Paternal uniparental disomy of chromosome 2 resulting in a concurrent presentation of Crigler-Najjar syndrome type I and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

This is the first report of the concurrent development of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and Crigler-Najjar syndrome type 1 (CNs1) inherited via uniparental disomy of chromosome 2, which are both autosomal recessive pathologies. Through an expanded newborn metabolic panel, a male infant was identified as having an acylcarnitine pattern typical for LCHADD, later confirmed to be caused by a well-characterized pathogenic variant in the HADHA gene located at 2p23. Prolonged non-hematologic jaundice requiring repetitive phototherapy prompted further genetic analysis, leading to the identification of another genetic abnormality consistent with CNs1, which was caused by a novel pathogenic variant in the UGT1A1 gene located at 2q37. The two identified point mutations in chromosome 2 were homozygous and present on separate arms, which indicated potential uniparental disomy. Microarray analysis of the genetic material from the patient and his parents confirmed paternal isodisomy of chromosome 2. Further studies are needed to identify other possible pathogenic variants located on the same defective chromosome, evaluate the combined effect of the two metabolic abnormalities, and plan the best possible treatment and care.

Specification and guideline for technical aspects and scanning parameter settings of neonatal lung ultrasound examination.

Lung ultrasound (LUS) is now widely used in the diagnosis and monitor of neonatal lung diseases. Nevertheless, in the published literatures, the LUS images may display a significant variation in technical execution, while scanning parameters may influence diagnostic accuracy. The inter- and intra-observer reliabilities of ultrasound exam have been extensively studied in general and in LUS. As expected, the reliability declines in the hands of novices when they perform the point-of-care ultrasound (POC US). Consequently, having appropriate guidelines regarding to technical aspects of neonatal LUS exam is very important especially because diagnosis is mainly based on interpretation of artifacts produced by the pleural line and the lungs. The present work aimed to create an instrument operation specification and parameter setting guidelines for neonatal LUS. Technical aspects and scanning parameter settings that allow for standardization in obtaining LUS images include (1) select a high-end equipment with high-frequency linear array transducer (12-14 MHz). (2) Choose preset suitable for lung examination or small organs. (3) Keep the probe perpendicular to the ribs or parallel to the intercostal space. (4) Set the scanning depth at 4-5 cm. (5) Set 1-2 focal zones and adjust them close to the pleural line. (6) Use fundamental frequency with speckle reduction 2-3 or similar techniques. (7) Turn off spatial compounding imaging. (8) Adjust the time-gain compensation to get uniform image from the near-to far-field.

Longitudinal assessment of cardiac function in extremely low birth weight children at 7 and 11 years of age: implications for adult medicine.

BACKGROUND: The long-term impact of extreme prematurity on cardiac structure and function has not been fully evaluated. AIMS: The aim of the study was to assess cardiac condition at 11 years of age in a local cohort of extremely low birth weight (ELBW) children born between 2002 and 2004 and to compare it to a previous study in the same group at 7 years of age. METHODS: Sixty-four children with ELBW (median birth weight of 890 g) and 36 children born at full term underwent echocardiography and physical examination. RESULTS: M-mode echocardiography parameters, expressed as z-scores for body surface area (mean [SD]), showed significant differences in left ventricular end-diastolic dimension (-1.01 [0.91] vs 0.35 [0.71]; P < 0.001), left ventricular end-systolic dimension (-0.29 [0.92] vs 0.57 [0.65]; P < 0.001), aorta dimension (0.63 [1.14] vs 1.63 [1.30]; P < 0.001), and left atrial dimension (-1.75 [0.97] vs -0.01 [0.86]; P < 0.001) between the study group and controls at 11 years of age. Fractional shortening (FS) and ejection fraction (EF) were higher in the ELBW children than in their full-term counterparts (33.6 [5.5] vs 30.8 [4.34]; P = 0.009 and 0.63 [0.07] vs 0.58 [0.06]; P = 0.005, respectively) at a mean age of 11 years. CONCLUSIONS: The ELBW children had smaller hearts than full-term controls at both 7 and 11 years of age. The FS and EF were elevated in the group of 11-year-old ELBW children. We observed comparable progress in cardiac growth (approximately 20%) in premature and full-term children over a 4-year study period.

