RINT1 Bi-allelic Variations Cause Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities.

Pediatric acute liver failure (ALF) is life threatening with genetic, immunologic, and environmental etiologies. Approximately half of all cases remain unexplained. Recurrent ALF (RALF) in infants describes repeated episodes of severe liver injury with recovery of hepatic function between crises. We describe bi-allelic RINT1 alterations as the cause of a multisystem disorder including RALF and skeletal abnormalities. Three unrelated individuals with RALF onset ≤3 years of age have splice alterations at the same position (c.1333+1G>A or G>T) in trans with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del) in RINT1. ALF episodes are concomitant with fever/infection and not all individuals have complete normalization of liver function testing between episodes. Liver biopsies revealed nonspecific liver damage including fibrosis, steatosis, or mild increases in Kupffer cells. Skeletal imaging revealed abnormalities affecting the vertebrae and pelvis. Dermal fibroblasts showed splice-variant mediated skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay. Fibroblasts also revealed decreased RINT1 protein, abnormal Golgi morphology, and impaired autophagic flux compared to control. RINT1 interacts with NBAS, recently implicated in RALF, and UVRAG, to facilitate Golgi-to-ER retrograde vesicle transport. During nutrient depletion or infection, Golgi-to-ER transport is suppressed and autophagy is promoted through UVRAG regulation by mTOR. Aberrant autophagy has been associated with the development of similar skeletal abnormalities and also with liver disease, suggesting that disruption of these RINT1 functions may explain the liver and skeletal findings. Clarifying the pathomechanism underlying this gene-disease relationship may inform therapeutic opportunities.

Understanding the evolving phenotype of vascular complications in telomere biology disorders.

Vascular complications such as bleeding due to gastrointestinal telangiectatic anomalies, pulmonary arteriovenous malformations, hepatopulmonary syndrome, and retinal vessel abnormalities are being reported in patients with telomere biology disorders (TBDs) more frequently than previously described. The international clinical care consortium of telomere-associated ailments and family support group Dyskeratosis Congenita Outreach, Inc. held a workshop on vascular abnormalities in the TBDs at the National Cancer Institute in October 2017. Clinicians and basic scientists reviewed current data on vascular complications, hypotheses for the underlying biology and developed new collaborations to address the etiology and clinical management of vascular complications in TBDs.

Gamma Glutamyltransferase Reduction Is Associated With Favorable Outcomes in Pediatric Primary Sclerosing Cholangitis.

Adverse clinical events in primary sclerosing cholangitis (PSC) happen too slowly to capture during clinical trials. Surrogate endpoints are needed, but no such validated endpoints exist for children with PSC. We evaluated the association between gamma glutamyltransferase (GGT) reduction and long-term outcomes in pediatric PSC patients. We evaluated GGT normalization (< 50 IU/L) at 1 year among a multicenter cohort of children with PSC who did or did not receive treatment with ursodeoxycholic acid (UDCA). We compared rates of event-free survival (no portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or liver-related death) at 5 years. Of the 287 children, mean age of 11.4 years old, UDCA was used in 81% at a mean dose of 17 mg/kg/day. Treated and untreated groups had similar GGT at diagnosis (314 versus 300, P= not significant [NS]). The mean GGT was reduced at 1 year in both groups, with lower values seen in treated (versus untreated) patients (99 versus 175, P= 0.002), but 5-year event-free survival was similar (74% versus 77%, P= NS). In patients with GGT normalization (versus no normalization) by 1 year, regardless of UDCA treatment status, 5-year event-free survival was better (91% versus 67%, P< 0.001). Similarly, larger reduction in GGT over 1 year (> 75% versus < 25% reduction) was also associated with improved outcome (5-year event-free survival 88% versus 61%, P= 0.005). Conclusion:A GGT < 50 and/or GGT reduction of > 75% by 1 year after PSC diagnosis predicts favorable 5-year outcomes in children. GGT has promise as a potential surrogate endpoint in future clinical trials for pediatric PSC.

Management of pediatric hepatocellular carcinoma: A multimodal approach.

HCC is rare in the pediatric population, but is the second most common liver malignancy in children. Survival rates for primary unresectable HCC have been dismal. The objective of this study was to describe our experience with a multimodal approach for the management of unresectable HCC in two adolescent patients and to review the literature. Both patients are currently alive with no recurrence at 51 and 29 months post-transplant. Multimodality treatment involving chemotherapy with doxorubicin, cisplatin, and sorafenib; TACE; timely liver transplantation; and post-transplant therapy with sorafenib and mTOR inhibitors may help improve outcomes and prolong survival in pediatric patients with unresectable HCC.

