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Purpose of review Polyposis syndromes are rare but significant entities that often present during childhood and adolescence. Polyposis syndromes should remain high on the differential diagnoses for any child presenting with rectal bleeding, protein-losing enteropathy or intussusception in the setting of multiple polyps in the gastrointestinal tract. There are three primary paediatric polyposis syndromes: Juvenile polyposis syndrome (JPS), Familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome (PJS). This review will cover recent guidelines for these conditions and advances in genetic testing. Recent findings The first set of paediatric guidelines were released in 2019 by the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) for FAP, JPS and PJS. Even with advances in genetic testing, a significant proportion of patients with polyposis syndromes have no identifiable genetic mutations. Recent research has shown that polyps behave differently in patients with and without disease-causing variants, emphasizing the role of genetic testing in the diagnosis and management of polyposis syndromes. Summary Polyposis syndromes in the paediatric population are growing due to increased recognition and advances in genetic testing. A timely diagnosis and surveillance of a paediatric polyposis syndrome are pivotal for the management of disease burden and early identification of cancers within the gastrointestinal tract and beyond. Paediatricians, paediatric gastroenterologists, paediatric oncologists and paediatric surgeons should be familiar with the presentation and comorbidities of polyposis syndromes in children and adolescents. Further research into genotype-phenotype correlations is needed to tailor the care for paediatric patients with polyposis syndromes.

Hamartomatous polyposis syndromes (HPS) are a heterogeneous spectrum of diseases that are characterized by diffuse hamartomatous polyps lining the gastrointestinal (GI) tract together with extra-GI manifestations. Classical HPS includes juvenile polyposis syndrome, Peutz-Jeghers syndrome, PTEN hamartoma tumor syndrome and hereditary mixed polyposis syndrome. Patients with HPS have a higher risk of GI and extra-GI malignancies than the general population, although the underlying mechanisms remain unclear and are obviously different from the carcinogenesis of classical adenocarcinoma and colitis-associated malignancy. In this review we aimed to clarify the risks, possible mechanism and endoscopic surveillance of HPS-associated GI malignancies.

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.

BackgroundJuvenile 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 presentationA 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 inBMPR1A. 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.ConclusionsJuvenile 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.

International audience; 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.

Background Juvenile polyps are the most common type of polyps in children but are rare in adults. Inflammatory bowel disease (IBD) patients have a similar spectrum of symptoms as patients with juvenile polyps. Both patients with juvenile polyps and those with active IBD have high fecal calprotectin levels. Four cases of children with ulcerative colitis (UC) with solitary juvenile polyps and one case of an adult with UC with juvenile polyposis syndrome have been reported upon diagnosis of UC, while there have been no cases of adults with UC with solitary juvenile polyp reported in the literature. Case summary A 37-year-old man with a 12-year history of UC was admitted to our clinic because of increased stool frequency. UC was diagnosed at the age of 25. As the lesion was confined to the rectum, sulfasalazine suppositories or mesalazine suppositories were used. The patient was followed in an outpatient clinic, and colonoscopy was performed every one or two years. The latest examination was undertaken three years prior in the presence of proctitis. Recently, the patient complained of three to five bowel movements a day. There was mucus in the stool but no visible blood. Colonoscopy revealed a solitary polyp, about 1.5 cm in diameter, with a short and broad peduncle in the transverse colon surrounded by congestive and edematous mucosa. The patient had no family history of colorectal polyps or cancer. The polyp was successfully removed by endoscopic mucosal resection. Histopathological examination revealed that the polyp was a juvenile polyp without any malignant signs. Immunohistochemical staining for p53 showed wild-type expression and p53 overexpression was not detected. Ki-67 labeling index was 3%. Conclusion This is the first case of an adult UC patient with a solitary juvenile polyp at the 12-year follow-up. The correlation between juvenile polyps and the activity of IBD needs further study.

Juvenile polyposis syndrome (JPS) is a rare disease with an autosomal dominant inheritance pattern characterized by the development of multiple hamartomatous polyps in the gastrointestinal tract. The most frequent signs and symptoms are recurrent abdominal pain, rectal bleeding, anemia, and iron deficiency. The treatment of JPS is symptomatic, requiring serial endoscopic polypectomies or intestinal resections in the most severe cases. We describe the clinical case of a patient with JPS with a childhood juvenile polyposis phenotype because of a mutation on the SMAD4 gene, who received treatment with sirolimus successfully.

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. 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. 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%. 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.

