Genetic landscape of pediatric acute liver failure of indeterminate origin.

BACKGROUND AND AIMS: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. APPROACH AND RESULTS: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation. CONCLUSIONS: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics.

Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study. APPROACH AND RESULTS: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings. CONCLUSIONS: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.

Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency.

BACKGROUND AND AIMS: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. APPROACH AND RESULTS: This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] µmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 µmol/L (P = 0.05) tended to be associated with improved NLS. CONCLUSIONS: Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.

Genotype correlates with the natural history of severe bile salt export pump deficiency.

BACKGROUND & AIMS: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date. METHODS: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category. RESULTS: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 µmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001). CONCLUSIONS: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS. LAY SUMMARY: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.

Cardiovascular Risk Assessment in Pediatric Liver Transplant Patients.

OBJECTIVES: Cardiovascular (CV) diseases play a leading role in the mortality of adult liver transplant (LT) recipients. However, data regarding CV risk factors in children after LT remain sparse. The present study assessed the presence of CV risk factors and signs of CV impairment in LT children. METHODS: A total of 42 LT recipients (21 men, age 9.93 ±â€Š3.57 years) were studied. Body composition [body mass index standard deviation score, percentage of body fat (by bioimpedance analysis)], lipid profiles, glycemic control, blood pressure, and arterial stiffness [assessed by aortic pulse wave velocity (PWV)] were evaluated. The effect of different treatment modalities [tacrolimus (TAC) (n = 30) or cyclosporine (CyA) (n = 11)] was also analyzed. RESULTS: Almost 18% of children were overweight or obese. Patients on TAC had a significantly higher body fat mass and percentage of body fat compared with the CyA group (P < 0.02). Borderline to high lipid values were present in 40% of patients. Children on CyA had higher serum cholesterol levels compared to TAC (P < 0.004). Nineteen percent of patients had hypertension. Half of the patients had glomerular filtration rate values <90 mL/min/1.73 m, whereas PWV values were above the 95th percentile in 12%. CONCLUSIONS: Increased body fat, chronic kidney disease, high lipid content, hypertension, and increased arterial stiffness are already present and are in part related to the type of immunosuppression regimen in LT children >5 years following transplantation. Long-term follow-up is needed to evaluate their impact on CV health and survival.

Similarities and Differences in Allocation Policies for Pediatric Liver Transplantation Across the World.

OBJECTIVES: We aimed to investigate national allocation policies for pediatric liver transplantation (LT). METHOD: A survey was prepared by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Hepatology Committee in collaboration with the North American Studies of Pediatric Liver Transplantation consortium. The survey was sent to pediatric hepatologists and transplant surgeons worldwide. National data were obtained from centrally based registries. RESULTS: Replies were obtained from 15 countries from 5 of the world continents. Overall donation rate varied between 9 and 35 per million inhabitants. The number of pediatric LTs was 4 to 9 per million inhabitants younger than 18 years for 13 of the 15 respondents. In children younger than 2 years mortality on the waiting list (WL) varied between 0 and 20%. In the same age group, there were large differences in the ratio of living donor LT to deceased donor LT and in the ratio of split liver segments to whole liver. These differences were associated with possible discrepancies in WL mortality. CONCLUSIONS: Similarities but also differences between countries were detected. The described data may be of importance when trying to reduce WL mortality in the youngest children.

The Health Care Transition of Youth With Liver Disease Into the Adult Health System: Position Paper From ESPGHAN and EASL.

