Juvenile Polyposis Syndrome

Juvenile polyposis syndrome is associated with the development of hamartomatous juvenile polyps in the gastrointestinal tract. Common symptoms include gastrointestinal bleeding, anemia, diarrhea, and abdominal pain. 


Juvenile polyposis syndrome is associated with the development of hamartomatous juvenile polyps in the gastrointestinal tract. Common symptoms include gastrointestinal bleeding, anemia, diarrhea, and abdominal pain. 

Disease Name 
Juvenile polyposis syndrome (JPS)
Hereditary hemorrhagic telangiectasia (HHT)
Disease Information 

Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder caused by mutations in the BMPR1A and SMAD4 genes. It occurs in 1/100,000 to 1/160,000 individuals and predisposes to development of polyps and cancer in the gastrointestinal tract.1 The term “juvenile” refers to the tissue composition of the hamartomatous polyps (not the age of onset), although these are also the most common polyp type seen in children.  Polyps most often develop in the colon and rectum, but they also occur in the stomach and small intestine.  Colorectal cancer risk is estimated at 40-50%, and gastric cancer risk is up to 21%.1-3

JPS can present in two different forms: typical JPS and JPS of infancy. Most individuals with JPS have symptoms by age 20.4 Juvenile polyposis of infancy involves the entire digestive tract and has the poorest prognosis, with symptoms including diarrhea, severe GI bleeding, and exudative enteropathy. This form of JPS is very rare, and death often occurs at an early age in patients with this.5

SMAD4 mutations are also associated with hereditary hemorrhagic telangiectasia (HHT). Among individuals with JPS due to SMAD4 mutations, the majority of them also display symptoms of HHT, including epistaxis, arteriovenous malformations, and/or telangiectases.6,7 More details can be found here. Therefore, clinical evaluation for HHT symptoms is recommended in individuals with SMAD4 mutations.8

Mutations in the BMPR1A and SMAD4 genes cause approximately equal numbers of JPS cases, together accounting for 45-60% of JPS. Sequence variant mutations explain 40-45% of cases, and the remaining 10-15% of detectable cases are caused by gross deletions of either gene.2,9-10 In addition Juvenile polyps have also been seen in individuals with PTEN mutations.9

Testing Benefits & Indication 

Published guidelines recommend that individuals who meet the following criteria be evaluated for JPS:11

  • ≥5 colorectal juvenile polyps 
  • Any juvenile polyps throughout the gastrointestinal tract

Genetic testing can enable:

  • Confirmation of diagnosis in symptomatic individuals
  • Appropriately targeted surveillance in at-risk relatives who are tested
  • The opportunity for prevention and/or early detection of cancer in mutation carriers
Test Description 

BMPR1A and SMAD4 coding exons 1-11 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-11.Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology, using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.12  Gross deletion/duplication analysis of BMPR1A and SMAD4 using read-depth from NGS data is also performed. Any copy number changes detected by NGS are confirmed by multiplex ligation-dependent probe amplification (MLPA) and/or targeted chromosomal microarray.

Mutation Detection Rate 

Ambry’s BMPR1A and SMAD4 testing is capable of detecting greater than 99.9% of described mutations in the genes, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
8604 BMPR1A and SMAD4 Gene Sequence and Deletion/Duplication Analyses 14-21
2822 BMPR1A Specific Site Analysis 7-14
1686 SMAD4 Specific Site Analysis 7-14


  1. Chow E and Macrae F. A review of juvenile polyposis syndrome. J Gastroenterol Hepatol. 2005. 20:1634-1640.
  2. Aretz S, et al. High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet. 2007. 44(11):702-9.
  3. Jasperson KW. Genetic testing by cancer site: colon (polyposis syndromes). Cancer J. 2012 Jul-Aug;18(4):328-33.
  4. Coburn MC, et al. Malignant potential in intestinal juvenile polyposis syndromes. Ann Surg Oncol. 1995. 2(5):386-91.
  5. Sachatello CR, et al. Juvenile gastrointestinal polyposis in a female infant: report of a case and review of the literature of a recently recognized syndrome. Surgery. 1974. 75(1):107-14.
  6. O’Malley M, et al. The prevalence of hereditary hemorrhagic telangiectasia in juvenile polyposis syndrome. Dis Colon Rectum. 2012. 55:886–92.
  7. Wain KE, et al. Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review. Genet Med. 2014. 16(8):588-93.
  8. Gallione CJ, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). The Lancet. 2004. 363(9412):852-9.
  9. van Hattem WA, et al. Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis. Gut. 2008. 57(5):623-7.
  10. Calva‐Cerqueira D, et al. The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis. Clin Genet. 2009. 75(1):79-85.
  11. Syngal S, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015. 110(2):223-62.
  12. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.