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Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal vascular dysplasia characterized by the presence of mucocutaneous telangiectasia and arteriovenous malformations in solid organs. The Curaçao criteria and/or detection of ALK1, ENG, and SMAD4 gene mutations are used for diagnosis. Juvenile Polyposis Syndrome (JPS) is diagnosed according to the number and localization of juvenile polyps, and family history of JPS. Both entities have a low prevalence. Mutation of SMAD4 leads to a combined syndrome of these two conditions called HHT-JPS Overlap Syndrome. We aim to describe the clinical characteristics associated with this condition focusing on long term follow up and review of the literature. A cross-sectional descriptive study of HHT-JPS cases from an HHT Institutional Registry was designed. Patients were eligible for this case series if they fulfilled both HHT and JPS diagnostic criteria and/or mutation on SMAD4. A comprehensive review was conducted on the clinical phenotype associated with HHT and its gastrointestinal involvement. Fourteen patients from eleven families in 788 previously HHT-diagnosed patients met the inclusion criteria. The ages ranged between 25 and 70 years old and 12 were females. In addition to the typical signs/symptoms of HHT, two distinct phenotypes were observed. Nine patients predominantly exhibited initially upper, while five showed predominantly initially lower gastrointestinal involvement. Numerous musculoskeletal and cardiovascular anomalies were also identified. The observed phenotypic diversity, particularly in gastrointestinal involvement, underscores the need for tailored clinical approaches. Comprehensive assessments identified associated musculoskeletal and cardiovascular anomalies, emphasizing the systemic nature of HHT-JPS., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background and Aims: Juvenile polyposis syndrome (JPS) is a rare hereditary autosomal dominant cancer-predisposition syndrome caused by germline pathogenic variants (PVs) located in SMAD4 or BMPR1A genes. Accurate clinical and endoscopic data regarding the evolution of gastric lesions remain sparse., Methods: Clinical, endoscopic, genetic, and pathologic data from patients with SMAD4 or BMPR1A PVs included between 2007 and 2020 in the French network on rare digestive polyposis (RENAPOL [French National Polyposis Register]) database were prospectively collected to address uncertainties regarding gastric involvement., Results: Thirty-six patients were included: 25 (69.5%) had SMAD4 PVs, and 11 had BMPR1A PVs. For SMAD4 PV carriers, median age at inclusion was 43.0 years (range, 10-78 years). At baseline EGD, 22 (88%) of 25 patients exhibited at least 1 gastric juvenile polyp, and 5 (20%) of 25 had macroscopic signs of inflammatory gastritis. Early gastric disease was mostly located under the cardia, then progressed to the gastric antrum and body. During a mean follow-up period of 55.0 months, 12 of 25 patients had gastric disease progression (ie, new juvenile polyps [91.6%], diffuse gastric involvement [41.6%], inflammatory flat progression [25%]). Among 62 biopsies, low-grade dysplasia was observed in 5 (7.5%) samples from 2 patients. Nine carriers (36%) underwent gastrectomy (mean age, 47.2 years) due to diffuse gastric involvement or worsening clinical symptoms. Gastric adenocarcinoma (T1) was found in 1 gastrectomy specimen. Among the 11 patients with BMPR1A PVs, 2 had gastric hamartomatomas at baseline EGD, none with dysplasia or symptoms., Conclusions: Gastric involvement in JPS seems to be progressive over a lifetime, initiates in the cardia area, and mostly involves SMAD4 PV carriers., Competing Interests: Disclosure All authors disclosed no financial relationships., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. All rights reserved.)

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., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

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., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background: Infantile Juvenile polyposis of infantile (JPI) is a rare and aggressive form of juvenile polyposis syndrome (JPS) typically diagnosed in the first year of life. It often carries a poor prognosis due to chronic gastrointestinal bleeding, protein-losing enteropathy, malnutrition and immune deficiency., Case Presentation: We report a case of a girl initially presented with pallor at 7 months of age, which progressed to gastrointestinal bleeding and protein-losing enteropathy. Endoscopic examination, which included both upper gastrointestinal endoscopy and enteroscopy, showed diffuse polyposis. Histopathology results indicated the presence of juvenile polyps with no dysplasia in all removed polyps. Genetic testing identified a 2.1 Mb deletion on chromosome 10q23.2q23.31 involving the phosphatase and tensin homolog (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A) genes. Treatment with sirolimus initiated at 10 months of age led to a reduction in the need for blood and albumin infusions, improved patient growth, and quality of life. While the frequency of endoscopic evaluations decreased with sirolimus, regular endoscopic polypectomy every 5 months remained necessary. However, discontinuation of sirolimus resulted in polyp recurrence after 2 months due to pneumonia., Conclusion: This case highlights sirolimus treatment can alleviate many complications of JPI, it does not eliminate the need for aggressive polypectomy., (© 2024. The Author(s).)

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.

