Tracking of bone mass from childhood to puberty: a 7-year follow-up. The CHAMPS study DK.

Bone mass in childhood is highly influenced by puberty. At the same age, bone mass was higher for pubertal than pre-pubertal children. A high level of tracking during 7 years from childhood through puberty was shown, indicating that early levels of bone mass may be important for later bone health. INTRODUCTION: Bone mass development in childhood varies by sex and age, but also by pubertal stage. The objectives of this study were to (1) describe bone mass development in childhood as it relates to pubertal onset and to (2) determine the degree of tracking from childhood to adolescence. METHODS: A longitudinal study with 7 years of follow-up was initiated in 2008 to include 831 children (407 boys) aged 8 to 17 years. Participants underwent whole body dual-energy X-ray absorptiometry (DXA) scanning, blood collection to quantify luteinizing hormone levels, and Tanner stage self-assessment three times during the 7-year follow-up. Total body less head bone mineral content, areal bone mineral density, and bone area were used to describe development in bone accrual and to examine tracking over 7 years. RESULTS: Bone mass in pubertal children is higher than that of pre-pubertal children at the same age. Analysing tracking with quintiles of bone mass Z-scores in 2008 and 2015 showed that more than 80% of participants remained in the same or neighbouring quintile over the study period. Tracking was confirmed by correlation coefficients between Z-scores at baseline and 7-year follow-up (range, 0.80-0.84). CONCLUSIONS: Bone mass is highly influenced by pubertal onset, and pubertal stage should be considered when examining children's bone health. Because bone mass indices track from childhood into puberty, children with low bone mass may be at risk of developing osteoporosis later in life.

Prenatal pesticide exposure and PON1 genotype associated with adolescent body fat distribution evaluated by dual X-ray absorptiometry (DXA).

Many modern pesticides have endocrine disrupting abilities and early-life exposure may affect growth and disease risk later in life. Previously, we reported associations between prenatal pesticide exposure and higher childhood body fat content measured by anthropometry. The associations were affected by child PON1 Q192R genotype. We aimed to study whether prenatal pesticide exposure was still associated with body fat content and distribution in the children at puberty and the potential impact of both maternal and child PON1 Q192R genotype. In this prospective cohort study of 247 children born by occupationally exposed or unexposed women (greenhouse workers and controls) two follow-up examinations (age 10-15 and 11-16 years) including simple anthropometry, skinfold measurements, pubertal staging and blood sampling were performed. Total and regional fat% was determined by dual X-ray absorptiometry (DXA) at age 10-15. Prenatal pesticide exposure was associated with increased total, android, and gynoid fat percentage (DXA) at age 10-15 years after adjustment for sex, socioeconomic status, and puberty (all ß = 0.5 standard deviation score (SDS) p < 0.05). Stratified by sex, the associations were significant in girls (total fat: ß = 0.7 SDS, android-gynoid ratio: ß = 0.1, both p < 0.05), but not in boys. Carrying the R-allele (child or mother, separately, or both) augmented the differences between exposed and unexposed children (total fat: ß = 1.0 SDS, ß = 0.8 SDS, p < 0.05, respectively, and ß = 1.2 SDS, p < 0.01). No exposure-related differences were found if either the child or mother had the QQ wild-type. At age 11-16, exposed children tended to have a higher total fat% estimated by skinfolds than unexposed children (p = 0.06). No significant associations between prenatal exposure and body mass index or waist circumference were found. Prenatal pesticide exposure was associated with higher adolescent body fat content, including android fat deposition, independent of puberty. Girls appeared more susceptible than boys. Furthermore, the association depended on maternal and child PON1 Q192R genotype.

ESPGHAN position paper on management of percutaneous endoscopic gastrostomy in children and adolescents.

