AIM:With improved diagnostics and therapy, more children and adolescents with chronic and rare diseases are reaching adulthood. As a result, the need for adult medicine specialists for the continued care of these patients is increasing. In this survey, the patients at the University Hospital Innsbruck for Pediatrics (departments: Gastroenterology and Hepatology, Hematology and Oncology, Nephrology, Endocrinology, Diabetology, Rheumatology, Neuropediatrics, Inherited metabolic Disorders, Pulmonology and Allergology, Cardiology, and Cystic Fibrosis) who are due for transition were recorded. This survey was intended to serve as a basis for identifying potential improvements at the interface between pediatrics and adult medicine. METHODS:As a cross-sectional survey, the number of patients in the pediatric specialty departments for the year 2023 was recorded. The total number (n = 12,078) was divided into under 16 years of age (n = 9635), between 16 and 18 years of age (n = 1288), and over 18 years of age (n = 1155). To explore the challenges of transition, semi-structured interviews were conducted with the heads of the pediatric specialty areas or with a deputy. RESULTS:Of the 12,078 patients, 21.83% of patients in the field of inherited metabolic disorders and 14.01% of patients in the field of cardiology (congenital heart defects) were over 18 years of age. In the fields of cystic fibrosis and hematology and oncology, the proportion of patients over 18 years of age was 53.87% and 19.67%, respectively. In these two fields, patients remain under pediatric care by agreement, and the care of these patients is subject to a clearly defined transition process within the clinic. In the remaining departments, a completed transition process can be observed. The interviews confirmed the available figures by describing the status of the transition in each department. CONCLUSION:In summary, the transition is already taking place in the majority of pediatric specialty departments. There is potential for further development in the fields of inherited metabolic disorders and cardiology, while the fields of cystic fibrosis and hematology and oncology have their own transition model.

Durch verbesserte Diagnostik und Therapie erreichen mehr Kinder und Jugendliche mit chronischen und seltenen Erkrankungen das Erwachsenenalter. Infolgedessen steigt der Bedarf an Erwachsenen-medizinischer weiterer Betreuung dieser Patientinnen und Patienten. In der vorliegenden Erhebung wurden die Patientinnen und Patienten an der Universitätsklinik Innsbruck für Pädiatrie (Bereiche: Gastroenterologie und Hepatologie, Hämatologie und Onkologie, Nephrologie, Endokrinologie, Diabetologie, Rheumatologie, Neuropädiatrie, angeborene Stoffwechselstörungen, Pneumologie und Allergologie, Kardiologie und Cystische Fibrose) erfasst, die einer Transition bedürfen, als Grundlage für das Verbesserungspotenzial an der Schnittstelle zwischen Pädiatrie und Erwachsenenmedizin. Als Querschnittserfassung wurde die Anzahl der Patientinnen und Patienten der pädiatrischen Spezialbereiche für das Jahr 2023 erfasst. Die Gesamtanzahl (n = 12.078) wurde eingeteilt in unter 16 Jahre (n = 9635), zwischen 16 und 18 Jahren (n = 1288) und über 18 Jahre (n = 1155). Zu den Herausforderungen der Transition wurden halbstrukturierte Interviews mit den Leitern und Leiterinnen der pädiatrischen Spezialbereiche bzw. mit einer Stellvertreterin oder einem Stellvertreter geführt. Von den 12.078 Betroffenen waren im Bereich Angeborene Stoffwechselstörungen 21,83

