Mutations in RPSA and NKX2-3 link development of the spleen and intestinal vasculature.

Idiopathic intestinal varicosis is a developmental disorder defined by dilated and convoluted submucosal veins in the colon or small bowel. A limited number of families with idiopathic intestinal varices has been reported, but the genetic cause has not yet been identified. We performed whole-exome and targeted Sanger sequencing of candidate genes in five intestinal varicosis families. In four families, mutations in the RPSA gene were found, a gene previously linked to congenital asplenia. Individuals in these pedigrees had intestinal varicose veins and angiodysplasia, often in combination with asplenia. In a further four-generation pedigree that only showed intestinal varicosities, the RPSA gene was normal. Instead, a nonsense mutation in the homeobox gene NKX2-3 was detected which cosegregated with the disease in this large family with a LOD (logarithm of the odds) score of 3.3. NKX2-3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice. Our results provide a molecular basis for familial idiopathic intestinal varices. We provide evidence for a relationship between the molecular pathways underlying the development of the spleen and intestinal mucosal vasculature that is conserved between humans and mice. We propose that clinical management of intestinal varices, should include assessment of a functional spleen.

Intestinal Failure and Aberrant Lipid Metabolism in Patients With DGAT1 Deficiency.

BACKGROUND & AIMS: Congenital diarrheal disorders are rare inherited intestinal disorders characterized by intractable, sometimes life-threatening, diarrhea and nutrient malabsorption; some have been associated with mutations in diacylglycerol-acyltransferase 1 (DGAT1), which catalyzes formation of triacylglycerol from diacylglycerol and acyl-CoA. We investigated the mechanisms by which DGAT1 deficiency contributes to intestinal failure using patient-derived organoids. METHODS: We collected blood samples from 10 patients, from 6 unrelated pedigrees, who presented with early-onset severe diarrhea and/or vomiting, hypoalbuminemia, and/or (fatal) protein-losing enteropathy with intestinal failure; we performed next-generation sequencing analysis of DNA from 8 patients. Organoids were generated from duodenal biopsies from 3 patients and 3 healthy individuals (controls). Caco-2 cells and patient-derived dermal fibroblasts were transfected or transduced with vectors that express full-length or mutant forms of DGAT1 or full-length DGAT2. We performed CRISPR/Cas9-guided disruption of DGAT1 in control intestinal organoids. Cells and organoids were analyzed by immunoblot, immunofluorescence, flow cytometry, chromatography, quantitative real-time polymerase chain reaction, and for the activity of caspases 3 and 7. RESULTS: In the 10 patients, we identified 5 bi-allelic loss-of-function mutations in DGAT1. In patient-derived fibroblasts and organoids, the mutations reduced expression of DGAT1 protein and altered triacylglycerol metabolism, resulting in decreased lipid droplet formation after oleic acid addition. Expression of full-length DGAT2 in patient-derived fibroblasts restored formation of lipid droplets. Organoids derived from patients with DGAT1 mutations were more susceptible to lipid-induced cell death than control organoids. CONCLUSIONS: We identified a large cohort of patients with congenital diarrheal disorders with mutations in DGAT1 that reduced expression of its product; dermal fibroblasts and intestinal organoids derived from these patients had altered lipid metabolism and were susceptible to lipid-induced cell death. Expression of full-length wildtype DGAT1 or DGAT2 restored normal lipid metabolism in these cells. These findings indicate the importance of DGAT1 in fat metabolism and lipotoxicity in the intestinal epithelium. A fat-free diet might serve as the first line of therapy for patients with reduced DGAT1 expression. It is important to identify genetic variants associated with congenital diarrheal disorders for proper diagnosis and selection of treatment strategies.

Pediatric Achalasia in the Netherlands: Incidence, Clinical Course, and Quality of Life.

