Clinical findings in 39 individuals with Bohring-Opitz syndrome from a global patient-driven registry with implications for tumor surveillance and recurrence risk.

Bohring-Opitz syndrome (BOS) is a rare genetic condition caused by pathogenic variants in ASXL1, which is a gene involved in chromatin regulation. BOS is characterized by severe intellectual disabilities, distinctive facial features, hypertrichosis, facial nevus simplex, severe myopia, a typical posture in infancy, variable anomalies, and feeding issues. Wilms tumor has also been reported in two individuals. We report survey data from the largest known cohort of individuals with BOS with 34 participants from the ASXL Patient-Driven Registry and data on five additional individuals with notable findings. Important or novel findings include hepatoblastoma (n = 1), an additional individual with Wilms tumor, two families with a parent who is mosaic including a pair of siblings, birth weights within the normal range for the majority of participants, as well as presence of craniosynostosis and hernias. Data also include characterization of communication, motor skills, and care level including hospitalization frequency and surgical interventions. No phenotype-genotype correlation could be identified. The ASXL Registry is also presented as a crucial tool for furthering ASXL research and to support the ASXL community.

Magnetic resonance venography to evaluate cerebral sinovenous thrombosis in infants receiving therapeutic hypothermia.

BACKGROUND: The incidence of cerebral sinovenous thrombosis (CSVT) in infants receiving therapeutic hypothermia for neonatal encephalopathy remains controversial. The aim of this study was to identify if the routine use of magnetic resonance venography (MRV) in term-born infants receiving hypothermia is associated with diagnostic identification of CSVT. METHODS: We performed a retrospective review of 291 infants who received therapeutic hypothermia from January 2014 to March 2020. Demographic and clinical data, as well as the incidence of CSVT, were compared between infants born before and after adding routine MRV to post-rewarming magnetic resonance imaging (MRI). RESULTS: Before routine inclusion of MRV, 209 babies were cooled, and 25 (12%) underwent MRV. Only one baby (0.5%) was diagnosed with CSVT in that period, and it was detected by structural MRI, then confirmed with MRV. After the inclusion of routine MRV, 82 infants were cooled. Of these, 74 (90%) had MRV and none were diagnosed with CSVT. CONCLUSION: CSVT is uncommon in our cohort of infants receiving therapeutic hypothermia for neonatal encephalopathy. Inclusion of routine MRV in the post-rewarming imaging protocol was not associated with increased detection of CSVT in this population. IMPACT: Cerebral sinovenous thrombosis (CSVT) in infants with NE receiving TH may not be as common as previously indicated. The addition of MRV to routine post-rewarming imaging protocol did not lead to increased detection of CSVT in infants with NE. Asymmetry on MRV of the transverse sinus is a common anatomic variant. MRI alone may be sufficient in indicating the presence of CSVT.

Amplitude-Integrated Electroencephalography Evolution and Magnetic Resonance Imaging Injury in Mild and Moderate to Severe Neonatal Encephalopathy.

OBJECTIVE: This study aimed to describe the evolution of amplitude-integrated electroencephalography (aEEG) in neonatal encephalopathy (NE) during therapeutic hypothermia (TH) and evaluate the association between aEEG parameters and magnetic resonance imaging (MRI) injury. STUDY DESIGN: aEEG data of infants who underwent TH were reviewed for background, sleep wake cycling (SWC), and seizures. Conventional electroencephalography (cEEG) background was assessed from the reports. Discordance of background on aEEG and cEEG was defined if there was a difference in the severity of the background. MRI injury (total score ≥ 5) was assessed by using the Weeke scoring system. RESULTS: A total of 46 infants were included; 23 (50%) with mild NE and 23 (50%) with moderate to severe NE. Comparing mild NE with moderate to severe NE, the initial aEEG background differed with more mild being continuous (70 vs. 52%), with fewer being discontinuous (0 vs. 22%) and flat tracing (0 vs. 4%), whereas burst suppression (4 vs. 4%) and low voltage (26 vs. 18%) did not differ. There was a notably common discordance between the background assessment on cEEG with aEEG in 82% with continuous and 40% low voltage aEEG background. MRI abnormalities were identified in four infants with mild NE and seven infants with moderate to severe NE. MRI injury was associated with aEEG seizures in infants with moderate to severe NE. CONCLUSION: aEEG seizures are useful to predict MRI injury in moderate to severe NE infants. There is a large discrepancy between aEEG, cEEG, and MRI in neonates treated by TH. KEY POINTS: · MRI injury was identified in 29% of moderate NE infants and in 50% of severe NE infants.. · aEEG seizures were associated with MRI injury in the moderate to severe NE infants.. · MRI injury was identified in 16% infants with mild NE.. · Mild NE infants with normal aEEG were unlikely to have MRI injury.. · There was a large discrepancy between aEEG, cEEG, and MRI in infants treated by TH..