ABSTRACT Introduction Loss‐of‐function variants in NONO cause an X‐linked syndromic neurodevelopmental disorder (MRXS34), characterized by developmental delay, corpus callosum abnormalities, dysmorphic features, feeding difficulties, and congenital heart disease, most commonly left ventricular noncompaction cardiomyopathy (LVNC). Long‐term outcome data remain limited. Methods A 14‐year‐old boy with LVNC and syndromic neurodevelopmental features underwent exome sequencing and subsequently NONO transcript analysis. A literature search was conducted using the terms “NONO variant” and “NONO mutation”. Results Exome sequencing identified a hemizygous NONO variant, c.348G>A, absent from population databases. This silent mutation was predicted in silico to cause exon 4 skipping, resulting in a frameshift and a premature termination codon p.(Asn52Argfs*31). This prediction was confirmed by RT‐PCR, and it was demonstrated that the aberrant transcript was subject to nonsense‐mediated mRNA decay. The patient displayed the characteristic NONO‐associated phenotype with rapid cardiac deterioration requiring pulsatile left ventricular assist device implantation at 1 year of age, and orthotopic heart transplantation at 2 years of age. At 14 years, graft function remains stable. An emergency hemicolectomy due to volvulus was performed at 12 years of age. A literature search identified 32 live‐born patients and 11 fetuses with NONO loss‐of‐function mutations. Intellectual disability, particularly affecting language development, LVNC, a recognizable facial phenotype, dystrophy, and lean habitus were nearly invariantly present. Conclusion This report further emphasizes the core phenotype caused by NONO loss‐of‐function, describes the second individual with heart transplantation, and indicates an underrecognized prevalence of gastrointestinal features.

Biallelic pathogenic variants in DHCR7 result in decreased activity of 7-dehydrocholesterol (7-DHC) reductase, which converts 7-DHC to cholesterol, and causes Smith–Lemli–Opitz syndrome (SLOS). Elevated serum 7-DHC levels are indicative of SLOS as are intellectual disability (ID), growth retardation, microcephaly, craniofacial anomalies, and 2–3 toe syndactyly. Additional congenital malformations may be present in SLOS, and broad clinical variability has been recognized in SLOS. Rarely, biallelic pathogenic DHCR7 variants were reported with low-normal and normal intelligence quotient (IQ) and development. We report here a pair of siblings with mild global developmental delay, infrequent epileptic seizures, and elevated serum 7-DHC levels, associated with the homozygous DHCR7 variant c.988G>A (p.Val330Met). Remarkably, neither sibling displayed congenital anomalies nor dysmorphisms. Quattro-exome sequencing performed for global delay and mild ID in both siblings did not identify other ID causes. c.988G>A affects a highly conserved amino acid and displays a relatively high global population allele frequency of 0.04%, with absence of homozygotes from the population database gnomADv4.1.0. Our observation leads us to suggest that DHCR7 variant c.988G>A and other DHCR7 variants might be generally considered as underlying non-syndromic ID.

Background:Since summer 2024, passive immunization with nirsevimab (Beyfortus®) has been recommended for all infants in Austria to prevent severe respiratory syncytial virus (RSV) infection. Maternal vaccination with RSVpreF (Abrysvo®), which provides transplacental protection, became available in autumn 2023. The expected public health benefits of these preventive strategies depend largely on widespread acceptance; however, real-world data from Austria are unavailable. Objective:This study aimed to assess the acceptance and impact of RSV immunization strategies during the 2024/2025 season in Tyrol, Austria. Methods:A retrospective study was conducted analyzing all live births at three Tyrolean maternity wards (Innsbruck, Hall, and Schwaz) from 5 December 2024 to 15 April 2025. Immunization rates were analyzed, and RSV-related hospitalization frequency and duration were compared to pre-pandemic seasons. Results:Of 1,156 newborns, 57% received nirsevimab and 12% were protected by maternal RSVpreF protection, resulting in an overall coverage of almost 70%. RSV-related hospitalizations for infants under 1 year of age significantly decreased from 151 in pre-pandemic seasons to 47 in the post-nirsevimab season (p = 0.018). During the post-nirsevimab season, the median age at hospital admission was significantly higher (p < 0.001), and the length of stay was shorter (p = 0.031). Importantly, none of the hospitalized infants received nirsevimab, and only one was born to a vaccinated mother. Conclusion:Our findings highlight the positive impact of both RSV immunization strategies-nirsevimab and RSVpreF vaccine-while underscoring the need to enhance public awareness and education to improve immunization rates. Future immunization programs must be strengthened to provide better protection for the pediatric population and reduce RSV-associated morbidity in early life.

