Cowden syndrome

Overview

Cowden syndrome is a rare genetic disorder characterized by the development of multiple noncancerous, tumor-like growths called hamartomas and an increased risk of developing certain types of cancer. It is part of a group of conditions known as PTEN hamartoma tumor syndromes. Individuals with Cowden syndrome are particularly at risk for breast, thyroid, and endometrial (uterine) cancers. The syndrome typically presents in adolescence or early adulthood and can affect multiple organ systems, including the skin, gastrointestinal tract, brain, and reproductive organs.

Causes

Cowden syndrome is most commonly caused by mutations in the PTEN gene (phosphatase and tensin homolog), which is a tumor suppressor gene located on chromosome 10. PTEN helps regulate cell growth, and mutations can lead to uncontrolled cellular proliferation and the formation of tumors. The condition follows an autosomal dominant inheritance pattern, meaning a person only needs one copy of the altered gene from either parent to be affected. In about 80% of cases, a PTEN mutation is found; in others, no known mutation is identified, but the clinical features still meet diagnostic criteria.

Symptoms

Symptoms of Cowden syndrome vary widely among individuals but may include:

• Multiple hamartomas: Benign growths on the skin, mucous membranes, and internal organs

• Skin and mucosal lesions: Trichilemmomas (benign hair follicle tumors), oral papillomas, and acral keratoses (wart-like lesions on hands and feet)

• Macrocephaly: Abnormally large head size, often present from birth

• Breast changes: Fibrocystic disease, benign breast tumors, or breast cancer (especially in women)

• Thyroid abnormalities: Goiter, benign nodules, or thyroid cancer (particularly follicular carcinoma)

• Endometrial abnormalities: Including uterine cancer or polyps in females

• Gastrointestinal polyps: Often asymptomatic but may cause discomfort or bleeding

• Neurological signs: Lhermitte-Duclos disease (a rare cerebellar tumor), developmental delays in some cases

Diagnosis

Diagnosis of Cowden syndrome involves a combination of clinical evaluation, family history, and genetic testing. Diagnostic criteria include both major and minor features, and a confirmed PTEN mutation supports the diagnosis. Diagnostic steps include:

• Clinical assessment: Thorough evaluation of skin lesions, family history, and organ involvement

• Imaging studies: Ultrasound, MRI, or CT scans to assess the thyroid, breasts, and brain

• Endoscopy: To identify gastrointestinal polyps

• Genetic testing: Identification of a pathogenic PTEN mutation confirms the diagnosis

• Biopsy: Of skin or internal lesions to confirm hamartomas or rule out malignancy

Treatment

There is no cure for Cowden syndrome, so management focuses on surveillance and early detection of cancers and complications. Treatment involves:

• Regular screening: For breast, thyroid, endometrial, and colorectal cancers starting at an early age

• Prophylactic surgery: In high-risk cases, such as preventive mastectomy in women with a strong family history of breast cancer

• Removal of symptomatic lesions: Skin or gastrointestinal polyps may be removed if problematic

• Hormonal therapy: For endometrial issues or to manage risk factors

• Multidisciplinary care: Coordination between dermatologists, geneticists, endocrinologists, gastroenterologists, and oncologists

• Genetic counseling: For patients and family members to understand inheritance and reproductive options

Prognosis

With careful monitoring and appropriate medical care, individuals with Cowden syndrome can lead relatively normal lives. However, the lifetime risk of developing cancer, especially breast (up to 85%), thyroid (up to 35%), and endometrial (up to 28%) cancers, is significantly elevated. Early diagnosis, regular surveillance, and preventive strategies can greatly improve outcomes and reduce cancer-related mortality. Lifelong medical follow-up is essential.