Neil Shah

Inflammatory Bowel Disease and Mutations Affecting the Interleukin-10 Receptor

BACKGROUNDnThe molecular cause of inflammatory bowel disease is largely unknown.nnnMETHODSnWe performed genetic-linkage analysis and candidate-gene sequencing on samples from two unrelated consanguineous families with children who were affected by early-onset inflammatory bowel disease. We screened six additional patients with early-onset colitis for mutations in two candidate genes and carried out functional assays in patients peripheral-blood mononuclear cells. We performed an allogeneic hematopoietic stem-cell transplantation in one patient.nnnRESULTSnIn four of nine patients with early-onset colitis, we identified three distinct homozygous mutations in genes IL10RA and IL10RB, encoding the IL10R1 and IL10R2 proteins, respectively, which form a heterotetramer to make up the interleukin-10 receptor. The mutations abrogate interleukin-10-induced signaling, as shown by deficient STAT3 (signal transducer and activator of transcription 3) phosphorylation on stimulation with interleukin-10. Consistent with this observation was the increased secretion of tumor necrosis factor alpha and other proinflammatory cytokines from peripheral-blood mononuclear cells from patients who were deficient in IL10R subunit proteins, suggesting that interleukin-10-dependent negative feedback regulation is disrupted in these cells. The allogeneic stem-cell transplantation performed in one patient was successful.nnnCONCLUSIONSnMutations in genes encoding the IL10R subunit proteins were found in patients with early-onset enterocolitis, involving hyperinflammatory immune responses in the intestine. Allogeneic stem-cell transplantation resulted in disease remission in one patient.

Infant colitis—it's in the genes

Department of Immunology, Division of Infection and Immunity, University College London, Royal Free Hospital, London, UK (E-O Glocker MD, M Perro MSc, Prof B Grimbacher MD); Department of Haematology, University Hospital Freiburg, Freiburg, Germany (N Frede); Department of Paediatric Laboratory Medicine (Prof N Sebire MD) and Department of Paediatric Gastroenterology (M Elawad MD, N Shah MD), Great Ormond Street Hospital, University College London, London, UK

Interleukin-10 and Interleukin-10–Receptor Defects in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic inflammatory disease characterized by abdominal pain, bloody diarrhoea, and malabsorption leading to weight loss. It is considered the result of inadequate control of an excessive reaction of the immune system to the resident flora of the gut. Like other primary immunodeficiencies, IL-10 and IL-10 receptor (IL10R) deficiency present with IBD and demonstrate the sensitivity of the intestine to any changes of the immune system. Both IL-10 and IL10R deficiency cause severe early-onset enterocolitis and can be successfully treated by hematopoietic stem cell transplantation (HSCT).

Identifying and managing cow's milk protein allergy

Cows milk protein (CMP) is usually one of the first complementary foods to be introduced into the infants diet and is commonly consumed throughout childhood as part of a balanced diet. CMP is capable of inducing a multitude of adverse reactions in children, which may involve organs like the skin, gastrointestinal (GI) tract or respiratory system. The diagnosis of CMP-induced adverse reactions requires an understanding of their classification and immunological basis as well as the strengths and limitations of diagnostic modalities. In addition to the well-recognised, immediate-onset IgE-mediated allergies, there is increasing evidence to support the role of CMP-induced allergy in a spectrum of delayed-onset disorders ranging from GI symptoms to chronic eczema. The mainstay of treatment is avoidance of CMP; this requires dietetic input to ensure that this does not lead to any nutritional compromise. This review is intended to highlight the broad spectrum of manifestations of CMP allergy and to offer an approach to the diagnosis and treatment thereof.

Feeding difficulties and foregut dysmotility in Noonan’s syndrome

PURPOSE Noonan’s syndrome is a common dysmorphic syndrome in which failure to thrive and gastrointestinal symptoms are frequent but poorly understood. DESIGN Twenty five children with Noonan’s syndrome were investigated by contrast radiology, pH monitoring, surface electrogastrography (EGG), and antroduodenal manometry (ADM). RESULTS Sixteen had poor feeding and symptoms of gastrointestinal dysfunction. All 16 required tube feeding. Seven of 25 had symptoms of foregut dysmotility and gastro-oesophageal reflux. In the most symptomatic children (four of seven) EGG showed fasting frequency gradient loss along the stomach fundus and pylorus with antral postprandial frequency loss. ADM showed shortened fasting cycle length, with abnormal phase III and shortened postprandial activity containing phasic contractions. IMPLICATIONS Gastroduodenal motor activity was reminiscent of 32–35 week preterm patterns. The feeding difficulties appear to resolve as gut motility matures. In Noonan’s syndrome, feeding problems appear to be the result of delayed gastrointestinal motor development.

