IRAK1 Duplication in MECP2 Duplication Syndrome Does Not Increase Canonical NF-κB-Induced Inflammation.

PURPOSE: Besides their developmental and neurological phenotype, most patients with MECP2/IRAK1 duplication syndrome present with recurrent and severe infections, accompanied by strong inflammation. Respiratory infections are the most common cause of death. Standardized pneumological diagnostics, targeted anti-infectious treatment, and knowledge of the underlying pathomechanism that triggers strong inflammation are unmet clinical needs. We investigated the influence of IRAK1 overexpression on the canonical NF-κB signaling as a possible cause for excessive inflammation in these patients. METHODS: NF-κB signaling was examined by measuring the production of proinflammatory cytokines and evaluating the IRAK1 phosphorylation and degradation as well as the IκBα degradation upon stimulation with IL-1ß and TLR agonists in SV40-immortalized fibroblasts, PBMCs, and whole blood of 9 patients with MECP2/IRAK1 duplication syndrome, respectively. RESULTS: Both, MECP2/IRAK1-duplicated patients and healthy controls, showed similar production of IL-6 and IL-8 upon activation with IL-1ß and TLR2/6 agonists in immortalized fibroblasts. In PBMCs and whole blood, both patients and controls had a similar response of cytokine production after stimulation with IL-1ß and TLR4/2/6 agonists. Patients and controls had equivalent patterns of IRAK1 phosphorylation and degradation as well as IκBα degradation upon stimulation with IL-1ß. CONCLUSION: Patients with MECP2/IRAK1 duplication syndrome do not show increased canonical NF-κB signaling in immortalized fibroblasts, PBMCs, and whole blood. Therefore, we assume that these patients do not benefit from a therapeutic suppression of this pathway.

[Kidney Cysts and Cystic Nephropathies in Children - A Consensus Guideline by 10 German Medical Societies]. / Nierenzysten und zystische Nierenerkrankungen bei Kindern (AWMF S2k-Leitlinie).

This consensus-based guideline was developed by all relevant German pediatric medical societies. Ultrasound is the standard imaging modality for pre- and postnatal kidney cysts and should also exclude extrarenal manifestations in the abdomen and internal genital organs. MRI has selected indications. Suspicion of a cystic kidney disease should prompt consultation of a pediatric nephrologist. Prenatal management must be tailored to very different degrees of disease severity. After renal oligohydramnios, we recommend delivery in a perinatal center. Neonates should not be denied renal replacement therapy solely because of their age. Children with unilateral multicystic dysplastic kidney do not require routine further imaging or nephrectomy, but long-term nephrology follow-up (as do children with uni- or bilateral kidney hypo-/dysplasia with cysts). ARPKD (autosomal recessive polycystic kidney disease), nephronophthisis, Bardet-Biedl syndrome and HNF1B mutations cause relevant extrarenal disease and genetic testing is advisable. Children with tuberous sclerosis complex, tumor predisposition (e. g. von Hippel Lindau syndrome) or high risk of acquired kidney cysts should have regular ultrasounds. Even asymptomatic children of parents with ADPKD (autosomal dominant PKD) should be monitored for hypertension and proteinuria. Presymptomatic diagnostic ultrasound or genetic examination for ADPKD in minors should only be done after thorough counselling. Simple cysts are very rare in children and ADPKD in a parent should be excluded. Complex renal cysts require further investigation.

Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight Infants: The ETTNO Randomized Clinical Trial.

