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Background: Functional gastrointestinal disorders (FGIDs) are common during the pediatric age. FGIDs are not related to biochemical or structural abnormalities. However, since they have a high prevalence, several studies have evaluated an overlap between FGIDs and organic diseases. Individuals with celiac disease (CD) have been shown to be at an increased risk for functional abdominal pain, even if they adhere well to a gluten-free diet (GFD). Little information is available for the pediatric age group. The aims of our study were to evaluate the prevalence of FGIDS in CD children 1 year after diagnosis and to compare the prevalence of FGIDs in CD children on a GFD with processed foods compared with those on a GFD with natural products. Aim: To assess the prevalence of FGIDs in children with CD after 1 year of follow-up and to compare the prevalence of FGIDs in children with CD on a GFD with processed foods and in children on a GFD with natural products. Methods: We recruited pediatric patients aged 1-18 years with a new CD diagnosis. Participants were randomized to two groups: Group A on a GFD with processed foods (diet 1); and group B on a GFD with natural products (diet 2). Clinical monitoring, diet assessment and the questionnaire on pediatric gastrointestinal symptoms-Rome IV version were performed at diagnosis (T0) and after 12 mo of follow-up (T1). Dietary intake was assessed using a 3-d food diary record. Data from the diaries were evaluated using WinFood nutrient analysis software. We assessed the prevalence of FGIDs at T1 and the correlation with the type of GFD. Results: We registered 104 CD children, with 55 patients in group A (53.0%) and 49 patients in group B (47.0%). Initially, 30 of the 55 (54.5%) CD children were symptomatic in group A, while 25 of 49 (51.0%) were symptomatic in group B. At T1, in spite of a low or negative serology for CD, FGIDs prevalence was 10/55 (18.0%) in group A and 8/49 (16.3%) in group B, with no statistically significant difference between the two groups (P = 0.780). At T1 the macro- and micronutrient intake was similar across the two groups with no significant differences in nutrient analysis. However, in both groups at T1 we found that a lower prevalence of FGIDs (P = 0.055) was associated with an inferior caloric (odds ratio = 0.99, 95% confidence interval: 0.99-1.00) and fat (odds ratio = 0.33, 95% confidence interval: 0.65-0.95) intake. Conclusion: Our results showed that CD children on a GFD have gastrointestinal symptoms with an elevated prevalence of FGIDs. Our study suggests that developing FGIDs may be linked to caloric intake and percentage of food fat, but it does not change between a GFD with processed foods or a GFD with natural products. However, long-term monitoring is required to evaluate a correlation between FGIDs and various types of GFDs.

Background Celiac disease (CD) is an autoimmune enteropathy in which HLA-DQ haplotypes define susceptibility. Our aim was to evaluate if belonging to a certain HLA-DQ class risk could be associated to the clinical, serological and histological presentation of CD. Methods We performed a retrospective observational monocentric study including all 300 patients diagnosed with CD, who underwent HLA typing. Clinical, serological and histological data was collected from clinical records and their association with HLA-DQ class risk was verified through statistical tests. Results In our sample mean age at onset was 6.7 ± 4.2 years, with a prevalence of females (n = 183; 61%), typical symptoms (n = 242; 80.6%) and anti-tTG IgA ≥ 100 U/mL (n = 194; 64.7%). Family history was present only in 19% (n = 57) of patients, and it was not significantly associated with any of the clinical and demographical data analyzed or the belonging to a certain HLA-DQ class risk. We found in the male population more frequently a coexistence of CD and atopic syndrome (males: n = 47; 40.2%; females: n = 50; 27.3%; p = 0.020). Early age of onset, instead, was associated with typical symptoms (m = 6.4 ± 4; p = 0.045) and elevated liver enzymes (m = 5 ± 3.8; p m = 8.2 ± 4; p = 0.01). We observed statistically significant influences of HLA class risk on antibodies and liver enzymes levels: G1, G4 and G2 classes showed more frequently anti-tTG IgA ≥ 100 U/mL (n = 44; 80%, n = 16; 69.6%, n = 48; 67.6% respectively; p-value = 0.037), and in patients from G2 class we found enhanced liver enzymes (n = 28; 39.4%; p-value = 0.005). HLA class risk was still significantly associated with anti-tTG ≥ 100 (p = 0.044) and with hypertransaminasemia (p = 0.010) after a multiple logistic regression adjusted for the effect of gender, age at onset and family history. Conclusions We failed to prove an association between HLA-DQ genotypes and the clinical features in our CD pediatric patients. Although, our results suggest an effect of the DQB1–02 allele not only on the level of antibodies to tTG, but possibly also on liver involvement.