GLYCEMIC VARIABILITY IS ASSOCIATED WITH TREATMENT REQUIRING RETINOPATHY OF PREMATURITY: A Case-Control Study.

PURPOSE: To assess the association between glycemic variability (GV) and Type 1 retinopathy of prematurity (ROP) in infants with birth weights of less than 1,251 g. METHODS: A case-control study of infants with birth weights of less than 1,251 g who developed Type 1 ROP (n = 20) was conducted. Controls had a less severe ROP or no eye disease and were individually matched for gestational age and birth weight (n = 40). Odds ratios of ROP were calculated based on multiple factors including oxygen exposure, respiratory support, incidence of hyperglycemia, and GV. For glucose measurements, a continuous glucose monitoring system was used. RESULTS: There were no significant differences in gender, antenatal steroid administration, severity of illness, and Apgar score. Univariate analyses suggest increased risk for the development of Type 1 ROP based on incidence of intraventricular hemorrhage Grade 3 or 4 (P = 0.048), duration of oxygen exposure (P = 0.003), incidence of hyperglycemia over 150 mg/dL (P = 0.01), and GV according to significantly higher SD (P = 0.002), coefficient of variation (P = 0.001), and mean amplitude of glucose excursion (P = 0.008). Using a multiple regression model, increased risk of Type 1 ROP was only found to be associated with duration of oxygen exposure and higher GV. CONCLUSION: Our study demonstrates a relationship between GV and the development of severe ROP.

Glycemic variability in continuous glucose monitoring negatively correlates with gestational age in very low birth weight infants.

Introduction: High glycemic variability is commonly observed in intensive care patients, both in pediatrics and adults. The aim of the study was to evaluate the correlation between gestational age and glycemic variability in cohort of very low birth infants.Patients and methods: A prospective, single-center, open cohort study enrolled 74 very low birth weight infants with a mean birth weight of 1066 g. Continuous glucose monitoring system (Guardian Real-Time CGM®, Medtronic, Northridge, CA, USA) was used to measure glucose levels. Spearman's rank correlation coefficients were calculated for glycemic variability indices and gestational age. Multiple linear regression analyses were used to assess the adjusted effect of multiple glycemic variability variables.Results: The correlations between all calculated glycemic variability indices and gestational age were negative. In multiple regression analysis, all glycemic variability indices negatively correlated with gestational age and positively correlated with mean interstitial fluid glucose concentration.Conclusions: Glycemic variability in very low birth weight infants correlates with gestational age and mean glucose concentrations.

Lung ultrasound reduces the number of chest X-rays in newborns with pneumothorax.

OBJECTIVE: Aim of the study: To determine the impact of lung ultrasonography as an imaging method used to diagnose and monitor newborns with symptomatic pneumothorax and to assess the risk factors for pneumothorax and the outcomes in newborns with symptomatic pneumothorax. PATIENTS AND METHODS: Material and methods: A single-centre retrospective study enrolled patients born after 32 weeks of gestation, with a diagnosis of pneumothorax in the first week of life. The 118 patients who were included in the study were divided into two groups. Group A (51 infants) comprised those children who were treated between 2007 and 2010, while group B (n=67) those from the years 2013 to 2016. The children from group A were monitored with repeated chest X-rays. Those from group B received repeated lung ultrasonography supported by chest X-ray in those cases where there was diagnostic uncertainty. Comparison was made between the groups with respect to pneumothorax risk factors, treatment methods and the use of imaging during the period of treatment. The statistical analysis used χ2, Mann-Whitney and Student's t-tests. RESULTS: Results: There were no significant demographic or clinical differences between the two groups. Both the use of nCPAP (nasal continuous positive airway pressure) (p<0.001) and diagnosed perinatal asphyxia (p=0.036) were higher in group B. Congenital pneumonia occurred more often in group A (p=0.041). Earlier detection of pneumothorax (p=0.001) and shorter hospital stay (p=0.03) were observed in group B. However, the total number of imaging (lung ultrasound and chest X-ray combined) was higher (p<0.001) in group B. CONCLUSION: Conclusion: This study confirmed the usefulness of lung ultrasound in monitoring newborns with pneumothorax, moreover significantly limiting X-ray radiation.

