PTEN Hamartoma Tumor Syndrome - Cowden Syndrome

Actionability Pediatric Summary Report

Gene: PTEN (HGNC:9588)
Mode(s) of Inheritance:Autosomal Dominant
Literature Search: 07/11/2014
Curation Status: In Preparation (0.0.0)
Release History
Related Reports
Adult Summary Report: (2.1.0)

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

Actionability Assertions

Gene Condition (MONDO ID) OMIM ID Final Assertion
PTEN N/A () 158350 Assertion Pending

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
No scores were found.

Prevalence of the Genetic Condition

The true prevalence of PTEN hamartoma tumor syndrome (PHTS) is unknown. PHTS includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Adult Lhermitte-Duclos disease, PTEN-related Proteus syndrome, Proteus-like syndrome, and autism spectrum disorders with macrocephaly. The incidence of PHTS is unknown. However, the incidence of CS has been reported to be 1 in 200,000, although it is likely to be underestimated due to the difficulties associated with making a clinical diagnosis of the disease given the common findings associated with this syndrome and the variable expression of disease.
View Citations

(2019) URL: www.nccn.org., Hall JE, et al. (2013) PMID: 22431287, Online Medelian Inheritance in Man. (2016) OMIM: 158350, (2014) URL: www.orpha.net., C Eng, et al. (2001) NCBI: NBK1488, Stanich PP, et al. (2014) PMID: 24587660

Clinical Features (Signs / symptoms)

PHTS encompasses a spectrum of clinical phenotypes historically described as distinct entities, though not all current guidelines have incorporated this new terminology. Therefore, this report presents recommendations and evidence as they are available from existing guidelines, which may target a specific clinical phenotype. Given PHTS exhibits variable expressivity and a general lack of genotype/phenotype correlation, it is appropriate to consider the entire PHTS spectrum in the context of a secondary finding in PTEN. PHTS is associated with multiple hamartomas and/or cancerous lesions in various organs and tissues, including the skin, mucous membranes, breast, thyroid, endometrium, and brain. Mucocutanuous lesions are a main feature of PHTS and include facial trichilemmomas, facial papules, acral keratoses, and oral cavity verrucoid or papillomatous papules. Macrocephaly is a common manifestation. Multiple hamartomatous polyps of varying histologic types distributed throughout the colon and other intestines occur, and may range from few to numerous (even hundreds). PHTS is associated with an increased risk of breast, thyroid, gastric, colon cancers. Renal cell carcinoma and malignant melanoma are also associated with PHTS. Though it is not well-defined, women with PHTS may have a risk of endometrial cancer. Additional features of PHTS may include pigmented macules of the glans penis, cerebellar dysplastic gangliocytoma, lipomas, intellectual disability, and vascular anomalies.
View Citations

(2019) URL: www.nccn.org., Hall JE, et al. (2013) PMID: 22431287, Online Medelian Inheritance in Man. (2016) OMIM: 158350, (2014) URL: www.orpha.net., C Eng, et al. (2001) NCBI: NBK1488, Syngal S, et al. (2015) PMID: 25645574, Stanich PP, et al. (2014) PMID: 24587660

Natural History (Important subgroups & survival / recovery)

A meta-analysis of patients with CS indicated a mean age of presentation of 38 years, with a range of 3 to 77 years. By the third decade, 99% of affected individuals develop the mucocutaneous lesions, as well as acral and plantar keratoses. The average age for thyroid disease is 32 years. The average age of breast cancer diagnosis is between 38 and 50 years. The median age of epithelial thyroid cancer onset is 37 years, but has been diagnosed before the age of 18 years and as early as 6 years. Elevated risk for endometrial cancer, colorectal cancer, and renal cell carcinoma starts in the late 30s and early 40s. Individuals are more likely to develop bilateral and multifocal cancer in paired organs. Women with PHTS have been reported to have a 2-fold higher cancer risk compared to men. Some PHTS phenotypes present with congenital malformations and severe tissue overgrowth childhood.
View Citations

(2019) URL: www.nccn.org., Hall JE, et al. (2013) PMID: 22431287, (2014) URL: www.orpha.net., C Eng, et al. (2001) NCBI: NBK1488

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

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 %
Most of the available evidence on penetrance relates specifically to CS, however it has been suggested that patients with other PHTS diagnoses associated with PTEN pathogenic variants should be assumed to have CS-associated cancer risks.
Tier Not provided View Citations

(2019) URL: www.nccn.org.