Purpose. Immune system of some autistic patients could be abnormally triggered by gluten/casein assumption. The prevalence of antibodies to gliadin and milk proteins in autistic children with paired/impaired intestinal permeability and under dietary regimen either regular or restricted is reported.Methods. 162 ASDs and 44 healthy children were investigated for intestinal permeability, tissue-transglutaminase (tTG), anti-endomysium antibodies (EMA)-IgA, and total mucosal IgA to exclude celiac disease; HLA-DQ2/-DQ8 haplotypes; total systemic antibodies (IgA, IgG, and IgE); specific systemic antibodies:α-gliadin (AGA-IgA and IgG), deamidated–gliadin-peptide (DGP-IgA and IgG), total specific gliadin IgG (all fractions:α,β,γ, andω),β-lactoglobulin IgG,α-lactalbumin IgG, casein IgG; and milk IgE, casein IgE, gluten IgE, -lactoglobulin IgE, andα-lactalbumin IgE.Results. AGA-IgG and DPG-IgG titers resulted to be higher in ASDs compared to controls and are only partially influenced by diet regimen. Casein IgG titers resulted to be more frequently and significantly higher in ASDs than in controls. Intestinal permeability was increased in 25.6% of ASDs compared to 2.3% of healthy children. Systemic antibodies production was not influenced by paired/impaired intestinal permeability.Conclusions. Immune system of a subgroup of ASDs is triggered by gluten and casein; this could be related either to AGA, DPG, and Casein IgG elevated production or to impaired intestinal barrier function.

OBJECTIVES Existing studies usually do not measure the free vitamin D in pediatric patients with inflammatory bowel disease (IBD) and not consider the effect of inflammation on vitamin D levels. The aim of our study was to evaluate the concentrations of vitamin D-binding protein (VDBP), total and free 25-hydroxyvitamin-D (25(OH)D), and to correlate these values with the disease activity markers. METHODS Newly diagnosed children with IBD and a group of healthy controls (HCs) were enrolled. VDBP and total and free 25(OH)D levels were measured by enzyme-linked immunosorbent assay and compared using the Student t test. In each patient with IBD, the activity scores of disease and the main inflammation markers were correlated to total and free 25(OH)D levels. C-reactive protein was also measured in the control group, and it was related to VDBP by a linear regression test for all the groups. RESULTS Fifty-one consecutive children were enrolled: IBD = 33, HC = 18. Levels of total 25(OH)D were higher in HC than in patients with IBD (P = 0.01). The free/total 25(OH)D ratio was, however, higher in patients with IBD compared to HC (P

BACKGROUND Recurrent abdominal pain (RAP) is a common disorder in childhood. However, it is not clear what the incidence of organic disease is, in the absence of "alarm" symptoms or signs. The aim of this study was to clarify if the performance of diagnostic tests can be useful in revealing underlying organic disorders. METHODS The participants were 4- to 16-year-old children, who had been referred to our tertiary care pediatric center. A total of 98 children (48 males, 50 females) with RAP but without any alarm symptoms or signs were selected. In the 98 selected children, the performance of diagnostic tests for suspected organic diseases was recommended. RESULTS Fourteen children refused diagnostic tests. Forty-eight out of 84 children with RAP without any alarm symptoms and signs received a diagnosis of organic disease. Nineteen (22.6%) patients resulted positive for lactose intolerance. Seventeen patients (20.2%) were affected by celiac disease. Two (2.4%) patients were positive for cow milk allergy. Nine (10.7%) patients resulted positive for ureteral calculosis. One (1.2%) was affected by teniasis. Thirty-three children of the 38 children tested positive for lactose intolerance, celiac disease or cow-milk allergy were completely symptom-free at the 6 months follow-up and the remaining five patients reported a significant lower mean level of pain severity overall. Seven of 9 children with calculosis improved symptomatology. At the next follow-up six children were again suffering from RAP. CONCLUSIONS Children with RAP should be referred to pediatric gastroenterologists if symptoms persist; testing should be performed even in the absence of alarm signs because of the high prevalence of underlying organic pathologies.