Background: Both hereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) are known to be caused by SMAD4 pathogenic variants, with overlapping symptoms for both disorders in some patients. Additional connective tissue disorders have also been reported. Here, we describe carriers of SMAD4 variants followed in an HHT reference centre to further delineate the phenotype., Methods: Observational study based on data collected from the Clinical Investigation for the Rendu-Osler Cohort database., Results: Thirty-three participants from 15 families, out of 1114 patients with HHT, had an SMAD4 variant (3%).Regarding HHT, 26 out of 33 participants (88%) had a definite clinical diagnosis based on Curaçao criteria. Complication frequencies were as follows: epistaxis (n=27/33, 82%), cutaneous telangiectases (n=19/33, 58%), pulmonary arteriovenous malformations (n=17/32, 53%), hepatic arteriovenous malformations (AVMs) (n=7/18, 39%), digestive angiodysplasia (n=13/22, 59%). No cerebral AVMs were diagnosed.Regarding juvenile polyposis, 25 out of 31 participants (81%) met the criteria defined by Jass et al for juvenile polyposis syndrome. Seven patients (21%) had a prophylactic gastrectomy due to an extensive gastric polyposis incompatible with endoscopic follow-up, and four patients (13%) developed a digestive cancer.Regarding connective tissue disorders, 20 (61%) had at least one symptom, and 4 (15%) participants who underwent echocardiography had an aortic dilation., Conclusion: We describe a large cohort of SMAD4 variant carriers in the context of HHT. Digestive complications are frequent, early and diffuse, justifying endoscopy every 2 years. The HHT phenotype, associating pulmonary and hepatic AVMs, warrants systematic screening. Connective tissue disorders broaden the phenotype associated with SMAD4 gene variants and justify systematic cardiac ultrasound and skeletal complications screening., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: A constitutional disease-causing variant (DCV) in the SMAD4 or BMPR1A genes is present in 40%-60% of patients with juvenile polyposis syndrome (JPS). The aim of this study was to characterize the clinical course and polyp burden in children with DCV-positive JPS compared to DCV-negative JPS., Methods: Demographic, clinical, genetic, and endoscopic data of children with JPS were compiled from eight international centers in the ESPHGAN/NASPGHAN polyposis working group., Results: A total of 124 children with JPS were included: 69 (56%) DCV-negative and 55 (44%) DCV-positive (53% SMAD4 and 47% BMPR1A) with a median (interquartile range) follow-up of 4 (2.8-6.4) years. DCV-positive children were diagnosed at an older age compared to DCV-negative children [12 (8-15.7) years vs. 5 (4-7) years, respectively, p < 0.001], had a higher frequency of family history of polyposis syndromes (50.9% vs. 1.4%, p < 0.001), experienced a greater frequency of extraintestinal manifestations (27.3% vs. 5.8%, p < 0.001), and underwent more gastrointestinal surgeries (16.4% vs. 1.4%, p = 0.002). The incidence rate ratio for the development of new colonic polyps was 6.15 (95% confidence interval 3.93-9.63, p < 0.001) in the DCV-positive group compared to the DCV-negative group, with an average of 12.2 versus 2 new polyps for every year of follow-up. There was no difference in the burden of polyps between patients with SMAD4 and BMPR1A mutations., Conclusions: This largest international cohort of pediatric JPS revealed that DCV-positive and DCV-negative children exhibit distinct clinical phenotype. These findings suggest a potential need of differentiated surveillance strategies based upon mutation status., (© 2024 The Author(s). Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Constitutional loss of SMAD4 function results in Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia Overlap Syndrome (JP-HHT). A retrospective multi-centre case-note review identified 28 patients with a pathogenic SMAD4 variant from 13 families across all Scottish Clinical Genetics Centres. This provided a complete clinical picture of the Scottish JP-HHT cohort. Colonic polyps were identified in 87% (23/28) and gastric polyps in 67% (12/18) of screened patients. Complication rates were high: 43% (10/23) of patients with polyps required a colectomy and 42% (5/12) required a gastrectomy. Colorectal cancer occurred in 25% (7/28) of patients, at a median age of 33 years. Pulmonary arteriovenous malformations were identified in 42% (8/19) of screened patients. 88% (23/26) and 81% (17/21) of patients exhibited JP and HHT features respectively, with 70% (14/20) demonstrating features of both conditions. We have shown that individuals with a pathogenic SMAD4 variant are all at high risk of both gastrointestinal neoplasia and HHT-related vascular complications, requiring a comprehensive screening programme., (© 2024. The Author(s).)

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 BMPR 1 A . 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.

Background: Metagenomic next-generation sequencing (mNGS) is a culture-independent massively parallel DNA sequencing technology and it has been widely used for rapid etiological diagnosis with significantly high positivity rate. Currently, clinical studies on evaluating the influence of previous antimicrobial therapy on positivity rate of mNGS in PJIs are rarely reported. The present study aimed to investigate whether the positivity rate of mNGS is susceptible to previous antimicrobial therapy., Methods: We performed a prospective trial among patients who undergone hip or knee surgery due to periprosthetic joint infection (PJI) to compare the positivity rate of culture and mNGS between cases with and without previous antimicrobial therapy, and the positivity rates between cases with different antimicrobial-free intervals were also analysed., Results: Among 131 included PJIs, 91 (69.5%) had positive cultures and 115 (87.8%) had positive mNGS results. There was no significant difference in the positivity rate of deep-tissue culture and synovial fluid mNGS between cases with and without previous antimicrobial therapy. The positivity rate of synovial fluid culture was higher in cases with previous antimicrobial therapy. The positivity rates of mNGS in synovial fluid decreased as the antimicrobial-free interval ranged from 4 to 14 days to 0 to 3 days., Conclusion: mNGS is more advantageous than culture with a higher pathogen detection rate. However, our data suggested that antimicrobial agents may need to be discontinued more than 3 days before sampling to further increase the positivity rate of mNGS for PJIs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hao, Bian, Qing, Ma, Li, Xu and Wen.)

