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RASopathies are a group of neurodevelopmental syndromes caused by germline variants in genes of the Ras/MAP/ERK pathway. Growth failure, neurological involvement, and pain represent the main features of these conditions. ERK signaling cascade plays a crucial role in nociception and visceral pain and it is likely implicated in the genesis of neuropathic pain and maintenance of altered pain states. We studied the prevalence of abdominal pain and functional gastrointestinal (GI) disorders in a large sample of individuals with RASopathies. A brief pain inventory questionnaire and semi-structured dedicated interview were used to investigate presence and localization of pain. A Rome IV questionnaire was used to screen for functional GI disorders. Eighty patients with clinical and molecular diagnoses of RASopathy were recruited (42 with Noonan syndrome; 17 with Costello Syndrome and 21 with cardio-facio-cutaneous syndrome). Overall, the prevalence of abdominal pain was 44% and prevalence of functional GI disorders was 78% with constipation, abdominal pain, and aerophagia being the most frequently detected ones. A significant association was found between pain and irritable bowel syndrome, functional constipation and aerophagia. Children with RASopathies have a high prevalence of functional gastrointestinal disorders. These children could represent a good in vivo model to study neuropathic pain, visceral hypersensitivity and gut-brain axis disorders.

BACKGROUND Antroduodenal manometry (ADM) and histopathology are currently employed to aid the diagnosis of pediatric intestinal pseudo-obstruction (PIPO). Limited data are available on the reliability of ADM analysis and its correlation with histopathology. We aimed to develop a protocol for enhanced analysis of ADM contractile patterns, including a scoring system, and explore whether this provided better correlation with histopathology. METHODS Children referred with suspected PIPO between April 2012-December 2019 who underwent both ADM and full-thickness biopsies were included. ADM tracings were analyzed using both standard (conventional ADM) and novel (enhanced ADM) motility parameters. A novel ADM score (GLASS score) was generated based on the enhanced ADM analysis. Conventional and enhanced ADM analyses were then correlated with histopathology. RESULTS Forty patients were included. Using conventional clinical criteria, 29 of these were diagnosed with PIPO and the other 11 with non-PIPO diagnoses. Twenty-three of the PIPO patients had abnormal histopathology: 6 myopathy, 4 neuropathy, 3 neuro-myopathy, and 10 non-specific changes. No agreement in diagnosis was found between conventional ADM analysis and histopathology (ϰ = 0.068; p = 0.197), whereas the latter significantly correlated with enhanced ADM analysis (ϰ = 0.191; p = 0.003). The enhanced ADM score was significantly higher in PIPO versus non-PIPO (16.0 vs. 8.0; p

To evaluate clinical, endoscopic, and pH-impedance measures in a cohort of children with esophageal atresia and concomitant eosinophilic esophagitis (EoE) and compared it with disease-matched controls, to identify predictive factors for the development of EoE and esophageal stricture.We reviewed 63 patients with esophageal atresia assessed for refractory upper gastrointestinal symptoms between January 2015 and September 2017 at 2 tertiary referral centers. All patients underwent upper gastrointestinal endoscopy and pH-impedance monitoring. Based on esophageal histology, patients were classified as (1) esophageal atresia without evidence of esophagitis; (2) esophageal atresia with evidence of esophagitis (including esophageal eosinophilia not meeting the criteria for EoE); (3) esophageal atresia with concomitant EoE. Age and sex matched patients with gastroesophageal reflux disease were used as disease controls.The presence of atopy and peripheral eosinophilia at baseline were significantly associated with EoE (P .05). Although there was a tendency toward an increased number of strictures in patients with esophageal atresia-EoE, this did not reach statistical significance (P = .06). Higher esophageal acid exposure time and lower baseline impedance values were significantly associated with eosinophilic infiltration (P .05 and P .01, respectively). Using logistic regression analysis, the presence of mucosal eosinophilia was the most predictive factor for stricture formation (P .05).A history of atopy and the presence of peripheral eosinophilia in patients with esophageal atresia are predictive factors for the development of EoE, which in turn is a predictive factor for stricture occurrence. Higher esophageal acid exposure time and lower baseline impedance are associated with esophageal eosinophilic infiltration, suggesting their value in selecting which patients with esophageal atresia should undergo endoscopic examination.

Introduction/Background In the last decade, Neurogastroenterology & Motility (N&M) has become a major clinical speciality in both paediatric and adult gastroenterology, encompassing gastrointestinal (GI) conditions from classic motility disorders, such as achalasia and intestinal pseudo-obstruction, to functional GI disorders (FGID). The latter represents one of the most challenging and common groups of disorders managed by both primary care practitioners and GI specialists. Appropriate transition is particularly challenging due to the complexity of this group of patients and a holistic approach, including dietetic, psychology, psychiatry, social work, physiotherapy and occupational therapy, is characteristically required. In the last year, a formal transition pathway has been developed between GOSH and UCLH N&M services. Aim We aimed to review the clinical features and the complex needs of a group of young people transitioned from a paediatric to adult N&M. Method All patients aged 13–24 transitioned to the UCLH N&M service over a period of 6 months were retrospectively reviewed. Demographic data, diagnosis, diet, biopsychosocial complexities, including multiple speciality involvement, polypharmacy, and known psychiatric and/or neurodevelopmental disorders were reported. Results Ninety-two patients (70.7% Female) under the neuro-gastroenterology adolescent and young-adult service were included into the analysis, of which 72.8% were 13–18 years of age, 23.9% 19–22 years of age and 3.3% 22–24 years of age. Twenty-seven patients (29.3%) were diagnosed with an underlying motility disorders, 59 (64.1%) with FGID and 8 (8.7%) with GI-allergy. The majority of patients (80.5%) were under one or more additional medical specialities, with 28.3% under 3 or more medical specialities. Polypharmacy was common within this cohort, with 61% of patients being on 3 or more medications, whilst only 1.1% of patients required no medication to manage the symptoms. The majority of patients (56.5%) had mental health or developmental needs, such as anxiety (25%), depression (12%), eating disorders (5.4%), and learning difficulties (14.1%). Psychological interventions were necessary in 69% of the patients, whilst dietetic interventions in 76% of patients. Summary/Conclusion Our study confirms the need for multidisciplinary support from the specialist adolescent medicine team to provide medical and psychological care when highly demanding complex patients are transitioned between a paediatric and an adult N&M services. Our data strongly supports a specialist adolescent transition hub model to ensure the delivery of developmentally appropriate healthcare, which has been shown to improve long-term health outcomes for young people with complex conditions. Although N&M expertise at GOSH lies in caring for patients up to 18 years, adolescent expertise is limited, as it is nationally. Conversely, UCLH has a unique expertise in complex and specialist adolescent care, which could assist the transition planning for those children with the most complex needs. Based on our data, children with motility and functional-GI disorders commonly require a transition plan spanning multiple adult services and require the expertise of the adolescent MDT including psychology, social work, youth work, psychiatry, physiotherapy and occupational therapy. A commissioned joint transition service between GOSH and UCLH would facilitate best practice and provide an exemplar of clinical care for young people with complex health problems.

