Whole-exome sequencing for genetic diagnosis of idiopathic liver injury in children.

Genome-wide approaches, such as whole-exome sequencing (WES), are widely used to decipher the genetic mechanisms underlying inter-individual variability in disease susceptibility. We aimed to dissect inborn monogenic determinants of idiopathic liver injury in otherwise healthy children. We thus performed WES for 20 patients presented with paediatric-onset recurrent elevated transaminases (rELT) or acute liver failure (ALF) of unknown aetiology. A stringent variant screening was undertaken on a manually-curated panel of 380 genes predisposing to inherited human diseases with hepatobiliary involvement in the OMIM database. We identified rare nonsynonymous variants in nine genes in six patients (five rELT and one ALF). We next performed a case-level evaluation to assess the causal concordance between the gene mutated and clinical symptoms of the affected patient. A genetic diagnosis was confirmed in four rELT patients (40%), among whom two carried novel mutations in ACOX2 or PYGL, and two had previously-reported morbid variants in ABCB4 or PHKA2. We also detected rare variants with uncertain clinical significance in CDAN1, JAG1, PCK2, SLC27A5 or VPS33B in rELT or ALF patients. In conclusion, implementation of WES improves diagnostic yield and enables precision management in paediatric cases of liver injury with unknown aetiology, in particular recurrent hypertransaminasemia.

Food protein-induced allergic proctocolitis in infants is associated with low serum levels of macrophage inflammatory protein-3a.

BACKGROUND: Food protein-induced allergic proctocolitis (FPIAP) is a nonimmunoglobulin (IgE)-mediated food hypersensitivity and the exact mechanisms that cause FPIAP are unknown. Chemokines play crucial roles in the development of allergic diseases. OBJECTIVE: To examine serum levels of a group of chemokines in infants with FPIAP. METHODS: In 67 infants with FPIAP and 65 healthy infants, we measured serum levels of mucosa-associated epithelial chemokine (MEC/CCL28), thymus-expressed chemokine (TECK/CCL25), CX3CL1 and macrophage inflammatory protein (MIP)-3a/CCL20. RESULTS: Infants with FPIAP had a lower median value of MIP3a/CCL20 than healthy infants [0.7 (0-222) vs. 4 (0-249) pg/mL, respectively] (p < 0.001). Infants with MIP3a/CCL20 levels ≤0.95 pg/mL have 13.93 times more risk of developing FPIAP than infants with MIP3a/CCL20 levels >0.95 pg/mL. Serum MEC/CCL28, TECK/CCL25, and CX3CL1 levels were similar between the infants with FPIAP and the control group. CONCLUSION: MIP3a/CCL20 serum levels were reduced in infants with FPIAP compared with healthy controls. Whether this finding has a role in pathogenesis remains to be determined.

Expected Life Expectancy on Liver Transplantation and Aging Donor.

In this study, our aim was to show the life expectancy according to donor age groups at 1, 3, 5, 10, 15, and 20 years after liver transplant in liver transplant recipients. In this retrospective study, we analyzed the survival rate of 236 patients who had liver transplant procedures between 1988 and 2021. The 5-year life expectancy of recipients with donors over age 50 years in the literature has been shown to vary between 50% and 80%. Little information could be found on life expectancy after 10, 15, and 20 years in other studies. In the studies from Haberal and colleagues, life expectancy at 10, 15, and 20 years was 49%, 42%, and 42%, respectively. This study presents an evidence-based example of the use of elderly donors to enlarge the donor pool.

Evaluation of Vitamin D Levels in Children With Liver Transplant.

