Juvenile polyposis syndrome (JPS) is an inherited autosomal dominant condition that predisposes to the development of juvenile polyps throughout the gastrointestinal (GI) tract, and it poses an increased risk of GI malignancy. Germline causative variants were identified in the SMAD4 gene in a subset (20%) of JPS cases. Most SMAD4 germline genetic variants published to date are missense, nonsense, and frameshift mutations. SMAD4 germline alterations predicted to result in aberrant splicing have rarely been reported. Here, we report two unrelated Italian families harboring two different SMAD4 intronic variants, c.424+5G>A and c.425-9A>G, which are clinically associated with colorectal cancer and/or juvenile GI polyps. In silico prediction analysis, in vitro minigene assays, and RT-PCR showed that the identified variants lead to aberrant SMAD4 splicing via the exonization of intronic nucleotides, resulting in a premature stop codon. This is expected to cause the production of a truncated protein. This study expands the landscape of SMAD4 germline genetic variants associated with GI polyposis and/or cancer. Moreover, it emphasizes the importance of the functional characterization of SMAD4 splicing variants through RNA analysis, which can provide new insights into genetic disease variant interpretation, enabling tailored genetic counseling, management, and surveillance of patients with GI polyposis and/or cancer.

Juvenile polyposis syndrome lies within the family of hamartomatous polyposis syndromes characterized by polyps that appear benign but harbor an increased risk of colorectal and gastric cancer. This 27-year-old man with severe ulcerative colitis was discovered to have concomitant juvenile polyposis syndrome during diagnostic workup for gastrointestinal bleeding. The implications of this rare association complicate both diagnostic and treatment modalities since both diseases confer an increased risk of cancer.

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterized by multiple juvenile polyps in the gastrointestinal tract, often associated with mutations in genes such as Smad4 and BMPR1A. This study explores the impact of Smad4 knock-out on the development of intestinal polyps using collaborative cross (CC) mice, a genetically diverse model. Our results reveal a significant increase in intestinal polyps in Smad4 knock-out mice across the entire population, emphasizing the broad influence of Smad4 on polyposis. Sex-specific analyses demonstrate higher polyp counts in knock-out males and females compared to their WT counterparts, with distinct correlation patterns. Line-specific effects highlight the nuanced response to Smad4 knock-out, underscoring the importance of genetic variability. Multimorbidity heat maps offer insights into complex relationships between polyp counts, locations, and sizes. Heritability analysis reveals a significant genetic basis for polyp counts and sizes, while machine learning models, including k-nearest neighbors and linear regression, identify key predictors, enhancing our understanding of juvenile polyposis genetics. Overall, this study provides new information on understanding the intricate genetic interplay in the context of Smad4 knock-out, offering valuable insights that could inform the identification of potential therapeutic targets for juvenile polyposis and related diseases.

Germline SMAD4 pathogenic variants (PVs) cause juvenile polyposis syndrome (JPS), which is known for an increased risk of gastrointestinal juvenile polyps and gastrointestinal cancer. Many patients with SMAD4 PV also show signs of hereditary hemorrhagic telangiectasia (HHT) and some patients have aneurysms and dissections of the thoracic aorta. Here we describe two patients with a germline SMAD4 PV and a remarkable clinical presentation including multiple medium-sized arterial aneurysms. More data are needed to confirm whether the more extensive vascular phenotype and the other described features in our patients are indeed part of a broader JPS spectrum.

Juvenile polyposis syndrome (JPS) is a rare disease characterized by multiple hamartomatous polyps in the gastrointestinal tract, associated with pathogenic variants of BMPR1A and SMAD4. We present the description of SMAD4 mosaicism in a 30-year-old man who had caecum adenocarcinoma, 11 juvenile colon polyps and epistaxis since childhood. We conducted NGS polyposis and CRC panel analysis on DNA extracted from two polyps, revealing a likely pathogenic SMAD4 variant: NM_005359.5:c. 1600C>T, p.(Gln534*). This variant was then identified at a very low frequency on blood and normal colonic tissue, by targeted visualization of previously obtained NGS data. These findings support the presence of a likely pathogenic mosaic SMAD4 variant that aligns with the patient\'s phenotype. Given the relatively frequent occurrence of de novo SMAD4 mutations, somatic mosaicism could account for a significant proportion of sporadic JPS patients with unidentified pathogenic variants. This case underscores the diagnosis challenge of detecting mosaicism and emphasizes the importance of somatic analyses.

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BACKGROUND: BMPR1A-mediated signaling transduction plays an essential role in intestinal growth. Variations of BMPR1A lead to a rare autosomal dominant inherited juvenile polyposis syndrome (JPS) with high probability of developing into colorectal cancer (CRC). Nonsense and frameshift variations, generating premature termination codons (PTCs), are the most pathogenic variants in the BMPR1A gene.
OBJECTIVE: This study aimed to investigate the molecular genetic etiology in a Chinese family with three generations of CRC.
METHODS: Pathogenic variants of 18 known CRC susceptibility genes were examined in a Chinese CRC family through multigene panel testing using the next-generation sequencing platform. The candidate gene variant was validated in the family members by Sanger sequencing. Potential biological functions of the gene variant were further investigated in the RKO colon cancer cell line.
RESULTS: A novel nonsense variant (c.1114A > T, p.Lys372*) of BMPR1A was identified in the CRC family. This variant generated a PTC at the kinase domain and caused nonsense-mediated mRNA decay. Read-through inducing reagents G418 and PTC124 partially restored BMPR1A expression and its following signaling pathway.
CONCLUSIONS: The identification of the novel BMPR1A variant enriched the genotype-phenotype spectrum of BMPR1A. Meanwhile, our finding also provided support for future PTC-targeting therapy for BMPR1A-mediated JPS and CRC.

