The portal for rare diseases and orphan drugs

The prevalence of Cowden syndrome 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. The most commonly, but not uniformly, reported manifestations are macrocephaly (specifically, megalencephaly), mucocutaneous lesions, thyroid abnormalities, fibrocystic disease and carcinoma of the breast, gastrointestinal hamartomas, multiple early onset uterine leiomyomas, and developmental delay. Macrocephaly and rarely dysmorphic facies, if present, are evident at birth. Malignancies such as breast cancer (with an 85% lifetime risk), epithelial thyroid cancer, renal cancer and endometrial carcinoma often appear later in life. Clinicians should consider other red flags of a CS diagnosis which includes Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma which is pathognomonic of CS), mucocutaneous stigmata such as trichilemmomas and papillomatous papules (believed to exist in 100% of CS patients by age 30), ganglioneuromatous gastrointestinal polyps, glycogenic acanthosis, pediatric differentiated (non-medullary) thyroid cancer and endometrial cancer diagnosed relatively early.

It is now believed that 25% of CS and CS-like cases are caused by germline mutations in PTEN (10q23), which encodes a dual-specificity phosphatase. Patients with CS/CS-like phenotypes that do not have PTEN involvement have been found to have germline promoter methylation of KLLN (up to 30%), germline variations in SDHB-D (10%), or germline mutations in AKT1 and PIK3CA (10%). More recently, germline SEC23B and USF3 were identified in PTEN wildtype CS/CS-like patients with differentiated thyroid cancer as a predominant phenotype.

The International Cowden Consortium 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 to aid clinicians at the point of care. Finding germline mutations in PTEN or other causal genes confirms diagnosis.

Juvenile-polyposis syndrome, Peutz-Jeghers syndrome, Birt-Hogg-Dubé syndrome, Gorlin syndrome and neurofibromatosis type 1.

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 germline 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 are multidisciplinary and based on genotype. Once a PTEN germline mutation is identified, surveillance guidelines should be followed. Thyroid ultrasound should begin once a mutation is identified, starting at the age of 7. A colonoscopy and biennial renal imaging should begin between the ages of 35-40, unless symptomatic. Women should perform monthly breast self-examinations and yearly breast screenings as well as transvaginal ultrasounds (postmenopausal) or endometrial biopsies beginning at the age of 35.

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.