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, coloured 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). Major criteria from the International Cowden Consortium (ICC) include breast cancer (with an 85% lifetime risk), epithelial thyroid cancer, macrocephaly and endometrial carcinoma. Minor criteria include visceral manifestations that can be benign or malignant involving the thyroid (thyroglossal duct cyst, adenoma), digestive tract (colon diverticulitis, hepatic cysts, glycogenic acanthosis), genital tract (functional menstrual cycle troubles, ovarian teratomas), skeleton (dysmorphic facies macrocephaly, bone cysts), breast (fibrocystic disease, nipple and areola anatomic abnormalities), and neurological system (meningioma, developmental delay, autism spectrum).
It is now believed that 25% of CS cases are caused by germline mutations in the phosphatase and tensin homolog (PTEN) gene (10q23) gene, 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 variation in SDHB, SDHC or SDHD (10% of cases), or germline mutations in AKT1 and PIK3CA (10% of cases).
The ICC diagnostic criteria for CS lists the pathognomic (mucocutaneous lesions, LDD), major and minor criteria used to diagnose this disease. An operational diagnosis is given if a patient displays the pathognomonic, 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 paediatric criteria 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 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.