Juvenile polyposis syndrome in children: The impact of SMAD4 and BMPR1A mutations on clinical phenotype and polyp burden.

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.

ACG Clinical Report and Recommendations on Transition of Care in Children and Adolescents With Hereditary Polyposis Syndromes.

Transition of care (TOC) in adolescents and young adults (AYAs) with chronic gastrointestinal disorders has received increased attention, especially in those with inflammatory bowel disease. AYAs with hereditary polyposis syndromes are a heterogeneous group of patients with overlapping and complex medical needs. These patients are particularly vulnerable because of the risk of loss of continuity of care and subsequent poor disease outcomes. The Pediatric Committee of the American College of Gastroenterology commissioned a report with recommendations on TOC in AYAs with hereditary polyposis syndromes. This report aims at achieving best practice by both pediatric and adult gastroenterologists despite the paucity of published evidence in this population reflected in the included PRISMA report. Therefore, the group extrapolated findings from the literature related to other chronic gastrointestinal disorders, and a high degree of expert consensus was scored for all recommendations. The report addresses TOC through identifying shared domains followed by specific recommendations in disease management, including models of care, providers and patient and socioeconomic factors relevant to TOC. Areas of strong emphasis include the need for early planning, flexibility in the transition process to maintain continuity during major surgical procedures, patient and family psychological readiness, liaison among team members addressing transition, and changing insurance coverage in this population.

Polyp Progression in Paediatric Patients With Familial Adenomatous Polyposis: A Single-centre Experience.

OBJECTIVES: Prophylactic colectomy at a premalignant stage is the cornerstone of management of familial adenomatous polyposis (FAP). Before surgery, colonoscopy surveillance is recommended in children with FAP. This study aimed to examine the natural history of FAP in children by evaluating adenoma progression and factors influencing timing of colectomy. METHOD: Patients with FAP younger than 18 years at first surveillance colonoscopy and who had undergone more than 1 colonoscopy were identified. Demographic, endoscopic, genetic, and surgical data were retrieved. Cumulative adenoma (polyp) counts were obtained while accounting for any polypectomies during the study period. The rate of polyp progression and factors influencing the timing of colectomy were evaluated. RESULTS: Eighty-four patients (50% boys; mean age at first colonoscopy 13 years [standard deviation 1.97]) were identified, of which 83 had a family history of FAP. At first colonoscopy, 67 (79%) had <100 adenomas and 29 (35%) had colonic polyps identified despite rectal sparing. The median rate of polyp progression per patient was 12.5 polyps/year (range 0-145). Of the 45 (54%) patients who had undergone surgery, 41 (91%) underwent colectomy with ileorectal or ileodistal sigmoid anastomosis. Polyp progression did not alter the choice of surgical intervention in any patient. CONCLUSION: Our results suggest that adenoma number remains relatively stable in the majority of children under surveillance. Tailored surveillance intervals according to phenotype are a more appropriate strategy as recommended by recently published guidelines.

Management of Juvenile Polyposis Syndrome in Children and Adolescents: A Position Paper From the ESPGHAN Polyposis Working Group.

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.

Management of Familial Adenomatous Polyposis in Children and Adolescents: Position Paper From the ESPGHAN Polyposis Working Group.

Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, characterized by the development of hundreds to thousands of adenomas in the colorectum, with implications in children and adolescents. Almost all adult patients will develop colorectal cancer if they are not identified and treated early enough. Identifying and screening for FAP commences in adolescence. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the adenomatous polyposis (APC) gene. This European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) position paper provides a guide for diagnosis, assessment, and management of FAP in children and adolescents.This is the first position paper regarding FAP published by ESPGHAN. Literature from PubMed, Medline, and Embase was reviewed and in the absence of evidence, recommendations reflect the opinion of paediatric and adult experts involved in the care of polyposis syndromes. Because many of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, these of the recommendations are supported on expert opinion. This position paper will instruct on the appropriate management and timing of procedures in children and adolescents with FAP.

Management of Peutz-Jeghers Syndrome in Children and Adolescents: A Position Paper From the ESPGHAN Polyposis Working Group.

