Handbook of Genetic Counseling/Cowden Syndrome

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Cowden Syndrome

Contracting[edit | edit source]

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Medical and Family Histories[edit | edit source]

  • 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[edit | edit source]

  • 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[edit | edit source]

  • 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[edit | edit source]

  • 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[edit | edit source]

  • 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[edit | edit source]

  • 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
    • 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[edit | edit source]

  • 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[edit | edit source]

  • 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[edit | edit source]

  • 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[edit | edit source]

  • 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[edit | edit source]

The information in this outline was last updated in 2002.