Pediatric Gastrointestinal Histopathology in Patients With Tetratricopeptide Repeat Domain 7A (TTC7A) Germline Mutations: A Rare Condition Leading to Multiple Intestinal Atresias, Severe Combined Immunodeficiency, and Congenital Enteropathy.

Mutations in the tetratricopeptide repeat domain 7A (TTC7A) gene are a rare cause of congenital enteropathy that can result in significant morbidity. TTC7A deficiency leads to disruption of the intestinal epithelium. The histopathology of this condition has been partly described in case reports and clinical studies. This manuscript describes an in-depth investigation of the pediatric gastrointestinal pathology of the largest histologically examined cohort with confirmed TTC7A mutations reported to date and, for the first time, compared the findings to age-matched and sex-matched control patients with intestinal atresia not thought to be associated with TTC7A mutations. Hematoxylin and eosin-stained slides of endoscopically obtained mucosal biopsies and surgical resection specimens from 7 patients with known TTC7A mutations were examined retrospectively. The microscopic findings were found to be on a spectrum from atresia-predominant to those with predominantly epithelial abnormalities. Several unique histopathologic characteristics were observed when compared with controls. These included neutrophilic colitis and prominent lamina propria eosinophilia throughout the gastrointestinal tract. Striking architectural abnormalities of the epithelium were observed in 4 of the 7 patients. The 5 patients with intestinal atresia demonstrated hypertrophy and disorganization of the colonic muscularis mucosae accompanied by bland spindle cell nodules within the intestinal wall. The components of the latter were further elucidated using immunohistochemistry, and we subsequently hypothesize that they represent obliterated mucosa with remnants of the muscularis mucosae. Finally, atrophic gastritis was noted in 4 patients. In conclusion, the unique histopathologic characteristics of TTC7A mutation-associated enteropathy described herein more fully describe this novel disease entity in infants who present with congenital enteropathy or enterocolitis.

Leukocytoclastic vasculitis in an adolescent with ulcerative colitis: Report of a case and review of the literature.

An adolescent female with long-standing, difficult-to-control ulcerative colitis developed leukocytoclastic vasculitis, a rare cutaneous extra-intestinal manifestation of the inflammatory bowel disease. The authors provide a literature review on leukocytoclastic vasculitis complicating ulcerative colitis. Furthermore, the clinical features of leukocytoclastic vasculitis are compared and contrasted with the more common cutaneous extra-intestinal manifestations of inflammatory bowel disease, erythema nodosum, and pyoderma gangrenosum.

Multicenter, randomized, double-blind study comparing 10, 20 and 40 mg pantoprazole in children (5-11 years) with symptomatic gastroesophageal reflux disease.

OBJECTIVE: To evaluate symptom improvement in 53 children (aged 5-11 years) with endoscopically proven gastroesophageal reflux disease (GERD) treated with pantoprazole (10, 20 and 40 mg) using the GERD Assessment of Symptoms in Pediatrics Questionnaire. METHODS: The GERD Assessment of Symptoms in Pediatrics Questionnaire was used to measure the frequency and severity over the previous 7 days of abdominal/belly pain, chest pain/heartburn, difficulty swallowing, nausea, vomiting/regurgitation, burping/belching, choking when eating and pain after eating. Individual symptom scores were based on the product of the frequency and usual severity of each symptom. The sum of the individual symptom score values made up the composite symptom score (CSS). The primary end point was the change in the mean CSS from baseline to week 8. RESULTS: Mean frequency and severity of each symptom significantly decreased (from P < 0.006 to P < 0.001) over time. Similar significant decreases in CSS at week 8 versus baseline (P < 0.001) were seen in all groups. Significant decreases from baseline in CSS were noted from weeks 1 to 8 in the 20-mg (P < 0.003) and 40-mg (P < 0.001) groups. The 20- and 40-mg doses were significantly (P < 0.05) more effective than the 10-mg dose in improving GERD symptoms at week 1. Adverse events were similar among the treatment groups. CONCLUSIONS: Pantoprazole (20 and 40 mg) is effective in reducing endoscopically proven GERD symptoms in children. Both 20 and 40 mg pantoprazole significantly reduced symptoms as early as 1 week.

