Human TGF-ß1 deficiency causes severe inflammatory bowel disease and encephalopathy.

Transforming growth factor (TGF)-ß1 (encoded by TGFB1) is the prototypic member of the TGF-ß family of 33 proteins that orchestrate embryogenesis, development and tissue homeostasis1,2. Following its discovery 3 , enormous interest and numerous controversies have emerged about the role of TGF-ß in coordinating the balance of pro- and anti-oncogenic properties4,5, pro- and anti-inflammatory effects 6 , or pro- and anti-fibrinogenic characteristics 7 . Here we describe three individuals from two pedigrees with biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy. The proteins encoded by the mutated TGFB1 alleles were characterized by impaired secretion, function or stability of the TGF-ß1-LAP complex, which is suggestive of perturbed bioavailability of TGF-ß1. Our study shows that TGF-ß1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans.

Symptoms and Mucosal Changes Stable During Rapid Increase of Pediatric Celiac Disease in Norway.

OBJECTIVES: We aimed to study whether the incidence of pediatric celiac disease (CD) in South-Eastern Norway changed from 2000 to 2010. We also examined whether there was a change in symptoms and histopathological morphology in the duodenal biopsies during the same period. METHODS: In 3 hospitals in South-Eastern Norway, records from pediatric patients (0-14.9 years) diagnosed with CD during two 3-year periods (2000-2002 and 2008-2010) were reviewed. Only cases with a duodenal biopsy diagnosis of CD classified as Marsh grade 2 and 3a-c were included. Frequencies of symptoms, anthropometric data, and laboratory results were compared, in addition to re-examinations of histological sections from one of the hospitals. RESULTS: A total of 400 cases were diagnosed with a female to male ratio of 1.5:1. The incidence rate for 2000 to 2002 was 15.9 cases per 100,000 person-years (95% confidence interval 12.8-19.4), compared with 45.5 cases per 100,000 person-years during 2008 to 2010 (95% confidence interval 40.5-50.9), P < 0.001. The relative frequencies of symptoms and the distribution of histopathological changes were similar in the 2 periods, whereas weight z scores and hemoglobin levels were significantly lower in the first period. CONCLUSIONS: We found a 3-fold increase in the incidence rate for CD in the Norwegian pediatric population during the decade 2000 to 2010. Slightly higher weight and hemoglobin levels at diagnosis in the latter period may be due to improved CD awareness. Unaltered relative frequencies of symptoms and histopathological changes in the gut, however, suggest a true increase of CD in Norwegian children.

Nissen fundoplication in children with cerebral palsy: influence on rate of gastric emptying and postprandial symptoms in relation to protein source in caloric liquid meals.

BACKGROUND & AIMS: The aim was to study the influence of Nissen fundoplication on rate of gastric emptying and postprandial symptoms in relation to protein source in liquid meals in children with cerebral palsy. METHODS: Ten children with cerebral palsy and Nissen fundoplication and ten with cerebral palsy without Nissen fundoplication were studied. Patients had gastrostomy and received two meals, double-blinded, in random order, on separate days. Meals contained a standardised carbohydrate and fat base plus one of two protein modules (Meal A: 100% casein; Meal B: 40% casein/60% whey). The (13)C octanoic acid breath test was used to assess gastric emptying. Postprandial symptoms were recorded. Results are given as median. RESULTS: For meal A and B, respectively, time until 50% of the meal had emptied (T1/2) was 110 in the Nissen fundoplication- and 181 min in the non-Nissen fundoplication group, (p = 0.35) and 50 and 85 min (p = 0.25). Seven in the Nissen fundoplication group reported postprandial symptoms to meal B, none in the non-Nissen fundoplication group (p < 0.01). CONCLUSIONS: Compared with cerebral palsy-children without Nissen fundoplication, those with Nissen fundoplication have postprandial symptoms more frequently after receiving a rapid emptying meal. Gastric emptying alone, however, does not seem to explain the symptom occurrence. ClinicalTrials.gov: UUSKBK 28200706.

The effect of protein composition in liquid meals on gastric emptying rate in children with cerebral palsy.

BACKGROUND & AIM: Dysmotility, nausea and vomiting are common among children with cerebral palsy. This study aimed to evaluate influence of protein composition on rate of gastric emptying and study the relation between gastric emptying and postprandial gastrointestinal symptoms. METHODS: 15 children with cerebral palsy, using gastrostomy, received four liquid test meals on separate days in random order. The meals contained a standard carbohydrate and fat base plus one of four protein modules (100% casein (A), hydrolysed whey (B), amino acids (C) and 40% casein/60% whey (D)) with a total energy of 1 kcal/ml. The (13)C octanoic acid breath test was applied to assess gastric emptying. RESULTS: When comparing half emptying time (T(1/2)) of the fast emptying meals (meal B, C and D) with the slowest emptying meal (meal A), more rapid emptying was demonstrated for meal D (p < 0.001). For meal D, emptying was significantly faster in children with postprandial symptoms than in those without (p < 0.01). CONCLUSION: In children with cerebral palsy using gastrostomy, gastric emptying is influenced by type of protein in the meal. The present results also suggest that there is a relation between rapid gastric emptying and postprandial gastrointestinal symptoms. CLINICALTRIALS.GOV: UUSKBK 28200706.

