Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released - Under Revision 1.1.0
• GENE/GENE PANEL: PTEN
• Condition: PTEN Hamartoma Tumor Syndrome - Cowden Syndrome
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• PTEN ⇔ 158350: Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Breast cancer / Regular screening	2	3C	2B	3	10CB
Thyroid cancer / Thyroid ultrasounds	2	2C	2B	3	9CB

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The true prevalence of Cowden syndrome (CS) is unknown. [1, 2, 3, 4, 5, 6]

Clinical Features

CS is part of the PTEN hamartoma tumor syndrome (PHTS) spectrum. CS is a cancer syndrome associated with a high risk of hamartomas and/or cancerous lesions in various organs and tissues, including the skin, mucous membranes, breast, thyroid, endometrium, and brain. Macrocephaly is a common manifestation. Hamartomatous polyps of the colon and other intestines also occur. Renal cell carcinoma and malignant melanoma may be minor component neoplasias of CS. [1, 3, 5, 4, 6]

Natural History

More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s. By the third decade, 99% of affected individuals develop the mucocutaneous stigmata, as well as acral and plantar keratoses. The average age of breast cancer diagnosis is between 38 and 46 years. The median age of epithelial thyroid cancer onset is 37 years. Elevated risk for endometrial cancer, colorectal cancer, and renal cell carcinoma starts in the late 30s and early 40s. [1, 3]

2. How effective are interventions for preventing harm?

Patient Management

Information on the effectiveness of the patient management recommendations below was not available.

At diagnosis: individuals should undergo a physical examination, paying particular attention to skin, mucous membranes, thyroid, and breasts; urinalysis; and medical genetics consultation. Individuals diagnosed after ages 35 and 40 should undergo colonoscopy and renal imaging, respectively. Women diagnosed after age 30 should undergo breast screening and transvaginal ultrasound. (Tier 4) [3]

Dermatologic management may be indicated for some patients. (Tier 2) [1]

Risk-reduction mastectomy and hysterectomy should be discussed on a case-by-case basis. (Tier 2) [1]

CS patients should be educated about the signs and symptoms of cancer. (Tier 2) [1]

Surveillance

CS patients should undergo annual comprehensive examinations. (Tier 2) [1]

Women should be breast aware starting at age 18, including periodic, consistent breast self-exam. Clinical breast exam, every 6-12 months, should begin at age 25, or 5-10 years before the earliest known breast cancer in the family. (Tier 2) [1]

Women should undergo annual mammography and breast MRI screening starting at age 30-35 or individualized based on earliest age of onset in the family. (Tier 2) [1, 7]

Women should consider annual random endometrial biopsies and/or ultrasound beginning at age 30-35. (Tier 2) [1]

Individuals with CS should receive annual thyroid ultrasounds starting at age 18 or 5-10 years before the earliest known thyroid cancer in the family, whichever is earlier. (Tier 2) [1]

Individuals with CS should undergo colonoscopy, starting at age 35, then every 5 years, or more frequently if patient is symptomatic or polyps are found. (Tier 2) [1]

Consider renal ultrasound starting at age 40, then every 1-2 years. (Tier 2) [1]

Circumstances to Avoid

Because of the propensity for rapid tissue regrowth, it is recommended that cutaneous lesions be excised only if malignancy is suspected or symptoms are significant. (Tier 4) [3]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Information on the prevalence of PTEN mutations was not available.

Penetrance

More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s. By the third decade, 99% of affected individuals develop the mucocutaneous stigmata. (Tier 3) [3, 1]

Among individuals meeting the diagnostic criteria for CS, the cumulative lifetime risk of any cancer is 89%. (Tier 3) [1]

The lifetime risk of breast cancer for females with a PTEN pathogenic variant is 77-85%, with 50% penetrance by age 50. (Tier 3) [3, 6]

Lifetime risk of epithelial thyroid cancer ranges from 21-38%. (Tier 3) [3, 1, 6]

Relative Risk

Information on relative risk was not available for the Adult context.

Expressivity

The high variability in disease expression is highlighted by the fact that clinical diagnosis in an individual is based on three of eight possible major diagnostic criteria, or two major criteria and three of eleven possible minor criteria. (Tier 2) [1]

4. What is the Nature of the Intervention?

Nature of Intervention

Management of CS includes regular invasive and non-invasive screening tests and the possible recommendation of prophylactic organ removal for affected women.

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Given the age of development of cancers in CS patients, general population screening would not allow for prophylactic measures to be taken. The increased cancer surveillance in this population will allow detection of tumors at the earliest, most treatable stages. (Tier 4) [3]

Date of Search: 07.11.2014

Reference List

1. NCCN Guidelines® Genetic/Familial High-Risk Assessment Breast and Ovarian. (2019) Website: https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf

2. Hall JE, Abdollahian DJ, Sinard RJ. Thyroid disease associated with Cowden syndrome: A meta-analysis. Head Neck. (2013) 35(8):1189-94.

3. PTEN Hamartoma Tumor Syndrome (PHTS). Gene Reviews. (2014) Website: http://www.ncbi.nlm.nih.gov/books/NBK1488/

4. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet. (2000) 37(11):828-30.

5. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. COWDEN SYNDROME 1; CWS1. MIM: 158350: 2016 Aug 18. World Wide Web URL: http://omim.org.

6. PTEN hemartoma tumor syndrome. Orphanet. (2014) Website: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=306498

7. Magnetic Resonance Imaging for Breast Cancer Screening, Pre-Operative Assessment, and Follow-up. NCG. (2012) Website: https://www.guideline.gov/content.aspx?id=34595