promoter, PTEN coding sequence, or in its 5′ and 3′ un-translated section. These factors are ensuing the reduction of the conversion or influence catalytic inactivation, under development, or uneven PTEN protein distribution, which may undertake quick degradation.

Animal study provide the evidence that Pten heterozygosity and tissue-specific removal leads to dysplasic and hyperplastic alterations in the skin, colon and prostate, and involve in the spontaneous development of the tumor, This supports the concept of the PTEN has a causal relationship with the development of the hamartoma syndromes. (1,2)

Cowden Syndrome Symptoms

The most commonly symptoms associated with Cowden syndrome are enlisted below, may all the symptoms are not prominent to every cases, but possibility of development of the symptoms included are:

• Non cancerous skin bumps (Hamartomas)
• Melanin (skin pigment) become reduced
• Skin lumps
• Lumps in mucous membrane
• Breast fibrocystic disease
• risk of breast cancer development is increased
• risk of thyroid cancer development is increased
• Goiter
• risk of skin cancer (melanoma) development is increased
• Cafe au lait spots: These spots are mainly developed due to a neurocutaneous disorder (neurofibromatosis). The spots are present in a very restricted manner in every macula and evenly distributed. They are formed due to hyper-pigmentation and the color of the lesions are varies from light brown to dark brown and famous as “coffee with milk” in general. The color of the spots are usually light for infants and gradually darken and larger in size with increasing of age, and at they are fast growing symptoms, therefore within 2 years of age of the child has become more prominent spots. The spots size varies from 1 – 2 cm to 20 cm, with smooth or irregular border.
• Risk of meningioma development is increased
• GI tract, especially in intestinal mucosa polyps formation is common
• Risk of endometrial cancer development is increased
• Head size become enlarged
• Delayed mental development
• Cognitive impairment
• Non-malignant brain tumor – Lhermitte-Duclos disease (3,4,5)

Treatment

There is no standard therapy offered for Cowden syndrome. Ongoing research tried hard to search targeted chemotherapy, but maximum in a trial period.

Drug researchers get positive tumor inhibiting effect with rapamycin. As the Cowden syndrome is associated with certain prominent action of Akt and mTOR in excessive cell proliferated lesions due to Pten removal. It has been observed in animal studies that rapamycin has an inhibitory effect on mTOR.

In addition, rapamycin is effective against treatment different biomarkers of the targeted tissues, which includes fast revert the mucocutaneous papillomatous lesions present in the face and limbs, acral keratosis, and abnormalities of nipples, attendant with a noticeable reduction of the increased levels of pS6, and all these findings support the drug efficiency. Moreover, the early therapeutic intervention  with rapamycin prohibited the progression of Cowden syndrome and increase life expectancy with animal model. (2)

Life expectancy

Patient with Cowden syndrome has greater risk of breast cancer (20% to 50% patients with CS have breast cancer) and thyroid cancer (3% to 10% ), therefore life expectancy is less with delayed diagnosis and treatment approach. (6)

Pictures

Image 4 – lesions on maxillary gingiva

Source – http://escholarship.org/

References

1. Cowden syndrome, Genetic Home Reference, US National Library of Medicine; Retrieve from: https://ghr.nlm.nih.gov/condition/cowden-syndrome#diagnosis
2. Cristiane H. Squarize, Rogerio M. Castilho, and J. Silvio Gutkind, (2008); Chemoprevention and Treatment of Experimental Cowden’s Disease by mTOR Inhibition with Rapamycin; doi: 10.1158/0008-5472.CAN-08-0922; Retrieve from: http://cancerres.aacrjournals.org/content/68/17/7066.full.html
3. Symptoms of Cowden’s syndrome; Retrieve from: http://www.rightdiagnosis.com/c/cowdens_syndrome/symptoms.htm
4. Shah KN, (2010);  The diagnostic and clinical significance of café-au-lait macules; Pediatr Clin North Am. 2010 Oct;57(5):1131-53. doi: 10.1016/j.pcl.2010.07.002, Retrieve from: http://www.ncbi.nlm.nih.gov/pubmed/20888463
5. William D James, (2016); Cafe Au Lait Spots; Retrieve from: http://emedicine.medscape.com/article/911900-overview
6. Marcia S. Brose, Thomas C. Smyrk, Barbara Weber, and Henry T. Lynch; Cancer-Associated Genodermatoses; Holland-Frei Cancer Medicine. 6th edition. Retrieve from: http://www.ncbi.nlm.nih.gov/books/NBK13680/