Although some cases have been reported, there is not enough evidence to indicate an association between Cowden syndrome and the development of male breast cancer. Up to 75% demonstrate benign breast conditions such as intraductal papillomatosis, fibroadenomas, and fibrocystic changes. However, there is currently not enough evidence to determine if benign breast disease occurs more frequently in Cowdens patients as compared to individuals without a hereditary cancer syndrome.Central Nervous System
Macrocephaly is observed in 84% of patients with Cowden syndrome. It typically occurs due to an abnormally enlarged brain, or megalencephaly. Patients may also exhibit dolichocephaly. Varying degrees of autism spectrum disorder and intellectual disability have been reported as well. Lhermitte-Duclos disease is a benign cerebellar tumor that typically does not manifest until adulthood in patients with Cowden syndrome. Genetics
Cowden syndrome is inherited in an autosomal dominant fashion. Germline mutations in PTEN (phosphatase and tensin homolog), a tumor suppressor gene, are found in up to 80% of Cowdens patients. Several other hereditary cancer syndromes, such as Bannayan-Riley-Ruvalcaba syndrome, have been associated with mutations in the PTEN gene as well. PTEN negatively regulates the cytoplasmic receptor tyrosine kinase pathway, which is responsible for cell growth and survival, and also functions to repair errors in DNA. Thus, in the absence of this protein, cancerous cells are more likely to develop, survive, and proliferate.Recently, it was discovered that germline heterozygous mutations in SEC23B, a component of coat protein complex II vesicles secreted from the endoplasmic reticulum, are associated with Cowden syndrome.
At birth or in childhood, classic features of Cowdens include pigmented genital lesions, lipomas, epidermal nevi, and cafe-au-lait spots. Squamous cell carcinomas of the skin may also occur.Thyroid
Two thirds of patients have thyroid disorders, and these typically include benign follicular adenomas or multinodular goiter of the thyroid. Additionally, Cowdens patients are more susceptible to developing thyroid cancer than the general population. It is estimated that less than 10 percent of individuals with Cowden syndrome may develop follicular thyroid cancer. Cases of papillary thyroid cancer have been reported as well.Female and Male Genitourinary
Females have an elevated risk of developing endometrial cancers, which is highest for those under the age of 50. Currently, it is not clear whether uterine leiomyomata (fibroids) or congenital genitourinary abnormalities occur at an increased rate in Cowden syndrome patients as compared to the general population. The occurrence of multiple testicular lipomas, or testicular lipomatosis, is a characteristic finding in male patients with Cowden syndrome.Gastrointestinal
Polyps are extremely common as they are found in about 95% of Cowden syndrome patients undergoing a colonoscopy. They are numerous ranging from a few to hundreds, usually of the hamartomatous subtype, and distributed across the colon as well as other areas within the gastrointestinal tract. Other types of polyps that may be encountered less frequently include ganglioneuromatous, adenomatous, and lymphoid polyps. Diffuse glycogenic acanthosis of the esophagus is another gastrointestinal manifestation associated with Cowden syndrome.Breast
Females are at an increased risk of developing breast cancer, which is the most common malignancy observed in Cowdens patients.