Very-early-onset Inflammatory Bowel Disease in an Infant with a Partial RIPK1 Deletion.

The monogenic causes of very-early-onset inflammatory bowel disease (VEO-IBD) have been defined by genetic studies, which were usually related to primary immunodeficiencies. Receptor-interacting serine/threonine-protein kinase-1 (RIPK1) protein is an important signalling molecule in inflammation and cell death pathways. Its deficiency may lead to various clinical features linked to immunodeficiency and/or inflammation, including IBD. Here, we discuss an infant with malnutrition, VEO-IBD, recurrent infections and polyathritis who has a homozygous partial deletion in RIPK1 gene.

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.

Management of gastrointestinal and nutritional problems in children on home invasive mechanical ventilation.

In recent decades, the patient survival is increased due to advances in intensive care units and development of modern mechanic ventilators. Unfortunately, it is not always possible to wean these children from mechanical ventilation. Recently, after placement a tracheostomy tube, these children can be supported at home with noninvasive or invasive mechanical ventilation. Most of the children who need ventilation support at home have neurological impairment. The nutritional issues and gastrointestinal (GI) complications are well defined in critically ill patients, but there are very limited studies on children with tracheostomy. Considering that majority of the patients have neuromuscular disorders, the nutritional and GI problems of the children with tracheostomy are discussed in light of the knowledge of critically ill patients.

A Rare Case of "Periportal Cuffing" as an Incidental Finding on 18F-FDG PET/CT.

A 7-year-old boy with known diagnosis of hereditary spherocytosis and ulcerative colitis was referred for 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography after detection of a 28 mm lesion suspicious for malignancy in spleen on upper abdomen magnetic resonance imaging (MRI). As an incidental finding, a moderately increased uptake of 18F-FDG was observed in periportal region with no definable mass. MRI revealed compatible findings with "periportal cuffing" as described on ultrasonography.

The frequency of Duchenne muscular dystrophy/Becker muscular dystrophy and Pompe disease in children with isolated transaminase elevation: results from the observational VICTORIA study.

Introduction: Elevated transaminases and/or creatine phosphokinase can indicate underlying muscle disease. Therefore, this study aims to determine the frequency of Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD) in male children and Pompe disease (PD) in male and female children with isolated hypertransaminasemia. Methods: This multi-center, prospective study enrolled patients aged 3-216 months with serum alanine transaminase (ALT) and/or aspartate transaminase (AST) levels >2× the upper limit of normal (ULN) for ≥3 months. Patients with a known history of liver or muscle disease or physical examination findings suggestive of liver disease were excluded. Patients were screened for creatinine phosphokinase (CPK) levels, and molecular genetic tests for DMD/BMD in male patients and enzyme analysis for PD in male and female patients with elevated CPK levels were performed. Genetic analyses confirmed PD. Demographic, clinical, and laboratory characteristics of the patients were analyzed. Results: Overall, 589 patients [66.8% male, mean age of 63.4 months (standard deviation: 60.5)] were included. In total, 251 patients (188 male and 63 female) had CPK levels above the ULN. Of the patients assessed, 47% (85/182) of male patients were diagnosed with DMD/BMD and 1% (3/228) of male and female patients were diagnosed with PD. The median ALT, AST, and CPK levels were statistically significantly higher, and the questioned neurological symptoms and previously unnoticed examination findings were more common in DMD/BMD patients than those without DMD/BMD or PD (p < 0.001). Discussion: Questioning neurological symptoms, conducting a complete physical examination, and testing for CPK levels in patients with isolated hypertransaminasemia will prevent costly and time-consuming investigations for liver diseases and will lead to the diagnosis of occult neuromuscular diseases. Trial Registration: Clinicaltrials.gov NCT04120168.

Evaluation of Gastrointestinal System Complaints and Comorbidities in Pediatric Familial Mediterranean Fever Patients.

