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 1.0.1
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: STK11
• Condition: Peutz-Jeghers Syndrome
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• STK11 ⇔ 0008280 (peutz-jeghers syndrome; pjs): Moderate Actionability

Actionability Rationale

There was substantial variability in the individual assertion between moderate and strong. Discussion for strong included clinical experience in terms of managing patients indicated higher effectivenss than indicated in the report. In addition to the intervention scores, it is plausible that anticipatory guidance to suspect intussusception could reduce morbidity, but it was not possible to quantify that evidence. The additive effect of moderate actionability of the two interventions with two outcomes, supported the argument for a strong assertion.

Final Consensus Scores

Gene Condition Pairs: STK11 ⇔ 0008280 (OMIM:175200)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity and mortality from GI cancer / Surveillance to detect GI cancer and guide initiation of GI cancer treatment	2	3A	2B 1	2	9AB
Morbidity from intussusception / Surveillance to detect polyps and guide initiation of polyp treatment	2	3C	2C	2	9CC

1. Downgraded due to extrapolating from other hereditary cancer syndromes (FAP, Lynch syndrome) - note this evidence is not in the report.

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

Prevalence of the Genetic Condition

Peutz-Jeghers syndrome (PJS) is a rare cancer syndrome, which likely represents a small proportion of cancer prevalence. Specifically for colorectal cancer (CRC), PJS accounts for less than 0.01% of cases. The population prevalence of PJS is estimated to be approximately 1 in 50,000. [1, 2, 3, 4, 5]

Clinical Features

PJS is associated with mucocutaneous pigmentation, gastrointestinal polyps, and increased cancer risk. The mucocutaneous pigmentation presents as dark blue to dark brown macules in the perioral area and on the buccal mucosa. Hyperpigmented macules on the fingers are also common. The hamartomatous (benign, tumor-like) polyps are most common in the small intestine but can also occur in the stomach, colon, and extra-intestinal sites such as the renal pelvis, bronchus gallbladder, nasal passages, bladder and ureters. Patients are at an increased risk for a variety of epithelial cancers including CRC, gastric, pancreatic, breast, and ovarian cancers as the most common. Women are at risk of ovarian sex-cord tumors with annular tubules, a benign neoplasm, and adenoma malignum of the cervix, a rare aggressive cancer. Males are at risk of testicular tumors of sex cord and Sertoli-cell type. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10]

Natural History

Roughly 45% of individuals with PJS have no family history. Mucocutaneous pigmentation is typically the first sign of PJS, presenting in childhood and typically fading in puberty or adulthood, but less so with the buccal mucosa. Polyps associated with PJS do not undergo malignant change in childhood. Polyp-related symptoms (bleeding, anemia, and abdominal pain due to intussusception, obstruction, or infarction), which can require multiple emergency laparotomies and bowel resections, appear by age 10 in 33% of cases and by age 20 in 50% of cases. Median age of first intussusception is 10 to 16 years, with the earliest episodes occurring at 1 to 5 years. Approximately 95% of intussusceptions occur in the small bowel, 5% in the colon. No differences in cancer risk by sex have been noted. PJS can occur in any racial or ethnic group.
The average age of a cancer diagnosis is estimated at 42, with 5% being diagnosed with any cancer by age 30, 31% by age 50, and 85% by age 70. [2, 3, 4, 5, 6, 8, 9, 10]

2. How effective are interventions for preventing harm?

Patient Management

To establish the extent of disease after initial diagnosis, consultation with a clinical geneticist and/or genetic counselor is recommended. (Tier 4) [3]

Due to the rarity of PJS and complexities of diagnosing and managing these individuals, referral to a specialized team or centers with expertise is recommended. Any early symptoms, prior to the initiation of surveillance, should be evaluated thoroughly. There are limited data regarding the efficacy of various screening modalities in PJS. (Tier 2) [11]

Pharmacotherapeutic chemoprevention should be offered according to guidelines for high-risk women. (Tier 2) [12]

No direct evidence on the effectiveness of pharmacotherapeutic chemoprevention in patients with STK11 pathogenic variants was identified. Evidence is based on patients defined as high-risk based on a family history of breast, ovarian or related (prostate/pancreatic cancer) or with a BRCA1/2 and/or TP53 pathogenic variant. In these populations, high quality evidence from two randomized trials suggests the incidence of breast cancer is lower in patients given tamoxifen than in those given a placebo (RR=0.65; 95% CI: 0.56-0.74). Longer term follow-up from one of these trials found that over a median of 16 years, there was a significant reduction in the occurrence of all breast cancers in the tamoxifen group (HR=0.71; 95% CI: 0.60 to 0.83; p<0.0001). However, no significant difference was found in breast-cancer specific mortality (OR=1.19; 95% CI: 0.68-2.10; p=0.8). (Tier 1) [12, 13]

