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Cowden Syndrome
Contracting
- What were you told about why you were referred?
- What would you like to learn today?
- Do you have any questions or concerns that you would like us to address?
Medical and Family Histories
- Breast cancer? Endometrial cancer? Benign or malignant tumor of thyroid?
- Renal cell carcinomas, melanoma, glioblastoma?
- Hamartomas of colon, GI tract?
- Macrocephaly? Mental retardation?
- Facial or oral mucocutaneous lesions (trichilimmomas)?
- Fibrocystic breast disease?
- Lipomas or fibromas?
- Lhermitte-Duclos disease (hamartoma of cerebellum) - altered gait or seizures?
Etiology
- Multiple hamartoma syndrome with high risk for benign and malignant tumors of breast, thyroid, and endometrium
- Part of PTEN hamartoma tumor syndrome (PHTS)
- Includes Cowden syndrome, Bannayan-Riley-Ruvalcaba, Proteus syndrome, and Proteus-like syndrome
- Causes hamartomas and cancer due to PTEN mutations
- PTEN mutations and Cowden syndrome:
- Mutations identified in approximately 80% of individuals with a clinical diagnosis
- Located at 10q23.3
- PTEN gene is a tumor suppressor gene
- Mediates cell-cycle arrest and apoptosis
- Part of subclass of dual-specificity phosphatases that remove phosphates from tyrosine, serine, and threonine
- May play a role in cell migration
- Has 9 exons
- Germline mutations have been found throughout gene except exon 9
- 76% of mutations result in truncated protein, haploinsufficiency, or dysfunctional protein
- True prevalence is unknown due to underdiagnosis
- Diagnosis of Cowden sydrome difficult to establish
- Variable presentation
- Symptoms may be subtle
- Estimated to be 1 in 200,000 - probably higher
- Diagnosis of Cowden sydrome difficult to establish
Clinical Features
- Multiple hamartoma syndrome
- High risk for benign and malignant tumors of thyroid breast and endometrium
- Usually presents by late 20's - over 90% of affected people have some features
- Mucocutaneous features present by 30's (99%)
- Trichilemmomas
- Papillomatous papules
- Acral and plantar keratosis
- Macrocephaly or dolichocephaly common
- Tumor risks
- 25-50% lifetime risk of breast cancer
- Average age 38-46 years at diagnosis
- Up to 67% risk for benign breast disease
- Male breast cancer has been reported
- About 10% lifetime risk for thyroid cancer
- Usually follicular, sometimes papillary - never medullary
- Not clear if average age of diagnosis is same as for general population
- Benign multinodular goiter, adenomatous nodules, and follicular adenomas in up to 75% of patients
- May be 5-10% risk for endometrial cancer
- Not well defined
- Benign uterine fibroids are common
- Skin cancers, renal cell carcinomas, and brain tumors seen occasionally
- Lhermitte-Duclos disease
- Rare central nervous system tumor
- Called cerebellar dysplastic gangliocytoma
- Colorectal cancer has been observed rarely in families
- 25-50% lifetime risk of breast cancer
Genetic approach
- three-generation family tree (focus on macrocephaly, breast/thyroid disease, learning disability)
- AD, 50% risk (risk of having of Bannayan-Riley-Ruvalcaba as well as Cowden)
- Mucocutaneous signs (found >90%) could be the only manifestations
- 2/3 have breast and/or thyroid disorder
Treatment/Management Options
- Increased breast cancer screening
- Women should have monthly self exams, annual clinical exams at age 25, and annual mammograms at 30 (or 5 years before youngest age at diagnosis)
- Men should do monthly self breast exams
- Endometrial cancer screening
- Annual blind repel (suction) biopsies in premenopausal women beginning at age 35 (or 5 years before youngest age at diagnosis)
- Annual transvaginal ultrasound exam with biopsy of suspicious findings for postmenopausal women
- Comprehensive annual physical exam
- For men and women starting at age 18 (or 5 years before youngest component cancer diagnosis in family)
- Focus on skin changes and thyroid changes, including baseline ultrasound
- Follow American Cancer Society for colon cancer screening
- GI tract may have hamartomatous polyps not thought to increase cancer risk
- Baseline colonoscopy at 50 years unless symptoms arise earlier
- Annual fecal occult blood testing with sigmoidoscopy every 5 years or colonoscopy every 10 years
- Annual urinalysis to detect renal carcinoma
Diagnosis
