Cowden Disease (Multiple Hamartoma Syndrome)

Updated: Jun 24, 2016
  • Author: Katherine H Fiala, MD; Chief Editor: William D James, MD  more...
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Overview

Background

Cowden disease, also termed Cowden syndrome and multiple hamartoma syndrome, is an autosomal dominant condition with variable expression that can be associated with a mutation in the PTEN gene on arm 10q, as reported by Liaw et al. [1] Originally described in 1963 by Lloyd and Dennis, Cowden disease (multiple hamartoma syndrome) was named after the family in which it was first reported. [2] A broader category, PTEN (phosphatase and tensin homolog) hamartoma tumor syndrome includes Cowden disease (multiple hamartoma syndrome), Bannayan-Riley-Ruvulcaba syndrome (BRRS), Proteus syndrome, and Proteus-like syndrome, which all have PTEN mutations.

Cowden disease (multiple hamartoma syndrome) causes hamartomatous neoplasms of the skin and mucosa, GI tract, bones, CNS, eyes, and genitourinary tract. Skin is involved in 90-100% of cases, and the thyroid is involved in 66% of cases.

Mucocutaneous features of Cowden disease (multiple hamartoma syndrome) include trichilemmomas, oral mucosal papillomatosis, acral keratoses, and palmoplantar keratoses. Cowden disease (multiple hamartoma syndrome) is associated with the development of several types of malignancy, which is why recognition of individuals with the syndrome is important. In particular, a marked increase is seen in the incidence of breast carcinoma in women and of thyroid carcinoma in both men and women. Reports also exist of several other types of malignancies, such as colon cancer and renal cell carcinoma, in patients with Cowden disease (multiple hamartoma syndrome).

Note the clinical image below.

A patient with trichilemmoma papules on the face. A patient with trichilemmoma papules on the face.
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Pathophysiology

Traditionally, Cowden disease (multiple hamartoma syndrome) is caused by a mutation in the PTEN tumor suppressor gene (also termed MMAC1 or TEP1) on band 10q23.3. The protein product of the gene is a phosphatase that negatively controls the phosphoinositide 3-kinase–signaling pathway for regulating cell growth and survival by dephosphorylating the 3 position of phosphoinositide.

The original reports of families studied at tertiary referral centers found PTEN mutations in 80% of patients clinically diagnosed with Cowden disease. [1] However, newer prospective reports of unrelated individuals identified PTEN mutations in approximately 25% of individuals studied. [3] The relationship between Cowden disease and PTEN mutations is under investigation. Deep sequencing techniques have identified PTEN mosaicism not detected by traditional techniques. [4] Another study discovered germline mutations downstream in the phosphoinositide 3-kinase–signaling pathway. [5] Additional mutations related to the Cowden disease phenotype have been reported. [6, 7]

The PTEN protein is believed to promote cell death. A mutation that causes loss of the protein's function may result in overproliferation of cells, resulting in hamartomatous growths. Part of this overproliferation may be due to some interaction between the PTEN tumor suppressor gene and a more widely known tumor suppressor gene, TP53.PTEN mutations have been found to occur most frequently in association with endometrial cancer, glioblastomas, and prostate cancer. [8]

Identical mutations in PTEN have been described in Bannayan-Ruvulcaba-Riley syndrome (BRRS). Alternate names for BRRS include Bannayan-Zonana syndrome, Riley-Smith syndrome, and Ruvulcaba-Myhre-Smith syndrome. [9] Patients with BRRS have a much lower predisposition to cancer, which suggests that a mutation in the PTEN gene is not the only factor responsible for the clinical features of the disease.

A percentage of patients with Proteuslike syndromes, adult Lhermitte-Duclos disease (LDD), and autismlike disorders associated with macrocephaly have also demonstrated PTEN mutations.

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Epidemiology

Frequency

Internationally, more than 300 cases have been published, including separate studies of several generations of affected family members, as reported by Tok Celebri et al. [10] The prevalence of Cowden disease (multiple hamartoma syndrome) is estimated to be approximately 1 case per 200,000 population; however, it is likely more prevalent because many features of Cowden disease (multiple hamartoma syndrome) are found in the general population and the diagnosis may be overlooked, which leads to underdiagnosis. Penetrance is thought to be nearly complete; it approaches 90% by age 20 years. [11]

Sex

Males and females inherit the mutated gene in equal number; it is autosomal dominant. Cutaneous manifestations of Cowden disease (multiple hamartoma syndrome) are similar in both sexes. However, the incidence of malignancies varies depending on the sex. For example, males are more likely to develop thyroid cancer, while females are at greater risk for breast cancer.

Age

Although the mutant gene is inherited, the onset of clinical manifestations of Cowden disease (multiple hamartoma syndrome) varies in age, ranging from birth to age 46 years.

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Prognosis

Morbidity and mortality from Cowden disease (multiple hamartoma syndrome) primarily is associated with increased frequency of malignant tumors. Benign tumors that develop in Cowden disease (multiple hamartoma syndrome) patients also can cause significant morbidity. At least 40% of Cowden disease (multiple hamartoma syndrome) patients have a minimum of one malignant primary tumor, although with long-term follow-up care, this number may be higher. Yen et al have reported patients with more than 1 malignancy. [12] Many of the cancers are curable if detected early. Close follow-up care of these patients is necessary.

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Patient Education

Counsel patients regarding the increased risk for malignancy, especially thyroid cancer and breast cancer in women, and the need for close follow up and cancer screening with their physicians. Instruct patients about the early signs of the most common cancers for which they are at risk.

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