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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare monogenic disorder, associated with endocrine deficiencies and non-endocrine involvement. Gastrointestinal (GI) manifestations appear in approximately 25% of patients and are the presenting symptom in about 10% of them. Limited awareness among pediatricians of autoimmune enteropathy (AIE) caused by destruction of the gut endocrine cells in APECED patients delays diagnosis and appropriate therapy. We describe an 18-year-old female presenting at the age of 6.10 years with hypoparathyroidism, oral candidiasis and vitiligo. The clinical diagnosis of APECED was confirmed by sequencing the autoimmune regulator-encoding (AIRE) gene. Several characteristics of the disease—Hashimoto’s thyroiditis, Addison’s disease, diabetes mellitus type 1 and primary ovarian insufficiency—developed over the years. She had recurrent episodes of severe intractable hypocalcemia. Extensive GI investigations for possible malabsorption, including laboratory analyses, imaging and endoscopy with biopsies were unremarkable. Revision of the biopsies and chromogranin A (CgA) immunostaining demonstrated complete loss of enteroendocrine cells in the duodenum and small intestine, confirming the diagnosis of AIE. Management of hypocalcemia was challenging. Only intravenous calcitriol maintained calcium in the normal range. Between hypocalcemic episodes, the proband maintained normal calcium levels, suggesting a fluctuating disease course. Repeated intestinal biopsy revealed positive intestinal CgA immunostaining. The attribution of severe hypocalcemic episodes to AIE emphasizes the need for increased awareness of this unique presentation of APECED. The fluctuating disease course and repeated intestinal biopsy showing positive CgA immunostaining support a reversible effect of GI involvement. CgA immunostaining is indicated in patients with APECED for whom all other investigations have failed to reveal an explanation for the malabsorption.

Objectives The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) 2012 guidelines, enabled for the first time, a nonbiopsy approach in the diagnosis of celiac disease (CD). We aimed to prospectively assess 4 tissue-transglutaminase (tTg) IgA assays of 4 random-access analyzers and examine their accuracy in diagnosing CD without a biopsy. Methods We enrolled 186 consecutive children referred to upper endoscopy and intestinal biopsy. One group included 109 patients with positive tTg that was referred for suspected CD. Another group included 77 patients with negative tTg referred because of other indications. All participants had a blood sample taken at the time of endoscopy. Samples were tested with 4 tTg IgA assays on automated analyzers and 1 Elisa kit. All intestinal biopsies were evaluated by a local pathologist, a central pathologist, and a CD expert blinded to each other. CD was diagnosed when full agreement was reached. Analytical performance of the assays included precision with controls and samples, lot to lot variation, and carryover. Results In our cohort, all tested tTg IgA-automated assays showed sensitivities above 98% and specificities above 99%. ROC analysis demonstrated AUC (area under the curve) >0.99 for all 4 analyzers. The positive-predictive values (PPV) were all >0.99 and negative-predictive values (NPV) were >0.97. The Elisa kit had sensitivity of 95%, specificity of 96%, AUC of 0.96, PPV of 0.98 and NPV of 0.93. Conclusion CD can be accurately diagnosed without biopsy based on tTg IgA levels at least 10 times the ULN using the 4 high-volume random-access analyzers used in our study.

Background & Aims: Dietary therapies based on exclusion of usual dietary elements induce remission in children with Crohn's disease (CD), whereas re-exposure induces rebound inflammation. We investigated whether a short trial of dietary therapy, to identify patients with and without a rapid response or remission on the diet (DiRe), can be used to predict success or failure of long-term dietary therapy. Methods: We collected data from the multicenter randomized trial of the CD exclusion diet (CDED). We analyzed data from 73 children with mild to moderate CD (mean age, 14.2 ± 2.7 y) randomly assigned to groups given either exclusive enteral nutrition (EEN, n = 34) or the CDED with 50% (partial) enteral nutrition (n = 39). Patients were examined at baseline and at weeks 3 and 6 of the diet. Remission was defined as CD activity index scores below 10 and response was defined as a decrease in score of 12.5 points or clinical remission. Inflammation was assessed by measurement of C-reactive protein. Results: At week 3 of the diet, 82% of patients in the CDED group and 85% of patients in the EEN group had a DiRe. Median serum levels of C-reactive protein had decreased from 24 mg/L at baseline to 5.0 mg/L at week 3 (P

