Clinical features and genetic variations of severe neonatal hyperbilirubinemia:Five case reports

BACKGROUND Neonatal hyperbilirubinemia is a common problem faced by pediatricians.The role of genetic factors in neonatal jaundice has been gradually recognized.This study aims to identify genetic variants that influence the bilirubin level in five patients using next-generation sequencing(NGS).CASE SUMMARY Five neonates with severe hyperbilirubinemia were retrospectively studied.They exhibited bilirubin encephalopathy,hypothyroidism,ABO blood type incompatibility hemolysis,glucose-6-phosphate dehydrogenase(G6PD)deficiency and premature birth,respectively.A customized 22-gene panel was designed,and NGS was carried out for these neonates.Eight variations(G6PD c.G1388A,HBA2 c.C369G,ABCC2 c.C3825G,UGT1A1 c.G211A,SPTB c.A1729G,EPB41 c.G520A,c.1213-4T>G and c.A1474G)were identified in these five neonates.Genetic mutations of these genes are associated with G6PD deficiency,thalassemia,Dubin-Johnson syndrome,Gilbert syndrome,hereditary spherocytosis,and hereditary elliptocytosis.One of the neonates was found to have compound variants of the EPB41 splice site c.1213-4T>G and c.G520A(p.E174K),but no elliptocyte was seen on his blood smear of 4 years old.CONCLUSION Pathological factors of severe neonatal hyperbilirubinemia are complicated.Genetic variants may play an important role in an increased risk of neonatal hyperbilirubinemia,and severe jaundice in neonates may be related to a cumulative effect of genetic variants.

Intensive phototherapy vs.exchange transfusion for the treatment of neonatal hyperbilirubinemia:a multicenter retrospective cohort study

Background:Intensive phototherapy(IPT)and exchange transfusion(ET)are the main treatments for extreme hyperbilirubinemia.However,there is no reliable evidence on determining the thresholds for these treatments.This multicenter study compared the effectiveness and complications of IPT and ET in the treatment of extreme hyperbilirubinemia.Methods:This retrospective cohort study was conducted in seven centers from January 2015 to January 2018.Patients with extreme hyperbilirubinemia that met the criteria of ET were included.Patients were divided into three subgroups(low-,medium-,and high-risk)according to gestational week and risk factors.Propensity score matching(PSM)was performed to balance the data before treatment.Study outcomes included the development of bilirubin encephalopathy,duration of hospitalization,expenses,and complications.Mortality,auditory complications,seizures,enamel dysplasia,ocular motility disorders,athetosis,motor,and language development were evaluated during follow-up at age of 3 years.Results:A total of 1164 patients were included in this study.After PSM,296 patients in the IPT only group and 296 patients in the IPT plus ET group were further divided into the low-,medium-,and high-risk subgroups with 188,364,and 40 matched patients,respectively.No significant differences were found between the IPT only and IPT plus ET groups in terms of morbidity,complications,and sequelae.Hospitalization duration and expenses were lower in the low-and medium-risk subgroups in the IPT only group.Conclusions:In this study,our results suggest that IPT is a safe and effective treatment for extreme hyperbilirubinemia.The indication of ET for patients with hyperbilirubinemia could be stricter.However,it is necessary to have a contingency plan for emergency ET as soon as IPT is commenced especially for infants with risk factors.If IPT can be guaranteed and proved to be therapeutic,ET should be avoided as much as possible.

Semi-Quantitative Analysis of Brain MR Imaging in 76 Cases of Neonatal Indirect Hyperbilirubinemia

Background: Neonatal hyperbilirubinemia is indeed common. However, severe nerve injuries and bilirubin encephalopathy are rare and only occur in the unusual cases of extreme hyperbilirubinemia. Objectives: To investigate brain magnetic resonance imaging (MRI) changes and their correlations with perinatal predisposing factors in neonates with indirect hyperbilirubinemia, via regions of interest (ROIs) analysis. Methods: Seventy-six neonates with a gestational age of ≥35 weeks diagnosed with neonatal indirect hyperbilirubinemia or bilirubin encephalopathy all underwent brain MRI during hospitalization. Depending on peak total serum bilirubin (TSB), they were assigned to group A (<221 μmol/L), B (≥221 μmol/L μmol/L), C (≥42 μmol/L μmol/L), or D (≥428 μmol/L). The globus pallidus and the white matter around the anterior horn of the lateral ventricle and posterior horn of the lateral ventricle were selected as the ROIs. Average optical densities (AODs) of the ROIs and the cerebrospinal fluid region were measured. The ratio between the AODs was designated as the relative optical density (ROD), and used to determine relative signal intensity. Results: RODs of the globus pallidus were significantly lower in group D than in all other groups. TSB and the ratio of TSB to serum albumin concentration (B/A) was significantly negatively correlated with ROD in theglobus pallidus. Corrected age was significantly negatively correlated with the ROD of the ROIs. Conclusions: Semi-quantitative image analysis is a feasible method to assess conventional brain MRI for neonatal indirect hyperbilirubinemia. The signal intensity of the globus pallidus in T1-weighted images was significantly correlated with TSB level and B/A.

EXPERIMENTAL AND CLINICAL STUDY ON BILIRUBIN NEUROTOXICITY DETECTED BY VISUAL EVOKED POTENTIALS TO FLASH

Objective Evaluate the sensitivity and reliability of visual evoked potential to flash (F-VEP) in detecting bilirubin neurotoxicity and approach the risk parameters of bilirubin neurotoxicity in hyper-bilirubinemia newborns. Methods Based on the successful establishment of animal models for acute bilirubin encephalopathy by intraperitoneal infusion of bilirubin with a dosage of 100～200μg/g body weight to 1-week-old guinea pigs, the F-VEP was recorded in animal models and human neonates with hyperbilirubinemia, and the sensitivity and reliability of F-VEP in detecting bilirubin neurotoxicity were evaluated. Results F-VEP features and its P1 latency significantly correlated to brain adenosine triphosphate (ATP) level, neurobeha-vioral and neuropathological changes in experimental bilirubin encephalopathy; neonates with hyperbiliru-binemia showed significant F-VEP changes characterized by absence of P1 or P1 latency prolonged in 1～7-day-old newborns, especially when the jaundice was caused by immun oincompatibility and infectious diseases. Conclusion F-VEP would be a good discriminator for bilirubin neurotoxicity, and can become a promising technique in monitoring bilirubin encephalopathy.

新生儿高胆红素血症神经毒性机制及其干预

高胆红素血症是新生儿期的常见疾病，其主要并发症之一为胆红素脑病。未结合胆红素可通过血脑屏障造成神经系统损伤。听觉中枢对胆红素高度敏感，听觉核团受累后可出现听力下降甚至失聪、言语分辨率下降等临床表现。目前，由于胆红素神经毒性机制尚未完全明确，因此临床上对胆红素脑病缺乏有效且可靠的药物治疗方法。探索胆红素神经毒性机制及其防治的研究有望为胆红素脑病患儿的康复提供新的希望。