Adherence to Biopsy and Follow-Up Guidelines in a Population-Based Cohort of Children With Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated condition that is becoming more widely recognized in children. Recent EoE practice guidelines provide clear recommendations on adequate biopsy sampling at diagnostic endoscopy and necessity of close follow-up endoscopy with biopsy to ensure mucosal healing with therapy.1 Despite these recommendations, adherence to biopsy guidelines, time to first follow-up endoscopy, and overall surveillance endoscopy rates have not been robustly studied. Using a population-based cohort of children diagnosed with EoE in Utah, we assessed adherence to guidelines across multiple provider types, including academic pediatric gastroenterologists (PGIs), private practice PGIs, and adult-trained providers performing endoscopy in children.

Quantitative Liver Fibrosis Using Collagen Hybridizing Peptide to Predict Native Liver Survival in Biliary Atresia: A Pilot Study.

BACKGROUND/RATIONALE: Biliary atresia (BA) is a cholangiopathy characterized by bile flow obstruction due to destruction of the biliary tree. Without surgical correction with Kasai portoenterostomy (KPE), BA leads to death or liver transplant (LTx). Early-onset, progressive liver fibrosis is a defining characteristic of BA. Collagen hybridizing peptide (CHP) is a synthetic peptide which binds to denatured collagen strands allowing quantification of fibrosis. This technique has not been used on human liver tissue. The aim of this pilot study was to evaluate the utility of CHP as a measurement of quantitative fibrosis to allow earlier survival with native liver prognostication. RESULTS: We identified 21 patients with wedge liver biopsies available, of which 14 required LTx. No deaths occurred. Patients requiring LTx tended to be girls with a significantly different mean bilirubin (P = 0.002), albumin (P = 0.001), and alanine aminotransferase (P = 0.03) at 3 months post-KPE. By 1 year post-KPE, 50% of patients in the high CHP intensity group required LTx versus 27% in the low CHP. Overall, fibrosis as quantified by CHP at time of KPE was associated with more than 3 times the risk of requiring LTx by 4 years of age (hazard ratio 3.6, 95% confidence interval 1.15-10.93, P = 0.03). When controlling for sex and total bilirubin >2 mg/dL and albumin at 3 months post-KPE, it predicted nearly 7 times the risk of LTx (hazard ratio 6.89, 95% confidence interval 1.38-34.32, P = 0.02). CONCLUSION: Our results suggest that quantitative assessment of fibrosis at the time of KPE holds promise as an earlier predictor of LTx requirement in BA. A larger study is justified to assess quantitative fibrosis as a BA prognostic tool.

Incidence and Prevalence of Pediatric Eosinophilic Esophagitis in Utah Based on a 5-Year Population-Based Study.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is often detected in children and is considered to be a rare disease, with prevalence values reported to be below 60 cases per 100,000 persons. To determine whether the incidence of EoE in children in Utah exceeds estimates from regional reports, we calculated incidence and prevalence values over a 5-year period. METHODS: Using consensus guidelines for the diagnosis of EoE, we reviewed pathology records from the Intermountain Healthcare pathology database, from July 1, 2011 through June 31, 2016. We collected data on 10,619 pediatric patients with available esophageal biopsy results, and identified cases of esophageal eosinophilia (>14 eosinophils in a high-power microscopy field in an endoscopic biopsy). An EoE case required the presence of esophageal eosinophilia, symptoms of esophageal dysfunction, and the absence of co-morbid conditions that may cause esophageal eosinophilia. Annual pediatric EoE incidence and prevalence values were calculated per 100,000 children, based on averaged pediatric population estimates from census figures of Utah in 2010 and 2016. RESULTS: We identified 1281 unique pediatric patients who met criteria for esophageal eosinophilia. Of those, 1060 patients met criteria for newly diagnosed EoE. Over the 5-year period studied, the average annual pediatric EoE incidence in Utah was 24 cases per 100,000 children. The prevalence in year 5 of the study was 118 cases per 100,000 children. CONCLUSION: In a population-based study of children in Utah, we found the incidence and prevalence of pediatric EoE to be higher than previously reported. This could be due to the prominence of EoE risk factors in this region, as well as Utah's searchable medical record system that allows for reliable case ascertainment. Further studies of this type could increase disease awareness, prompting early referral to pediatric gastroenterologists and trials to strengthen evidence-based, algorithmic approaches to EoE diagnosis and treatment in children.