Background: Juvenile Polyposis Syndrome (JPS) is a rare autosomal dominant hereditary disorder characterized by the development of multiple hamartomatous gastrointestinal polyps. Here, we present a case of JPS with a mosaic variant in SMAD4., Methods: Exome sequencing TRIO analysis, using germline DNA from the biological mother and father along with the index case (IC)., Results: A 46-year-old male with no family history of cancer presented with chronic iron deficiency anemia and was diagnosed with massive gastric polyposis (≥100 polyps). At the age of 59, he underwent a total gastrectomy, revealing numerous polyps occupying the entire gastric mucosa, including a 5 cm gastric hyperplastic polyp with high-grade dysplasia and focal adenocarcinoma. TRIO analysis identified the c.386A>C p.(Asn129Thr) variant in the SMAD4 gene at an allele frequency (AF) of 22%, suggesting its mosaic origin. Subsequently, the variant was found in heterozygosity in the IC's son, who exhibited two subcentimeter polyps in the colon and seven inflammatory gastric polyps with gastric inflammatory areas and hyperplasia, suggesting that the c.386A>C p.(Asn129Thr) variant in SMAD4 segregated with the phenotype., Conclusion: Our study provides evidence supporting the classification of the c.386A>C p.(Asn129Thr) variant in SMAD4 as a likely pathogenic variant. This finding contributes to improved accuracy in the diagnosis and genetic counseling of JPS., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Gastric juvenile polyposis (GJP) is frequently associated with the development of gastric cancer. However, there are no reports of gastric cancer in patients with GJP diagnosed using magnifying endoscopy with narrow-band imaging (M-NBI) and successfully treated by endoscopic submucosal dissection (ESD). A 50-year-old woman was referred to our hospital. Conventional white-light endoscopy revealed numerous aggregated polyps with reddish and whitish areas in the gastric cardia. M-NBI revealed a regular microvascular pattern (MVP) and regular microsurface pattern (MSP) in the reddish area of the lesion, and they were diagnosed as non-cancerous polyps. There was a clear demarcation line between the reddish and whitish areas, with irregular MVP plus irregular MSP in the whitish area, which was diagnosed as early gastric cancer. The horizontal extent of the cancer was precisely identified using M-NBI, and the en bloc resection of cancerous lesions was performed using ESD. Histopathological examination of the resected specimen showed that the reddish area comprised a hyperplastic foveolar epithelium. Conversely, the whitish area was diagnosed as a well-differentiated adenocarcinoma. The cancer was limited to the mucosa, lymphovascular invasion was negative, and horizontal and vertical margins were free from cancerous tissue. According to surveillance endoscopy, there has been no recurrence 11 years after ESD. This is the first report demonstrating that M-NBI is useful for making a precise diagnosis of cancer in juvenile polyposis and that ESD can be an option for the treatment of such a cancer., (© 2022. Japanese Society of Gastroenterology.)

Juvenile polyposis syndrome (JPS) is a childhood polyposis syndrome with up to a 50% lifetime risk of gastrointestinal cancer. Germline pathogenic variants in BMPR1A and SMAD4 are responsible for around 40% of cases of JPS, but for the majority of individuals, the underlying genetic cause is unknown. We identified a family for which polyposis spanned four generations, and the proband had a clinical diagnosis of JPS. Next-generation sequencing was conducted, followed by Sanger sequencing confirmation. We identified an internal deletion of the FOCAD gene in all family members tested that altered the reading frame and is predicted to be pathogenic. We conclude that inactivation of the FOCAD gene is likely to cause JPS in this family., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Juvenile polyposis represents an heterogeneous disease as different genetic dominant backgrounds have been evidenced leading to different clinical presentations. It is associated in some patients with a different syndrome, Hereditary Hemorragic Telangiectasia, justifying a complementary and different management. Recent international recommendations help in managing this very rare disease, and this management should probably be restricted to expert centers able to take care of the multiple manifestations and risks of these patients and families. This paper will focus on the poorly known and evaluated aspects of juvenile polyposis, excluding the colonic involvement and epidemiology that are addressed in a different article of this issue., (Copyright © 2022. Published by Elsevier Ltd.)

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This US Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management., (Copyright © 2022 by The American College of Gastroenterology, American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy.)

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S. Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management., (Copyright © 2022 American Society for Gastrointestinal Endoscopy, the American Gastroenterological Association, and the American College of Gastroenterology. Published by Elsevier Inc. All rights reserved.)

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management., (Copyright © 2022 American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and The American College of Gastroenterology. Published by Elsevier Inc. All rights reserved.)

Juvenile polyposis syndrome (JPS) is a rare precancerous condition that confers an increased risk of developing gastrointestinal cancers. The inheritance pattern is autosomal dominant. JPS should be clinically suspected when the other hamartomatous polyposis syndromes are excluded (i.e., Peutz- Jeghers and Cowden), in presence of numerous juvenile polyps in the colorectum or in other GI locations. Among the syndromic features, JPS can present with concomitant extra-intestinal manifestations, above all cutaneous manifestations such as telangiectasia, pigmented nevi, and skeletal stigmata. Pathogenic germline variants of either BMPR1A or SMAD4 cause the syndrome. In JPS a cumulative risk of CRC of 39-68% has been estimated. The oncological risk justifies and imposes prevention strategies that aim at the cancer risk reduction through endoscopic screening, as recommended by international scientific societies. The aim of this review is to summarize clinical and genetic features of JPS and to elucidate the steps of the clinical management from diagnosis to surveillance., (Copyright © 2022. Published by Elsevier Ltd.)