OBJECTIVE: To assess incidence and clinical course of Dutch patients with achalasia diagnosed before 18 years of age as well as their current symptoms and quality of life (QoL). STUDY DESIGN: Retrospective medical chart review and a cross-sectional study assessing current clinical status using the Eckardt score and reflux disease questionnaire. General QoL was measured using Kidscreen-52 for patients <18 years of age or to 36-Item Short Form Health Survey for patients ≥18 years of age. RESULTS: Between 1990 and 2013, 87 children (mean age 11.4 ± 3.4 years, 60% male) diagnosed with achalasia in the Netherlands were included. Mean incidence was 0.1/100,000/y (range 0.03-0.21). Initial treatment was pneumodilation (PD) in 68 (79%) patients and Heller myotomy (HM) in 18 (21%) patients. Retreatment was required more often after initial PD compared with initial HM (88% vs 22%; P < .0001). More complications of initial treatment occurred after HM compared with PD (55.6% vs 1.5%; P < .0001). Three esophageal perforations were seen after HM (16.7%), 1 after PD (1.5%). Sixty-three of 87 (72%) patients were prospectively contacted. Median Eckardt score was 3 (IQR 2-5), with 32 patients (44.5%) having positive scores suggesting active disease. Reflux disease questionnaire scores were higher after initial HM vs PD (1.71 [0.96-2.90] vs 0.58 [0-1.56]; P = .005). The 36-Item Short Form Health Survey (n = 52) was lower compared with healthy population norms for 7/8 domains. Kidscreen-52 (n = 20) was similar to population norms. CONCLUSIONS: Pediatric achalasia is rare and relapse rates are high after initial treatment, especially after pneumodilation, but with more complications after HM. Symptoms often persist into adulthood, without any clinical follow-up. QoL in adulthood was decreased.

Adalimumab therapy in children with Crohn disease previously treated with infliximab.

OBJECTIVES: Adalimumab, a humanised anti-tumour necrosis factor antibody, is an effective treatment in adult patients with refractory Crohn disease (CD). The available literature on its efficacy in children remains limited. We aimed to evaluate the real-world efficacy in paediatric patients with CD and compare the efficacy between infliximab (IFX) nonresponders and patients who lost response to IFX. METHODS: All Dutch patients with CD receiving adalimumab before the age of 18 years after previous IFX therapy were identified. We analysed longitudinal disease activity, assessed by the mathematically weighted Pediatric Crohn's Disease Activity Index (wPCDAI) or the physician global assessment (PGA), and adverse events (AEs). RESULTS: Fifty-three patients with CD were included. Twelve patients received monotherapy and the others received combination treatment with thiopurines (n = 21), methotrexate (n = 11), steroids (n = 7), or exclusive enteral nutrition (n = 2). Median follow-up was 12 months (interquartile range 5-23). Remission was reached in 34 patients (64%, wPCDAI < 12.5 or PGA = 0) after a median of 3.3 months, and maintained by 50% for 2 years. Eleven patients (21%) reached response but not remission (decrease in wPCDAI ≥ 17.5 or decrease in PGA). Eighteen patients (34%) failed adalimumab treatment because of nonresponse (n = 4), lost response (n = 11), or AEs (n = 3). More IFX nonresponders failed adalimumab treatment than patients who lost response to IFX (2/3 vs 8/34, hazard ratio 18.8, 95% confidence interval 1.1-303.6). Only 1 patient encountered a serious AE, a severe but nonfatal infection. CONCLUSIONS: In clinical practice, adalimumab induces remission in two-thirds of children with IFX refractory CD.

Intestinal obstruction syndromes in cystic fibrosis: meconium ileus, distal intestinal obstruction syndrome, and constipation.

Meconium ileus at birth, distal intestinal obstruction syndrome (DIOS), and constipation are an interrelated group of intestinal obstruction syndromes with a variable severity of obstruction that occurs in cystic fibrosis patients. Long-term follow-up studies show that today meconium ileus is not a risk factor for impaired nutritional status, pulmonary function, or survival. DIOS and constipation are frequently seen in cystic fibrosis patients, especially later in life; genetic, dietary, and other associations have been explored. Diagnosis of DIOS is based on suggestive symptoms, with a right lower quadrant mass confirmed on abdominal radiography, whereas symptoms of constipation are milder and of longer standing. In DIOS, early aggressive laxative treatment with oral laxatives (polyethylene glycol) or intestinal lavage with balanced osmotic electrolyte solution and rehydration is required, which now makes the need for surgical interventions rare. Constipation can generally be well controlled with polyethylene glycol maintenance treatment.