BACKGROUND AND AIMS:The pathophysiology of pediatric inflammatory bowel disease (PIBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is not entirely understood. Dysregulation of the intestinal microbiome is recognized as both a disease-driving and a potential therapeutic target. This study aimed to systematically analyze gut microbiome compositions and its applicability as a biomarker for disease progress and treatment response. METHODS:Bibliographic and nucleotide databases were searched. Raw 16S-rRNA sequencing reads were subjected to a uniform downstream dada2/phyloseq pipeline to extract taxonomy, community structure, and abundance information. Patient metadata were extracted from publications, and study authors were contacted for further details if required. RESULTS:Twenty-six studies comprising 3956 stool samples (CD 41%, UC 36%, 23% healthy) were included in the analyses. Median age of individuals was 12 (interquartile range 4). Sex distribution was comparable. Alpha diversity was reduced between the healthy and both UC and CD treatment-naïve groups (P < .001) and further reduced with increasing clinical disease activity. Beta diversity revealed altered community structure in treatment-naïve children with PIBD (P < .001). This alteration remained in patients in clinical remission (P < .001). Machine learning models discriminated between treatment-naïve patients with CD or UC with an area under the receiver operating characteristics curve (AUROC) of 98%. Microbial communities differed between patient responders versus nonresponders to treatment (P < .001). Further, microbial community profiling distinguished treatment response (eg, steroid, nutrition, or TNFα) with AUROCs of 82%-90%. CONCLUSIONS:Gut microbial community structure is substantially altered in active and inactive PIBD and may be utilized as a biomarker for differentiating PIBD subtype and predicting treatment response.

Ezrin, encoded by EZR, is a central module of epithelial polarity and links membrane proteins to the actin cytoskeleton directly or indirectly through scaffold proteins in the epithelium. Ezrin knockout mice fail to thrive and do not survive past weaning. We identified a homozygous EZR loss-of-function (LoF) variant, c.356dup, by exome sequencing in an infant with intractable diarrhea and failure to thrive, who died from septicemia at 5 months of age. The variant localized within a homozygous region of 13.2 Mb in the proband, is consistent with inheritance identical-by-descent from the consanguineous parents, and segregated with disease in the proband’s family. EZR transcript analyses in a heterozygous carrier showed that the variant triggers nonsense-mediated mRNA decay. Homozygous EZR LoF variants have not been reported in public databases. In this study, we generated a Caco-2 EZR knockout cell line to investigate the role of ezrin in human intestinal epithelia. Our analyses used electron and immunofluorescence microscopy to assess structural changes in the knockout cells. We observed significant disorganization of the terminal web region, microvillus rarefaction and abnormal branching. Furthermore, the absence of ezrin resulted in the mislocalization of the ezrin-interacting scaffold protein Na+/H + exchanger regulatory factor-1. In conclusion, this represents the first documentation of complete ezrin deficiency in humans, highlighting the essential and non-redundant functions of the protein in maintaining intestinal physiology.

OBJECTIVES:Biliary strictures (BS) remain frequent after pediatric liver transplantation (pLT) and best management practices are still lacking. This study systematically assesses efficacy of stricture treatment by percutaneous transhepatic cholangiography and drainage (PTCD). METHODS:Online databases were searched for studies on PTCD treatment of BS after pLT from the year 2000 to 2024. Efficacy and safety profile of PTCD were analyzed. Influence of various risk factors on outcome parameters was compared by meta-regression. RESULTS:Twenty-seven observational studies with 802 patients undergoing PTCD for BS met the inclusion criteria. Incidence of BS was 13.1% (95% confidence interval [CI]: 10.3-16.1) in 6543 patients reported who underwent pLT between 1989 and 2020. Overall efficacy of PTCD to achieve stricture resolution was 78.3% (95% CI: 66.5-80.4). Drainage duration longer or shorter than 109.1 days did not impact on achievement of resolution with efficacies of 76.5% (95% CI: 65.4-86.2) in short versus 75.1% (95% CI: 61.9-86.5, p = 0.87) in long drainage. Overall recurrence rate after stricture resolution was 16.0% (95% CI: 7.5-26.3). Drainage duration longer or shorter than 109.1 days did not affect recurrence rate which was 17.4% (95% CI: 3.3-37.3) in short versus 20.9% (95% CI: 14.0-28.5, p = 0.68) in long drainage duration. Overall rate of procedure-related complications was 9.9% (95% CI: 2.6-20.0, p = 0.99) and was not influenced by drainage duration. CONCLUSIONS:PTCD is efficient to treat BS after pLT. Drainage time does not impact efficacy, recurrence rate, and complication rate. Randomized trials are necessary to determine the best treatment protocol concerning drainage duration and intervals between interventions.

