A Case of X-Linked Adrenal Hypoplasia Congenital (AHC) Due to Large Deletion of NR0B1 (DAX1) and Contiguous Gene.

X-linked adrenal hypoplasia congenita (AHC) is caused predominantly by mutations in the NR0B1 (DAX1) gene. Among these, X-linked AHC due to a large deletion of NR0B1 is extremely rare. In Korea, the first case was reported in 2005, and there have been no further documented cases since then. Herein, we report a unique case of X-linked AHC caused by an entire gene deletion that includes the NR0B1 gene and seven other genes. A seven-day-old boy presented to a pediatric endocrine clinic with prolonged postnatal jaundice, skin hyperpigmentation, hyponatremia, and hyperkalemia, suggestive of an adrenal crisis. In genetic analysis, next-generation sequencing panel for congenital adrenal hyperplasia (CAH) showed no variants. However, chromosomal microarray results revealed large deletion of Xp21.2 (29,655,007_30,765,126) including eight protein-coding genes (NR0B1, IL1RAPL1, GK, MAGEB1-4, TASL). In cases of atypical adrenal insufficiency and genetically undiagnosed CAH, NR0B1-related AHC should be suspected, as Xp21 deletion is very rare and not detected in NGS, making microarray the best option for genetic diagnosis.

Recurrent neonatal sepsis and progressive white matter injury in a premature newborn culture-positive for group B Streptococcus: A case report.

RATIONALE: Group B Streptococcus (GBS) remains a principal pathogen causing neonatal sepsis and meningitis, particularly in premature infants with relatively insufficient immunity. Recurrence may occur uncommonly, largely associated with subclinical mucosal persistence or repetitive exposure to exogenous sources. White matter injury (WMI) including cystic periventricular leukomalacia (PVL) has been associated with intrauterine infection/inflammation, and neonatal infection as a more significant predictor including postnatal sepsis and recurrent infection, even without microbial neuroinvasion. Furthermore, clinical and experimental evidence of WMI by some bacteria other than GBS without central nervous system invasion has been reported. However, there is little evidence of WMI associated with neonatal GBS sepsis in the absence of meningitis in the literature. PATIENT CONCERNS: A newborn at 30+4 weeks' gestation with low birthweight presented with 2 episodes (with a 13-day interval with no antibiotic therapy) of neonatal sepsis culture-proven for GBS with early-onset presentation after clinical chorioamnionitis via vertical GBS transmission and the associated conditions including prematurity-related neonatal immunodeficiency and persistent mucosal GBS carriage after the first antibiotic treatment. The perinatal GBS infection was complicated by progressive WMI presenting with ventriculomegaly and cystic PVL without a definite evidence of meningitis, intraventricular hemorrhage, and documented cerebral hypoxia or hypoperfusion conditions including septic shock. DIAGNOSES: Recurrent group B streptococcal sepsis and cystic PVL with ventriculomegaly. INTERVENTIONS: Two episodes of GBS sepsis were treated with 15-day parenteral antibiotic therapy, respectively. OUTCOMES: Resolution of the recurrent GBS sepsis without further relapses, however, complicated by WMI and subsequent about 6 months delay in motor development at 12 months' corrected age. LESSONS: This case suggests WMI associated with GBS bacteremia without central nervous system entry by viable GBS and also shows that in premature infants, intrauterine GBS infection with no interventions may lead to extensive and persistent GBS colonization, early-onset and recurrent GBS disease, and WMI. Postnatal as well as intrauterine infection/inflammation controls with maternal prophylaxis may be pivotal for prevention and limiting the magnitude of neurologic injury.

Portal vein thrombosis and food protein-induced allergic proctocolitis in a premature newborn with hypereosinophilia: a case report.