Gastrointestinal dysmotility is a common problem in a subgroup of children with intestinal failure (IF), including short bowel syndrome (SBS) and pediatric intestinal pseudo-obstruction (PIPO). It contributes significantly to the increased morbidity and decreased quality of life in this patient population. Impaired gastrointestinal (GI) motility in IF arises from either loss of GI function due to the primary disorder (e.g., neuropathic or myopathic disorder in the PIPO syndrome) and/or a critical reduction in gut mass. Abnormalities of the anatomy, enteric hormone secretion and neural supply in IF can result in rapid transit, ineffective antegrade peristalsis, delayed gastric emptying or gastroesophageal reflux. Understanding the underlying pathophysiologic mechanism(s) of the enteric dysmotility in IF helps us to plan an appropriate diagnostic workup and apply individually tailored nutritional and pharmacological management, which might ultimately lead to an overall improvement in the quality of life and increase in enteral tolerance. In this review, we have focused on the pathogenesis of GI dysmotility in children with IF, as well as the management and treatment options.

Objectives and Study: Congenital chloride diarrhea (CCD) is a rare, autosomal recessive disorder caused by mutations in the SLC26A3 gene encoding a transmembrane chloride/bicarbonate ion exchanger mainly expressed in the apical brush border of the ileal and colonic epithelium. Lifelong, secretory, chloride-rich diarrhea and hypochloremic, hypokalemic metabolic alkalosis are characteristic. Histological evidence of bowel inflammation is not typically described in CCD and has only been reported in a few patients. Methods: We report four cases of CCD who received adequate resuscitation with appropriate replacement of their fecal salt and water losses. Three had associated inflammatory bowel changes at endoscopy. The index case of CCD who developed frankly bloodstained diarrhea aged 7 months was found to have histologically confirmed colitis at endoscopy. An electronic search of the hospital database to identify all patients with confirmed CCD was performed. A further three children underwent de novo diagnostic evaluation and treatment. A retrospective case note review was undertaken to determine the incidence and subtype of inflammatory bowel disease (IBD) by clinical, endoscopic, and histological means. Results: Four children with genetically confirmed CCD were identified, two being female. The first girl had a granulomatous colitis with ulceration. She went into remission with a combination of steroids and azathioprine. Immunosuppression was subsequently discontinued without a further flare of colitis. A second girl was found to have patchy inflammatory changes in the small bowel and focal active colitis. A third patient, a boy, demonstrated mild inflammatory changes in the small bowel with apoptotic debris and mild inflammation in the colon. A fourth patient did not develop intestinal inflammation. Conclusion: Our case series highlights the potential association of CCD with panenteric inflammation. While our cohort was small, CCD is rare and three out of four children referred to our tertiary referral center were affected. While early diagnosis and adequate salt replacement therapy are crucial in CCD management, the clinician should also be aware of bowel inflammation as a potential cause of failure of CCD therapy to control bowel symptomatology. Further insight is needed to understand the underlying patho-mechanism giving rise to bowel inflammation in this group.

Basidiobolomycosis is a rare fungal disease caused by Basidiobolus ranarum. Involvement of the gastrointestinal tract is unusual and poses both a diagnostic and therapeutic challenge, as clinical signs are non-specific and predisposing risk factors are lacking. It can mimick inflammatory bowel disease, primary immunodeficiency, or a malignancy and should be considered in patients who do not respond to standard therapy. We present the case of a 22 months old boy with confirmed colonic Basidiobolomycosis, who presented with severe eosinophilic inflammation of the gastrointestinal tract. Panfungal PCR performed on DNA extracted directly from a tissue sample confirmed the presence of Basidiobolus. He made a full recovery with a combination of surgery and prolonged targeted antifungal medication.

Background Blue Rubber Bleb Nevus Syndrome (BRBNS) is a rare, severe, sporadically occurring disorder characterized by multiple venous malformations. Aims To present and analyze a case series of pediatric patients with BRBNS and to describe diagnostic approaches and management options applied. Patients and methods Multicenter, retrospective study, evaluating the diagnosis and management of children with BRBNS. Results Eighteen patients diagnosed with BRBNS were included. Cutaneous venous malformations were observed in 78% and gastrointestinal venous malformations in 89%. Lesions were also found in other organs including muscles, joints, central nervous system, eyes, parotid gland, spine, kidneys and lungs. Gastrointestinal lesions were more common in the small intestine than in stomach or colon. The management varied significantly among centers. Endoscopic therapy and surgical therapy alone failed to prevent recurrence of lesions. In younger children and in patients with musculoskeletal or other organ involvement, sirolimus was used with 100% success rate in our series (5 patients treated) although poor compliance with subtherapeutic sirolimus trough levels led to recurrence in a minority. Conclusions Considering the multi-organ involvement in BRBNS, diagnosis and management requires a multidisciplinary approach. The treatment includes conservative, medical, endoscopic and surgical options. Prospective multicenter studies are needed to identify the optimal management of this rare condition.