Alterations in the gut microbiome affect the development and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH). We analyzed microbiomes of obese children with and without MASLD, MASH, and healthy controls. Electronic databases were searched for studies on the gut microbiome in children with obesity with/without MASLD or MASH, providing shotgun-metagenomic-sequencing data. Nine studies and an additionally recruited cohort were included. Fecal microbiomes of children with MASLD (n = 153) and MASH (n = 70) were significantly different in alpha- and beta-diversity (p < 0.001) compared to obese (n = 58) and healthy (n = 132). Species Faecalibacterium_prausnitzii and Prevotella_copri are differentially abundant between obese, MASLD and MASH groups. XGBoost and random forest-models accurately predict MASLD over obesity with an AUROC of 87% and MASH over MASLD with 89%. Pathway-abundance-based models accurately predict MASLD over obesity with an AUROC of 81% and MASH over MASLD with 88%. The composition of the gut microbiome is altered with increasing hepatic fibrosis and concomitant species-abundance increase of Prevotella_copri (p = 0.0082). Machine-learning models discriminate pediatric from adult MASH with an AUROC of 97%. The gut microbial composition is increasingly altered in children with the progression of MASLD toward MASH. This can be utilized as a fecal biomarker and highlights the impact of diet on the gut microbiome for disease intervention.

Background A rise in paediatric cases of acute hepatitis of unknown origin (AHUO) was observed in 2022, some requiring liver transplantation. A link to adeno-associated virus 2 infection and CD4 + T-cell mediated disease was reported in cohorts in the UK and USA but does not explain all cases. Objective To determine the intrahepatic immune cell interactions in the inflamed liver and a possible contribution of SARS-CoV-2 infection. Design Patients with acute non-A non-E hepatitis (10/12 AHUO, 2/12 subacute) during February 2022–December 2022 undergoing liver biopsy were recruited in a European patient cohort. Hepatological, virological, histopathological and highly multiplexed spatial and single-cell analyses of liver biopsies were performed. Results Patients were negative for adenoviral and SARS-CoV-2 PCR. Three patients had a positive adenoviral serology and 10/12 patients had a history or serological evidence of SARS-CoV-2 infection. Imaging mass cytometry identified significant intrahepatic immune infiltration with an enrichment of CD8 + T-cells. The highest CD8 infiltration and concomitant peripheral immune activation were observed in patients with the most severe hepatitis. CD8 + T-cell infiltration was connected to histomorphological interface hepatitis and bridging necrosis. Cellular neighbourhood analysis indicated disease-associated microanatomic interactions between CX3CR1 + endothelial and myeloid cell populations, interacting with effector CD8 + T-cells suggesting a pathogenic cellular triad. Of note, we detected intrahepatic SARS-CoV-2 antigens in ACE2-expressing cells in the areas with significant pathology in 11/12 samples using several different detection methods. 10/12 patients were treated with corticosteroid therapy and no liver transplantation was required. Conclusions We identified a possible manifestation of an immune-mediated postacute sequel to COVID-19 associated with a characteristic immune infiltrate in children with AHUO. COVID-19 testing should be considered in paediatric AHUO.