The natural history of primary sclerosing cholangitis in 781 children: A multicenter, international collaboration.

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long-term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long-term outcome. We identified 781 patients, median age 12 years, with 4,277 person-years of follow-up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event-free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC-inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5-0.9, and 0.7, 95% confidence interval 0.5-0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long-term outcome. CONCLUSION: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC-inflammatory bowel disease are more favorable disease phenotypes. (Hepatology 2017;66:518-527).

Prospective Clinical Trial of Rifaximin Therapy for Patients With Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease in which emerging data suggest that oral antibiotics may offer therapeutic effects. We enrolled patients with PSC in a 12-week, open-label pilot study to investigate the efficacy and safety of 550 mg of oral rifaximin twice daily. The primary end point was serum alkaline phosphatase (ALK) at 12 weeks. Secondary end points included (1) serum bilirubin, gamma-glutamyl transpeptidase, and Mayo PSC risk score; (2) fatigue impact scale, chronic liver disease questionnaire, and short form health survey (SF-36) scores; and (3) adverse effects (AEs). Analyses were performed with nonparametric tests. Sixteen patients were enrolled, among whom the median age was 40 years; 13 (81%) were male, 13 had inflammatory bowel disease, and baseline ALK was 342 IU/mL (interquartile range, 275-520 IU/mL). After 12 weeks of treatment, there were no significant changes in ALK (median increase of 0.9% to 345 IU/mL; P = 0.47) or any of the secondary biochemical end points (all P > 0.05). Similarly, there were no significant changes in fatigue impact scale, chronic liver disease questionnaire, or SF-36 scores (all P > 0.05). Three patients withdrew from the study due to AEs; 4 others reported mild AEs but completed the study. In conclusion, although some antibiotics may have promise in treating PSC, oral rifaximin, based on the results herein, seems inefficacious for this indication. Future studies are needed to understand how the antimicrobial spectra and other properties of antibiotics might determine their utility in treating PSC.

Silent Tyrosinemia Type I Without Elevated Tyrosine or Succinylacetone Associated with Liver Cirrhosis and Hepatocellular Carcinoma.

Tyrosinemia type I (TYRSN1, TYR I) is caused by fumarylacetoacetate hydrolase (FAH) deficiency and affects approximately one in 100,000 individuals worldwide. Pathogenic variants in FAH cause TYRSN1, which induces cirrhosis and can progress to hepatocellular carcinoma (HCC). TYRSN1 is characterized by the production of a pathognomonic metabolite, succinylacetone (SUAC) and is included in the Recommended Uniform Screening Panel for newborns. Treatment intervention is effective if initiated within the first month of life. Here, we describe a family with three affected children who developed HCC secondary to idiopathic hepatosplenomegaly and cirrhosis during infancy. Whole exome sequencing revealed a novel homozygous missense variant in FAH (Chr15(GRCh38):g.80162305A>G; NM_000137.2:c.424A > G; NP_000128.1:p.R142G). This novel variant involves the catalytic pocket of the enzyme, but does not result in increased SUAC or tyrosine, making the diagnosis of TYRSN1 problematic. Testing this novel variant using a rapid, in vivo somatic mouse model showed that this variant could not rescue FAH deficiency. In this case of atypical TYRSN1, we show how reliance on SUAC as a primary diagnostic test can be misleading in some patients with this disease. Augmentation of current screening for TYRSN1 with targeted sequencing of FAH is warranted in cases suggestive of the disorder.

A novel GBE1 gene variant in a child with glycogen storage disease type IV.

Glycogen storage disease type IV is an autosomal recessive disorder of carbohydrates caused by deficiency of amylo-1-4-glycanoglycosyltransferase, which leads to accumulation of amylopectin-like polysaccharides in tissues including liver, heart and neuromuscular system. More than 40 different mutations in the glycogen branching enzyme gene (GBE1) have been described. In this study, we report a 2-year-old boy who presented with developmental delay and muscle weakness. He subsequently was diagnosed with glycogen storage disease type IV based on a liver biopsy histology and electron microscopy. Glycogen branching enzyme activity was in the low range. Genetic analysis demonstrated a novel heterozygous variant (c.760A>G; p.Thr254Ala) in exon 6 of the GBE1 gene, which is believed to be pathogenic. This variant was inherited from the patient's mother who was asymptomatic with normal glycogen branching enzyme activity. Whole-exome sequencing failed to reveal additional variations in the GBE1 gene.