Lung ultrasound in the diagnosis of neonatal respiratory failure prior to patient transport.

PURPOSE: Lung ultrasound (LUS) at the point-of-care is a new method that is increasingly used in neonatology. The aim of this study was to determine the utility of the addition of LUS prior to the interhospital transport of neonates with respiratory failure. METHODS: LUS was performed on 50 newborns with respiratory failure prior to transport to a tertiary neonatal intensive care unit. We analyzed the performance of LUS for diagnosing the cause of respiratory failure, the concordance between LUS, chest X-ray (CXR) and final clinical diagnosis, and the impact of LUS on clinical decision making before transport. RESULTS: LUS sensitivity for the diagnosis of respiratory distress syndrome was 91.3% (95%CI: 70.5-98.5%), and specificity was 92.6% (95%CI: 74.2-98.7%), whereas sensitivity and specificity of CXR were 69.6% (95%CI: 47.0-85.9%) and 81.5% (95%CI: 61.2-92.9%), respectively. For the recognition of pneumothorax (PTX) LUS had a sensitivity of 83.3% (95%CI: 36.5-99.1%) and a specificity of 100% (95%CI: 89.9-100%). For CXR, sensitivity was 16.7% (95%CI: 0.01-63.5%) and specificity was 97.7% (95%CI: 86.4-99.9%). The agreement between LUS and CXR in diagnosing the cause of respiratory failure was substantial (κ of 0.57 [95%CI: 0.40-0.74]) and the agreement between LUS and the final clinical diagnosis was very good (κ of 0.86 [95%CI: 0.74-0.98]). In 42% of the patients, a LUS examination prior to transport indicated the need for endotracheal tube repositioning or PTX decompression. CONCLUSION: LUS may be a reliable imaging technique for differentiating the causes of respiratory failure before neonatal transport. Use of LUS may optimize the care of infants during transport.

Impact of early glycemic variability on mortality and neurologic outcome of very low birth weight infants: Data from a continuous glucose monitoring system.

OBJECTIVE: Background: Glycemic variability (GV) has been a matter of interest in recent years. However, glycemic variability in preterm infants has not been adequately investigated. Objectives: To evaluate the impact of glycemic variability obtained from continuous glucose monitoring on mortality and neurologic outcomes: grade 3 or 4 intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and retinopathy of prematurity (ROP) requiring treatment among very low birth weight infants. PATIENTS AND METHODS: Material and methods:A prospective, single-center, open cohort study enrolled 74 very low birth weight infants with a mean birthweight of 1066 g (+/-267). A continuous glucose monitoring system (CGM) was used to measure glucose during the first week of life. The impact of glycemic variability (standard deviation SD; coefficient of variation CV; and mean amplitude of glucose excursion MAGE) on mortality and neurologic outcomes of infants was evaluated. RESULTS: Results: Univariate analysis revealed that glycemic variability occurring during the first week of life was not be associated with mortality before term-equivalent age and PVL. Higher GV was associated with grade 3 or 4 IVH (CV p=0.025; MAGE p=0.032) and ROP requiring treatment (SD p=0.019; CV p=0.026; MAGE=0.029). However, logistic regression models did not show a significant association between GV occurring during the first week of life and grade 3 or 4 IVH (MAGE OR 2.64; 95% CI 0.71-9.92) or ROP requiring treatment (MAGE OR 1.74; 95% CI 0.57-5.32). CONCLUSION: Conclusions: Further prospective studies are needed to fully investigate the impact of GV on mortality and morbidity in premature infants. The potential benefits of reducing glucose blood fluctuations in VLBW infants need to be addressed.

Defining Glycemic Variability in Very Low-Birthweight Infants: Data from a Continuous Glucose Monitoring System.