A 43-year-old woman was suffering from epigastric pain. Her gastroscopy revealed polyposis of the stomach, and her biopsy revealed a hyperplastic polyp. During the 18-month follow-up, the polyps proliferated, and the patient was referred to our institute for further investigation and treatment. A juvenile gastric polyposis diagnosis was made. She refused to have the surgery despite the fact that it was necessary due to the anemia and hypoalbuminemia she was experiencing. Endoscopic biopsy results revealed gastric cancer at a follow-up visit 2 years and 3 months later; thus, a laparoscopic total gastrectomy was performed. Pathological examination revealed adenocarcinomas that were scattered and well-differentiated, with hyperplastic polyps in the background. No lymph node metastasis was found. Despite the fact that juvenile gastric polyposis is a pathologically benign disease, there have been numerous case reports of surgery being performed due to anemia, hypoalbuminemia, or gastric cancer associated with the disease. When gastric cancers are discovered in cases of juvenile gastric polyposis, they are usually in an early stage, making them a good candidate for laparoscopic total gastrectomy.

Background: Juvenile polyposis syndrome (JPS) is one of the hereditary polyposis syndromes caused by abnormal regulation of transforming growth factor β signaling because of mutations in BMPR1A and SMAD4. Juvenile polyposis syndrome patients with SMAD4 mutations develop cardiovascular events, whereas those with BMPR1A usually do not. Analysis of genetic mutations in JPS patients can be helpful in devising suitable strategies for medical management. In this study, we demonstrate the pathogenicity of a novel intronic mutation in BMPR1A using mRNA extracted from colonic mucosa of a boy with JPS., Methods: Genomic DNA extracted from peripheral blood and total RNA isolated from the colonic mucosa were used for DNA sequencing and reverse transcription polymerase chain reaction (RT-PCR) analyses, respectively., Results: A 13-year-old boy, with no previous medical history, presented to the hospital complaining of bloody stools. Colonoscopy revealed multiple polyps in the colon, and the resected polyps were compatible with juvenile polyps. Sequencing analysis revealed a novel intronic mutation (c.778+5G>C) in BMPR1A. Reverse transcription polymerase chain reaction analysis of RNA extracted from the colonic mucosa showed an aberrant splicing form of BMPR1A. Trio analysis showed that his mother also had the same BMPR1A mutation. She was diagnosed with cancer of the cecum and polyposis of the colon at the age of 41., Conclusion: We demonstrate the presence of a novel BMPR1A intronic mutation that exhibits splicing abnormality in a family with JPS. Further research and development will help elucidate the genotype-phenotype relationship in JPS., (© 2021 Japan Pediatric Society.)

Ultra-rare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mammalian target of rapamycin (mTOR) inhibition (adverse events, disease progression, time to colectomy and mortality) in patients with JPI. Among 25 JPI patients identified (mean age of onset 13 months), seven received mTOR inhibitors (everolimus, n = 2; or sirolimus, n = 5). Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio = 0.27, 95% confidence interval = 0.07-0.954, P = 0.042) and resulted in significant improvements in the serum albumin level (mean increase = 16.3 g/l, P = 0.0003) and hemoglobin (mean increase = 2.68 g/dl, P = 0.0077). Long-term mTOR inhibitor treatment was well tolerated over an accumulated follow-up time of 29.8 patient years. No serious adverse events were reported. Early therapy with mTOR inhibitors offers effective, pathway-specific and personalized treatment for patients with JPI. Inhibition of the phosphoinositol-3-kinase-AKT-mTOR pathway mitigates the detrimental synergistic effects of combined PTEN-BMPR1A deletion. This is the first effective pharmacological treatment identified for a hamartomatous polyposis syndrome., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

BACKGROUND Juvenile polyposis syndrome is an uncommon, autosomal-dominant hereditary disease that is distinguished by multiple polyps in the stomach or intestinal tract. It is associated with a high risk of malignancy. Pathogenic variants in SMAD4 or BMPR1A account for 40% of all cases. CASE REPORT A 49-year-old woman underwent esophagogastroduodenoscopy because of exacerbation of anemia. She had numerous erythematous polyps in most parts of her stomach. Based on biopsy findings, juvenile polyposis syndrome (JPS) was suspected morphologically, but there was no evidence of malignancy. Colonoscopy showed stemmed hyperplastic polyps and an adenoma; video capsule endoscopy revealed no lesions in the small intestine. After preoperative surveillance, laparoscopic total gastrectomy with D1 lymph node dissection was performed to prevent malignant transformation. The pathological diagnosis was juvenile polyp-like polyposis with adenocarcinoma. In addition, a germline pathogenic variant in the SMAD4 gene was detected with genetic testing. CONCLUSIONS JPS can be diagnosed with endoscopy and genetic testing. Further, appropriate surgical management may prevent cancer-related death in patients with this condition.