Background Iron deficiency anemia in celiac disease is related to impaired duodenal mucosal uptake, due to villous atrophy. Iron enters the enterocytes through an apical divalent metal transporter, DMT1. Different DMT1 transcripts have been identified, depending on the presence of an iron-responsive element that allows DMT1 up-regulation during iron starvation. An intronic DMT1 polymorphism, IVS4+44C>A, has been associated with metal toxicity, and the CC-carriers show high iron levels. Aims This study investigates the association between DMT1 IVS4+44C>A and anemia in a cohort of 387 Italian celiac children, and the functional role of the polymorphism. Methods and results By association analysis, we found that DMT1 IVS4+44-AA genotype confers a four-fold risk of developing anemia, despite of atrophy degree. By analysis of mRNA from gastroesophageal biopsies, we found that total DMT1 is significantly upregulated in presence of mild, but not severe, atrophy, independently from IVS4+44C>A variant, and in normal but not in atrophic CC-biopsies. Moreover, we found that A-allele is associated to preferential expression of the DMT1 transcripts lacking the iron-responsive element, thus limiting the DMT1 overexpression that normally occurs to respond to iron starvation. Discussion Possibly, the IVS4+44-AA-related dysregulation of the iron-induced changes in DMT1 expression is not able to impair iron absorption in physiological condition. However, if exacerbated by the concomitant massive loss of functional absorbing tissue paralleling worsened stages of villus atrophy, it might be ineffective in counteracting iron deficiency, despite of DMT1 overexpression. Conclusion We suggest, for the first time, that celiac disease may unmask the contribution of the DMT1 IVS4+44C>A polymorphism to the risk of anemia.

Oral rehydration therapy is the recommended treatment for acute childhood gastroenteritis. The aim of this study was to assess the efficacy and safety of gelatin tannate plus oral rehydration compared with oral rehydration alone. We conducted a multicenter, parallel, randomized, controlled, single-blind, prospective, open-label trial. A central randomization center used computer generated tables to allocate treatments. The study was performed in two medical centers in Italy. Sixty patients 3–72 months of age with acute gastroenteritis were recruited (median age 18 months; age range 3–66 months): 29 received an oral rehydration solution (ORS) and 31 an ORS plus gelatin tannate (ORS + G). The primary outcome was the number of bowel movements 48 and 72 h after initiating treatment. Secondary outcomes were: duration of diarrhea, stool characteristics and adverse events. No patient was lost at follow-up. No significant difference in the number of bowel movements after 48 h was reported (2.7 ± 1.3 ORS + G; 3.2 ± 0.8 ORS; p = 0.06), although the ORS + G group showed a significant improvement in stool consistency (3.7 ± 1.0 vs. 4.3 ± 0.8; p = 0.005). At 72 h, a significant reduction in bowel movements was reported in the ORS + G group compared with the ORS group (1.0 ± 1.4 vs. 2.0 ± 1.7; p = 0.01). Mean duration of diarrhea was significantly lower in the ORS + G group than in the ORS only group (76.8 ± 19.2 vs. 108 ± 24.0 h; p

Summary: Gyrate atrophy of the choroid and retina is an autosomal recessive chorioretinal dystrophy which leads to a slowly progressive loss of vision. The primary defect is due to a deficiency of the enzyme ornithine δ-aminotransferase, which is responsible for markedly elevated levels of ornithine in plasma and other body fluids. Although several therapeutic regimens have been proposed, the reduction in ornithine accumulation obtained by reducing the intake of its precursor arginine (semisynthetic low-arginine diet) is the one most practised. In this clinical and molecular study we report a patient with hyperornithinaemia and gyrate atrophy of the choroid and retina who had been diagnosed when she was 3 years 9 months old. She also presented mild mental retardation, delayed language development and speech defects. The patient has recently been found to be homozygous for the new Gly91Arg amino acid substitution of the enzyme ornithine δ-aminotransferase. This mutation lies in a region of the mature protein that is considered crucial for the mitochondrial targeting activity. In this patient, a 28-year treatment with a completely natural low-protein diet (0.8 g/kg per day of natural protein) has been able to significantly reduce ornithine plasma levels, and to greatly delay the natural progression of the chorioretinal changes. This study suggests that, in the long-term treatment of gyrate atrophy, the efficacy in slowing the progression of chorioretinal changes and the palatability of a completely natural low-protein diet make this treatment a potentially viable alternative in patients refusing the semisynthetic diet.