OBJECTIVES: This European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) position statement provides a comprehensive guide for health care providers to manage percutaneous endoscopic gastrostomy tubes in a safe, effective, and appropriate way. METHODS: Relevant literature from searches of PubMed, CINAHL, and recent guidelines was reviewed. In the absence of evidence, recommendations reflect the expert opinion of the authors. Final consensus was obtained by multiple e-mail exchange and during 3 face-to-face meetings of the gastroenterology committee of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. RESULTS: Endoscopically placed gastrostomy devices are essential in the management of children with feeding and nutritional problems. The article focuses on practical issues such as indications and contraindications. CONCLUSIONS: The decision to place an endoscopic gastrostomy has to be made by an appropriate multidisciplinary team, which then provides active follow-up and care for the child and the device.

Management guidelines of eosinophilic esophagitis in childhood.

OBJECTIVES: Eosinophilic esophagitis (EoE) represents a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. With few exceptions, 15 eosinophils per high-power field (peak value) in ≥1 biopsy specimens are considered a minimum threshold for a diagnosis of EoE. The disease is restricted to the esophagus, and other causes of esophageal eosinophilia should be excluded, specifically proton pump inhibitor-responsive esophageal eosinophilia. This position paper aims at providing practical guidelines for the management of children and adolescents with EoE. METHODS: Relevant literature from searches of PubMed, CINAHL, and recent guidelines was reviewed. In the absence of an evidence base, recommendations reflect the expert opinion of the authors. Final consensus was obtained during 3 face-to-face meetings of the Gastroenterology Committee and 1 teleconference. RESULTS: The cornerstone of treatment is an elimination diet (targeted or empiric elimination diet, amino acid-based formula) and/or swallowed, topical corticosteroids. Systemic corticosteroids are reserved for severe symptoms requiring rapid relief or where other treatments have failed. Esophageal dilatation is an option in children with EoE who have esophageal stenosis unresponsive to drug therapy. Maintenance treatment may be required in case of frequent relapse, although an optimal regimen still needs to be determined. CONCLUSIONS: EoE is a chronic, relapsing inflammatory disease with largely unquantified long-term consequences. Investigations and treatment are tailored to the individual and must not create more morbidity for the patient and family than the disease itself. Better maintenance treatment as well as biomarkers for assessing treatment response and predicting long-term complications is urgently needed.

A practical guide for the diagnosis of primary enteric nervous system disorders.

OBJECTIVE: Primary gastrointestinal neuropathies are a heterogeneous group of enteric nervous system (ENS) disorders that continue to cause difficulties in diagnosis and histological interpretation. Recently, an international working group published guidelines for histological techniques and reporting, along with a classification of gastrointestinal neuromuscular pathology. The aim of this article was to review and summarize the key issues for pediatric gastroenterologists on the diagnostic workup of congenital ENS disorders. In addition, we provide further commentary on the continuing controversies in the field. RESULTS: Although the diagnostic criteria for Hirschsprung disease are well established, those for other forms of dysganglionosis remain ill-defined. Appropriate tissue sampling, handling, and expert interpretation are crucial to maximize diagnostic accuracy and reduce interobserver variability. The absence of validated age-related normal values for neuronal density, along with the lack of correlation between clinical and histological findings, result in significant diagnostic uncertainties while diagnosing quantitative aberrations such as hypoganglionosis or ultrashort Hirschsprung disease. Intestinal neuronal dysplasia remains a histological description of unclear significance. CONCLUSIONS: The evaluation of cellular quantitative or qualitative abnormalities of the ENS for clinical diagnosis remains complex. Such analysis should be carried out in laboratories that have the necessary expertise and access to their own validated reference values.

Diagnostic approach and management of cow's-milk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines.