Background Combined pH-impedance monitoring has been suggested as the investigation of choice for diagnosing gastro-oesophageal reflux in children. Although it is superior to oesophageal pH monitoring in detecting all types of reflux episodes (acid, weakly acidic and alkaline) with the ability to evaluate symptom association with reflux events, it is still limited by the lack of true paediatric normal value and the high cost involved (equipment and personnel). Objective To produce a position statement on behalf of the Motility Working Group of the British Society of Paediatric Gastroenterology, Hepatology and Nutrition on the indications and practical application of combined oesophageal pH-impedance monitoring in children. Methods Up-to-date review of available evidence. Results This document provides a practical guide to clinician on indications, methods and results interpretation of paediatric multichannel intraluminal impedance pH (MII-pH). Conclusions MII-pH is increasingly used by paediatricians as the diagnostic tool for assessing gastro-oesophageal reflux disease and symptom association. There is wide variation in paediatric practice and a need for standardised practice.

Background ‘Intractable constipation’ (IC) is constipation unresponsive to 3 months of optimal conventional treatment. Colonic manometry (CM) is recommended as a diagnostic modality for evaluation of these children. This study aimed to review outcomes of children with IC who were managed surgically at a single tertiary care center. Methods Records of children with IC who were treated with ACE (antegrade colonic enema), colostomy, or ileostomy (2006–2018) were reviewed. “Success” was defined as adequate evacuation without need for further unplanned surgery. Data are median (range). Results Sixty-seven children underwent surgery, of whom 56 with preoperative CM were included. Age at surgery was 8.6 (3.3–15.1) years. Eight had normal manometry and underwent ACE with 75% success. Thirty-six had left-sided dysfunction and underwent ACE (18), colostomy (14) or ileostomy (4) as initial intervention with 61, 70, and 100% success. Twelve with pancolonic dysfunction underwent ACE (6) or ileostomy (6) with 60 and 100% success. Twenty underwent repeat manometry 2.2 years (10 months–7.6 years) after surgery. Of 18 with stoma, 8 had resolution or improvement and of these, 7 underwent stoma reversal with a simultaneous ACE. Two patients with ACE had improvement, 1 is still on ACE washouts, and 1 is off all treatment. Ten with persistent dysfunction remain diverted. At 3.2 years (4 months–9.9 years) follow-up, 18 remain on ACE washouts, 9 have colostomy, 19 ileostomy, and 10 are off treatment and doing well. Conclusion We present a large series of patients who were surgically managed for IC. CM may guide therapy in these children. Type of study Retrospective comparative study Level of evidence Level III.

Defecatory disorders in children, including chronic constipation (CC) and fecal incontinence (FI), are common conditions worldwide and have a significant impact on children, their families, and the healthcare system. Anorectal manometry (ARM) and high-resolution anorectal manometry (HRAM) are relatively novel tools for the assessment of anal sphincter function and rectal sensation and have contributed significantly to improving the understanding of the anorectum as a functional unit. ARM has been recognized as the investigation of choice for adults with symptoms of defecation disorders, including fecal incontinence (FI), evacuation difficulties, and constipation. Although it is the gold standard tool in adults, it has yet to be formally accepted as a standardized diagnostic tool in the pediatric age, with limited knowledge regarding indications, protocol, and normal values. ARM/HRAM is slowly becoming recognized among pediatricians, but given that there are currently no agreed guidelines there is a risk that will lead to diversity in practice. The British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN)-Motility Working Group (MWG) therefore has taken the opportunity to provide guidance on the use of ARM/HRAM in children with CC and/or FI.

AIM The role of adalimumab in medically refractory ulcerative colitis (UC) in children remains to be defined. The aim of this study was to describe 11 cases of paediatric patients who received adalimumab as a second-line anti-TNF-α treatment for paediatric UC. METHODS A retrospective review of all patients with UC who received adalimumab between April 2008 and October 2013 at our hospital was conducted. Clinical efficacy and safety were assessed. RESULTS Eleven patients (three boys, eight girls) with a median age of 13.8 years (5.7-16.6 years) were included. All patients had been previously treated with infliximab. Six patients achieved and maintained clinical remission, with a median duration of treatment of 25 months. One patient was successfully weaned off adalimumab after 26 months of therapy. Treatment was unsuccessful in four out of 11 patients (36%) who underwent colectomy 4-13 months (median 7 months) from the first adalimumab dose. The remaining patient developed extensive rash and was switched to alternative therapy. CONCLUSION In this case series, our experience shows that there is a role for adalimumab as a combination therapy in a subgroup of children with refractory UC.

Background In adults ERCP and endoscopic ultrasound (EUS) are standard methods of evaluating and treating many hepatopancreaticobiliary (HPB) conditions. HPB disease is being diagnosed with increasing frequency in children but information about role of ERCP and EUS and their outcomes in this population remain limited. Therefore the aims of this study were to describe the paediatric ERCP and EUS experience from a large tertiary referral HPB centre, and to systematically compare outcomes with those of other published series. Methods All patients

Background The colo-anal reflex is a distinct reflex whereby the internal anal sphincter (IAS) relaxes in association with colonic high amplitude propagating contractions (HAPCs) in contrast to the recto-anal inhibitory reflex (RAIR), which is characterized by IAS relaxation upon rectal distension. The RAIR is mediated by the myenteric plexus and therefore absent in Hirschsprung disease. We retrospectively assessed the presence and the characteristics of the colo-anal reflex in children in whom large bowel continuity had been surgically disrupted to assess the role of the extrinsic nervous system in the reflex. Methods High-resolution (HR) colonic manometry and HR-anorectal manometry were used to evaluate both colonic and anal motor activity in ten children with treatment-unresponsive slow transit constipation (STC), who had previously undergone left-sided colostomy formation with consequent disruption of the bowel continuity, and in two children with Hirschsprung's disease (HSCR), who had previously undergone distal colon resection followed by Duhamel pull-through. Eight children with STC, normal colonic motor activity, and preserved large bowel continuity served as a control group. The presence and characteristics of colo-anal reflex were analyzed. Key results In the study group, all patients showed the presence of both normal HAPCs and the presence of the colo-anal reflex. In two cases of HSCR, RAIR was absent; however, both patients demonstrated a colo-anal reflex. Conclusions In children with disrupted continuity of the colon and/or abnormal anal reflex, the colo-anal reflex is still preserved suggesting that it is mediated by a different pathway from the RAIR, possibly an extrinsic neural pathway.