OBJECTIVE: Familial Mediterranean fever (FMF) is the most prevalent hereditary autoinflammatory disease among children. Abdominal pain and various gastrointestinal system (GIS) manifestations may arise directly from FMF or concomitantly with FMF. This study aimed to evaluate GIS complaints and findings other than classic peritonitis attacks in patients with FMF and to interpret concomitant GIS and hepatic disorders in these patients. METHODS: The medical and genetic findings of patients with FMF who attended our clinic between December 2011 and December 2021 were reviewed. Gastrointestinal system symptoms, liver function tests, abdominal images, and endoscopic and histopathological data were extracted from medical records. RESULTS: A total of 576 pediatric patients (female, 52.3%) diagnosed with FMF were included. Among them, almost one-fifth displayed GIS complaints, such as abdominal pain, defecation problems, and dyspepsia, distinct from typical FMF attacks. High serum aminotransferase levels were detected in 18.4% of the patients, with viral infections being the most common cause of moderate/severe hypertransaminasemia. In addition, during follow-up, 26.9% of them were referred to the pediatric gastroenterology department. At least 1 gastroenterological and hepatobiliary disorder was detected in 17.5% of the patients because of organic and functional GIS disorders or hepatobiliary disorders, such as gastroesophageal reflux disease, esophagitis, functional dyspepsia, and inflammatory bowel diseases. CONCLUSION: Various GIS and hepatic disorders can be encountered in children with FMF. The spectrum of these complaints and pathologies can range from frequently observed health problems to more severe diseases.

Growth, tolerance and safety outcomes with use of an extensively hydrolyzed casein-based formula in infants with cow's milk protein allergy.

Objective: To evaluate growth, tolerance and safety outcomes with use of an extensively hydrolyzed casein-based formula (eHCF) in infants with cow's milk protein allergy (CMPA). Methods: A total of 226 infants (mean ± SD age: 106.5 ± 39.5 days, 52.7% were girls) with CMPA who received eHCF comprising at least half of the daily dietary intake were included. Data on anthropometrics [weight for age (WFA), length for age (LFA) and weight for length (WFL) z-scores] were recorded at baseline (visit 1), while data on infant feeding and stool records, anthropometrics and Infant Feeding and Stool Patterns and Formula Satisfaction Questionnaires were recorded at visit 2 (on Days 15 ± 5) and visit 3 (on Days 30 ± 5). Results: From baseline to visit 2 and visit 3, WFA z-scores (from -0.60 ± 1.13 to -0.54 ± 1.09 at visit 2, and to -0.44 ± 1.05 at visit 3, p < 0.001) and WFL z-scores (from -0.80 ± 1.30 to -0.71 ± 1.22 at visit 2, and to -0.64 ± 1.13 at visit 3, p = 0.002) were significantly increased. At least half of infants never experienced irritability or feeding refusal (55.7%) and spit-up after feeding (50.2%). The majority of mothers were satisfied with the study formula (93.2%), and wished to continue using it (92.2%). Conclusions: In conclusion, eHCF was well-accepted and tolerated by an intended use population of infants ≤ 6 months of age with CMPA and enabled adequate volume consumption and improved growth indices within 30 days of utilization alongside a favorable gastrointestinal tolerance and a high level of parental satisfaction.

Not all enteropathies are coeliac disease! Report of an infant with microvillus inclusion disease.

Primary enteropathies of infancy comprise of epithelial defects including microvillus inclusion disease, tufting enteropathy, and enteroendocrine cell dysgenesis and autoimmune enteropathies. The diseases in this group cause severe chronic (>2-3 weeks) diarrhoea starting in the first weeks of life and resulting in failure to thrive in the infant. Duodenal biopsies show moderate villous shortening together with crypt hyperplasia which are the main features causing resemblance to coeliac disease. We, hereby, report a term-born male infant of consanguineous parents. His two siblings died during infancy. He developed watery, urine-like diarrhea on the 3rd day of his life. On the postnatal 6th day he weighed 2750 grams, became dehydrated and had metabolic acidosis. Upper GI endoscopy performed on the postnatal 20th day appeared normal. Light microscopic examination of the duodenal biopsy showed moderate villous blunting, with mildly increased inflammatory cells in the lamina propria or and intraepithelial lymphocytosis. Enterocytes at the villous tips showed an irregular vacuolated appearance in the apical cytoplasm with patchy absence of the brush border demonstared by PAS and CD10. Electron microscopy revealed intracytoplasmic inclusions that were lined by intact microvilli in the apical cytoplasm of enterocytes. As he was dependent on TPN and aggressive intravenous fluid replacement he was hospitalized throughout his life. He died when he was 3 years and 4 months old. Paediatric coeliac disease is in the differential diagnosis of primary enteropathies of childhood. The differentiation lies on duodenal biopsy interpretation together with genetic analysis to detect the underlying genetic defect in childhood enteropathies.

Early period intensive care follow-up after liver transplantation in children: a single center experience.