Peutz-Jeghers syndrome (PJS) is a well-described inherited syndrome, characterized by the development of gastrointestinal polyps, and characteristic mucocutaneous freckling. Development of small bowel intestinal polyps may lead to intussusception in children may require emergency laparotomy with potential loss of bowel. Gastrointestinal polyps may lead to bleeding and anemia. This European Society for Paediatric Gastroenterology Hepatology and Nutrition position paper provides a guide for diagnosis, assessment, and management of PJS in children and adolescents and guidance on avoiding complications from PJS or from the endoscopic procedures performed on these patients.This is the first position paper regarding PJS published by European Society for Paediatric Gastroenterology Hepatology and Nutrition. Literature from PubMed, Medline, and Embase was reviewed and in the absence of evidence, recommendations reflect the opinion of pediatric and adult experts involved in the care of polyposis syndromes. Because many of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, some of the recommendations are based on expert opinion. This position paper will be helpful in the appropriate management and timing of procedures in children and adolescents with PJS.

Use of Infliximab Biosimilar Versus Originator in a Pediatric United Kingdom Inflammatory Bowel Disease Induction Cohort.

OBJECTIVES: The aim of the study was to summarize short-term effectiveness, safety, and cost of using infliximab biosimilar (IFX-B) drugs, (Inflectra [Hospira] and Remsima [NAAP]) compared to originator infliximab (IFX-O) (Remicade [MSD]) in biologic naive pediatric inflammatory bowel disease in the United Kingdom. METHODS: Prospective audit of patients starting anti-tumour necrosis factor (TNF) therapy. Disease severity, response to treatment, and remission rate was measured by Pediatric Crohn's Disease Activity Index (PCDAI) and/or Physician Global Assessment. RESULTS: Between March 2015 and February 2016, 278 patients (175 IFX-O, 82 IFX-B, and 21 Adalimumab) were started on anti-TNF therapy. This was compared with collected data on 398 patients started on IFX-O from 2011 to 2015. At initiation, median PCDAI was 36 (20,48) (n = 42) in the IFX-O group and 28 (20,40) (n = 29) in the IFX-B group, (P = 0.08). Immunosuppression rates were similar: 150/175 (86%) for IFX-O and 65/82 (79%) for IFX-B (P > 0.05). Post induction, median PCDAI score was 5 (0,11) (n = 19) and 0 (0,8) (n = 15) in the IFX-O and IFX-B groups, respectively (P = 0.35). There was no difference in response to treatment using Physician Global Assessment 85% (n = 28) in IFX-O group and 86% (n = 19) in IFX-B group (P > 0.05). Adverse events at initiation and post induction were not different between both groups (P > 0.05). Using conservative calculations, £875,000 would have been saved for a 1-year period with universal adoption of biosimilars in patients who were instead treated with IFX-O. CONCLUSIONS: IFX-B is likely as effective as IFX-O in treating IBD in comparable pediatric populations. Sites should adopt infliximab biosimilar for new starts due to cost reduction with no difference in other parameters.

Diagnostic error in children presenting with acute medical illness to a community hospital.

OBJECTIVE: To determine incidence and aetiology of diagnostic errors in children presenting with acute medical illness to a community hospital. DESIGN: A three-stage study was conducted. Stage 1: retrospective case note review, comparing admission to discharge diagnoses of children admitted to hospital, to determine incidence of diagnostic error. Stage 2: cases of suspected misdiagnosis were examined in detail by two reviewers. Stage 3: structured interviews were conducted with clinicians involved in these cases to identify contributory factors. SETTING: UK community (District General) hospital. PARTICIPANTS: All medical patients admitted to the paediatric ward and patients transferred from the Emergency Department to a different facility over a 90-day period were included. MAIN OUTCOME MEASURES: Incidence of diagnostic error, type of diagnostic error and content analysis of the structured interviews to determine frequency of emerging themes. RESULTS: Incidence of misdiagnosis in children presenting with acute illness was 5.0% (19/378, 95% confidence interval (CI) 2.8-7.2%). Diagnostic errors were multi-factorial in origin, commonly involving cognitive factors. Reviewers 1 and 2 identified a median of three and four errors per case, respectively. In 14 cases, structured interviews were possible; clinicians believed system-related errors (organizational flaws, e.g. inadequate policies, staffing or equipment) contributed more commonly to misdiagnoses, whereas reviewers found cognitive factors contributed more commonly to diagnostic error. CONCLUSIONS: Misdiagnoses occurred in 5% of children presenting with acute illness and were multi-factorial in aetiology. Multi-site longitudinal studies further exploring aetiology of errors and effect of educational interventions are required to generalize these findings and determine strategies for mitigation.