BACKGROUND: Glucose variability (GV) is a matter of interest for researches in recent years. It is connected with oxidative stress, which is crucial in the development of multiple complication of prematurity. However, glycemic variability in preterm infants was poorly investigated. This study aims to investigate glycemic variability obtained from a continuous glucose monitoring (CGM) system in a cohort of very low-birthweight (VLBW) infants. METHODS: A prospective, single-center, open cohort study enrolled 74 VLBW infants with a mean birthweight of 1066 g and median gestational age of 28 weeks. A CGM system (Guardian Real-Time CGM®, Medtronic, Northridge, CA) was used to measure interstitial glucose concentration. The glycemic variability was calculated using EasyGV. RESULTS: Most glycemic variability indices in VLBW infants showed log-normal distribution and for these, geometric mean ÷/ × geometric standard deviation (GSD) was calculated: M-value 2.28 (÷/ × 1.82), mean amplitude of glycemic excursions (MAGE) 1.89 (÷/ × 1.34), average daily risk ratio (ADRR) 2.22 (÷/ × 2.56), lability index 0.46 (÷/ × 1.71), J-index 0.46 (÷/ × 1.71), low blood glucose index 2.05 (÷/ × 1.66), high blood glucose index 1.11 (÷/ × 2.44), continuous overlapping net glycemic action (CONGA) 5.54 (÷/ × 1.16), mean of daily differences (MODD) 1.23 (÷/ × 1.38), and coefficient of variation 1.15 (÷/ × 1.31). Only SD of glucose concentration showed a normal distribution: arithmetic mean 1.24 (+/-0.37). ADRR, J-index, MODD, CONGA, and MAGE are moderately to strongly correlated with SD. CONCLUSIONS: In our cohort of VLBW infants, almost all glycemic variability indices showed skewed positive distribution. The natural central tendency measure for the log-normally distributed data is the geometric mean and for statistical variation is the GSD.

Preterm Glycosuria - New Data from a Continuous Glucose Monitoring System.

BACKGROUND: Careful control of glucose homeostasis is essential for infants with very low birth weight (VLBW). In clinical practice, blood and urine glucose levels are monitored; however, their correlation has not been fully investigated in VLBW infants. OBJECTIVES: To evaluate the correlation between interstitial fluid glucose concentration (ISFG), glycosuria, and urine output among VLBW infants through continuous glucose monitoring (CGM). METHODS: A prospective, single-center, open cohort study enrolled 74 VLBW infants with a mean birth weight of 1,066 g. CGM (Guardian Real-Time CGM®; Medtronic, Northridge, CA, USA) was used to measure glucose. The urine output was calculated using 4-hour intervals. Reagent strips were used for semiquantitative measurement of glycosuria. RESULTS: The CGM delivered 102,334 glucose measurements. 2,684 urine samples were checked for glycosuria, of which 92.06% remained negative. Corresponding glycemia in samples without glycosuria remained normoglycemic (median 103 mg/dL; 10-90th percentile 80-144 mg/dL). The median glucose concentrations for samples in ascending glycosuria categories 1+, 2+, 3+, and 4+ were 152, 181, 214, and 222 mg/dL, respectively. A moderate correlation between ISFG and urine output was found for categories ≥1+ (rs = 0.56; 95% confidence interval 0.42-0.68; p < 0.001). The urine output was significantly lower when glycosuria was absent (p < 0.05). Polyuria was observed only in glycosuria 4+ (median urine output 9.9; interquartile range 7.4-12.2 mL/kg/h). CONCLUSIONS: The renal glucose threshold in VLBW infants is between 150 and 180 mg/dL. A negative result for glycosuria is a reliable screening test to exclude hyperglycemia. Occurrence of glycosuria ≥1+ is an indication to test blood glucose.

The safety of pulmonary ultrasonography in the neonatal intensive care unit.

