Tumour ReviewCowden syndrome
Introduction
Cowden syndrome (CS) or disease (CD) was first described by Lloyd and Dennis (1963) in a report of a patient called Rachel Cowden, after whom the syndrome was named, with an apparently new syndrome characterised by multiple hamartomas, unusual skin and facial findings, abnormal CNS findings, and fibrocystic breast disease.1 Nine years later, Weary et al. (1972) confirmed the existence of this new syndrome with the description of five additional patients with similar clinical findings.2
In 1996, the International Cowden Consortium identified germline PTEN (phosphatase and tensin homologue on chromosome 10) mutations as the cause for CS.3 CS is now well recognized as a highly variable, autosomal-dominant hereditary cancer susceptibility syndrome characterised by multiple hamartomas and increased risk of developing malignant transformation. These lesions can arise in derivatives of any of three embryonic germ cell layers.4
The incidence of CS before gene identification was estimated to be 1:1000,000.3 However, after identifying the gene, Nelen et al. (1999) estimated the prevalence of CS to be between 1 in 200,000 and 1 in 250,000 based on projected figures from a Dutch clinical epidemiological study.5 Even this has been argued to be an underestimate given the difficulty in diagnosis of CS due to its variable expression and the fact that many of the component features are subtle, occur in the general population and can be easily missed. There appears to be a female preponderance and most reported cases are in caucasians.6 The age at which CS is diagnosed varies between 13 and 65 years of age.7 The evidence for these demographic data comes from older reviews of published cases which predate the development of the consortium diagnostic criteria and is probably not supported by current clinical experience with PTEN testing. Furthermore it is likely that the gender difference reflects the diagnostic criteria which are biased towards females through the inclusion of breast and uterine findings.
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Diagnostic criteria
Diagnosis is based mainly on clinical criteria. Clinical criteria were proposed by Salem and Steck (1983)7 and have been subsequently revised, modified and established by the International Cowden Consortium for the diagnosis of CS. More recently in the United States the National Comprehensive Cancer Network (NCCN) have published CS testing criteria based on pathognomonic criteria, and major and minor diagnostic criteria, which are outlined in Table 1.8
CS is diagnosed when the patient shows one
Mucocutaneous lesions
The characteristic mucocutaneous features of CS are found in almost 100% of cases.[9], [10], [11] The age of onset of these characteristic mucocutaneous lesions ranges from birth to 46 years (average 22 years).10 Giannada (1980) in her thesis classified the skin lesions into 6 groups (lichenoid papules, acral keratoses, translucent keratoses of the palm, verrucous lesions, papillomatous lesions, and mixed lesions).12 The more recent NCCN criteria for the testing of CS only distinguish between
Genetics of Cowden syndrome
CS is an autosomal dominant inherited disease with incomplete penetrance and variable expressivity.56 Nelen et al. (1996) localised the gene responsible for CS to chromosome 10q22–23 by an extensive linkage study in 12 families.3 Li et al. (1997) refined the location of the gene to chromosome 10q23.3.57 The gene is known as PTEN (phosphatase and tensin homologue deleted on chromosome 10 [MIM 601728]) but has also been given the names MMAC1 (mutated in multiple advanced cancers) and TEP1
Surveillance and management
The management of CS is summarized in Table 2.8 The key to managing the risk of cancer in CS is early identification and diagnosis of patients with CS. Clinicians need to be educated and be vigilant for the signs of CS. Obtaining an accurate three-generation family history is important including both maternal and paternal family histories of cancer seeing as CS is inherited in an autosomal dominant fashion and can occur through both male and female transmission.86 The recommendations for
Conclusion
In summary CS is an autosomal dominant cancer syndrome with a high risk of many malignancies. Early recognition of CS is critical to the early diagnosis of potential associated carcinomas of various visceral organs. Improved understanding of the genetic and molecular basis of this syndrome is likely to lead to advances in both the diagnostic and preventative care afforded to patients with CS. In the meantime doctors from many specialties can play an important role in identifying the plethora of
Conflict of interest statement
None declared.
References (91)
- et al.
Cowden’s disease (multiple hamartoma and neoplasia syndrome). A case report and review of the English literature
J Am Acad Dermatol
(1983) - et al.