Infliximab dependency in pediatric Crohn's disease: long-term follow-up of an unselected cohort.

BACKGROUND: Infliximab is effective for induction and maintenance of remission in Crohn's disease. It is unknown how long patients should be kept on infliximab therapy. The primary aim of this study was to assess duration of effective maintenance therapy and infliximab dependency in pediatric CD patients initially responding to infliximab therapy. METHODS: All pediatric patients treated with infliximab by pediatric gastroenterologists in the Netherlands because of severe luminal or fistulizing CD with initial response to infliximab therapy were reviewed. Duration of therapy, clinical response and adverse events were recorded. RESULTS: Sixty-six CD patients (37 boys) in 10 hospitals were initially responding to infliximab therapy. Mean age at the start of infliximab therapy was 14.5 years (range, 8.1-18.5 years). Mean follow-up since infliximab was started was 41.3 months (range 12-165). In total, 991 infusions were administered. Analysis demonstrates that 15.2% of patients had prolonged response, while 56.1% were infliximab dependent and 28.8% lost response. In total, 10 patients (15.2%) developed an infection during infliximab therapy and 8 (12.1%) had an immediate allergic reaction. CONCLUSIONS: Good clinical response to maintenance infliximab therapy was seen in 70% of patients. Infliximab maintenance therapy seems very effective and safe in pediatric CD. However, more than half of the patients in this cohort is dependent on repeated infliximab infusions. The number of infliximab infusions received when patients lost response to infliximab was diverse. There was no statistical difference regarding response to infliximab therapy when started early as compared to later in the course of Crohn's disease.

A dietary fiber mixture versus lactulose in the treatment of childhood constipation: a double-blind randomized controlled trial.

BACKGROUND: Constipation is a common problem in children. As first-line treatment, increased dietary fiber is often advocated. To our knowledge, however, no large studies evaluating the effect of dietary fibers in childhood constipation have been published. PATIENTS AND METHODS: A randomized, double-blind, prospective controlled study was performed. Patients received either a fiber mixture or lactulose in a yogurt drink. After a baseline period of 1 week, patients were treated for 8 weeks followed by 4 weeks of weaning. Polyethylene glycol 3350 was added if no clinical improvement was observed after 3 weeks. Using a standardized bowel diary, parents recorded defecation frequency during the treatment period. In addition, incontinence frequency, stool consistency, presence of abdominal pain and flatulence, necessity for step-up medication, and dry weight of feces were recorded, as were adverse effects. RESULTS: A total of 147 children were eligible; 12 children wished not to participate. Of the remaining children, 65 were randomized to treatment with fiber mixture and 70 to treatment with lactulose. In all, 97 children completed the study. No difference was found between the groups after the treatment period concerning defecation frequency (P = 0.481) and fecal incontinence frequency (P = 0.084). However, consistency of stools was softer in the lactulose group (P = 0.01). Abdominal pain and flatulence scores were comparable (P = 0.395 and P = 0.739, respectively). The necessity of step-up medication during the treatment period was comparable (P = 0.996), as were taste scores (P = 0.657). No serious adverse effects were registered. CONCLUSIONS: A fluid fiber mixture and lactulose give comparable results in the treatment of childhood constipation.