Objectives Studies of adults and children with celiac disease have reported an increased risk of overweight during gluten-free diet (GFD). The fat mass and obesity-associated gene (FTO) variant rs9939609 has been associated with increased risk of developing obesity in children and adults. Methods In our study, we analyzed the effect of this variant on weight gain in a cohort of 280 children with celiac disease on GFD. Results We found that after a mean follow-up time of 3.0 years on GFD, FTO polymorphism influenced significantly the mean change in body mass index z score (P = 0.01). Conclusions We conclude that the FTO gene contributes to determine weight changes in children with celiac disease on GFD.

Aims: The role of esophageal clearance is still scarcely investigated in patients with gastroesophageal reflux disease (GERD). We aimed to assess esophageal clearance in adolescents by means of bolus clearance time (BCT) and to verify if there is any difference among subgroups of GERD patients according to endoscopic and impedance-pH monitoring findings. Methods: We revised endoscopic and impedance-pH monitoring (off-therapy) data of 28 consecutive adolescents (range 12–16 years). We evaluated acid exposure time (AET), total number of reflux episodes, baseline impedance (BI), and BCT. According to impedance-pH monitoring features, adolescents were grouped into pH/MII negative (normal AET and normal number of refluxes), and pH/MII positive (abnormal AET and/or abnormal number of refluxes). This latter were further subgrouped on the basis of abnormal/normal AET (pH+/-) and abnormal/normal number of refluxes (MII+/-). Finally, adolescents were also classified as erosive and non erosive reflux disease (ERD, NERD). Results: We observed 22 pH/MII positive adolescents (7 ERD and 15 NERD). Eight patients were further subgrouped as pH+/MII-, 6 as pH-/MII+ and 8 as pH+/MII+. BCT values (in seconds) progressively decreased from pH+/MII+, pH+/MII-, pH-/MII+ to pH-/MII- (34.5 ± 8.1 vs. 22.0 ± 7.2 vs. 16.4 ± 4.5 vs. 10.1 ± 2.1, respectively; p < 0.001), whereas BI gradually increased (1236 ± 358 vs. 1592 ± 762 vs. 1854 ± 567 vs. 3256 ± 743, respectively; p < 0.001). There was an inverse correlation between BCT and BI, and a direct correlation between BCT and AET (p < 0.0001) and ERD presence (p < 0.0001). Conclusions: BCT seems to reflects reflux severity, and it is inversely correlated to BI, a marker of mucosal integrity, supporting the role of esophageal clearance in the GERD pathophysiology.

We describe an infant with juvenile chronic myelogenous leukemia (JCML), the diagnosis of which was made by the characteristic clinical and hematologic findings. The absence of a related HLA-compatible donor for bone marrow transplantation coupled with the awareness that chemotherapy is usually ineffective prompted our decision to treat the patient with lymphoblastoid interferon-alpha [alpha(Ly)-IFN]. During the 26-month course of treatment with alpha(Ly)-IFN an incomplete regression of hematologic and clinical findings was achieved. The above results, along with the easy administration and absence of considerable side effects, suggest that alpha(Ly)-IFN may be a useful therapeutic tool in patients affected by JCML awaiting bone marrow transplantation.

Background To evaluate whether the addition of a probiotic could improve Helicobacter pylori (H.P.) eradication rates and reduce the side effects of treatment in children. Methods Between July 2008 and July 2011 all patients with a clinical, laboratory and endoscopic diagnosis of H.P. positive gastritis referred to our Unit were included in the study. Patients suffering from allergy to any of drugs used in the study, with previous attempts to eradicate H.P. and those who received antibiotics, PPIs or probiotics within 4 weeks were excluded from the present study. Patients were randomized into two therapy regimens (group A and B): both groups received standard triple treatment (omeprazole, amoxicillin and clarithromycin) while only group B patients were also given a probiotic (Probinul - Cadigroup). Patients compliance was evaluated at the end of the treatment. Successful eradication was defined as a negative 13 C-urea breath test (C13-ubt) result four weeks after therapy discontinuation. Results A total of 68 histopathologically proven H.P.-infection children (32 male and 36 females) were included in the study. All of the patients in both groups used more than 90% of the therapies and no patients were lost at follow up. All side effects were selflimiting and disappeared once the therapy was terminated. Epigastric pain was observed in 6 (17.6%) group A vs 2 (5.8%) group B patients (P Conclusion The addition of a probiotic formula to triple therapy significantly decreased the frequency of epigastric pain, nausea, vomiting and diarrhea.