Juvenile polyposis syndrome (JPS) patients can have a significantly high burden of polyposis. Patient who undergoes prophylactic colectomy for polyps not amenable to endoscopic treatments requires close clinical surveillance to negate risk of malignancy from interval polyposis.

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

Hereditary causes due to mutations and defects in certain genes account for roughly 5% to 10% of all colorectal cancers. These inherited syndromes have been associated with a 60% to 100% lifetime risk for development of colorectal cancer, depending on the genetic syndrome, and many also carry an increased risk for multiple extracolonic malignancies. In this second part of a review series on hereditary cancer syndromes, the focus will be to provide guidance on the features and management of the most commonly encountered hereditary colorectal cancers and polyposis conditions including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, and hamartomatous polyposis.

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.

Juvenile polyposis syndrome is a rare autosomal-dominant disorder characterized by multiple hamartomatous polyps in the gastrointestinal tract. It is associated with an increased risk of gastrointestinal cancer. We report the case of a 49-year-old woman presenting with proximal muscle weakness, weight loss, severe anemia, and melena. One year before, the diagnosis of a "fundic gland polyposis" was presumed after endoscopic evaluation for iron deficiency anemia had shown numerous polyps limited to the gastric mucosa. On admission, the diagnosis of dermatomyositis was made based on laboratory results with a marked elevated creatine kinase as well as the presence of characteristic clinical findings and muscle histology. Upper endoscopy revealed multiple pedunculated, edematous polyps in the stomach without apparent cancerous lesions intraluminally. Infiltration of the muscular layer was not detectable on endoscopic ultrasound. Histopathological examination of the polyps showed smooth outer surfaces and multiple dilated cystic glands, consistent with hamartomatous juvenile-type polyps. Magnetic resonance imaging revealed a peritoneal mass close to the greater curvature of the stomach, which was identified as a poorly differentiated adenocarcinoma by laparoscopic sampling. Immunohistochemical analysis of resected polyps was remarkable for a loss of SMAD4 expression, a finding that is very commonly observed in patients with gastric juvenile polyposis syndrome. Despite initial treatment response to glucocorticoids and chemotherapy, the patient died 5 months later due to progressive illness. Patients with gastric juvenile polyposis and SMAD4 mutations are at a high risk of developing gastric cancer; hence, early gastrectomy should be considered.Das juvenile Polyposis-Syndrom ist eine seltene autosomal-dominant erbliche Erkrankung, die durch multiple hamartomatöse Polypen im Gastrointestinaltrakt gekennzeichnet ist. Das Krankheitsbild ist mit einem erhöhten Risiko für die Entstehung gastrointestinaler Malignome assoziiert. Wir berichten über eine 49-jährige Patientin, die sich mit proximal betonter Muskelschwäche, Gewichtsverlust, Anämie und Meläna in unserer Klinik vorstellte. Ein Jahr zuvor hatte sich bei der endoskopischen Abklärung einer Eisenmangelanämie ein auf die Magenschleimhaut beschränkter Polypenbefall gezeigt, der als „Drüsenkörperzystenpolyposis“ interpretiert wurde. Bei deutlich erhöhter Kreatinkinase sowie passender Symptomatik und Histologie wurde die Diagnose einer Dermatomyositis gestellt. In der Gastroskopie zeigten sich multiple gestielte ödematöse Polypen ohne Hinweise auf eine eindeutig maligne intraluminale Raumforderung und ohne endosonographischem Anhalt auf wandinfiltrierendes Wachstum. Histologisch waren die untersuchten Polypen mit ihrer glatten Oberfläche und multiplen dilatierten Drüsenstrukturen vereinbar mit hamartomatösen juvenilen Polypen. Kernspintomografisch stellte sich in Nachbarschaft zur großen Magenkurvatur eine peritoneale Raumforderung dar, die nach laparoskopischer Probenentnahme als Adenokarzinom identifiziert wurde. Die immunhistochemische Untersuchung resezierter Polypen ergab eine fehlende SMAD4-Expression, was eine sehr häufige Veränderung bei Patienten mit juvenilem Polyposis-Syndrom des Magens darstellt. Nach initialem Therapieansprechen auf Glukokortikoide und Chemotherapie verstarb die Patientin fünf Monate später an ihrer progredienten Erkrankung. Patienten mit gastraler juveniler Polyposis und SMAD4-Mutation haben ein hohes Malignomrisiko, weshalb eine frühe Gastrektomie erwogen werden sollte.

Patient: Female, 49-year-old Final Diagnosis: Juvenile polyposis syndrome Symptoms: Anemia Medication:— Clinical Procedure: Surgery Specialty: Gastroenterology and Hepatology • Genetics Objective: Rare disease 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.