OBJECTIVE: Introduction: Due to specific anatomy of children are more vulnerable to the carcinogenic effects of ionizing radiation from chest X-rays. Lung ultrasound (LUS) is a validated procedure which can easily be used in diagnosing pathologies of the neonatal lung. However, experimental studies have shown that low frequency ultrasound may induce pulmonary capillary hemorrhage (PCH). Aim of the study: To evaluate the potential relationship between lung ultrasound and pulmonary hemorrhage in very low birth weight infants. PATIENTS AND METHODS: Patients and methods: We analysed the medical records of very low birth weight infants admitted to our neonatal tertiary centre between 2008 and 2011 (group 1), when CXR was the main procedure used to evaluate the respiratory system, and between 2013 and 2016 (group 2), when LUS became a routine procedure, replacing the chest X-ray. RESULTS: Results: 297 infants were enrolled in the first group and 286 in the second group, respectively. There was no difference in the frequency of pulmonary hemorrhages between the two groups (p=1). In the first group there was only one episode of PCH and in the second group no PCH was seen. Statistically significant differences were seen in a number of patients with pulmonary hemorrhage risk factors: surfactant administration (p<0.001), mechanical ventilation (p=0.0003), and hemodynamically significant patent ductus arteriosus (p=0.025). CONCLUSION: Conclusions: Routine lung ultrasound appears to be safe in very low birth weight infants; there were no episodes of pulmonary hemorrhage.

Prediction of severe retinopathy of prematurity using the WINROP algorithm in a cohort from Malopolska. A retrospective, single-center study.

INTRODUCTION: Retinopathy of prematurity (ROP) is one of the leading avoidable causes of blindness in childhood in developed countries. Accurate diagnosis and treatment are essential for preventing the loss of vision. WINROP (https://www.winrop.com) is an online monitoring system which predicts the risk for ROP requiring treatment based on gestational age, birth weight, and body weight gain. AIM: To validate diagnostic accuracy of the WINROP algorithm for the detection of severe ROP in a single centre cohort of Polish, high-risk preterm infant population. MATERIAL AND METHODS: Medical records of neonates born before 32 weeks of gestation admitted to the third level neonatal centre in a 2-year retrospective investigation 79 patients were included in the study: their gestational age, birth weight and body weight gain were set in the WINROP system. The algorithm evaluated the risk for ROP divided into low or high-risk of disease and identified infants with high risk of developing severe ROP (type 1 ROP). RESULTS: Out of 79 patients 37 received a high-risk alarm, of whom 22 developed severe ROP. Low-risk alarm was triggered in 42 infants; five of them developed type 1 ROP. The sensitivity of the WINROP was found to be 81.5% (95% CI 61.9-93.7), specificity 71.2% (95% CI 56.9-82.9), negative predictive value (NPV) 88.1% (95% CI 76.7-94.3), and positive predictive value (PPV) 59.5 (95% CI 48.1-69.9), respectively. The accuracy of the test significantly increased after combined WINROP and surfactant therapy as an additional factor - sensitivity 96.3% (95% CI 81.0-99.9), specificity 63.5% (95% CI 49.0-76.4), NPV 97.1% (95% CI 82.3-99.6), and PPV 57.8 (95% CI 48.7-66.4). CONCLUSIONS: The WINROP algorithm sensitivity from the Polish cohort was not as high as that reported in developed countries. However, combined with additional factors (e.g. surfactant treatment) it can be useful for identifying the risk groups of sight-threatening ROP. The accuracy of the WINROP algorithm should be validated in a large multi-center prospective study in a Polish population of preterm infants.

Longitudinal assessment of renal size and function in extremely low birth weight children at 7 and 11 years of age.

