Association of TNFSF15 polymorphisms in Korean children with Crohn's disease.

BACKGROUND: Genome-wide association studies have identified tumor necrosis factor superfamily member 15 (TNFSF15) as a Crohn's disease (CD)-related gene. The aim of this study was to evaluate the association between five TNFSF15 polymorphisms and CD in Korean children and analyze their genotypes in relation to phenotype. METHODS: Five single-nucleotide polymorphisms of TNFSF15 (rs3810936, rs6478108, rs6478109, rs7848647, rs7865494) were genotyped in 108 CD patients and in 599 healthy controls. Risk allele, genotype, and haplotype were analyzed in CD patients and controls, and genotype-phenotype relationships were studied. RESULTS: There were significant associations of rs3810936, rs6478108, rs6478109, rs7848647 with CD in Korean pediatric patients (P = 6.5×10(-8), P = 1.3×10(-8), P = 3.7×10(-8), P = 2.9×10(-8), respectively). The adjusted OR (aOR) for the homozygous risk allele genotype was significantly higher than that for the homozygous genotype for the opposite allele: rs3810936, aOR, 5.36 (95%CI: 2.61-10.98, P = 4.6×10(-6)); rs6478108, aOR, 6.62 (95%CI: 3.03-14.46, P = 2.2×10(-6)); rs6478109, aOR, 6.24 (95%CI: 2.85-13.66, P = 4.6×10(-6)); rs7848647, aOR, 6.32 (95%CI: 2.89-13.81, P = 3.8×10(-6)). The risk allele of rs3810936 was associated with later symptom onset, later diagnosis, and the presence of perianal lesion (P = 0.013, P = 0.016 and P = 0.029). CONCLUSION: There was a significant association of TNFSF15 with pediatric CD in Korean patients.

Genome-wide association study of Crohn's disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations.

OBJECTIVE: Crohn's disease (CD) is an intractable inflammatory bowel disease (IBD) of unknown cause. Recent meta-analysis of the genome-wide association studies (GWAS) and Immunochip data identified 163 susceptibility loci to IBD in Caucasians, however there are limited studies in other populations. METHODS: We performed a GWAS and two validation studies in the Korean population comprising a total of 2311 patients with CD and 2442 controls. RESULTS: We confirmed four previously reported loci: TNFSF15, IL23R, the major histocompatibility complex region, and the RNASET2-FGFR1OP-CCR6 region. We identified three new susceptibility loci at genome-wide significance: rs6856616 at 4p14 (OR=1.43, combined p=3.60×10(-14)), rs11195128 at 10q25 (OR=1.42, combined p=1.55×10(-10)) and rs11235667 at 11q13 (OR=1.46, combined p=7.15×10(-9)), implicating ATG16L2 and/or FCHSD2 as novel susceptibility genes for CD. Further analysis of the 11q13 locus revealed a non-synonymous single nucleotide polymorphism (SNP) (R220W/rs11235604) in the evolutionarily conserved region of ATG16L2 with stronger association (OR=1.61, combined p=2.44×10(-12)) than rs11235667, suggesting ATG16L2 as a novel susceptibility gene for CD and rs11235604 to be a potential causal variant of the association. Two of the three SNPs (rs6856616 (p=0.00024) and rs11195128 (p=5.32×10(-5))) showed consistent patterns of association in the International IBD Genetics Consortium dataset. Together, the novel and replicated loci accounted for 5.31% of the total genetic variance for CD risk in Koreans. CONCLUSIONS: Our study provides new biological insight to CD and supports the complementary value of genetic studies in different populations.

Long-term outcomes of pediatric living donor liver transplantation at a single institution.

There have only been a few studies on the long-term outcomes and prognostic factors after pediatric LDLT. We conducted a retrospective, single-center assessment of the outcomes as well as the demographic and clinical factors that influenced the poor outcomes in 113 children aged <16 (median age 21 months; 6 months-15.5 yr) who underwent 115 LDLTs, predominantly for biliary atresia (60.9%) and FHF (14.8%), between 1994 and 2006 at Asan Medical Center. Left lateral segment or left lobe grafts were implanted into most of these children (86.9%) according to routine procedures. The overall rates of graft survival at one, five, and 10 yr were 89.6%, 83.0%, and 81.5%, respectively, and the overall rates of patient survival were 92.9%, 86.3%, and 84.8%, respectively. Virus-related disease (41.2%) and chronic rejection (29.4%) were the major causes of mortality. On multivariate analysis, UNOS status 1a and 1b and chronic rejection were significant risk factors for both graft and patient loss, whereas the PELD score >25 was a significant risk factor for graft loss. Patient and graft survival may be related not only to post-operative complications, but also to the patient's preoperative clinical condition.

Characteristics and trends in the incidence of inflammatory bowel disease in Korean children: a single-center experience.

