Anja Stein

Association of migraine‐like headaches with Schimke immuno‐osseous dysplasia

Schimke immuno‐osseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia, nephropathy, and T‐cell deficiency. SIOD is caused by mutations in the putative chromatin remodeling protein SMARCAL1. We report an 8‐year‐old boy with SIOD and recurrent, severe, refractory migraine‐like headaches. Through a retrospective questionnaire‐based study, we found that refractory and severely disabling migraine‐like headaches occur in nearly half of SIOD patients. We have also found that the vasodilator minoxidil provided symptomatic relief for one patient. We hypothesize that these headaches may arise from an intrinsic vascular, neuroimmune, or neurovascular defect resulting from loss of SMARCAL1 function.

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

Vici syndrome is a progressive neurodevelopmental multisystem disorder caused by mutations in the autophagy gene EPG5. Byrne et al. characterise the phenotype of 50 affected children, revealing callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, immune dysfunction, developmental delay and microcephaly. Downregulation of epg5 in Drosophila results in autophagic abnormalities and progressive neurodegeneration.

Thrombocytopenia in the First 24 Hours After Birth and Incidence of Patent Ductus Arteriosus

BACKGROUND: Experimental studies suggest that platelet-triggered ductal sealing is critically involved in definite ductus arteriosus closure. Whether thrombocytopenia contributes to persistently patent ductus arteriosus (PDA) in humans is controversial. This was a retrospective study of 1350 very low birth weight (VLBW; <1500 g) infants, including 592 extremely low birth weight (ELBW; <1000 g) infants. METHODS: All infants who had a platelet count in the first 24 hours after birth and an echocardiogram performed on day of life 4 to 5 were included. The incidence of thrombocytopenia was analyzed in infants with and without PDA, and in those who did or did not undergo PDA intervention. The impact of thrombocytopenia, gestational age, birth weight, gender, and sepsis on PDA was determined by receiver operating characteristic curve, odds ratio, and regression analyses. RESULTS: Platelet numbers within the first 24 hours after birth did not differ between VLBW/ELBW infants with and without spontaneous ductal closure. Platelet numbers were not associated with subsequent PDA treatment. Low platelet counts were not related to failure of pharma-cologic PDA treatment and the need for subsequent surgical ligation. Lower gestational age or birth weight, male gender, and sepsis were linked to the presence of PDA in VLBW infants on day of life 4 to 5. CONCLUSIONS: Thrombocytopenia in the first 24 hours after birth was not associated with PDA in this largest VLBW/ELBW infant cohort studied to date. Impaired platelet function, due to immaturity and critical illness, rather than platelet number, might play a role in ductus arteriosus patency.

Epidemic Microclusters of Blood-Culture Proven Sepsis in Very-Low-Birth Weight Infants: Experience of the German Neonatal Network

Introduction We evaluated blood culture-proven sepsis episodes occurring in microclusters in very-low-birth-weight infants born in the German Neonatal Network (GNN) during 2009–2010. Methods Thirty-seven centers participated in GNN; 23 centers enrolled ≥50 VLBW infants in the study period. Data quality was approved by on-site monitoring. Microclusters of sepsis were defined as occurrence of at least two blood-culture proven sepsis events in different patients of one center within 3 months with the same bacterial species. For microcluster analysis, we selected sepsis episodes with typically cross-transmitted bacteria of high clinical significance including gram-negative rods and Enterococcus spp. Results In our cohort, 12/2110 (0.6%) infants were documented with an early-onset sepsis and 235 late-onset sepsis episodes (≥72 h of age) occurred in 203/2110 (9.6%) VLBW infants. In 182/235 (77.4%) late-onset sepsis episodes gram-positive bacteria were documented, while coagulase negative staphylococci were found to be the most predominant pathogens (48.5%, 95%CI: 42.01–55.01). Candida spp. and gram-negative bacilli caused 10/235 (4.3%, 95%CI: 1.68% –6.83%) and 43/235 (18.5%) late-onset sepsis episodes, respectively. Eleven microclusters of blood-culture proven sepsis were detected in 7 hospitals involving a total 26 infants. 16/26 cluster patients suffered from Klebsiella spp. sepsis. The median time interval between the first patient’s Klebsiella spp. sepsis and cluster cases was 14.1 days (interquartile range: 1–27 days). First patients in the cluster, their linked cases and sporadic sepsis events did not show significant differences in short term outcome parameters. Discussion Microclusters of infection are an important phenomenon for late-onset sepsis. Most gram-negative cluster infections occur within 30 days after the first patient was diagnosed and Klebsiella spp. play a major role. It is essential to monitor epidemic microclusters of sepsis in surveillance networks to adapt clinical practice, inform policy and further improve quality of care.

Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?

BackgroundArteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1). However, the mechanism by which the vascular and pulmonary disease arises in SIOD remains unknown.MethodsWe reviewed the records of 65 patients with SMARCAL1 mutations. Molecular and immunohistochemical analyses were conducted on autopsy tissue from 4 SIOD patients.ResultsThirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema. The arteriosclerosis was characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented and disorganized elastin fibers, and the pulmonary disease was characterized by panlobular enlargement of air spaces. Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression.ConclusionsThis first comprehensive study of the vascular and pulmonary complications of SIOD shows that these commonly cause morbidity and mortality and might arise from impaired elastogenesis. Additionally, the effect of SMARCAL1 deficiency on elastin expression provides a model for understanding other features of SIOD.

Dental Abnormalities in Schimke Immuno-osseous Dysplasia

Described for the first time in 1971, Schimke immuno-osseous dysplasia (SIOD) is an autosomal-recessive multisystem disorder that is caused by bi-allelic mutations of SMARCAL1, which encodes a DNA annealing helicase. To define better the dental anomalies of SIOD, we reviewed the records from SIOD patients with identified bi-allelic SMARCAL1 mutations, and we found that 66.0% had microdontia, hypodontia, or malformed deciduous and permanent molars. Immunohistochemical analyses showed expression of SMARCAL1 in all developing teeth, raising the possibility that the malformations are cell-autonomous consequences of SMARCAL1 deficiency. We also found that stimulation of cultured skin fibroblasts from SIOD patients with the tooth morphogens WNT3A, BMP4, and TGFβ1 identified altered transcriptional responses, raising the hypothesis that the dental malformations arise in part from altered responses to developmental morphogens. To the best of our knowledge, this is the first systematic study of the dental anomalies associated with SIOD.

NOD2 Loss-of-Function Mutations and Risks of Necrotizing Enterocolitis or Focal Intestinal Perforation in Very Low-birth-weight Infants

Background:NOD2 loss-of-function mutations, that is, R702W [rs2066844], G908R [rs2066845], and Leu1007fsinsC [rs5743293], have been linked to inflammatory bowel diseases. It is yet unknown whether these variants are also associated with necrotizing enterocolitis (NEC) or focal intestinal perforation (FIP) in infants of very low birth weight (VLBW). Methods:To test this hypothesis, we genotyped 9082 VLBW infants with European ancestry enrolled in a prospective, population-based cohort study of the German Neonatal Network. We assessed the effect of the NOD2 gene variants on the risk for major morbidities of the gastrointestinal tract, that is, NEC/FIP requiring surgery in multivariable logistic regression analyses. Results:In the whole cohort of VLBW infants, carriers of ≥2 NOD2 variant alleles had an increased risk for NEC requiring surgery (odds ratio [OR], 3.57; 95% confidence interval [CI], 1.27–10.04; P = 0.03) and NEC or FIP requiring surgery (OR, 3.81; 95% CI, 1.70–8.51; P = 0.004) as compared with wild-type genotypes. In a multivariable logistic regression analysis including gestational age, birth weight, gender, multiple birth, and inborn delivery, the association between ≥2 NOD2 variant alleles and NEC surgery (OR, 4.14; 95% CI, 1.41–12.12; P = 0.009), FIP surgery (OR, 3.50; 95% CI, 1.02–12.04; P = 0.047), and NEC or FIP surgery (OR, 4.10; 95% CI, 1.74–9.73; P = 0.001) proved to be independent. We also performed a regression analysis in the subgroup of infants with available information on Lactobacillus acidophilus/Bifidobacterium infantis probiotic supplementation (n = 3638). Although probiotics had a protective effect on NEC and NEC or FIP requiring surgery, the NOD2 variants had no significant impact in this subgroup. Conclusions:VLBW infants carrying ≥2 NOD2 genetic risk factors of inflammatory bowel disease in adults have an increased risk for severe gastrointestinal complications, such as NEC requiring surgery. Therefore, infants might benefit from NOD2 genotyping followed by supplementation with probiotics. Replication studies are needed along with genome-wide arrays to allow risk-adapted prevention and therapeutic strategies.

Clinical Relevance of Pathogens Detected by Multiplex PCR in Blood of Very-Low-Birth Weight Infants with Suspected Sepsis - Multicentre Study of the German Neonatal Network.

