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.

Mucosal prolapse syndrome mimicking Peutz-Jeghers syndrome in a pediatric patient.

Mucosal prolapse syndrome (MPS) is a rare group of benign conditions characterized by a set of unifying histologic findings thought to be the result of repeated mucosal shearing and submucosal vascular congestion caused by straining. This set of conditions is often misdiagnosed as other polyposis syndromes, inflammatory bowel disease, or malignancy due to its clinical presentation, appearance, and rarity. We report a case of a 15-year-old male who presented with painless rectal bleeding. He was found to have four rectal polyps thought to be due to Peutz-Jeghers syndrome. A repeat colonoscopy with biopsies a year later revealed a diagnosis of MPS. Our case highlights the morphologic similarity between hamartomatous polyp and mucosal prolapse histology. Since MPS is a rare diagnosis even among the adult population, it has not been well described in pediatrics. This syndrome should be on the differential diagnosis for pediatric rectal polyps to prevent unnecessary invasive testing and a delay in treatment.

Polygenic early-onset colorectal cancer in pediatric patients.

Colorectal cancer in the pediatric population is a rare but transpirable phenomenon. The occurrence should prompt suspicion for underlying genetic mutations in the setting of a hereditary cancer predisposition syndrome. In this series, we outline three pediatric patients with colonic adenocarcinoma who were found to have one or more germline mutations. The presence of compound mutations may lead to a hypermutator phenotype resulting in earlier presentation of colorectal cancer in childhood and adolescence. The diagnosis of colorectal cancer in pediatric patients warrants timely recognition, multigene panel testing, genetic counseling for the patient and family, and increased surveillance for intestinal and extra-intestinal tumors.

Effectiveness and Complication Rate of Percutaneous Endoscopic Gastrostomy Placement in Pediatric Oncology Patients.

PURPOSE: Malnutrition is a significant issue for pediatric patients with cancer. We sought to evaluate the effectiveness and complication rate of percutaneous endoscopic gastrostomy (PEG) placement in pediatric oncology patients. METHODS: A retrospective chart review was performed on 49 pediatric oncology patients undergoing PEG placement at Johns Hopkins All Children's Hospital between 2000 and 2016. Demographic and clinical characteristics, complications, absolute neutrophil count at time of PEG placement and at time of complications, length of stay, and mortality were identified. Weight-for-age Z-scores were evaluated at time of- and six months post-PEG placement. RESULTS: The overall mean weight-for-age Z-score improved by 0.73 (p<0.0001) from pre- (-1.11) to post- (-0.38) PEG placement. Improvement in Z-score was seen in patients who were malnourished at time of PEG placement (1.14, p<0.0001), but not in those who were not malnourished (0.32, p=0.197). Site infections were seen in 12 (24%), buried bumper syndrome in five (10%), and tube dislodgement in one (2%) patient. One patient (2%) with fever was treated for possible peritonitis. There were no cases of other major complications, including gastric perforation, gastrocolic fistula, clinically significant bleeding, or PEG-related death documented. CONCLUSION: Consistent with previous studies, our data suggests a relationship between site complications (superficial wound infection, buried bumper syndrome) and neutropenia. Additionally, PEG placement appears to be an effective modality for improving nutritional status in malnourished pediatric oncology patients. However, larger prospective studies with appropriate controls and adjustment for potential confounders are warranted to confirm these findings.

Paediatric polyposis syndromes: burden of disease and current concepts.

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.

mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion.

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.

Gastric Xanthoma in the Pediatric Population: A Possible Herald for Malignancy?

Gastric xanthoma is frequently an incidental finding on upper endoscopy in adults. Gastric xanthomas (GX) can be mistaken for malignancies and warrant prompt histologic diagnosis. The underlying etiology is not fully understood; however, it has been linked to Helicobacter pylori gastritis and gastric cancer. GX in the pediatric population is largely unreported in the literature. Because of the relative rarity, documentation with case reports are essential to provide as much data as possible to see if there is a correlation between GX and malignant potential in the pediatric population. Our group is reporting two cases, a 10-year-old male and a 7-year-old male, both who presented with chronic dysphagia, upper abdominal pain, nausea, vomiting, and loss of appetite. Upper endoscopies for both patients revealed small polypoid lesions located in the antrum with foamy histiocytes on histology, leading to the diagnosis of gastric xanthoma.

Non-Surgical Management of Gastroduodenal Fistula Caused by Ingested Neodymium Magnets.

Foreign body ingestions pose a significant health risk in children. Neodymium magnets are high-powered, rare-earth magnets that is a serious issue in the pediatric population due to their strong magnetic force and high rate of complications. When multiple magnets are ingested, there is potential for morbidity and mortality, including gastrointestinal fistula formation, obstruction, bleeding, perforation, and death. Many cases require surgical intervention for removal of the magnets and management of subsequent complications. However, we report a case of multiple magnet ingestion in a 19-month-old child complicated by gastroduodenal fistula that was successfully treated by endoscopic removal and supportive care avoiding the need for surgical intervention. At two-week follow-up, the child was asymptomatic and upper gastrointestinal series obtained six months later demonstrated resolution of the fistula.

Endoscopic Balloon Dilation for Treatment of Congenital Antral Web.

Congenital antral webs are a rare but relevant cause of gastric outlet obstruction in infants and children. The condition may lead to feeding refusal, vomiting, and poor growth. Due to the relative rarity of the disease, cases of congenital antral web are frequently misdiagnosed or diagnosed with significant delay as physicians favorably pursue diagnoses of pyloric stenosis and gastric ulcer disease, which are more prevalent. We report a case of an eight-month-old female who presented with persistent non-bilious emesis, feeding difficulties, and failure to thrive and was discovered to have an antral web. The web was successfully treated with endoscopic balloon dilation, which resolved her symptoms. Two years later, the patient remains asymptomatic and is thriving with weight at the 75th percentile for her age.

Cholestasis beyond the Neonatal and Infancy Periods.

Cholestasis results from impairment in the excretion of bile, which may be due to mechanical obstruction of bile flow or impairment of excretion of bile components into the bile canaliculus. When present, cholestasis warrants prompt diagnosis and treatment. The differential diagnosis of cholestasis beyond the neonatal period is broad and includes congenital and acquired etiologies. It is imperative that the clinician differentiates between intrahepatic and extrahepatic origin of cholestasis. Treatment may be supportive or curative and depends on the etiology. Recent literature shows that optimal nutritional and medical support also plays an integral role in the management of pediatric patients with chronic cholestasis. This review will provide a broad overview of the pathophysiology, diagnostic approach, and management of cholestasis beyond the neonatal and infancy periods.