Respiratory Syncytial Virus-Specific Antibodies and Atopic Diseases in Children: A 10-Year Follow-Up.

BACKGROUND: Respiratory syncytial virus (RSV) stimulates the production of specific immunoglobulin (Ig) E and IgG4 antibodies as a hallmark of the Th2 immune response. In this paper, we evaluated the occurrence of atopic diseases in 10-year-old children who were positive for RSV-specific IgG antibodies during infancy. METHODS: The prospective follow-up of 72 children included a physical examination, an International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and the determination of RSV-specific antibodies and total and allergen-specific IgE. RESULTS: Children with asthma had their first wheezing episode at a younger age (χ2 8.097, df = 1, p = 0.004). RSV-specific IgG4 levels at year one were positively correlated with atopic dermatitis (AD) (tau_b = 0.211, p = 0.049) and current AD (tau_b = 0.269, p = 0.012); and RSV-specific IgE levels were positively correlated with allergic rhinitis (AR) (tau_b = 0.290, p = 0.012) and current AR (tau_b = 0.260, p = 0.025). Positive RSV-specific IgE at the age of one increased the chances of asthma occurrence by 5.94 (OR = 5.94, 95% CI = 1.05-33.64; p = 0.044) and the chances of AR by more than 15 times (OR = 15.03, 95% CI = 2.08-108.72; p = 0.007). A positive family history of atopy increased the chances of asthma occurrence by 5.49 times (OR = 5.49, 95% CI = 1.01-30.07; p = 0.049), and a longer duration of exclusive breastfeeding lowered that chance (OR = 0.63, 95% CI = 0.45-0.89; p = 0.008). Prenatal smoking increased the chances of AR occurrence by 7.63 times (OR = 7.63, 95% CI = 1.59-36.53; p = 0.011). CONCLUSION: RSV-specific IgE and RSV-specific IgG4 antibodies could be risk markers for the development of atopic diseases in children.

Respiratory syncytial virus specific immunoglobulin G4 antibodies and atopic diseases in children.

BACKGROUND: It has been proposed that RSV infection stimulates RSV specific IgE and IgG4 production as a hallmark of Th2 immune response, which can contribute to the development of allergic sensitization and atopic diseases. This study intends to examine the occurrence of atopic diseases in children (wheezing bronchitis, food allergy, atopic dermatitis) and their connection with RSV specific IgE and IgG4 during the first two years of life. METHODS: Prospective follow-up from the moment of birth was performed in 127 children with positive RSV specific IgG antibodies at age 1 and 92 children were followed-up until two years of age. The assessment included a structured interview, clinical examination, total blood eosinophils, serum total IgE and allergen specific IgE antibodies, RSV specific IgG, IgG3, IgG4 and IgE antibodies. RESULTS: Significant correlation was found between positive RSV IgG4 antibodies at year one and atopic dermatitis (Tau_b=0.201, P=0.025), as well as food allergy development (Tau_b=0.205, P=0.023). RSV specific IgG4 antibodies to RSV at year one showed significant prediction of increased total and/or allergen specific IgE (odds ratio 2.73 and 95% confidence interval 1.07 - 7.00, P=0.036). In our regression model, the children who had positive RSV IgG4 antibodies had a 2.73 times higher likelihood of having increased positive total and/or allergen specific IgE during the first two years of life. CONCLUSIONS: RSV specific IgG4 antibodies could be a marker of risk for the development of atopic sensitization to inhaled and food allergens, development of food allergy and atopic dermatitis in atopic children.

Sources of variability in expiratory flow profiles during sleep in healthy young children.

Standard lung function tests are not feasible in young children, but recent studies show that the variability of expiratory tidal breathing flow-volume (TBFV) curves during sleep is a potential indirect marker of lower airway obstruction. However, the neurophysiological sources of the TBFV variability in normal subjects has not been established. We investigated sleep stages and body position changes as potential sources for the TBFV curve variability. Simultaneous impedance pneumography (IP), polysomnography (PSG) and video recordings were done in 20 children aged 1.4-6.9 years without significant respiratory disorders during sleep. The early part of expiratory TBFV curves are less variable between cycles of REM than NREM sleep. However, within individual sleep cycles, TBFV curves during N3 are the least variable. The differences in TBFV curve shapes between sleep stages are the main source of overnight variability in TBFV curves and the changes in body position have a lesser impact.

