Cowden Syndrome: Gateway to Multiple Hamartomas

Introduction

Cowden syndrome is a rare inherited disorder with many noncancerous growths (hamartomas) and an increased risk of developing cancer. It occurs in about 1 in 200,000 individuals. Hamartomas associated with Cowden's syndrome can be commonly seen in different body parts, such as the mouth, skin, and gastrointestinal tract. However, it may also occur in the uterus, thyroid, soft tissues, breast, and brain. The affected individuals with Cowden's syndrome may have other signs and symptoms like skin changes, large head, developmental delays, learning disabilities, autism spectrum disorder, and blood vessel problems. In addition, people with Cowden syndrome show an increased risk of developing thyroid, breast, kidney, rectum, colon, and endometrial cancers.

What Is Cowden Syndrome?

Cowden syndrome (Cowden's disease) is an inherited condition characterized by hamartomas (noncancerous overgrowths) and an increased risk of thyroid, breast, kidney, and uterine cancers. Even though Cowden syndrome is primarily considered a dermatologic condition, it is a multisystem disorder involving developmental disorders. The signs and symptoms associated with Cowden syndrome usually appear in the affected population at around 20 to 29 years of age. The most common malignancies associated with Cowden syndrome are adenocarcinoma of the breast (around 20 percent), adenocarcinoma of the thyroid (7 percent), and skin squamous cell carcinomas (4 percent), and the remaining affect uterus, colon, and kidney.

What Are the Causes of Cowden Syndrome?

Cowden syndrome is mainly associated with changes in the PTEN, WWP1, or KLN genes. Around 25 percent of patients with Cowden syndrome have mutations in the PTEN gene. The proteins coded by the PTEN gene act as tumor suppressors and prevent uncontrolled growth and division of cells. Mutations in the PTEN gene cause the formation of hamartomas.

How Is Cowden Syndrome Inherited?

Cowden syndrome is autosomal dominant. Each child of an affected individual has a 50 percent chance of inheriting the disease. Thus one copy of the altered gene can cause the condition. In some cases, it may occur because of new mutations.

What Are the Symptoms of Cowden Syndrome?

Cowden syndrome is a multisystem disorder, and the physical signs and symptoms can be seen in various organ systems.

The most common symptoms of Cowden syndrome include:

• Skin - Patients affected with Cowden syndrome show characteristic findings with papillomatous papules(noncancerous,skin-colored bumps), lipomas (noncancerous fatty growths), and trichilemmomas(noncancerous growth from the hair follicles). Most people develop papillomas on their tongue or gums, having a cobblestone appearance. Some people with Cowden syndrome may also develop palmar keratosis (dark spots on feet and hands), freckles on the penis, vascular malformations, epidermal nevi, and pigmented genital spots. The skin findings of Cowden syndrome are often present in patients during their late twenties.

• Central Nervous System - Around 84 percent of patients with Cowden syndrome have macrocephaly (large head size), usually due to an abnormally enlarged brain (megalencephaly). In addition, some people develop a noncancerous cerebellum tumor, known as Lhermitte-Duclos disease. Varying degrees of intellectual disability and an autism spectrum disorder have been reported in patients with Cowden syndrome.

• Breast - Women with Cowden syndrome develop noncancerous growths of various types in their breasts. Up to 75 percent of women with Cowden syndrome demonstrate breast conditions such as fibroadenomas, intraductal papillomatosis, and fibrocystic changes.

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• Gastrointestinal System - Abnormal tissue growth (polyps) is common in patients (95 percent) with Cowden syndrome. They are multiple, ranging from a few to hundreds, distributed across the colon and other areas of the gastrointestinal tract. Different polyps, such as lymphoid polyps, ganglioneuromatous and adenomatous, are seen less frequently in Cowden syndrome. In addition, some people may have diffuse glycogenic acanthosis affecting the esophagus.

• Male and Female Genitourinary System - Females with Cowden syndrome have an increased risk of developing uterine (endometrial) cancers, usually for those below 50 years of age. Women with Cowden syndrome can also have an enhanced incidence of benign fibroid tumors involving the uterus. Testicular lipomatosis or testicular lipomas is seen in male patients with Cowden syndrome.

• Thyroid - The majority of the patients with Cowden syndrome have thyroid disorders. It includes multinodular goiter or follicular adenomas of the thyroid. As a result, Cowden's patients are at higher risk of developing thyroid cancer than the general population.

How Is Cowden Syndrome Diagnosed?

A diagnostic criterion is used for the identification and diagnosis of Cowden syndrome. It includes major criteria and minor criteria. The diagnosis depends on the following conditions.

1. Three major criteria are met or must include gastrointestinal hamartomas, macrocephaly, and Lhermitte-Duclos.

2. Two major criteria and three minor criteria are present.

The major and minor criteria used for Cowden syndrome are the following:

Major Criteria -

• Breast cancer.

• Thyroid cancer.

• Endometrial cancer.

• Macrocephaly.

• Gastrointestinal hamartomas.

• Macular pigmentation of the penis.

• Lhermitte-Duclos disease.

• Acral keratosis.

• Oral papillomas.

• Mucocutaneous neuromas.

• Multiple trichilemmomas.

• Multiple mucocutaneous lesions.

Minor Criteria -

• Colon cancer.

• Autism spectrum disorder.

• Lipomas.

• Renal cell carcinoma.

• Intellectual disability.

• Esophageal glycogenic acanthosis.

• Testicular lipomatosis.

• Vascular anomalies.

• Thyroid cancer.

• Thyroid lesions.

How Can We Treat Cowden Syndrome?

There is no specific treatment for Cowden syndrome. Patients undergo lifelong monitoring for noncancerous and cancerous growths to detect and treat them early. Specialized breast cancer screening is done in women every month from the age of eight to diagnose breast cancer. Another treatment for Cowden syndrome involves the management of malignancies. The benign lesions are not treated unless they become symptomatic and show cancerous changes. In cases of severe malignancies involving the breast, mastectomy, and thyroidectomy are done. Numerous treatment options, such as topical agents, cryosurgery, laser ablation, curettage, and excision, can be used in those cases.

Conclusion

Cowden syndrome is a rare inherited condition due to mutations in the PTEN gene that codes for proteins responsible for normal cell growth and development regulation. Alterations in the normal cellular growth and division result in an abnormal growth in various organs in the human body. As a result, Cowden syndrome patients may have noncancerous growths in several parts of the body, known as hamartomas, and an increased risk of developing various cancers.