BACKGROUND: Peripheral blood eosinophilia is identified in numerous medical conditions associated with allergic, infectious, and inflammatory processes mostly as reactive eosinophilia with or without tissue eosinophilia. In hospitalized neonates, eosinophilia is common with an inverse relationship with gestational age and occurs solely as mild eosinophilia in the majority of cases. In the literature, eosinophilia has been proposed as a possible risk factor for venous thromboembolism. However, few reports are found on thromboembolic events including portal vein thrombosis (PVT) associated with eosinophilia in the newborn period. Neonates, particularly preterm infants, are vulnerable to thrombosis due to the immature and developing hemostatic system with little reserve capacity, which occurs as catheter-related thrombosis in most cases. CASE PRESENTATION: A male newborn at 34+ 5 weeks' gestation presented with a left portal venous thrombus and hematochezia after initial cow's milk feeding in the setting of blood hypereosinophilia for a prolonged period of time without central venous catheterization. The infant was diagnosed with PVT and food protein-induced allergic proctocolitis (FPIAP) and showed complete resolution of the conditions with expectant management with food avoidance, including the normalized eosinophil count. CONCLUSIONS: Our experience suggests that in the setting of hypereosinophilia with a prolonged duration in premature neonates, FPIAP should be suspected in case of hematochezia in otherwise healthy infants, and considering the increased thrombotic risk by the hypereosinophilia and premature newborn status, evaluation for neonatal thrombosis may be needed, including PVT with the potential risk for the more serious, but uncommon, late complications encompassing portal hypertension.

Clinical characteristics predicting abnormal brain magnetic resonance image findings in hypoxic-ischemic encephalopathy infants.

BACKGROUND: The aim of this study was to elucidate the specific clinical characteristics associated with abnormal brain magnetic resonance image (MRI) findings in hypoxic ischemic encephalopathy (HIE) infants in order to discern how to predict poorer outcomes more accurately. METHODS: A retrospective data analysis of HIE infants admitted to the neonatal intensive care unit of a tertiary hospital was performed. Baseline perinatal information and physical and neurological findings were compared in HIE infants according to the presence of abnormal brain MRI findings. RESULTS: A total of 69 infants were enrolled in the study. Of these, 48(69.6%) infants received therapeutic hypothermia, and 60(87.0%) infants presented abnormal findings on brain MRI. Decreased muscle tone and lower Apgar scores were more often observed in infants with abnormal MRI results(P<0.05). The presence of hypotonia and 1- and 5-minute Apgar scores equal to or less than the yielded cut-off values (5.5 and 7.5, respectively)were associated with a 7.23-, 9.14-, 9.78-fold increased risk of having abnormal brain MRI results. CONCLUSIONS: As muscle tone and Apgar scores were associated with abnormal brain MRI findings in HIE infants, these clinical characteristics may serve as early indicators of poor neurodevelopmental outcomes and signal the need for special attention and in-depth follow-up by MRI.

Hypotension within 1 week of life associated with poor short- and long-term outcomes in very low birth weight infants.

We examined whether hypotension in very low birth weight infants aged⩽1 week was associated with hospital morbidities and overall mortality. Further, we studied whether hypotension was associated with poor neurodevelopmental outcomes in these patients at the corrected age of 18 months. A total of 166 very low birth weight infants were studied during this period. Hospital outcomes and neurodevelopmental outcomes at the corrected age of 18 months were evaluated. Among the 166 very low birth weight infants, 95 patients (57.2%) experienced hypotension at⩽1 week and were associated with an increased incidence of morbidities and mortality. At the corrected age of 18 months, hypotension of the⩽1 week group had significantly lower scores in all three - cognitive, language, and motor - composites of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) screening tests. In addition, a multivariable logistic regression analysis showed that longer mechanical ventilation and periventricular leukomalacia were additionally associated with worse cognitive and language neurodevelopmental outcomes. Hypotension in very low birth weight infants within 1 week of life was associated with increased morbidities and overall mortality. It was also associated with an increased risk of cognitive and language outcomes.

Impact of histologic chorioamnionitis on pulmonary hypertension and respiratory outcomes in preterm infants.