Menetrier's disease (MD) is a rare disease characterized macroscopically by gastric rugae thickening and microscopically by foveolar hyperplasia with glandular atrophy, resulting in luminal protein loss. Different treatment strategies, including antibiotics, prednisone, octreotide, and monoclonal antibodies, have yielded varying degrees of success. Here, we present a rare complication of MD with a gastric outlet obstruction from a large adenoma. However, prior to this complication, dramatic clinical and laboratory improvements were observed after 12 months of treatment with subcutaneous octreotide. We also present a review of the literature for the role of octreotide in the treatment of MD.

Colonic polyps are common in children presenting with bright red rectal bleeding without pain. Although these polyps are almost benign and can be removed endoscopically, a detailed clinical evaluation is necessary to identify the children who have the risk to have colorectal cancer in the future. Isolated juvenile polyps are usually single hamartomatous tumors and carry a minimal risk for cancer, whereas juvenile polyposis syndrome and Peutz–Jeghers syndrome have multiple polyps with a higher cancer incidence. Also in familial adenomatous polyposis syndrome, there is 100% risk for colorectal cancer in the adulthood. These syndromes are associated with an increased risk of extraintestinal cancers. Familial inheritance should be investigated in every child, and genetic screening and colonoscopic evaluation should be planned for the relatives of the patient. This chapter focuses on pediatric surgical perspective to colon polyps and summarizes colon anatomy and colonoscopy technic in children, genetics, polyposis syndromes, surveillance, and treatment of the colorectal polyps.

Juvenile polyposis syndrome is a rare inherited disorder that afflicts the gastrointestinal system. It usually occurs as a result of gene mutations; to date, several gene mutations, including those involving the bone morphogenetic protein receptor type IA (BMPR1A) gene, have been implicated in heralding the onset of the ailment. The disease is characterized by the infiltration of the gastrointestinal system with numerous hamartomas, which are predominantly benign. However, if left untreated, the hamartomas can undergo malignant transformations. Timely diagnosis and prompt surgical intervention are, therefore, imperative in portending favorable disease outcomes. We hereby delineate the case of a patient who presented with rectal prolapse and bleeding per rectum. Further diagnostic workup revealed the presence of polyps throughout the colon and the rectum, thereby insinuating a diagnosis of non-familial juvenile polyposis syndrome. The patient was managed through open surgery and continues to do well with no indications of disease recurrence.

A 41-year-old woman with irritable bowel syndrome symptoms presented for colonoscopy after her mother was diagnosed with multiple juvenile colon polyps positive for Bone morphogenic protein receptor type-1A ( BMPR1A ) mutation and subsequently colon cancer at age 64. Colonoscopy revealed multiple

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.

Objectives: infection with the bacteria Helicobacter pylori has been classified as class 1 carcinogen associated with increasing susceptibility of gastritis and gastric carcinoma. This study is aiming at investigating the prevalence of H. pylori in colon polyps and colon cancer lesions. A descriptive cross-sectional hospital-based study was conducted between February and June 2017. Sixty-nine formalin fixed paraffin blocks from colon polyps and colon cancer lesions to detect H. pylori using immunohistochemistry technique.Results: Of the Sixty-nine patients included in the study, 39 (56.5%) males and 30 (43.5%) were females, their age ranged from 21 to 80 years with a mean age of 47.1 ± 19.7. Of the 69 colon polyps and colon cancer cases, 44 (63.8%) were diagnosed as adenocarcinoma, 10 (14.5%) colitis, 15 (21.7%) juvenile polyposis syndrome. The results of immunohistochemistry technique showed the presence of 16 (23.2%) positive patients for H. pylori infection. Of these 16, 13 (81.3%) patients were off those diagnosed with adenocarcinoma and the remaining 3 (18.7%) patients were diagnosed with juvenile polyps. the results of H. pylori detection among the different colon polyps and colon cancer diagnosis was showing a statistically significant association for H. pylori infection and adenocarcinoma, P value 0.028.