BACKGROUND: There are a lack of studies describing a longitudinal association between preterm delivery and renal complications later in life. We assessed renal size and function in preterm infants born with extremely low birth weight (ELBW) during 4 years of follow-up, comparing these parameters to age-matched children born full term (term controls). METHODS: The results of selected renal laboratory tests [levels of cystatin C, creatinine, blood urea nitrogen (BUN)] and of renal ultrasound evaluations were compared between the ELBW group and the term control group at age 7 and 11 years. RESULTS: The study population consisted of 64 children born with ELBW (ELBW children) who had been recruited at birth and 36 children born at term (term children) who took part in both follow-up assessments. Renal ultrasound examination revealed a significantly smaller renal volume in the 7- and 11-year-old ELBW children compared to the term controls [right kidney volume: 50.8 vs. 61.2 ml/m(2), respectively, at 7 years (p <0.01) and 51.4 vs. 58.2 ml/m(2), respectively, at 11 years (p <0.01); left kidney volume: 51.4 vs. 60.3 ml/m(2), respectively, at 7 years (p <0.01) and 55.2 vs. 60.7 ml/m(2), respectively, at 11 years (p = 0.02)]. Renal function in ELBW children was also affected. Serum cystatin C levels were significantly higher in ELBW children than in the controls at 7 years of age, and this difference remained statistically significant at 11 years of age [0.63 vs. 0.59 mg/l, respectively, at 7 years (p = 0.02) and 0.72 vs. 0.61 mg/l, respectively, at 11 years (p = 0.01)]. Six ELBW children also had elevated cystatin C levels (0.97-1.11 mg/l) at 11 years of age. Cystatin C levels were within normal range in the ELBW children at age 7 years and in term children in both follow-up studies. BUN levels were higher in ELBW children at the age of 11 years (4.49 vs. 4.15 mmol/l; p = 0.028). CONCLUSION: Continued follow-up of these patients will reveal whether the observed worsening in renal function will persist into adulthood.

THE INCIDENCE OF HYPERGLYCAEMIA IN VERY LOW BIRTH WEIGHT PRETERM NEWBORNS. RESULTS OF A CONTINUOUS GLUCOSE MONITORING STUDY--PRELIMINARY REPORT.

AIM: To determine the incidence of hyperglycaemia in very low birth weight preterm newborns. To assess risk factors in hyperglycemia and outcome in groups of children with and without clinically significant hyperglycaemia. MATERIAL AND METHODS: The prospective study included newborns with very low birth weight in whom the continuous glucose monitoring system was used for glucose measurements. A standardized hyperglycaemia treatment schedule was implemented and a uniform nutrition strategy introduced. The patients were divided into groups: group A--patients with under 5% of the readings over 150 mg/dL of glucose (control group), group B--patients with more than 5% of the readings over 150 mg/dL of glucose and under 5% of the readings over 180 mg/dL of glucose (mild hyperglycaemia), and group C--patients with over 5% of the readings > 180 mg/dL or on insulin treatment (moderate or severe hyperglycaemia). RESULTS: 63 patients were included in the study. Their mean gestational age was 27.7 weeks (SD:2.4), the mean birth weight was 1059g (SD: 262 g). Hyperglycaemia was detected in 27 (42.9%), including mild hyperglycaemia in 19 (30.2%), and moderate or severe hyperglycaemia in 8 (12.7%) neonates. Lower gestational age (p = 0.02) and higher CRIB IIscore (p < 0.01) were positively associated with hyperglycaemia. Early-onset sepsis (p < 0.01) was associated with higher glucose levels as well. A significantly higher mortality rate on the 28th day of life (p = 0.02), depending on the severity of hyperglycemia, was noted. No adverse effects related to the continuous glucose monitoring system were observed. CONCLUSIONS: The study confirmed the usefulness and safety of the continuous glucose monitoring system in VLBW neonates. A continuous glucose monitoring system should be used in neonatal intensive care units as a standard method.

Novel mutation-deletion in the PHOX2B gene of the patient diagnosed with Neuroblastoma, Hirschsprung's Disease, and Congenital Central Hypoventilation Syndrome (NB-HSCR-CCHS) Cluster.

