We conclude that crypt fission was present predominantly during infancy, and crypt hyperplasia occurred during both infancy and childhood.

Background and objectives:Gastro-oesophageal reflux disease (GORD) is a common gastrointestinal disorder with a genetic component. Our aim was to identify genetic factors associated with GORD.Patients and methods:Four separate patient cohorts were analysed using a step-wise approach. (1) Whole genome linkage analysis was performed in 36 families. (2) Candidate genes were tested for GORD association in a trio cohort. (3) Genetic association was replicated in a case–control cohort. We also investigated genetic association to hiatus hernia (HH). (4) Protein expression was analysed in oesophageal biopsies.Results:A region on chromosome 2, containing collagen type III alpha 1 (COL3A1), was identified (LOD = 3.3) in families with dominant transmission of GORD, stratified for hiatus hernia (HH). COL3A1 showed significant association with GORD in an independent paediatric trio cohort (pcorr = 0.003). The association was male specific (pcorr = 0.018). The COL3A1 association was replicated in an independent adult case control cohort (pcorr = 0.022). Moreover, male specific association to HH (pcorr = 0.019) was found for a SNP not associated to GORD. Collagen type III protein was more abundant in oesophageal biopsies from male patients with GORD (p = 0.03).Conclusion:COL3A1 is a disease-associated gene in both paediatric and adult GORD. Furthermore, we show that COL3A1 is genetically associated with HH in adult males. The GORD- and HH-associated alleles are different, indicating two separate mechanisms leading to disease. Our data provides new insight into GORD aetiology, identifying a connective tissue component and indicating a tissue remodelling mechanism in GORD. Our results implicate gender differences in the genetic risk for both for GORD and HH.

Background: Persistent crying in infancy is common and may be associated with gastroesophageal reflux disease (GERD) and/or non-IgE-mediated cow's milk protein allergy (CMPA). We aimed to document upper gastrointestinal motility events in infants with CMPA and compare these to findings in infants with functional GERD. Methods: Infants aged 2 to 26 weeks with persistent crying, GERD symptoms and possible CMPA were included. Symptoms were recorded by 48-hour cry-fuss chart and validated reflux questionnaire (infant GERD questionnaire [IGERDQ]). Infants underwent a blinded milk elimination-challenge sequence to diagnose CMPA. GERD parameters and mucosal integrity were assessed by 24-hour pH-impedance monitoring before and after cow's milk protein (CMP) elimination. 13C-octanoate breath testing for gastric emptying dynamics, dual-sugar intestinal permeability, fecal calprotectin, and serum vitamin D were also measured. Results: Fifty infants (mean age 13 ± 7 weeks; 27 boys) were enrolled. On the basis of CMP elimination-challenge outcomes, 14 (28%) were categorized as non-IgE-mediated CMPA, and 17 (34%) were not allergic to milk; 12 infants with equivocal findings, and 7 with incomplete data were excluded. There were no baseline differences in GERD parameters between infants with and without CMPA. In the CMPA group, CMP elimination resulted in a significant reduction in reflux symptoms, esophageal acid exposure (reflux index), acid clearance time, and an increase in esophageal mucosal impedance. Conclusions: In infants with persistent crying, upper gastrointestinal motility parameters did not reliably differentiate between non-IgE-mediated CMPA and functional GERD. In the group with non-IgE-mediated CMPA, elimination of CMP significantly improved GERD symptoms, esophageal peristaltic function, and mucosal integrity.

BackgroundHigh‐resolution esophageal manometry (HREM), derived esophageal pressure topography metrics (EPT), integrated relaxation pressure (IRP), and distal latency (DL) are influenced by age and size. Combined pressure and intraluminal impedance also allow derivation of metrics that define distension pressure and bolus flow timing. We prospectively investigated the effects of esophageal length on these metrics to determine whether adjustment strategies are required for children.MethodsFifty‐five children (12.3 ± 4.5 years) referred for HREM, and 30 healthy adult volunteers (46.9 ± 3.8 years) were included. Studies were performed using the MMS system and a standardized protocol including 10 × 5 mL thin liquid bolus swallows (SBM kit, Trisco Foods) and analyzed via Swallow Gateway (www.swallowgateway.com). Esophageal distension pressures and swallow latencies were determined in addition to EGJ resting pressure and standard EPT metrics. Effects of esophageal length were examined using partial correlation, correcting for age. Adult‐derived upper limits were adjusted for length using the slopes of the identified linear equations.Key ResultsMean esophageal length in children was 16.8 ± 2.8 cm and correlated significantly with age (r = 0.787, P = .000). Shorter length correlated with higher EGJ resting pressure and 4‐s integrated relaxation pressures (IRP), distension pressures, and shorter contraction latencies. Ten patients had an IRP above the adult upper limit. Adjustment for esophageal length reduced the number of patients with elevated IRP to three.Conclusions & InferencesWe prospectively confirmed that certain EPT metrics, as well as potential useful adjunct pressure‐impedance measures such as distension pressure, are substantially influenced by esophageal length and require adjusted diagnostic thresholds specifically for children.

ObjectiveWnt-β-catenin signalling is essential for intestinal stem cells. Our aim was to investigate the relationship between intestinal stem cells and crypt fission which peaks during infancy.DesignDuodenal biopsies were obtained during endoscopy to assess the severity of reflux oesophagitis of 15 infants, children and teenagers, which would not affect the duodenum. Samples of small intestine were also obtained from rats 7–72 days of life. Crypt fission was assessed using microdissection of 100 whole crypts and recording the percentage of bifid crypts. Intestinal LGR5+ stem cells were identified by in situ hybridisation. Rats were treated with Dickkopf to block Wnt-β-catenin signalling.ResultsCrypt fission peaked during infancy before declining after 3–4 years in humans and after 21 days of life in rats. Occasional mitotic figures were seen in bifid crypts during early fission. Stem cells were elevated for a greater period during infancy and childhood in humans. Clustering of Paneth cells was present around the stem cells at the crypt base. Dickkopf reduced the number of stem cells and crypt fission to 45% and 29%, respectively, of control values, showing dependence of both crypt fission and Lgr5+ stem cells on Wnt signalling. However, Dickkopf did not decrease mitotic count per crypt, indicating a difference in signalling between stem cells and their progeny in the transit amplifying zone.ConclusionCrypt fission peaks during infancy and is dependent on intestinal stem cells. This is relatively hidden by ‘a cloak of invisibility’ due to the low proliferation of stem cells.