Ileal pouch anal anastomosis in pediatric familial adenomatous polyposis: a 24-year review of operative technique and patient outcomes.

BACKGROUND: Total proctocolectomy with ileal pouch anal anastomosis (IPAA) is the operative procedure of choice for familial adenomatous polyposis (FAP) patients. We review 24years of operative experience and outcomes in pediatric patients with FAP. METHODS: Patients with FAP, age<20years, presenting to a single institution between 1987 and 2011 were included. Operative technique and outcomes were reviewed retrospectively. Primary outcomes included postoperative complications (30days), long-term bowel function, and polyp recurrence at the anal anastomosis. RESULTS: 95 patients with FAP underwent IPAA. Mean age at IPAA was 15.5years with a mean follow-up of 7.6years. 29 patients underwent 1-stage IPAA, 65 patients had a two-stage IPAA, and 1 patient underwent a 3-stage procedure. 67 patients had an open procedure, 25 underwent a laparoscopic approach, and more recently 3 patients underwent single incision laparoscopic IPAA. Patients with 1-stage IPAA demonstrate better long term bowel control vs. 2-stage IPAA patients (10.7% vs. 36.0% occasional incontinence, p=0.018). However, 1-stage IPAA patients suffered increased short-term complications, such as anastomotic leak (17.2% vs. 0%, p=0.002) and reoperation (20.7% vs. 4.6%, p=0.02) compared to 2-stage IPAA. Anal anastomosis polyp recurrence occurred in 22.7% of 1-stage patients and 10.0% of 2-stage patients. Short-term complications, polyp recurrence, or long-term continence were equivalent between open and laparoscopic cases. CONCLUSION: Single-stage IPAA in children with FAP is associated with better bowel control but increased anastomotic leak, reoperative rate, and polyp recurrence. In experienced hands, laparoscopic IPAA is equivocal to open IPAA.

The natural history of familial adenomatous polyposis syndrome: a 24 year review of a single center experience in screening, diagnosis, and outcomes.

PURPOSE: Understanding the natural history of Familial Adenomatous Polyposis (FAP) will guide screening and aid clinical management. METHODS: Patients with FAP, age ≤20years presenting between 1987 and 2011, were reviewed for presentation, diagnosis, extraintestinal manifestations, polyp burden, family history, histology, gene mutation, surgical intervention, and outcome. RESULTS: One hundred sixty-three FAP patients were identified. Diagnosis was made by colonoscopy (69%) or genetic screening (25%) at mean age of 12.5years. Most children (58%) were asymptomatic and diagnosed via screening due to family history. Rectal bleeding was the most common (37%) symptom prompting evaluation. Colon polyps appeared by mean age of 13.4years with >50 polyps at the time of diagnosis in 60%. Cancer was found in 1 colonoscopy biopsy and 5 colectomy specimens. Family history of FAP was known in 85%. 53% had genetic testing, which confirmed APC mutation in 88%. Extraintestinal manifestations included congenital hypertrophy of the retinal pigment epithelium (11.3%), desmoids (10.6%), osteomas (6.7%), epidermal cysts (5.5%), extranumerary teeth (3.7%), papillary thyroid cancer (3.1%), and hepatoblastoma (2.5%). Six patients died secondary to FAP. CONCLUSIONS: Clinical presentation and manifestations in pediatric FAP are variable. We suggest an individualized patient-oriented screening algorithm that allows for earlier screening and appropriate management.

Wandering spleen as a cause of mesenteric and portal varices: a new etiology?

Wandering spleen is a rare clinical entity characterized by spleen hypermobility due to lack or weakness of one or more splenic ligaments. We report two patients with the diagnosis of wandering spleen with portal and mesenteric varices. A 16 year-old girl presented with abdominal pain, an abdominal mass and pancytopenia. A 12 year-old girl presented with an abdominal mass only. Imaging studies revealed both patients had a viable but torsed wandering spleen in association with portal, splenic and mesenteric varices. Both were treated with splenectomy and had resolution of their symptoms. Imaging confirmed complete resolution of all varices at 30 month and 11 year follow up respectively. These cases represent the first report of a wandering spleen causing portal and mesenteric venous partial obstruction leading to varices; splenectomy resolved these findings post-operatively.

Pediatric MR elastography of hepatic fibrosis: principles, technique and early clinical experience.