OBJECTIVE: The clinical relevance of esophageal baseline impedance (BI) remains to be determined. In the present study, we explored the impact of gastroesophageal reflux disease (GERD) and esophageal dysmotility on BI. METHODS: A total of 18 children with esophageal atresia, 26 children with GERD, and 17 controls prospectively underwent esophagogastroduodenoscopy and pH-impedance monitoring. BI was measured in both proximal and distal esophagus. Gastroesophageal reflux (GER) and bolus transit indicators were defined according to published criteria. RESULTS: Patients with esophageal atresia showed significantly lower proximal and distal BI values (952 [716-1811] Ω; 895 [284-1189] Ω; respectively) compared with those with GERD (3015 [2368-3975] Ω; 2231 [1770-3032] Ω, P < 0.001 and

Multichannel intraluminal impedance combined with pH (MII-pH) is the gold standard test for diagnosing gastro-esophageal reflux disease (GERD). It provides an opportunity to study acid and non-acid GOR and temporal association between symptoms and reflux. Accurate catheter placement is essential to prevent erroneous recording of reflux events. The aims of our study were to assess the accuracy of our devised method in predicting the catheter length for MII-pH in children (Great Ormond Street Hospital (GOSH) Table) and to compare the results with Strobel and Monreau methods.Retrospective review of all records of infants and children who underwent MII-pH studies between January to October 2014. Desired catheter position was calculated using Strobel, Monreau and GOSH formulas and compared to X ray position.One hundred and forty-four children were included; mean age was 5.1 (±4.5) years, 73 males and 71 females. In the whole group, the correlation between desired catheter position and GOSH Table was 0.95, for Strobel was 0.84, and Monreau was 0.85. In the first group (age3 years), the correlation was: GOSH Table 0.91, Strobel 0.56, and Monreau 0.6; in the second group (3-10 years): GOSH Table 0.78, Strobel 0.82, and Monreau 0.82; the third group (10 years): GOSH 0.81, Strobel 0.43, and Monreau 0.43.GOSH Table is an accurate method to estimate the insertion length of MII-pH catheters from nares to a point of approximately two vertebral bodies above the diaphragm in children. Although radiography is required to confirm final catheter position, using GOSH Table will reduce the need for repeated catheter manipulation after initial insertion and will reduce the use of a mathematically complicated formulae.

To report outcomes of children with constipation refractory to medical management and manometrically proven distal colonic dysmotility, managed with rectosigmoidectomy followed by Duhamel operation (Duhamel). Children who underwent a Duhamel from 2009 onwards for intractable constipation and left colonic dysmotility were retrospectively reviewed. The primary end point was resolution of constipation, and secondary end point was postoperative complications. Continuous data were median (range). 11 patients (4 males) had Duhamel at 11 years (5–16) with constipation started from 2 years (1–8). Hirschsprung’s disease was excluded. All Duhamels were performed with a covering ileostomy: 9 following a Hartmann procedure, one following a previously failed reversal of Hartmann, and one Duhamel performed with a pre-existing ileostomy. All ileostomies were subsequently closed. Median resection length was 22 cm (11–31). Length of stay was 8 days (5–23). Follow-up was 5 years (0.5–7). Age at final review was 15 years (10–18). Resolution of constipation occurred in nine patients (4 required antegrade continence enemas (ACE), 5 with laxative); two had persistent constipation and faecal incontinence despite ACE, ultimately requiring an ileostomy. Two postoperative small bowel obstructions required laparotomy. Duhamel performed in children with manometrically proven distal colonic dysmotility yielded 82% resolution of refractory constipation; half of them subsequently needed ACE.

Summary Background The diagnostic corroboration of the relationship between gastro-oesophageal reflux disease (GERD) and chronic cough remains challenging. Aims To compare oesophageal mucosal intercellular space diameter (ISD) in children with GERD, children with gastro-oesophageal reflux (GER)-related cough (GrC) and a control group, and to explore the relationship between baseline impedance levels and dilated ISD in children with GER-related cough. Methods Forty children with GERD, 15 children with GrC and 12 controls prospectively underwent oesophagogastroduodenoscopy (EGD) with oesophageal biopsies taken 2–3 cm above squamocolumnar junction. ISD were quantified using transmission electron microscopy. Impedance-pH monitoring with evaluation of baseline impedance in the most distal impedance channel was performed in both patient groups. Results A significant difference in mean ISD values was found between GrC patients (0.9 ± 0.2 μm) and controls (0.5 ± 0.2 μm, P

Achalasia is a rare esophageal motility disorder: its optimal treatment in children is still a matter of debate. Records of children treated for achalasia, over an 18-year period, were reviewed.Forty-eight children (median age at diagnosis 10 years; range 3-17 years) were identified. Twenty-eight patients were initially treated with Heller's myotomy (HM) and 20 with balloon dilatation (BD). At last follow-up (median 3 years; range 1-5.5 years), 43.8% (21/48) of children were symptom free. The number of asymptomatic children was significantly higher among those treated initially with HM compared to BD (HM 15/28, 53.6% BD 6/20, 30%, p 0.05). All children who underwent BD required HM due to symptom recurrence. The median (range) total number of procedures was significantly higher in the BD group (BD 3 (1-7); HM 1 (1-5); p 0.05) with a shorter time to the second intervention (BD 14 months, 95%CI 4-24; HM 58 months, 95%CI 38-79; p 0.05). Of 108 procedures, esophageal perforation occurred in two children after HM (two out of 48 HM procedures in total, 4%) and one child after BD (1/60, 1.7%).Less than half of children with achalasia are symptom free after initial treatment with either BD or HM. HM, however, when performed as first procedure, provided longer symptom-free period and reduced need for subsequent intervention. What is Known: • Balloon dilatation (BD) and Heller's myotomy (HM) are safe and effective treatment options for achalasia. • Controversy, however, exists regarding the most effective initial therapeutic approach. What is New: • HM with or without fundoplication may represent the initial therapeutic approach of choice. • Initial BD may negatively affect the outcome of a subsequent HM.