Importance: Red blood cell transfusions are commonly administered to infants weighing less than 1000 g at birth. Evidence-based transfusion thresholds have not been established. Previous studies have suggested higher rates of cognitive impairment with restrictive transfusion thresholds. Objective: To compare the effect of liberal vs restrictive red blood cell transfusion strategies on death or disability. Design, Setting, and Participants: Randomized clinical trial conducted in 36 level III/IV neonatal intensive care units in Europe among 1013 infants with birth weights of 400 g to 999 g at less than 72 hours after birth; enrollment took place between July 14, 2011, and November 14, 2014, and follow-up was completed by January 15, 2018. Interventions: Infants were randomly assigned to liberal (n = 492) or restrictive (n = 521) red blood cell transfusion thresholds based on infants' postnatal age and current health state. Main Outcome and Measures: The primary outcome, measured at 24 months of corrected age, was death or disability, defined as any of cognitive deficit, cerebral palsy, or severe visual or hearing impairment. Secondary outcome measures included individual components of the primary outcome, complications of prematurity, and growth. Results: Among 1013 patients randomized (median gestational age at birth, 26.3 [interquartile range {IQR}, 24.9-27.6] weeks; 509 [50.2%] females), 928 (91.6%) completed the trial. Among infants in the liberal vs restrictive transfusion thresholds groups, respectively, incidence of any transfusion was 400/492 (81.3%) vs 315/521 (60.5%); median volume transfused was 40 mL (IQR, 16-73 mL) vs 19 mL (IQR, 0-46 mL); and weekly mean hematocrit was 3 percentage points higher with liberal thresholds. Among infants in the liberal vs restrictive thresholds groups, the primary outcome occurred in 200/450 (44.4%) vs 205/478 (42.9%), respectively, for a difference of 1.6% (95% CI, -4.8% to 7.9%; P = .72). Death by 24 months occurred in 38/460 (8.3%) vs 44/491 (9.0%), for a difference of -0.7% (95% CI, -4.3% to 2.9%; P = .70), cognitive deficit was observed in 154/410 (37.6%) vs 148/430 (34.4%), for a difference of 3.2% (95% CI, -3.3% to 9.6%; P = .47), and cerebral palsy occurred in 18/419 (4.3%) vs 25/443 (5.6%), for a difference of -1.3% (95% CI, -4.2% to 1.5%; P = .37), in the liberal vs the restrictive thresholds groups, respectively. In the liberal vs restrictive thresholds groups, necrotizing enterocolitis requiring surgical intervention occurred in 20/492 (4.1%) vs 28/518 (5.4%); bronchopulmonary dysplasia occurred in 130/458 (28.4%) vs 126/485 (26.0%); and treatment for retinopathy of prematurity was required in 41/472 (8.7%) vs 38/492 (7.7%). Growth at follow-up was also not significantly different between groups. Conclusions and Relevance: Among infants with birth weights of less than 1000 g, a strategy of liberal blood transfusions compared with restrictive transfusions did not reduce the likelihood of death or disability at 24 months of corrected age. Trial Registration: ClinicalTrials.gov Identifier: NCT01393496.

[Therapy Options for Infants with Congenital Cytomegalovirus Infection - Implications for Setting Up Neonatal Screening Programs]. / Therapeutische Optionen bei konnataler Zytomegalievirus (CMV)-Infektion ­ Implikationen für die Einführung eines Screeningprogramms.

INTRODUCTION: The number of diseases covered by universal neonatal screening in Germany has risen steadily from 1 (phenylketonuria) in 1968 to 17 (with hearing impairment and congenital hip dysplasia) in 2018. Treatment, however, of disorders diagnosed by screening may harm children, as failed neuroblastoma screening has shown. There are several pilot studies to detect congenital cytomegalovirus (CMV) infection but no consensus as to the treatment of the infants identified. METHODOLOGY: Systematic search for studies investigating therapy of congenital CMV infection, using PubMed and the WHO International Clinical Trials Registry Platform (ICTRP). RESULTS: We found only one controlled trial that randomized infants with symptomatic congenital CMV infection (involving the central nervous system) to treatment (intravenous ganciclovir for 6 weeks) or no treatment. Treatment was associated with significantly less hearing deterioration. A second trial comparing 6 weeks vs. 6 months of treatment with valganciclovir, an oral prodrug of ganciclovir, found no benefit for hearing but modestly improved developmental outcomes associated with 6 months of treatment. In contrast, an open-label registry reported benefits for infants with congenital CMV infection and isolated hearing who received valganciclovir for 12 months, with hearing improvement in 2/3 of cases after a median follow-up of 4½ years. CONCLUSIONS: Antiviral treatment of neonates with congenital CMV infection and few symptoms including isolated hearing loss remains controversial. A generally accepted therapy, however, is pivotal before introducing universal or targeted screening for congenital CMV infection.

[What is the Optimal Minimum Provider Volume in the Provision of Care for Preterm Infants with a Birth Weight below 1250 g in Germany?] / Wie hoch ist die optimale Mindestmenge für die Behandlung Frühgeborener mit einem Geburtsgewicht unter 1250 g in Deutschland?

