Many inborn errors of immunity (IEI) manifest with hallmarks of both immunodeficiency and immune dysregulation due to uncontrolled immune responses and impaired immune homeostasis. A subgroup of these disorders frequently presents with autoimmunity and lymphoproliferation (ALPID phenotype). After the initial description of the genetic basis of autoimmune lymphoproliferative syndrome (ALPS) more than 20 years ago, progress in genetics has helped to identify many more genetic conditions underlying this ALPID phenotype. Among these, the majority is caused by a group of autosomal-dominant conditions including CTLA-4 haploinsufficiency, STAT3 gain-of-function disease, activated PI3 kinase syndrome, and NF-κB1 haploinsufficiency. Even within a defined genetic condition, ALPID patients may present with staggering clinical heterogeneity, which makes diagnosis and management a challenge. In this review, we discuss the pathophysiology, clinical presentation, approaches to diagnosis, and conventional as well as targeted therapy of the most common ALPID conditions.

IntroductionHuman milk oligosaccharides (HMOs) are important components of human milk having diverse functions in the development of infants. Randomized controlled trials (RCTs) have demonstrated that infant formulas with the HMOs 2′-fucosyllactose (2′FL) and lacto-N-neotetraose (LNnT) are safe, well-tolerated, and support normal growth. This study aimed to generate real-world evidence (RWE) on growth and gastrointestinal (GI) tolerance in infants consuming a formula with 1 g/L 2′FL and 0.5 g/L LNnT, including a mixed feeding group not studied before in RCTs.Participants and methodsThis 8-week open-label prospective multicenter study was conducted in Germany and Austria, and included groups of healthy, exclusively breastfed infants (BF), exclusively formula-fed infants (FF) who received the HMO-formula, and infants mixed fed with both HMO formula and human milk (MF). Co-primary outcomes were anthropometry and gastrointestinal tolerance via validated Infant Gastrointestinal Symptom Questionnaire (IGSQ). Secondary outcomes included formula satisfaction and adverse events (AEs).ResultsOne-hundred six infants completed the study (46 FF, 22 MF, and 38 BF). Mean anthropometric z-scores were comparable between groups and generally within ± 0.5 of WHO medians at week 8. IGSQ composite scores demonstrated good GI tolerance in all groups with no significant group differences at week 4 or 8. IGSQ composite scores in FF improved during the course of the study and parents provided high satisfaction ratings for the HMO-formula. Four potentially product-related AEs were reported in FF (no in MF).ConclusionsIn this RWE study examining an infant formula with HMOs, growth and GI tolerance outcomes were confirming the good tolerance and safety of this early feeding option previously reported in RCTs.

Bronchopulmonary dysplasia (BPD) is a multifactorial disease occurring as a consequence of premature birth, as well as antenatal and postnatal injury to the developing lung. BPD morbidity and severity depend on a complex interplay between prenatal and postnatal inflammation, mechanical ventilation, and oxygen therapy as well as associated prematurity-related complications. These initial hits result in ill-explored aberrant immune and reparative response, activation of pro-fibrotic and anti-angiogenic factors, which further perpetuate the injury. Histologically, the disease presents primarily by impaired lung development and an arrest in lung microvascular maturation. Consequently, BPD leads to respiratory complications beyond the neonatal period and may result in premature aging of the lung. While the numerous prenatal and postnatal stimuli contributing to BPD pathogenesis are relatively well known, the specific cell populations driving the injury, as well as underlying mechanisms are still not well understood. Recently, an effort to gain a more detailed insight into the cellular composition of the developing lung and its progenitor populations has unfold. Here, we provide an overview of the current knowledge regarding perinatal origin of BPD and discuss underlying mechanisms, as well as novel approaches to study the perturbed lung development.