BACKGROUND: Medical advances have dramatically improved the long-term prognosis of children and adolescents with once-fatal hepatobiliary diseases. However, there is no generally accepted optimal pathway of care for the transition from paediatric care to the adult health system. AIM: The purpose of this position paper is to propose a transition process for young people with paediatric onset hepatobiliary diseases from child-centred to adult-centred healthcare services. METHODS: Seventeen ESPGHAN/EASL physicians from 13 countries (Austria, Belgium, France, Germany, Hungary, Italy, the Netherlands, Norway, Poland, Spain, Sweden, Switzerland, and United Kingdom) formulated and answered questions after examining the currently published literature on transition from childhood to adulthood. PubMed and Google Scholar were systematically searched between 1980 and January 2018. Quality of evidence was assessed by the Grading of Recommendation Assessment, Development and Evaluation (GRADE) system. Expert opinions were used to support recommendations whenever the evidence was graded weak. All authors voted on each recommendation, using the nominal voting technique. RESULTS: We reviewed the literature regarding the optimal timing for the initiation of the transition process and the transfer of the patient to adult services, principal documents, transition multi-professional team components, main barriers, and goals of the general transition process. A transition plan based on available evidence was agreed focusing on the individual young people's readiness and on coordinated teamwork, with transition monitoring continuing until the first year of adult services.We further agreed on selected features of transitioning processes inherent to the most frequent paediatric-onset hepatobiliary diseases. The discussion highlights specific clinical issues that will probably present to adult gastrointestinal specialists and that should be considered, according to published evidence, in the long-term tracking of patients. CONCLUSIONS: Transfer of medical care of individuals with paediatric onset hepatobiliary chronic diseases to adult facilities is a complex task requiring multiple involvements of patients and both paediatric and adult care providers.

Wilson's Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition.

BACKGROUND: Clinical presentations of Wilson's disease (WD) in childhood ranges from asymptomatic liver disease to cirrhosis or acute liver failure, whereas neurological and psychiatric symptoms are rare. The basic diagnostic approach includes serum ceruloplasmin and 24-hour urinary copper excretion. Final diagnosis of WD can be established using a diagnostic scoring system based on symptoms, biochemical tests assessing copper metabolism, and molecular analysis of mutations in the ATP7B gene. Pharmacological treatment is life-long and aims at removal of copper excess by chelating agents as D-penicillamine, trientine, or inhibition of intestinal copper absorption with zinc salts. Acute liver failure often requires liver transplantation. This publication aims to provide recommendations for diagnosis, treatment, and follow-up of WD in children. METHODS: Questions addressing the diagnosis, treatment, and follow-up of WD in children were formulated by a core group of ESPGHAN members. A systematic literature search on WD using MEDLINE, EMBASE, Cochrane Database from 1990 to 2016 was performed focusing on prospective and retrospective studies in children. Quality of evidence was assessed according to the GRADE system. Expert opinion supported recommendations where the evidence was regarded as weak. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using the nominal voting technique.

Diagnosis and Management of Pediatric Autoimmune Liver Disease: ESPGHAN Hepatology Committee Position Statement.

Paediatric autoimmune liver disease is characterized by inflammatory liver histology, circulating autoantibodies, and increased levels of IgG, in the absence of a known etiology. Three conditions have a likely autoimmune pathogenesis: autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis, and de novo AIH after liver transplantation. Two types of pediatric AIH are recognized according to seropositivity for smooth muscle and/or antinuclear antibody (AIH-1) or liver kidney microsomal type 1 and/or anti-liver cytosol type 1 antibodies (AIH-2).Pertinent issues addressing the diagnosis, treatment, and long-term follow-up were formulated by a core group of ESPGHAN members. They have commissioned the first authors with execution of this project. Initially, they have performed a systematic literature search on MEDLINE, ResearchGate, and Mendeley databases during the last 30 years and produced a document focusing on prospective and retrospective studies in children. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique.

Treatment of Chronic Hepatitis C Virus Infection in Children: A Position Paper by the Hepatology Committee of European Society of Paediatric Gastroenterology, Hepatology and Nutrition.

