Cowden disease = داء كودن |
Cowden disease 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) 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.
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. lA 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
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
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
Minor criteria
Operational diagnosis in an individual
Operational diagnosis in a family in which one individual is diagnostic for Cowden disease (multiple hamartoma syndrome)
CausesCowden 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.
Laboratory StudiesBecause 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:
Imaging StudiesInitiate annual or biannual screening mammograms early in women, and perform them regularly to screen for breast cancer. See Medical Care for considerations regarding prophylactic mastectomy. Mammograms in men may be considered, especially if clinically indicated, but men’s risk for breast cancer may not be increased over the general male population. Chest radiography may be performed, as may thyroid scanning. Consider MRI of the brain if CNS symptoms are present to exclude Lhermitte-Duclos disease (dysplastic gangliocytoma of cerebellum). Based on a report by Lok et al, obtaining baseline head MRI findings from all patients diagnosed with Cowden disease (multiple hamartoma syndrome) may be reasonable because 35% of the Cowden disease (multiple hamartoma syndrome) patients studied had significant findings when one was obtained.16 Significant CNS symptoms (including headache or other focal neurologic signs) also may indicate the need for a follow-up head MRI in Cowden syndrome patients. A study of Lhermitte-Duclos disease patients using positron emission tomography suggested that these patients should be followed regularly in case of progression of these lesions.18 Perform barium swallow and enema to exclude hamartomas of the GI tract. Alternatively, upper and lower GI endoscopy may be used. Routine occult blood tests should also be performed, although the real increased risk of colon cancer is yet to be determined. Polyps in Cowden syndrome patients may be nonadenomatous, but these hamartomatous polyps have been documented to progress to colonic adenocarcinoma.19 Perform intravenous pyelography if indicated clinically or if urinalysis shows an abnormality. Additionally, ultrasonography of the testes can also be considered. Seven of 8 patients with Cowden syndrome were shown to have testicular lipomatosis.14 Other TestsA multitude of methodologies are available to detect PTEN deletions in patients suspected to have Cowden disease (multiple hamartoma syndrome). Multiple ligation-dependent probe amplification (MLPA) is currently preferred. Other methods include Southern blotting, monochromosomal hybrid analysis, real-time polymerase chain reaction, and semiquantitative multiplex polymerase chain reaction.7
ProceduresPerform fine-needle aspiration or surgical biopsy on thyroid nodules found on physical examination or thyroid imaging studies. Consider upper and lower GI endoscopy as a screening procedure or to obtain a biopsy specimen of lesions found on the barium study. Esophageal glycogenosis is very suggestive of Cowden disease (multiple hamartoma syndrome). Submit skin biopsy specimens to a dermatopathologist for pathologic diagnosis of potential trichilemmomas or sclerotic fibromas. Histologic FindingsTrichilemmomas are lobular proliferations of squamoid cells, often with a distinctive clear (glycogenated) appearance that resembles the outer root sheath of the hair follicle. Peripheral palisading of the lobules is apparent. Lobules often are bound by a thickened eosinophilic basement membrane. A small risk of trichilemmal carcinoma exists, as reported by O'Hare et al in 1 case.21
Medical CareAccording to the National Comprehensive Cancer Network 2008, management guidelines for Cowden disease (multiple hamartoma syndrome) include the following:
Surgical CareSurgical care of facial papules may include the following:
ConsultationsConsult the following specialists as determined necessary by laboratory test results and physical examination findings:
MedicationSystemic therapy with retinoids may temporarily control some of the cutaneous lesions of Cowden disease (multiple hamartoma syndrome). Topical treatment usually is unsatisfactory.
RetinoidsThese agents are partially effective in treating cutaneous lesions. Acitretin (Soriatane)Retinoic acid analog similar to etretinate and isotretinoin. Acitretin is the main metabolite of etretinate and has demonstrated clinical effects close to those seen with etretinate. Mechanism of action is suspected to be through its ability to cause increased differentiation of cells.
Adult10-50 mg PO qd PediatricNot recommended |