We aimed to evaluate the association between the presence of histologic chorioamnionitis (HC) and development of pulmonary hypertension (PH) during neonatal intensive care unit (NICU) stay. Data of preterm infants born at 32 weeks of gestation or less were reviewed. The development of PH and other respiratory outcomes were compared according to the presence of HC. Potential risk factors associated with the development of PH during NICU stay were used for multivariable logistic regression analysis. A total of 188 infants were enrolled: 72 in the HC group and 116 in the no HC group. The HC group infants were born at a significantly shorter gestational age and lower birthweight, with a greater proportion presenting preterm premature rupture of membrane (pPROM) > 18 h before delivery. More infants in the HC group developed pneumothorax ( P = 0.008), and moderate and severe bronchopulmonary dysplasia (BPD; P = 0.001 and P = 0.006, respectively). PH in the HC group was significantly more frequent compared to the no HC group (25.0% versus 8.6%, P = 0.002). Based on a multivariable logistic regression analysis, birthweight ( P = 0.009, odds ratio [OR] = 0.997, 95% confidence interval [CI] = 0.995-0.999), the presence of HC ( P = 0.047, OR = 2.799, 95% CI = 1.014-7.731), and duration of invasive mechanical ventilation (MV) > 14 days ( P = 0.015, OR = 8.036, 95% CI = 1.051-43.030) were significant factors. The presence of HC and prolonged invasive MV in infants with lower birthweight possibly synergistically act against preterm pulmonary outcomes and leads to the development of PH. Verification of this result and further investigation to establish effective strategies to prevent or ameliorate these adverse outcomes are needed.

Echocardiographic assessment of patent ductus arteriosus in very low birthweight infants over time: prospective observational study.

BACKGROUND: We aimed to determine the echocardiographic parameters that can predict the presence of patent ductus arteriosus (PDA) and haemodynamically significant ductus arteriosus (HSDA) at different time points. METHODS: Echocardiogram was performed on postnatal days 3 and 7(D3-Echo and D7-Echo, respectively) in 71 very low birthweight infants with a median gestational age of 28.0 weeks. We first assessed the correlation between D3-Echo findings among infants with ductal patency and persistent ductal patency on D7-Echo. We subsequently assessed the correlation between D7-Echo findings and ultimate need for PDA treatment. RESULTS: Forty-nine (69.0%) infants had ductal patency on D3-Echo, and 32(65.3%) of these had persistent PDA on D7-Echo. Twenty of the latter (62.5%) underwent PDA treatment at a median chronological age of 19 days. PDA treatment was significantly correlated with DA size and DA peak-systolic-to-end-diastolic velocity(S/D) ratio on D3- and D7-Echo. Receiver operating characteristic curve analysis revealed that DA size ≥2.040 mm and S/D ratio ≥2.016 had fair sensitivity, specificity, and predictive values for PDA treatment. CONCLUSION: The significance of different echocardiographic parameters associated with future ductal patency or HSDA depends on the time of assessment. DA size and S/D ratio on day 7 are two reliable indicators of the need for future PDA treatment.

Impacts of therapeutic hypothermia on cardiovascular hemodynamics in newborns with hypoxic-ischemic encephalopathy: a case control study using echocardiography.

PURPOSE: The effects of therapeutic hypothermia (TH) on hemodynamics in newborns with hypoxic-ischemic encephalopathy (HIE) were evaluated. MATERIALS AND METHODS: Thirty-two neonates (gestational age, 39.4 ± 1.3 weeks) who had TH for HIE and echocardiographic hemodynamic assessments during TH and post-TH period were studied. Gestational-age-matched 34 healthy neonates were enrolled for comparison. RESULTS: During TH, patients had significantly decreased left ventricular cardiac output (LVCO), descending aorta blood flow (DABF), and DABF/LVCO ratio, and increased resistive index of DA compared to controls. Upper body blood flow (UBBF) remained unchanged but UBBF/LVCO ratio significantly increased during TH. Urine output decreased significantly during TH and increased after rewarming, and showed significant positive correlation with DABF/LVCO ratio. Sixteen patients (50%) showed hypoxic-ischemic (HI) lesions on brain magnetic resonance imaging (MRI) and had significantly increased UBBF/LVCO ratio during TH compared to patients without HI lesions. Patients with UBBF/LVCO ratio >55% had significantly higher risk of having HI lesions on brain MRI (odds ratio 13.0; 95% CI, 2.4-70.2). CONCLUSIONS: Decrease in cardiac output and descending aorta blood flow, and preferential cerebral redistribution of cardiac output along with an increase in systemic peripheral vascular resistance may affect systemic organ perfusion and cerebral metabolism.