Hereditary mixed polyposis syndrome (HMPS) is a rare autosomal dominant disorder characterized by a mixture of typical and/or atypical juvenile polyps, adenomas and hyperplastic polyps, resulting in an increased risk of colorectal cancer. In HMPS, four different germline BMPR1A variants from five unrelated families have been reported. This study is the first to report HMPS within a Japanese family. The proband underwent repeated colonoscopic polypectomies over a 5-year period, since the age of 67. Histological examination of these resected polyps revealed adenomas, juvenile-like polyps and hyperplastic changes. Genetic testing was conducted to identify the causative genes for hereditary gastrointestinal cancer syndromes, including BMPR1A. We detected a germline variant, c.72_73delGA, in BMPR1A. The proband’s elder brother, younger sister and nephew have also undergone repeated colonoscopic polypectomies at other clinics. His sister and nephew underwent genetic testing, and the same BMPR1A variant was identified., We report a novel germline BMPR1A variant, c.72_73delGA, in a Japanese family with HMPS-2.

Juvenile polyposis syndrome is an autosomal-dominant disorder characterized by the presence of hundreds of gastrointestinal polyps. The genes most commonly found are BMPR1A and SMAD4. The latter has been linked to vascular malformations and hereditary hemorrhagic telangiectasias. We present the case of a young woman diagnosed with juvenile polyposis syndrome and SMAD-4 mutation, who developed embolic strokes from an atrial septal aneurysm and patent foramen ovale. This case highlights the propensity of patients with juvenile polyposis syndrome and SMAD-4 mutations to develop atrial septal aneurysm and patent foramen ovale, and warrants appropriate cardiac workup in at-risk individuals.

Hereditary hemorrhagic telangiectasia (HHT), also called Osler-Weber-Rendu syndrome, is an autosomal dominant genetic disease that affects the vasculature of numerous organs. The prevalence of HHT is estimated to be between 1.5 and 2 persons per 10,000. While there is still much to learn about this condition, there is an increasing understanding its underlying pathophysiology, genetic basis, presentations, and management. Recognizing that the clinical manifestations of HHT can involve a number of organ systems will provide clinicians with a higher index of suspicion for the disease. This early diagnosis and genotyping can greatly reduce mortality for a patient with HHT through appropriate screening for complications. This review will focus on the gastrointestinal manifestations of HHT and how these can dictate treatment and prognosis.

The risk of malignant tumors developing in association with juvenile polyposis syndrome (JPS) was evaluated to explore the optimal treatment for this rare disease. We reviewed the data on JPS cases reported in Japan between January, 1971 and March, 2016. A total of 171 cases were evaluable. Of these 171 patients, 83 (48.5%) were female and the median age at diagnosis was 28 years (range 1–80 years). The polyps were located in the stomach alone (n = 62; 36.3%), in the stomach and intestine (n = 47; 27.4%), or in the colorectum alone (n = 62; 36.3%). The sites of malignant tumors were the stomach (n = 31), colorectum (n = 29), small intestine (n = 2), breast (n = 1), and thyroid (n = 1). The lifetime risk (at 70 years) of any malignant tumor was 86.2%. The lifetime risk of gastric cancer was 73.0% and that of colorectal cancer was 51.1%. The risk of these cancers developing was dependent on the type of polyp distribution. Long-term surveillance of the stomach and colorectum based on the phenotype of JPS seems a reasonable approach to monitor these patients for the development of malignant tumors.

Aims Massive gastric polyposis is a rare entity that is often associated with juvenile polyposis syndrome (JPS). The aim of this study was to evaluate the clinicopathological features of 22 patients with abundant gastric juvenile-type or hyperplastic-like polyps. Methods and results The study included 12 males and 10 females with a median age of 48 years (range: 13–79 years). Fourteen (64%) patients carried a diagnosis of JPS, and three had prior gastrointestinal adenocarcinomas. Patients without known JPS presented at an older median age (60 years versus 40 years; P = 0.0068). Clinical symptoms included nausea, vomiting, and abdominal pain; 23% of patients were asymptomatic. Eighteen cases showed complete or near-complete carpeting of the gastric mucosa by innumerable polyps, ranging from a few millimetres to ~100 mm. Most polyps formed long, bulbous projections and had characteristic histological features, including a smooth outer contour, prominent stromal oedema, and widely spaced, often cystically dilated glands lined by foveolar epithelium; some polyps had less stroma and more hyperplastic foveolar epithelium. All had normal underlying or adjacent mucosa. Four (18%) cases harboured adenocarcinoma, and seven (32%) others showed dysplasia. SMAD4 immunohistochemical staining showed patchy loss in polyps from 19 of 20 cases tested. Five of six (84%) patients tested had a germline SMAD4 mutation. Conclusions Massive gastric juvenile-type polyposis can occur in patients with and without known JPS, and may mimic different conditions, such as other polyposis syndromes and Menetrier disease. Pathologists play an important role in disease classification, as some patients lack a family or personal history of JPS, have few if any colonic polyps, and may not harbour diagnostic germline mutations.