Hereditary hemorrhagic telangiectasia (HHT) (Osler-Weber-Rendu Syndrome) is a rare autosomal dominant vascular disorder characterized by the presence of multiple arteriovenous malformations (AVMs) and recurrent bleeding episodes. The diagnosis is based on the Curacao criteria: (i) spontaneous recurrent epistaxis, (ii) mucocutaneous telangiectasia, (iii) AVMs of visceral organs, and (iv) first degree relatives with a similar condition (1). Due to a common genetic pathway and SMAD4 gene mutation, juvenile polyposis syndrome (JPS) may coexist with HHT (2). The disease burden is high in overlapping HHT/JPS, but digital clubbing may be the only physical finding. Continuous meticulous management may improve the quality of life and reduce the risk of complications. In 2000, a 15-year-old female patient was diagnosed with HHT based on epistaxis, multiple pulmonary AVMs, and a father who had similar symptoms. Other visceral AVMs were excluded. No telangiectasia was noted. On several occasions, pulmonary AVMs were managed with coil embolization (Figure 1), which successfully led to the resolution of dyspnea and cyanosis. Recurrent gastrointestinal bleedings led to severe transfusion-dependent anemia. Multiple polyps in the stomach, small intestine, and colon were repeatedly endoscopically removed, confirming the coexisting JPS. Genetic testing was not performed. Proctocolectomy was performed to prevent malignant transformation in the digestive tract. Telangiectasias are the dermatological hallmark of the HHT and occur in up to 90% of patients with the typical onset in childhood, becoming more apparent with increasing age. They are most frequently found on the face, with highest incidence on the nose, lips, tongue, and ears, followed by the fingertips, trunk, and feet; telangiectasia is recognized as the most common of the three criteria required for the diagnosis of HHT (1). Interestingly, no cutaneous telangiectasia developed in our patient during years of follow-up. However, pulmonary AVMs led to digital clubbing of her both fingers and toes (Figure 2). Digital clubbing is the focal enlargement of the connective tissue in the terminal phalanges, consequently changing the shape of nails, which become abnormally curved and shiny. It is associated with various infectious, neoplastic, inflammatory, and vascular conditions (3). Despite its well-known prevalence in certain conditions, the pathogenesis of this phenomenon remains elusive. Vascular, neural, and hormonal mechanisms have been considered, implicating the role of a wide range of substances, such as prostaglandins, bradykinin, estrogen, platelet-derived growth factor, hepatocyte growth factor, and growth hormone, however, none of these mechanisms provide a unifying explanation (4,5). In digital clubbing, the increased vascularity in the nail-bed leads to hyperplasia of fibrous tissue and edema, resulting in a loss of the hyponychial angle, fluctuance of the nail-bed, and an abnormal phalangeal depth ratio (5). The clinical assessment of the clubbing is based on the measurement of the distal phalangeal depth (DPD) of the finger (at the nail base) and the interphalangeal depth (IPD). A DPD/IPD ratio >1 is defined as clubbing, while a DPD/IPD ratio <1 is defined as normal (3). Clubbing is a potentially reversible phenomenon provided that the underlying condition is cured (4,5). In the context of pulmonary AVMs, abnormal communication between the pulmonary artery and pulmonary vein outside the capillary bed leads to right-to-left shunt physiology that clinically presents as dyspnea, cyanosis, and clubbing. Embolization of AVMs as the first-line therapy resolved systemic symptoms in our patient, and therefore no other treatment options were pulmonary considered further. However, 20 years later, despite the treatment, the severe clubbing of her both fingers and toes remained (Figure 2). Based on our findings, HHT should be considered in differential diagnosis of patients with digital clubbing resulting from AVMs, in particular when no skin telangiectasia is present.

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., (©2020 American Association for Cancer Research.)

Juvenile polyposis syndrome (JPS) and hereditary haemorrhagic telangiectasia (HHT) are rare autosomal dominant diseases, where symptoms manifest at childhood. A 32-year-old man with no family history of JPS or HHT with SMAD4 gene mutation who developed signs and symptoms only at the age of 32, when he was an adult. In this article, we highlight the steps taken to diagnose this rare pathology, explain its pathophysiology and management., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Juvenile polyposis syndrome (JPS) is a rare genetic gastrointestinal disorder with hidden and variable clinical features. Early detection is crucial for good prognosis., Patient Concerns: A 20-year-old female went to hospital for fever, and was unexpectedly diagnosed as JPS during treatment. She reported no clinical signs or family history of JPS., Diagnosis: Blood routine examination on hospital admission suggested a moderate anemia. Bone marrow cytology and leukemia fusion gene test were performed to rule out leukemia. Other examinations including ultrasound and computed tomography were also conducted for differential diagnosis. Further electronic colonoscopy identified more than 20 pedicle polyps located at her ileocecum and rectum. Mutation analysis detected a novel de novo pathogenic variant, c.910C>T (p.Gln304Ter) within bone morphogenetic protein receptor type 1A gene, establishing the diagnosis of JPS., Interventions: The patient was treated with endoscopic interventions. We also provided a genetic counseling for this family., Outcomes: The patient's polyps were removed, some of which already had adenomatous changes. The patient received surveillance of hereditary colorectal cancer according to guidelines., Lessons: Variable features and lack of family history probably lead to a great underestimation of potential JPS population. It is recommended to perform genetic testing by a multigene panel in individuals who have suspected symptoms of polyposis.

Juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT) are both relatively rare hereditary disorders. Some patients with the SMAD4 gene mutation develop both JPS and HHT, a condition termed JPS-HHT. We herein report a case of childhood-onset JPS-HHT. At nine years old, the patient underwent colonoscopy under suspicion of Crohn's disease, which revealed multiple polyps. A genetic analysis for familial adenomatous polyposis and Peutz-Jeghers syndrome found no mutations. After several years, extraintestinal manifestations, such as repeated epistaxis and several telangiectasias in the upper palate and stomach, were identified, which led to the performance of gene mutation analysis for SMAD4. As a result, a missense mutation in exon 8, codon 361 from arginine to cysteine (c.1081 C>T) was found. Based on this finding, the patient underwent cerebral magnetic resonance angiography, pulmonary perfusion scintigraphy and thoracoabdominal contrast computed tomography. The examination revealed that she had pulmonary arteriovenous fistulas and arteriovenous malformations in both the liver and right mammary gland. Thus, continuous surveillance for vascular lesions and gastrointestinal cancer is scheduled. Making a precise diagnosis of JPS-HHT can lead to the detection of asymptomatic complications and enable appropriate future disease management.