Therapeutic hypothermia in infants with hypoxic-ischemic encephalopathy and reversible persistent pulmonary hypertension: short-term hospital outcomes.

AIM: Neonatal hypoxic ischemic encephalopathy (HIE) patients are at times accompanied by persistent pulmonary hypertension (PPHN), which is by itself another risk factor of adverse outcomes. We aimed to assess the outcome of therapeutic hypothermia (TH) in these patients whom we managed to reverse the shunt flow, as they are expected to be at much higher risk of adverse neurodevelopmental outcome. METHODS: We reviewed the medical records of 116 HIE infants (13 with PPHN and 103 without PPHN) who underwent TH between 2012 and 2016. We analyzed the short-term hospital outcomes and brain study results (electroencephalogram and magnetic resonance imaging) of TH in these patients. RESULTS: While infants with PPHN were significantly more likely to be outborn or have meconium aspiration syndrome, and required a longer duration of inotrope and intensive care support, electroencephalographic and brain magnetic resonance findings did not significantly differ according to PPHN status. CONCLUSION: Based on our study, the hospital outcomes of infants with HIE accompanied by reversible PPHN who underwent TH were in general not significantly graver than those not accompanied by PPHN. Our results suggest that undergoing TH may be more beneficial in HIE infants with PPHN and the risks for possible adverse effects may not be as so high.

Long-term postnatal steroid effect in very low birth weight infants.

We examined whether hydrocortisone exposure≤1week in very low birth weight infants (VLBWI) was associated with poor neurodevelopmental outcomes at corrected 18months. Further, the clinical factors associated with worse long term outcome were also evaluated. Of a total of 191 VLBWI, the clinical data for these infants relating were retrospectively collected for analysis. Among the 191 VLBWI, 115 (60.2%) infants were exposed to early postnatal hydrocortisone≤1week of life in our NICU of Seoul St. Mary's Hospital, The Catholic University of Korea between December 2012 and December 2014. The morbidities were significantly higher in the group with early hydrocortisone exposure group. At corrected age of 18months, 109/183 (59.6%) infants in the early hydrocortisone exposure group had significantly lower scores in all three (cognitive, language and motor) composites of Bayley Scales of Infant and Toddler Development III. The multivariable logistic regression analysis showed that only periventricular leukomalacia (PVL) is consistently associated with poor long-term outcomes. Our results suggest that early hydrocortisone exposure≤1week in VLBWI may not increase the risk for poor long-term outcomes compared to those not exposed. Only PVL is considered as a risk factor for poor long-term neurodevelopmental outcomes.

Timing of surgical ligation and morbidities in very low birth weight infants.

