Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released Status (Pediatric): Passed (Consensus scoring is Complete) P

Condition: Juvenile polyposis syndrome
Mode(s) of Inheritance: Autosomal Dominant
Actionability Assertion
Gene Disease Pairs(s)
Final Assertion
SMAD40017380 (juvenile polyposis syndrome)
Moderate Actionability
BMPR1A0017380 (juvenile polyposis syndrome)
Moderate Actionability
Actionability Rationale
All experts agree with the computed assertion of moderate as data concerning the strength of evidence for the effectiveness of interventions are currently limited and there is a lack of evidence of likelihood in an unselected population.
Note: The assertion of moderate for the SMAD4 gene is for both the JPS (juvenile polyposis syndrome) and HHT (hereditary hemorrhagic telangiectasia) phenotypes. SMAD4 was evaluated separately for JPS and HHT and the AWG landed on an assertion of moderate for both, though we acknowledge there are no well-established genotype-phenotype correlations for SMAD4 to delineate between the phenotypes.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Morbidity and mortality from GI neoplasia / Evaluation and surveillance by specialist to guide treatment

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The population incidence of juvenile polyposis syndrome (JPS) has been estimated to be 1:16,000 to 1:100,000. Population prevalence for JPS was not available.
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Clinical Features
(Signs / symptoms)
JPS is characterized by predisposition to hamartomatous polyps in the gastrointestinal tract, specifically in the stomach, small intestine, colon, and rectum. JPS is traditionally defined by the presence of five or more juvenile polyps in the colon. JPS is associated with an increased risk of cancer, with most of that risk attributed to colon cancer. Histological differences and topographical distribution within the gastrointestinal tract serve to distinguish between JPS and Peutz-Jeghers syndrome. The number of polyps in individuals with JPS varies, with dozens to many hundreds of polyps present in the fully developed syndrome. The polyps vary in size from small sessile nodules to pedunculated lesions that are ≥3cm in diameter. If the polyps are left untreated, they may cause bleeding, anemia, abdominal pain, and intussusception. Additional symptoms can include diarrhea, protein-losing enteropathy, prolapsing polyps, and passage of tissue per rectum. Patients frequently present in childhood with rectal bleeding, but presentation may be related to extraintestinal manifestations, which can have significant health implications. Extraintestinal findings in people with JPS can include cardiac issues (such as mitral valve prolapse), vascular, and cranial/skeletal issues (such as macrocephaly). Most juvenile polyps are benign; however, malignant transformation can occur.
In patients with germline pathogenic variants in SMAD4, additional features of gastric polyposis, gastric cancer, and a JPS–hereditary hemorrhagic telangiectasia (HHT) overlap syndrome are common. A high frequency of pulmonary arteriovenous malformations (with digital clubbing) and epistaxis have been consistently noted in individuals with SMAD4-related HHT. Most individuals with JPS who have a SMAD4 germline pathogenic variant have one or more clinical features of HHT. [HHT is addressed in a separate actionability report]
PAWG HHT report link:
AAWG HHT report link:
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Natural History
(Important subgroups & survival / recovery)
Polyps may develop at any age from infancy through to adulthood. The term ‘juvenile’ refers to the polyp type rather than to the age of onset, although most individuals with JPS have some polyps by 20 years of age. JPS usually manifests during childhood with polyps beginning to appear in the first decade of life. The average age at clinical diagnosis is 18.5 years.