Surveillance

A baseline colonoscopy and upper endoscopy are recommended, starting at age 8 to early teens depending on the guideline. If polyps are present, repeat every 2-3 years or earlier if symptoms occur. If no polyps are identified, some guidelines recommend repeating again at age 18, while other guidelines recommend repeating every 3 years. After age 18, repeat every 2-3 years, depending on the guideline. After age 50, repeat every 1-3 years, depending on the guideline. One retrospective study evaluated a series of 63 patients with a clinical diagnosis of PJS from 48 families, with a median age of 20 years (age range 3-59 years). Baseline investigations were performed in 12 of these patients and the remaining 51 patients were followed for 683 patient years, with a median of 10 years (range 2-41 years). Screening found that 17 patients had developed significant gastroduodenal or colonic polyps. There were 39 colon polyps and 20 large (>1 cm) gastroduodenal polyps detected in these patients. No luminal GI cancers were diagnosed. (Tier 2) [2, 4, 5, 7, 10, 11, 14]

Small bowel video capsule endoscopy (VCE) or MRI enterography are recommended starting at age 8-10. If polyps are present, repeat every 2-3 years or earlier if symptoms occur. If no polyps are identified, some guidelines recommend repeating again at age 18 while other guidelines recommend repeating every 2-3 years regardless of if polyps are identified. After age 18, repeat every 2-3 years (Tier 2) [2, 4, 5, 7, 10, 11]

Two guidelines recommend monthly up to annual breast self-examinations (beginning age 18). Biannual clinical breast exams (starting age 20-30, depending on guideline), and annual breast imaging (starting at age 20-35, depending on guideline) are recommended. Breast imaging modalities vary by guideline, with most guidelines recommending MRI combined with mammogram. There is currently insufficient data on the role and outcome of breast cancer screening in STK11 pathogenic variant carriers, so recommendations are based on the high lifetime risk of breast cancer and the precedents established in other hereditary breast cancer syndromes (e.g. due to BRCA1/2 pathogenic variants). (Tier 2) [2, 4, 5, 7, 11, 13, 14]

No direct evidence on the effectiveness of breast cancer surveillance in patients with STK11 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 pathogenic variant 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) [13]

Magnetic resonance cholangiopancreatography with contrast or endoscopic ultrasound is recommended, starting at age 30-35 depending on the guideline, and repeat every 1-2 years. Early initiation age may be considered, such as 10 years younger than the earliest age of onset in the family. One guideline recommends that this surveillance be performed at a center of expertise (Tier 2) [2, 4, 5, 7, 14]

Testicular exam and observation for feminizing changes are recommended annually starting at birth to age 10, depending on the guideline. Some guidelines recommend continuing until age 12; others do not provide an age to discontinue. (Tier 2) [2, 4, 5, 7, 11, 14]

Pap smear and pelvic exam are recommended annually starting at age 18-25. Two guidelines also recommend pelvic or transvaginal ultrasound annually starting at age 25. (Tier 2) [2, 4, 5, 7, 11]

Patients should have annual physical exams and hemoglobin analysis. (Tier 2) [2]

Circumstances to Avoid

No agents that increase the risk for polyp development or for cancers have been described. (Tier 4) [3]

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

Mode of Inheritance

Autosomal Dominant [1, 2, 3, 4, 5, 6, 8, 9, 10, 11]

Prevalence of Genetic Variants

The population prevalence of STK11 pathogenic variants was not available. Between 80-96% of patients with PJS are estimated to have a pathogenic variant in STK11. (Tier 3) [1, 2, 3, 4, 5, 10]

Penetrance

The cumulative cancer risk by ages 60-70 are estimated as 37-93% for any cancer and for the two most common types of cancer the risks are 38-66% for gastrointestinal cancer and 13-18% for gynecological cancer. (Tier 1) [2]

Cumulative intussusception risk is estimated at 50-68% during childhood, with 15-30% requiring surgery before the age of 10 years. (Tier 3) [10]

To date all reported individuals with pathogenic variants in STK11 have shown clinical manifestations. (Tier 4) [3]

Lifetime risk for specific cancers are: 39% colon, 29% stomach, 13% small intestine, 11-36% pancreas, 32-54% breast, 18-21% ovary, 10% cervix, 9% uterus, 9% testes and 7-17% lung. (Tier 3) [11]

GI polyps occur in 88-100% of patients. (Tier 3) [4]

Mucocutaneous pigmentation, which presents in childhood and can fade in puberty or adulthood, is seen in >95% of cases. (Tier 3) [4]