>= 40 %
The estimated penetrance of PTEN pathogenic variants is high, at approximately 80%. More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s.
Tier 3 View Citations

(2019) URL: www.nccn.org., C Eng, et al. (2001) NCBI: NBK1488

>= 40 %
By the third decade, 99% of affected individuals develop the mucocutaneous stigmata
Tier 3 View Citations

(2019) URL: www.nccn.org., Hall JE, et al. (2013) PMID: 22431287, C Eng, et al. (2001) NCBI: NBK1488

>= 40 %
Among individuals meeting the diagnostic criteria for CS, the cumulative lifetime risk of any cancer is 89%.
Tier 2 View Citations

(2019) URL: www.nccn.org.

>= 40 %
The lifetime risk of breast cancer for females with CS has been estimated at 25-50%, though a higher cumulative lifetime risk of 77-85% in individuals with CS or PTEN pathogenic variants has been reported.
Tier 3 View Citations

(2019) URL: www.nccn.org., C Eng, et al. (2001) NCBI: NBK1488

5-39 %
A meta-analysis of 181 patients with CS reported that 53% had thyroid disease, with thyroid pathology including goiter (41%), adenoma (25%), follicular carcinoma (7%), thyroiditis (7%), papillary carcinoma (6%), cancer (unknown type) (3%), medullary carcinoma (1%), and hyperthyroidism (1%). In addition, 54% of patients had mucocutaneous lesions, 39% had gastrointestinal lesions, 31% had breast lesions, and 28% had macrocephaly.
Tier 1 View Citations

Hall JE, et al. (2013) PMID: 22431287

5-39 %
Estimates of the lifetime risk of endometrial cancer ranges from 5-28%. Lifetime risk of renal cell cancer ranges from 15-35%.
Tier 3 View Citations

(2019) URL: www.nccn.org., C Eng, et al. (2001) NCBI: NBK1488, Syngal S, et al. (2015) PMID: 25645574

5-39 %
Colonic polyps are found in up to 95% of CS patients undergoing colonoscopy with hamartomatous as the most common histologic type, occurring in up to 29%. CS is also associated with a 9-16% lifetime risk of colorectal cancer.
Tier 3 View Citations

(2019) URL: www.nccn.org., C Eng, et al. (2001) NCBI: NBK1488, Syngal S, et al. (2015) PMID: 25645574

5-39 %
The estimated cumulative lifetime risk for melanoma is 6%.
Tier 3 View Citations

(2019) URL: www.nccn.org.

>= 40 %
It has been estimated that approximately 80-100% of individuals with CS have macrocephaly.
Tier 3 View Citations

(2019) URL: www.nccn.org.

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

Unknown
No information on relative risk was identified.

Expressivity

PHTS clinical phenotypes with variable expression and age-related penetrance have been found in individuals within the same family with the same PTEN variant. CS and BRRS are considered to be the same disorder with variable expression and age-related penetrance.
Tier 3 View Citations

Online Medelian Inheritance in Man. (2016) OMIM: 158350, C Eng, et al. (2001) NCBI: NBK1488

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Patient Management

To establish the extent of disease and needs of an individual diagnosed, the following evaluations are recommended:

• Complete medical history and family history

• Physical examination, paying particular attention to skin, mucous membranes, thyroid, and breasts

• In children, consideration of neurodevelopmental evaluation

• Urinalysis with cytospin

• Consultation with a clinical geneticist and/or genetic counselor.

Tier 4 View Citations

C Eng, et al. (2001) NCBI: NBK1488

Psychomotor assessment should be considered at diagnoses in children, including brain MRI if symptoms are present.
Tier 2 View Citations

(2019) URL: www.nccn.org.

The option of risk-reducing mastectomy and hysterectomy should be discussed on a case-by-case basis.
Tier 2 View Citations

(2019) URL: www.nccn.org.