OBJECTIVES: In 2017, the European Medicines Agency and the Food and Drug Administration approved the use of the fixed-dose combination of ledipasvir/sofosbuvir and of the combination of sofosbuvir and ribavirin for treatment of adolescents (12-17 years or weighing >35 kg) with chronic hepatitis C virus (HCV) genotype 1, 4, 5, and 6 and genotype 2 and 3 infections, respectively. Although trials with direct-acting antivirals are ongoing for younger children, the only available treatment in the United States and Europe for those <12 years is still the dual therapy of pegylated interferon and ribavirin. There is currently a lack of a systematic approach to the care of these patients. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition developed an evidence-based position paper for the management of chronic HCV infection in children. METHODS: A systematic literature search and meta-analysis were performed using MEDLINE and Embase from June 1, 2007 to June 1, 2017. The approach of the Grading of Recommendations Assessment, Development and Evaluation was applied to evaluate outcomes. European Society of Pediatric Gastroenterology, Hepatology and Nutrition Committee members voted on each recommendation, using the nominal voting technique. RESULTS: The efficacy of the different direct-acting antivirals combinations tested was higher, the relapse and the treatment discontinuation rates lower when compared to pegylated interferon and ribavirin. CONCLUSIONS: This position paper addresses therapeutic management issues including goals, endpoints, indications, contraindications, and the optimal treatment regimen in children with chronic HCV infection.

[Solid organ transplantation in childhood]. / Szervtranszplantáció gyermekkorban.

Paediatric organ transplantation today is considered and accepted and widely available therapy in children with end-stage organ failure. It is important to know that in childhood, diseases leading to end-stage organ failure differ from those in adults. Beside this, in children there are different surgical and paediatric challenges before and after transplantation (size differences of the patient and donor organ, special and paediatric infections, different pharmacokinetics and pharmacodynamics of immunosuppressive drugs, noncompliance). However, paediatric organ transplantation in the last decades became a success story of the Hungarian health care owing to several working groups in Hungary and outside the country. Orv Hetil. 2018; 159(46): 1948-1956.

Attempt to Determine the Prevalence of Two Inborn Errors of Primary Bile Acid Synthesis: Results of a European Survey.

OBJECTIVE: Inborn errors of primary bile acid (BA) synthesis are genetic cholestatic disorders leading to accumulation of atypical BA with deficiency of normal BA. Unless treated with primary BA, chronic liver disease usually progresses to cirrhosis and liver failure before adulthood. We sought to determine the prevalence of 2 common disorders, 3ß-hydroxy-Δ-C27-steroid dehydrogenase (3ß-HSD) and Δ-3-oxosteroid-5ß-reductase (Δ-3-oxoR) deficiencies and to describe current diagnostic and treatment strategies among different European paediatric hepatology centres. METHODS: A total of 52 clinical paediatric centres were approached and 39 centres in 21 countries agreed to participate in the Web-based survey. The survey comprised questions regarding general information, number of cases, diagnostic, and therapeutic management. RESULTS: Seventeen centres located in 11 countries reported patients with inborn errors in primary BA synthesis, 22 centres never had cases diagnosed. In total, we could identify 63 patients; 55 with 3ß-HSD and 8 with Δ-3-oxoR deficiency in 21 countries. The minimum estimated combined prevalence of these diseases was 1.13 cases per 10 million (0.99 and 0.14 for 3ß-HSD and Δ-3-oxoR deficiencies, respectively). The surveyed colleagues indicated their main challenges to be the rarity of diseases and the lack of convenient laboratory facilities nearby. CONCLUSION: We have identified the largest cohort of patients with 3ß-HSD or Δ-3-oxoR deficiency described so far. These diseases are likely underdiagnosed mainly due to unawareness of their existence and the lack of laboratory facilities.

Early and Late Factors Impacting Patient and Graft Outcome in Pediatric Liver Transplantation: Summary of an ESPGHAN Monothematic Conference.

As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long-term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications.

Hepatitis E in Children: A Position Paper by the ESPGHAN Hepatology Committee.