Gastric cancer is a common disease worldwide, typically associated with acquired chronic inflammation in the stomach, related in most instances to infection by Helicobacter pylori. A small percentage of cases occurs in familial clusters, and some of these can be linked to specific germline mutations. This article reviews the historical background to the current understanding of familial gastric cancer, focuses on the entity of hereditary diffuse gastric cancer, and also reviews the risks for gastric cancer related to a number of other familial genetic diseases.

Highlights • The development of polyps is a rare genetic defect. • juvenile polyposis syndrome are at greater risk of colorectal and gastric cáncer. • The only treatment to avoid the risk of malignancy is total resection., Introduction Juvenile polyposis syndrome it is an uncommon autosomal dominant inherited condition. Hamartomatous polyps can affect the entire gastrointestinal tract but usually predominates in the colon. We introduce a case of juvenile polyposis syndrome presented with massive gastric polyposis that requires a total gastrectomy. Case presentation A 22-year-old man presented symptoms of chronic upper gastrointestinal bleeding. Gastroscopy showed massive gastric polyposis. Initially endoscopic polypectomy was performed, but due to the progressive symptoms, a total gastrectomy was then performed. Histology confirmed massive gastric juvenile polyposis. Conclusion Massive gastric polyposis it is an uncommon manifestation of juvenile polyposis syndrome.

Hereditary gastrointestinal (GI) cancer syndromes due to specific germline mutations are characterized by an increased risk of GI tract malignancies, extra-GI tract cancers, and benign abnormalities. These syndromes include Lynch syndrome, familial adenomatous polyposis, juvenile polyposis syndrome, Peutz-Jeghers syndrome, Cowden syndrome, hereditary diffuse gastric cancer, and hereditary pancreatic cancer. Timely identification of the responsible genes will help predict future cancer risks in these patients and their family members. Early detection of cancers is possible with appropriate screening methods; risk-reducing measures will help in cancer prevention. Select malignancies and benign conditions associated with these syndromes have distinctive imaging features that can aid in classifying the syndromes. Imaging also plays a pivotal role in screening and surveillance of patients as well as their at-risk relatives and is invaluable for follow-up of treated malignancies. The American College of Gastroenterology has established specific guidelines for diagnosis and management of hereditary GI cancer syndromes. Knowledge of the imaging features of various pathologic conditions and screening strategies will guide appropriate management of patients and at-risk family members. ©RSNA, 2019.

International audience; 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.

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.

Juvenile polyposis syndrome (JPS) is a non-cancerous benign growth predominant in a young population with an estimated incidence of one in 1, 00,000 to 1, 60,000 per year. It is a rare genetic presentation, which can occur sporadically as well. There is a 39% evident risk of developing colorectal carcinoma. Herein, we present an unusual case of a 13-year-old girl from a rural area with a negative family history of juvenile polyposis, who had complaints of rectal prolapse and rectal bleeding which were more pronounced after defecation. Her contrast computed tomography (CT) scan revealed a distended large bowel studded with multiple juvenile polyps throughout, the largest of which was detected on the mid rectum. Colo-colic intussusception was also found due to a large polyp at the hepatic flexure, inferiorly extending up to ascending colon and caecum. Pan proctocolectomy with ileoanal J pouch anastomosis was performed, bearing in mind the risk for colorectal cancer and her general state of health.

Background Juvenile polyposis syndrome (JPS) is a rare genetic disorder due to germline mutations in BMPR1A or in SMAD4 that are both tumor suppressor genes. The main clinical manifestation is the presence of multiple hamartomatous polyps preferentially located in gastrointestinal tract, mostly in colorectal site. The polyps can degenerate and lead to inherited malignant tumors. Materials and Methods Among 3157 patients with malignant and benign tumors diagnosed in Brazzaville teaching hospital, 43 persons with polyposis in colorectal tube were recruited. The positive diagnosis was based on endoscopic examination, World Health Organization and JASS guidelines clinical criteria, histopathological analysis and next-generationsequencing of DNAs extracted from peripheral blood of the patients. Results Among 43 patients having polyposis, two were male patients identified with JPS representing 4.65% of polyposis and 0.06% of all tumors. Histological examination revealed typical JPS features. In those two males, whole genome comparative microarray did not identify relevant copy number imbalances. DNA sequencing of a comprehensive gene cancer genes panel identified specific mutations in the BMPR1A and SMAD4 genes. Conclusion We have shown that BMPR1A and SMAD4 gene disorders are responsible for JPS in congolese patients as well and a novel mutation has been identified in one individual. As the condition predisposes highly to hereditary colorectal cancer, a comprehensive assessment of the JPS including genetic testing should be implemented in order to facilitate early diagnosis in Congo Brazzaville.