Background: Patients with germline variants in SMAD4 can present symptoms of both juvenile polyposis syndrome (JPS) and Hereditary Hemorrhagic Telangiectasia (HHT): JP-HHT syndrome. Next-Generation Sequencing (NGS) techniques disclose causative sequence variants in around 90% of HHT patients fulfilling the Curaçao criteria. Here we report a translocation event involving SMAD4 resulting in JP-HHT., Methods: A patient fulfilling the Curaçao criteria was analyzed for variants in ENG, ACVRL1, and SMAD4 using standard techniques. Whole-genome sequencing (WGS) using both short-read NGS technology and long-read Oxford Nanopore technology was performed to define the structural variant and exact breakpoints., Results: No pathogenic variant was detected in ENG, ACVRL1, or SMAD4 in DNA extracted from blood. Due to abortus habitualis, the proband´s daughter was submitted for chromosomal analysis, and a cytogenetically balanced chromosomal reciprocal translocation t(1;18)(p36.1;q21.1) was detected in the daughter and the patient. The balanced translocation segregated with both gastrointestinal cancer and HHT in the family. WGS provided the exact breakpoints of the reciprocal translocation proving disruption of the SMAD4 gene., Discussion: A disease-causing reciprocal translocation between chromosome 1 and 18 with a breakpoint in the SMAD4 locus co-segregated with JP-HHT in an extended family. This observation warrants further analysis for chromosomal rearrangements in individuals with clinical HHT or JP-HHT of unknown cause., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: Juvenile polyposis syndrome (JPS) is a rare autosomal dominant hereditary disorder characterized by the development of multiple distinct juvenile polyps in the gastrointestinal tract with an increased risk of colorectal cancer. Germline mutations in two genes, SMAD4 and BMPR1A, have been identified to cause JPS., Case Presentation: Here, we report a germline heterozygous missense variant (c.299G > A) in exon 3 BMPR1A gene in a family with juvenile polyposis. This variant was absent from the population database, and concluded as de novo compared with the parental sequencing. Further sequencing of the proband's children confirmed the segregation of this variant with the disease, while the variant was also predicted to have damaging effect based on online prediction tools. Therefore, this variant was classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines., Conclusions: Germline genetic testing revealed a de novo germline missense variant in BMPR1A gene in a family with juvenile polyposis. Identification of the pathogenic variant facilitates the cancer risk management of at-risk family members, and endoscopic surveillance is recommended for mutation carriers.

Purpose: Mutations of the SMAD4 gene can result in a distinct syndrome with combined clinical features of both juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT). Even though it is known that patients with the overlap syndrome are at increased risk for colorectal malignancies and bleeding, the outcomes of this patient population have not been extensively studied., Methods: Retrospective study aiming to describe the phenotype and clinical outcomes of patients with genetically confirmed JP-HHT combined syndrome in a single large tertiary center in North America., Results: A total of 22 patients were identified, the majority females (59%) with a median age diagnosis at 24 years. Polyps were more commonly seen in the lower gastrointestinal (GI) tract, and tubular adenomas were seen in 50%. Epistaxis and pulmonary arteriovenous malformations (AVM) were the most common manifestations of HHT, with a median Curacao score of 3 [1-4]. Hospitalization for gastrointestinal bleeding and cerebrovascular events occurred at a rate of 28% and 4%, respectively. Two patients had GI malignancies, one rectal and one small bowel adenocarcinoma. Overall mortality was 14%., Conclusions: Patients with the combined JP-HHT syndrome remain at risk for life-threatening vascular complications and gastrointestinal malignancies; close follow-up is necessary to minimize morbidity and mortality in this patient population.

Purpose: Juvenile polyposis syndrome (JPS) is a rare, autosomal-dominantly inherited cancer predisposition caused in approximately 50% of cases by pathogenic germline variants in SMAD4 and BMPR1A. We aimed to gather detailed clinical and molecular genetic information on JPS disease expression to provide a basis for management guidelines and establish open access variant databases., Methods: We performed a retrospective, questionnaire-based European multicenter survey on and established a cohort of SMAD4/BMPR1A pathogenic variant carriers from the medical literature., Results: We analyzed questionnaire-based data on 221 JPS patients (126 kindreds) from ten European centers and retrieved literature-based information on 473 patients. Compared with BMPR1A carriers, SMAD4 carriers displayed anemia twice as often (58% vs. 26%), and exclusively showed overlap symptoms with hemorrhagic telangiectasia (32%) and an increased prevalence (39% vs. 13%) of gastric juvenile polyps. Cancer, reported in 15% of JPS patients (median age 41 years), mainly occurred in the colorectum (overall: 62%, SMAD4: 58%, BMPR1A: 88%) and the stomach (overall: 21%; SMAD4: 27%, BMPR1A: 0%)., Conclusion: This comprehensive retrospective study on genotype-phenotype correlations in 694 JPS patients corroborates previous observations on JPS in general and SMAD4 carriers in particular, facilitates recommendations for clinical management, and provides the basis for open access variant SMAD4 and BMPR1A databases.

Competing Interests: Competing interests: None declared.