BACKGROUND: Inflammatory bowel disease (IBD) is rare in Asian children and few reports on pediatric IBD have appeared. AIMS: We, therefore, investigated the incidence trends and clinical characteristics of pediatric IBD in Korea. METHODS: We enrolled 48 children with Crohn's disease (CD) and 14 children with ulcerative colitis (UC) from 1996 to 2007. Trends in annual enrollment and clinical characteristics were retrospectively evaluated by medical record review. RESULTS: During the 12 years of observation, the number of new enrollments gradually increased. CD showed male predominance (33 boys, 15 girls), but more females presented with UC (4 boys, 10 girls). A relevant family history was observed in 3 (4.9%) of the 61 unrelated families. The most common presenting symptom was abdominal pain (67%) in CD and hematochezia (93%) in UC. Growth delay was observed in 10% of CD patients, but not in any of the UC patients. In CD, colonic involvement occurred in 87% of patients, ileal involvement in 87%, and both the small bowel and colon were affected in 75%. With UC, pancolitis occurred in 43% of patients, left-sided colitis in 36%, and proctitis in 21%, including all three patients with appendiceal orifice inflammation. The most frequent disease behavior was inflammatory in 85% of patients, but perianal fistula was noted in 50% of CD patients. CONCLUSION: This study showed that the incidence of pediatric IBD has been rapidly increasing in Korea in recent years. Relevant family history is less prevalent and phenotypic expression differs from what is seen in Western countries.

Clinical characteristics and VPS33B mutations in patients with ARC syndrome.

OBJECTIVES: ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome is a rare, fatal cause of neonatal intrahepatic cholestasis without known treatment modalities and has recently been ascribed to a mutation in the VPS33B gene. We assessed the clinical characteristics and investigated the VPS33B mutations in Korean patients with ARC syndrome. PATIENTS AND METHODS: We reviewed the medical records of 6 patients with ARC syndrome among 90 patients with neonatal cholestasis from 2000 to 2005 and assessed the relative incidence rate ratio, clinical symptoms, laboratory findings, and pathological findings. DNA samples from 5 patients, 4 parents, and 2 fetuses were analyzed for VPS33B mutations. RESULTS: The relative incidence rate ratio was 1/7 that of biliary atresia (95% CI 0.33-0.06). All 6 patients presented with ichthyosis and recurrent infection, and failed to thrive with the 3 main symptoms. All of the patients died within the age of 12 months. They had various severities of cholestasis, metabolic acidosis, nephrogenic diabetes insipidus, chronic diarrhea, platelet abnormalities, and central nervous system anomalies. We identified 1 novel c.403+2T>A splice-site mutation, 2 frame-shift mutations (c.1509_1510insG, c.790_791del), 1 nonsense mutation (c.661C>A), and 1 known nonsense mutation (c.1518C>T) in the VPS33B gene. Prenatal diagnosis was performed in 2 different families. CONCLUSIONS: This study indicates that the incidence of ARC syndrome is not as rare as has been thought. We found 4 novel and 1 known mutations in ARC syndrome patients and performed prenatal diagnosis in 2 families, which will facilitate genetic diagnosis and counseling for affected families.

[Usefulness of multichannel intraluminal impedance-pH metry in children with suspected gastroesophageal reflux disease].

BACKGROUND/AIMS: pH monitoring of the esophagus has been considered as the gold standard for the measurement of acid reflux. However, it has several limitations related to its inability to detect nonacid reflux. We conducted this study to characterize the proportion of acid and non-acid reflux events in children using pH-multichannel intraluminal impedance (MII) monitoring and to determine the correlation of the symptom index with non-acid and acid reflux events. METHODS: Seventy-five children, aged from 9 days to 12 years, underwent 24 hour pH-MII monitoring at Asan Medical Center from March 2006 to June 2007. We investigated the underlying disease and main problems related to gastroesophageal reflux (GER) of the patients, the number of acid and nonacid reflux, symptom index, symptom sensitivity index in pH monitoring only and pH-MII monitoring. RESULTS: While 2,247 reflux events were detected by MII, and only 967 reflux events were detected by pH probe alone. The percentage of acid reflux was 43% (967) and that of non-acid was 57% (1,280). The non-acid reflux increased at postprandial time (p<0.001). The symptom index increased when measured by pH-MII (31.1%) compared with those by pH probe alone (8.2%) (p=0.003). CONCLUSIONS: This study suggests that significant number of GER include non-acid reflux which cannot be detected by pH probe alone, therefore combining pH with MII monitoring is a valuable diagnostic tool for diagnosing GER in children.

Appendiceal Orifice Inflammation in an 8-Year-Old Girl with Ulcerative Colitis Complicating Wilson's Disease.

Appendiceal orifice inflammation (AOI) may occur as a skipped lesion in ulcerative colitis (UC). Cases of ulcerative colitis complicated by Wilson's disease have also been reported. We report herein a case of AOI that occurred as a missed lesion in an 8-year-old girl with UC complicating Wilson's disease, which is rare in children.