Background & Aims Quantification of the human S100A8/S100A9 tetrameric protein complex in stool, referred to as fecal calprotectin, is an extensively validated biomarker supporting the diagnosis and management of gastrointestinal diseases. Here, we studied the quaternary protein structures (termed configuration) of S100A8 and S100A9 and their biological function in inflammatory bowel diseases (IBD). Methods We dissected fecal S100A8 and S100A9 configurations in patients with IBD by size-exclusion chromatography coupled with tandem mass spectrometry and systematically defined human S100A8 and S100A9 homodimer functions compared with the calprotectin heterotetramer (CP) in the intestine of mice and in human epithelium and T cells. Moreover, we report a protein interaction network of fecal S100A8 and S100A9 in IBD. Results Stool from patients with active IBD contained abundant S100A8 and S100A9 dimers besides CP. Fecal S100A9 detection associated with clinical and endoscopic disease activity in IBD patients with low CP concentration. Oral exposure to human recombinant S100A8 and S100A9 homodimers, but not to CP, worsened intestinal inflammation in toxic and genetic mouse models. Functional profiling revealed that human S100A8 and S100A9 homodimers enhanced activation of cluster of differentiation 4+ and 8+ T cells, which promoted experimental colitis. In turn, genetic inactivation of S100a9 protected against experimental enteritis and colitis, and pharmacologic inhibition of S100A9 ameliorated chronic colitis. Conclusions Collectively, this study links the detection of fecal S100A9 dimers with clinical and endoscopic disease activity in IBD and identifies inflammatory actions of S100A8 and S100A9 homodimers in the intestine. Our findings pave the way for novel diagnostic and therapeutic approaches in patients with inflammatory diseases of the intestine.

The osteo-oto-hepato-enteric (O2HE) syndrome is a severe autosomal recessive disease ascribed to loss-of-function mutations in the Unc-45 myosin chaperone A (UNC45A) gene. The clinical spectrum includes bone fragility, hearing loss, cholestasis, and life-threatening diarrhea associated with microvillus inclusion disease-like enteropathy. Here, we present molecular and functional analysis of the UNC45A c.710T>C (p.Leu237Pro) missense variant, which revealed a unique pathogenicity compared with other genetic variants causing UNC45A deficiency. The UNC45A p.Leu237Pro mutant retained chaperone activity, prevented myosin aggregation, and supported proper nonmuscle myosin II (NMII) filament formation in patient fibroblasts and human osteosarcoma (U2OS) cells. However, the mutant formed atypically stable oligomers and prevented chaperone-myosin complex dissociation, thereby inhibiting NMII functions. Similar to biallelic UNC45A deficiency, this resulted in impaired intracellular trafficking, defective recycling, and abnormal retention of transferrin at various endocytic sites. In particular, coexpression of wild-type protein attenuated the pathogenic effects of the variant by inhibiting excessive oligomer formation. Our results elucidate the pathogenic mechanisms and recessive characteristics of this variant and may aid in the development of targeted therapies.

A total of 14 patients are known with the nonsyndromic enteropathy caused by biallelic deletions (∆L and ∆S) or truncating mutations affecting PERCC1 or its adjacent regulatory region. PERCC1 is so far in gnomAD only annotated in the GRCh38 reference sequence. Parenteral nutrition is required throughout childhood and often in adolescence.

PURPOSE:This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment.METHODS:Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data.RESULTS:In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency.CONCLUSION:In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.

Introduction Chronic intestinal pseudo-obstruction(CIPO),defined as chronic constipation without mechanical obstruction of the gastrointesti-nal tract[1,2],often presents with a truly chameleon-like symp-tomatology including irregular defecation,abdominal pain and distension,nausea,vomiting,and sometimes fluid/electrolyte imbalance.Although diarrhea was found in ≤17％of CIPO cases,its nature,however,has not been precisely described.Serious deviations of electrolyte and acid-base status,to the best of our knowledge,have not been reported.