No direct evidence on the effectiveness of risk-reducing surgery in patients with PHTS or PTEN pathogenic variants was identified. Findings from 2 observational studies and 3 decision analysis studies suggest that risk-reducing subcutaneous/total mastectomy has a beneficial effect in terms of significantly reducing the risk of breast cancer in women with a family history of breast cancer, or with BRCA1/2 pathogenic variants. One of the observational studies found that risk-reducing mastectomy was also associated with a reduction in breast cancer mortality in women with a family history of breast cancer. Among the two observational studies, one found no cases of invasive breast cancer among women who had undergone bilateral total mastectomy over 3 years (compared to 8/63 patients undergoing surveillance only). The second study showed a reduction in the risk of breast cancer of 89.5% in moderate-risk women who had undergone mastectomy and a reduction of 90-94% among high-risk women. The risk reduction for death among women undergoing mastectomy was 100% among moderate-risk women, and 81-94% among high-risk women.
Tier 1 View Citations

National Collaborating Centre for Cancer (UK), et al. (2013) PMID: 25340237

Surveillance

Patients should undergo annual comprehensive physical examinations starting at age 18 years or 5 years before the youngest age of diagnosis of a component cancer in the family, whichever comes first. Patients should also be educated regarding the signs and symptoms of cancer.
Tier 2 View Citations

(2019) URL: www.nccn.org.

Breast cancer surveillance is recommended to start at age 40 with annual mammography. Earlier surveillance, beginning at age 30, may be considered. No direct evidence on the effectiveness of breast cancer surveillance in patients with PHTS or PTEN pathogenic variants was identified. Evidence cited in guidelines was based on patients with a BRCA1/2 pathogenic variant or a family history of breast cancer. One guideline summarizes that low quality evidence suggests a disease-specific survival benefit with mammographic surveillance in women aged less than 50 years with a family history of breast cancer. First, an observational study found that death from breast cancer was less likely in women aged less than 50 years with family history whose breast cancer was diagnosed during mammographic surveillance compared to a control group of unscreened women of similar age who developed breast cancer (lead time adjusted HR=0.24; 95% CI: 0.09-0.66]). Second, a study modelled death from breast cancer in a mammographic surveillance study in women with a family history aged less than 50 years and a control group from another study, using prognostic features at diagnosis and underlying risk. Projected ten-year death from breast cancer was lower in the mammographic surveillance group than in the control group of unscreened women of similar age (RR=0.80; 95% CI: 0.66-0.96). Third, a retrospective study found that death from any cause was less likely in BRCA1/2 mutation carriers aged between 28 and 77 years diagnosed with breast cancer during an intensive mammographic surveillance program than in those diagnosed outside this program (HR=0.44; 95% CI: 0.25-0.77]).
Tier 1 View Citations

National Collaborating Centre for Cancer (UK), et al. (2013) PMID: 25340237

Endometrial cancer screening through endometrial biopsy every 1 to 2 years may be considered. However, there are no data on screening for endometrial cancer in CS patients and thus no proven benefit. Patient education is encouraged regarding the symptoms of endometrial cancer including the necessity of a prompt response to symptoms such as abnormal bleeding. Prompt reporting promotes early detection of endometrial cancer.
Tier 2 View Citations

(2019) URL: www.nccn.org.

Patients should receive annual thyroid ultrasound and thyroid exam starting at time of diagnosis, including in childhood.
Tier 2 View Citations

(2019) URL: www.nccn.org., Syngal S, et al. (2015) PMID: 25645574

No evidence for effectiveness for thyroid surveillance in PHTS patients was found. A single study comparing familial adenomatous polyposis (FAP) patients with screen-detected thyroid cancer to those with incident thyroid cancers showed that screening led to detection of smaller tumors with fewer positive lymph nodes.
Tier 2 View Citations

Herzig D, et al. (2017) PMID: 28796726

Patients should undergo colonoscopy and esophagogastroduodenoscopy. The age to begin varies across guidelines, from age 15 to 35. The frequency also varies across guidelines, from every 2 to every 5 years.
Tier 2 View Citations

