Background：Most of systematic review or metaanalysis of neonates with moderatetosevere hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia were published before 2012, and then several RCT studies have been completed. This systematic review and metaanalysis is part of Evidencebased Treatment Guidelines for Hypoxic and Ischemic Encephalopathy in Fullterm Children (2022).
Objective：To study the longterm neurological outcomes of hypothermia alone and hypothermia plus agents for moderate to severe HIE.
Design：Systematic review and metaanalysis.
Methods：English literature was searched in PubMed, Embase, Cochrane and CINAHL from the establishment of databases to November 12, 2021 and Chinese literature was searched in SinoMed from the establishment to December 6, 2021. Literature was selected through preliminary screening by reading titles and abstracts and rescreening by reading full texts. Exclusion criteria for rescreening (meeting one of the following option) included: a. Neonates were with congenital malformations; b. Hypothermia occurred beyond 12 h after birth; c. The core temperature was not between 33℃35.0℃ during the treatment or hypothermia did not last for 72 hours; d. The followup was less than 18 months in the hypothermia group or less than 12 months in the hypothermia plus agents group. e. Hypothermia is not taken as the intervention. GRADE was used to evaluate the evidence system. Metaanalysis was performed using Revman 5.4 and R. Publication bias was analyzed for the evidence body with more than 10 articles. Main outcome measures：The incidence of death and longterm major neurodevelopmental outcome after the 18month followup.
Results：Fourteen articles of hypothermia were enrolled in the analysis, including 13 RCTs and 1 NRSI, involving 1 091 neonates in the intervention group (hypothermia) and 1 087 neonates in the control group (supportive care). Selective head cooling (SHC) and whole body cooling (WBC) were in 6 articles and 8 articles respectively. Followup were completed from 18 to 30 months in 13 articles, and 6 to 7 years in 1 article. Hypothermia significantly decreased the incidence of death and / or moderate to severe disability by 27% (RR=0.73，95%CI：0.670.80，I2=0，P＜0.01), including moderate encephalopathy (by 41%), severe encephalopathy (by 19%), SHC (by 30%), WBC (by 25%), cerebral palsy (by 36%), but did not reduce the incidence of hearing and visual impairment. There was no significant difference in the incidence of adverse effects including arrhythmia, severe hypotension, abnormal coagulation, thrombocytopenia, persistent pulmonary hypertension, sepsis, venous thrombosis and skin breakage without deleterious consequences. Ten articles of hypothermia plus agents were enrolled in the analysis, including EPO (4 articles), xenon (2 articles), stem cells (2 articles), melatonin (1 article) and topiramate (1 article). Followup were completed more than 18 months in 3 articles between the hypothermia and the control group (supportive care). There was no significant difference in the incidence of death and disability between hypothermia plus melatonin or topiramate or xenon and hypothermia alone (RR=1.08, 95%CI: 0.591.98, P=0.80). Conclusion：Therapeutic hypothermia reduced the risk of death and neurological disability of neonates with moderate to severe hypoxic ischemic encephalopathy by 27%. Further research of hypothermia combined with agents is needed.
Background：Mild neonatal hypoxic-ischemic encephalopathy (HIE) has been considered to have better long-term outcomes. In recent years, there was evidence that the long-term outcomes of mild HIE were worse than those of normal children.
Objective：To explore whether mild neonatal HIE benefits from hypothermia therapy.
Design：Systematic review and meta-analysis.
Methods：Literature was searched in databases of PubMed, Embase, Cochrane, CINAHL from the establishment to Dec 6,2021, and in database of SinoMed from the establishment to Nov 12, 2021. Retrieved papers were first screened by titles and abstracts. A second phase of screening was subsequently undertaken to screen papers for exclusion criteria as follows either: a. the diagnosis of mild neonatal HIE failing to meet the modified Sarnat standard; b. neonates with congenital malformations; c. failure to extract the outcome data of neonatal mild HIE; d. the follow-up time <12 months. GRADE methodology was used to rate the quality of evidence body. Publication bias analysis was adopted for more than 10 articles in either evidence body, and extracted data were analyzed using Revman 5.4 and R. The I2 test was used for heterogeneity. If I2≤50%, the fixed effect model should be adopted; if I2>50%, the random effect model should be adopted.
Main outcome measures：Rate of death and major neurodevelopmental disabilities at more than 12 months.