Celiac disease (CD) is a chronic inflammatory disease of the small bowel that occurs with the ingestion of gluten, found in several grains products. Although HLA-DQ2 variant is required for the gluten-derived peptide gliadin presentation by antigen-presenting cells to T-cells, non-HLA genetic factors account for the majority of heritable risk. Several genome-wide association studies have identified susceptibility loci for CD on chromosome 1. Cells of the immune system express the Cannabinoid Receptor type 2 (CB2), a plasma-membrane receptor activated by both endogenous and exogenous cannabinoids. Consistent data evidence that CB2 is linked to a variety of immune functional events and that, in the course of an inflammatory process, an increased number of receptors becomes available for activation. The Cannabinoid Receptor type 2 gene (CNR2; GeneID1269) maps on 1p36.11. In order to investigate the possible involvement of CB2 in CD establishment, immunohistochemistry toward CB2 receptor and CD4+ cells in small bowel biopsies from celiac children and association analysis, through TaqMan assay, of a CNR2 common missense variant, rs35761398 (CAA/CGG), resulting in the aminoacidic substitution of Glutamine at codon 63 with Arginine (Q63R), in a cohort of 327 South Italian children have been performed. We observed in this study that CB2 is up-regulated in CD small bowel biopsies and CNR2 rs35761398 is significantly associated with CD (χ 2 = 37.064; d.f. 1; p = 1.14 × 10 -9). Our findings suggest a role of CB2 in CD. The Q63R variant, increasing more than six-fold the risk for CD susceptibility, might eventually represent a novel molecular biomarker for CD risk stratification. Indeed, we provide here further evidence that CB2 receptor plays a critical role in autoimmunity susceptibility and indicates that it represents a molecular target to pharmacologically modulate the immune components in CD. © 2012 Elsevier Ltd.

Background Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is a strong candidate gene in autoimmunity susceptibility. In particular, the CTLA4 CT60 A/G dimorphism has been associated with celiac disease (CD) and was reported to be strongly associated with autoimmune thyroid disease (AITD). Aims This study aimed to investigate the possible influences of the CTLA4 CT60 A/G polymorphism in the susceptibility of Italian children to CD and in the predisposition to develop AITD in children with CD. Patients and methods We genotyped 317 Italian celiac children, including 44 patients (13.9%) who developed AITD after CD diagnosis and 350 controls. Results The CTLA4 CT60 GG genotype distribution did not show any significant difference between children with CD and control population (p = 0.4). On the contrary, the frequency of the GG genotype was significantly higher in patients with CD complicated with AITD than in control subjects (p = 0.002) and CD patients without AITD (p = 0.02). Conclusion Our data show a significant effect of the CTLA4 CT60G allele at the homozygous state on the risk of developing AITD in children with CD and suggest that the reported association of the CTLA4 CT60 A/G polymorphism with CD is limited to the subgroup of patients who are or will be complicated with AITD.

Fanconi's anemia (FA) is a rare, genetically heterogeneous, autosomal recessive disorder characterized by bone marrow failure, congenital abnormalities, chromosome instability, and increased susceptibility to neoplasia. Congenital abnormalities vary in location and in severity and not all patients are affected. Although the primary defect of FA is unknown, hypersensitivity to the clastogenic effect of agents that introduce cross-links in the DNA, such as diepoxybutane (DEB), is a marker of the FA phenotype in patients suffering from aplastic anemia without the physical characteristics of the syndrome and, conversely, in cases with abnormalities in the preanemic phase. We report the case of two dizygotic twins suffering from FA with discordant hematologic data. The DEB test repeated several times in various laboratories yielded conflicting results, whereas cell cycle studies by flow cytometry revealed a pattern typical of FA patients. Moreover, the flow cytometric pattern was correlated with the clinical severity of the disease.