OBJECTIVES: This guideline provides recommendations for the diagnosis and management of suspected cow's-milk protein allergy (CMPA) in Europe. It presents a practical approach with a diagnostic algorithm and is based on recently published evidence-based guidelines on CMPA. DIAGNOSIS: If CMPA is suspected by history and examination, then strict allergen avoidance is initiated. In certain circumstances (eg, a clear history of immediate symptoms, a life-threatening reaction with a positive test for CMP-specific IgE), the diagnosis can be made without a milk challenge. In all other circumstances, a controlled oral food challenge (open or blind) under medical supervision is required to confirm or exclude the diagnosis of CMPA. TREATMENT: In breast-fed infants, the mother should start a strict CMP-free diet. Non-breast-fed infants with confirmed CMPA should receive an extensively hydrolyzed protein-based formula with proven efficacy in appropriate clinical trials; amino acids-based formulae are reserved for certain situations. Soy protein formula, if tolerated, is an option beyond 6 months of age. Nutritional counseling and regular monitoring of growth are mandatory in all age groups requiring CMP exclusion. REEVALUATION: Patients should be reevaluated every 6 to 12 months to assess whether they have developed tolerance to CMP. This is achieved in >75% by 3 years of age and >90% by 6 years of age. Inappropriate or overly long dietary eliminations should be avoided. Such restrictions may impair the quality of life of both child and family, induce improper growth, and incur unnecessary health care costs.

Coeliac disease diagnosis: ESPGHAN 1990 criteria or need for a change? Results of a questionnaire.

BACKGROUND AND OBJECTIVES: A revision of criteria for diagnosing coeliac disease (CD) is being conducted by The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). In parallel, we have performed a survey aimed to evaluate present practices for CD among paediatric gastroenterologists and to learn their views on the need for modification of present criteria for CD diagnosis. PATIENTS AND METHODS: Questionnaires were distributed to experienced paediatric gastroenterologists (ESPGHAN members) via the Internet. RESULTS: Overall, 95 valid questionnaires were available for analysis, pertaining to 28 different countries, with the majority of responders treating patients with CD for >15 years. Only about 12% of the responders comply with present criteria, noncompliance being related mainly to the challenge policy. Approximately 90% request a revision and modification of the present criteria. Forty-four percent want to omit the small bowel biopsy in symptomatic children with positive anti-tissue transglutaminase immunoglobulin (Ig) A or endomysial IgA antibodies, especially if they are DQ2/DQ8 positive. For silent cases detected by screening with convincingly positive anti-tissue transglutaminase IgA or EMA IgA, about 30% consider that no small bowel biopsy should be required in selected cases. Adding human leukocyte antigen typing in the diagnostic workup was asked for by 42% of the responders. As for gluten challenge, a new policy is advocated restricting its obligation to cases whenever the diagnosis is doubtful or unclear. CONCLUSIONS: Based on these opinions, revision of the ESPGHAN criteria for diagnosing CD is urgently needed.

European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease.

OBJECTIVE: Diagnostic criteria for coeliac disease (CD) from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) were published in 1990. Since then, the autoantigen in CD, tissue transglutaminase, has been identified; the perception of CD has changed from that of a rather uncommon enteropathy to a common multiorgan disease strongly dependent on the haplotypes human leukocyte antigen (HLA)-DQ2 and HLA-DQ8; and CD-specific antibody tests have improved. METHODS: A panel of 17 experts defined CD and developed new diagnostic criteria based on the Delphi process. Two groups of patients were defined with different diagnostic approaches to diagnose CD: children with symptoms suggestive of CD (group 1) and asymptomatic children at increased risk for CD (group 2). The 2004 National Institutes of Health/Agency for Healthcare Research and Quality report and a systematic literature search on antibody tests for CD in paediatric patients covering the years 2004 to 2009 was the basis for the evidence-based recommendations on CD-specific antibody testing. RESULTS: In group 1, the diagnosis of CD is based on symptoms, positive serology, and histology that is consistent with CD. If immunoglobulin A anti-tissue transglutaminase type 2 antibody titers are high (>10 times the upper limit of normal), then the option is to diagnose CD without duodenal biopsies by applying a strict protocol with further laboratory tests. In group 2, the diagnosis of CD is based on positive serology and histology. HLA-DQ2 and HLA-DQ8 testing is valuable because CD is unlikely if both haplotypes are negative. CONCLUSIONS: The aim of the new guidelines was to achieve a high diagnostic accuracy and to reduce the burden for patients and their families. The performance of these guidelines in clinical practice should be evaluated prospectively.

Sex-specific association of the human PTPN22 1858T-allele with type 1 diabetes.