BACKGROUND: Juvenile polyposis syndrome (JPS) is an autosomal dominant, inherited disorder characterized by multiple hyperproliferative polyps of the gastrointestinal tract, particularly of the colon, rectum, and stomach. SMAD4 mutations are frequently associated with multiple polyposis of the stomach; the condition causes severe bleeding and hypoproteinemia, which may progress to severe dysplasia and adenocarcinoma formation. We report our experience with the first case of total gastrectomy with pancreaticoduodenectomy following two partial jejunectomies for JPS, who presented with refractory anemia and protein-losing gastroenteropathy due to polyposis of the stomach and duodenum.
METHODS: A 33-year-old Japanese man presented with the chief complaint of shortness of breath on exertion. His family history included gastric polyposis (mother, aunt, and cousin) and cerebral infarction (grandmother). Blood testing at the initial visit indicated iron-deficiency anemia, whereas endoscopy revealed multiple polyps in the duodenum and jejunum. Genetic testing revealed a 4 bp deletion (TGAA) in exon 5 of the SMAD4 gene; two partial small bowel resections were performed, but polyps grew in the remaining stomach, duodenum, and small intestine. The patient developed hypoalbuminemia and anemia, and required central venous nutrition and blood transfusion. However, because the hyponutrition and anemia remained poorly controlled, a total gastrectomy with concomitant pancreaticoduodenectomy was performed. Malnutrition and anemia improved, and there was no polyp recurrence in the remaining intestinal tract at 18 months after the surgery.
CONCLUSIONS: We report a case of JPS with refractory anemia and protein-losing gastroenteropathy that was treated with total gastrectomy with concomitant pancreaticoduodenectomy. Although the surgery was highly invasive, the patient\'s nutritional status and anemia improved postoperatively, and the treatment was successful. However, to determine the appropriate surgical procedure, a detailed examination of the gastrointestinal lesions and the effects of the surgical invasion on nutritional status must be undertaken.

BACKGROUND: Juvenile polyposis syndrome (JPS), a rare autosomal dominant syndrome, affects one per 100 000 births, increasing lifetime cancer risk by 9 - 50%. Around 40-60% of JPS cases are caused by disease-causing variants (DCV) in SMAD4 or BMPR1A genes, of which SMAD4 accounts for 20-30%.
OBJECTIVE: To characterise genotype-phenotype correlations between sites and types of variants within SMAD4 to JPS phenotypes, to inform diagnosis, screening, and management of JPS.
METHODS: Online search databases utilised included Ovid MEDLINE, Embase Classic + Embase and PubMed, using search terms classified by MeSH on Demand. Adjacency operators, word truncation and Boolean operators were employed. 110 articles were included in the review, collating 291 variants from the literature.
RESULTS: In SMAD4 + JPS patients, most variants are located around SMAD4\'s MH2 domain (3\' end). Extracolonic involvement, massive gastric polyposis and a more aggressive phenotype have been associated with SMAD4 + JPS, predisposing to gastric cancer. This has contributed to an overall higher incidence of GI cancers compared to other genes causing JPS, with DCVs mostly all within the MH2 domain. Genetically related allelic disorders of SMAD4 also have variants in this region, including hereditary haemorrhagic telangiectasia (HHT) alongside SMAD4 + JPS, and Myhre syndrome, independent of JPS. Similarly, with DCVs in the MH2 domain, Ménétrier\'s disease, hypertrophic osteoarthropathy and juvenile idiopathic arthritis have been seen in this population, whereas cardiac pathologies have occurred both alongside and independently of SMAD4 + JPS with DCVs in the MH1 domain.
CONCLUSIONS: Truncating and missense variants around the MH2 region of SMAD4 are most prevalent and pathogenic, thus should undergo careful surveillance. Given association with extracolonic polyposis and higher GI cancer risk, endoscopic screening should occur more frequently and at an earlier age in SMAD4 + JPS patients than in patients with other causative genes, with consideration of Ménétrier\'s disease on upper GI endoscopy. In addition, HHT should be evaluated within 6 months of diagnosis, alongside targeted clinical examination for extraintestinal manifestations associated with SMAD4 + JPS. This review may help modify clinical diagnosis and management of SMAD4 + JPS patients, and aid pathogenicity classification for SMAD4 DCVs through a better understanding of the phenotypes.

BACKGROUND: Juvenile polyposis syndrome (JPS) is a rare hereditary polyposis disease frequently associated with an autosomal-dominant variant of the SMAD4 or BMPR1A gene. It often manifests with symptoms in children and adolescents and is infrequently diagnosed in asymptomatic adults. Establishing the diagnosis is important as patients with JPS have a high risk of developing gastrointestinal cancer and require genetic counselling and close routine follow-up.
METHODS: We report on the case of a 56-year-old female diagnosed with JPS after genetic testing revealed a rare variant of the BMPR1A gene BMPR1A c.1409T>C (p.Met470Thr). She was initially referred for colonoscopy by her general practitioner after testing positive on a screening faecal immunochemical test and subsequently found to have polyposis throughout the entire colorectum on her index screening colonoscopy. The patient was asymptomatic with a normal physical examination and no related medical or family history. Blood tests revealed only mild iron deficiency without anemia. To date, there has only been one other reported case of JPS with the same genetic variant. Subsequent colonoscopies were organised for complete polyp clearance and the patient was returned for surveillance follow-up.
CONCLUSIONS: JPS patients can present with no prior symptoms or family history. Genetic testing plays an important diagnostic role guiding management.