Missense Mutations of the Pro65 Residue of PCGF2 Cause a Recognizable Syndrome Associated with Craniofacial, Neurological, Cardiovascular, and Skeletal Features.

PCGF2 encodes the polycomb group ring finger 2 protein, a transcriptional repressor involved in cell proliferation, differentiation, and embryogenesis. PCGF2 is a component of the polycomb repressive complex 1 (PRC1), a multiprotein complex which controls gene silencing through histone modification and chromatin remodelling. We report the phenotypic characterization of 13 patients (11 unrelated individuals and a pair of monozygotic twins) with missense mutations in PCGF2. All the mutations affected the same highly conserved proline in PCGF2 and were de novo, excepting maternal mosaicism in one. The patients demonstrated a recognizable facial gestalt, intellectual disability, feeding problems, impaired growth, and a range of brain, cardiovascular, and skeletal abnormalities. Computer structural modeling suggests the substitutions alter an N-terminal loop of PCGF2 critical for histone biding. Mutant PCGF2 may have dominant-negative effects, sequestering PRC1 components into complexes that lack the ability to interact efficiently with histones. These findings demonstrate the important role of PCGF2 in human development and confirm that heterozygous substitutions of the Pro65 residue of PCGF2 cause a recognizable syndrome characterized by distinctive craniofacial, neurological, cardiovascular, and skeletal features.

Overnight Video-Polysomnographic Studies in Children with Intractable Epileptic Encephalopathies.

BACKGROUND The aim of this study was to assess sleep architecture and respiration during sleep in children with intractable epileptic encephalopathies using overnight video-polysomnography (V-PSG). MATERIAL AND METHODS Between 2015 to 2017 overnight V-PSG recordings were made for 31 children (22 boys and 9 girls) with intractable epileptic encephalopathy with a mean age of 6.78±3.61 years and a mean body mass index (BMI) of 15.83±3.16 kg/m3. Thirty-one healthy children were matched for sex, age, and BMI as the control group. The phases of sleep studied included rapid eye movement (REM) sleep, and non-REM (NREM) phases NREM 1, NREM 2, and NREM 3. Respiratory function during sleep was evaluated. RESULTS Children with epileptic encephalopathies receiving antiepileptic treatment had significantly decreased total sleep time (TST) (p=0.038), significantly increased percentage of NREM1 (p=0.033), and a significantly lower percentage of total REM (p<0.0001), compared with the control group. All children 31/31 (100%) with epileptic encephalopathies had interictal epileptiform discharges, and 4/31 (12.9%) had ictal events. The number of respiratory events did not differ significantly between the two groups (p=0.118), but children in the epileptic encephalopathy group had a significantly shorter average duration (p=0.008) and longest duration (p=0.048) of respiratory events. Average (p=0.006) and least (p=0.0004) oxygen saturation (SatO2) were significantly lower in children with epileptic encephalopathies compared with the control group. CONCLUSIONS Children with epileptic encephalopathies had altered sleep architecture and marked oxygen desaturation, which supports the need for referral of children with epileptic encephalopathy for overnight sleep evaluation.

Prenatal diagnosis of complex phenotype in a 13-week-old fetus with an interstitial multigene deletion 20q13.13.-q13.2 by chromosomal microarray.

We report the first trimester three-dimensional ultrasonographic findings in a 13-week-old fetus with complex phenotype and a de novo 4.7 Mb multigene deletion encompassing chromosome region 20q13.13-q13.2 detected by chromosomal microarray. Fetal sonography detected radial-ray anomalies in the form of bilateral absence of thumbs and the left club hand deformity. The presence of single atrioventricular canal instead of the atrial septal defect typical for Holt-Oram syndrome pointed us to rather suspect the SALL4 related diseases. Central nervous system anomaly in the form of enlarged lateral brain ventricles with choroid plexus shifted backwards was not previously reported as a part of SALL4 related disorders. The pregnancy was terminated at 14 + 3 weeks of pregnancy and the autopsy confirmed ultrasonographic findings. Deleted region included 38 genes, where only SALL4, ADNP and KCNB1 heterozygote pathogenic variants were described to be cause of syndromic forms. Radial ray anomalies are common part of clinical picture of SALL4 related disorders. Despite the lack of prenatally described cases, we hypothesized that maldevelopment of lateral brain ventriculomegaly could be very early sonographic sign of disturbed ADNP expression causing Helsmoortel-Van der Aa syndrome, but in some extent also of KCNB1 related early-onset epileptic encephalopathy. Furthermore, the possible dosage-dependent influence of recessive genes located in this region cannot be also excluded. The use of genome-wide technologies enables the detection of subtle chromosomal imbalances and more precise familial genetic counseling regarding actual and future pregnancies.