OBJECTIVES: Vitamin D deficiency is common in pediatric chronic liver disease despite oral replacement. We evaluated vitamin D deficiency before and after liver transplant and the relationship between posttransplant and pretransplant vitamin D deficiency and graft rejection. MATERIALS AND METHODS: Pediatric recipients with chronic liver disease (N =138) were divided into 4 groups: cholestatic liver diseases, cirrhosis, metabolic disorders, and acute liver failure. Pretransplant and posttransplant vitamin D levels, liver function tests, Pediatric End-Stage Liver Disease scores, rejection activity index scores by graft liver biopsy, and posttransplant patient survival were recorded. RESULTS: There were 62 (45%) female and 76 (55%) male participants (mean transplant age, 6.1 ± 5.6 years). Pretransplant mean available vitamin D of 90 patients was 25.2 ± 20.9 ng/mL, with 36 (40%) within reference range. Posttransplant level for 109 patients was 27.3 ± 18 ng/mL, with 64 (58.7%) within reference range. Pretransplant and posttransplant levels were available for 61 patients, and mean pretransplant levels were lower than posttransplant levels (23.7 ± 19.3 vs 28.3 ± 16.9 ng/mL; P = .01). Patients with cholestatic liver disease had lower pretransplant vitamin D levels (P = .04), which disappeared after transplant. Pretransplant vitamin D levels were positively correlated with serum albumin levels (r = 0.20) in all patients and negatively correlated with total/direct bilirubin (r = 0.29 and r = -0.30) in those with liver diseases and cirrhosis. No correlations were found between pretransplant vitamin D levels and Pediatric End-Stage Liver Disease scores, rejection activity index scores, and posttransplant mortality. CONCLUSIONS: Vitamin D deficiency is prevalent in pediatric chronic liver disease before and after transplant, especially for cholestatic liver diseases. However, no association between vitamin D levels and liver graft rejection or patient survival was noted. We recommend close monitoring and individualized vitamin D supplementation before and after liver transplant.

SCYL1 deficiency: A rare entity with challenging neurological manifestations after liver transplantation.

BACKGROUND: Pediatric acute liver failure (PALF) with undetermined etiology is associated with higher liver transplantation and lower spontaneous recovery (transplant-free) rates. The diagnostic odyssey in PALF cases hinders appropriate management and follow-up after liver transplantation. Advances in whole exome sequencing analysis have already been successful at identifying new genetic causes of PALF. CASE PRESENTATION: We report a 17-year-old girl who underwent liver transplantation at the age of 7 months due to acute liver failure and presented later with abnormal neurological manifestations, that is, gait disturbances, dysarthria, and mental retardation that led us to the diagnosis of SCYL1 deficiency. CONCLUSION: PALF cases should be screened for possible underlying genetic disorders. Genetic studies and reanalysis of whole-genome sequencing data may help identify new cases and clarify the genotype-phenotype correlation. SCYL1 deficiency should be suspected in PALF patients who develop neurological involvement after LT. Early diagnosis is vital for proper management of ALF crises in SCYL1 deficiency patients. Despite the reported favorable outcomes of ALF crises in SCYL1 deficiency, liver transplantation decision should be discussed on a case-by-case basis.

Association of Liver Transplant and Attention-Deficit Hyperactivity Disorder: A Single-Center Experience.

OBJECTIVES: This prospective cohort study aimed to determine the prevalence of attention-deficit hyperactivity disorder and to reveal how the diagnosis of attention-deficit/hyperactivity disorder can be made most accurately in children with liver transplant. MATERIALS AND METHODS: We studied a group of 62 children from 6 and 18 years old who underwent liver transplant at least 1 year previous to our study and who were followed up in the Department of Pediatric Gastroenterology. A child and adolescent psychiatrist evaluated all liver transplant patients for attention- deficit hyperactivity disorder based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. The Kiddie Schedule for Affective Disorders and Schizophrenia (in Turkish) was applied to the children. The Kiddie Schedule and the Conners Parent Rating Scale were applied to the children's parents. The Conners Teacher Rating Scale was applied to the children's teachers. RESULTS: The frequency of attention-deficit hyperactivity disorder in the sample was found to be 24.5% according to Kiddie Schedule, 45.9% according to the Conners Parent Rating Scale, and 24% according to the Conners Teacher Rating Scale. However, clinical examination showed that 9.67% of the children had attention-deficit hyperactivity disorder. CONCLUSIONS: We concluded that detailed clinical examination is more important than neuropsychological tests and scales when diagnosing attention-deficit hyperactivity disorder in pediatric liver transplant recipients.