Nuclear-encoded disorders of mitochondrial translation are clinically and genetically heterogeneous. Genetic causes include defects of mitochondrial aminoacyl-tRNA synthetases, and factors required for initiation, elongation and termination of protein synthesis as well as ribosome recycling. We report on a new case of myopathy, lactic acidosis and sideroblastic anemia (MLASA) syndrome caused by defective mitochondrial tyrosyl aminoacylation. The patient presented at 1 year with anemia initially attributed to iron deficiency. Bone marrow aspirate at 5 years revealed ringed sideroblasts but transfusion dependency did not occur until 11 years. Other clinical features included lactic acidosis, poor weight gain, hypertrophic cardiomyopathy and severe myopathy leading to respiratory failure necessitating ventilatory support. Long-range PCR excluded mitochondrial DNA rearrangements. Clinical diagnosis of MLASA prompted direct sequence analysis of the YARS2 gene encoding the mitochondrial tyrosyl-tRNA synthetase, which revealed homozygosity for a known pathogenic mutation, c.156C>G;p.F52L. Comparison with four previously reported cases demonstrated remarkable clinical homogeneity. First line investigation of MLASA should include direct sequence analysis of YARS2 and PUS1 (encoding a tRNA modification factor) rather than muscle biopsy. Early genetic diagnosis is essential for counseling and to facilitate appropriate supportive therapy. Reasons for segregation of specific clinical phenotypes with particular mitochondrial aminoacyl tRNA-synthetase defects remain unknown. © 2013 Wiley Periodicals, Inc.

Lower threshold and widening indications for paediatric gastrointestinal endoscopy have resulted in a significant increase in the numbers of endoscopic procedures performed in infants. Despite this, knowledge of gastrointestinal mucosal findings in this age group is limited and data on the clinical usefulness of endoscopy are lacking.All of the children younger than 1 year referred to a single tertiary paediatric gastroenterology unit during the period June 1987 to August 2007 who underwent gastrointestinal endoscopy were identified and the clinical indications and histological outcomes were reviewed.A total of 933 gastroesophageal duodenoscopies and 439 colonoscopies were performed in 1024 cases in a total of 823 infants. In order of frequency, clinical indications were diarrhoea (51%), failure to thrive (41.2%), symptoms of reflux (27.1%), and rectal bleeding (8.5%). Mucosal biopsies were insufficient for assessment in only 2.4% of cases. Mucosal histology was normal in 33.8%, whereas histological abnormalities were identified in 63.8%. Specific histological diagnoses included microvillous inclusion disease, autoimmune enteropathy, graft-versus-host disease post-bone marrow transplantation, tufting enteropathy, and disaccharidase deficiency. There was only 1 colonic perforation complicating endoscopy in a total of 889 cases for which relevant information was available (0.1%).In two-thirds of cases, histological abnormalities were detected that influenced management following endoscopic examination and mucosal biopsy in infants. Endoscopy with biopsies is a greatly informative test with low failure and complication rates in the first year of life.

Cystic fibrosis (CF) is a multisystem disorder intrinsically associated with inflammation of mucosal surfaces. Because inflammation can result in enteric neuromuscular dysfunction we hypothesized that terminal ileitis in patients with CF may predispose to distal ileal obstruction syndrome (DIOS).Full-thickness terminal ileal tissues from 6 children with CF and severe DIOS, 6 infants with complicated meconium ileus (MI), and 6 children with non-CF intestinal atresia were studied.Lymphocyte-predominant mucosal and transmural ileal inflammation was present in 6 of 6 patients with DIOS. Lymphocytic ganglionitis was present in 4 of 6 although numbers of myenteric neurons were not decreased (5/5). Myocyte proteins were preserved (6/6). Mild submucosal fibrosis was common in DIOS (5/6) and transformation of submucosal fibroblasts to a myofibroblastic phenotype was noted in 4 of 6. Inflammatory changes were distinct from those described in fibrosing colonopathy. Antroduodenal manometry in an individual who had experienced MI/DIOS was consistent with a neuropathic pseudo-obstructive process. Submucosal or transmural lymphocyte predominant inflammation was also present in 6 of 6 infants with complicated MI, which, when coupled with submucosal myofibroblast proliferation (5/6), appeared highly predictive of CF rather than non-CF atresia. Histological findings at birth were similar, although milder, than those seen in DIOS, suggesting that these changes are a primary abnormality in CF.Submucosal or transmural inflammation of the ileum is common in newborns with CF and MI and older children with DIOS. Severe recurrent DIOS should be investigated with seromuscular and mucosal biopsy of the ileum to seek a transmural ileitis potentially amenable to anti-inflammatory therapies.

BACKGROUND AND AIMS: Functional dyspepsia in childhood is commonly triggered by food allergen in sensitised individuals. We investigated the topography of eosinophils and mast cells in gastric antral lamina propria, the interaction of mast cell products with mucosal nerve fibres, and changes in gastric antral muscle slow wave activity in children with atopy and non-atopy-related functional dyspepsia. PATIENTS AND METHODS: Open label study of gastric mucosal cow's milk challenge in 10 atopic and 6 nonatopic children (ages 2-12 years) investigated consecutively with gastroscopy for functional dyspepsia. Simultaneous surface electrogastrography and milk challenge were undertaken and laser scanning fluorescence microscopy used to examine the association of mast cell tryptase with mucosal nerves in the gastric mucosa before and after challenge. RESULTS: Eosinophils and mast cells within the lamina propria were increased in number in children with atopic functional dyspepsia and degranulated rapidly after cow's milk challenge in the atopic group. For degranulating eosinophils, median = 13.0% (interquartile range = 3.7-31.0) premilk versus 32.0% (12.0-42.0) after milk biopsies (P < 0.05); for degranulating mast cells, 5.35% (2.7-10.9) premilk biopsies versus 18.75% (12.9-22.1) after milk biopsies (P < 0.05). No such differences were seen in nonatopic patients. Mast cells were closely associated with mucosal nerve fibres and released tryptase, which colocalised with proteinase-activated receptors on mucosal nerve fibres. The gastric antral slow wave became abnormal within 2 minutes of antigen challenge in atopics with an increase in dominant frequency instability coefficient (P < 0.005), decrease in 3 cycles per minute myoelectrical activity (P < 0.01), and increase in bradygastria (P < 0.01). CONCLUSIONS: Early-onset neuroimmune interactions induced by cow's milk in the gastric mucosa of atopic children are associated with rapid disturbance of gastric myoelectrical activity and dyspeptic symptoms.

Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Its pathogenesis is not completely understood, though the prevailing model is that the intestinal flora drives a strong intestinal T helper 1 (Th1)/Th17 type immune response and inflammation in the genetically susceptible host. This leads to overly aggressive T-cell responses to normal bacteria causing tissue damage. Intestinal homeostasis and maintenance of tolerance to harmless antigens in the intestine has been shown to be maintained by CD4+ CD25+ T regulatory cells (Treg) in animal models of inflammatory bowel diseases. Here we investigated whether Infliximab, a chimeric monoclonal antibody directed against tumour necrosis factor (TNF)-alpha shown to be highly effective in the treatment of CD, has any effect on mucosal CD4+ CD25+ (FOXP3+) Tregs. Colonic mucosal biopsies from children with active Crohn's disease treated in vivo with Infliximab and controls were analysed to determine FOXP3 expression by immunofluorescence and reverse transcription-polymerase chain reaction. We observed that FOXP3+ T cells were significantly reduced in mucosa of CD patients with active disease compared with controls and restored to normal following Infliximab treatment. The frequency of FOXP3+ cells and mRNA expression was significantly increased in CD mucosa from patients treated in vivo with Infliximab compared with CD patients treated with conventional therapies. In conclusion, we show that Infliximab treatment does not solely neutralize soluble TNF-alpha, but also affects activation and possibly expansion of mucosal regulatory T cells. We suggest that anti TNF-alpha immunotherapy can also restore mucosal homeostasis in Crohn's disease.

Benign oesophageal strictures may occur as a complication of caustic ingestion or severe gastro-oesophageal reflux or as a sequela of oesophageal surgery and other fibrosing conditions. The traditional initial treatment of oesophageal strictures is intraluminal dilation; however, even if frequent, this occasionally may not provide adequate oesophageal lumen capacity or give significant symptom-free intervals, and restricturing after dilation is difficult and challenging. Topical postdilation application of an antifibrotic agent, mitomycin-C, in the treatment of an oesophageal stricture has been described.Eight centres participated, with a total of 16 patients (4 girls), median age 48 (range 0-276) months. The causes of stricture were as follows: caustic (10), post-trachea-oesophageal fistula repair (2), peptic (2), Crohn disease (1), and dystrophic epidermolysis bullosa (1). The median (range) length and diameter of the strictures were as follows: 22 mm (8-50 mm) and 1.5 mm (1-6 mm). Of the 16 patients, 15 had undergone repeated dilations varying from 3 to more than 1000 (daily self-bouginage) before mitomycin-C, and the median interval between dilations was 4 weeks. Mitomycin-C 0.1 mg/mL was applied after dilation for a median time of 3.5 minutes and a median of 3 (1-12) times.Major success, both endoscopic and clinical improvement or cure, occurred in 10 of 16 patients. In 3 of 16 patients the interval period between dilations increased dramatically. Failure of therapy was considered in 3 of 16. All of the patients remained symptom free for a follow-up time of as long as 5 years.Postdilation application of topical mitomycin-C resulted in major success in 62.5% of patients and partial success in 19%, and it may be a useful strategy in oesophageal strictures of differing causes that are refractory to repeated perendoscopic dilation.

Inflammation of the blood vessels (vasculitis) is uncommon in childhood with the exception of Henoch–Schonlein purpura and Kawasaki’s disease. The disease can be classified according to the size of blood vessel affected. The gastrointestinal (GI) clinical manifestations vary according to the size and type of blood vessel involved but include GI bleeding, gastrointestinal ulceration, GI obstruction, GI perforation and abdominal pain. Nonspecific mucosal inflammation might also be present. Diagnosis is often delayed because the presentation is so varied. Diagnostic evaluation may include GI panendoscopy, videocapsule endoscopy, abdominal ultrasound and/or MRI and visceral angiography. Treatment is disease and presentation specific.

We evaluated the effect of bowel preparation on colonic transit time (CTT) measured by the radio-opaque marker test in children with constipation. All children underwent 2 radio-opaque marker-CTT tests, both in cleansed and uncleansed bowel state. Our findings confirm that the state of colonic fecal filling may significantly influence CTT.

Objectives: Indeterminate intestinal inflammation may result from a variety of inflammatory conditions in addition to ulcerative colitis and Crohn disease. The primary systemic vasculitides may present with intestinal inflammation and an indeterminate colitis. We set out to describe a series of children with primary systemic vasculitis who initially presented with clinical features suggestive of inflammatory bowel disease (IBD) to establish criteria that might help discriminate between IBD and primary systemic vasculitis. Methods: Ten children (6 boys, median age at presentation 8.9 years, range 0.9-14.5 years) satisfied inclusion criteria. Results: All had abdominal pain, weight loss, diarrhea (6 of 10 bloody) and laboratory evidence of a severe acute phase response. Extraintestinal clinical features included vasculitic rash, renal impairment, myalgia, testicular pain and polyarthritis. Endoscopy showed vascular changes or other macroscopic findings suggestive of vasculitis in 5 of 10 patients. Gut histology revealed indeterminate chronic inflammatory mucosal changes and one patient with small artery fibrinoid necrosis in the submucosal vessels. Extraintestinal biopsy was performed in 6 patients and had a higher yield for the demonstration of vasculitis than intestinal biopsy. The results of selective visceral angiography was suggestive of vasculitis in all patients, but was normal in 7 cases of treatment-unresponsive classic IBD. Treatment comprised corticosteroid and azathioprine in all patients. Cyclophosphamide was given to 7 of 10 patients. Conclusions: Extraintestinal manifestations and inflammatory responses that may be disproportionate to the degree of intestinal inflammation provide clues to the presence of an underlying primary systemic vasculitis, and these data suggest that selective visceral angiography plays a key role in the diagnosis of vasculitis in this context. It is important to identify and treat any vasculitic component because failure to do so may result in consequential morbidity or mortality.