Data on inflammatory bowel disease (IBD) phenotypes among the Arab population in Israel or in the neighboring Arab countries is scarce. We aimed to assess differences in disease phenotype among Arab and Jewish children living in Israel. We performed a retrospective chart review of pediatric IBD cases, which were diagnosed at the Schneider Children’s Medical Center and Ha’Emek Medical Center in Israel between 2000 and 2014. Demographic, clinical, and phenotypic variables were compared between Arabs and Jews from Eastern (Sephardic) and Western (Ashkenazi) origin. Seventy-one Arab children with IBD were compared with 165 Ashkenazi and 158 Sephardic Jewish children. Age and gender did not differ between groups. Sephardic and Ashkenazi Jewish Crohn’s disease (CD) patients had significantly more stenotic behavior (24 and 26 vs. 5%, p = 0.03) and less fistulzing perianal disease (15 and 11 vs. 31%, p = 0.014) compared with Arab patients. Arab children with ulcerative colitis (UC) had more severe disease at diagnosis compared to Sephardic and Ashkenazi Jews reflected by higher Pediatric UC Activity Index (45 vs. 35 and 35, respectively, p = 0.03). Arab patients had significantly lower proportion of anti-Saccharomyces cerevisiae antibodies positivity (in CD) and perinuclear anti-neutrophil cytoplasmic antibodies positivity (in UC) than both Sephardic and Ashkenazi Jewish children (23 vs. 53 and 65%, p = 0.002 and 35 vs. 60 and 75%, respectively, p = 0.002). Arab and Jewish children with IBD differ in disease characteristics and severity. Whether genetic or environmental factors are the cause for these differences is yet to be determined.

Background: Paediatric ulcerative colitis [UC] is more extensive than adult disease, and more often refractory to mesalamine. However, no prospective trials have evaluated mesalamine enemas for inducing remission in children. Our goal was to evaluate the ability of mesalamine enemas to induce remission in mild to moderate paediatric UC refractory to oral mesalamine. Methods: This was an open-label arm of a previously reported randomised controlled trial of once-daily mesalamine in active paediatric UC [MUPPIT trial]. Children aged 4-18 years, with a Paediatric Ulcerative Colitis Activity Index [PUCAI] score of 10-55, were enrolled after failing at least 3 weeks of full-dose oral mesalamine. Patients treated with steroids or enemas in the previous month and those with isolated proctitis were excluded. Children received Pentasa (R) enemas 25 mg/kg [up to 1g] daily for 3 weeks with the previous oral dose. The primary endpoint was clinical remission by Week 3. Results: A total of 38 children were enrolled (mean age 14.6 +/- 2.3 years; 17/38 [45%] with extensive colitis). Clinical remission was obtained in 16 [42%] and response was obtained in 27 [71%] at Week 3. Eight children deteriorated and required steroids. There were no differences in baseline parameters between those who entered or failed to enter remission, including disease extent [43% in left-sided and 41% in extensive colitis] and disease activity [44% in mild and 41% in moderate activity]. Conclusion: Clinical remission can be markedly increased in children who are refractory to oral mesalamaine by adding mesalamine enemas for 3 weeks, before commencing steroids.

CD55 (complement decay-accelerating factor) inhibits the alternative and classical arms of the complement pathway. Three patients with protein-losing enteropathy and a genetic variant predicted to result in loss of function of CD55 had a response to eculizumab.

AIM Elevated levels of anti-tissue transglutaminase (anti-tTG) antibody may spontaneously normalise in children with newly diagnosed type 1 diabetes, even if they eat gluten. The prevalence of this phenomenon and predictors of a subsequent coeliac disease (CD) diagnosis were determined. METHODS The medical records of children diagnosed with type 1 diabetes at Ha'Emek Medical Centre, Israel, from 2007 to 2015, were retrospectively reviewed for elevated anti-tTG antibody levels. Demographic, clinical, laboratory and histological findings were compared between CD patients and those with transient coeliac serology. RESULTS Of 425 patients with new onset type 1 diabetes, 34 (8%) had elevated anti-tTG antibodies: CD was diagnosed in 14, anti-tTG normalisation occurred in 13 and duodenal biopsies did not suggest CD in seven without anti-tTG antibody normalisation. Protective factors for a subsequent CD diagnosis were older age (p = 0.009) and mildly elevated anti-tTG antibody levels at the time of the type 1 diabetes diagnosis (p = 0.007), and decreased anti-tTG levels within six months of diagnosis (p = 0.03). CONCLUSION Serological follow-up of a diet containing gluten is recommended for children who have newly diagnosed type 1 diabetes and slightly elevated anti-tTG antibodies with no symptoms that suggest CD.