Long-Term Social Outcomes of Pediatric Liver Transplant Recipients: Transition From Childhood to Adulthood.

OBJECTIVES: Chronic disorders may negatively affect people's learning status, marital status, occupational life, and social life. Liver transplant is the only curative treatment for chronic liver diseases. This study was undertaken to evaluate the psychosocial effects of liver transplant in adult patients who had undergone liver transplant during the pediatric period compared with psychosocial facts in the general population. MATERIALS AND METHODS: We retrospectively reviewed adult patients (>18 years of age) who had received liver transplant as children. We compared sex, age at the time of transplant, current age, type of donor, graft survival status, marital status, age at first delivery, number of children, educational status, and occupational status in the study population versus the general (normal) population. To compare the liver transplant patients included in the study with the general population correctly, we used data from the Turkish Statistical Institute. RESULTS: Among 77 liver transplant patients included in our study, the mean age at transplant was 10.9 years (range, 0.5-16 y) and the mean age at the time of the study was 25.2 years (range, 18-42 y). Of the patients, 61 (79.2%) were single and 16 (20.8%) were married. Patients in the study population married at a younger age than the general population (25.5 vs 28.1 y for men, 24.3 vs 25.4 y for women). Of 16 married patients, 9 (56.2%) had a healthy child or children. The percentage of patients who graduated from higher education or were continuing their higher education process was higher in our study population than in the general population (36.3% vs 22.8%). Among our study population, 37 patients (48%) were workers. CONCLUSIONS: Liver transplant had no negative effects on the social, educational, and professional lives among adults in our study who received transplants in the pediatric period.

Chronic enteropathy associated with SLCO2A1 gene and hereditary fructose intolerance: A coincidence of two rare diseases.

Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a rare disorder characterized by multiple small intestine ulcers. Patients with CEAS typically present with chronic anemia and gastrointestinal bleeding. Besides CEAS, SLCO2A1 mutations cause primary hypertrophic osteoarthropathy (PHO) which is considered as an extraintestinal manifestation in CEAS patients. Since CEAS and Crohn's disease are clinically indistinguishable, patients are often misdiagnosed with Crohn's disease. Herein, we describe a 4-year-old Turkish girl with CEAS due to homozygous pathogenic variant (c.656C > T) in SLCO2A1 with concomitant hereditary fructose intolerance (HFI) caused by homozygous pathogenic variant (c.1005C > G) in ALDOB. Prompt restriction of fructose, sucrose and sorbitol resulted in hepatomegaly regression and mild amelioration of patient's symptoms. Despite budesonide and azathioprine treatments, patient's protein losing enteropathy and chronic anemia did not improve. Although previous CEAS cases were reported from East Asian countries, it is likely to occur in people from other geographic areas. CEAS seems to be underdiagnosed and high index of suspicion is required for the diagnosis of this rare entity. Patients with prior diagnosis of Crohn's disease with no response to immunosuppressive treatment or anti-TNF therapy should be re-evaluated for possible CEAS diagnosis.

Clinical Features and Outcomes Following SARS-CoV-2 Infection in Pediatric Liver Transplant Patients.

OBJECTIVES: Several studies suggest that chronic immunosuppression in pediatric liver transplant patients may affect the severity and mortality rates of SARS-CoV-2 infection. MATERIALS AND METHODS: We assessed a total of 118 pediatric liver transplant recipients for SARS-CoV-2 infection, aged 1 to 18 years, followed between March 2019 and January 2022. We compared the clinical characteristics and outcomes of SARS-CoV-2 infection in pediatric liver transplant patients to 187 non-liver transplant pediatric patients with SARSCoV-2 infection who had been diagnosed at our institution between March 15, 2020, and December 31, 2020. Demographic data, clinical features, and laboratory findings from the patients were retrospectively collected from hospital reports and telephone inquiries. RESULTS: A total of 20 liver transplant patients with SARS-CoV-2 infection were identified. Median age of liver transplant recipients with SARS-CoV-2 infection was higher than non-liver transplant pediatric patients with SARS-CoV-2 (14.8 [range, 7-16] vs 6.8 [range, 2-14] years; P = .016). There were no significant differences in mild and moderate disease courses of SARS-CoV-2 infection between liver transplant recipients and non-liver transplant pediatric patients (18 [90.0%] vs 133 [71.1%] patients [P = .188] and 2 [10%] vs 49 [26.2%] patients [P = .118], respectively). Fever was less frequently observed in liver transplant patients with SARS-CoV-2 infection compared with non-liver transplant patients (55.0% vs 80.2%; P = .015). We found no intergroup differences in sex (P = .342), hospitalization rate (P = .161), and overall clinical presentation. CONCLUSIONS: Despite the immunosuppression regimens, liver transplant patients in our series survived SARS-CoV-2 infection without serious sequelae and without graft rejection. Overall, liver transplant and non-liver transplant pediatric patients with SARSCoV-2 infection experienced a mild disease course.

