Handbook of Genetic Counseling/Cowden Syndrome

Cowden Syndrome

Contracting

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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

Clinical Features

Multiple hamartoma syndrome
- High risk for benign and malignant tumors of thyroid breast and endometrium
- Usually presents by late 20s - over 90% of affected people have some features
- Mucocutaneous features present by 30s (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

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^{[check spelling]} 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
- 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
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
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.