Introduction In the German Neonatal Network (GNN) 10% of very-low-birth weight infants (VLBWI) suffer from blood-culture confirmed sepsis, while 30% of VLBWI develop clinical sepsis. Diagnosis of sepsis is a difficult task leading to potential over-treatment with antibiotics. This study aims to investigate whether the results of blood multiplex-PCR (SeptiFast®) for common sepsis pathogens are relevant for clinical decision making when sepsis is suspected in VLBWI. Methods We performed a prospective, multi-centre study within the GNN including 133 VLBWI with 214 episodes of suspected late onset sepsis (LOS). In patients with suspected sepsis a multiplex-PCR (LightCycler SeptiFast MGRADE-test®) was performed from 100 μl EDTA blood in addition to center-specific laboratory biomarkers. The attending neonatologist documented whether the PCR-result, which was available after 24 to 48 hrs, had an impact on the choice of antibiotic drugs and duration of therapy. Results PCR was positive in 110/214 episodes (51%) and blood culture (BC) was positive in 55 episodes (26%). Both methods yielded predominantly coagulase-negative staphylococci (CoNS) followed by Escherichia coli and Staphylococcus aureus. In 214 BC—PCR paired samples concordant results were documented in 126 episodes (59%; n = 32 were concordant pathogen positive results, n = 94 were negative in both methods). In 65 episodes (30%) we found positive PCR results but negative BCs, with CoNS being identified in 43 (66%) of these samples. Multiplex-PCR results influenced clinical decision making in 30% of episodes, specifically in 18% for the choice of antimicrobial therapy and in 22% for the duration of antimicrobial therapy. Conclusions Multiplex-PCR results had a moderate impact on clinical management in about one third of LOS-episodes. The main advantage of multiplex-PCR was the rapid detection of pathogens from micro-volume blood samples. In VLBWI limitations include risk of contamination, lack of resistance testing and high costs. The high rate of positive PCR results in episodes of negative BC might lead to overtreatment of infants which is associated with risk of mortality, antibiotic resistance, fungal sepsis and NEC.

Establishment of a Family-centred Care Programme with Follow-up Home Visits: Implications for Clinical Care and Economic Characteristics

BACKGROUND Elternberatung Frühstart is a family-centred care programme for very preterm infants and seriously ill neonates and their parents. The uniqueness of this programme is in its consistency and continuity in parental counselling from pregnancy at risk to follow-up home visits. PATIENTS AND METHODS Family-centred care is provided by specialised nurses, a social education worker, a case manager, a psychologist and neonatologists. They give support and information to parents and facilitate transition to home including co-ordination of health care services and support networks. The programme starts with information for parents at risk of preterm delivery to lessen their anxieties and worries. After birth, parental bonding is encouraged and parents are involved in daily care procedures. The following weeks focus on communication, information and education in order to enhance parental competence. Discharge planning and coordinated follow-up visits involve the family doctor and several members of the welfare and health care system. One of the key objectives is to prevent re-hospitalisation. Over a 4 year period 330 families participated. Funding is provided by: 1) the hospital, from admission to discharge equivalent to one full-time nursing staff, 2) charity donations for follow-up visits and 3) health care insurance for social medical aftercare (Bunter Kreis) following §43, 2 SGB V in severe cases. RESULTS As a result of this programme, the median length of stay was reduced by 24 days; the number of patients that stayed longer than average were reduced by 64% in the group of patients born < 1 500 g. At the same time the patient throughput increased from 243 to 413. CONCLUSION To conclude, a family-centred care programme with coordinated follow-up increases parental satisfaction, reduces the length of the hospital stay and is therefore profitable.

Pandemic A/H1N1(2009) influenza infections in very-low-birth-weight infants--a case series from the German Neonatal Network.

6 cases of clinical influenza A/H1N1(2009) infections were reported within the multi-center German Neonatal Network (GNN) during the primary hospital stay in the pandemic season 2009/2010 and 2010/2011. Clinical symptoms varied from transient hyperthermia to apnea and severe respiratory distress. 1 fatal course with systemic inflammatory response after perinatal transmission of A/H1N1(2009) was observed. Oseltamivir treatment in 3/6 infants was without side effects. The reported cases have major implications for the management of VLBW infants: i) fatal courses after perinatal transmission are possible, ii) postnatal A/H1N1(2009) infection may result in life threatening events at a time when the infant is otherwise stable, iii) vaccination should be recommended for parents and medical staff to avoid nosocomial transmission, iv) more data are needed on the benefit and harm of antiviral drugs in preterm infants, v) neonatologists should suspect A/H1N1(2009) infection when unexplained sepsis-like or respiratory symptoms occur in VLBW infants.