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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-1β 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-1β 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-1β 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-1β. 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. [ABSTRACT FROM AUTHOR]

Evidence of neural crest cell origin of a DICER1 mutant CNS sarcoma in a child with DICER1 syndrome and NRAS-mutant neurocutaneous melanosis DICER1 mutant CNS sarcoma, neural crest cell, neurocutaneous melanosis, pseudo-meissnerian corpuscle, DNA methylation profiling, NRAS (B) Synopsis: A multistep process of accumulating genetic events during embryogenesis in neural crest cell precursor cells leads to tumour formation and transformation in a DICER1 mutant sarcoma. Keywords: DICER1 mutant CNS sarcoma; DNA methylation profiling; neural crest cell; neurocutaneous melanosis; NRAS; pseudo-meissnerian corpuscle EN DICER1 mutant CNS sarcoma DNA methylation profiling neural crest cell neurocutaneous melanosis NRAS pseudo-meissnerian corpuscle 1 5 5 09/07/22 20221001 NES 221001 Key Points DICER1 mutant CNS sarcomas can arise in patients with neurocutaneous melanosis and DICER1 syndrome. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

Objective: To determine if survival rates of preterm infants receiving active perinatal care improve over time.Design: The German Neonatal Network is a cohort study of preterm infants with birth weight <1500 g. All eligible infants receiving active perinatal care are registered. We analysed data of patients discharged between 2011 and 2016.Setting: 43 German level III neonatal intensive care units (NICUs).Patients: 8222 preterm infants with a gestational age between 22/0 and 28/6 weeks who received active perinatal care.Interventions: Participating NICUs were grouped according to their specific survival rate from 2011 to 2013 to high (percentile >P75), intermediate (P25-P75) and low (Main Outcome Measures: Death by any cause before discharge.Results: Total survival increased from 85.8% in 2011-2013 to 87.4% in 2014-2016. This increase was due to reduced mortality of NICUs with low survival rates in 2011-2013. Survival increased in these centres from 53% to 64% in the 22-24 weeks strata and from 73% to 84% in the 25-26 weeks strata.Conclusions: Our data support previous reports that active perinatal care of very immature infants improves outcomes at the border of viability and survival rates at higher gestational ages. The high total number of surviving infants below 24 weeks of gestation challenges national recommendations exclusively referring to gestational age as the single criterion for providing active care. However, more data are needed before recommendations for parental counselling should be reconsidered.Trial Registration: Approval by the local institutional review board for research in human subjects of the University of Lübeck (file number 08-022) and by the local ethic committees of all participating centres has been given. [ABSTRACT FROM AUTHOR]

Gastrointestinal complications during the neonatal period, i.e. necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP), are associated with adverse short-term outcome in very-low-birthweight infants (VLBWI, <1500 g birth weight). However, little is known about the neurological outcome of survivors at school age. We analysed data of 2241 infants followed-up at the age of 6 years. To determine the effect of NEC and SIP on cognitive outcome in consideration of other important confounding factors, we used multivariable logistic regression models. In addition, infants with surgical diagnosis of NEC (n = 43) or SIP (n = 41) were compared to NEC (n = 43) or SIP (n = 41) negative controls using Mahalanobis distance matching. Infants with a history for NEC had a three times increased risk (RR 3.0 [1.8–4.2], p < 0.001) to develop IQ scores <85 while history of surgical SIP did not increase the relative risk for lower IQs at school age (RR 1.0 [0.4–2.1], p = 1.000). In a matched-cohort analysis, we confirmed that infants with surgical NEC had lower mean IQ results than unaffected controls (±SD) (85±17 vs. 94±14, p = 0.023) while no differences were found for history of SIP. Our results reflect that the different aetiology and inflammatory extent of NEC and SIP may lead to disparate neurodevelopment trajectories. Hence, our data suggest a potential role of early gut-brain axis distortion in infants with NEC which needs to be further explored. [ABSTRACT FROM AUTHOR]