Numerous pediatric conditions result in hepatic fibrosis. As treatments develop for the underlying disorders, a non-invasive assessment of liver fibrosis would be beneficial as an adjunct or possible replacement for the traditional gold standard, liver biopsy. Magnetic resonance elastography is a noninvasive imaging technique that has been used successfully in adults for identification and assessment of liver fibrosis. This review describes the basic principles of MR elastography as well as the technical aspects specific to children. Clinical pediatric applications, limitations and areas for future research are described.

Feasibility and application of 3-dimensional ultrasound for measurement of gastric volumes in healthy adults and adolescents.

OBJECTIVES: Abnormal gastric accommodation to a meal results in dyspepsia. Current methods to measure gastric volume (GV) are invasive or involve ionizing radiation. The aims of this study were to compare fasting and postprandial (PP) GVs measured by (99m)Tc-single photon emission computed tomography (SPECT) and 3-dimensional ultrasound (3D-US) in adults, to assess the performance characteristics of 3D-US measurement of GV during fasting and postprandially, and to develop normative data of GVs in 24 healthy adolescents. PATIENTS AND METHODS: Eleven adults underwent SPECT and 3D-US simultaneously to measure GV, and a second 3D-US alone within 1 week of the first study. Twenty-four adolescents underwent 1 3D-US measurement. Each study included fasting, a 300-mL Ensure meal, and 0 to 30-minute PP GV measurements. RESULTS: 3D-US identifies GV accommodation to 300mL Ensure. Delta (0-30 minutes average PP fasting) GV was 444mL (median, interquartile range [IQR]=422, 534) for 3D-US and 543mL (median, IQR=486, 564) for SPECT (P=0.15). There were larger interindividual coefficients of variation for GV by 3D-US (60.3% fasting and 21.3% average PP) compared with 19% fasting and 9.2% PP for SPECT. Intraindividual coefficients of variation for the 2 3D-US measurements in adults were 84% fasting and 44% average PP. The estimated GVs for the adolescent group (median [25th-75th IQR]) were 33 (18-53)mL fasting, 330 (284-357)mL 30 minutes PP, and 281 (240-324)mL for delta GV. CONCLUSIONS: 3D-US is a promising method to measure GV accommodation to a meal. Large coefficients of variation reflect the learning stage in development of this promising technique.

Liver transplantation for pulmonary vascular complications of pediatric end-stage liver disease.

PURPOSE: Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH) are poorly understood pulmonary complications of end-stage liver disease (ESLD). We present a case series of children with HPS and PPH. METHODS: After institutional review board approval, query of our medical database identified children 0 to 18 years of age with ESLD diagnosed with HPS or PPH. Data were collected via chart review. RESULTS: We identified 7 children with either HPS (n = 5) or PPH (n = 2). Patients with HPS presented with progressive dyspnea over a mean of 7 months (range, 4-12 months) at a mean of 13 years (range, 5-17 years) of age. Pulmonary shunting by albumin perfusion scan averaged 41% (range, 20%-66%) with an initial mean resting SpO(2) of 88% (range, 84%-94%) and mean SpO(2) during exertion of 79% (range, 60%-89%). Four patients required supplemental O(2) and, upon United Network for Organ Sharing (UNOS) appeal, received pediatric model for ESLD (or Child-Pugh) score exceptions, enabling them to undergo orthotopic liver transplant (OLT) within 1-2 months. The fifth patient was initially rejected by the UNOS regional review board, but 6 months of worsening hypoxemia led to OLT 2 months after successful UNOS appeal. All patients with HPS undergoing OLT experienced complete resolution of hypoxemia within 8 months. Both children with PPH were treated with intravenous epoprostenol, which lowered or stabilized mean pulmonary artery pressure and bridged them to OLT within 7 months of listing. Overall, there were no pulmonary complications; however, 1 patient with PPH expired shortly after OLT. The remaining patients are alive at a median follow-up of 27 months (range, 6-96 months). CONCLUSION: Hepatopulmonary syndrome and PPH are uncommon complications of ESLD in children. Epoprostenol can bridge PPH patients to OLT. OLT leads to rapid resolution of HPS and PPH and currently represents the only successful treatment for these children.

Predictors of family risk for celiac disease: a population-based study.