(2019) URL: www.nccn.org., Syngal S, et al. (2015) PMID: 25645574

No evidence was identified related to effectiveness of colonoscopy and other gastrointestinal surveillance in individuals with PHTS. Evidence based on screening in individuals with Lynch Syndrome (LS) and FAP indicates a decrease in the risk of colorectal cancer (CRC). In a systematic review evaluating both conditions, five out of six studies in patients with LS found a significantly reduced incidence rate of CRC with surveillance (OR estimates ranged from 0.11 to 0.35), while the sixth study reporting an OR of 0.93 was not significant. Two out of four LS studies showed a significant reduction in CRC-related mortality with surveillance (OR estimates range from 0.04 to 0.17), while three of the four LS studies reported no mortality in the study arm with surveillance. Among individuals with FAP, 26 of 27 studies showed a statistically significant reduction in CRC incidence with surveillance (ORs ranged from 0.01 to 0.37) in screened patients compared to those who presented symptomatically with polyposis/CRC outside of a screening program. Eight FAP studies examined CRC mortality, all of which showed a significant reduction in CRC mortality (ORs ranged from <0.01 to 0.16) in screened (N= 1028) versus symptomatic groups (N= 947). Two FAP studies provided evidence for complete prevention of CRC-related deaths during surveillance, although the duration of follow-up was short (2-4 years).
Tier 1 View Citations

Barrow P, et al. (2013) PMID: 24227356

Surveillance for renal cell carcinoma utilizing annual urine analysis with cytology and possible renal ultrasound is recommended. Age to start varies across guidelines, from age 18 to 40 years.
Tier 2 View Citations

(2019) URL: www.nccn.org., Syngal S, et al. (2015) PMID: 25645574

Melanoma surveillance is recommended to begin by age 18 years with annual physical cutaneous examination.
Tier 2 View Citations

(2019) URL: www.nccn.org., Syngal S, et al. (2015) PMID: 25645574

No data regarding the effectiveness of melanoma surveillance in pathogenic PTEN variant carriers was found. A systematic review addressing visual screening for skin cancer identified no trials addressing the effectiveness of skin cancer screening on morbidity and mortality in average-risk individuals. One ecological study found that after the implementation of a population based skin cancer screening program the population age- and sex-adjusted melanoma mortality decreased by 48% with an absolute mortality difference of 0.8 melanoma deaths per 100,000 persons. Eight observational studies examined the association between lesion thickness or stage at diagnosis and mortality. All studies demonstrated a consistent linear increase in the risk of melanoma mortality with increasing tumor thickness. Tumor thickness >4.0mm was associated with a hazard ratio of 3.1-32.6 in multivariate models, indicating increased risk of melanoma mortality compared with thinner lesions.
Tier 1 View Citations

Wernli KJ, et al. (2016) PMID: 27458949

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 View Citations

C Eng, et al. (2001) NCBI: NBK1488

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Nature of Intervention

Management of PHTS includes multiple, periodic 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 PHTS 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 View Citations

C Eng, et al. (2001) NCBI: NBK1488

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Gene Condition Associations
OMIM Identifier Primary MONDO Identifier Additional MONDO Identifiers
PTEN 158350

References List

Barrow P, Khan M, Lalloo F, Evans DG, Hill J. (2013) Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome. The British journal of surgery. 100(13):1719-31.

C Eng. PTEN Hamartoma Tumor Syndrome. (2001) [Updated Jun 02 2016]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1488/

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/

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

Herzig D, Hardiman K, Weiser M, You N, Paquette I, Feingold DL, Steele SR. (2017) The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Inherited Polyposis Syndromes. Diseases of the colon and rectum. 60(9):881-894.

National Collaborating Centre for Cancer (UK). (2013) . Familial Breast Cancer: Classification and Care of People at Risk of Familial Breast Cancer and Management of Breast Cancer and Related Risks in People with a Family History of Breast Cancer.

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

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

Stanich PP, Pilarski R, Rock J, Frankel WL, El-Dika S, Meyer MM. (2014) Colonic manifestations of PTEN hamartoma tumor syndrome: case series and systematic review. World journal of gastroenterology. 20(7):1833-8.

Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW. (2015) ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. The American journal of gastroenterology. 110(2):223-62; quiz 263.

Wernli KJ, Henrikson NB, Morrison CC, Nguyen M, Pocobelli G, Blasi PR. (2016) Screening for Skin Cancer in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 316(4):436-47.

Early Rule-Out Summary

This topic passed the early rule out stage

Findings of Early Rule-Out Assessment

  1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition?
  2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways?

    3. a. Patient Management

    b. Surveillance or Screening

    c. Circumstances to Avoid

  3. Is there an intervention that is initiated during childhood (<18 years of age) in an undiagnosed child with the genetic condition?
  4. Does the disease present outside of the neonatal period?
  5. Is this condition an important health problem?
  6. Is there at least on known pathogenic variant with at least moderate penetrance (≥40%) or moderate relative risk (≥2) in any population?