Efficacy of Home Telemonitoring versus Conventional Follow-up: A Randomized Controlled Trial among Teenagers with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Conventional follow-up of teenagers with inflammatory bowel diseases [IBD] is done during scheduled outpatient visits regardless of how well the patient feels. We designed a telemonitoring strategy for early recognition of flares and compared its efficacy with conventional follow-up. METHODS: We used a multicentre randomized trial in patients aged 10-19 years with IBD in clinical remission at baseline. Participants assigned to telemonitoring received automated alerts to complete a symptom score and send a stool sample for measurement of calprotectin. This resulted in an individual prediction for flare with associated treatment advice and test interval. In conventional follow-up the health check interval was left to the physician's discretion. The primary endpoint was cumulative incidence of disease flares. Secondary endpoints were percentage of participants with a positive change in quality-of-life and cost-effectiveness of the intervention. RESULTS: We included 170 participants [84 telemonitoring; 86 conventional follow-up]. At 52 weeks the mean number of face-to-face visits was significantly lower in the telemonitoring group compared to conventional follow-up [3.6 vs 4.3, p < 0.001]. The incidence of flares [33 vs 34%, p = 0.93] and the proportion of participants reporting positive change in quality-of-life [54 vs 44%, p = 0.27] were similar. Mean annual cost-saving was €89 and increased to €360 in those compliant to the protocol. CONCLUSIONS: Telemonitoring is as safe as conventional follow-up, and reduces outpatient visits and societal costs. The positive impact on quality-of-life was similar in the two groups. This strategy is attractive for teenagers and families, and health professionals may be interested in using it to keep teenagers who are well out of hospital and ease pressure on overstretched outpatient services. TRIAL REGISTRATION: NTR3759 [Netherlands Trial Registry].

Total biliary diversion as a treatment option for patients with progressive familial intrahepatic cholestasis and Alagille syndrome.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) with low gamma-glutamyl transpeptidase (GGT) and Alagille syndrome are associated with persistent cholestasis and severe pruritus. Various types of biliary diversion have been used to reduce this pruritus and prevent liver dysfunction. We report our experience concerning the efficacy and safety of total biliary diversion (TBD) as an additional treatment option. METHODS: TBD was performed in four PFIC patients and one patient with Alagille syndrome, and was accomplished by anastomosing a jejunal segment to the choledochal duct terminating as an end stoma, or by disconnecting the choledochal duct after previous cholecystojejunocutaneostomy. RESULTS: TBD resulted in a marked improvement of symptoms and biochemical parameters in all PFIC patients. Despite relief of pruritus, cholestasis persisted in the Alagille patient. During 5-15years of follow-up, no clinical signs of fat malabsorption such as diarrhea or weight loss were encountered. However, to maintain adequate levels of fat-soluble vitamins, especially of vitamin K, substantial supplementation was necessary. CONCLUSIONS: Total biliary diversion can be a useful surgical treatment option for patients with low-GGT PFIC and possibly also Alagille syndrome, when partial biliary diversion is insufficient. It can be performed without inducing clinical signs of fat malabsorption although individualized supplementation of fat-soluble vitamins with careful monitoring is warranted.

Development of inflammatory bowel disease in patients with juvenile idiopathic arthritis treated with etanercept.

OBJECTIVE: With the increasing use of etanercept for juvenile idiopathic arthritis (JIA) new possible adverse events are reported including new autoimmune diseases. Our purpose was to examine if the incidence of inflammatory bowel disease (IBD) in patients with JIA using etanercept is higher than in the healthy age-matched population. We give the clinical characteristics of the IBD in patients with JIA using etanercept. METHODS: The national JIA registries for etanercept of The Netherlands, Germany, Finland, Denmark, and Italy were searched for patients with JIA and IBD. The total number of patient-years was used to calculate incidence. The physicians of the identified patients were asked to give clinical details. RESULTS: Thirteen cases of IBD in JIA patients were identified in the registries between 1999 and 2008. The IBD incidence in JIA patients while using etanercept was 362 per 100,000 patient-years under etanercept, about 43 times higher than in the general pediatric population. Clinical presentation of IBD in JIA patients using etanercept was similar to that in non-JIA patients. The median time between onset of JIA and onset of IBD was 6 years and 10 months. The time between the start of etanercept and the first appearance of IBD symptoms was between 9 days and 4.5 years. CONCLUSION: The incidence of IBD in JIA patients using etanercept seems to be markedly increased, analyzing data from European registries. This incidence of IBD in the etanercept registries cannot be compared to the incidence of IBD in JIA patients using other treatment without etanercept, because such registries do not exist yet in all European countries. These findings are in keeping with a report of 8 new IBD cases occurring in French children with JIA using etanercept. These findings illustrate the need for large international disease-specific registries focused on outcome and pharmacovigilance.