Practical dietary management of protein energy malnutrition in young children with cow’s milk protein allergy

To cite this article: Meyer R, Venter C, Fox AT, Shah N. Practical dietary management of protein energy malnutrition in young children with cow’s milk protein allergy. Pediatric Allergy Immunology 2012: 23: 307–314.

Cow's Milk Challenge Increases Weakly Acidic Reflux in Children with Cow's Milk Allergy and Gastroesophageal Reflux Disease

OBJECTIVEnTo assess and compare the pattern of reflux in a selected population of infants with cows milk (CM) allergy (CMA) and suspected gastroesophageal reflux disease (GERD) while on dietary exclusion and following challenge with CM.nnnSTUDY DESIGNnSeventeen children (median age: 14 months) with a proven diagnosis of CMA and suspected GERD underwent 48-hour multichannel intraluminal impedance-pH monitoring. For the first 24 hours, the infants were kept on amino acid-based formula, and for the subsequent 24 hours, they were challenged with CM.nnnRESULTSnThe total reflux episodes and the number of weakly acidic episodes were higher during CM challenge compared with the amino acid-based formula period [total reflux episodes: 105 (58-127.5) vs 65 (39-87.5), Pxa0<xa0.001; weakly acidic episodes: 53 (38.5-60.5) vs 19 (13-26.5), P < .001; median (25th-75th)]. No differences were found for either acid or weakly alkaline episodes (not significant). The number of weakly acidic episodes reaching the proximal, mid, and distal esophagus was higher during CM challenge (P < .001). No differences were found in either acid exposure time or number of long-lasting episodes (not significant).nnnCONCLUSIONSnIn children with CMA and suspected GERD, CM exposure increases the number of weakly acidic reflux episodes. CM challenge during 48-hour multichannel intraluminal impedance-pH monitoring identifies a subgroup of patients with allergen-induced reflux, and in selected cases of children with CMA in whom GERD is suspected, its use could be considered as part of diagnostic work-up.

Gastrointestinal endoscopy and mucosal biopsy in the first year of life: indications and outcome.

Objectives: 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. Methods: 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. Results: 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%). Conclusions: 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.

Feeding difficulties in children with food protein-induced gastrointestinal allergies

There is paucity of data on the prevalence of feeding difficulties in Food Protein‐Induced Gastrointestinal Allergies (FPIGA) and their clinical characteristics. However, it is a commonly reported problem by clinicians. We set out to establish the occurrence of feeding difficulties in children with FPIGA, the association with gastrointestinal and extra‐intestinal symptoms and number of foods eliminated from the diet.

Manifestations of food protein induced gastrointestinal allergies presenting to a single tertiary paediatric gastroenterology unit

BackgroundFood protein induced gastrointestinal allergies are difficult to characterise due to the delayed nature of this allergy and absence of simple diagnostic tests. Diagnosis is based on an allergy focused history which can be challenging and often yields ambiguous results. We therefore set out to describe a group of children with this delayed type allergy, to provide an overview on typical profile, symptoms and management strategies.MethodsThis retrospective analysis was performed at Great Ormond Street Children’s Hospital. Medical notes were included from 2002 – 2009 where a documented medical diagnosis of food protein induced gastrointestinal allergies was confirmed by an elimination diet with resolution of symptoms, followed by reintroduction with reoccurrence of symptoms. Age of onset of symptoms, diagnosis, current elimination diets and food elimination at time of diagnosis and co-morbidities were collected and parents were phoned again at the time of data collection to ascertain current allergy status.ResultsData from 437 children were analysis. The majority (67.7%) of children had an atopic family history and 41.5% had atopic dermatitis at an early age. The most common diagnosis included, non-IgE mediated gastrointestinal food allergy (n = 189) and allergic enterocolitis (n = 154) with symptoms of: vomiting (57.8%), back-arching and screaming (50%), constipation (44.6%), diarrhoea (81%), abdominal pain (89.9%), abdominal bloating (73.9%) and rectal bleeding (38.5%). The majority of patients were initially managed with a milk, soy, egg and wheat free diet (41.7%). At a median age of 8 years, 24.7% of children still required to eliminate some of the food allergens.ConclusionsThis large retrospective study on children with food induced gastrointestinal allergies highlights the variety of symptoms and treatment modalities used in these children. However, further prospective studies are required in this area of food allergy.