Myhre syndrome (MIM 139210) is a rare autosomal-dominant disorder characterised by short stature, brachydactyly, facial dysmorphism (short palpebral fissures, prognathism and short philtrum), developmental delay with mental retardation or/and behavioural troubles, progressive deafness of mixed conductive and sensory type and a trio of thickened skin, generalised muscle hypertrophy and restricted joint mobility. Life-threatening complications (obesity, arterial hypertension and bronchopulmonary insufficiency) are observed in the course of the disease leading to an early death. In 2011, SMAD4 (SMAD family member 4) has been identified as the disease-causing gene. All mutations identified so far are de novo heterozygous missense mutations, mainly involving Ile500. While SMAD4 inactivation is reported in juvenile polyposis syndrome with increased colorectal cancer risk, no increased tumoural risk has been observed in Myhre syndrome. SMAD4 is a key mediator of TGF-β (transforming growth factor beta)/BMP (bone morphogenetic protein) signalling and the understanding of the consequences of SMAD4 mutations during development will decipher new regulatory network related to TGF-β/BMP signalling. Key Concepts Myhre syndrome is a rare genetic condition of autosomal-dominant inheritance due to SMAD4 mutations affecting Arg496 or Ile500 residues. Myhre syndrome is characterised by short stature, brachydactyly, facial dysmorphism, developmental delay, progressive deafness and a trio of thickened skin, generalised muscle hypertrophy and restricted joint mobility. Myhre syndrome is associated to a risk of early death due to possibly life-threatening health conditions (obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis and pericarditis). Similar to mothers against decapentaplegic family member 4 (SMAD4) encodes the common partner SMAD of the eight-member family of SMAD proteins. SMAD4 aggregates into heterotrimer with the receptor-regulated SMADs (R-SMADs) once they are activated by phosphorylation by transmembrane serine–threonine receptor kinases in response to stimulation of TGF-β, activin or BMP receptor pathways. The SMAD4 mutations identified in Myhre syndrome are expected to disturb the monoubiquitination of SMAD4 which occurs at Lys519 and also to disturb the function of the SMAD heterotrimer which regulates the expression of target genes. Germline heterozygous mutations in SMAD4 are known to cause juvenile polyposis syndrome (JPS) and JPS-hereditary hemorrhagic telangiectasia. The SMAD4 mutations observed in JPS and JPS-HHT include nonsense, missense, splice-site changes and deletions, consistent with a loss-of-function mechanism. Increased tumoural risk has not been observed so far in Myhre syndrome. The development of tissue-specific mouse models of Smad4 deficiency further highlighted the important role of Smad4 in a wide range of embryonic developmental processes. Keywords: development; life-threatening complications; SMAD4; TGB/BMP; ossification

While it is true that only a small proportion of patients develop gastrointestinal cancer in the setting of an inherited syndrome, it is important for the medical oncologist to recognize this unique group of patients for several reasons. First, genetic testing of the tumor can have implications for the patient’s prognosis and may help tailor chemotherapy in this age of personalized cancer medicine. Second, affected patients are often at risk for other malignancies either within the gastrointestinal tract or involving other organ systems and, as such, are in need of close clinical surveillance. Lastly, the oncologist is in an excellent position to encourage genetic counseling and testing of at-risk family members. In this chapter we will review familial adenomatous polyposis (FAP) syndrome and hereditary nonpolyposis colon cancer (HNPCC), aka Lynch syndrome, in some detail. We will also discuss polyposis syndromes other than FAP, namely, Peutz-Jegher syndrome and juvenile polyposis as well as hereditary diffuse gastric cancer and inherited pancreatic cancer syndromes.

The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Polyposis Working Group developed recommendations to assist clinicians and health care providers with appropriate management of patients with juvenile polyposis. This is the first juvenile polyposis Position Paper published by ESPGHAN with invited experts. Many of the published studies were descriptive and/or retrospective in nature, consequently after incorporating a modified version of the GRADE system many of the recommendations are based on expert opinion. This ESPGHAN Position Paper provides a guide for diagnosis, assessment, and management of juvenile polyposis syndrome in children and adolescents, and will be helpful in the appropriate management and timing of procedures in children and adolescents. The formation of international collaboration and consortia is proposed to monitor patients prospectively to advance our understanding of juvenile polyposis conditions.