Insulin is used to treat neonatal hyperglycaemia when blood glucose concentrations are consistently high, and to treat neonatal diabetes. Within this brief report, a review of the existing literature is conducted to determine if intravenous administration of insulin should be proceeded by priming of the intravenous system, adding of albumin, or non-priming to get a stable insulin dose. Within this literature search, we focused on experimental insulin adsorption data (in vitro studies).

BackgroundA series of noxae can evoke the termination of nephron formation in preterm and low birth weight babies. This results in oligonephropathy with severe consequences for health in the later life. Although the clinical parameters have been extensively investigated, little is known about the initial damage. Previous pathological findings indicate the reduction in width of the nephrogenic zone and the lack of S-shaped bodies. Current morphological investigations suggest that due to the mutual patterning beside the forming nephron, also its structural neighbors, particularly the interjacent interstitium, must be affected. However, beside the findings on integrative and mastering functions, systematic microanatomical data explaining the configuration of the interstitium at the developing nephron in the fetal kidney during advanced pregnancy is not available. Therefore, this work explains the typical features.ResultsThe generated data depicts that the progenitor cells, nephrogenic niche, pretubular aggregate, and mesenchymal-to-epithelial transition are restricted to the subcapsular interstitium. During the proceeding development, only the distal pole of the renal vesicles and comma- and S-shaped bodies stays in further contact with it. The respective proximal pole is positioned opposite the peritubular interstitium at the connecting tubule of an underlying but previously formed nephron. The related medial aspect faces the narrow peritubular interstitium of a collecting duct (CD) ampulla first only at its tip, then at its head, conus, and neck, and finally at the differentiating CD tubule. The lateral aspect starts at the subcapsular interstitium, but then it is positioned along the wide perivascular interstitium of the neighboring ascending perforating radiate artery. When the nephron matures, the interstitial configuration changes again.ConclusionsThe present investigation illustrates that the interstitium at the forming nephron in the fetal kidney consists of existing, transient, stage-specific, and differently far matured compartments. According to the developmental needs, it changes its shape by formation, degradation, fusion, and rebuilding.

BackgroundExclusive enteral nutrition (EEN) is the first-line therapy for pediatric-onset Crohn’s disease (CD) patients. CEDATA-GPGE® is the largest patient registry for children and adolescents with inflammatory bowel disease (IBD) in Europe, collecting data from over 5000 patients since 2004 in Germany and Austria. Since the application of EEN over 8 weeks is difficult and a high dropout rate is often described, the mode of application including a supporting structure is crucial for success. The aim of this study was to ascertain the variation in the application of EEN across the participating centers and to associate these with the outcome.ResultsThirty-one centers responded to the survey (81.6%). 88.5% of CD patients were recommended EEN for induction therapy, 71.8% actually started with EEN, and 22.1% terminated the EEN prematurely. The duration of EEN typically lasted 6 to 8 weeks, and the polymeric formula was mainly used. 80.6% of the clinics added flavorings to the formulas. After EEN, the most preferred diet for maintenance therapy was a healthy, well-balanced diet considering individual intolerances.ConclusionsEEN is widely recommended as an induction therapy by the German and Austrian pediatric gastroenterologists for children and adolescents with CD. However, this questionnaire-based study has shown a wide variation in EEN protocols used by the different pediatric clinics of CEDATA-GPGE®.

Polycystic kidney diseases (PKD) are severe forms of genetic kidney disorders. The two main types of PKD are autosomal recessive and autosomal dominant PKD (ARPKD, ADPKD). While ARPKD typically is a disorder of early childhood, patients with ADPKD often remain pauci-symptomatic until adulthood even though formation of cysts in the kidney already begins in children. There is clinical and genetic overlap between both entities with very variable clinical courses. Subgroups of very early onset ADPKD may for example clinically resemble ARPKD. The basis of the clinical variability in both forms of PKD is not well understood and there are also limited prediction markers for disease progression for daily clinical life or surrogate endpoints for clinical trials in ARPKD or early ADPKD.As targeted therapeutic approaches to slow disease progression in PKD are emerging, it is becoming more important to reliably identify patients at risk for rapid progression as they might benefit from early therapy. Over the past years regional, national and international data collections to jointly analyze the clinical courses of PKD patients have been set up. The clinical observations are complemented by genetic studies and biorepositories as well as basic science approaches to elucidate the underlying molecular mechanisms in the PKD field. These approaches may serve as a basis for the development of novel therapeutic interventions in specific subgroups of patients. In this article we summarize some of the recent developments in the field with a focus on kidney involvement in PKD during childhood and adolescence and findings obtained in pediatric cohorts.