Fulminating acute ulcerative colitis (UC) is a potentially life threatening medical emergency. Up to 30% of individuals respond poorly to corticosteroids alone and second line medical or surgical therapies are indicated. We describe the successful use of chimeric anti-CD25 therapy in 4 such children poorly responsive to combined therapy with intravenous steroids and calcineurin inhibitors with a pretreatment predictive risk of colectomy of 85-100%. Clinical disease activity scores normalized within 72 hours of anti-CD25 administration and colonic histology provided evidence of mucosal healing within 10-14 days. None required emergency colectomy. Anti-CD25 is efficacious in fulminating UC and randomized placebo controlled trials appear indicated.

Cuperus R, Schappi M G, Shah N, Lindley K J, Milla P J & Smith V V (2005) Histopathology46, 73-80 Hypertrophic eosinophilic gastroenteropathy is associated with reduced enterocyte apoptosisAims : To investigate the cause of grossly elongated villi in four children presenting with obstruction due to a novel form of eosinophilic gastroenteropathy in which there was profound hyperplasia of the intestinal villi with grossly increased villous/crypt ratio and prominent mucosal eosinophilia. Increased eosinophils were also present in the muscularis propria and submucosa. All had intermittent diarrhoea and signs of a protein-losing enteropathy. Methods and results : The cause of the grossly elongated villi was investigated by studying enterocyte proliferation (Ki67), survival factors (bcl-2) and apoptosis (TUNEL) in these patients (n = 4) and normal (jejunum n = 6, ileum n = 6) and disease (n = 6) controls. The most remarkable finding was that apoptotic enterocytes were undetectable in the elongated villi. Conclusions : It seems likely that a defect in the regulation of apoptosis of the epithelium occurs which could explain the remarkable hyperplasia of the villi seen

Congenital hyperinsulinism (CHI) is a genetically and phenotypically diverse syndrome. Key management issues involve early diagnosis by ensuring that appropriate samples are taken at the point of hypoglycaemia, prevention of recurrent hypoglycaemia, and detailed characterisation of the clinical, biochemical, and genetic features of each case. Infants with persistent diazoxide resistant CHI require evaluation at specialist referral centres equipped to differentiate those with focal (fo-HI) and diffuse (di-HI) pancreatic disease. Fo-HI is treated with selective pancreatic resection but di-HI is treated by surgery only if intensive medical management regimes are not efficacious.

Dunne, Mark J., Karen E. Cosgrove, Ruth M. Shepherd, Albert Aynsley-Green, and Keith J. Lindley. Hyperinsulinism in Infancy: From Basic Science to Clinical Disease. Physiol Rev 84: 239–275, 2004; 10.1152/physrev.00022.2003.—Ion channelopathies have now been described in many well-characterized cell types including neurons, myocytes, epithelial cells, and endocrine cells. However, in only a few cases has the relationship between altered ion channel function, cell biology, and clinical disease been defined. Hyperinsulinism in infancy (HI) is a rare, potentially lethal condition of the newborn and early childhood. The causes of HI are varied and numerous, but in almost all cases they share a common target protein, the ATP-sensitive K+channel. From gene defects in ion channel subunits to defects in β-cell metabolism and anaplerosis, this review describes the relationship between pathogenesis and clinical medicine. Until recently, HI was generally considered an orphan disease, but as parallel defects in ion channels, enzymes, and metabolic pathways also give rise to diabetes and impaired insulin release, the HI paradigm has wider implications for more common disorders of the endocrine pancreas and the molecular physiology of ion transport.

We have previously described the only reported case of human proprotein convertase 1 (PC1) deficiency, in a female (Subject A) with obesity, hypogonadism, hypoadrenalism, and reactive hypoglycemia. We now report the second case of human PC1 deficiency (Subject B), also due to compound heterozygosity for novel missense and nonsense mutations. While both subjects shared the phenotypes of obesity, hypoadrenalism, reactive hypoglycemia, and elevated circulating levels of certain prohormones, the clinical presentation of Subject B was dominated by severe refractory neonatal diarrhea, malabsorptive in type. Subsequent investigation of Subject A revealed marked small-intestinal absorptive dysfunction, which was not previously clinically suspected. We postulate that PC1, presumably in the enteroendocrine cells, is essential for the normal absorptive function of the human small intestine. The differences in the nature and severity of presentation between the two cases cannot readily be explained on the basis of allelic heterogeneity, as the nonsense and missense mutations from both subjects had comparably severe effects on the catalytic activity of PC1. Despite Subject A's negligible PC1 activity, some mature ACTH and glucagon-like peptide 17-36(amide) were detectable in her plasma, suggesting that the production of these hormones, at least in humans, does not have an absolute dependence on PC1. The presence of severe obesity and the absence of growth retardation in both subjects contrast markedly with the phenotype of mice lacking PC1 and suggest that the precise physiological repertoire of this enzyme may vary between mammalian species.