The role of UGT1A1*28 mutation in jaundiced infants with hypertrophic pyloric stenosis.

Hypertrophic pyloric stenosis (HPS) may be accompanied by jaundice, a condition referred to as the icteropyloric syndrome (IPS). It has long been suspected that the etiology of IPS is an early manifestation of Gilbert's syndrome (GS). Clinical features common to both GS and IPS include jaundice precipitated by fasting and improved with feeding. Prevalence of jaundice in HPS is similar to that of clinically apparent GS in the general population. Discovery of a mutation in the promoter region of the bilirubin uridine diphosphate glucuronosyl transferase gene (UGT1A1*28) as the most common cause of GS has provided a tool to determine the role of GS in IPS. The aims of this study were to determine 1) the prevalence of IPS in a large group of infants with HPS, 2) whether disease severity contributed to the manifestation of IPS, and 3) whether GS played a role in IPS. Radioactive PCR and sequencing were used to determine the presence of UGT1A1*28 mutations. We determined a prevalence of IPS of 14.3% in HPS. Infants with IPS had significantly higher levels of alkalosis than infants with HPS alone. GS mutations were 4-fold higher in IPS (43.8%) than HPS (10.7%). In conclusion, the frequency of jaundice in HPS is similar to that of clinically apparent GS in the general population. Manifestation of IPS results from a more severe degree of metabolic disturbance and the presence of GS mutations.

Colonic chicken-skin mucosa in children with polyps is not a preneoplastic lesion.

Colonic polyps are common both in adults and children; however, the malignant potential varies according to the type of polyp. Most childhood polyps are solitary juvenile polyps, which have negligible malignant potential. Chicken-skin mucosa (CSM) is an endoscopic finding initially described associated with adenomatous polyps and adenocarcinoma, suggesting a preneoplastic lesion. Subsequently, CSM was described in association with juvenile polyps, suggesting that this mucosal finding is not a precursor to dysplasia. To determine whether CSM represents a preneoplastic lesion, we studied endoscopic colonic mucosal biopsies for markers of cell replication (Ki-67) and malignant transformation (p53) in mucosal biopsies of CSM, normal colonic tissue, tubular adenomas, and adenocarcinomas. Samples were subjected to immunostaining for the presence of Ki-67 and p53. The degree of Ki-67-positive staining cells was similar for CSM and normal colonic tissue, whereas there was significantly increased staining for both tubular adenomas and adenocarcinomas. There was no evidence of p53 staining in CSM and normal colonic mucosa, whereas there was varying degrees of staining in tubular adenomas and adenocarcinomas. The association of CSM with benign juvenile polyps and the absence of histologic markers for increased replication and malignant transformation support the notion that this endoscopic finding is not preneoplastic. Rather, CSM arises in proximity to polyps of all histologic types because of local mucosal damage.

Developmental expression of endothelial nitric oxide synthase (eNOS) in the rat liver.

Transition from fetal to postnatal life requires significant changes in cardiac, pulmonary, and hepatic blood flow. As such, there must be changes in vascular control in these vascular systems. Vascular resistance, a major contributor to blood flow, is mediated in the ductus arteriosus and pulmonary vasculature by endothelial nitric oxide synthase (eNOS). This study was conducted to determine the ontogeny of hepatic eNOS expression and activity. Additionally, the expression and activity of inducible nitric oxide synthase (iNOS) was measured to determine whether perinatal hypoxia resulted in detectable levels. NOS mRNA and proteins were determined by reverse transcription PCR assay and semiquantitative Western blot analysis, respectively. NOS activity was measured by the formation of [14C]-citrulline from [14C]-arginine. Localization of eNOS within the liver was determined by immunohistochemistry. eNOS mRNA was detectable at low levels at 18-d gestation and increased after birth, reaching a maximum level (4.5-fold increase) at 20 d of life. Parallel patterns for eNOS protein and activity were seen, with 6.9-fold and 16.1-fold increases, respectively. In the prenatal rat, eNOS was localized to areas of extramedullary hematopoiesis, with little signal in the sinusoids. Postnatally, there was a decrease in staining in the hematopoietic cells and a gradual increase in the staining of the endothelium of the sinusoids and central veins. iNOS mRNA and protein could not be detected at any age. eNOS expression and activity are developmentally regulated, increasing after birth coincident with an initial relative hypoxia and an increase in shear forces upon closure of the ductus venosus.