Results：1,839 articles were identified through database searching. A total of 113 full-text articles were assessed for eligibility and 24 articles were included in this review. The review was conducted for 4 RCTs, 7 cohort studies, and 13 case series reports. A total of 21 literature reported nervous system disability by dichotomous variables, and three literature reported nervous system disability by continuous ones. Follow-up time in 16 articles was from 12 months to 3 years, and 9 articles over 3 years (1 article reported neurological disability at 24 months and 7 years old respectively). No deaths were reported in the 24 articles during the observation period. A total of 369 infants with mild neonatal HIE was reported in 21 articles with dichotomous variables and the results showed that the incidence of major neurodevelopmental disabilities in mild HIE survivors was 21% (95%CI: 0.14-0.29), I2=80%, and there was publication bias (Egger test, t=4.68, P<0.01). The incidence of major neurodevelopmental disabilities was 11% (95%CI: 0.00-0.23) on therapeutic hypothermia (6 articles) and 21 percent (95%CI: 0.13-0.29) on non-therapeutic hypothermia (19 articles). There was no difference (OR=0.78, 95%CI: 0.27-2.31, I2=0) in the incidence of major neurodevelopmental disabilities between mild HIE patients treated with therapeutic hypothermia and those not treated with therapeutic hypothermia (4 RCTs), and patients who received non-therapeutic hypothermia compared with normal children (4 cohort studies) had higher incidence of major neurodevelopmental disabilities (OR=19.06, 95%CI: 7.01-51.85, I2=42%). The incidence of neurological disability was 20 percent (95%CI: 11%-29%) in subgroups whose follow-up time was from 12 months to 3 years and 24 percent (95%CI: 11%-36%) in over 3 years.
Conclusion：When patients diagnosed with mild HIE was followed up until the age of 3 years old, the potential incidence of major neurodevelopmental disabilities increased to 24%, and benefits of combining with support treatment of therapeutic hypothermia as auxiliary is greater than the disadvantages.
Background：Currently, there are differences in the outcomes of risk-stratified treatment in pediatric acute T lymphocytic leukemia (T-ALL).
Objective：To explore the association between biological characteristics and clinical features, early treatment responses and longterm outcomes of pediatric T-ALL.
Design：Retrospective cohort study.
Methods：The immunophenotypic markers and fusion genes at diagnosis and its association with clinical features, early treatment response and long-term outcomes of T-ALL patients treated with CCLG-ALL-2008 protocol in Beijing Children's Hospital affiliated to Capital Medical University from March 2008 to September 2018 were retrospectively analyzed.
Main outcome measures：Event free survival (EFS) and overall survival (OS). Results：A total of 101 children with T-ALL were enrolled, including 76 males (75.25%). SIL-TAL1 was the most common fusion gene (21.8%, 22/101) and the proportion of patients classified into high-risk of SIL-TAL1+ was significantly higher than that of SIL-TAL1-. The expression rate of stem cell marker CD34 was 45.5% (46/101). The expression of CD2 was associated with high peripheral white blood cell; the expression of CD34 was associated with poor prednisone response and high minimal residual disease (MRD) at day 15; the expression of CD33 was associated with morphological non-remission and high MRD at the end of induction; while the expression of CD10 was associated with good prednisone response. By K-M analysis, positive SIL-TAL1, poor response to prednisone treatment, non-remission of bone marrow morphology on day 15, high MRD at day 33 and classification of high-risk were associated with adverse EFS and OS (P＜0.05 respectively) . Furthermore, MRD≥1% at day 33 and SIL-TAL1 positive were also validated as independent prognostic factors for EFS and OS. The hazard ratios of MRD ≥1% at day 33 for EFS was 1.96 (95%CI: 1.114-3.452, P=0.020) and for OS was 2.062 (95%CI: 1.138-3.734, P=0.017); SIL-TAL1+ for EFS was 2.536 (95%CI: 1.053-6.104, P=0.038) and for OS was 2.921 (95%CI: 1.144-7.457, P=0.025).
Conclusion：T-ALL is a group of heterogeneous diseases. SIL-TAL1 and early MRD can predict the long-term prognosis on the MRD based treatment protocol.
Background：Intrahepatic cholestasis of pregnancy (ICP) may lead to adverse neonatal outcomes.
Objective：To investigate the risk factors of Neonatal Intensive Care Unit (NICU) admission of newborns delivered by mothers with ICP within 24 hours after birth.