H syndrome: 5 new cases from the United States with novel features and responses to therapy.

BACKGROUND: H Syndrome is an autosomal recessive disorder characterized by cutaneous hyperpigmentation, hypertrichosis, and induration with numerous systemic manifestations. The syndrome is caused by mutations in SLC29A3, a gene located on chromosome 10q23, which encodes the human equilibrative transporter 3 (hENT3). Less than 100 patients with H syndrome have been described in the literature, with the majority being of Arab descent, and only a few from North America. CASE PRESENTATION: Here we report five pediatric patients from three medical centers in the United States who were identified to have H syndrome by whole exome sequencing. These five patients, all of whom presented to pediatric rheumatologists prior to diagnosis, include two of Northern European descent, bringing the total number of Caucasian patients described to three. The patients share many of the characteristics previously reported with H syndrome, including hyperpigmentation, hypertrichosis, short stature, insulin-dependent diabetes, arthritis and systemic inflammation, as well as some novel features, including selective IgG subclass deficiency and autoimmune hepatitis. They share genetic mutations previously described in patients of the same ethnic background, as well as a novel mutation. In two patients, treatment with prednisone improved inflammation, however both patients flared once prednisone was tapered. In one of these patients, treatment with tocilizumab alone resulted in marked improvement in systemic inflammation and growth. The other had partial response to prednisone, azathioprine, and TNF inhibition; thus, his anti-TNF biologic was recently switched to tocilizumab due to persistent polyarthritis. Another patient improved on Methotrexate, with further improvement after the addition of tocilizumab. CONCLUSION: H syndrome is a rare autoinflammatory syndrome with pleiotropic manifestations that affect multiple organ systems and is often mistaken for other conditions. Rheumatologists should be aware of this syndrome and its association with arthritis. It should be considered in patients with short stature and systemic inflammation, particularly with cutaneous findings. Some patients respond to treatment with biologics alone or in combination with other immune suppressants; in particular, treatment of systemic inflammation with IL-6 blockade appears to be promising. Overall, better identification and understanding of the pathophysiology may help devise earlier diagnosis and better treatment strategies.

Biochemical abnormalities in Pearson syndrome.

Pearson marrow-pancreas syndrome is a multisystem mitochondrial disorder characterized by bone marrow failure and pancreatic insufficiency. Children who survive the severe bone marrow dysfunction in childhood develop Kearns-Sayre syndrome later in life. Here we report on four new cases with this condition and define their biochemical abnormalities. Three out of four patients presented with failure to thrive, with most of them having normal development and head size. All patients had evidence of bone marrow involvement that spontaneously improved in three out of four patients. Unique findings in our patients were acute pancreatitis (one out of four), renal Fanconi syndrome (present in all patients, but symptomatic only in one), and an unusual organic aciduria with 3-hydroxyisobutyric aciduria in one patient. Biochemical analysis indicated low levels of plasma citrulline and arginine, despite low-normal ammonia levels. Regression analysis indicated a significant correlation between each intermediate of the urea cycle and the next, except between ornithine and citrulline. This suggested that the reaction catalyzed by ornithine transcarbamylase (that converts ornithine to citrulline) might not be very efficient in patients with Pearson syndrome. In view of low-normal ammonia levels, we hypothesize that ammonia and carbamylphosphate could be diverted from the urea cycle to the synthesis of nucleotides in patients with Pearson syndrome and possibly other mitochondrial disorders.

Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE.