In those who develop cancer, the mean age of colon cancer is 44 years, with a range of 15 to 68 years and the median age of upper GI cancer is 58 years with a range of 21 to 73 years. These cancer rates may change over time with the implementation of screening of young at-risk individuals and the removal of polyps before cancer develops.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Individuals with SMAD4 pathogenic variants should also be evaluated for HHT. [HHT is addressed in a separate actionability report]
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At the time of initial diagnosis of JPS, a baseline evaluation of patients should include a clinical history and genetic counseling, complete blood count, colonoscopy, and upper endoscopy. (Tier 4)
For patients with a pathogenic variant in BMPR1A or SMAD4, referral to a specialized team and participation in available clinical trials is recommended (Tier 2)
Any new signs/symptoms of GI disease, regardless of the surveillance interval of the patient, should receive timely workup in both the pediatric and adult populations (Tier 2)
Colectomy and ileorectal anastomosis or proctocolectomy and ileal pouch-anal anastomosis should be considered for polyp-related symptoms, or when the polyps cannot be managed endoscopically. One case series reported on long-term outcomes of colonic surgery in 13 patients, with a clinical diagnosis of JPS (molecular status unknown), presenting with symptomatic colon polyps (median age at diagnosis=10 years, range=1-50 years). Eight patients had their rectum removed during the study period; 5 had an ileal pouch-anal anastomosis, one had a Koch pouch as a restorative surgery, and 2 had an end ileostomy. No relation was observed between the number of colonic and rectal polyps and the type of surgery or the need for proctectomy. Patients were followed up a median of 3 years (range=2-24 years) after their final operations. During this period, one patient (20%) who underwent restorative proctectomy and 4 patients (80%) whose rectums were preserved required multiple endoscopic polypectomies for recurrent polyps in the pouch (first patient) or their rectums (the other 4 patients). The patient who underwent the Koch procedure required surgery for recurrent polyps in her pouch. (Tier 2)
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In severe cases, if anemia cannot be controlled endoscopically or prevents optimal surveillance, gastrectomy should be considered. Additionally, complete, or partial gastrectomy may be indicated for patients with advanced dysplasia, gastric cancer, or even massive gastric polyposis that cannot be controlled endoscopically. (Tier 2)
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Anemia treatment includes iron replacement (oral or parenteral if needed) and red blood cell transfusion (Tier 4)
Colonoscopy is recommended in patients with JPS. Recommended starting age ranges vary across guidelines from 12-18, while frequency ranges from annually to every 3 years. One guideline suggests that once no polyps are identified by this screening during childhood, the screening can resume at age 18 years. The frequency of screening may be determined by the findings of the previous endoscopy. One retrospective review of a registry of 44 patients with JPS undergoing routine surveillance (380 patient-years follow up) of the upper and lower GI tract has reported surveillance results. Screening detected 767 colonic polyps and 20 adenomatous polyps in the colorectum. Five patients were identified requiring colorectal surgery. Two patients developed colorectal cancer while undergoing surveillance. (Tier 2)
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Upper endoscopy is recommended in patients with JPS. Recommended starting age ranges across guidelines from 12-25 years, while frequency ranges from annually to every 3 years. One guideline suggests that once no polyps are identified by this screening during childhood, the screening can resume at age 18 years. One guideline suggests gene specific ages to initiate surveillance (at age 18 years for those with SMAD4 pathogenic variants and at age 25 years in those with BMPR1A pathogenic variants). The frequency of screening is determined by the findings of the previous endoscopy. Among the retrospective registry of JPS patients, gastroduodenal polyps were found in 37% of patients and two patients were identified with adenomatous polyps of the stomach. Two patients identified required gastrectomy. One patient developed cancer while undergoing surveillance. (Tier 2)
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Periodic enteroscopy, capsule endoscopy and/or CT enterography may be used for surveillance of the small intestine. (Tier 2)
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A case series of small-bowel capsule endoscopy of ten adults (median age 39.2 years) with documented JPS identified 2 patients that had small-bowel polyps beyond the range of standard gastroscopy identified at capsule endoscopy. Duodenal polyps were detected in a third patient at capsule endoscopy not previously detected by standard gastroscopy. (Tier 5)
Annual physical exam and complete blood count is recommended; one guideline only recommends this for individuals with SMAD4 pathogenic variants. (Tier 2)
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Circumstances to Avoid
None identified for the JPS phenotype.
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
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Prevalence of Genetic Variants
No estimates were identified for the prevalence of SMAD4 or BMPR1A pathogenic variants. It is estimated that 20-80% of individuals with a clinical diagnosis of JPS are found to exhibit pathogenic variants in the SMAD4 or BMPR1A genes. Approximately 25% of individuals have JPS due to a de novo pathogenic variant. (Tier 3)
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(Include any high risk racial or ethnic subgroups)
Multiple juvenile polyps are found in the colorectum (98%), stomach (14-83%), jejunum and ileum (7%), and duodenum (7-33%) in individuals with JPS. Polyps in JPS are thought to have the potential for malignant transformation with dysplasia present in 8% of resected polyps in one series. (Tier 3)
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Life-time risk of colorectal cancer death (without surveillance) for JPS is 1 in 6. (Tier 3)
Risk of colon cancer is 17-22% by age 35 years and approaches 68% by age 60 years. Estimates for the lifetime risk of colorectal cancer range from 10-68%, though a more recent synthesis estimates a range of 38-68%. Mean age of colorectal cancer has been reported to be 44 years with a range of 15 to 68 years. (Tier 3)
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Estimates of lifetime risk of upper GI cancer (stomach, pancreas, and small bowel) with JPS is 21%, with a mean age of diagnosis of 58 years, and a range of 21-73 years. (Tier 3)
Individuals with gastric polyposis (incidence 65-83%), usually in association with pathogenic variants in SMAD4, are also at risk for gastric cancer, with the lifetime risk estimated to be at least 25-30% and the mean age for gastric cancer has been reported to be 54 years. (Tier 3)
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Relative Risk
(Include any high risk racial or ethnic subgroups)
In a cohort of patients with JPS (n=84), the relative risk of developing colorectal cancer was found to be 34.0 (95% CI, 14.4 to 65.7). (Tier 3)
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Genotype-phenotype correlations are inconsistent, with variable of age at presentation and number of polyps even in the same family with JPS. (Tier 3)
A study of 35 patients identified through a registry with germline pathogenic variants in SMAD4 or BMPR1A, evaluated phenotype differences between the two genes. Median age at the time of clinical diagnosis was 17 (3-65) years. Overall median follow-up after diagnosis of JPS was 11 (1-33) years. They found similar colonic polyposis phenotypes with the SMAD4 and BMPR1A genes. Individuals with SMAD4 pathogenic variants were more likely to have a higher number of gastric polyps (0 versus 14 patients in the BMPR1A and SMAD4 groups respectively with at least 50 polyps, 5 versus 9 patients with 1-49 polyps, 0 versus 1 patient with no polyps, 3 versus 3 patients with unknown GI phenotype; p=0.041). Additionally, no patient with a BMPR1A pathogenic variant was diagnosed with cancer, while four individuals with SMAD4 pathogenic variants developed cancer. The risk of gastrointestinal cancer risk in these patients with JPS and a SMAD4 pathogenic variant was 11% (3 of 27). (Tier 3)
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4. What is the Nature of the Intervention?