BACKGROUND & AIMS: There is an elevated prevalence of celiac disease (CD) in family members (FMs) of CD patients, but most prior studies have been done on selected populations. Our aim was to determine the clinical, serologic, and genetic predictors of CD in FMs of a population-based cohort of index cases. METHODS: Index cases from southeast Minnesota provided contact information for their first-degree relatives. FMs were examined for endomysial antibodies (EMAs), tissue transglutaminase antibodies (tTGAs), and HLA-DQ genotyping. Two questionnaires were applied, Bowel Disease Questionnaire and Short Form Health Survey. Intestinal biopsies were offered if there were any positive autoantibody or seronegative FMs with gastrointestinal symptoms and HLA-DQ at risk for CD. RESULTS: We recruited 111 index cases that had 579 FMs, of whom 344 (59%) were investigated. The average screening rate among families was 65%. A positive tTGA test was found in 47 (14%), 33 with a positive EMA test. CD was diagnosed in 39 (21 males), with an estimated prevalence of 11% (lambda(R) = 16.1). All affected FMs carried the at-risk genotypes. Twenty-one (54%) had "silent" disease, most with severe intestinal villous atrophy. Carrying HLA-DQ2 (odds ratio, 16.1; 95% confidence interval, 2.1-123) and being a sibling (odds ratio, 2.5; 95% confidence interval, 1.1-5.8) are high-risk factors for CD. CONCLUSIONS: CD is more common in first-degree relatives than previously reported in the United States, with siblings having the greatest risk. There is male preponderance of new cases, and many had silent disease despite severe histologic injury. A more proactive case-finding strategy in FMs might improve the diagnostic rate of CD in North America.

A population-based study of the frequency of corticosteroid resistance and dependence in pediatric patients with Crohn's disease and ulcerative colitis.

BACKGROUND: The goal of this study was to examine the 1-year outcome after the first course of systemic corticosteroids in an inception cohort of pediatric patients with inflammatory bowel disease. METHODS: All Olmsted County (Minnesota) residents diagnosed with Crohn's disease (n = 50) or ulcerative colitis (n = 36) before 19 years of age from 1940 to 2001 were identified. Outcomes at 30 days and 1 year after the initial course of corticosteroids were recorded. RESULTS: Twenty-six patients with Crohn's disease (65%) and 14 with ulcerative colitis (44%) were treated with corticosteroids before age 19. Thirty-day outcomes for corticosteroid-treated Crohn's disease were complete remission in 16 (62%), partial remission in 7 (27%), and no response in 3 (12%), with 2 of these patients requiring surgery. Thirty-day outcomes for treated ulcerative colitis were complete remission in 7 (50%), partial remission in 4 (29%), and no response in 3 (21%). One-year outcomes for Crohn's disease were prolonged response in 11 (42%) and corticosteroid dependence in 8 (31%), whereas 7 (27%) were postsurgical. One-year outcomes for ulcerative colitis were prolonged response in 8 (57%) and corticosteroid dependence in 2 (14%), whereas 4 (29%) were postsurgical. CONCLUSIONS: Most pediatric patients with inflammatory bowel disease initially responded to corticosteroids. However, after 1 year, 58% of pediatric patients with Crohn's disease and 43% of pediatric patients with ulcerative colitis either were steroid dependent or required surgery. This finding emphasizes the need for early steroid-sparing medications in pediatric inflammatory bowel disease.

Clinical and molecular characterization defines a broadened spectrum of autosomal recessive polycystic kidney disease (ARPKD).