Nonsurgical Therapy for Solitary Rectal Ulcer Syndrome.

The treatment of solitary rectal ulcer syndrome (SRUS) remains problematic and is less than ideal. Prospective, well-designed studies assessing the efficacy of treatment for SRUS are few; most of the knowledge imparted for treating SRUS is experiential. As such, firm treatment recommendations can not be made. Rather, a conservative, stepwise, individualized approach must be employed. Diagnostic modalities should be incorporated in the management scheme to direct treatment when indicated. Management must include patient reassurance that the underlying lesion is benign, because complete "cures" are uncommon in those with SRUS. The goals of therapy should be discussed with the patient prior to initiating treatment. Although the ultimate goal is macroscopic and microscopic healing, a realistic goal is cessation or minimization of symptoms. We outline a reasonable approach to the management of SRUS. Histologic confirmation of SRUS should prompt a discussion of the presumed pathogenic mechanisms with the patient. Conservative therapy with dietary fiber, bowel retraining, and bulk laxatives should be employed. If symptoms persist, the patient should receive a trial of sucralfate enemas for 6 weeks. Individuals who respond should continue conservative therapy. However, if symptoms persist, defecography can be done to assess for inappropriate puborectalis contraction and occult rectal mucosal prolapse. Patients with inappropriate contraction of the puborectalis can be offered biofeedback. Patients with occult rectal mucosal prolapse can be considered for surgery. However, the risks, benefits, and success rates of surgery should be discussed at length, prior to any procedure being performed. Rectopexy or Delorme's procedure offer the best success rates to date; however, the choice of surgical procedure must take into account the experience of the surgeon and wishes of the patient.

Unsedated upper endoscopy in children.

BACKGROUND: EGD is essential to the investigation and treatment of GI disorders in children. Although safe, EGD has the potential for complications, in particular cardiopulmonary abnormalities associated with intravenous sedation. EGD is often performed in adults without sedation. Unsedated EGD is occasionally performed in children but has not been subjected to study. This study assessed the safety, efficacy, and feasibility of unsedated EGD in children. METHODS: Selected, highly motivated children requiring EGD were offered the choice of sedation or no sedation for the procedure. Children recorded scores for pain (face scale) and anxiety (vertical visual analogue scale) before and after EGD. In addition, the times required to prepare the patient, perform the EGD, and recover the patient were recorded. RESULTS: There was no difference in age, gender, or pre-EGD pain scores between children selecting sedation or no sedation. However, children selecting sedation had significantly higher pre-EGD anxiety scores than those who chose no sedation. Successful completion of EGD was similar for sedated (96.3%) and unsedated (95.2%) children. Post-EGD scores for anxiety were significantly decreased in those receiving sedation and unchanged in children who received no sedation. There was no significant change in post-EGD pain score in either group. Nearly 80% of children undergoing unsedated EGD would elect to forego sedation if EGD was needed again. Total procedure time was significantly longer in sedated versus unsedated children, reflecting longer preparation and recovery. CONCLUSIONS: Unsedated EGD can be performed safely and successfully in children with good patient tolerance. There was a significant decrease in total procedure time for children who have unsedated EGD. Unsedated EGD should be considered a viable option for motivated children.

The inflammatory polyp-fold complex in children.

The inflammatory polyp-fold complex (IPFC) is an uncommon endoscopic or radiologic finding in children. In this complex, an inflammatory polyp at the gastroesophageal junction is present, often in continuity with a prominent gastric fold. Histologically, there is an inflammatory infiltrate in otherwise benign gastric and esophageal mucosa. We report four cases of IPFC in children, all associated with reflux esophagitis. In two patients who underwent repeat endoscopy, acid suppression therapy led to a decrease in the size of the polyp and histologic improvement of esophagitis. Four case studies in children with IPFC are presented, followed by a literature review of this endoscopic finding as it applies to children.