Solitary juvenile polyp is a nonneoplastic condition but needs to be differentiated from a premalignant condition juvenile polyposis syndrome.

Gastrointestinal “juvenile-like (inflammatory/hyperplastic) mucosal polyps” (JLIHMPs) have been proposed as a neurofibromatosis type 1 (NF1)-specific gastrointestinal manifestation. Juvenile polyposis syndrome (JPS) has also been reported in a NF1 patient, harboring concurrent NF1 and SMAD4 germline mutations. Additionally, NF1-like cafe-au-lait spots have been described in biallelic mismatch repair deficiency, another condition featuring gastrointestinal polyps. The SMAD4 and BMPR1A genes that are involved in 50–60% of JPS cases have not been investigated in the ~ 20 published cases of NF1-associated JLIHMPs with the exception of the abovementioned patient with concomitant JPS and NF1. NF1 defects have been found in the only two cases exhaustively tested. Therefore, JLIHMP has been questioned as an independent, NF1-specific entity. Incidental associations between NF1 and gastrointestinal polyposes at risk for gastrointestinal carcinoma should not be overlooked, given their implications in terms of clinical surveillance. We describe two patients featuring JLIHMPs in clinically/genetically proven NF1, in the absence of SMAD4 and BMPR1A mutations. In one case, the intervening mucosa was markedly inflamed, unlike JPS. We suggest that JLIHMP probably represents a gastrointestinal lesion specific to NF1.

Juvenile polyposis syndrome (JPS) may coexist with hereditary hemorrhagic telangiectasia (HHT) due to implication of the SMAD4 gene in a subset of both diseases. To the best of our knowledge, we present the first case in the radiologic literature on the MRI findings in a patient with this rare combined diagnosis undergoing workup for burden of disease.

Patients with germline mutations in SMAD4 can present symptoms of both juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT): the JP-HHT syndrome. The complete phenotypic picture of this syndrome is only just emerging. We describe the clinical characteristics of 14 patients with SMAD4-mutations. The study was a retrospective, register-based study. SMAD4 mutations carriers were identified through the Danish HHT-registry, the genetic laboratories - and the genetic departments in Denmark. The medical files from relevant departments were reviewed and symptoms of HHT, JPS, aortopathy and family history were noted. We detected 14 patients with SMAD4 mutations. All patients had polyps removed and 11 of 14 fulfilled the diagnostic criteria for JPS. Eight patients were screened for HHT-symptoms and seven of these fulfilled the Curacao criteria. One patient had aortic root dilation. Our findings support that SMAD4 mutations carriers have symptoms of both HHT and JPS and that the frequency of PAVM and gastric involvement with polyps is higher than in patients with HHT or JPS not caused by a SMAD4 mutation. Out of eight patients screened for aortopathy, one had aortic root dilatation, highlighting the need for additional screening for aortopathy.

Colorectal polyps are among the common causes for rectal bleeding in children. We studied the clinical, colonoscopic, and histopathological features of colorectal polyps and polyposis syndrome in Indian children and adolescents. Medical records of children and adolescents with colorectal polyps and polyposis syndrome were retrospectively reviewed from 2001 to 2014 at Department of Gastroenterology, in large tertiary care center of Mumbai. A total of 120 patients were found to have colonic polyps during study period. Mean age of presentation in children was 7.31 ± 4.05 years (range 2 to 19 years), with male-to-female ratio of 2.16:1. Rectal bleeding was presenting symptom in 95.8 % with mean duration of 12.6 ± 15 months. Majority of polyps (77.5 %) were juvenile, and 97.2 % were located in left colon. Solitary polyps were seen in 76.6 %, multiple polyps in 11.6 %, juvenile polyposis syndrome in 6.6 %, familial adenomatous polyposis in 4.2 %, and Peutz-Jeghers syndrome in 0.8 % of the children. The polyposis syndrome group had higher age at presentation (p = 0.00006), greater likelihood of anemia, abdominal pain, and diarrhea (p = 0.0001, 0.0002, and 0.0051, respectively). Likelihood of adenomatous change in polyps was higher in polyposis syndrome group (p = 0.0003). Left colonic polyps were more common in non-polyposis group, whereas pan-colonic polyps were more common in polyposis syndrome group (p

