eMedicine Specialties > Dermatology > Internal Medicine

Cowden Disease (Multiple Hamartoma Syndrome)

Author: Kendall Adkisson, MD, Resident Physician, Scott and White Dermatology
Coauthor(s): Katherine H Fiala, MD, Assistant Professor, Department of Dermatology, Scott and White Northside Clinic
Contributor Information and Disclosures

Updated: Apr 26, 2010

Introduction

Background

Cowden disease, also termed Cowden syndrome and multiple hamartoma syndrome, is an autosomal dominant condition with variable expression that results most commonly (80%) from 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 Proteuslike syndrome, which all have PTEN mutations. Rare cases of Cowden disease (multiple hamartoma syndrome) are due to a germline mutation in the BMPR1A (bone morphogenetic proteins) gene.

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.

Pathophysiology

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 regulates the function of other proteins by removing phosphate groups from those molecules. The PTEN protein product negatively controls the phosphoinositide 3-kinase–signaling pathway for regulating cell growth and survival by dephosphorylating the 3 position of phosphoinositide.

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.³

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.⁴ 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.

Approximately 18% of Cowden disease (multiple hamartoma syndrome) patients are negative for PTEN mutations and have no identified genetic explanation for their clinical features. Various other possible mechanisms of PTEN inactivation have been explored, but no clear answer has been identified.⁵

Frequency

International

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.⁶ 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.⁷

Mortality/Morbidity

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.

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.

Clinical

History

Most patients present to the physician because of cutaneous manifestations. Individuals suspected of having Cowden disease (multiple hamartoma syndrome) should be questioned carefully about other family members with malignancies, especially concerning the breast and thyroid. A more detailed family history, including other cutaneous and mucosal lesions and cancers, as well as the developmental and neurologic abnormalities, may be helpful. A full review of systems also is warranted.

Physical

A baseline full physical examination with yearly follow-up examinations to help detect early changes resulting from malignancies is an essential component of Cowden disease (multiple hamartoma syndrome) patients' management. The physical signs that may be present with Cowden disease (multiple hamartoma syndrome) are discussed below.

Mucocutaneous surfaces

In 90-100% of patients, 1 of 4 types of mucocutaneous lesions is present.

Cutaneous facial papules are present. Most patients exhibit either flesh-colored, flat-topped lichenoid, or elongated verrucoid papules. The lesions may have a central keratin-plugged center and a diameter ranging from 1-5 mm. Typically, large numbers of lesions are present and have a predisposition for the periorificial region. Most of these lesions are trichilemmomas. Note the image below.

Oral lesions are common. Papules are 1-3 mm with a smooth surface and a whitish appearance and are present in the gingival, labial, and palatal surfaces of the mouth in more than 80% of patients. Lesions often coalesce into confluent sheets, which are described as having a cobblestone appearance. Histologically, they are benign fibromas. Thickening or furrowing of the tongue (scrotal tongue) also may be present. Note the image of oral lesions below.

Acral keratoses are flesh-colored or slightly pigmented smooth or verrucoid papules on the dorsal hands and feet, and they occur in more than 60% of patients. The lesions must be differentiated from verruca plana and acrokeratosis verruciformis.

Palmoplantar keratoses are noted. Approximately 40% of Cowden disease (multiple hamartoma syndrome) patients have translucent punctate keratoses on the palms or soles. These need to be distinguished from benign keratoses and arsenic-induced keratoses.

Other cutaneous lesions may occur. Less frequently noted lesions include lipomas, neuromas, and hemangiomas and sclerotic fibromas. A report in 2006 documents multiple mucosal neuromas as the presenting sign of Cowden syndrome, adding this syndrome to the differential diagnosis list for multiple mucosal neuromas.⁸ Multiple sclerotic fibromas are also documented by Requena et al as a cutaneous marker for Cowden disease (multiple hamartoma syndrome).⁹

Head, nose, eyes, and throat

Findings may include macrocephaly (in as many as 80% of patients), adenoid facies, eye findings (in as many as 13% of patients, including angioid streaks, myopia), small jaw, and a high-arched palate.

Thyroid lesions

Abnormalities of the thyroid are present in approximately 60% of patients. Manifestations include goiter, benign adenomas, thyroglossal duct cysts, and follicular adenocarcinomas. Patients should be followed carefully for the development of thyroid carcinoma.