BACKGROUND: Liver transplantation (LT) is a well-established, life-saving treatment for children with irreversible acute and chronic liver failure (LF). We aimed to evaluate the factors associated with morbidity and mortality in the early period of LT in children by reviewing our pediatric intensive care unit (PICU) experience. METHODS: We reviewed children`s medical records followed in the PICU after LT between May 2015-August 2021, including demographic parameters, indications for LT, operative variables, respiratory and circulatory support requirements, LT-related complications and survival. RESULTS: During this period, 40 pediatric patients who underwent LT were evaluated. LT was performed in 35 (87.5%) cases of chronic liver disease and 5 (12.5%) cases of acute liver failure. Twenty-four patients had chronic liver failure due to cholestatic liver disease. The patients` Pediatric Risk of Mortality (PRISM) III score was 18.82±SD (2-58) at PICU admission. 1-year survival was 87.5%, and overall survival was 85%. Younger age, low body weight, preoperative pediatric end-stage liver disease (PELD), and model for end-stage liver disease (MELD) values of 20 and higher were important risk factors for unfavorable outcomes after living donor liver transplantation (LDLT). These risk factors are both associated with technically more challenging vascular and bile duct reconstruction and higher complication rates, and increased mortality during the early period after LT. CONCLUSIONS: The early period of optimum PICU management in pediatric LT recipients is crucial for successful outcomes, which is also related to the patients` characteristics, disease severity scores, and surgical procedures.

A Rare Contiguous Gene Deletion Leading to Trichothiodystrophy Type 4 and Glutaric Aciduria Type 3.

Introduction: Trichothiodystrophy type 4 and glutaric aciduria type 3 are rare autosomal recessive disorders caused by biallelic variants in the MPLKIP and SUGCT genes on chromosome 7p14, respectively. Trichothiodystrophy type 4 is characterized by neurologic and cutaneous abnormalities. Glutaric aciduria type 3 is a rare metabolic disorder with inconsistent phenotype and elevated urinary excretion of glutaric acid. Case Presentation: Here, we report on an infant presenting with hypotonia, failure to thrive, microcephaly, dysmorphic features, brittle hair, hypertransaminasemia, and recurrent lower respiratory tract infections. Microarray analysis revealed a homozygous microdeletion involving the MPLKIP and SUGCT genes, which are located close to each other. Conclusion: Copy number variations should be considered in patients with coexisting clinical expression of different genetic alterations. To the best of our knowledge, our patient is the second case with co-occurrence of trichothiodystrophy type 4 and glutaric aciduria type 3, resulting from a contiguous gene deletion.

Diagnostic Dilemma of Lactic Acidosis in an Infant After Liver Transplant: A Case Report.

Thiamine is the cofactor of many enzymes involved in energy metabolism. Patients under total parenteral nutrition are at risk for thiamine deficiency if there is renal thiamine loss or increased thiamine requirements to mitigate systemic diseases. Thiamine deficiency symptoms include seizures, neuropathy, ataxia, peripheral vasodilation, myocardial insufficiency, sudden collapse, and death. In this report, we present an infant liver transplant recipient with progressive lactic acidosis that responded well to thiamine replacement to mitigate a lack of thiamine in total parenteral nutrition.

Turkish Validity-Reliability Study of the Celiac Disease-Specific Pediatric Quality of Life Scale.

BACKGROUND: Celiac disease is an autoimmune enteropathy triggered by the presence of gluten. There are Celiac Disease Dutch-Child Quality of Life Scale, Celiac-Specific Pediatric Quality of Life Scale for children/adolescents patients to measure the quality of life. In this study, due to lack of quality of life scales for children with celiac in Turkey, we aimed at Turkish adaptation of the Celiac-Specific Pediatric Quality of Life Scale. METHODS: This methodological study was conducted in Ankara University Faculty of Medicine, Cebeci Hospital Hospital between July 2019 and July 2020. A total of 192 children were included. Reliability was demonstrated by the Cronbach's alpha coefficient. Structural validity was evaluated using explanatory factor analysis and confirmatory factor analysis. The Statistical Package for Social Sciences (SPSS) 22.0 and Amos were used in analyses. RESULTS: In 8-12 age groups; Cronbach's alpha was 0.92 in negative emotions dimension, 0.88 in school dimension, and 0.74 in enjoyment dimension. In explanatory factor analysis, Kaiser-Meyer-Olkin measure of sampling adequacy value was 0.698, Bartlett's test of sphericity was significant (P < .001). Variance explained was 75.8%. In confirmatory factor analysis, X2/df was 3.26, root mean square error of approximation value was 0.07, comparative fit index value was 0.96. In 13-18 age groups; Cronbach's alpha was 0.87 in social dimension, 0.84 in uncertainty dimension, 0.78 in isolation dimension, and 0.83 in limitations dimension. In explanatory factor analysis, Kaiser-Meyer-Olkin measure of sampling adequacy was 0.684, Bartlett's test of sphericity was significant (P < .001). Variance explained was 68.6%. In confirmatory factor analysis, X2/sd value was 3.78, root mean square error of approximation value was 0.061, and comparative fit index value was 0.961. CONCLUSION: Cronbach's alpha values of the groups were found to be above 0.70. Kaiser-Meyer-Olkin values were above 0.5 in terms of sample size, Bartlett's tests for sphericity were significant in terms of correlations between variables, root mean square error of approximation values were below 0.08, comparative fit index and goodness of fit index values were above 0.95 in terms of model fit. If the scales have been found to be valid and reliable, it is recommended for use in Turkey.

