Cowden Disease (Multiple Hamartoma Syndrome)

Updated: Jun 27, 2023
  • Author: Katherine H Fiala, MD; Chief Editor: William D James, MD  more...
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Practice Essentials

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]

Signs and symptoms

Also see Presentation.

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. Notably, Cowden disease has been documented in association with Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum). [2]

Mucocutaneous features of Cowden disease include trichilemmomas, oral mucosal papillomatosis, acral keratoses, and palmoplantar keratoses. Cowden disease 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.

Note the clinical image below.

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


Also see Workup.

Because a large number of hamartomas and malignancies have been reported in patients with Cowden disease (multiple hamartoma syndrome), monitoring patients closely using appropriate laboratory procedures is essential. Perform the following laboratory studies at baseline and as indicated clinically in subsequent years:

  • CBC count: Anemia can be a sign of malignancy (usually from GI blood loss), and an abnormal WBC count may indicate a lymphoproliferative disorder.

  • Thyroid function tests: A high risk of thyroid disease (including goiter, Hashimoto thyroiditis, adenomas, and carcinomas) exists in patients with Cowden disease (multiple hamartoma syndrome); therefore, routine monitoring is appropriate. [3]

  • Urinalysis: Check for proteinuria or hematuria that may indicate kidney or bladder neoplasia.

  • Chemistry panels: These should include a calcium level to screen for parathyroid disease and liver function tests to detect possible hepatocellular carcinoma.

  • Skin biopsy: Perform skin biopsy for the pathologic diagnosis of potential trichilemmomas or sclerotic fibromas.


See Guidelines for National Comprehensive Cancer Network 2018 management recommendations.

Systemic treatments (ie, acitretin) may be used to control some of the cutaneous manifestations of the disease; however, recurrence of lesions is typical after treatment is discontinued. [4]

Surgical care of facial papules may include the following:

  • Chemical peels

  • Laser resurfacing

  • Surgery and/or shave excisions only if symptomatic or malignancy is suspected because surgical removal may be complicated by recurrence or keloid formation



Originally described in 1963 by Lloyd and Dennis, Cowden disease (multiple hamartoma syndrome) was named after the family in which it was first reported. [5] 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.



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. [6] The relationship between Cowden disease and PTEN mutations is under investigation. Deep sequencing techniques have identified PTEN mosaicism not detected by traditional techniques. [7] Another study discovered germline mutations downstream in the phosphoinositide 3-kinase–signaling pathway. [8] Additional mutations related to the Cowden disease phenotype have been reported. [9, 10]

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. [11]

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. [12] 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.



Cowden disease (multiple hamartoma syndrome) is associated with a mutation in the tumor suppressor gene PTEN (also termed MMAC1 or TEP1) on band 10q23. PTEN is a lipid phosphatase that removes phosphate groups from signaling molecules. This activity normally restricts growth and survival signals, allowing for normal cell death. When PTEN is mutated, some cells are allowed to proliferate, sometimes (as in cancer) uncontrollably.

Cowden disease is inherited as an autosomal dominant condition. The percent of cases resulting from new mutations is unknown.

Other mutations have been identified in patients with Cowden disease phenotype include PIK3CA, AKT1, BMPR1A (bone morphogenetic proteins) gene, and KLLN. [8, 9, 10]

An infant with Proteus syndrome born to a mother with Cowden syndrome also correlates these 2 diseases with the PTEN mutation. [13]




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. [14] 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 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. [15]


Males and females inherit the mutated gene in equal number; it is autosomal dominant. Cutaneous manifestations of Cowden disease 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.


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



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 patients also can cause significant morbidity. At least 40% of Cowden disease 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. [16] Many of the cancers are curable if detected early. Close follow-up care of these patients is necessary.


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.

Patients should know the risk of colon cancer associated with colon polyposis. [17]  Patients should also follow regularly with an ophthalmologist due to the risk of ocular pathology. [18]