A novel mutation in TRMT5 associated with idiopathic non-cirrhotic portal hypertension and hepatopulmonary syndrome: Case report of two siblings.

Non-cirrhotic portal hypertension (NCPH) is a rare clinical entity in children. Familial clusters of idiopathic non-cirrhotic portal hypertension (INCPH) were previously reported in cases with deoxyguanosine kinase (DGOUK) and potassium calcium-activated channel subfamily N member 3 (KCNN3) mutations. Herein, we report two siblings who had a novel mutation in mitochondrial tRNA methyltransferase 5 (TRMT5) gene and presented with hepatopulmonary syndrome and later diagnosed as INCPH. Autosomal recessive inheritance of this mutation may suggest a role of TRMT5 mutations in the development of NCPH. Screening of TRMT5 mutations could be considered when familial INCPH is suspected.

Seventeen Years of Pediatric Liver Transplantation Experience for Cirrhosis and Hepatocellular Carcinoma.

OBJECTIVES: This was a retrospective analysis of liver transplant for pediatric patients with liver cirrhosis and hepatocellular carcinoma. MATERIALS AND METHODS: Fourteen pediatric patients with chronic liver disease and hepatocellular carcinoma underwent liver transplant from 2004 to 2021. Preexisting diseases were tyrosinemia (n = 6), progressive familial intrahepatic cholestasis type 2 (n = 2) and type 3 (n = 3), cryptogenic cirrhosis (n = 2), hepatitis B and D (n = 1), and biliary atresia (n = 1). RESULTS: Mean age was 9.43 ± 4.9 years (range, 13 months to 16 years). Three patients had 1 tumor, 4 had 2 tumors, and 7 had multiple (≥3) lesions. Six patients were classified as Pretreatment Extent of Disease Staging System for Hepatoblastoma (PRETEXT) stage IV, 3 as stage II, and 5 as stage I. Some patients received systemic chemotherapy before (n = 4) or after transplant (n = 3) or transarterial chemoembolization and microwave ablation pretransplant (n = 1). Hepatocellular carcinoma posttransplant recurrence was observed at 23, 47, and 108 months in 3 patients (21%). Recurrence sites were omentum (n = 1) and liver graft (n = 2). One patient was treated with hepatic resection, radiofrequency ablation, and radiotherapy, while the other received radiofrequency ablation and chemotherapy for graft tumor recurrence. Relapse-free patient survival rates were 92%, 82.5%, and 72.2% at 2, 4, and 10 years, respectively. Four recipients (28.5%) died; posttransplant cause of death was infection at 19 (n = 1) and 188 months (n = 1) or hepatocellular carcinoma recurrence at 79 (n = 1) and 165 months (n = 1). Median follow-up was 178 months (range, 13-204 months). Mean estimated survival was 171.25 ± 16.6 months. Overall patient posttransplant survival was 100%, 92.3%, 92.3%, 83%, and 72% at 1, 2, 5, 10, and 15 years, respectively. CONCLUSIONS: Hepatocellular carcinoma was mainly associated with inherited liver diseases in our pediatric series. Liver transplant provided a long-term survival advantage to pediatric patients with preexisting cirrhosis and hepatocellular carcinoma.

Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease.

Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.

Fecal calprotectin levels in Helicobacter pylori gastritis in children.

BACKGROUND: Fecal calprotectin is an important inflammatory marker in intestinal diseases and is not routinely used in the upper gastrointestinal system disorders. The aim of this study was to show whether there is a relationship between fecal calprotectin levels and Helicobacter pylori (H pylori) gastritis in children and to determine the association of fecal calprotectin levels with gastric biopsy results in terms of chronic inflammation and neutrophil activity. METHODS: Patients with the complaints of the upper gastrointestinal system (epigastric pain, heartburn, nausea and vomiting) who were planned to undergo endoscopy were enrolled prospectively. The presence of H pylori was defined according to the gastric antrum biopsy results. Fecal calprotectin level was tested in the stool sample of the patients. The fecal calprotectin levels, upper gastrointestinal endoscopy and gastric biopsy results of 89 patients were evaluated. RESULTS: H pylori was found to be positive in the gastric biopsies of 51 (57.3%) patients. In the H pylori positive group mean fecal calprotectin level was 74.8 ± 67 µg/g, and in the H pylori negative group mean fecal calprotectin level was 52.7 ± 46 µg/g and the difference was significant (p= 0.039). We also found a significant relationship between fecal calprotectin levels and gastric neutrophil activity grades (p= 0.034). CONCLUSIONS: Mean fecal calprotectin levels were found to be higher in H pylori positive subjects in our study. Fecal calprotectin levels were correlated with gastric neutrophil activity grades. Fecal calprotectin represents gastric neutrophilic inflammation. When interpreting a high fecal calprotectin level, H pylori infection should be kept in mind.

First Report of Treatment with Pancreas-Sparing Duodenectomy in a Child with Primary Intestinal Lymphangiectasia.

Pancreas-sparing duodenectomy (PSD) is a known surgical technique used in patients with duodenal pathologies in the adult age group. We present a 3-year-old female patient with intestinal lymphangiectasia who underwent PSD. This is the first case in which this surgical technique was used in childhood. We believe that PSD can be used in the pediatric age group for benign pathologies. Introducing a stent to the common bile duct and the main pancreatic duct is not a requirement, especially if the ampulla is preserved as a "button" duodenal patch.

Prevalence of Infections in Infants Within the First 6 Months of Liver Transplant.

OBJECTIVES: In this retrospective study, we aimed to determine the most common infectious agents in infants within the first 6 months of liver transplant. MATERIALS AND METHODS: Thirty-four infant patients with median age of 8 months (range, 4-12 mo) at the time of liver transplant were retrospectively evaluated. We evaluated causative organisms in bloodstream cultures and in subclavian catheter, urine, and intra-abdominal drainage fluid cultures. We also evaluated Epstein-Barr and cytomegalovirus infections by polymerase chain reaction in all recipients. RESULTS: The most common isolated bacteria from the bloodstream were Klebsiella pneumoniae, Staphylococcus epidermidis, and Enterococcus faecium. Staphylococcus epidermidis was the most common isolated bacteria from subclavian catheter cultures. Klebsiella pneumoniae was the most common bacteria isolated from intra-abdominal drainage fluid. Only 1 recipient had cytomegalovirus infection during this period. CONCLUSIONS: Our study showed a high incidence of Klebsiella pneumoniae infections in infants after liver transplant. New prophylactic antibiotic strategies can be promoted to prevent Klebsiella pneumoniae infections in infants.

Efficacy of Levetiracetam for Epilepsy in Pediatric Liver Transplant Recipients With Posterior Reversible Encephalopathy Syndrome.