Endoscopy in pediatric polyposis syndromes: why, when and how.

Single or multiple polyps are frequently encountered during colonoscopy among children and adolescents and may be indicative of hereditary polyposis syndrome (HPS). The management of children with single or multiple polyps is guided by the number of polyps, their distribution and the histological findings. Children with HPS carry a high risk of complications, including intestinal and extra-intestinal malignancies. The goals of surveillance in pediatric HPS are to treat symptoms, monitor the burden of polyps and prevent short- and long-term complications. Therefore, the management of children with HPS is based on therapeutic endoscopy. The strategy of therapeutic endoscopy is a careful assessment and characterization of the polyps and performing polypectomies using advanced endoscopic techniques. A multidisciplinary approach, comprising clinical, interventional endoscopy, cancer surveillance and support of familial and emotional aspects is essential in the management of children with HPS.

Feasibility of video capsule endoscopy in the management of children with Peutz-Jeghers syndrome: a blinded comparison with barium enterography for the detection of small bowel polyps.

OBJECTIVES: Peutz-Jeghers syndrome (PJS) in children may present with anaemia, intussusception, or obstruction from an early age and surgery is common. Prophylactic polypectomy may reduce subsequent complications. Traditional barium enterography (BE) has poor sensitivity and requires significant radiation. We compared the performance of capsule endoscopy (CE) with BE in children with PJS. MATERIALS AND METHODS: Children with PJS (ages 6.0-16.5 years) were prospectively recruited and underwent BE followed by CE, each reported by expert reviewers blinded to the alternate modality. Number of "significant" (>10 mm) and total number of polyps were recorded. Child preference was assessed using a visual analogue questionnaire. Definitive findings were assessed at laparotomy or enteroscopy, when performed. RESULTS: There was no significant difference for >10 mm polyp detection. Six polyps were found in 3 children by both modalities: 3 polyps in 2 children at CE, 3 polyps in 1 child at BE (P=0.50). Re-review of 1 CE identified 3 polyps that were missed in 1 child at initial reading. Significantly more <10 mm polyps were identified by CE than BE: 61 vs 6 (P=0.02). CE was significantly more comfortable than BE (median score CE 76 [interquartile range 69-87] vs BE 37 [interquartile range 31-68], P=0.03) and was the preferred investigation in 90% (P=0.02). CONCLUSIONS: CE is a feasible, safe, and sensitive test for small bowel polyp surveillance in children with PJS. It is significantly more comfortable than BE and is the preferred test of most children for future surveillance. There is a learning curve for reporting CE studies in PJS and appropriate training is essential.

Practical management of polyposis syndromes.

Hereditary bowel tumours are usually part of a distinct syndrome which require management of both intestinal and extra-intestinal disease. Polyposis syndromes include: Familial adenomatous polyposis, MUTYH-associated polyposis, Serrated polyposis syndrome, Peutz-Jeghers syndrome, Juvenile polyposis syndrome and PTEN-hamartomatous syndromes. Of all colorectal cancers (CRC), 5%-10% will be due to an underlying hereditary CRC syndrome. Diagnosis and management of polyposis syndromes is constantly evolving as new scientific and technological advancements are made with respect to identifying causative genes and increased sophistication of endoscopic therapy to treat polyps. This, in addition to data yielded from meticulous record-keeping by polyposis registries has helped to guide management in what are otherwise relatively rare conditions. These data help guide clinical management of patients and their 'at-risk' relatives. Diagnosis is both genetic where possible but clinical recognition is key in the absence of an identifiable causative gene. Furthermore, some syndromes can overlap which can additionally complicate diagnosis. The principle goals of polyposis management are first to manage and treat the presenting patient and then to identify 'at-risk' patients, through screening and predictive genetic testing, endoscopic surveillance to allow therapy and guide surgical prophylaxis. Due to the complexity of diagnosis and management, patients and their families should be referred to a genetics centre or a polyposis registry where dedicated management can take place.