Co-Occurring Atypical Galactosemia and Wilson Disease.

Introduction: Classic galactosemia is a disorder of the galactose metabolism and is inherited as an autosomal recessive disease. It is caused by a complete or severe deficiency of galactose-1-phosphate uridyltransferase (GALT), and in rare cases, atypical galactosemia can manifest at older ages. Wilson disease (WD) is a disorder of the copper metabolism that, like galactosemia, is inherited as an autosomal recessive disease. Hepatic, neurological, or psychiatric symptoms can be seen, independently or in combination, and symptoms vary from family to family. We present here a patient diagnosed with both WD and galactosemia. Case Presentation: A 6-year-old girl was referred to our center with elevated transaminase levels and hepatosplenomegaly. The child, birthweight of 2,200 g, was born to first-degree consanguineous parents after a full-term uneventful pregnancy and was hospitalized in the neonatal period due to indirect hyperbilirubinemia, gastrointestinal bleeding, diarrhea lasting 2 weeks, and elevated liver enzymes. Hepatosplenomegaly was evident at the time of admission, a cataract was detected, and a neuropsychiatric evaluation revealed borderline mental capacity, as well as cognitive and speech retardation. Metabolic investigations revealed no specific findings other than trace positivity of reducing substances in the urine. A liver biopsy revealed copper accumulation in hepatocytes and low ceruloplasmin levels. Although WD was suspected in the patient, this diagnosis did not explain the intellectual disability, behavioral disorder, or cataract findings. A genetic analysis revealed homozygous mutations in the ATP7B and GALT genes. The galactose-1-phosphate uridyltransferase enzyme level was found to be low, and the patient was diagnosed with coexisting WD and galactosemia. Conclusion: Coexistences of rare genetically transmitted diseases can be seen in countries where consanguineous marriages are common (Saudi Arabia, Iran, Pakistan, etc.), as in our country, Turkey.

The clinical variations and diagnostic challenges of deoxyguanosine kinase deficiency: a descriptive case series.

OBJECTIVES: Deoxyguanosine kinase (DGUOK) deficiency is one of the leading causes of the mitochondrial DNA-depletion syndromes (MDDS) associated with hepatocerebral involvement. Herein, we present four cases of DGUOK deficiency to emphasize the clinical variability of disease and the challenges in the diagnosis of DGUOK deficiency. CASE PRESENTATION: Hepatomegaly, hyperlactatemia, elevated alpha fetoprotein (AFP), alanine, and transaminase levels were detected in all patients, and cholestasis, coagulopathy, and hypotonia were common findings. All patients had a low birth weight, one patient underwent liver transplantation (LT). Clinical and laboratory findings of two patients and one patient suggested neonatal hemochromatosis and type 1 tyrosinemia, respectively. All patients were diagnosed with DGUOK deficiency by performing molecular genetic analysis. CONCLUSIONS: Mitochondrial DNA-depletion syndromes should be kept in mind in cases in which hypotonicity, lactic acidosis, and neonatal cholestasis are observed. DGUOK deficiency may present in different clinics suggesting neonatal hemochromatosis or tyrosinemia type 1.

3D-reconstruction and heterotopic implantation of reduced size monosegment or left lateral segment grafts in small infants: A new technique in pediatric living donor liver transplantation to overcome large-for-size syndrome.

