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.