Objective To describe a mother and her 2 sons affected by idiopathic intracranial hypertension (IIH), associated in the sons with root irritation symptom. Unlike the other 4 families reported previously, obesity was not present in our patients. Design Case reports. Setting Department of pediatrics in a university school of Medicine, Naples, Italy. Patients A mother (aged 36 years) and her 2 sons (aged 14 and 9 years) developed IIH at different times. Neuroimaging showed an empty sella in the mother, while IIH was associated with spinal and radicular pain in her 2 sons. The mother and the younger son developed permanent visual loss. Conclusions Ophthalmologic follow-up in our patients indicates that IIH is a chronic disease. Surgical treatment should be considered an option.

Carbamate and organophosphate pesticides are widely used all over the world. Poisoning with these substances may produce both immediate and delayed neurotoxic effects. We report the case of a 4-year-old boy who was admitted to the Pediatric Department of the Second University of Naples for evaluation of stupor, lethargy, severe hypotonia, generalized weakness of his arms and legs, ataxia, dysmetria, miosis, excessive salivation and tearing. The pesticide carbaryl (1-naphthyl-N-methylcarbamate) was identified in blood and urine samples. On admission, magnetic resonance imaging (MRI) was unremarkable; on day 11, MRI showed central pontine myelinolysis. The demyelination improved after 4 months and disappeared after 2 years. Various underlying and concomitant diseases have been described in children with central pontine myelinolysis but, to our knowledge, the finding of pontine myelinolysis after carbamate poisoning has not yet been described.

A 4.5-year-old boy was admitted to three different hospitals because of a tendency towards dehydration and polyuria, along with normal blood pressure, hypochloraemia, hypokalaemia, metabolic alkalosis and an impaired urinary concentrating ability. A renal biopsy failed to reveal juxtaglomerular hyperplasia. The clinical and laboratory findings failed to improve despite supplementation with potassium chloride and treatment with indomethacin. The urine was found to contain frusemide. The parents denied any drug administration to the boy. The child is now doing well more than 1 year after separation from his mother. Since ingestion of diuretic cannot be differentiated from true Bartter syndrome by blood and urinary electrolyte measurements alone, a diuretic screen is warranted in children with findings consistent with Bartter syndrome.

The authors report a case of congenital rubella in a 7-month-old female infant presenting a Blueberry Muffin Rash. Blueberry Muffin Syndrome is a cutaneous manifestation characterized by widespread maculo papular lesions of a reddish-blue or magenta colour, due to persistent dermal erythropoiesis in patients with congenital viral infections.

Background Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten. Gluten-sensitive individuals (GS) cannot tolerate gluten and may develop gastrointestinal symptoms similar to those in CD, but the overall clinical picture is generally less severe and is not accompanied by the concurrence of tissue transglutaminase autoantibodies or autoimmune comorbidities. By studying and comparing mucosal expression of genes associated with intestinal barrier function, as well as innate and adaptive immunity in CD compared with GS, we sought to better understand the similarities and differences between these two gluten-associated disorders. Methods CD, GS and healthy, gluten-tolerant individuals were enrolled in this study. Intestinal permeability was evaluated using a lactulose and mannitol probe, and mucosal biopsy specimens were collected to study the expression of genes involved in barrier function and immunity. Results Unlike CD, GS is not associated with increased intestinal permeability. In fact, this was significantly reduced in GS compared with controls (P = 0.0308), paralleled by significantly increased expression of claudin (CLDN) 4 (P = 0.0286). Relative to controls, adaptive immunity markers interleukin (IL)-6 (P = 0.0124) and IL-21 (P = 0.0572) were expressed at higher levels in CD but not in GS, while expression of the innate immunity marker Toll-like receptor (TLR) 2 was increased in GS but not in CD (P = 0.0295). Finally, expression of the T-regulatory cell marker FOXP3 was significantly reduced in GS relative to controls (P = 0.0325) and CD patients (P = 0.0293). Conclusions This study shows that the two gluten-associated disorders, CD and GS, are different clinical entities, and it contributes to the characterization of GS as a condition associated with prevalent gluten-induced activation of innate, rather than adaptive, immune responses in the absence of detectable changes in mucosal barrier function.