The present study examined whether early patent ductus arteriosus (PDA) surgical ligation at ≤2 weeks of life was associated with increased morbidities and mortality in very low birth weight infants (VLBWIs) who were diagnosed with hemodynamically significant (hs) PDA. Between December 2013 and December 2015, a total of 407 VLBWIs were admitted, of whom 145 (35.6%) infants were diagnosed with an hs PDA. The clinical data for these infants were retrospectively collected for analysis. Among the 145 VLBWIs with an hs PDA, 58 (40%) infants had surgical ligation for PDA; of these, 29 (50%) infants had early ligation (EL; ligation at ≤2 weeks of life) and 29 (50%) infants had late ligation (LL; ligation at ≥2 weeks of life). The mean gestational age and birth weight were significantly lower in the PDA-ligated group compared with the nonligated group. In addition, pulmonary hypertension at ≤1 week of life and neonatal seizures were significantly more prevalent in the ligated group (P < 0.05). Increased rate of ROP laser treatment, bronchopulmonary dysplasia, longer hospital stays, and longer duration of mechanical ventilation were found in ligated group (P < 0.05). However, the morbidities and mortality did not differ significantly between the EL and LL groups. Pulmonary hypertension at ≤1 week of life was significantly associated with LL (P = 0.019), which was consistently a risk factor for hs PDA ligation in our multivariable logistic regression analysis. EL was not significantly associated with increased hospital morbidities and mortality in VLBWIs with hs PDA. Pulmonary hypertension at ≤1 week of life can be a risk factor for the need for surgical ligation of hs PDA.

Changes in lactate dehydrogenase are associated with central gray matter lesions in newborns with hypoxic-ischemic encephalopathy.

PURPOSE: Biomarkers may predict neurological prognosis in infants with hypoxic-ischemic encephalopathy (HIE). We evaluated the relationship between serum lactate dehydrogenase (LDH) and brain magnetic resonance imaging (MRI), which predicts neurodevelopmental outcomes, in order to assess whether LDH levels are similarly predictive. MATERIALS AND METHODS: Medical records were reviewed for infants with HIE and LDH levels were assessed on the first (LDH1) and third (LDH3) days following birth. Receiver operating characteristic curves were obtained in relation to central gray matter hypoxic-ischemic lesions. RESULTS: Of 92 patients, 52 (56.5%) had hypoxic-ischemic lesions on brain MRI, and 21 of these infants (40.4%) had central gray matter lesions. LDH1 and LDH3 did not differ; however, the percentage change (ΔLDH%) was significantly higher in infants with central gray matter lesions (36.9% versus 6.6%, p = 0.006). With cutoffs of 187 (IU/L, ΔLDH) and 19.4 (%, ΔLDH%), the sensitivity, specificity, positive predictive value and negative predictive value were 71.4, 69.0, 40.5 and 89.1%, respectively. The relative risk was 5.57 (p = 0.001). CONCLUSION: Changes in serum LDH may be a useful biomarker for predicting future neurodevelopmental prognosis in infants with HIE.

Expanded criteria for retinopathy of prematurity screening in moderately preterm infants: Single-center pilot study.

BACKGROUND: While developed countries seek to lower the gestational age and birthweight parameters in retinopathy of prematurity (ROP) screening, older, larger infants still develop ROP in other parts of the world. The aim of this study was therefore to define criteria to identify potential ROP developers who are outliers of the common screening range. METHODS: A retrospective medical record review was performed in 147 inborn moderately preterm infants admitted to the neonatal intensive care unit during the study period. Univariate and logistic regression analysis was carried out. RESULTS: Forty-two infants developed ROP. Gestational age (31.4 ± 1.1 vs 32.4 ± 1.0 weeks, P = 0.000) and birthweight (1607.7 ± 339.4 vs 1846.4 ± 317.2 g, P = 0.000) were lower in those who developed ROP. Respiratory distress syndrome (P = 0.026) and documented sepsis (P = 0.003) were significant comorbidities on univariate analysis. Inotrope need >72 h starting in the first week of life (P = 0.004; OR, 5.181) and more than three transfusions of packed red blood cells (P = 0.028; OR, 3.891) were also significant, both on univariate and multivariate analysis. CONCLUSIONS: In moderately preterm infants, status should be evaluated in order to effectively select candidates for ROP screening without missing potential ROP developers.

The hospital outcomes compared between the early and late hypothermia-treated groups in neonates.

