Cowden Disease -Multiple Hamartoma Syndrome

Background: Cowden disease (CD), 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. A broader category, "PTEN (phosphatase and tensin homolog) hamartoma tumor syndrome," has been suggested as a name to combine multiple phenotypic presentations all due to PTEN genetic diseases. Rare cases of CD are due to a germline mutation in BMPR1A (bone morphogenetic proteins).

CD 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 CD include trichilemmomas, oral mucosal papillomatosis, acral keratoses, and palmoplantar keratoses. CD 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 occurring in patients with CD.

Pathophysiology: CD is caused by a mutation in the PTEN tumor suppressor gene (also termed MMAC1 or TEP1) on band 10q23. 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.

Identical mutations in PTEN have been described by Tok Celebri et al in Bannayan-Zonana syndrome, and patients with either syndrome share some clinical features. Patients with Bannayan-Zonana syndrome 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 small percentage of patients with Proteus and Proteus-like syndromes have also demonstrated PTEN mutations.

Frequency:

• Internationally: Internationally, over 200 cases have been published, including separate studies of several generations of affected family members, as reported by Tok Celebri et al.

Mortality/Morbidity: Morbidity and mortality from CD primarily is associated with increased frequency of malignant tumors. Benign tumors that develop in CD patients also can cause significant morbidity.

Sex: Males and females inherit the mutated gene in equal numbers. Cutaneous manifestations are similar in both sexes. The incidence of malignancies varies depending on the sex, eg, males are more likely to develop thyroid cancer, while females are at greater risk for breast cancer.

Physical: A baseline full physical examination with yearly follow-up examinations to help detect early changes resulting from malignancies is an essential component of CD patients' management. The following physical signs may be present with CD:

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

• Cutaneous facial papules: 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 that have a predisposition for the periorificial region. Most of these lesions are trichilemmomas.

• Oral lesions: 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.

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

• Palmoplantar keratoses: Approximately 40% of CD 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.

• Head, nose, eyes, and throat

• 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

• 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 CD. It also has been reported by Fackenthal et al in 2 men.

• 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 CD patients, the malignant potential of polyps is low. Esophageal glycogen acanthosis has been documented in several patients with CD.

• Genitourinary tract

• The most common genitourinary tract manifestations are ovarian cysts and leiomyomas.

• The most serious genitourinary tract manifestation is endometrial cancer.

• Teratomas, adenocarcinomas of the urethra and cervix, transitional carcinomas, renal cell carcinomas, and benign urethral polyps have been reported.

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

• CNS abnormalities: Lhermitte-Duclos disease currently is considered to be part of CD 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 CD have been reported.

• Diagnostic criteria: The International Cowden Syndrome Consortium has proposed operational criteria for the diagnosis of CD. Unfortunately their "pathognomonic" criteria (which includes facial trichilemmomas, acral keratoses, papillomatous papules, and mucosal lesions) are not specific enough for use by dermatologists. The other and more useful criteria are the following:

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

• 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) 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 are met, but one must include either macrocephaly or Lhermitte-Duclos disease
    
  • One major and 3 minor criteria are met.
    
  • Four minor criteria are met.
    

• Operational diagnosis in a family in which one individual is diagnostic for CD
  • Any single major criterion with or without minor criteria is met.
  • Two minor criteria are met.
    

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