Dermatology Online Journal

Cowden's syndrome
Olympia Kovich MD, and David Cohen MD MPH
Dermatology Online Journal 10 (3): 3

From the Ronald O. Perelman Department of Dermatology, New York University

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Abstract

A 59-year-old woman initially presented with facial papules, which were consistent with trichilemmomas on histopathologic examination. Her course was complicated by breast, endometrial, and renal-cell carcinomas, as well as a multinodular goiter that necessitated a thyroidectomy. Cowden's syndrome is a rare autosomal dominant syndrome that is characterized by hamartomas of ectodermal, mesodermal, and endodermal origin as well as an increased risk of breast, thyroid, and endometrial neoplasias. Medical management includes screening for breast cancer and thyroid abnormalities, and performing other age-specific examinations. Treatment of facial papules includes topical 5-fluorouracil, isotretinoin, curettage, laser ablation, or surgical excision.

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Clinical synopsis

History.—A 59-year-old woman presented with a 20-year history of papules on the dorsa of the hands and feet. The patient developed a benign tumor of the breast at age 16 and a bone cyst of the femur at age 21. She did not seek evaluation until she was 36 for facial papules that have been present since age 16. She developed breast cancer at age 45; treatment consisted of mastectomy and chemotherapy. The patient reported that her facial papules disappeared while she received chemotherapy but later recurred. Three years later, she underwent a total abdominal hysterectomy for endometrial carcinoma. At age 46, she developed hyperthyroidism, which was attributed to a multinodular goiter. Because her symptoms were not controlled by medication, she underwent a thyroidectomy three years later. The patient developed breast cancer in the contralateral breast at age 52 and underwent mastectomy with reconstruction. Five years later, bilateral partial nephrectomies were performed for renal cell carcinoma.

The patient received treatment with liquid nitrogen for the facial papules. Most recently she was referred for possible laser treatment. Surgical removal of oral lesions has been performed periodically.

Physical Examination.—Numerous, firm, flat-topped, skin-colored papules were present on the periorbital and perioral regions and on the nasolabial folds. In addition, a filiform papule was noted on the right nasolabial fold. Hyperkeratotic, verrucous papules were present on the dorsa of the hands and feet. There are no oral lesions.

Figure 1	Figure 2

Laboratory Data.—The patient underwent genetic testing, and a mutation in the PTEN gene was found.

Diagnosis.—Cowden's syndrome.

Comment

Cowden's syndrome is an uncommon, although likely underreported, autosominal dominant disorder that is characterized by hamartomatous tumors of all three germ layers and by an increased risk of breast, thyroid, and endometrial neoplasia. Pathognomonic criteria include mucocutaneous lesions, found in over 90 percent of patients; these comprise facial trichilemmomas, acral keratoses, papillomatous papules, and mucosal lesions [1]. Mucocutaneous lesions appear most commonly in the second and third decades; facial papules are the most frequent finding [2]. Coalescing mucosal lesions with a predilection for the buccal and gingival mucosae lead to the characteristic cobblestone-like pattern that is found in 40 percent of patients [2].

The most common extracutaneous feature, which occurs in two thirds of patients, is thyroid disease; this may manifest as goiter, thyroid dysfunction, thyroiditis, or thyroid cancer. Thyroid cancer occurs in 7 percent of patients and represents the second most common malignant condition found in Cowden's syndrome [3]. Fibrocystic breast disease and fibroadenomas arise in approximately 75 percent of female patients. Carcinoma of the breast is the most common malignant condition to occur in patients with Cowden's syndrome and is found in 22 percent of women. The age of onset is comparable to that of the general population with carcinoma of the breast [2].

Hamartomatous polyps of the intestinal tract also have been reported in 40-60 percent of patients [2]. A recent case report described a patient in whom Cowden's syndrome was suspected and subsequently confirmed solely on the basis of gastrointestinal polyposis in the absence of cutaneous findings [3].

Germline mutations in PTEN, a tumor suppressor gene, have been identified in 80 percent of probands with Cowden's syndrome [1]. Over 80 different mutations have been identified [4]. A subset of patients without intragenic PTEN mutations have deletions and mutations in the PTEN promoter [5]. Hamartomas in Cowden's syndrome occur without loss of the second PTEN allele, while malignant tumors require complete inactivation of PTEN and other somatic mutations [6]. Management of Cowden's syndrome is aimed primarily at early detection of malignant conditions. Therefore, periodic mammograms are recommended as well as thyroid function studies, thyroid scans, basic laboratory tests, a pap smear, and ultrasound evaluation of the uterus. Treatment of facial papules has included topical 5-fluorouracil, oral isotretinoin, curettage, laser ablation, or surgical excision.

References

1. Waite KA, Eng C. Protean PTEN: form and function. Am J Human Genet 2002; 70:829.

2. Hildenbrand C, et al. Cowden Syndrome: diagnostic skin signs. Dermatology 2001; 202:362.

3. McGarrity TJ, et al. GI polyposis and glycogenic acanthosis of the esophagus associated with PTEN mutation positive Cowden syndrome in the absence of cutaneous manifestations. Am J Gastroenterol 2003; 98:1429.

4. Bussaglia E, et al. PTEN mutations in eight Spanish families and one Brazilian family with Cowden syndrome. J Invest Dermatol 2002; 118:639.

5. Zhou XP, et al. Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. Am J Hum Genet 2003; 73:404.

6. Reifenberger J, et al. Cowden's disease: clinical and molecular genetic findings in a patient with a novel PTEN germline mutation. Br J Dermatol 2003;148:1040 .

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