- Consensus criteria for clinical diagnosis have been established (International Cowden Consortium 2000)
- Pathognomonic criteria
- Defining characteristic of Cowden syndrome
- Mucocutaneous lesions
- Trichilemmomas on face
- Acral keratoses (thickened area of skin that may be red, yellow, or brown)
- Papillomatous lesions
- Mucosal lesions
- Major criteria
- Breast cancer
- Thyroid cancer
- Macrocephaly
- Lhermitte-Duclos disease (LDD)
- Endometrial carcinoma
- Minor criteria
- Other thyroid lesions
- Mental retardation
- Hamartomatous intestinal polyps
- Fibrocystic breast disease
- Lipomas
- Fibromas
- GU tumors or malformations (uterine fibroids and renal cell carcinoma)
- Criteria for diagnosis
- Pathognomic mucocutaneous lesions if there are:
- Six or more facial papules, with three or more trichilemmoma
- Cutaneous facual papules and oral mucosal papillomatosis
- Oral mucosal papillomatosis and acral keratoses
- Six or more palmo-plantar keratoses
- Macrocephaly or LDD with one other major criteria
- One major and three minor criteria
- Four minor criteria
- Pathognomic mucocutaneous lesions if there are:
- If affected family member has already been identified, diagnosis requires:
- A pathognomonic mucocutaneous lesion
- Any one major criterion with or without minor criteria
- Two minor criteria
- Pathognomonic criteria
- Pathologic review to confirm histopathology of lesions
- Molecular genetic testing
- Failure to detect mutation does not does not exclude clinical diagnosis
- Full sequencing of PTEN gene
- Available clinically
- Virtually all missense mutations believed to be deleterious
- Genotype-phenotype correlation
- Families with PTEN mutations more likely to develop breast disease than those without identified mutations
- Missense mutations and mutations 5' to or within phosophatase core are associated with more severe phenotype
- Southern blotting and monochromosomal hybrid analysis available by research
Differential Diagnosis
- Other PHTS syndromes
- Banayan-Riley-Ruvalcaba (BRR)
- Mutational spectra overlap, autosomal dominant (AD), PTEN mutations 60%
- Complex, highly variable disorder with much in common with Cowden (macrocephaly, association with breast, thyroid, endometrial and gut hamartomas)
- Diagnosis relies on macrocephaly, hamartomatous intestinal polyposis, vascular malformations, lipomas, and pigmented macules of glans penis
- Hypotonia, gross motor and learning-speech delay, may have seizures, mild hypertelorism.
- Proteus syndrome
- Highly variable and appears to only affect some organs or tissues
- Sporadic occurrence, progressive course, and connective tissue nevi
- Can cause disproportionate limb growth
- Recently a proteus-like syndrome has been described but is as yet undefined
- Banayan-Riley-Ruvalcaba (BRR)
- Juvenile polyposis syndrome
- Causes hamartomatous polyps in GI tract and high colorectal cancer risk
- Clinical diagnosis of exclusion
- Two susceptibility genes have been identified
- Peutz Jeghers syndrome
- High risk of intestinal carcinomas and breast cancers
- Pigmentation of peri-oral region is defining characteristic
- Polyps are often symptomatic
- Possibly also consider NF1 or Nevoid basal cell carcinoma (Gorlin) syndrome
Psychosocial Issues
- Anxiety surrounding new diagnosis of disorder that cannot be "cured"
- Requires patient compliance with screening measures - burden of many appointments
- Family thoughts on causes of cancer or other indications
- Past experiences with cancer in family and friends
Resources
- Cowden's Syndrome Foundation
- Phone: 734-944-8313
- Web: communities.msn.com/cowdensyndrome/supportinfo.msnw
- Email: Rosalita@msn.com
- American Cancer Society
- Phone: 800-227-2345
- Web: www.cancer.org
- The National Alliance of Breast Cancer Organizaations
- Phone: 888-806-2226
- Web: www.nabco.org
- Email: NABCOinfo@aol.com
References
- Eng, Charis. "Cowden Syndrome." Journal of Genetic Counseling (1997) 6 :81.
- Eng, Charis. "Will the Real Cowden Syndrome Please Stand Up?" Journal of Medical Genetics (2000) 37:0-2.
- Schneider, Katherine. Counseling About Cancer (2002).
- "PTEN Hamartoma Tumor Syndrome (PHTS)." GeneReviews. www.genereviews.org
Notes
The information in this outline was last updated in 2002.
Material obtained under GFDL Licence from http://en.wikibooks.org/wiki/Handbook_of_Genetic_Counseling
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