INTRODUCTION: Numerous studies have investigated volume-outcome relationships in the treatment of very low birth weight infants. However, studies addressing the identification of optimal thresholds when introducing minimum provider volumes for treatment of these infants do not exist. METHODS: Publicly available data (www.perinatalzentren.org) of more than 56,000 infants weighing less than 1250 g at birth (NB<1250) and treated in level-1 perinatal centers (highest level in Germany) between 2010 and 2018 was used for statistical analysis. Potentially avoidable deaths after the introduction of minimum provider volumes were calculated by deducting observed deaths from estimated deaths based on logistic regression models for every existing empirical provider volume. Various smoothing functions were used to ascertain optimal thresholds for minimum provider volumes. RESULTS: Independent of the observation period or smoothing technique, the highest number of potentially avoidable deaths was observed for minimum provider volumes of 50-60 NB<1250 per year. Introducing a minimum provider volume of 50 without a transition period would reduce the number of level-1 perinatal centers to a quarter of the current number in Germany. Approximately 60% of NB<1250 would have to be reallocated. CONCLUSION: Analyses of resulting geographical distances are needed in the preparation of minimum provider volumes for treatment of NB<1250 in Germany. Such analyses should include perinatal centers expected to reach minimum provider volumes after subsequent reallocation in the future.

Infectious and immunologic phenotype of MECP2 duplication syndrome.

MECP2 (methyl CpG binding protein 2) duplication causes syndromic intellectual disability. Patients often suffer from life-threatening infections, suggesting an additional immunodeficiency. We describe for the first time the detailed infectious and immunological phenotype of MECP2 duplication syndrome. 17/27 analyzed patients suffered from pneumonia, 5/27 from at least one episode of sepsis. Encapsulated bacteria (S.pneumoniae, H.influenzae) were frequently isolated. T-cell immunity showed no gross abnormalities in 14/14 patients and IFNy-secretion upon ConA-stimulation was not decreased in 6/7 patients. In 6/21 patients IgG2-deficiency was detected - in 4/21 patients accompanied by IgA-deficiency, 10/21 patients showed low antibody titers against pneumococci. Supra-normal IgG1-levels were detected in 11/21 patients and supra-normal IgG3-levels were seen in 8/21 patients - in 6 of the patients as combined elevation of IgG1 and IgG3. Three of the four patients with IgA/IgG2-deficiency developed multiple severe infections. Upon infections pronounced acute-phase responses were common: 7/10 patients showed CRP values above 200 mg/l. Our data for the first time show systematically that increased susceptibility to infections in MECP2 duplication syndrome is associated with IgA/IgG2-deficiency, low antibody titers against pneumococci and elevated acute-phase responses. So patients with MECP2 duplication syndrome and low IgA/IgG2 may benefit from prophylactic substitution of sIgA and IgG.

Similar adverse outcome rates with high or low oxygen saturation targets in an area with low background mortality.

Background: Randomized controlled trials have indicated reduced mortality rates in very preterm infants assigned to high compared to low oxygen saturation (SpO2) target levels, accompanied by higher rates of retinopathy of prematurity and bronchopulmonary dysplasia. However, the benefit-to-harm ratio may depend on the local background mortality risk. We therefore aimed to quantify the risk-benefit ratios of different SpO2 target ranges in 10 tertiary newborn intensive care units (NICUs) in East Germany. Methods: In a retrospective multicenter study, 1,399 infants born between 2008 and 2012 at a gestational age between 24 0/7 and 27 6/7 weeks and with a birthweight below 1,250 g were grouped according to the hospital's target SpO2 range [high oxygen saturation group (HOSG) above 90%], low oxygen saturation group (LOSG) below 90%] and the compliance of units with their target SpO2 range. The association between neonatal morbidities, neurodevelopmental outcomes, selected treatment strategies, and target SpO2 ranges was calculated using chi-squared and Mann Whitney U tests. Results: Nine of the ten participating NICUs met their SpO2 target ranges. Five units were considered as HOSG, and five units were considered as LOSG. Necrotizing enterocolitis and intraventricular hemorrhage grade ≥ 2 occurred significantly more frequently in the HOSG than in the LOSG (8.4% vs. 5.1%, p = 0.02; and 26.6% vs. 17.7%, p < 0.001). No significant differences in the mortality rate and the rate of retinopathy of prematurity were found. Conclusion: In our patient population, a lower SpO2 target range was not associated with increased safety risks in extremely preterm infants. We cannot be sure that our outcome differences are associated with differences in oxygen saturations due to the retrospective study design and the differences in site practices.

