Phenotypic Differences in Juvenile Polyposis Syndrome With or Without a Disease-causing SMAD4/ BMPR1A Variant

Cancer Prev Res (Phila). 2021 Feb;14(2):215-222. doi: 10.1158/1940-6207.CAPR-20-0348. Epub 2020 Oct 23.


Juvenile polyposis syndrome (JPS) is a clinically diagnosed hamartomatous polyposis syndrome that increases the risk of gastrointestinal cancer. Approximately 40%-50% of JPS is caused by a germline disease-causing variant (DCV) in the SMAD4 or BMPR1A genes. The aim of this study was to characterize the phenotype of DCV-negative JPS and compare it with DCV-positive JPS. Herein, we analyzed a cohort of 145 individuals with JPS from nine institutions, including both pediatric and adult centers. Data analyzed included age at diagnosis, family history, cancer history, need for colectomy/gastrectomy, and polyp number and location. Compared with DCV-positive JPS, DCV-negative JPS was associated with younger age at diagnosis (P < 0.001), lower likelihood of having a family history of JPS (P < 0.001), and a lower risk of colectomy (P = 0.032). None of the DCV-negative individuals had gastric or duodenal polyps, and polyp burden decreased after the first decade compared with DCV-positive JPS. Subgroup analysis between SMAD4 and BMPR1A carriers showed that SMAD4 carriers were more likely to have a family history of JPS and required gastrectomy. Taken together, these data provide the largest phenotypic characterization of individuals with DCV-negative JPS to date, showing that this group has distinct differences compared with JPS due to a SMAD4 or BMPR1A variant. Better understanding of phenotype and cancer risk associated with JPS both with and without a DCV may ultimately allow for individualized management of polyposis and cancer risk.Prevention Relevance: Juvenile Polyposis Syndrome (JPS) is a gastrointestinal cancer predisposition syndrome requiring lifelong surveillance, however there is limited data comparing individuals with and without a germline disease-causing variant in SMAD4 or BMPR1A Herein we show that individuals with JPS without an underlying disease-causing variant have distinct phenotypic differences including lack of upper gastrointestinal polyps and lower rates of a family history of JPS, suggesting that a different approach to management may be appropriate in this population.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Aged
  • Bone Morphogenetic Protein Receptors, Type I / genetics*
  • Child
  • Child, Preschool
  • Colectomy / standards
  • Colectomy / statistics & numerical data*
  • Colonoscopy / standards
  • Colonoscopy / statistics & numerical data
  • Female
  • Follow-Up Studies
  • Germ-Line Mutation
  • Humans
  • Intestinal Polyposis / congenital*
  • Intestinal Polyposis / diagnosis
  • Intestinal Polyposis / genetics
  • Intestinal Polyposis / therapy
  • Male
  • Medical History Taking / statistics & numerical data
  • Middle Aged
  • Neoplastic Syndromes, Hereditary / diagnosis
  • Neoplastic Syndromes, Hereditary / genetics*
  • Neoplastic Syndromes, Hereditary / therapy
  • Practice Guidelines as Topic
  • Precision Medicine / methods
  • Precision Medicine / statistics & numerical data
  • Smad4 Protein / genetics*
  • Watchful Waiting / standards
  • Watchful Waiting / statistics & numerical data*
  • Young Adult


  • SMAD4 protein, human
  • Smad4 Protein
  • BMPR1A protein, human
  • Bone Morphogenetic Protein Receptors, Type I

Supplementary concepts

  • Juvenile polyposis syndrome