BackgroundImmune thrombocytopenia (ITP) is an autoimmune disease associated with isolated thrombocytopenia, which is caused by an imbalance between platelet production and platelet destruction. Petechial and mucous membrane hemorrhages are characteristic of ITP, but life-threatening bleeding rarely occurs. Depending on the bleeding symptoms, ITP can be treated with glucocorticoids (GC), intravenous immunoglobulins (IVIG), or in severe cases, platelet transfusions. Mild bleeding does not necessarily require therapy. Using the German Surveillance Unit for rare Pediatric Diseases (ESPED) we conducted a prospective survey on ITP patients in all German Children's Hospitals between September 2018 and August 2019. We collected data on ITP, including the clinical course, therapy implementation recommendations (according to the Association of German Scientific Medical Societies guidelines), outcome, and influence of treatment regimens depending on the treating physician´s experience with ITP patients.ResultsOf the 287 recorded cases of children with ITP, 268 questionnaires were sent to the authors. Two hundred seventeen of the questionnaires fulfilled the inclusion criteria. ITP affected boys and girls similarly, and the median age of manifestation was 3.5 years. The main reasons for hospitalization were thrombocytopenia, bleeding signs, hematomas, and/or petechiae. Bleeding scores were ≤ 3 in 96% of children, which corresponded to a low-to-moderately low risk of bleeding. No life-threatening bleeding was documented. The most common therapies were IVIG (n = 59), GC (n = 33), or a combination of these (n = 17). Blood products (i.e., red blood cells, platelet concentrate, and fresh frozen plasma) were given to 13 patients. Compared to the established guidelines, 67 patients were over-treated, and 2 patients were under-treated.ConclusionsAdherence to German ITP treatment guidelines is currently limited. To improve patient safety and medical care, better medical training and dissemination of the guidelines are required in line with targeted analyses of patients with serious bleeding events to identify potential risk constellations.

Leptin (LEP) and leptin receptor (LEPR) play a major role in energy homeostasis, metabolism, and reproductive function. While effects of biallelic likely pathogenic variants (-/-) on the phenotype are well characterized, effects of mono-allelic likely pathogenic variants (wt/-) in the LEP and LEPR gene on the phenotype compared to wild-type homozygosity (wt/wt) have not been systematically investigated. We identified in our systematic review 44 animal studies (15 on Lep, 29 on Lepr) and 39 studies in humans reporting on 130 mono-allelic likely pathogenic variant carriers with 20 distinct LEP variants and 108 heterozygous mono-allelic likely pathogenic variant carriers with 35 distinct LEPR variants. We found indications for a higher weight status in carriers of mono-allelic likely pathogenic variant in the leptin and in the leptin receptor gene compared to wt/wt, in both animal and human studies. In addition, animal studies showed higher body fat percentage in Lep and Lepr wt/- vs wt/wt. Animal studies provided indications for lower leptin levels in Lep wt/- vs. wt/wt and indications for higher leptin levels in Lepr wt/- vs wt/wt. Data on leptin levels in human studies was limited. Evidence for an impaired metabolism in mono-allelic likely pathogenic variants of the leptin and in leptin receptor gene was not conclusive (animal and human studies). Mono-allelic likely pathogenic variants in the leptin and in leptin receptor gene have phenotypic effects disposing to increased body weight and fat accumulation.