Background: Juvenile polyposis syndrome (JPS) is a rare disorder characterized by the presence of multiple juvenile polyps in the gastrointestinal tract, and germline mutations in SMAD4 or BMPR1A. Due to its rarity and complex clinical manifestation, misdiagnosis often occurs in clinical practice., Case Presentation: A 42-year-old man with multiple pedunculated colorectal polyps and concomitant rectal adenocarcinoma was admitted to our hospital. His mother had died of colon cancer. He was diagnosed with familial adenomatous polyposis (FAP) and underwent total proctocolectomy and ileal pouch anal anastomosis. Two polyps were selected for pathological examination. One polyp had cystically dilated glands with slight dysplasia. The other polyp displayed severe dysplasia and was diagnosed as adenoma. Three years later, his 21-year-old son underwent a colonoscopy that revealed more than 50 pedunculated colorectal juvenile polyps. Both patients harbored a germline pathogenic mutation in BMPR1A. Endoscopic resection of all polyps was attempted but failed. Finally, the son received endoscopic resection of polyps in the rectum and sigmoid colon, and laparoscopic subtotal colectomy. Ten polyps were selected for pathological examination. All were revealed to be typical juvenile polyps, with cystically dilated glands filled with mucus. Thus, the diagnosis of JPS was confirmed in the son. A review of the literatures revealed that patients with JPS can sometimes have adenomatous change. Most polyps in patients with JPS are benign hamartomatous polyps with no dysplasia. A review of 767 colorectal JPS polyps demonstrated that 8.5% of the polyps contained mild to moderate dysplasia, and only 0.3% had severe dysplasia or cancer. It is difficult to differentiate juvenile polyps with dysplasia from adenoma, which could explain why juvenile polyps have been reported to have adenomatous changes in patients with JPS. Therefore, patients with JPS, especially those with concomitant dysplasia and adenocarcinoma, might be easily diagnosed as FAP in clinical practice., Conclusions: Juvenile polyp with dysplasia is often diagnosed as adenoma, which might lead to the misdiagnosis of JPS as FAP. The differential diagnosis of JPS versus FAP, should be based on comprehensive evaluation of clinical presentation, endoscopic appearance and genetic investigations; not on the presence or absence of adenoma.

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant predisposition to hamartomatous polyps within the gastrointestinal tract, at high risk for malignant transformation. BMPR1A and SMAD4 loss-of-function variants account for 50% of the cases. More specifically, point mutations and structural abnormalities in BMPR1A lead to a highly penetrant yet variable phenotype of JPS. Intriguingly, in the developmental disorder caused by a recurrent 10q22.3q23.1 7 Mb deletion which includes BMPR1A, juvenile polyps have never been reported. We present the case of a young adult harboring this recurrent deletion, in a context of intellectual disability, ventricular septal defect and severe juvenile polyposis syndrome diagnosed at the age of 25 years, requiring a surgical preventive colectomy. She developed a gastric adenocarcinoma from which she died at the age of 32. We hypothesize that with the current available pangenomic CNV arrays, the diagnosis of 10q22.3q23.1 deletion is often made several years before the onset of the digestive phenotype, which could explain the absence of reports for juvenile polyps. This observation highlights the importance of an active digestive surveillance of patients with 10q22.3q23.1 deletion., (Copyright © 2019. Published by Elsevier Masson SAS.)

Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk., Competing Interests: Competing interests: KJM: Medical advisory board of Bowel Cancer UK, Lynch Syndrome UK. JH and FL: FAP trial (now closed) with funding awarded to NHS trust research facility. JE: Advisory board Lumendi, Boston Scientific; Speaker fees Olympus, Falk. MDR: Speaker fees: SwissSCWeb, Pentax; Research Grant: Olympus; Consultancy: Norgine., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Juvenile polyps (JPs) are the most common gastrointestinal polyps diagnosed in children. There is paucity of evidence differentiating polyp burden groups and the presence and significance of neoplastic changes., Methods: A retrospective chart review of patients, ages birth through 18 years with nonsyndromic JPs was performed from 2003 to 2017. Abstracted data included basic demographics, age, clinical presentation, colonoscopy findings, and pathology report. Slides of polyps with neoplasia were reviewed by a pathologist., Results: A total of 213 subjects underwent 326 procedures and 435 polypectomies. Subjects with positive family history, positive gene mutations, or numerous (>10) polyps were excluded. Groups were defined by polyp number (1, 2-4, 5-10). Polyp recurrence on repeat colonoscopy was significantly related to polyp burden (1 polyp: 1.5%/2-4 polyps 19.2%/5-10 polyps 82.6%: P < 0.001). Polyp distribution was significantly different amongst different groups with isolated polyps favoring a distal distribution. JPs harboring adenomatous foci were reported in 26 (12%) patients. JPs harboring adenomatous foci were significantly more likely to be proximally distributed but the presence of adenomatous transformation within the polyps did not correlate with polyp number or the likelihood of polyp recurrence on repeat colonoscopy., Conclusions: JP recurrence is positively and significantly related to polyp burden. JP harbored adenomatous changes independent of polyp number, underscoring a possible malignant potential in JPs. In the absence of a consistent genotype or pedigree, the presence of adenomatous transformation within JPs cannot be construed as a biomarker for syndromic juvenile polyposis.