BACKGROUND AND OBJECTIVE: The incidence of hypoxic ischemic encephalopathy (HIE) in developed countries is estimated to be 1.5 per 1000 live births. The primary aim of this study was to analyze whether earlier hypothermia (≤1 h) improves hospital outcomes in survivors who underwent therapeutic hypothermia (TH) when compared with late TH (>1 h). METHOD: Forty-nine (70%) newborns received TH for 72 h, within 6 h of birth; the remaining 21 received standard care. We divided the TH-treated newborns into early and late groups; early cooling was considered when TH was started ≤1 h after birth; late cooling was considered when started >1 h. RESULTS: The early TH group consisted of 20 of 49 (41%) infants; the late TH group consisted of 29 (59%) infants. Apgar score at 1 min and the initial calcium level was significantly lower in the early (≤1 h) TH infants; there were significantly more inborns in the early TH group (p = 0.008). Infants in the late TH group manifested more clinical seizures followed by more abnormal EEG findings, longer ventilator care and longer hospitalization (p = 0.001). TH-related complications and mortality were not significantly different between the two groups. CONCLUSIONS: Early TH (≤1 h) had lower Apgar score at 1 min and initial calcium level, but had decreased incidence of clinico-electrical seizures among HIE infants. Also, ventilator support and hospitalization period were longer in the late TH group.

Risk factor profile of massive pulmonary haemorrhage in neonates: the impact on survival studied in a tertiary care centre.

OBJECTIVE: Pulmonary haemorrhage (PH) in neonates is a fatal event leading to hazardous complications and even death. The aim of this study was to elucidate influential factors of the ultimate disease course that affect death or survival. METHODS: Infants treated for PH in our institution from March 2009 to December 2013 were retrospectively reviewed. Infants transferred from other hospitals were excluded. Infants were grouped into two categories, deceased or survived at neonatal intensive care unit discharge. Information regarding perinatal history, initial management and laboratory results were obtained and analysed for each group. RESULTS: Seventy infants fulfilled the inclusion criteria, 41 infants in the deceased group and 29 infants in the survived group. Overall, the infants in the deceased group displayed lower gestational age (27 and 1/7 ± 3.610 versus 29 and 3/7 ± 3.530 weeks, p = 0.009) and lower one-minute (2.342 ± 1.493 versus 4.035 ± 2.079, p < 0.001) and five-minute Apgar scores (2.342 ± 1.493 versus 4.035 ± 2.079, p < 0.001) and required aggressive resuscitation (p = 0.003) and a greater number of inotropes (2.195 ± 1.346 versus 1.069 ± 0.704, p < 0.001). Deceased infants were administered increased amounts of fluid during the first 24 h after birth (117.783 ± 32.325 versus 99.379 ± 17.728 mL/kg, p = 0.004). A relatively short prothrombin time impacted survival (p = 0.01), whereas platelet count was the only factor that significantly affected the time length from the onset of PH to death (p = 0.01). CONCLUSION: Infants with a lower gestational age in a compromised state are prone to die once PH develops. The initial management of fluid intake not to exceed the adequate limit is especially important in order to prevent PH-related deaths when correcting hypoalbuminemia and coagulopathy.

Outcomes of primary ligation of patent ductus arteriosus compared with secondary ligation after pharmacologic failure in very-low-birth-weight infants.

This study aimed to determine whether primary surgical closure of patent ductus arteriosus (PDA) is a risk factor for morbidity and mortality compared with secondary surgical ligation. The study enrolled 178 very-low-birth-weight infants. The surgical group included 34 patients who did not respond to pharmacologic intervention and eventually required ligation of their PDA as well as 35 patients who underwent direct ligation because of contraindications to the use of oral ibuprofen. The overall outcomes for the primary and secondary ligation groups were compared. The outcome during hospitalization showed no statistically significant difference in terms of morbidity and mortality between the two groups. The group that had primary ligation for PDA experienced more complications associated with premature birth such as lower gestational age and birth weight. The two groups did not differ significantly in terms of overall outcomes.