Nature of Intervention
Identified interventions include upper and lower gastrointestinal surveillance, polyp removal, and in rare cases, surgery to remove impacted organs (colon, stomach).
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
The average age at diagnosis is 18.5 years, but may be later, with rectal bleeding with anemia as the most common presenting symptom. Juvenile polyps are often first identified while evaluating a child for rectal bleeding and/or anemia from gastrointestinal blood loss, abdominal pain, or intussusception, or in some cases as an asymptomatic, incidental finding. Patients may lack overt clinical symptoms of SMAD4-related HHT but are at risk of asymptomatic arteriovenous malformation (AVMs) which can result in life threatening complications. (Tier 3)
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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 Disease Associations
Disease Associations
OMIM Identifier
Primary MONDO Identifier
Additional MONDO Identifiers
Reference List
1. 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.
2. Monahan KJ, Bradshaw N, Dolwani S, Desouza B, Dunlop MG, East JE, Ilyas M, Kaur A, Lalloo F, Latchford A, Rutter MD, Tomlinson I, Thomas HJW, Hill J. Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG). Gut. (2019)
3. J Larsen Haidle, JR Howe. Juvenile Polyposis Syndrome. 2003 May 13 [Updated 2015 Dec 03]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from:
4. Cohen S, Hyer W, Mas E, Auth M, Attard TM, Spalinger J, Latchford A, Durno C. Management of Juvenile Polyposis Syndrome in Children and Adolescents: A Position Paper From the ESPGHAN Polyposis Working Group. J Pediatr Gastroenterol Nutr. (2019) 68(1536-4801):453-462.
5. Boland CR, Idos GE, Durno C, Giardiello FM, Anderson JC, Burke CA, Dominitz JA, Gross S, Gupta S, Jacobson BC, Patel SG, Shaukat A, Syngal S, Robertson DJ. Diagnosis and Management of Cancer Risk in the Gastrointestinal Hamartomatous Polyposis Syndromes: Recommendations From the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. (2022) 162(1528-0012):2063-2085.
6. Juvenile polyposis syndrome. Orphanet encyclopedia,
7. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME; JPHT. MIM: 175050: 2018 Apr 02. World Wide Web URL:
8. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. JUVENILE POLYPOSIS SYNDROME; JPS. MIM: 174900: 2018 Jun 27. World Wide Web URL:
9. Genetic/Familial High-Risk Assessment: Colorectal - (NCCN Guidelines). NCCN. (2022) Website:
10. PDQ Cancer Genetics Editorial Board. Genetics of Colorectal Cancer (PDQ®): Health Professional Version. (2002)
11. Achatz MI, Porter CC, Brugières L, Druker H, Frebourg T, Foulkes WD, Kratz CP, Kuiper RP, Hansford JR, Hernandez HS, Nathanson KL, Kohlmann WK, Doros L, Onel K, Schneider KW, Scollon SR, Tabori U, Tomlinson GE, Evans DGR, Plon SE. Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood. Clin Cancer Res. (2017) 23(1557-3265):e107-e114.
12. Postgate AJ, Will OC, Fraser CH, Fitzpatrick A, Phillips RK, Clark SK. Capsule endoscopy for the small bowel in juvenile polyposis syndrome: a case series. Endoscopy. (2009) 41(11):1001-4.
13. Scottish Intercollegiate Guidelines Network,. Diagnosis and management of colorectal cancer. A national clinical guideline. Scottish Intercollegiate Guidelines Network (SIGN). (2016) Website:
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