Type 1 diabetes (T1D) is a common organ-specific autoimmune disease of complex aetiology, involving the interaction of a large number of disease-associated genes. By comparison of a Danish population sample of 253 Caucasian children and adolescents with T1D and a control group consisted of 354 unrelated healthy blood donors, the present study provides evidence of an isolated association of the disease-associated PTPN22 1858T-allele with T1D to the female sex. Furthermore, the present data suggest that PTPN22 genotypes affect the age of onset in a sex-specific manner. The increased frequency of the risk allele and its association with age at onset in female T1D children and adolescents indicates that the genetic contribution to disease pathogenesis is more prominent in females in this population of Danish patients.

Expression of human PTPN22 alleles.

Considering the female predominance in most of the autoimmune disorders that associate with the PTPN22 Trp620 variant and the complexity by which this variant influences immunologic tolerance, the objective of this study was to ascertain if the allele-specific expression of the disease-associated Arg620Trp polymorphism is affected by cis-acting or sex-specific trans-acting factor/s (e.g. sex-hormones). The use of the allele-specific transcript quantification of the Arg620Trp encoding 1858T polymorphism revealed no difference in the expression of the 1858C- and T-alleles in non-stimulated peripheral blood mononuclear cells (PBMCs) from non-pregnant female subjects, male subjects or pregnant female subjects in first or third trimester (P=0.70), respectively. While the transcription of PTPN22 in anti-CD3/anti-CD28 stimulated PBMCs increased fourfold (P<0.0001) and 13-fold (P<0.0001) after 48 and 72 h of activation, respectively, the expression of PTPN22 1858C- and T-alleles increased to the same extent (P=0.64). The present result essentially excludes such phenomena as a partial explanation for the female predominance in most of the autoimmune disorders that associate with the PTPN22 Trp620 variant.

Eosinophilia in the upper gastrointestinal tract is not a characteristic feature in cow's milk sensitive gastro-oesophageal reflux disease. Measurement by two methodologies.

BACKGROUND: An association between cow's milk hypersensitivity (CMH) and gastro-oesophageal reflux disease (GERD) in childhood has been reported in the past decade. AIM: To assess whether biopsies from the upper gastrointestinal tract of children with cow's milk sensitive GERD have a specific allergic inflammatory pattern, and to compare two different techniques for measuring inflammatory cells in gastrointestinal biopsies. METHODS: GERD was diagnosed by means of endoscopy and oesophageal pH monitoring. Hypersensitivity to cow's milk was determined by an elimination diet and cow's milk challenge. Allergic inflammatory cells in upper gastrointestinal biopsies were identified by immunohistochemistry and their numbers were assessed by two different methods-counting the number of cells/high power field and using the computerised Cast-Grid system. RESULTS: Cow's milk sensitive GERD was identified in 10 of 17 children with severe GERD (median age, 7.8 years). Biopsies from children with endoscopic oesophagitis had significantly increased numbers of mast cells and T cells. No differences in the number of eosinophils, mast cells, or T cells were found between children with CMH and those with primary GERD. Several differences were found between the two different histological quantification methods. CONCLUSIONS: CMH was found not only in infants but also in school age children with GERD. Histology did not identify the cow's milk sensitive GERD subgroup. The computerised histological method provides a more complete evaluation based upon total biopsy area, and helped to limit the bias of uneven biopsy size.

A putative regulatory polymorphism in PD-1 is associated with nephropathy in a population-based cohort of systemic lupus erythematosus patients.

The association between polymorphisms in the programmed death (PD-1) gene and susceptibility to systemic lupus erythematosus (SLE) was determined using genomic DNA, isolated from a population-based cohort of 95 SLE patients and 155 healthy controls. Polymorphisms in the complete PD-1 gene except the large intron 1 were detected by sequencing. Furthermore, the patients were stratified according to the presence or absence of lupus nephropathy. The influence of the detected single nuclear polymorphisms (SNPs) on this specific clinical disease parameter was determined. In total, we identified 12 single nucleotide polymorphisms, of which six were novel and eight were considered to be rare (the frequency of the minor allele of these was less than 1% in our study populations). We found a significant association of an intronic 6867C/G SNP in the PD-1 gene with the presence of lupus nephropathy. As the 6867C/G SNP is located in a putative binding site for the transcriptional repressor ZEB, the associated allele of this SNP potentially alters the transcriptional regulation of PD-1. This report, for the first time, indicates that a 6867C/G SNP of the PD-1 gene is associated with lupus nephropathy in Caucasian SLE patients.