BACKGROUND & AIMS: Eosinophilic esophagitis is usually triggered by foods, by unclear mechanisms. We evaluated the roles of IgE and IgG4 in the development of eosinophilic esophagitis. METHODS: We performed a prospective, randomized, double-blind, placebo-controlled trial of adults with eosinophilic esophagitis given an antibody against IgE (omalizumab, n = 16) or placebo (n = 14) every 2-4 weeks for 16 weeks, based on weight and serum level of IgE. Endoscopy was performed, esophageal biopsy specimens were collected, and symptoms were assessed at baseline and at 16 weeks. Maximum numbers of eosinophils/high-power field were determined. Homogenates of esophageal biopsy specimens from 11 subjects with eosinophilic esophagitis and 8 without (controls) were assessed for IgM, IgA, and IgG subclasses. In a retrospective analysis, we performed immunofluorescence analysis of IgG4 in fixed esophageal tissues from 2 patients with eosinophilic esophagitis who underwent esophagectomy and 47 consecutive autopsies (controls). We also performed immunofluorescence analysis of IgG4 in esophageal mucosal biopsy specimens from 24 subjects with eosinophilic esophagitis and 9 without (controls). Finally, sera were collected from 15 subjects with eosinophilic esophagitis and from 41 without (controls), and assayed for total and food-reactive IgG4. RESULTS: Omalizumab did not alter symptoms of eosinophilic esophagitis or eosinophil counts in biopsy samples compared with placebo. Homogenates of esophageal tissues from patients with eosinophilic esophagitis had a 45-fold increase in IgG4 compared with controls (P < 3 × 10(-5)), but no significant increases in other IgG subclasses, IgM, or IgA. Sparse stromal deposits resembling immune complexes were found in 2 of 5 eosinophilic esophagitis biopsy specimens based on ultrastructural analysis. Esophagectomy samples from 2 patients with eosinophilic esophagitis contained 180 and 300 IgG4 plasma cells/maximal high-power field, mainly in the deep lamina propria; these levels were greater than in tissues from controls. Fibrosis essentially was exclusive to the lamina propria. Granular extracellular IgG4 was detected in biopsy specimens from 21 of 24 patients with eosinophilic esophagitis, but in none of the specimens from 9 controls (P = 6 × 10(-6)). The total serum level of IgG4 increased only slightly in patients with eosinophilic esophagitis, compared with controls. Subjects with eosinophilic esophagitis had increased serum levels of IgG4 that reacted with milk, wheat, egg, and nuts-the 4 foods that most commonly trigger this condition (P ≤ 3 × 10(-4) for each food). CONCLUSIONS: In a prospective trial, omalizumab did not reduce symptoms of eosinophilic esophagitis or tissue eosinophil counts compared with placebo. This finding, along with observed granular deposits of IgG4, abundant IgG4-containing plasma cells, and serum levels of IgG4 reactive to specific foods, indicate that, in adults, eosinophilic esophagitis is IgG4-associated, and not an IgE-induced allergy. ClinicalTrials.gov number: NCT 00123630.

Endoscopy in the diagnosis of intestinal graft-versus-host disease: is lower endoscopy with biopsy as effective in diagnosis as upper endoscopy combined with lower endoscopy?

BACKGROUND: Graft-versus-host disease (GvHD) causes morbidity and mortality in recipients of hematopoietic stem cell transplantation (SCT). This study assessed the distribution of GvHD in gastrointestinal (GI) biopsies from the upper and lower GI tract in pediatric patients who had undergone SCT and evaluated if there was correlation between biopsy findings and possible extra-intestinal manifestations of GvHD. PROCEDURE: We performed a retrospective chart review for all patients diagnosed with GvHD, who underwent both upper and lower endoscopy. We also reviewed pathology and clinical reports to determine which biopsy sites were diagnostic of GvHD and to evaluate for the possible presence of extra-intestinal manifestations GvHD at the time of biopsy. RESULTS: Twenty patients were identified who had undergone both upper and lower endoscopy for evaluation of GvHD. Patients with GvHD diagnosed on upper endoscopy also had GvHD identified in the sigmoid colon region 100% of the time (positive predictive value [PPV] = 1). In patients that were found to have underlying liver disease, GvHD was diagnosed in the sigmoid colon region 90% of the time (PPV = 0.9). CONCLUSION: Use of sigmoid biopsy for GvHD diagnosis is effective, safe, and less expensive compared to other endoscopic interventions.

