PTEN Hamartoma Tumor Syndrome - Cowden Syndrome

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 07/11/2014
• Curation Status: Released (1.0.2)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
No assertions found.

Actionability Assertion 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.

Actionability Scores

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

Severity of Outcome

Prevalence of the Genetic Condition

The true prevalence of Cowden syndrome (CS) is unknown.

Clinical Features (Signs / symptoms)

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.

Natural History (Important subgroups & survival / recovery)

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.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Unknown

Information on the prevalence of PTEN mutations was not available.

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

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

>= 40 %

Among individuals meeting the diagnostic criteria for CS, the cumulative lifetime risk of any cancer is 89%.

Tier 3

>= 40 %

The lifetime risk of breast cancer for females with a PTEN pathogenic variant is 77-85%, with 50% penetrance by age 50.

Tier 3

5-39 %

Lifetime risk of epithelial thyroid cancer ranges from 21-38%.

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

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

Intervention Effectiveness

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

Dermatologic management may be indicated for some patients.

Tier 2

Risk-reduction mastectomy and hysterectomy should be discussed on a case-by-case basis.

Tier 2

CS patients should be educated about the signs and symptoms of cancer.

Tier 2

Surveillance

CS patients should undergo annual comprehensive examinations.

Tier 2

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

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

Women should consider annual random endometrial biopsies and/or ultrasound beginning at age 30-35.

Tier 2

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

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

Consider renal ultrasound starting at age 40, then every 1-2 years.

Tier 2

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

Nature of 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.

Context: Adult

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.

Context: Adult

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers

References List

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

Eng C. (2000) Will the real Cowden syndrome please stand up: revised diagnostic criteria. Journal of medical genetics. 37(11):828-30.

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

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

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

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

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