Specifically Increased Rate of Infections in Children Post Measles in a High Resource Setting.

Objectives: Post-measles increased susceptibility to subsequent infections seems particularly relevant in low-resource settings. We tested the hypothesis that measles causes a specifically increased rate of infections in children, also in a high-resource setting. Methods: We conducted a retrospective cohort study on a large measles outbreak in Berlin, Germany. All children with measles who presented to hospitals in Berlin were included as cases, children with non-infectious and children with non-measles infectious diseases as controls. Repeat visits within 3 years after the outbreak were recorded. Results: We included 250 cases, 502 non-infectious, and 498 infectious disease controls. The relative risk for cases for the diagnosis of an infectious disease upon a repeat visit was 1.6 (95% CI 1.4-2.0, p < 0.001) vs. non-infectious and 1.3 (95% CI 1.1-1.6, p = 0.002) vs. infectious disease controls. 33 cases (27%), 35 non-infectious (12%) and 57 (18%) infectious disease controls presented more than three times due to an infectious disease (p = 0.01, and p = 0.02, respectively). This results in a relative risk of more than three repeat visits due to an infection for measles cases of 1.8 (95% CI 1.3-2.4, p = 0.01), and 1.4 (95% CI 1.0-1.9, p = 0.04), respectively. Conclusion: Our study demonstrates for the first time in a high-resource setting, that increased post-measles susceptibility to subsequent infections in children is measles-specific-even compared to controls with previous non-measles infections.

Corrigendum: Specifically increased rate of infections in children post measles in a high resource setting.

[This corrects the article DOI: 10.3389/fped.2022.896086.].

New clues for nephrotoxicity induced by ifosfamide: preferential renal uptake via the human organic cation transporter 2.

Anticancer treatment with ifosfamide but not with its structural isomer cyclophosphamide is associated with development of renal Fanconi syndrome leading to diminished growth in children and bone problems in adults. Since both cytotoxics share the same principal metabolites, we investigated whether a specific renal uptake of ifosfamide is the basis for this differential effect. First we studied the interaction of these cytotoxics using cells transfected with organic anion or cation transporters and freshly isolated murine and human proximal tubules with appropriate tracers. Next we determined changes in membrane voltage in proximal tubular cells to understand their differentiated nephrotoxicity. Ifosfamide but not cyclophosphamide was significantly transported into cells expressing human organic cation transporter 2 (hOCT2) while both did not interact with organic anion transporters. This points toward a specific interaction of ifosfamide with hOCT2, which is the main OCT isoform in human kidney. In isolated human proximal tubules ifosfamide also interacted with organic cation transport. This interaction was also seen in isolated mouse proximal tubules; however, it was absent in tubules from OCT-deficient mice, illustrating the biological importance of this selective transport. Ifosfamide decreased the viability of cells expressing hOCT2, but not that of control cells. Coadministration of cimetidine, a known competitive substrate of hOCT2, completely prevented this ifosfamide-induced toxicity. Finally, ifosfamide but not cyclophosphamide depolarized proximal tubular cells. We propose that the nephrotoxicity of ifosfamide is due to its selective uptake by hOCT2 into renal proximal tubular cells, and that coadministration of cimetidine may be used to prevent ifosfamide-induced nephrotoxicity.

Intact recovery from early 'acquired methylmalonic aciduria' secondary to maternal atrophic gastritis.

AIM: A 6-month-old infant with severe hyporegenerative anaemia, muscular hypotonia and developmental delay is reported, and the metabolic, diagnostic and therapeutic implications of this case are discussed. RESULTS: Diagnostic work-up disclosed vitamin B12 depletion with an elevated excretion of methylmalonic acid (MMA), but a normal plasma total homocysteine. MRI showed fronto-temporal atrophy and a delay in myelinization. The boy's disease was attributable to a maternal atrophic gastritis. After initiation of vitamin B12 supplementation, he quickly recovered regarding haematopoiesis and MMA excretion. His neurological development completely normalized during 18 months of follow-up including assessment by Bayley scores. CONCLUSION: As the majority of reported patients with this acquired form of methylmalonic aciduria show a persistent neurological deficit, early diagnosis of this condition is mandatory and should include sensitive markers of vitamin B12 depletion, namely MMA formation and plasma homocysteine.