Relative Risk

The relative risk, compared to the general population, for any type of cancer is 9.9-18, 50.5 for gastrointestinal cancer, 20.3 for gynecological and breast cancer. (Tier 1) [2, 8]

Expressivity

Variable expressivity is common; for example, some affected individuals in families with PJS may have only polyps or perioral pigmentation. (Tier 4) [3, 6, 9]

Significant interfamilial variability in the age at which polyps first appear is observed, suggesting that the natural history of polyps in a family may be a predictor of severity for offspring. (Tier 3) [3]

There do not appear to be genotype-phenotype correlations with pathogenic variant location in the STK11 gene. (Tier 3) [3, 4, 5]

4. What is the Nature of the Intervention?

Nature of Intervention

Current surveillance guidelines are highly intensive. Several of the surveillance modalities presented here are invasive and the frequency at which they are carried out presents a burden for patients with PJS. A retrospective series described two cases of perforation following resection of polyps >2 cm out of a cohort of 63 patients with a clinical diagnosis of PJS who underwent screening. [4, 5]

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

Chance to Escape Clinical Detection

Many patients would develop cancer well before the recommended age to initiate surveillance for breast cancer and CRC in the general population, making it less likely that cancer in these patients would be detected early. Patients are also encouraged to undergo surveillance for additional cancers not typical of routine monitoring of annual exams recommended in the general population. (Tier 2) [5]

Date of Search: 01.02.2020

Reference List

1. Dunlop MG. Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polypolis, juvenile polyposis, and Peutz-Jeghers syndrome. Gut. (2002) 51 Suppl 5:V21-7.

2. van Lier MG, Wagner A, Mathus-Vliegen EM, Kuipers EJ, Steyerberg EW, van Leerdam ME. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol. (2010) 105(6):1258-64; author reply 1265.

3. TJ McGarrity, CI Amos, MJ Baker. Peutz-Jeghers Syndrome. 2001 Feb 23 [Updated 2016 Jul 14]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1266

4. 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.

5. Beggs AD, Latchford AR, Vasen HF, Moslein G, Alonso A, Aretz S, Bertario L, Blanco I, Bulow S, Burn J, Capella G, Colas C, Friedl W, Moller P, Hes FJ, Jarvinen H, Mecklin JP, Nagengast FM, Parc Y, Phillips RK, Hyer W, Ponz de Leon M, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Tejpar S, Thomas HJ, Wijnen JT, Clark SK, Hodgson SV. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut. (2010) 59(7):975-86.

6. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. PEUTZ-JEGHERS SYNDROME; PJS. MIM: 175200: 2019 Jun 25. World Wide Web URL: http://omim.org.

7. Vangala DB, Cauchin E, Balmana J, Wyrwicz L, van Cutsem E, Guller U, Castells A, Carneiro F, Hammel P, Ducreux M, van Laethem JL, Matysiak-Budnik T, Schmiegel W. Screening and surveillance in hereditary gastrointestinal cancers: Recommendations from the European Society of Digestive Oncology (ESDO) expert discussion at the 20th European Society for Medical Oncology (ESMO)/World Congress on Gastrointestinal Cancer, Barcelona, June 2018. Eur J Cancer. (2018) 104:91-103.

8. Giardiello FM, Brensinger JD, Tersmette AC, Goodman SN, Petersen GM, Booker SV, Cruz-Correa M, Offerhaus JA. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology. (2000) 119(6):1447-53.

9. Peutz-Jeghers syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=2869

10. Latchford A, Cohen S, Auth M, Scaillon M, Viala J, Daniels R, Talbotec C, Attard T, Durno C, Hyer W. Management of Peutz-Jeghers Syndrome in Children and Adolescents: A Position Paper From the ESPGHAN Polyposis Working Group. J Pediatr Gastroenterol Nutr. (2019) 68(3):442-452.

11. NCCN. Genetic/Familial High-Risk Assessment: Colorectal. Version 3.2019. Publisher: NCCN. (2019) Accessed: 2020-01-09. Website: https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf

12. NCCN. Breast Cancer Risk Reduction. Version 1.2019. Publisher: NCCN. (2019) Accessed: 2020-01-09. Website: https://www.nccn.org/professionals/physician_gls/pdf/breast_risk.pdf

13. NICE. 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. Publisher: NICE. (2019) Accessed: 2020-01-30. Website: https://www.nice.org.uk/guidance/cg164

14. Paluch-Shimon S, Cardoso F, Sessa C, Balmana J, Cardoso MJ, Gilbert F, Senkus E. Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening. Ann Oncol. (2016) 27(suppl 5):v103-v110.