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