Asthma and overweight are associated with symptoms of gastro-oesophageal reflux.

AIM: To explore the prevalence of symptoms suggestive of gastro-oesophageal reflux disease (GERD) in asthmatics and controls, and to control for the possible effect of overweight. METHODS: The prevalence of GERD symptoms was assessed using a questionnaire about reflux symptoms in children with asthma (n=872, mean age 10.4 y, 65% males) compared to non-asthmatic controls (n=264, mean age 10.8 y, 48% males), and a symptom score was calculated. The association between GERD symptoms and overweight (age-adjusted BMI > 25) was assessed independently. RESULTS: A positive reflux symptom score was found in 19.7% of the asthmatics compared to 8.5% of the non-asthmatic control group (odds ratio (OR) 2.6, 95% CI 1.7-4.2). Overweight children reported GERD symptoms more frequently than children with normal weight (OR 1.8, 95% CI 1.2-2.6). Asthma and obesity remained significant predictors when analysed simultaneously by logistic regression analysis. One hundred and fifty-two children with asthma consented to an oesophageal pH study, and an abnormal pH study result (reflux index > 5.0) correlated positively with overweight (OR 4.9, 95% CI 2.2-11.0). CONCLUSION: The prevalence of symptoms associated with gastro-oesophageal reflux was increased in children with asthma and in overweight children. Overweight and asthma were independently associated with GERD symptoms, and overweight did not explain the higher frequency of GERD in asthma patients.

Gastroesophageal reflux disease in children: association between symptoms and pH monitoring.

OBJECTIVE: The prevalence of symptoms associated with gastroesophageal reflux disease (GERD) in patients with abnormal results of pH monitoring has been investigated in adults and infants. A questionnaire suitable for children between 7 and 16 years of age has been proposed, but this tool has so far not been validated. In the present study the items of the questionnaire are validated against results from an esophageal 24-h study of pH. MATERIAL AND METHODS: Ninety-nine children aged from 7 to 16 years referred from two outpatient clinics for suspected GERD completed the 7-point questionnaire regarding symptoms during the week prior to a pH study. The frequency of symptoms was investigated in patients with abnormal versus normal pH (reflux index >/< 5.0). A group of healthy children (n = 284) served as controls to estimate the frequency of symptoms in the normal population. RESULTS: It was found that 37/99 (37%) of patients had an abnormal pH study result. Regurgitation/vomiting yielded the best symptom discrimination, and was reported by 46% with abnormal versus 24% with normal pH-study results (p = 0.029). A weighted score including the five best discriminating symptoms was positive in 75% versus 44% (OR 3.78, CI 1.52-9.37, p = 0.006). In a comparison of children with abnormal pH studies and healthy controls, a correct diagnosis based on five symptoms could be obtained in 75% and 94%, respectively. CONCLUSIONS: A relatively weak association was found between reflux symptoms and a positive pH study in 7-16-year-old children referred for pH monitoring. Thus, the questionnaire is not a diagnostic tool, and its potential use is limited to epidemiological studies.

Recurrent abdominal pain: a five-year follow-up study.

To explore the long-term prognosis for children referred for recurrent abdominal pain (RAP), 44 children investigated for RAP 5 y ago were compared to a group of controls (n=88). The former RAP patients reported RAP, headache and school absence more frequently than controls. A high proportion of children referred with RAP have persistent symptoms, with more headache and school absence than controls. The diagnostic subgroup did not predict persistence of abdominal pain.

Pediatric inflammatory bowel disease in southeastern Norway: a five-year follow-up study.

OBJECTIVES: Few prospective population-based studies have been carried out on the incidence of inflammatory bowel disease (IBD). In a population-based study of pediatric IBD in southeastern Norway, patients <16 years at the time of diagnosis were followed up prospectively. The study reports on changes in diagnosis and clinical outcome 5 years after diagnosis. METHODS: From 1990 to 1993 new cases of IBD were registered in a population of 174,482 children aged less than 16 years. The patients' diagnoses were systematically evaluated 1 year after diagnosis and the patients were followed up clinically for up to 5 years after diagnosis. RESULTS: Sixteen cases of Crohn's disease (CD), 14 cases of ulcerative colitis (UC) and 3 cases of indeterminate colitis (IND) were initially registered. After 1 year IND were reclassified as UC (n=2) or CD (n=1). Altogether, 18% (6/33) had their diagnosis changed during the 5 years of follow-up, which yielded a mean annual incidence of 2.7/100,000 for CD and 2.0/100,000 for UC. Of the children with CD, more than 80% had relapses during the 5-year period, and 6 of 18 had surgery. Two-thirds of the children with UC had relapses during the 5-year period, and 3 patients underwent colectomy. CONCLUSIONS: An incidence of 4.7/100,000 is comparable to that found in most other studies made in Europe. The relationship between UC and CD in children was found to differ from that in the adult population. One of 5 patients had their diagnosis changed during the follow-up period. Pediatric UC seems to have a more serious course of disease than in the adult IBD population, which may be explained by the higher risk of pancolitis at diagnosis.