Differences in standardized neonatal encephalopathy exam criteria may impact therapeutic hypothermia eligibility.

BACKGROUND: Therapeutic hypothermia (TH) is routinely provided to those with moderate or severe neonatal encephalopathy (NE). Subtle differences exist in the standardized exams used to define NE severity. We aimed to assess if an infant's TH eligibility status differed if they were evaluated using either the NICHD/Neonatal Research Network's (NICHD-NRN) or TOBY/British Association of Perinatal Medicine's (TOBY-BAPM) neurological exam. METHODS: Encephalopathic infants ≥36 weeks with evidence of perinatal asphyxia and complete documentation of the neurological exam <6 h of age were included. TH eligibility using the NICHD-NRN and TOBY-BAPM criteria was determined based upon the documented exams. RESULTS: Ninety-one encephalopathic infants were included. Despite good agreement between the two exams (κ = 0.715, p < 0.001), TH eligibility differed between them (p < 0.001). A total of 47 infants were deemed eligible by at least one method-46 using NICHD-NRN and 35 using TOBY-BAPM. Of the 12 infants eligible per NICHD-NRN, but ineligible per TOBY-BAPM, two developed electrographic seizures and seven demonstrated hypoxic-ischemic cerebral injury. CONCLUSIONS: Both the NICHD-NRN and TOBY-BAPM exams are evidence-based. Despite this, there is a significant difference in the number of infants eligible for TH depending on which exam is used. The NICHD-NRN exam identifies a greater proportion as eligible. IMPACT: There are subtle differences in the NICHD-NRN and TOBY-BAPM's encephalopathy exams used to determine eligibility for TH. This results in a significant difference in the proportion of infants determined to be eligible for TH depending on which encephalopathy exam is used. The NICHD-NRN encephalopathy exam identifies more infants as being eligible for TH than the TOBY-BAPM encephalopathy exam. This may result in different rates of cooling depending on which evidence-based neurological exam for evaluation of encephalopathy a center uses.

The U.S. National Trend for Retinopathy of Prematurity.

OBJECTIVE: The use of supplemental oxygen in premature infants is essential for survival. However, its use has been associated with unintended complications. The restricted use of oxygen is associated with increased mortality and necrotizing enterocolitis (NEC), whereas its liberal use is associated with increased risk for retinopathy of prematurity (ROP). Although there is no clear consensus on the acceptable oxygen saturation range, clinicians have recently become more liberal with the use of oxygen. We aim to assess (1) the national trends for ROP in very low birth weight preterm infants, and (2) the associated trends in mortality, NEC, intraventricular hemorrhage (IVH), and length of hospital stay (LOS). STUDY DESIGN: We analyzed deidentified patient data from the National Inpatient Sample (NIS) of the Healthcare Cost and Utilization Project (HCUP) from 2002 to 2017. All infants with gestational age ≤32 weeks and birth weight <1,500 g were included. Trends in ROP, severe ROP, mortality, NEC, IVH, severe IVH, and LOS were analyzed using Jonckheere-Terpstra test. RESULTS: A total of 818,945 neonates were included in the study. The overall mortality was 16.2% and the prevalence of ROP was 17.5%. There was a significant trend for increased ROP over the years (p < 0.001). Severe ROP was also significantly increased (p < 0.001). This was associated with a significant trend for increased median LOS in survived infants (p < 0.001). Mortality was significantly decreased (p < 0.001), whereas NEC and severe NEC did not change over time (p = 0.222 and p = 0.412, respectively). CONCLUSION: There is a national trend for increased ROP and severe ROP over the 16 years of the study period. This trend was associated with a significant increase in the LOS in survived infants without change in NEC. KEY POINTS: · Prevalence of ROP and severe ROP has increased in VLBW infants over the 16-year study period.. · The prevalence of NEC did not change over the same time period.. · Increased ROP and severe ROP were consistent in all three GA and BW subgroups..

Late onset oxygen requirement following neonatal therapeutic hypothermia.

AIM: To investigate the characteristics of infants with neonatal encephalopathy (NE) receiving therapeutic hypothermia (TH) who developed late onset oxygen requirement during or after rewarming. METHODS: Infants were stratified by receiving (a) new onset isolated oxygen requirements during or after rewarming; (b) no respiratory support during hospital stay; and (c) invasive and/or non-invasive respiratory support before or during cooling. RESULTS: Of 136 infants treated with TH, 49 (36%) did not require any respiratory support, and 78 (57.4%) received invasive or non-invasive support before or during cooling. Nine infants (6.6%) developed late onset oxygen requirement. The late onset oxygen requirement started at median age of 3.8 days (IQR 3.6-5.2) and ended at median 7.5 days (IQR 5.8-12.7). Total hours of O2 exposure were median 62.0 (IQR 24.4-112.6). Maximum support was low-flow nasal cannula from 100% oxygen source with a flow rate of 40-250 mL/min. Infants in this group had higher Apgar scores, milder metabolic acidosis and no seizures. Three infants had diagnostic investigations without significant findings. CONCLUSION: A small percentage of neonates with NE developed late onset oxygen requirement during or after rewarming. Late oxygen requirement was associated with evidence of less severe perinatal hypoxia-ischaemia.