Austria partly spared its healthcare system from the catastrophic effects of the COVID-19 pandemic with an early lockdown. This led to a marked decrease in visits to the paediatric emergency department (PED) at the Medical University of Innsbruck. The PED is the central point of contact for patients under the age of 18 with any health concerns, except trauma. Approximately 18,700 patients visit the PED per year and 17.6% are admitted to the hospital. Paediatric primary care is mainly supplied by community-based paediatricians and general practitioners, who can refer patients to the ED. Patients are also brought in, without a referral, by their parents or ambulances. The costs of public sector medical services are covered by insurance and patients may choose where they are treated, within certain limits. Private services attract a surcharge. We have found that families increasingly visit the PED rather than see a community-based primary care physician first, even for minor issues.1 The Manchester Triage System (MTS) was used in the PED to assess the urgency levels, from one for immediate care required to five for non-urgent care. We compared the six weeks before and after Austria entered lockdown: 1 February to 15 March versus 16 March to April 30.2 Ethical approval was not required for the study. A study of emergency departments in British Columbia, Canada, found that visits to PEDs fell by 57%.3 Our previous paper reported 26% fewer PED visits during the spring 2020 pandemic lockdown than the same period in 2018.1 Figure 1 shows the daily visits to our PED during the 2020 study period, by MTS levels. Although overall admissions to inpatient care increased significantly, from 16.6% pre-lockdown to 22.9% during lockdown (z-test 484/2918 versus 186/811; z −4.2, p < 0.00001), the daily number decreased from 11 to four per day. The same pattern was seen for patients admitted to the paediatric intensive care unit at some point during their hospital stay. The proportion significantly increased from 2.1% to 3.5% (z-test 61/2918 versus 28/811; z −2.25, p = 0.02), whereas the number decreased from 1.4 to 0.6 per day. Remarkably, the distribution of MTS urgency levels remained unchanged (Cochran–Armitage trend test p = 0.09) (Figure 1), unlike the Canadian study, which reported more paediatric patients acute with illnesses attending emergency departments during lockdown.3 We believe there were two reasons for the substantial decrease in paediatric ED visits during lockdown, aside from seasonal fluctuations. The first was that children had reduced exposure to infectious diseases during the spring 2020 lockdown as schools were closed. In addition, infections account for a high proportion of encounters between paediatric patients and healthcare professionals and this is particularly true for urgent PED visits.4 Fewer PED visits may have reduced the chance of infections being transmitted. The second was that families may have avoided PEDs because they may have perceived hospitals as threatening environments during the COVID-19 pandemic. This appears to have raised thresholds for seeking medical advice, as reported by a study from Northern Italy.5 Our previous study found that substantial proportions of Austrian paediatric ED visits were for non-urgent problems and overcrowding was frequent.1 If health anxieties and increased thresholds were the principal cause of the reduced patient visits during lockdown, surely this would have been reflected in fewer less-urgent cases. However, an unexpected finding of our study was that there was no significant increase in more urgent cases during the lockdown than pre-lockdown period. Figure 1 shows that the distribution of the MTS levels remained unchanged. Our results can be explained by our hypotheses complementing one another. Lower levels of contagion from infectious diseases during lockdown led to a substantial decrease in urgent PED visits and a minor decrease in non-urgent patient visits. In the meantime, avoiding PEDs led to a further decrease in non-urgent patient visits. The combination of these two factors resulted in no change in the proportions of urgent and non-urgent visits. Comparisons with northern Italy, which borders our region and was very badly hit by the pandemic, offer interesting opportunities for speculation. Lazzerini et al. reported 12 cases with serious consequences due to delayed access to care in northern Italy,5 but we did not see this during our short study period. We also suspect that the fear of contamination and infection in our PED was lower. In conclusion, visits to our Austrian PED fell during the spring 2020 COVID-19 lockdown but, unexpectedly, this did not lead to a significant increase in more urgent cases when we compared the data with the pre-lockdown period. We thank Dr A S Knisely for his comments on the manuscript. The authors have no conflicts of interest to disclose.