INTRODUCTION: Neuroblastoma (NB), Hirschsprung disease (HSCR), Congenital Central Hypoventilation Syndrome (CCHS), clinically referred as the NB-HSCR-CCHS cluster, are genetic disorders linked to mutations in the PHOX2B gene on chromosome 4p12. SPECIFIC AIM: The specific aim of this project is to define the PHOX2B gene mutations as the genomic basis for the clinical manifestations of the NB-HSCR-CCHS cluster. PATIENT: A one day old male patient presented to the Jagiellonian University Medical College (JUMC), American Children Hospital, neonatal Intensive Care Unit (ICU) due to abdominal distention, vomiting, and severe apneic episodes. With the preliminary diagnosis of the NB-HSCR-CCHS, the blood and tissue samples were acquired from the child, as well as from the child's parents. All procedures were pursued in accordance with the Declaration of Helsinki, with the patient's Guardian Informed Consent and the approval from the Institutional Review Board. GENETIC/GENOMIC METHODS: Karyotyping was analyzed based upon Giemsa banding. The patient's genomic DNA was extracted from peripheral blood and amplified by polymerase chain reaction. Direct microfluidic Sanger sequencing was performed on the genomic DNA amplicons. These procedures were pursued in addition to the routine clinical examinations and tests. RESULTS: G-banding showed the normal 46 XY karyotype. However, genomic sequencing revealed a novel, heterozygous deletion (8 nucleotides: c.699-706, del8) in exon 3 of the PHOX2B gene on chromosome 4. This led to the frame-shift mutation and malfunctioning gene expression product. CONCLUSION: Herein, we report a novel PHOX2B gene mutation in the patient diagnosed with the NB-HSCR-CCHS cluster. The resulting gene expression product may be a contributor to the clinical manifestations of these genetic disorders. It adds to the library of the mutations linked to this syndrome. Consequently, we suggest that screening for the PHOX2B mutations becomes an integral part of genetic counseling, genomic sequencing of fetal circulating nucleic acids and / or genomes of circulating fetal cells prenatally, while preparing supportive therapy upon delivery, as well as on neonates' genomes of intubated infants, when breathing difficulties occur upon extubation. Further, we hypothesize that PHOX2B may be considered as a potential target for gene therapy.

Gene expression profiling in preterm infants: new aspects of bronchopulmonary dysplasia development.

RATIONALE: Bronchopulmonary dysplasia is one of the most serious complications observed in premature infants. Thanks to microarray technique, expression of nearly all human genes can be reliably evaluated. OBJECTIVE: To compare whole genome expression in the first month of life in groups of infants with and without bronchopulmonary dysplasia. METHODS: 111 newborns were included in the study. The mean birth weight was 1029 g (SD:290), and the mean gestational age was 27.8 weeks (SD:2.5). Blood samples were drawn from the study participants on the 5th, 14th and 28th day of life. The mRNA samples were evaluated for gene expression with the use of GeneChip® Human Gene 1.0 ST microarrays. The infants were divided into two groups: bronchopulmonary dysplasia (n=68) and control (n=43). RESULTS: Overall 2086 genes were differentially expressed on the day 5, only 324 on the day 14 and 3498 on the day 28. Based on pathway enrichment analysis we found that the cell cycle pathway was up-regulated in the bronchopulmonary dysplasia group. The activation of this pathway does not seem to be related with the maturity of the infant. Four pathways related to inflammatory response were continuously on the 5(th), 14(th) and 28(th) day of life down-regulated in the bronchopulmonary dysplasia group. However, the expression of genes depended on both factors: immaturity and disease severity. The most significantly down-regulated pathway was the T cell receptor signaling pathway. CONCLUSION: The results of the whole genome expression study revealed alteration of the expression of nearly 10% of the genome in bronchopulmonary dysplasia patients.

From a regional cohort of extremely low birth weight infants: cardiac function at the age of 7 years.