The autosomal recessive form of polycystic kidney disease (ARPKD) is generally considered an infantile disorder with the typical presentation of greatly enlarged echogenic kidneys detected in utero or within the neonatal period, often resulting in neonatal demise. However, there is an increasing realization that survivors often thrive into adulthood with complications of the ductal plate malformation, manifesting as congenital hepatic fibrosis and Caroli disease, becoming prominent. Previous natural history studies have concentrated almost exclusively on the infantile presenting group. However, developments in understanding the genetic basis of ARPKD, through identification of the disease gene, PKHD1, have allowed exploration of the etiology in patients with ARPKD-like disease or congenital hepatic fibrosis presenting later in childhood or as adults. In the current study we retrospectively reviewed the clinical records, and where possible performed PKHD1 mutation screening, in patients diagnosed with ARPKD or congenital hepatic fibrosis at the Mayo Clinic, Rochester, MN, from 1961 to 2004. Of a total of 133 cases reviewed, 65 were considered to meet the diagnostic criteria with an average duration of follow-up of 8.6 +/- 6.4 years. Fifty-five cases had ARPKD and 10 had isolated congenital hepatic fibrosis with no or minimal renal involvement. The patients were analyzed as 3 groups categorized by the age at diagnosis; <1 years (n = 22), 1-20 years (n = 23), and >20 years (n = 20). The presenting feature in the neonates was typically associated with renal enlargement, but in the older groups, more often involved manifestations of liver disease, including hepatosplenomegaly, hypersplenism, variceal bleeding, and cholangitis. During follow-up, 22 patients had renal insufficiency and 8 developed end-stage renal disease (ESRD), most from the neonatal group. Liver disease was evident on follow-up in all diagnostic groups but particularly prevalent in those diagnosed later in life. A total of 12 patients died, 6 in the neonatal period, but 86% of patients were alive at 40 years of age. The likelihood of being alive without ESRD differed significantly between the diagnostic groups with 36%, 80%, and 88% survival in the 3 diagnostic groups, respectively, 20 years after the diagnosis. Considerable evidence of intrafamilial phenotype variability was observed. Mutation analysis was performed in 31 families and at least 1 mutation was detected in 25 (81%), with 76% of mutant alleles detected in those cases. Consistent with the relatively mild disease manifestations in this population, the majority of changes were missense (79%) and no case had 2 truncating changes. Mutations were detected in all diagnostic groups, indicating that congenital hepatic fibrosis with minimal kidney involvement can result from PKHD1 mutation. The finding of 6 cases with no detected mutations may represent missed mutations or possible evidence of genetic heterogeneity. The current study indicates a broadened spectrum for the ARPKD phenotype and that later presenting cases with predominant liver disease should be considered part of ARPKD.

Clinical characteristics of eosinophilic esophagitis in children.

OBJECTIVES: The role of eosinophilic esophagitis (EE) in aerodigestive tract disorders in children is underestimated and overlooked, primarily because of a lack of understanding of this disorder by otolaryngologists. We sought to better characterize the clinical presentation of EE in order to increase awareness among otolaryngologists. METHODS: We retrospectively reviewed 71 children with biopsy-proven EE to determine the most common symptoms and laboratory findings that should increase the clinical suspicion of EE. RESULTS: Dysphagia, food impaction, and emesis were the most common symptoms in children with EE. Asthma was the most common airway diagnosis. Rhinosinusitis was the most common otolaryngological diagnosis. Food allergy was present in 60% of the children tested. Eighty-three percent of the children with elevated immunoglobulin E levels had thick linear streaking or patchy white exudate of the esophagus seen on esophagoscopy. Other major medical comorbidities existed in more than half of the children with EE, of which psychiatric disorders and other disorders of the aerodigestive tract were the most common. CONCLUSIONS: Eosinophilic esophagitis may contribute to treatment failure in patients with common and complicated aerodigestive tract disorders. To encourage clinicians to avoid overlooking the diagnosis, we present an evaluative algorithm to increase the suspicion of this entity.

Celiac disease in type 1 diabetes mellitus in a North American community: prevalence, serologic screening, and clinical features.

OBJECTIVES: To estimate the prevalence of cellac disease (CD) in pediatric and adult type 1 diabetes melitus in a defined population and to describe clinical features and HLA class II genotypes predictive of CD in screened patients with type 1 diabetes. PATIENTS AND METHODS: All residents of Olmsted County, Minnesota, with type 1 diabetes mellitus on the prevalence date January 1, 2001, were identified with the use of an established medical records linkage system (Rochester Epidemiology Project) and defined clinical criteria. Consenting patients underwent serologic screening with endomyslal antibody and tissue transglutaminase antibody testing and Intestinal biopsies to confirm the diagnosis of CD. A subset of screened patients also underwent HLA class II genotyping. Quality-of-life screening (Medical Outcomes Study 36-Item Short-Form Health Survey) was completed in a subset of patients at the time of serologic screening. RESULTS: Overall, 392 Olmsted County residents with type 1 diabetes on January 1, 2001, were Identified. A total of 158 patients with type 1 diabetes were tested, representing 40% (158/392) of the enumerated diabetic population, and 11 had biopsy-proven CD for an estimated point prevalence of 7.0% (95% confidence Interval, 3.5%-12.1%). Most CD-positive diabetic patients were asymptomatic and expressed an at-risk CD haplotype with at least one of but not both HLA DQ2 or DQ8. CONCLUSIONS: Celiac disease Is not rare In North American patients with type 1 diabetes, and most CD-positive diabetic patients are asymptomatic Irrespective of age at screening.