Pediatric Summary Report

Secondary Findings in Pediatric Subjects

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

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released - Under Revision 1.0.0
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: PTEN
• Condition: PTEN Hamartoma Tumor Syndrome - Cowden Syndrome
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• PTEN ⇔ 0008020 (cowden syndrome 1; cws1): 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

Gene Condition Pairs: PTEN ⇔ 0008020 (OMIM:158350)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity due to thyroid disease / Surveillance to detect thyroid lesions and guide treatment	2	2A	2C	3	9AC

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 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. [1, 2, 3, 4, 5, 6]

Clinical Features

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. [1, 2, 3, 4, 5, 6, 7]

Natural History

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. [1, 2, 4, 5]

2. How effective are interventions for preventing harm?

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) [5]

Psychomotor assessment should be considered at diagnoses in children, including brain MRI if symptoms are present. (Tier 2) [1]

The option of risk-reducing mastectomy and hysterectomy should be discussed on a case-by-case basis. (Tier 2) [1]

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) [8]

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) [1]

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) [8]

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) [1]

Patients should receive annual thyroid ultrasound and thyroid exam starting at time of diagnosis, including in childhood. (Tier 2) [1, 7]

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) [9]

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) [1, 7]

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) [10]

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) [1, 7]

Melanoma surveillance is recommended to begin by age 18 years with annual physical cutaneous examination. (Tier 2) [1, 7]

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) [11]

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) [5]

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

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. [1]

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) [1, 5]

By the third decade, 99% of affected individuals develop the mucocutaneous stigmata (Tier 3) [1, 2, 5]

Among individuals meeting the diagnostic criteria for CS, the cumulative lifetime risk of any cancer is 89%. (Tier 2) [1]

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) [1, 5]

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) [2]

Estimates of the lifetime risk of endometrial cancer ranges from 5-28%. Lifetime risk of renal cell cancer ranges from 15-35%. (Tier 3) [1, 5, 7]

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) [1, 5, 7]

The estimated cumulative lifetime risk for melanoma is 6%. (Tier 3) [1]

It has been estimated that approximately 80-100% of individuals with CS have macrocephaly. (Tier 3) [1]

Relative Risk

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) [3, 5]

4. What is the Nature of the Intervention?

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.

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 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. (Tier 4) [5]

Date of Search: 09.09.2019

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. 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.

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

5. C Eng. PTEN Hamartoma Tumor Syndrome. 2001 Nov 29 [Updated 2016 Jun 02]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1488

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

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

8. National Collaborating Centre for Cancer (UK). 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 (2013 Jun)

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

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

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