OBJECTIVES: Liver transplant is currently the most effective option for patients with end-stage liver disease. Seizures are the most common neurologic complication after liver transplant. Posterior reversible encephalopathy syndrome is a neurologic syndrome characterized by lethargy, seizures, visual disturbances, and radiologic findings of edema in the posterior regions of the cerebral hemispheres. Levetiracetam is prescribed for a broad spectrum of seizure types but does not have a specific indication for epilepsy in children after solid-organ transplant. Our aim was to investigate the efficacy and tolerability of levetiracetam in pediatric transplant recipients with posterior reversible encephalopathy syndrome and epilepsy. MATERIALS AND METHODS: We reviewed records of patients treated for epilepsy due to posterior reversible encephalopathy syndrome after liver transplant seen at our pediatric neurology clinic between January 2010 and March 2019. Patients were assessed clinically and by neurologic examination, electroencephalography, and cerebral magnetic resonance imaging. RESULTS: Among 134 children who had undergone liver transplant between 2010 and 2019, 10 patients (6 males, 4 females; age range,7-19 y) who were diag-nosed with posterior reversible encephalopathy syndrome and epilepsy were included in the study. All patients received levetiracetam at 20 mg/kg/day. After a mean follow-up of 28.9 months (range, 24-40 mo), 9 patients (90%) attained complete seizure freedom. One patient who had an underlying neurodegenerative disease (hemophagocytic syndrome) other than posterior reversible encephalopathy syndrome continued to have seizures under levetiracetam treatment. One patient had a mild adverse reaction (irritability) due to levetiracetam but did not require drug discontinuation. CONCLUSIONS: In this study, 90% of patients with posterior reversible encephalopathy syndrome became seizure free with levetiracetam treatment. Our findings suggest that levetiracetam has a favorable efficacy for epilepsy due to posterior reversible encephalopathy syndrome in pediatric liver transplant recipients with tolerable adverse effects.

Incidence, clinical features, and outcomes of food allergy in children who underwent liver transplant: 16-year experience.

Food allergies often develop after liver transplant, especially in young children. However, data are scarce on clinical characteristics and patient outcomes. When we evaluated our pediatric liver transplant patients over a 16-year period, food allergy incidence was 8% (19/236 patients). All patients with food allergies were <18 months old, with incidence in this age group of 19.2% (19/99). Two patients had a single food and 17 had multiple food allergies. Five patients showed only non-IgE-mediated food allergies. Eggs, milk, nuts, and wheat were the most common allergens. Presenting symptoms included diarrhea, flushing, angioedema attacks, wheezing/chronic cough, and vomiting. Seven patients had EBV, and two patients had CMV infections at time of food allergy diagnosis. Twelve patients had eosinophilia. Seven patients (36.8%) were able to regain tolerance to all food allergens. However, one patient with single nut allergy and three with multiple food allergies were still on allergen-eliminated diets. Eight patients with multiple food allergies gained tolerance to some of the food allergens. In conclusion, food allergies in our patients were mainly against multiple foods and IgE mediated. Infections like EBV and CMV may play a role in food allergies after liver transplant, especially in pretransplant-naive patients.

Liver Cirrhosis in a Patient with Crigler Najjar Syndrome.

INTRODUCTION: Crigler Najjar (CN) disease is a genetic disorder which results in increased unconjugated bilirubin level. Liver parenchyma was previously considered structurally normal. Recent reports describe significant fibrosis in the liver parenchyma of patients with CN syndrome. CASE REPORT: We present a patient with persistent unconjugated hyperbilirubinemia, clinically diagnosed as CN-2, with a UGT1 A1 p. H39D (c.115C > G) (His → Asp) mutation. She required hepatic transplantation at the age of 17.5 years for biliary cirrhosis. Explanted liver histopathology revealed regenerative cirrhotic nodules with dilated bile ducts filled with bile plugs. CONCLUSION: CN can develop significant hepatic fibrosis/cirrhosis requiring liver transplantation.

A Case of Shwachman-Diamond Syndrome who Presented with Hypotonia.

We present a patient with failure to thrive and severe hypotonia, who was initially suspected of having a neurometabolic disease but later diagnosed as Shwachman-Diamond syndrome (SDS), which was genetically confirmed. SDS is a multisystemic disease, which is characterized by exocrine pancreatic deficiency, bone marrow dysfunction with increased risk for malignant transformation, and skeletal abnormalities. It should be included in differential diagnosis of patients with failure to thrive and unexplained neurodevelopmental delay with neutropenia.