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Cowden syndrome (CS) is a difficult to recognize, under-diagnosed genodermatosis characterized by the presence of multiple hamartomas in various tissues and an increased risk for malignancies of the breast, thyroid, endometrium, kidney and colorectum. When CS is accompanied by germline PTEN mutations, it belongs to the PTEN hamartoma tumor syndrome (PHTS; see this term) group.
CS has been described in many ancestral groups. The prevalence is unknown but is estimated at 1/200,000.
Disease manifestations usually occur between the second and third decades of life but can appear at any age. Pathognomonic muco-cutaneous lesions (including a type of small, colored and multiple facial papules or trichilemomas) may be the first manifestations of the disease and are seen in many patients, as well as papillomatous papules and acral keratoses and Lhermitte-Duclos disease (LDD; see this term). Macrocephaly and dysmorphic facies, if present, are evident at birth. Malignancies such as breast cancer (with an 85% lifetime risk), epithelial thyroid cancer and endometrial carcinoma often appear later in life. Visceral manifestations that in some cases can involve the thyroid (thyroglossal duct cyst, adenoma), digestive tract (colon diverticulitis, hepatic cysts, glycogenic acanthosis), genital tract (functional menstrual cycle troubles, ovarian teratomas), skeleton (bone cysts), breast (fibrocystic disease, nipple and areola abnormalities), and neurological system (meningioma, developmental delay, autistic spectrum) have a highly variable age of onset.
It is now believed that 25% of CS cases are caused by germline mutations in the phosphatase and tensin homolog (PTEN) gene (10q23), that encodes PTEN, a dual-specifity phosphatase. Patients with CS and CS-like phenotypes that do not have PTEN involvement have been found to have a germline promoter methylation of KLLN (30% of cases), germline variations in SDHB, SDHC or SDHD (10% of cases), or germline mutations in AKT1 and PIK3CA (10% of cases).
The International Cowden Consortium (ICC) for CS lists the pathognomonic (mucocutaneous lesions, LDD), major (breast cancer, macrocephaly, thyroid cancer and endometrial cancer), and minor criteria used to diagnose this disease. An operational diagnosis is given if a patient displays the pathognomonic skin lesions, two or more major, one major and 3 or more minor, or 4 or more minor criteria. A quantitative scoring system for adults and a separate pediatric criteria system have now been created. Finding germline mutations in PTEN or other causal genes confirms diagnosis.
Differential diagnoses, juvenile-polyposis syndrome, Peutz-Jeghers syndrome, Birt-Hogg-Dubé syndrome, Gorlin syndrome and neurofibromatosis type 1 (see these terms).
Antenatal diagnosis is possible for at-risk pregnancies if the disease causing mutation is discovered in an affected family member.
CS is inherited autosomal dominantly. Genetic counseling can be offered to patients with PTEN mutations and asymptomatic family members should also be tested so that those with a mutation can be monitored before symptom onset.
Management and treatment
Management and treatment is multidisciplinary and is based on genotype. Once a PTEN germline mutation is identified, surveillance guidelines should be followed. Thyroid ultrasound should begin once a mutation is identified, even under the age of 18. A colonoscopy and biennial renal imaging should begin between the ages of 35-40. Women should perform monthly breast self-examinations and yearly breast screenings as well as transvaginal ultrasounds or endometrial biopsies beginning at the age of 30.
The pinpointing of the diagnosis (especially by gene) and instituting organ-specific surveillance at the right time results in a good prognosis. When advanced cancers occur before diagnosis is made, a poor outcome is common.