Juvenile polyposis syndrome (JPS) and hereditary mixed polyposis syndrome 2 (HMPS2)
The BMPR1A gene (MIM#:601299) encodes the Bone morphogenetic protein receptor type IA, a member of the transmembrane serine/threonine kinase family. This family mediates signaling initiated by the TGF-β superfamily, which is involved in the regulation of cellular proliferation of the intestinal lining.1
Germline mutations in BMPR1A have been identified in 20% of the cases of JPS,4,5 a condition with reported incidence of 1:16,000-1:100,000.6 Another 20% of JPS cases have been attributed to SMAD4,1 a gene that codes for a common intracellular mediator of the TGF-β signaling pathways,2,3 for which we also offer clinical testing.
BMPR1A and SMAD4 mutations may correlate with polyps with different histological profiles.1 Regardless of the causal gene, patients with JPS are susceptible to developing gastrointestinal (GI) hamartomatous polyps as early as in infancy, which, if left untreated, may result in bleeding and anemia.6 Even more importantly, 9%-50% of the families with JPS develop GI cancers, most commonly cancer of the colon, and less often, of the stomach, upper GI and pancreas.7 By age 35, the incidence of colorectal cancer in the patients with JPS is 17%-22%, approaching 68% by age 60 years.7 Patients with JPS and a SMAD4 mutation are more likely to have a family history of upper-GI polyps than are patients with mutations in BMPR1A or patients with no known mutations.6
BMPR1A mutations also cause HMPS2, which presents with atypical juvenile polyps and predisposition to colonic adenomas and carcinomas.8 HMPS2, like JPS, shows autosomal dominant inheritance.
About a quarter of the families with positive history of JPS have de novo mutations.6 Approximately 18% of the BMPR1A mutations are detectable by sequencing and a further 6% by multiple ligation-based probe amplification assay in patients who are negative for point mutations.6 Tumor tissues from mutation-positive cases typically also show loss of heterozygosity in BMPR1A.9 Of over 70 pathogenic mutations identified so far, about half are missense or nonsense mutations.10 Most of these mutations affect the protein kinase domain or, less often, the cysteine-rich extracellular domain.6 While the penetrance seems virtually complete, variability of expression is considerable, even within families.6 To date, germline mosaicism has not been reported for JPS.6
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