Three Novel EPCAM Variants Causing Tufting Enteropathy in Three Families.

Tufting enteropathy (TE) is caused by recessive EPCAM mutations, and is characterized by intractable diarrhea of congenital onset and disorganization of enterocytes. TE generally requires parenteral nutrition (PN) during childhood or intestinal bowel transplantation. We report three unrelated families with six children with TE. We highlight the high rate of disease-related mortality. We observe adequate weight gain with PN, but low to normal and stunted body length, supporting the recent notion that a short stature might be intrinsic to TE. The diagnosis of TE in the index patients from each family was delayed for months to years, even when clinical data, duodenal biopsies, or exome sequencing data were obtained early on. We identified three novel pathogenic EPCAM variants: a deletion of exon 1 that removes the ATG initiation codon, a missense variant c.326A > G (p.Gln109Arg), and nonsense mutation c.429G > A (p.Trp143*) in a compound heterozygous state with the Mediterranean splice site variant c.556-14A > G (Tyr186Phefs*6). Homozygosity for p.Gln109Arg was associated with absent EPCAM staining, and compound heterozygosity for p.Trp143*/Tyr186Phefs*6 was associated with reduced EPCAM staining in duodenal biopsies; such observations might contribute to a genotype-phenotype correlation in larger cohorts of TE patients. This study extends the clinical and molecular spectrum of TE.

A novel mutation in NEB causing foetal nemaline myopathy with arthrogryposis during early gestation.

Nemaline myopathies are a clinically and genetically heterogeneous group of congenital myopathies, mainly characterized by muscle weakness, hypotonia and respiratory insufficiency. Here, we report a male foetus of consanguineous parents with a severe congenital syndrome characterized by arthrogryposis detected at 13 weeks of gestation. We describe severe complex dysmorphic facial and musculoskeletal features by post mortem fetal examination confirming the prenatal diagnosis. Histomorphological and ultrastructural studies of skeletal muscle reveal mini-rods in myotubes caused by a novel homozygous splice-site mutation in NEB (NM_001164508, chr2:g.152,417,623C>A GRCh37.p11 | c.19,102-1G>T ENST00000397345.3). No rods were seen in the myocardium. We discuss the relevance of this mutation in the context of nemaline myopathies associated with early developmental musculoskeletal disorders.

Infant formula with cow's milk fat and prebiotics affects intestinal flora, but not the incidence of infections during infancy in a double-blind randomized controlled trial.

BACKGROUND: The postnatal intestinal colonization of human milk-fed and formula-fed infants differs substantially, as does the susceptibility to infectious diseases during infancy. Specific ingredients in human milk, such as prebiotic human milk oligosaccharides and a specifically structured fat composition with high proportion of beta-palmitic acid (beta-PA) promote the growth of intestinal bifidobacteria, which are associated with favorable effects on infants' health. The present study investigates whether addition of prebiotic galactooligosaccharides (GOS) in combination with higher amounts of beta-PA from cow's milk fat in infant formula positively affects gut microbiota and the incidence of infections in formula-fed infants. METHODS: In a double-blind controlled trial, formula-fed infants were randomly assigned to either receive an experimental formula containing a higher proportion of beta-PA (20-25%) from natural cow's milk fat, and a prebiotic supplement (0.5 g GOS/100 ml), or a standard infant formula with low beta-PA (< 10%), without prebiotics. A breast-fed reference group was also enrolled. After 12 weeks, fecal samples were collected to determine the proportion of fecal bifidobacteria. The number of infections during the first year of life was recorded. RESULTS: After 12 weeks, the proportion of fecal bifidobacteria was significantly higher in infants receiving formula with high beta-PA and GOS compared to control, and was similar to the breast-fed group (medians 8.8%, 2.5%, and 5.0% respectively; p < 0.001). The incidence of gastrointestinal or other infections during the first year of life did not differ between groups. CONCLUSIONS: The combination of higher amounts of beta-PA plus GOS increased significantly the proportion of fecal bifidobacteria in formula-fed infants, but did not affect the incidence of infections. TRIAL REGISTRATION: The study protocol was registered with Clinical Trials (Protocol Registration and Results System Trial ID: NCT01603719 ) on 05/15/2012 (retrospectively registered).