Endoscopic retrograde cholangiopancreatography in pancreatic and biliary tract disease in Korean children.

AIM: To assess the indications, findings, therapeutic procedures, safety, and complications of endoscopic retrograde cholangiopancreatography (ERCP) performed in Korean children. METHODS: The demographic characteristics, indications for ERCP, findings, therapeutic procedures, and complications of 122 pediatric patients who underwent 245 ERCPs in the Asan Medical Center between June 1994 and March 2008 were investigated. RESULTS: The mean age of the 122 patients was 8.0 +/- 4.2 years. Indications were biliary pathology in 78 (64.0%), pancreatic pathology in 43 (35.2%), and chronic abdominal pain in one. Biliary indications included choledochal cysts in 40, choledocholithiasis in 24, suspected sclerosing cholangitis in 8, trauma in 2, and other conditions in 4. Pancreatic indications included acute pancreatitis in 7, acute recurrent pancreatitis in 11, chronic pancreatitis in 20, trauma in 3, and pancreatic mass in 2. Of the 245 ERCPs, success rate was 98.4% and 190 (77.6%) were for therapeutic purposes, including endoscopic nasal drainage (51.8%), biliary sphincterotomy (38.0%), pancreatic sphincterotomy (23.3%), stent insertion (15.1%), stone extraction (18.8%), and balloon dilatation (11.0%). Complications were post-ERCP pancreatitis in 16 (6.5%), ileus in 23 (9.4%), hemorrhage in 2 (0.8%), perforation in 2 (0.8%), sepsis in 1 (0.4%), and impacted basket in 1 (0.4%). There were no procedure-related deaths, and most complications improved under supportive care. CONCLUSION: This study showed that there is a high incidence of choledochal cyst and diagnostic and therapeutic ERCP for the management of various biliary and pancreatic diseases was safe and effective in Korean children.

Living Donor Liver Transplantation in a Korean Child with Glycogen Storage Disease Type IV and a GBE1 Mutation.

Glycogen storage disease type IV (GSD-IV) is an autosomal recessive disease caused by a deficient glycogen branching enzyme (GBE), encoded by the GBE1 gene, resulting in the accumulation of abnormal glycogen deposits in the liver and other tissues. We treated a 20-month-old girl who presented with progressive liver cirrhosis and was diagnosed with GSD-IV, as confirmed by GBE1 gene mutation analysis, and underwent living related heterozygous donor liver transplantation. Direct sequencing of the GBE1 gene revealed that the patient was compound heterozygous for a known c.1571G>A (p.Gly264Glu) mutation a novel c.791G>A (Arg524Gln) mutation. This is the first report of a Korean patient with GSD-IV confirmed by mutation analysis, who was treated successfully by liver transplantation.

Efficacy of two triple eradication regimens in children with Helicobacter pylori infection.

Triple therapy with bismuth subsalicylate, amoxicillin, metronidazole (BAM) or with omeprazole, amoxicillin, clarithromycin (OAC) has been commonly used for the eradication of Helicobacter pylori infection. We compared the efficacy of these triple therapies in children with H. pylori infection. We retrospectively analyzed results in 233 children with H. pylori infection and treated with OAC (n=141) or BAM (n=92). Overall eradication rates of triple therapy with OAC and BAM were 74% and 85%, respectively, which showed no statistical difference. Our study showed that the triple therapy with BAM was more effective for the first-line eradication of H. pylori infection in Korean children, but has no statistical difference with OAC regimen.

Placement of covered retrievable expandable metallic stents for pediatric tracheobronchial obstruction.

PURPOSE: To evaluate the safety and clinical effectiveness of placement of covered retrievable expandable metallic stents in seven children with tracheobronchial obstruction. MATERIALS AND METHODS: Using bronchoscopic and fluoroscopic guidance, stent placement was performed in seven children (median age, 12 y; range, 2 mo-14 y). The stents were electively removed 6 months after placement or whenever there were symptom-producing complications. During the follow-up period, technical and clinical success, complications and related reinterventions, and long-term prognosis were retrospectively evaluated. RESULTS: Stent placement was technically successful for a total of eight stents in all seven patients. Stent removal was also successful for six stents in five patients; two stents were removed electively 6 months after placement, and four stents were removed due to symptom-producing complications. Clinical success defined as ventilator weaning, extubation, or dyspnea improvement was achieved in all patients 1 week after stent placement. A possible infection source in one stent and abundant granulation tissue caused by three stents necessitated removal of four stents in three patients. During the mean follow-up period of 18.7 months (range, 1-31 mo) after stent placement, three patients died due to the progression of underlying cardiopulmonary disease or malignancy. There were no deaths directly related to stent placement or related complications. CONCLUSION: Although the findings were based on a small series, placement of covered retrievable expandable metallic stents seems to be safe and effective for the treatment of pediatric tracheobronchial obstruction. Ventilator weaning, extubation, or dyspnea improvement was possible in all patients after stent placement.