Granulomatous appendicitis in a child.

Granulomatous appendicitis (GA) is a rare inflammatory condition affecting the appendix. We report a pediatric patient with GA in which symptoms resolved after appendectomy. Although the colon was grossly normal by endoscopy, microscopic examination revealed colitis without granuloma formation. GA may represent a variant of inflammatory bowel disease (IBD).

Unilateral sclerocornea and tracheal stenosis: unusual findings in a patient with Goldenhar anomaly.

The Goldenhar anomaly (GA) is a heterogeneous field defect of uncertain cause and wide variability of expression, characterized by facial phenotypes, usually asymmetric and unilateral, accompanied by various combinations and gradations of cardiac, skeletal, renal, and central nervous system defects. We report the pathologic findings in a 5-month-old boy with GA, tracheal stenosis, and left unilateral sclerocornea. To the best of our knowledge this is the first description of sclerocornea in a patient with GA.

Yolk sac tumor of the thyroid gland: a case report.

Extragonadal yolk sac tumors are uncommon and usually seen in sacrococcygeal, mediastinal, intracranial, and retroperitoneal sites. Yolk sac tumors of the head and neck region are rare, and the few reported cases have arisen in neonates or infants in conjunction with a teratoma or other germ cell tumor subtypes. We report a unique case of a pure yolk sac tumor presenting as a primary lesion in the right thyroid lobe of a 10-year-old girl. The diagnosis was suspected after fine-needle aspiration, and extensive sampling of the thyroidectomy specimen revealed no teratoma or other germ cell tumor. Serum α-fetoprotein levels were markedly elevated 6 days after excision, and imaging disclosed numerous bilateral pulmonary nodules suggestive of metastatic disease but did not reveal a mediastinal mass. The tumor has shown a favorable response to bleomycin, etoposide, and cisplatin chemotherapy. To the best of our knowledge, this is the 1st description of a primary pure yolk sac tumor of the thyroid.

The Stillbirth Collaborative Research Network (SCRN) placental and umbilical cord examination protocol.

The Stillbirth Collaborative Research Network (SCRN) was organized to study the scope and causes of stillbirth (SB) in the United States. The objective of this report is to describe the approach used for the placental examination performed as part of the study. The SCRN consists of a multidisciplinary team of investigators from five clinical sites, the National Institute of Child Health and Human Development, and the Data Coordination and Analysis Center. The study is a population-based cohort and nested case-control study, with prospective enrollment of women with SB and live births (LB) at the time of delivery. Detailed and standardized postmortem examination was performed on SB and placental examination in both groups. A total of 663 women with SB and 1932 women with LB were enrolled into the case-control study. In the SB group, there were 707 fetuses. Of these cases, 654 (98.6%) had placental examination. Of these LB controls, 1804 (93.4%) had placental examination. This is the largest prospective study to include population-based SB and LB, using standardized postmortem and placental examination, medical record review, maternal interview, collection of samples, and a multidisciplinary team of investigators collaborating in the analyses. Thus it has the potential to provide high-level evidence regarding the contribution of placental abnormalities to stillbirth.

Recurrence of achondrogenesis type 2 in sibs: Additional evidence for germline mosaicism.

Achondrogenesis Type II (ACG2) is a lethal skeletal disorder caused by a dominant mutation in the type II collagen gene (COL2A1). Familial cases have been reported, suggesting both germline and somatic mosaicism. We report on two pregnancies from the same couple with gross, radiologic, and microscopic findings of ACG2. Molecular analysis of the second infant demonstrated heterozygosity for a c.2303G > A transition (p.Gly768Asp) in exon 33 of the COL2A1 gene. Although this mutation could not be proven by molecular studies in the first infant, identical findings in two affected pregnancies support germline mosaicism as the cause of ACG2 in this family.