Breast disease

Carcinoma of the breast occurs in 20-36% of female patients and is one of the most serious consequences of Cowden disease (multiple hamartoma syndrome). Carcinoma of the breast also has been reported in 2 men with Cowden disease (multiple hamartoma syndrome).¹⁰ Fibrocystic disease and fibroadenomas are present in approximately 75% of patients.

GI tract

GI abnormalities are present in as many as 72% of patients. Polyps can occur in the esophagus, stomach, small or large intestine, or anus and are most common in the colon. Although Chen et al reported a few cases of adenocarcinoma of the colon in Cowden disease (multiple hamartoma syndrome) patients, the malignant potential of polyps is low.¹¹ Esophageal and gingival glycogen acanthosis has been documented in several patients with Cowden disease (multiple hamartoma syndrome).¹²

Genitourinary tract

The most common genitourinary tract manifestations are ovarian cysts and leiomyomas. The most serious genitourinary tract manifestation is endometrial cancer. One case of endometrial cancer has been reported in an adolescent.¹³

Teratomas, adenocarcinomas of the urethra and cervix, transitional carcinomas, renal cell carcinomas, and benign urethral polyps have been reported. In 2006, Woodhouse and Ferguson reported multiple bilateral hyperechoic testicular lesions in a small series of 8 male patients with documented PTEN mutations. Further testing indicated no effect on spermatogenesis or testicular function. Biopsies revealed lipomatosis in all but the youngest patient.¹⁴

Skeletal abnormalities

These include bone cysts, thoracic kyphosis, and kyphoscoliosis, as well as 1 case of osteosarcoma reported by Yen et al.¹⁵

CNS abnormalities

Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum) currently is considered to be part of Cowden disease (multiple hamartoma syndrome) and is caused by hamartomatous growths of the cerebellum. Patients have macrocephaly, slowly progressive cerebellar ataxia (which usually appears in adulthood), and signs of increased intracranial pressure. Cases of Lhermitte-Duclos disease occurring without any other evidence of Cowden disease (multiple hamartoma syndrome) have been reported.

Seven reports in the literature describe meningiomas in patients with Cowden disease (multiple hamartoma syndrome).¹⁶

Diagnostic criteria

The National Comprehensive Cancer Network 2008 has proposed operational criteria for the diagnosis of Cowden disease (multiple hamartoma syndrome) that have a few modifications from the original Cowden Syndrome Consortium. Unfortunately, the "pathognomonic" criteria (which include facial trichilemmomas, acral keratoses, papillomatous papules, and mucosal lesions) are not specific enough. The other and more useful criteria are described.

Major criteria

• Breast cancer
• Thyroid carcinoma, especially follicular thyroid carcinoma
• Macrocephaly (>97 percentile)
• Lhermitte-Duclos disease
• Endometrial cancer

Minor criteria

• Other thyroid lesions (eg, adenoma, multinodular goiter)
• Mental retardation (intelligence quotient <75)
• GI hamartomas
• Fibrocystic disease of the breast
• Lipomas
• Fibromas
• Genitourinary tumors (eg, uterine fibroids, renal cell carcinoma) or malformations

Operational diagnosis in an individual

• Mucocutaneous lesions alone meet the criteria if (1) 6 or more facial papules are present, of which 3 or more must be trichilemmomas; (2) cutaneous facial papules and oral mucosal papillomatosus are present; (3) oral mucosal papillomatosus and acral keratoses are present; or (4) 6 or more palmoplantar keratoses are present.
• Two major criteria, but one must include either macrocephaly or Lhermitte-Duclos disease
• One major and 3 minor criteria
• Four minor criteria

Operational diagnosis in a family in which one individual is diagnostic for Cowden disease (multiple hamartoma syndrome)

• One pathognomonic criterion
• Any single major criterion with or without minor criteria
• Two minor criteria
• History of Bannayan-Riley-Ruvulcaba syndrome

Causes

Cowden disease (multiple hamartoma syndrome) is caused by a mutation in the tumor suppressor gene PTEN (also termed MMAC1 or TEP1) on band 10q23. At least 80% of Cowden disease (multiple hamartoma syndrome) patients have a PTEN mutation. Sixty percent of Bannayan-Riley-Ruvalcaba syndrome patients have a similar mutation.

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 (multiple hamartoma syndrome) is inherited as an autosomal dominant condition. The percent of cases resulting from new mutations is unknown. An infant with Proteus syndrome born to a mother with Cowden syndrome also correlates these 2 diseases with the PTEN mutation.¹⁷

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