The Croatian Model of Integrative Prospective Management of Epilepsy and Pregnancy

Epilepsy is the most common neurological complication in pregnancy. Women with epilepsy have a higher risk of complications in pregnancy. In Croatia, women with epilepsy are treated by neurologists at tertiary centers according to the place of residence. We prospectively followed-up pregnancies in women with epilepsy and healthy controls, and analyzed the factors responsible for their delivery outcomes and development of their babies. Healthy pregnant women had a higher level of education and economic status, but pregnant women with epilepsy took folic acid in a higher proportion than controls, possibly due to timely preconception counseling. Complications during pregnancy depended on the number of antiepileptic drugs and epilepsy control. We noticed some behavioral and cognitive aspects in children exposed in utero to valproic acid, which required follow up. The rate of congenital malformations was not increased. In conclusion, women with epilepsy should receive preconception counseling about the risk for pregnancy, but also about the possibilities to minimize that risk. We have introduced a model of integrative management of pregnancy and epilepsy based on close collaboration among different clinical experts in Croatia, in order to provide prompt counseling and timely intervention.

Clinical sensitivity and specificity of multiple T2-hyperintensities on brain magnetic resonance imaging in diagnosis of neurofibromatosis type 1 in children: diagnostic accuracy study.

AIM: To determine the prevalence, number, and location of multiple (≥2) T2-hyperintensities on brain magnetic resonance imaging (MRI) in children with neurofibromatosis type 1 (NF1) and their correlation with age, and to establish their sensitivity, specificity, and accuracy for the diagnosis of NF1 in children, especially in the early age (2-7 years). METHODS: We performed a cross-sectional study of 162 patients with NF1 from Croatian Neurofibromatosis Association Database and 163 control children between the ages of 2 and 18 years who underwent brain MRI between 1989 and 2009. RESULTS: Multiple T2-hyperintensities were present in 74% of NF1 patients and 1.8% of controls. They were mainly located in the basal ganglia, brainstem, and cerebellum and were significantly decreased in prevalence and number in the older age. T2-hyperintensities had excellent diagnostic accuracy with the area under the receiver operating characteristic (ROC) curve of 0.849 and 95% confidence interval (CI) of 0.805-0.886. The diagnostic sensitivity, specificity, and accuracy rate of T2-hyperintensities for NF1 were highest in the youngest age (2-7 years): 81% (95% CI 71%-89.1%), 99% (95% CI 92.3%-100%), and 85.8 (95% CI 83.3-93.8), respectively. CONCLUSION: This study strongly suggests the inclusion of T2-hyperintensities on brain MRI on the list of diagnostic criteria for NF1, especially in children of early age, when the clinical penetration of the NF1 gene has not yet been completely finished.

Prospective surveillance of Croatian pregnant women on lamotrigine monotherapy--aspects of pre-pregnancy counseling and drug monitoring.

We prospectively surveyed 23 pregnant women with epilepsy on lamotrigine monotherapy and reported outcome of their pregnancies, including one fetal intrauterine death, one spontaneous abortion and two preterm deliveries. There were no congenital malformations in their offspring. Women with pregnancy planning and folic acid intake delivered babies with higher values of birth weight and birth length. There was large inter-patient variation during drug monitoring and in the need of dose adjustment. Individual approach to every woman and monotherapy with minimal effective lamotrigine dose with frequent drug monitoring enhances the possibility for successful pregnancy. The management of women with epilepsy should begin with pre-pregnancy counseling. Planned pregnancy enables periconceptional folic acid supplementation. Despite the small number of cases, these data indicate that la motrigine treatment during pregnancy might be relatively safe. Larger prospective studies are needed to obtain adequate power for statistical analysis including long-term cohort studies.