Background & Aims Exclusive enteral nutrition (EEN) is recommended for children with mild to moderate Crohn’s disease (CD), but implementation is challenging. We compared EEN with the CD exclusion diet (CDED), a whole-food diet coupled with partial enteral nutrition (PEN), designed to reduce exposure to dietary components that have adverse effects on the microbiome and intestinal barrier. Methods We performed a 12-week prospective trial of children with mild to moderate CD. The children were randomly assigned to a group that received CDED plus 50% of calories from formula (Modulen, Nestle) for 6 weeks (stage 1) followed by CDED with 25% PEN from weeks 7 to 12 (stage 2) (n = 40, group 1) or a group that received EEN for 6 weeks followed by a free diet with 25% PEN from weeks 7 to 12 (n = 38, group 2). Patients were evaluated at baseline and weeks 3, 6, and 12 and laboratory tests were performed; 16S ribosomal RNA gene (V4V5) sequencing was performed on stool samples. The primary endpoint was dietary tolerance. Secondary endpoints were intention to treat (ITT) remission at week 6 (pediatric CD activity index score below 10) and corticosteroid-free ITT sustained remission at week 12. Results Four patients withdrew from the study because of intolerance by 48 hours, 74 patients (mean age 14.2 ± 2.7 years) were included for remission analysis. The combination of CDED and PEN was tolerated in 39 children (97.5%), whereas EEN was tolerated by 28 children (73.6%) (P = .002; odds ratio for tolerance of CDED and PEN, 13.92; 95% confidence interval [CI] 1.68–115.14). At week 6, 30 (75%) of 40 children given CDED plus PEN were in corticosteroid-free remission vs 20 (59%) of 34 children given EEN (P = .38). At week 12, 28 (75.6%) of 37 children given CDED plus PEN were in corticosteroid-free remission compared with 14 (45.1%) of 31 children given EEN and then PEN (P = .01; odds ratio for remission in children given CDED and PEN, 3.77; CI 1.34–10.59). In children given CDED plus PEN, corticosteroid-free remission was associated with sustained reductions in inflammation (based on serum level of C-reactive protein and fecal level of calprotectin) and fecal Proteobacteria. Conclusion CDED plus PEN was better tolerated than EEN in children with mild to moderate CD. Both diets were effective in inducing remission by week 6. The combination CDED plus PEN induced sustained remission in a significantly higher proportion of patients than EEN, and produced changes in the fecal microbiome associated with remission. These data support use of CDED plus PEN to induce remission in children with CD. Clinicaltrials.gov no: NCT01728870 .

Background: Trials in adults suggested that, in ulcerative colitis [UC], once-daily [OD] dosing of 5-ASA [5-amino salicylic acid] may be as or more effective than twice-daily [BD] dosing. In this induction of remission, investigator-blinded, randomised controlled-trial, we aimed to compare effectiveness and safety of once-versus twice-daily mesalazine in paediatric UC. Methods: Children, aged 4-18 years with a PUCAI [Paediatric Ulcerative Colitis Activity Index] of 10-55 points at inclusion, were randomised in blocks of six with blinded allocation to OD or BD mesalazine, using a weight-based dosing table. The primary outcome was mean PUCAI score at Week 6. Results: A total of 83/86 randomised children were eligible and analysed: 43 in the OD group and 40 in the BD group (mean age 14 +/- 2.7 years, 43 [52%] males, 51 [62%] extensive colitis). The groups did not differ with regard to disease activity or any other parameter at baseline. There was no difference in median PUCAI score between the OD group and BD group at Week 6: 15 (interquartile range [IQR] 5-40) versus 10 [0-40]; p = 0.48]. Response was seen in 25 [60%] OD versus 25 [63%] BD dosing [p = 0.78]. Proportion of children in remission [PUCAI 0.2]. Conclusions: In this first randomised controlled trial in children, no differences were found between OD and BD dosing for any clinical outcome. Remission was achieved in 35% of children treated with mesalazine for active UC.

3-year-old girl was admitted for sudden onset of 12 hours of high fever, vomiting, malaise, and skin rash the day prior to admission, with no history of trauma or drugs. The patient showed a petechial and morbilliform rash, swelling, redness and a dry dark blue-purple lesion on the right big toe (Figure). Blood tests showed thrombocytopenia (18 10 9 /L), high C-reactive protein, and no signs of disseminated intravascular coagulation. A presumptive diagnosis of loxoscelism was made, based on the clinical picture in an endemic area during the warm season. The patient was treated with antibiotics until blood and wound cultures appeared negative and prednisone for 5 days, and was discharged after 4 days with resolution of the systemic symptoms and laboratory improvement. The dermonecrosis underwent desquamation and healing within 3 weeks. Loxoscelism describes the reactions and lesions caused by bites from spiders of the genus Loxosceles. 1-3 In Israel, certified bites of L rufescens have been reported and many cases of loxoscelism have been described. 1,4 Most bites are benign, but local and/or systemic reactions can appear. The typical local manifestation is dermonecrosis. Systemic symptoms include morbilliform rash, fever, chills, nausea, vomiting, malaise, arthralgia, and myalgia; hemolytic anemia and leukocytosis; less frequent thrombocytopenia, disseminated intravascular coagulation, renal failure, multiorgan failure, and even death, more commonly in children than in adults. 1-3 Loxosceles venom contains enzymes (hyaluronidase, alkaline phosphatase, esterase, and sphingomyelinase D2) responsible for tissue destruction and cytotoxicity. 1-3 The diagnosis is rarely based on identification of the spider. A presumptive diagnosis is made clinically, based on