BACKGROUND: Monosegmental grafts and reduced left lateral segment grafts have been introduced to overcome the problems of large-for-size grafts in pediatric living donor liver transplantation. Here, we introduce a new method of reduced size monosegment or left lateral segment grafts transplanted in the right diaphragmatic fossa heterotopically in small infants. METHODS: There were 4 infants who underwent living donor liver transplantation with heterotopically implanted reduced monosegmental or left lateral segment grafts at our center. The demographic, operative, postoperative, and follow-up data of these infants were collected from our prospectively designed database and reviewed. Technical details of the donor and recipient operation are shared and a supplemental provided. RESULTS: The mean recipient age was 7.5 ± 0.9 months (range: 5-10 months), and body weight was 5.9 ± 0.7 kg (range: 4.6-7.8). Primary diagnoses of the recipients were biliary atresia (n:3) and progressive familial intrahepatic cholestasis (n:1). Mean graft-recipient weight ratio was 3.3 ± 0.2. Reduced monosegment III grafts were used in 2 cases, and reduced left lateral segment grafts were used in the other 2 patients. Bile duct reconstruction was done by Roux-en-Y hepaticojejunostomy in 3 patients and duct-to-duct anastomosis in the remaining patient. All patients recovered from the liver transplantation operation and are doing well at a mean follow-up of 8 months. CONCLUSION: Living donor liver transplantation with heterotopically implanted reduced monosegmental or left lateral segment seems feasible for the treatment of neonates and extremely small infants. Further accumulation of cases and long-term follow-up are necessary to collect data for the establishment of this treatment modality.

Autoimmune atrophic gastritis: The role of Helicobacter pylori infection in children.

BACKGROUND: Autoimmune atrophic gastritis (AIG) is very rare in children. Despite a better understanding of histopathologic changes and serological markers in this disease, underlying etiopathogenic mechanisms and the effect of Helicobacter pylori (H pylori) infection are not well known. We aimed to investigate the relation between AIG and H pylori infection in children. MATERIALS AND METHODS: We evaluated the presence of AIG and H pylori infection in fifty-three patients with positive antiparietal cell antibody (APCA). Demographic data, clinical symptoms, laboratory and endoscopic findings, histopathology, and presence of H pylori were recorded. RESULTS: The children were aged between 5 and 18 years, and 28 (52.8%) of them were male. Mean age was 14.7 ± 2.6 years (median: 15.3; min-max: 5.2-18), and 10 (18.8%) of them had AIG confirmed by histopathology. In the AIG group, the duration of vitamin B12 deficiency was longer (P = .022), hemoglobin levels were lower (P = .018), and APCA (P = .039) and gastrin (P = .002) levels were higher than those in the non-AIG group. Endoscopic findings were similar between the two groups. Intestinal metaplasia was higher (P = .018) in the AIG group. None of the patients in the AIG group had H pylori infection (P = .004). One patient in the AIG group had enterochromaffin-like cell hyperplasia. CONCLUSIONS: Our results show that, in children, H pylori infection may not play a role in AIG. AIG could be associated with vitamin B12 deficiency, iron deficiency, and APCA positivity in children. APCA and gastrin levels should be investigated for the early diagnosis of AIG and intestinal metaplasia.

Assessment of cows milk-related symptom scoring awareness tool in young Turkish children.

BACKGROUND: The diagnosis of cows milk protein allergy (CMPA) is not always easy. Cow's Milk-related Symptom Score (CoMiSS) has been developed to raise the awareness of CMPA among the primary health-care providers. In this study, we aimed to evaluate the validity of CoMiSS as a diagnostic approach of CMPA in infants in our country. METHODS: Infants with a CoMiSS of more than 12 points were included. An elimination diet was implemented in these infants for 4 weeks, and CoMiSS was reapplied. Infants with a reduction of ≥3 points in CoMiSS were considered responsive to the elimination diet, and an open oral challenge test was performed. Infants with symptom recurrence were diagnosed with CMPA. RESULTS: The study included 168 infants. When they were included in the study, the first CoMiSS score was 13.6 ± 1.9. After the elimination diet, the number of responsive infants was 154 (91.7%). Of the infants, 91 (54.2%) were diagnosed with CMPA with positive challenge. The majority of the patients diagnosed with CMPA presented with gastrointestinal and/or dermatological symptoms (80.3%). Positive family history of allergy was more prevalent in CMPA(+) infants (P < 0.001). The mean atopic dermatitis score was higher in CMPA(+) infants (P = 0.001). Eosinophilia and cows milk-specific IgE (CM-sIgE) positivity were more prevalent in infants with CMPA (P = 0.01 and P < 0.001, respectively). CONCLUSIONS: CoMiSS is a valuable tool to evaluate CMPA in primary care. The presence of multiple symptoms, especially skin involvement, helps to recognise infants with CMPA. Family history and eosinophilia also support the diagnosis of CMPA.