BACKGROUND: Hepatitis E virus (HEV) is endemic in large parts of the developing world. Waterborne transmission of genotypes 1 or 2 commonly causes acute hepatitis, which is usually self-limited in healthy individuals. In addition, acute HEV infections also occur outside endemic areas, mostly related to foodborne transmission of HEV genotype 3. A growing number of publications in the last decade have reported chronic infection progressing to cirrhosis in immunosuppressed patients. It has also been suggested that HEV transmission may occur via contaminated blood products. This publication aims to provide recommendations for diagnosis, prevention, and treatment of HEV infection, particularly in children after solid organ transplantation. METHODS: A systematic PubMed literature search on HEV infection from 1990 to January 2016 was performed focusing on pediatric studies. The existing body of evidence was reviewed and recommendations were agreed upon following discussion and unanimous agreement by all members of the ESPGHAN Hepatology Committee during a consensus meeting in January 2016. In the absence of randomized controlled studies these recommendations were considered to be expert opinions. KEY RECOMMENDATIONS: Immunocompetent children with increased transaminases and/or extrahepatic manifestations should be considered for testing for evidence of HEV infection. Immunocompromised children with increased aminotransferases should be repeatedly tested for HEV and may require therapeutic intervention.

Indications and limitations of bariatric intervention in severely obese children and adolescents with and without nonalcoholic steatohepatitis: ESPGHAN Hepatology Committee Position Statement.

Morbid obesity is strongly associated with nonalcoholic fatty liver disease (NAFLD), which is one of the most common causes of chronic liver disease worldwide. The present best treatment for NAFLD and nonalcoholic steatohepatitis (NASH) is weight reduction through lifestyle modification. Because of frustrating inefficiency of such a therapeutic approach, bariatric surgery is increasingly performed in adolescents as an alternative option for weight reduction. Standards of care and consensus for indications are, however, scarce. We explore the indications and limitations of bariatric surgery in children with severe obesity with and without NASH and aim to provide guidance for the exceptional indications for adolescents with extreme obesity with major comorbidity that may benefit from these controversial interventions. Present evidence suggests that bariatric surgery can decrease the grade of steatosis, hepatic inflammation, and fibrosis in NASH. Uncomplicated NAFLD is not an indication for bariatric surgery. Roux-en-Y gastric bypass is considered a safe and effective option for adolescents with extreme obesity, as long as an appropriate long-term follow-up is provided. Laparoscopic adjustable gastric banding has not been approved by the Food and Drug Administration for use in adolescents and therefore should be considered investigational. Finally, sleeve gastrectomy and other types of weight loss surgery that have grown increasingly common in adults, still need to be considered investigational. Temporary devices may be increasingly being used in pediatrics; however, future studies, including a long-term risk analysis of patients who undergo surgery, are much needed to clarify the exact indications for bariatric surgery in adolescents.

Liver biopsy in children: position paper of the ESPGHAN Hepatology Committee.

Liver biopsy (LB) is still the criterion standard procedure for obtaining liver tissue for histopathological examination and a valuable tool in the diagnosis, prognosis, and management of many parenchymal liver diseases. The aim of this position paper is to summarise the present practice of paediatric LB and make recommendations about its performance. Although histological evaluation of the liver is important in assessing prognosis and exploring treatment, noninvasive techniques (ie, imaging, laboratory markers) may replace use of liver histology. The indications for LB are changing as present knowledge of aetiologies, pathomechanism, and therapeutic options in paediatric liver disease is evolving. Adult and paediatric literature was reviewed to assess the existing clinical practice of LB with focus on the technique, indications, risk of complications, and contraindications in paediatrics. This position paper presents types of LB, indications, complications, contraindications, and an essential checklist for paediatric LB.

[Post-transplantation lymphoproliferative disorder in childhood]. / Poszttranszplantációs lymphoproliferativ betegség gyermekkorban.