Background: Prenatally detected oligo- or even anhydramnios may – beside other reasons – be indicative for a diminished or absent urine production. The resulting clinical picture is a "Potter sequence" with arthrogrypotic joint contractions, a flat face and most importantly pulmonary hypoplasia. In severe cases this pulmonary hypoplasia can be life-limiting irrespective of the underlying lesion. Case presentation: Our patient initially presented with anhydramnios and normal kidneys at external ultrasonography after 31 weeks of pregnancy. Following spontaneous birth after 37 weeks of gestation, the baby boy was born with all the clinical signs of a "Potter-sequence" along with a severe pulmonary hypoplasia leading to insufficient oxygenation and ventilation. Despite all measures taken, the child died after 8 h of life. Beside life-limiting pulmonary hypoplasia postmortem examination again confirmed macroscopically normal kidneys, but microscopy showed compact and variable sized glomeruli, numerically reduced and immature tubules, a structurally altered renal vascular bed and an expanded medullar interstitium. Immunohistochemical studies revealed the absence of proximal convoluted tubules, shortened proximal straight tubules beside an immaturity and dysmorphogenesis of the other segments of the nephron, and thus proved renal tubular dysgenesis (RTD) as the underlying disease. A homozygous mutation c.377G>C (p.Arg126Pro) in exon 2 of the AGTR1 gene was found, leading to the exchange of a highly conserved arginine to proline. This mutation has not been reported in public databases so far. As expected, both consanguineous parents were heterozygous for this mutation. Conclusion: RTD has to be considered in an anuric fetus with apparently normal renal sonography in order to allow adequate prenatal counseling and – if indicated – palliative postnatal care. [ABSTRACT FROM AUTHOR]

The article presents cases of five children with acrodermatitis enteropathica (AE). First patient showed epidermal blistering and loose stools. Second patient showed perioral and acral skin blistering combined with diarrhea. Third patient showed perioral and acral blisters. Fourth and Fifth patients developed diarrhea, enoral, and perianal skin erosions. All patients showed symptoms of defect in intestinal zinc absorption and the symptoms disappeared after resuming zinc supplement.

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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 IgG-deficiency was detected - in 4/21 patients accompanied by IgA-deficiency, 10/21 patients showed low antibody titers against pneumococci. Supra-normal IgG-levels were detected in 11/21 patients and supra-normal IgG-levels were seen in 8/21 patients - in 6 of the patients as combined elevation of IgG and IgG. Three of the four patients with IgA/IgG-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/IgG-deficiency, low antibody titers against pneumococci and elevated acute-phase responses. So patients with MECP2 duplication syndrome and low IgA/IgG may benefit from prophylactic substitution of sIgA and IgG. [ABSTRACT FROM AUTHOR]

This paper describes a neonate with type II Gaucher disease. The phenotype was unusually severe with congenital ichthyosis, hepatosplenomegaly, muscular hypotonia, myoclonus and respiratory failure. Electron microscopy of the skin revealed lamellar body contents in the stratum corneum interstices, appearances considered to be typical of type II Gaucher disease. The baby died from respiratory failure 1 month postpartum having made no neurological progress. Molecular analysis identified a previously not reported homozygous null mutation, c.1505G→A of the β-glucocerebrosidase gene. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Hay-Wells syndrome is a rare form of ectodermal dysplasia, also known as AEC syndrome (Ankyloblepharon filiforme adnatum, Ectodermal effects, Cleft lip/palate). It is inherited in an autosomal dominant fashion with variable expression, featuring congenital abnormalities of skin, hair, teeth, nail, eccrine and mucous glands. We present a three-month-old boy, born to unaffected parents, with typical clinical findings of AEC syndrome. In this boy, a mutation Ile537Thr (c.1610C>T) in the sterile alpha motive (SAM) domain of the TP73L (p63) gene was detected. Because of the broad spectrum of related syndromes such as Rapp-Hodgkin syndrome, Bowen-Armstrong syndrome, CHAND syndrome and epidermolysis bullosa hereditaria, the diagnosis of AEC should be base don both clinical findings and genetic analysis. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- To investigate the growth of children from pregnancies with gestational diabetes mellitus (GDM) and its association with antenatal maternal, fetal, and recent anthropometric parameters of mother and father. RESEARCH DESIGN AND METHODS -- In 324 pregnancies of Caucasian women with GDM, BMI before pregnancy, maternal glycemic values, and measurements of the fetal abdominal circumference were recorded. The weight and height of infants were measured at birth and at follow-up at 5.4 years (range 2.5-8.5). In addition, somatic data from routine examinations at 6, 12, and 24 months and the BMI of parents at follow-up were obtained. BMI standard deviation scores (SDSs) were calculated based on age-correspondent data. RESULTS -- At all time points, BMI was significantly above average (+0.82 SDS at birth; +0.56 at 6, + 0.35 at 12, and + 0.32 at 24 months; and + 0.66 at follow-up; P < 0.001). BMI at birth was related to BMI at follow-up (r = 0.27, P < 0.001). The rate of overweight at follow-up was 37% in children with birth BMI ≥90th percentile and 25% in those with normal BMI at birth (P < 0.05). Abdominal circumference of third trimester and postprandial glucose values were related to BMI at follow-up (r = 0.22 and r = 0.18, P < 0.01). Recent maternal, paternal, and birth BMI were independent predictors of BMI at follow-up (r = 0.42, P < 0.001). Sixty-nine percent of children of parents with BMI ≥30 kg/m² were overweight at follow-up compared with 20% of those with parental BMI <30 kg/m² (P < 0.001). CONCLUSIONS -- Children of mothers with GDM have a high rate of overweight that is associated both with intrauterine growth and parental obesity. [ABSTRACT FROM AUTHOR]