Gastrointestinal polyps are commonly encountered during childhood and are one of the most common causes of rectal bleeding in this age group. Most polyps are benign and located in the colon, with the most frequent type being juvenile polyps. However, in older pediatric patients, if multiple polyps are present, in patients who have a positive family history, or if polyps are located outside of the colon, either adenomatous polyps or polyps associated with genetic abnormalities are more common.Imaging techniques such as ultrasound and computed tomographic colonoscopy have recently been utilized to identify simple juvenile colonic polyps in children with rectal bleeding in whom there is a high index of suspicion. Colonoscopy with polypectomy is still required for histologic evaluation and resection of the polyp. There have been significant advances in genetic testing and management of hereditary gastrointestinal cancer syndromes with onset in childhood or adolescence that may ultimately reduce long-term morbidity and mortality. In addition to enhanced gastrointestinal and extraintestinal malignancy screening for affected individuals, specific gene mutations within a given condition such as adenomatous polyposis coli may predict clinical course and timing of specific interventions such as colectomy. In other conditions such as phosphatase and tensin homolog hamartoma tumor syndrome, phenotype may not be predicted by genotype.Pediatricians, pediatric gastroenterologists, and adult gastroenterologists caring for children should understand how to differentiate benign polyps in the pediatric age group from those associated with a higher risk of complications including recurrence risk and risk of development of intestinal or extraintestinal malignancy. Recent advances in genetic testing, as well as development of consensus guidelines, are key in the identification, screening, and follow-up of children and adolescents with polyposis syndromes.

Identifying individuals with a genetic predisposition to developing familial colorectal cancer (CRC) is crucial to the management of the affected individual and their family. In order to do so, the physician requires an understanding of the different gene mutations and clinical manifestations of familial CRC. This review summarises the genetics, clinical manifestations and management of the known familial CRC syndromes, specifically Lynch syndrome, familial adenomatous polyposis, MUTYH-associated neoplasia, juvenile polyposis syndrome and Peutz-Jeghers syndrome. An individual suspected of having a familial CRC with an underlying genetic predisposition should be referred to a familial cancer centre to enable pre-test counselling and appropriate follow up.

Several polyposis syndromes of the gastrointestinal tract have been recognized which carry increased risk for cancer and have a genetic predisposition. There is a paucity of literature regarding the occurrence and the burden of colonic polyposis syndromes in the Indian subcontinent. This study attempts to highlight this hitherto unaddressed burden and the associated increased risk for inherited colonic cancer in this geographical location. A retrospective study of various colonic polyposis syndromes encountered at a tertiary centre in South India over a period of 8 years (2005 to 2012) was performed. The diagnosis in each case was made histologically with clinicopathological correlation. Fifty cases were identified as belonging to a colonic polyposis syndrome, during the study period. There were 27 males and 23 females with a median age of 36.5 years (range 19 months to 78 years). The commonest syndrome was familial adenomatous polyposis (n = 27; 54 %) followed by Peutz-Jeghers syndrome (n = 11), attenuated familial adenomatous polyposis (n = 7), juvenile polyposis syndrome (n = 3), hyperplasic polyposis syndrome (n = 1) and Cronkhite-Canada syndrome (n = 1). Colonic malignancy was documented at first presentation in 22 patients (44 %). Our study highlights the various colonic polyposis syndromes encountered in a tertiary care institution in Southern India.

Histopathologists are critical in the diagnosis of hereditary gastrointestinal tumours. This is increasingly important as genetic testing becomes more available and the benefits of anti-cancer surveillance in those at increased risk are realised. Cancer genetics services should include pathologists and be organised on multidisciplinary team lines. Hereditary cancer syndromes predispose to tumours throughout the GI tract. Lynch syndrome is the most prevalent hereditary GI cancer condition, responsible for ∼3.3% of all colorectal as well as other GI and extra-intestinal cancers. Tumour tests to diagnose Lynch syndrome are important in guiding genetic testing, and can be used systematically to screen cancers for the condition. Familial adenomatous polyposis and all the other forms of hereditary polyposis put together account for

Colorectal cancer (CRC) accounts for over 8% of all deaths annually worldwide. Between 2 and 5% of all CRCs occur due to inherited syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, Peutz–Jeghers syndrome, juvenile polyposis and Cowden/PTEN hamartoma syndrome. In addition, serrated polyposis is a clinically defined condition characterised by multiple colorectal serrated polyps and an increased risk of CRC but the genetics are not known. In most hereditary CRC syndromes, polyps undergo carcinogenesis, but the exact route to carcinoma seems to differ between the conditions. Discovery of the key germline mutations in these syndromes has been instrumental to our understanding of the underlying molecular mechanisms of colorectal carcinogenesis. This review summarises the genetic and pathological alterations in hereditary CRC syndromes.