Cowden’s disease: a rare but important manifestation of oral papillomatosis
Brit J Oral Maxillofac Surg
(1992) - et al.
Early diagnosis of multiple hamartoma and neoplasia syndrome (Cowden disease). The role of the dentist
Oral Surg, Oral Med, Oral Pathol, Oral Radiol, Endodont
(1995) - et al.
Multiple hamartoma syndrome
J Am Acad Dermatol
(1987) - et al.
The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases
Am J Human Genet
(1997) - et al.
Inherited mutations in PTEN that are associated with breast cancer, Cowden syndrome and juvenile polyposis
Am J Human Genet
(1997) - et al.
Clinical and pathological features of breast disease in Cowden’s syndrome: an under-recognized syndrome with an increased risk of breast cancer
Human Pathol
(1998) - et al.
Thyroid pathologic findings in patients with Cowden disease
Ann Diagn Pathol
(1999) - et al.
Multiple hamartoma syndrome. A report of a new case with associated carcinoma of the uterine cervix and angioid streaks of the eyes
J Am Acad Dermatol
(1980) - 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)
Cowden syndrome: report of a case with immunohistochemical analysis and review of the literature
Oral Surg, Oral Med, Oral Pathol, Oral Radiol Endodentol
PTEN modulates vascular endothelial growth factor-mediated signaling and angiogenic effects
J Biol Chem
PTEN hamartomatous tumor syndromes (PHTS): rare syndromes with great relevance to common cancers and targeted drug development
Crit Rev Oncol/Hematol
Protean PTEN: form and function
Am J Human Genet
A novel mutation of the PTEN gene in a Japanese patient with Cowden syndrome and bilateral breast cancer
Cancer Genet Cytogenet
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 Human Genet
Cowden syndrome-affected patients with PTEN promoter mutations demonstrate abnormal protein translation
Am J Human Genet
Differential expression of PTEN-targeting MicroRNAs miR-19a and miR-21 in Cowden syndrome
Am J Human Genet
Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes
Am J Human Genet
Cowden syndrome
Semi Oncol
Integrin-linked kinase (ILK) regulation of the cell viability in PTEN mutant glioblastoma and in vitro inhibition by the specific COX-2 inhibitor NS-398
Cancer Lett
Cowden’s disease: a possible new symptom complex with multiple system involvement
Ann Intern Med
Multiple hamartoma syndrome (Cowden’s disease)
Arch Dermatol
Localization of the gene for Cowden disease to 10q22–23
Nat Genet
Will the real Cowden syndrome please stand up: revised diagnostic criteria
J Med Genet
Novel PTEN mutations in patients with Cowden disease: absence of clear genotype–phenotype correlations
Eur J Human Genet
The Cowden syndrome: a clinical and genetic study in 21 patients
Clin Genet
Cowden disease or multiple hamartoma syndrome – cutaneous clue to internal malignancy
Eur J Dermatol
The cutaneous pathology of facial lesions in Cowden’s disease
J Cutan Pathol
Cowden’s syndrome
Dermatol Online J
Trichilemmomas in Cowden’s disease
J Am Med Assoc
Mucocutaneous papillomatous papules in Cowden’s syndrome
Clin Exp Dermatol
Cowden’s disease: a rare cause of oral papillomatosis
J Laryngol Otol
The dermatopathology of Cowden’s syndrome
Brit J Dermatol
PTEN hamartoma tumor syndromes
Eur J Human Genet
Multiple oral fibropapillomatosis as an initial manifestation of Cowden syndrome. Case report
Medicina Oral, Patologica Oral y Cirugia Bucal
Cowden’s disease – its importance for otolaryngologists
J Laryngol Otol
Cowden’s disease: a case report and review of the literature
J Dermatol Surg Oncol
Cowden’s disease. Adenomatous polyps. Periorifichal lentiginosis
Annales de Dermatologie et Venereologie
Mucocutaneous neuromas: an under-recognized manifestation of PTEN hamartoma-tumor syndrome
Arch Dermatol
Acral papular neuromatosis: an early manifestation of Cowden syndrome
Brit J Dermatol
Susceptibility to breast cancer: hereditary syndromes and low penetrance genes
Breast Dis
Cowden’s disease: a cutaneous marker of breast cancer
Cancer
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