Juvenile polyposis syndrome (JPS, OMIM #174900) is a genetic disease caused by heterozygous mutations in the BMPR1A or SMAD4 gene. It is characterized by the occurrence of juvenile hamartomatous gastrointestinal polyps and a predisposition to gastrointestinal tumors. In addition, mutations in the SMAD4 gene are also associated with hereditary hemorrhagic telangiectasia (HHT).
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|Gene products||Bone morphogenetic protein receptor type 1A (BMPR1A)
Mothers against decapentaplegic homolog 4 (SMAD4)
|Function||Tumor suppressors, associated with the TGF-β signaling pathway|
|Heredity||Autosomal dominant, around 67% de novo mutations|
|Prevalence||The incidence is between 1:16.000 and 1:100.000.|
|Genotype-phenotype correlation||SMAD4 mutations are associated with hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease).
SMAD4 mutations go hand-in-hand with a greater risk of polyps in the upper GI tract, whereby this phenotype presumably has a more aggressive progression and is associated with significant polyposis and a greater risk of gastric carcinomas.
Patients with an SMAD4 or BMPR1A mutation are more likely to have > 10 polyps in the lower GI tract and a positive family history of gastrointestinal malignancies than patients without evidence of a mutation.
|Penetrance||97% of patients develop colonic polyps, 68% gastric polyps, and 76% exhibit signs of HHT.
The cumulative lifetime risk of a colorectal carcinoma is 39%. The risk of a gastric carcinoma is 21% in patients with gastric polyps.
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Juvenile polyposis syndrome is suspected when the following findings apply:
Clinical Diagnostic Criteria
The diagnosis of “juvenile polyposis syndrome” is confirmed by the presence of one of the following findings:
The diagnosis of “juvenile polyposis syndrome” is confirmed by detection of a heterozygous germline mutation in the SMAD4 or BMPR1A gene through sequence analysis or deletion/duplication analysis. The use of panel examinations consisting of multiple genes as well as exome or genome sequencing may be helpful as well.
Hamartomatous polyps occur in both the upper and lower gastrointestinal tract and exhibit a wide variety of shapes and sizes: Both sessile and stalked polyps occur, and their number ranges between only a few to over 100 polyps. Juvenile polyps (whereby “juvenile” refers to the histology and not the age of the patient) may develop from infancy to adulthood. Most JPS patients exhibit polyps at the age of 20. Hemorrhaging, and resulting anemia, is a potential complication.
While most juvenile polyps are benign, malignant transformations may also occur. The incidence of colorectal carcinomas is 17-22% at 35 years of age, increasing to 68% at the age of 60. The average age at colon carcinoma diagnosis is 42. The incidence of gastric carcinomas is 21% in patients with gastric polyps.
Juvenile Polyposis Syndrome / Hereditary Hemorrhagic Telangiectasia (JPS/HHT Syndrome)
JPS/HHT syndrome can occur in patients with a SMAD4 mutation and exhibit variable manifestations of juvenile polyposis and HHT. The latter may be epistaxis, telangiectasia, arteriovenous malformations (AVS), or drumstick fingers. Clinical symptoms usually appear during early childhood, with pulmonary AVM and epistaxis almost always occurring. Complications of JPS/HHT syndrome may include anemia, migraines, and headaches.
In addition, a SMAD4 mutation may lead to thoracic aortic diseases such as aortic root dilation, aneurysms, and mitral valve dysfunctions.
An endoscopic polypectomy should be performed as early as possible and may reduce the risk of malignant transformation, hemorrhaging, or intestinal obstructions. When there are a large number of polyps or severe symptoms, a total or subtotal colectomy may be helpful.
JPS/HHT syndrome should be treated like other forms of hereditary hemorrhagic telangiectasia.
Patients with SMAD4 or BMPR1A Mutations or Clinically Diagnosed JPS:
Additionally for Patients with a SMAD4 Mutation:
Open Clinical Trials / Registries
Unfortunately, we are as yet unaware of any existing support groups for patients with juvenile polyposis syndrome. We will add new information as it becomes available.