Hypocapnia in early hours of life is associated with brain injury in moderate to severe neonatal encephalopathy.

OBJECTIVE: To evaluate the association between hypocapnia within the first 24 h of life and brain injury assessed by a detailed MRI scoring system in infants receiving therapeutic hypothermia (TH) for neonatal encephalopathy (NE) stratified by the stage of NE. STUDY DESIGN: This retrospective cohort study included infants who received TH for mild to severe NE. RESULTS: 188 infants were included in the study with 48% having mild and 52% moderate-severe NE. Infants with moderate-severe NE spent more time in hypocapnia (PCO2 ≤ 35 mmHg) and presented with more severe brain injury on MRI compared to mild cases. The MRI injury score increased by 6% for each extra hour spent in hypocapnic range in infants with moderate-severe NE. There was no association between hypocapnia and injury scores in mild cases. CONCLUSION: In infants with moderate-severe NE, the hours spent in hypocapnia was an independent predictor of brain injury.

Comparison of numerical and standard sarnat grading using the NICHD and SIBEN methods.

OBJECTIVE: The NICHD and SIBEN assessments are adapted from the Sarnat grade, and used to determine severity of neonatal encephalopathy (NE). We compare NICHD and SIBEN methods, and their ability to define a minimum threshold associated with significant cerebral injury. STUDY DESIGN: Between 2016 and 2019, 145 infants with NE (77-mild; 65-moderate; 3-severe) were included. NICHD and SIBEN grade and numerical scores were assigned. Kappa scores described agreement between methods, and ROC curves their ability to predict MR injury. RESULTS: Good agreement existed between grading systems (K = 0.86). SIBEN defined more infants as moderate, and less as mild, than NICHD (p < 0.001). Both numerical scores were superior to standard grades in predicting MR injury. CONCLUSION: Despite good agreement between methods, SIBEN defines more infants as moderate NE. Both numerical scores were superior to standard grade, and comparable to each other, in defining a minimum threshold for cerebral injury. Further assessment contrasting their predictive ability for long-term outcome is required.

Association of early cerebral oxygen saturation and brain injury in extremely preterm infants.

OBJECTIVE: To assess the association between cerebral saturation (crSO2) using Near-Infrared Spectroscopy (NIRS) and brain injury in extremely preterm infants. STUDY DESIGN: This retrospective study includes 62 infants (<28 weeks gestation) who underwent continuous NIRS monitoring in the first 5 days after birth. Median crSO2 were compared in 12 h increments between infants with and without germinal matrix/intraventricular hemorrhage (GM/IVH). crSO2 was also compared by IVH severity, onset, and by grade of injury on term equivalent MRI. RESULTS: After 48 h of life (HOL), infants with GM/IVH had significantly lower crSO2 than those without GM/IVH in analysis adjusted for potential confounding e.g., at 49-60 HOL (69.5 (66.2, 72.8) vs. 74.7 (71.8, 77.6), p = 0.023). There were no significant differences in crSO2 by IVH subcategory or injury severity on MRI. CONCLUSION: Clinical use of NIRS has the potential to identify crSO2 patterns associated with development of GM/IVH.

Diffuse correlation spectroscopy blood flow monitoring for intraventricular hemorrhage vulnerability in extremely low gestational age newborns.

In premature infants with an extremely low gestational age (ELGA, < 29 weeks GA), dysregulated changes in cerebral blood flow (CBF) are among the major pathogenic factors leading to germinal matrix/intraventricular hemorrhage (GM/IVH). Continuous monitoring of CBF can guide interventions to minimize the risk of brain injury, but there are no clinically standard techniques or tools for its measurement. We report the feasibility of the continuous monitoring of CBF, including measures of autoregulation, via diffuse correlation spectroscopy (DCS) in ELGA infants using CBF variability and correlation with scalp blood flow (SBF, served as a surrogate measure of systemic perturbations). In nineteen ELGA infants (with 9 cases of GM/IVH) monitored for 6-24 h between days 2-5 of life, we found a strong correlation between CBF and SBF in severe IVH (Grade III or IV) and IVH diagnosed within 72 h of life, while CBF variability alone was not associated with IVH. The proposed method is potentially useful at the bedside for the prompt assessment of cerebral autoregulation and early identification of infants vulnerable to GM/IVH.