Objective: to investigate whether relief of airway obstruction in laryngomalacia by aryepiglottoplasty affects gastro-oesophageal reflux. Methods: a prospective study of consecutive infants and children with suspected laryngomalacia. Gastro-oesophageal reflux was measured before and after diagnostic microlaryngobronchoscopy and aryepiglottoplasty. Results: of the six cases who underwent aryepiglottoplasty and completed the study, three had significant pre-operative reflux according to age. In this group the reflux improved significantly after aryepiglottoplasty. In the other three cases, reflux was not age-significant pre-operatively nor did it change significantly post-operatively. Conclusions: when partial airway obstruction due to laryngomalacia co-exists with gastro-oesophageal reflux, treatment of the airway problem improves respiratory symptoms in all cases and reduces gastro-oesophageal reflux in patients with age-significant reflux. This suggests that there are two clinical groups, those with severe, age-significant reflux, possibly caused by airway obstruction, whose gastro-oesophageal reflux benefits from aryepiglottoplasty; and those whose reflux is physiological and not influenced by aryepiglottoplasty. Therefore aryepiglottoplasty can be expected to reduce gastro-oesophageal reflux in those infants with laryngomalacia who have age-significant reflux.

We report the case of an 8-year-old child who presented with severe hyperinsulinaemic hypoglycaemia due to a pancreatic islet cell adenoma. In vivo, there was no beneficial response to the hyperglycaemia-inducing agent diazoxide and as a consequence the child underwent a subtotal pancreatectomy. In vitro studies of adenomatous beta-cells revealed no operational defects in ATP-sensitive potassium channel activity and appropriate responses to diazoxide. In comparison with patients with focal adenomatous hyperplasia, genetic analysis of the isolated adenoma showed no loss of heterozygosity for chromosome 11p15 and expression of the cyclin-dependent kinase inhibitor p57(kip2). This case illustrates that the excess insulin secretion from an infantile adenoma has an aetiology different from that observed in hyperinsulinism in infancy.

Background: Management of refractory inflammatory bowel disease (IBD) in children is challenging and once response to conventional medical therapy deviates from the expected, options are often limited. Sirolimus is commonly used in post-transplantation management and is used sparsely as rescue therapy in refractory Crohn's disease. In the present study, we report the efficacy of sirolimus as an adjuvant immunosuppressive therapy in a retrospective case review of a selected group of IBD children who were refractory to the conventional treatments. Methods: Medical records of children with refractory IBD unresponsive to conventional therapy and started on sirolimus between 2006 and 2012 were retrospectively reviewed. Clinical response, through Pediatric Ulcerative Colitis Activity Index (PUCAI) and Pediatric Crohn's Disease Activity Index (PCDAI), as well as intestinal inflammation, through specific histological scores, was evaluated. Results: The records of 14 patients were analyzed. Eleven of them had ulcerative colitis (UC) and 3 Crohn's disease (CD); mean age at diagnosis was 9.1 years (standard deviation 3.8). Of UC patients, 5 (45%) achieved clinical remission and 2 (18%) showed clinical response. All CD patients went into clinical remission. Mucosal healing was achieved by 5 children (45%) with UC and 2 (67%) with CD patients. One child with ulcerative colitis was weaned off adalimumab, while 2 children with CD were weaned off prednisolone and methotrexate successfully. Conclusion: Our data provide evidence that sirolimus seems to be effective as rescue therapy in a subgroup of children with severe IBD refractory to conventional therapies by inducing both clinical remission and mucosal healing.

Background Aprepitant (Emend, Merck Sharp & Dohme Ltd, Haarlem, the Netherlands), a neurokinin-1 receptor antagonist, prevents vomiting in a range of conditions. No data are available on its use in children with cyclical vomiting syndrome (CVS). Aim We investigated the efficacy of aprepitant as prophylactic treatment or acute intervention in CVS children refractory to conventional therapies. Methods Forty-one children (median age: 8 years) fulfilling NASPGHAN criteria treated acutely (RegA) or prophylactically (RegP) with aprepitant were retrospectively reviewed. Primary outcome was the clinical response (decrease in frequency and intensity of CVS episodes). Secondary outcomes were: number of CVS episodes/year, number of hospital admissions/year, CVS episode duration, number of vomits/h, symptom-free interval length (days), and school attendance percentage. The follow-up period was 18-60 months. Results Sixteen children received RegP and 25 RegA. One child on RegP stopped treatment due to severe migraine. At 12-months on intention-to-treat analysis, 13 children on RegP (81%) achieved either complete (3/16, 19%) or partial (10/16, 62%) clinical response. On RegA, 19 children (76%) had either complete (3/25, 12%) or partial (16/25, 64%) response (P = 0.8 vs. RegP). In both RegP and RegA, there was a significant decrease in CVS episodes/year, hospital admission number/year, CVS episode length, number of vomits/h, as well as an increase in symptom-free interval duration and school attendance percentage. Side effects were reported only in RegP (5/16, 31%) including hiccough (3/16, 19%), asthenia/fatigue (2/16, 12.5%), increased appetite (2/16, 12.5%), mild headache (1/16, 6%) and severe migraine (1/16, 6%). Conclusion Aprepitant appears effective for both acute and prophylactic management of paediatric cyclical vomiting syndrome refractory to conventional therapies.

Objective To evaluate the 4-year results following a randomised controlled trial (RCT) comparing open (ONF) and laparoscopic (LNF) Nissen fundoplication in children. Background It is assumed that long-term results of ONF and LNF are comparable. No randomised studies have been performed in children. Methods A follow-up study was performed in children randomised to ONF or LNF (clinicaltrials.gov identifier NCT00259961). Recurrent gastro-oesophageal reflux (GER) was documented by upper gastrointestinal contrast study and/or 24-h pH study. Nutritional status, retching and other symptoms were investigated. A questionnaire was used to assess the quality of life before and after surgery. Results Thirty-nine children were randomised to ONF (n=20) or LNF (n=19). There were 15 ONF and 16 LNF neurologically impaired children. One patient (ONF group) was lost to follow-up. Follow-up was 4.1 years (3.1–5.3) for ONF group and 4.1 years (2.6–5.1) for LNF group (p=0.9). Seven neurologically impaired children had died by the time of follow-up (3 ONF, 4 LNF). Incidence of recurrent GER was 12.5% in the ONF and 20% in the LNF (p=ns). One patient in each group underwent redo-Nissen fundoplication. Nutritional status improved in both groups, as indicated by a significant increase in weight Z-score (p