INTRODUCTION: Among possible complications of transplantation the post-transplant lymphoproliferative disease due to immunosuppressive therapy is of paramount importance. In most cases the direct modulating effect of Epstein-Barr virus on immune cells can be documented. AIM: The aim of the authors was to evaluate the incidence os post-transplant lymphoproliferative diseases in pediatric transplant patients in Hungary. METHOD: The study group included kidney, liver and lung transplant children followed up at the 1st Department of Pediatrics, Semmelweis University, Budapest and stem cell transplant children at Szent László Hospital, Budapest. Data were collected from 78 kidney, 109 liver and 17 lung transplant children as well as from 243 children who underwent allogenic stem cell transplantation. RESULTS: Between 1998 and 2012, 13 children developed post-transplant lymphoproliferative disorder (8 solid organ transplanted and 5 stem cell transplanted children). The diagnosis was based on histological findings in all cases. Mortality was 3 out of the 8 solid organ transplant children and 4 out of the 5 stem cell transplant children. The highest incidence was observed among lung transplant children (17.6%). CONCLUSIONS: These data indicate that post-transplant lymphoproliferative disease is a rare but devastating complication of transplantation in children. The most important therapeutic approaches are reduction of immunosuppressive therapy, chemotherapy and rituximab. Early diagnosis may improve clinical outcome and, therefore, routine polymerase chain reaction screening for Epstein-Barr virus of high risk patients is recommended.

Incidence, Paris classification, and follow-up in a nationwide incident cohort of pediatric patients with inflammatory bowel disease.

OBJECTIVES: The aim of the study was to evaluate the incidence, baseline disease characteristics, and disease location based on the Paris classification in pediatric inflammatory bowel disease (IBD) in the Hungarian nationwide inception cohort. In addition, 1-year follow-up with therapy was analyzed. METHODS: From January 1, 2007 to December 31, 2009, newly diagnosed pediatric patients with IBD were prospectively registered. Twenty-seven pediatric gastroenterology centers participated in the data collection ensuring the data from the whole country. Newly diagnosed patients with IBD younger than 18 years were reported. Disease location was classified according to the Paris classification. RESULTS: A total of 420 patients were identified. The incidence rate of pediatric IBD was 7.48/105 (95% confidence interval [CI] 6.34/105-8.83/105). The incidence for Crohn disease (CD) was 4.72/105 (95% CI 3.82-5.79), for ulcerative colitis (UC) 2.32/105 (95% CI 1.71-3.09), and for IBD-unclassified 0.45/105 (95% CI 0.22-0.84). Most common location in CD was L3 (58.7%); typical upper gastrointestinal abnormalities (ulcer, erosion and aphthous lesion) were observed in 29.9%. Extensive colitis in patients with UC (E4, proximal to hepatic flexure) was the most common disease phenotype (57%), whereas only 5% of children had proctitis. A total of 18.6% of patients had ever severe disease (S1). Frequency of azathioprine administration at diagnosis was 29.5% in patients with CD, and this rate increased to 54.6% (130/238) at 1-year follow-up. In UC, only 3.3% received azathioprine initially, and this rate elevated to 22.5% (25/111). Use of corticosteroid decreased from 50% to 15.3% in patients with UC. Rate of bowel resection in patients with CD during the first year of follow-up was 5%. CONCLUSIONS: The incidence of pediatric IBD in Hungary was among the higher range reported. This is the first large, nationwide incident cohort analyzed according to the Paris classification, which is a useful tool to determine the characteristic pediatric CD phenotype.

Case report: The spectrum of SMPD1 pathogenic variants in Hungary.

Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive disease caused by biallelic pathogenic variants in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. Acid sphingomyelinase deficiency is characterized by a spectrum of disease and is broadly divided into three types (ASMD type A, ASMD type A/B, and ASMD type B). More than 220 disease-associated SMPD1 variants have been reported, and genotype/phenotype correlations are limited. Here we report the first description of all six diagnosed acid sphingomyelinase deficiency cases in Hungary. Nine SMPD1 variants are present in this cohort, including 3 SMPD1 variants (G247D, M384R, and F572L), which have only been described in Hungarian patients. All described variants are deemed to be pathogenic. Eight of the variants are missense, and one is a frameshift variant. The treatment of an ASMD type A/B patient in this cohort using hematopoietic stem cell transplantation is also detailed. This study may help to support diagnosis, patient genetic counseling, and management of acid sphingomyelinase deficiency.