Ifosfamide (IFO) chemotherapy has been reported to result in deToni-Debré-Fanconi syndrome in a minority of patients only, but evaluation of tubular transport capacities has identified a substantial number of patients as having subclinical tubular dysfunction. After completion of combination chemotherapy employing IFO ( n=37) or IFO plus cisplatinum (CPL) ( n=27), glomerular and tubular function was assessed in 64 patients by the urinary excretion of transferrin, IgG, albumin, α-microglobulin (A1M) and N-acetyl-β- d-glucosaminidase. Sodium dodecyl sulphate polyacrylamide gel electrophoresis was performed in 21 patients. The determination of urinary marker proteins was compared with the glomerular filtration rate, the fractional phosphate and percent amino acid reabsorption. A reduced glomerular filtration rate was observed in 9.8% of patients. Tubular dysfunction was frequent, with a predominance of renal amino acid (57%) and A1M (48%) loss. IFO-mediated renal toxicity was dose dependent. CPL treatment resulted in significant enhancement of tubular toxicity induced by IFO, whereas concomitant gentamicin therapy did not affect tubular function. Measurement of urinary protein cannot replace other tests for tubular dysfunction in IFO-treated patients, because the spectrum of IFO-induced nephrotoxicity includes dysfunction of different and independent transport mechanisms of the proximal tubular system. Increased urinary A1M excretion is an important indicator of impaired tubular protein reabsorption. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Classic spinal muscular atrophy (SMA) is caused by mutations in the telomeric copy of SMN1. Its product is involved in various cellular processes, including cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins, pre-mRNA processing and activation of transcription. Spinal muscular atrophy with respiratory distress (SMARD) is clinically and genetically distinct from SMA. Here we demonstrate that SMARD type 1 (SMARD1) results from mutations in the gene encoding immunoglobulin pbinding protein 2 (IGHMBP2; on chromosome 11q13.2-q13.4). In six SMARD1 families, we detected three recessive missense mutations (exons 5, 11 and 12), two nonsense mutations (exons 2 and 5), one frameshift deletion (exon 5) and one splice donor-site mutation (intron 13). Mutations in mouse Ighmbp2 (ref. 14) have been shown to be responsible for spinal muscular atrophy in the neuromuscular degeneration (nmd) mouse, whose phenotype resembles the SMARD1 phenotype. Like the SMN1 product, IGHMBP2 colocalizes with the RNA-processing machinery in both the cytoplasm and the nucleus. Our results show that IGHMBP2 is the second gene found to be defective in spinal muscular atrophy, and indicate that IGHMBP2 and SMN share common functions important for motor neuron maintenance and integrity in mammals. [ABSTRACT FROM AUTHOR]

Reports on prolonged survival of an infant with congenital alveolar capillary dysplasia (ACD) syndrome, using treatment with inhaled nitric oxide (iNO) as a bridge to lung transplantation. Description of symptoms; Discovery of prematurely muscularized arterioles within the pulmonary acini, the typical findings of ACD combined with misalignment of pulmonary veins (MPV); Confirmation of ACD/MPV being a fatal disease by death of child both of respiratory distress and permanent pulmonary hypertension (PPHN).