SMAD4 Gene Mutations

Juvenile Polyposis Syndrome (JPS) and Hereditary Hemorrhagic Telangiectasia (HHT)




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Additional Information

SMAD4 gene

Associated Syndrome Name: Juvenile Polyposis Syndrome (JPS) and Hereditary Hemorrhagic Telangiectasia (HHT)

SMAD4 Summary Cancer Risk Table

Cancer Genetic Cancer Risk
ColorectalHigh Risk
GastricHigh Risk
PancreaticElevated Risk
OtherHigh Risk

SMAD4 gene Overview

Juvenile Polyposis Syndrome (JPS) and Hereditary Hemorrhagic Telangiectasia (HHT) 1, 2, 3, 4, 5
  • Individuals with SMAD4 mutations have both Juvenile Polyposis Syndrome (JPS) and Hereditary Hemorrhagic Telangiectasia (HHT).
  • Patients with JPS have a high risk for cancer as a result of hamartomatous polyps in the gastrointestinal system, particularly in the colon, rectum and stomach. The presence of these polyps is associated with a high risk for colorectal cancer, and can cause bleeding leading to anemia.
  • Patients with JPS also have an elevated risk for small bowel and pancreatic cancer.
  • This patient also has Hereditary Hemorrhagic Telangiectasia (HHT), which is associated with a high risk for life-threatening arteriovenous malformations of the lungs, brain and liver, as well as nosebleeds.
  • Recent studies suggest that patients with SMAD4 mutations have an increased risk for connective tissue disorders such as thoracic aortic disease, brain aneurysm, and lax skin and joints. The data for this are not yet conclusive and there are currently no medical management recommendations associated with connective tissue disorders for carriers of SMAD4 mutations.
  • Although there are high risks for cancer in patients with JPS, and high risks for life-threatening complications from the arteriovenous malformations found in patients with HHT, these risks can be greatly reduced with appropriate medical management. Guidelines from the National Comprehensive Cancer Network (NCCN) and the Scientific Advisory Committee of the HHT Foundation are listed below. It is recommended that patients with SMAD4 mutations and diagnoses of JPS and HHT be managed by a multidisciplinary team with experience in the prevention and treatment of the complications associated with these conditions.

SMAD4 gene Cancer Risk Table

Cancer Type Age Range Cancer Risk Risk for General Population
ColorectalTo age 425, 620%-25%<0.2%
To age 803, 5, 640%-50%3.0%
GastricTo age 803, 6Up to 21%0.6%
PancreaticTo age 803, 5, 6Rare, but elevated risk1%
Small BowelTo age 803, 5, 6Rare, but elevated risk0.2%
Other - Hereditary Hemorrhagic TelangiectasiaAll ages4HHT is associated with a high risk for life threatening arteriovenous malformations of the lungs, brain and liver as well as nosebleeds.NA

SMAD4 Cancer Risk Management Table

The overview of medical management options provided is a summary of professional society guidelines. The most recent version of each guideline should be consulted for more detailed and up-to-date information before developing a treatment plan for a particular patient.

This overview is provided for informational purposes only and does not constitute a recommendation. While the medical society guidelines summarized herein provide important and useful information, medical management decisions for any particular patient should be made in consultation between that patient and his or her healthcare provider and may differ from society guidelines based on a complete understanding of the patient’s personal medical history, surgeries and other treatments.

Cancer Type Procedure Age to Begin Frequency
(Unless otherwise indicated by findings)
ColorectalColonoscopy3, 7, 812 to 15 years, or earlier if symptoms are presentEvery 2 to 3 years
Monitor for rectal bleeding and/or anemia.2, 715 years, or earlier if symptoms are presentAnnually
Colorectal surgical evaluation and counseling.3, 7, 8Based on cancer diagnosis and/or polyp number, size and histologyNA
GastricUpper endoscopy3, 915 yearsEvery 2 to 3 years
PancreaticCurrently there are no specific medical management guidelines for pancreatic cancer risk in mutation carriers.NANA
Small BowelCapsule endoscopy715 years, or earlier if symptoms are presentIndividualized
Other - Hereditary Hemorrhagic TelangiectasiaMultiple screenings recommended, which may include brain MRI, contrast echocardiogram, and chest CT.4Some screenings are recommended within the first 6 months of lifeVaries

Information for Family Members

The following information for Family Members will appear as part of the MMT for a patient found to have a mutation in the SMAD4 gene.

A major potential benefit of myRisk genetic testing for hereditary cancer risk is the opportunity to prevent cancer in relatives of patients in whom clinically significant mutations are identified. Healthcare providers have an important role in making sure that patients with clinically significant mutations are informed about the risks to relatives, and ways in which genetic testing can guide lifesaving interventions.

Since SMAD4 mutations carry a risk for complications in children and some screenings are recommended to begin in infancy, mutation testing should occur within the first 6 months after birth.3


  1. O'Malley M, et al. The prevalence of hereditary hemorrhagic telangiectasia in juvenile polyposis syndrome. Dis Colon Rectum. 2012 55:886-892. PMID: 22810475.
  2. Larsen Haidle J, Howe JR. Juvenile Polyposis Syndrome. 2017 Mar 9. In: Pagon RA, et al., editors. GeneReviews® [Internet]. Available from PMID: 20301642.
  3. Provenzale D, et al. NCCN Clinical Practice Guidelines in Oncology® Genetic/Familial High-Risk Assessment: Colorectal. V 3.2019. Dec 13. Available at
  4. Faughnan ME, et al. HHT Foundation International - Guidelines Working Group. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011 48:73-87. PMID: 19553198.
  5. Howe JR, et al. The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol. 1998 5:751-6. PMID: 9869523.
  6. Fast Stats: An interactive tool for access to SEER cancer statistics. Surveillance Research Program, National Cancer Institute. (Accessed on 1-2-2017)
  7. Achatz MI, et al. Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood. Clin Cancer Res. 2017 23:e107-e114. PMID: 28674119.
  8. Syngal S, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015 110:223-62. PMID: 25645574.
  9. Ajani JA, et al. NCCN Clinical Practice Guidelines in Oncology®: Gastric Cancer. V 4.2019. Dec 20. Available at
Last Updated on 10-Dec-2020