# 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 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.