Severe gastroesophageal reflux disease and cow milk hypersensitivity in infants and children: disease association and evaluation of a new challenge procedure.

BACKGROUND: Gastroesophageal reflux disease (GERD) and cow milk hypersensitivity are frequent disorders of infancy. A possible causative association between these two entities has been suggested. OBJECTIVE: The primary aim was to elucidate whether a causative relationship between the two entities could be established in a population of infants and children. A secondary aim was to evaluate whether cow milk challenge during esophageal pH monitoring is useful as an objective method to identify this subgroup of patients. METHODS: Upper endoscopy followed by a 48-hour esophageal pH monitoring with cow's milk elimination diet at day 1 and challenge at day 2. Cow milk hypersensitivity was later verified by elimination diet and a second open (in patients < 3 years of age) or double-blind placebo-controlled (in patients > or = 3 years of age) challenge. Skin prick test, specific serum immunoglobulin E and skin patch test were used as supplementary procedures. Follow-up endoscopy and pH monitoring were performed after 3 months of treatment (omeprazole versus elimination diet dependent on evidence of food hypersensitivity). RESULTS: Eighteen of 42 investigated patients had severe GERD, defined as endoscopic esophagitis and/or a reflux index > 10%. Among these patients, a group of 10 patients with GERD and cow milk hypersensitivity was identified. This group had a significantly higher reflux index compared with children with primary GERD. No significant increase was noted in reflux index during simultaneous pH monitoring and milk challenge. CONCLUSIONS: An association between GERD and cow milk hypersensitivity was observed in both infants and children with severe GERD. Simultaneous cow milk challenge and pH monitoring had limited value as a method to identify this subgroup.

Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes.

The immunoreceptor programmed cell death-1 (PD-1) is reported to play an important role in the regulation of peripheral tolerance in rodents, and it was recently shown that a polymorphism in a regulatory site of the PD-1 gene is associated with susceptibility to the autoimmune disease systemic lupus erythematosus (SLE) in humans. We investigated the existence of single-nucleotide polymorphisms (SNPs) in the PD-1 gene in patients with type 1 diabetes in comparison with healthy control subjects, by analyzing 94 children and adolescents with type 1 diabetes diagnosed before their eighteenth birthday (male : female = 52 : 42) and 155 control subjects. Polymorphisms in the complete PD-1 gene (minus the large intron 1) were detected by sequencing. In total, we identified 14 SNPs, of which six have been previously described, including an intronic 7146G/A SNP. We found this polymorphism to be associated with the development of type 1 diabetes [found in 12.2% of diabetic individuals vs 6.8% in controls; odds ratio (OR) = 1.92]. The associated allele is previously shown to alter a transcription factor-binding site (RUNX1/AML1), and the results of this study suggest that this allele could act as an additional susceptibility allele to type 1 diabetes.

Gastrointestinal malformations in Funen county, Denmark--epidemiology, associated malformations, surgery and mortality.

AIM: To report the epidemiology, associated malformations, morbidity and mortality for the first 5 years of life for infants with gastrointestinal malformations (GIM). METHODS: Population-based study using data from a registry of congenital malformations (Eurocat) and follow-up data from hospital records. The study included livebirths, fetal deaths with a gestational age of 20 weeks and older and induced abortions after prenatal diagnosis of malformations born during the period 1980 - 1993. RESULTS: A total of 109 infants/fetuses with 118 GIM were included in the study giving a prevalence of 15.3 (12.6 - 18.5) cases per 10 000 births. Anal atresia was present in seven of the 9 cases with more than one GIM. There were 38 cases (35 %) with associated malformations and/or karyotype anomalies. Thirty-two of the 90 live-born infants died during the first 5 years of life with the majority of deaths during the first week of life. Mortality was significantly increased for infants with associated malformations or karyotype anomalies compared to infants with isolated GIM (p < 0.01). An uneventful surgical course was reported for 74 % of the 58 survivors. CONCLUSIONS: The prognosis for infants with GIM is highly dependent on the presence of associated malformations or karyotype anomalies. Surgery for GIM can be performed with low mortality. Morbidity is high for a small group of infants, but the majority of survivors have an uncomplicated surgical course.