Background: The bone morphogenetic protein (BMP) pathway is known to play an imperative role in bone, cartilage, and cardiac tissue formation. Truncating, heterozygous variants, and deletions of one of the essential receptors in this pathway, Bone Morphogenetic Protein Receptor Type1A (BMPR1A), have been associated with autosomal dominant juvenile polyposis. Heterozygous deletions have also been associated with cardiac and minor skeletal anomalies. Populations with atrioventricular septal defects are enriched for rare missense BMPR1A variants., Methods: We report on a patient with a homozygous missense variant in BMPR1A causing skeletal abnormalities, growth failure a large atrial septal defect, severe subglottic stenosis, laryngomalacia, facial dysmorphisms, and developmental delays., Results: Functional analysis of this variant shows increased chondrocyte death for cells with the mutated receptor, increased phosphorylated R-Smads1/5/8, and loss of Sox9 expression mediated by decreased phosphorylation of p38., Conclusion: This homozygous missense variant in BMPR1A appears to cause a distinct clinical phenotype., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Juvenile polyposis syndrome is a rare autosomal dominant condition characterized by multiple hamartomatous polyps throughout the gastrointestinal tract. Juvenile polyposis of infancy is a generalized severe form of juvenile polyposis syndrome associated with a poor prognosis. A 47-month-old female infant presented initially with gastrointestinal bleeding and protein-losing enteropathy at 4 months of age. At the age of 12 months, the condition worsened, requiring albumin infusions every 24 to 48 hours and red blood cell transfusions every 15 days. Upper gastrointestinal endoscopy, colonoscopy, and small-bowel enteroscopy revealed diffuse polyposis that was treated with multiple endoscopic polypectomies. Despite subtotal colectomy with ileorectal anastomosis, protein-losing enteropathy and bleeding persisted, requiring continued blood transfusions and albumin infusions. A chromosomal microarray revealed a single allele deletion in chromosome 10q23, involving both the PTEN and BMPR1A genes. Loss of PTEN function is associated with an increased activation of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway involved in cell proliferation. Treatment with sirolimus, an mTOR inhibitor, was initiated with the aim of inhibiting polyp growth. Soon after initiation of treatment with sirolimus, blood and albumin infusions were no longer needed and resulted in improved patient growth and quality of life. This case represents the first detailed report of successful drug therapy for life-threatening juvenile polyposis of infancy., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Objectives: Loss-of-function mutations of BMPR1A cause juvenile polyposis syndrome (JPS), but large genomic deletions in BMPR1A are rare, reported in few families only, and data regarding the associated phenotype are limited., Methods: We investigated clinical features and genomic data of 7 extended seemingly unrelated families with a genomic deletion of the entire coding region of BMPR1A. We defined mutation size, mutation prevalence, and tumor pathogenesis using whole-genome sequencing, targeted genotyping, and haplotype analysis., Results: Patients with JPS from 7 families of Bukharin Jewish ancestry carried a deletion of 429 kb, encompassing the BMPR1A coding sequence and 8 downstream genes. Haplotype analysis and testing controls identified this as a common founder mutation occurring in 1/124 individuals of Bukharin origin. Tumor testing did not demonstrate loss of heterozygosity. Among carriers, JPS was almost fully penetrant, but clinical features varied widely, ranging from mild to very severe, including pan-enteric polyps, gastritis, and colorectal, esophageal, and testicular cancer, and carriers with phenotypes, which would not have raised suspicion of JPS., Discussion: The phenotype in this large cohort was extremely variable, although all carriers shared the same variant and the same genetic background. New observations include a preponderance of adenomatous rather than juvenile polyps, possible association with testicular cancer, and unexpected upper gastrointestinal involvement.

We describe the case of a 16-year-old male patient with BMPR1A mutation and incidentally detected atrial septal defect (ASD). This patient was diagnosed with BMPR1A mutation through genetic testing and was attending for routine surveillance endoscopy when ASD was incidentally diagnosed. He was referred to cardiology outpatient clinic with plans for elective ASD closure. Through this case report we aim to discuss the pathophysiology of juvenile polyposis syndrome (JPS), highlight what we believe to be a novel presentation of comorbid BMPR1A mutation and ASD and hypothesise that patients with BMPR1A mutation and JPS may be at risk of previously unrecognised cardiovascular complications analogous to the previous association of SMAD4 JPS and cardiac abnormalities., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Hamartomatous polyposis syndromes (HPS) are rare autosomal-dominant inherited disorders associated with gastrointestinal (GI) tract and other cancers. HPS include Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), and phosphatase and tensin homolog hamartomatous tumor syndromes (PHTS). Diagnosis, management, and outcome prediction of HPS pose a clinical challenge. To characterize genotype, phenotype, histology and outcomes of individuals with HPS., Methods: A retrospective cohort study (2004-2017) of consecutive patients that were clinically diagnosed with HPS that visited a specialized GI oncology clinic. Demographic, clinicopathological, and genetic data were obtained from medical records., Results: Fifty-two individuals from 34 families were included. Common clinical manifestations were GI bleeding (40% JPS, 23% PJS, and 25% PHTS) and bowel obstruction (46.15% PJS and 11.4% JPS). Twenty patients (38.4%) underwent surgery, 5 of whom required multiple procedures. Higher polyp burden was associated with the need for surgery (P = 0.007). Polyp histology varied widely with 69.2% of patients exhibiting histology different from the syndrome hallmark. GI cancer history was positive in 65%, 40%, and 50% of JPS, PJS, and PHTS families, respectively. Five (9.6%) patients developed cancers (one patient each had small bowel-1, colon-1, and thyroid-1, one patient had both small bowel adenocarcinoma and breast cancer, and one had both breast cancer and liposarcoma). Twenty (38.4%) patients tested positive for STK11, PTEN, SMAD4, BMPR1A, or AKT1 mutations: Sanger sequencing and multi-gene next generation sequencing panels detected mutations in 40.9% and 100% of tested cases, respectively., Discussion: HPS patients present versatile phenotypes with overlapping clinical and histological characteristics. Polyp burden is associated with the need for surgery. Next-generation sequencing increases mutation detection.