BACKGROUND: The long-term impact of prematurity on cardiac structure and function has not yet been fully discovered. OBJECTIVES: To assess long-term cardiac complications in the regional cohort of extremely low birth weight (ELBW) children born in 2002-2004. MATERIAL AND METHODS: Eighty-one children born as ELBW infants (91% of the available cohort) with a median birth weight of 890 g (25-75th percentile: 760-950) were evaluated at the mean age of 6.7 years. The control group included 40 children born full-term, selected from one general practice in the district. Echocardiography and 24-hour ambulatory blood pressure measurements (ABPM) were performed. The primary outcome variable was the presence of cardiac complications such as left ventricular hypertrophy (LVH), diastolic dysfunction or systolic dysfunction. RESULTS: LVH was diagnosed in 4/81 ELBW children and 2/40 control children (p = 1.0). Concentric remodeling was detected in 8 (10%) subjects from the ELBW group and in 2 (5%) from the control group (p = 0.49). There were no patients with diastolic or systolic dysfunction in either group. After having expressed the results of M-mode echocardiography as z-scores for body surface area (BSA), statistically significant differences were observed for right-ventricle dimension in diastole (-1.49 ± 1.25 vs. -0.31 ± 0.91; p < 0.001), LV inner dimension in diastole (-0.53 ± 1.26 vs. 0.13 ± 0.94; p = 0.01) and left atrium (-0.93 ± 1.07 vs. -0.15 ± 1.02; p < 0.01). Heart rate (HR) was significantly faster in ELBW children (92.9 ± 8.4 vs. 86.7 ± 7.4 bpm; p = 0.01 adjusted for BSA) and they also had significantly higher night-time blood pressure [mean (z-score): 1.15 vs. 0.2; p = 0.02] without nocturnal dipping (night-time dipping <10%: 13 (16.7%) vs. 2 (5.2%), p = 0.13). CONCLUSIONS: No differences were found between the groups in the occurrence of cardiac complications. Ex-preterm ELBW children at age 6 may have a faster HR, smaller cardiac dimensions on echocardiography and higher nocturnal blood pressure. The clinical relevance of these findings is unknown.

Impact of antenatal glucocorticosteroids on whole-genome expression in preterm babies.

AIM: To study the impact that using antenatal steroid to treat threatened preterm delivery has on whole-genome expression. METHODS: A prospective whole-genome expression study was carried out on 50 newborn infants, delivered before 32 weeks gestation, who had been exposed to antenatal steroids, including 40 who had received a full antenatal steroid course. Seventy infants not exposed to antenatal steroids formed the control group. Microarray analyses were performed five and 28 days after delivery, and the results were validated by real-time PCR. The study was conducted between September 2008 and November 2010. RESULTS: Twenty thousand six hundred and ninety-three genes were studied in the infants' leucocytes. Thirteen were differentially expressed 5 days after delivery, but there were no differences at day 28. Four genes related to cancer or inflammation were up-regulated. Nine genes were down-regulated: six were Y-linked and associated with malignancies, graft-versus-host disease, male infertility and cell differentiation and three were associated with pre-eclampsia, oxidative stress and chloride/bicarbonate exchange. Seven gene pathways were up-regulated at day five and only one at day 28. These were associated with cell growth, cell cycle regulation, metabolism and apoptosis. CONCLUSION: Antenatal steroid therapy affects a limited number of genes and gene pathways in leucocytes in preterm babies at day five of life. The effect is short-lived, but long-term effects cannot be ruled out.

New insight into the pathogenesis of retinopathy of prematurity: assessment of whole-genome expression.

BACKGROUND: Retinopathy of prematurity (ROP) is one of the most common preventable causes of blindness and impaired vision among children in developed countries. The aim of the study was to compare whole-genome expression in the first month of life in groups of infants with and without ROP. METHODS: Blood samples were drawn from 111 newborns with a mean gestational age of 27.8 wk on the 5th, 14th, and 28th day of life (DOL). The mRNA samples were evaluated for gene expression with the use of human whole-genome microarrays. The infants were divided into two groups: no ROP (n = 61) and ROP (n = 50). RESULTS: Overall, 794 genes were differentially expressed on the 5th DOL, 1,077 on the 14th DOL, and 3,223 on the 28th DOL. In each of the three time points during the first month of life, more genes were underexpressed than overexpressed in the ROP group. Fold change (FC), which was used in analysis of gene expression data, ranged between 1.0 and 1.5 in the majority of genes differentially expressed. CONCLUSION: Pathway enrichment analysis revealed that genes in four pathways related to inflammatory response were consistently downregulated due to the following variables: ROP and gestational age.