IgE in unselected like-sexed monozygotic and dizygotic twins at birth and at 6 to 9 years of age: high but dissimilar genetic influence on IgE levels.

BACKGROUND: IgE is a major determinant of allergic disease. Twin analysis of serum levels of IgE has been carried out previously in children and adults with heritability estimates of 30% to 70% on the basis of ANOVA. OBJECTIVE: This study included the analysis of serum IgE in a population of 126 twins, 27 monozygotic pairs and 36 dizygotic pairs, studied at birth (cord blood [CB] IgE) and consecutively at the age of 6 to 9 years of age (serum IgE). METHODS: IgE was determined by means of RIA. ANOVA, correlation analysis, and structural equation modeling by maximal likelihood analysis was used for genetic analysis. RESULTS: Structural equation modeling by maximal likelihood analysis showed the best-fitting model to be the AE model (A for additive genetic variance and E for environmental variance) both at birth and later in childhood. The estimated heritability was 0.92 (95% CI, 0.84-0.95) for CB IgE and 0.78 (95% CI, 0.60-0.87) for serum IgE. The correlation between CB IgE and serum IgE was 0.04. CONCLUSIONS: The study demonstrated a higher genetic dependency of serum IgE than previously recognized. The low correlation between the IgE levels at birth and later in childhood suggested that different effector mechanisms may be operating at different ages.

Recurrent abdominal pain, food allergy and endoscopy.

Gastrointestinal food allergy, a well-recognized clinical entity, has a wide spectrum of clinical features, including cutaneous, respiratory and gastrointestinal symptoms and objective abnormalities. The gastrointestinal alterations in food allergy have been described throughout the gastrointestinal tract. Recurrent abdominal pain (RAP) is a common complaint in school-age children. The findings among children with RAP of an underlying food allergy associated with mucosal pathology of the foregut may support a causal relationship between food allergy and RAP. Further studies are needed to elucidate whether well-documented food allergy (based on double-blind placebo-controlled food challenges) is a major cause of RAP.

[Diagnostic benefit of gastrointestinal endoscopy in infants under one year of age--a two-year survey]. / Diagnostisk udbytte ved gastrointestinal endoskopi hos børn under et år--en toårs opgørelse.

INTRODUCTION: Gastrointestinal endoscopy in children is a well-established procedure. We reviewed our experience of endoscopy in infants below one year of age to evaluate indications, endoscopic findings, histology, and complications. MATERIAL AND METHODS: Twenty-eight infants were studied over a two-year period. Of these, 18 underwent upper endoscopy, six recto/sigmoidoscopy or colonoscopy, and four both procedures. RESULTS: The most common indication (10/22) for upper endoscopy was vomiting and suspicion of gastrooesophageal reflux disease. In these infants, 24-hour continuous monitoring of the oesophageal pH followed the procedure. Indications for lower endoscopy were rectal bleeding (n = 6) and intractable diarrhoea (n = 4). There were no complications to anaesthesia, endoscopy, or biopsy. Overall, there were endoscopic abnormalities in 82% and histological abnormalities in 75% of the infants. The diagnostic findings included rare disorders, such as eosinophilic gastroenteritis, microvillous inclusion disease, and chylomicron retention disease. Diagnosis of these diseases requires gastrointestinal biopsy. DISCUSSION: Gastrointestinal endoscopy is a safe procedure, which is a valuable part of the diagnostic work-up in a selected group of infants with long-lasting or severe gastrointestinal symptoms.