Design：Singlecenter casecontrol study.
Methods：From January 2015 to December 2019, the newborns whose mothers gave birth to a single baby at Maternal and Child Health Hospital of Chongiqng Yongchuan District and were diagnosed with ICP were selected as the study subjects. According to whether they were admitted to NICU within 24 hours of life, they were divided into NICU admission group and nonNICU admission group. Sample size was estimated that 131 newborns would be needed at least in each group. The clinical data of mothers and newborns were retrospectively analyzed, and the risk factors of NICU admission within 24 hours of life were analyzed by binary logistic regression model. Receiver operating characteristic (ROC) curve was used to predict the the independent risk for the NICU admission factors. Main outcome measures：The risk factors and predictive factors of NICU admission of newborns delivered by mothers with ICP within 24 hours of life.
Results：A total of 621 newborns (308 males) delivered by mothers with ICP were included. The average gestational age was 38.3 (37.0, 39.3) weeks, and the average birth weight was 3 148±461 g. There were 133 (21.4%) newborns admitted to NICU within 24 hours of life because of preterm(n=78), respiratory distress(n=20), hypoglycemia, poor response, infection and 488 newborns were not admitted to NICU. Compared with the nonNICU admission group, the gestational age, birth weight, 5 min Apgar score and gestational age at diagnosis of the NICU admission group were lower, and the ALT, AST, bile acid of last test, and preterm of the NICU admission group were higher, and the differences were statistically significant. One (0.16%) newborn died at followup within 28 days of life. Logistic regression analysis showed that small gestational age (OR=0.378, 95%CI: 0.3010.474, P<0.001), itch (OR=2.410, 95%CI: 1.4114.114, P=0.001), high bile acid (OR=1.016, 95%CI: 1.0031.028, P=0.012) and low BMI before pregnancy (OR=0.930, 95%CI: 0.8730.990, P=0.023) were the risk factors of NICU admission. The predictive factors of NICU admission of newborns delivered by mothers with ICP within 24 hours of life were as the follow: a. When those mothers were combined with itch, the sensitivity was 96.7% (95%CI: 90.8%99.3%) for the combination of gestational age (the optimal cutoff: ≤36.6 weeks), maternal bile acid (the optimal cutoff: >20 umol·L-1) and BMI before pregnancy (the optimal cutoff: ≤24 kg·m-2); b. When those mothers were not with itch, the sensitivity was 78.0% (95%CI: 62.4%82.4%) for the combination of gestational age (the optimal cutoff: ≤36.5 weeks), maternal bile acid (the optimal cutoff: >26.8 umol·L-1) and BMI before pregnancy (the optimal cutoff: ＞24 kg·m-2).
Conclusion：Small gestational age, itch, high bile acid level and low BMI before pregnancy of the mother were independent risk factors for NICU admission of newborns delivered by mothers with ICP. When those mothers were with itch, the sensitivity was 96.7% for the prediction of NICU admission through the combination of gestational age ≤36.6 weeks, maternal bile acid >20 umol·L-1 and BMI before pregnancy ≤24 kg·m-2.
Background：Childhood nonalcoholic fatty liver disease (NAFLD) can significantly increase the risk of cardiovascular disease in adults, however, the studies investigating the NAFLD prevalence in general children and adolescents were scarce and the longterm tendencies of NAFLD prevalence is unclear.
Objective：To assess the trend of NAFLD prevalence in children and adolescents. Design：A cross-sectional survey.
Methods：Resident students aged 11-17 years who annually participated in the 20142020 routine health checks in Shanghai, Minhang District were included for the analysis. Suspected NAFLD was defined by the elevation of 97.5 percentile of alanine aminotransferase (ALT) levels according to the age and sexspecific reference intervals for the healthy children. The general obesity and abdominal obesity were defined by the body mass index (BMI) and waist according to the China national standards for pediatric population. The annual prevalence change of NAFLD was depicted by calculating the average annual percentage change (AAPC) and 95% confidence intervals (CIs). We used logistic regression by adjusting BMI and waist circumference to assess the temporal trend of NAFLD prevalence over years.
Main outcome measures：NAFLD prevalence.
Results：The overall NAFLD prevalence was 5.1% increasing 2.5 times from 2014 to 2020 (2.1% to 7.4%), with an AAPC of 0.9% (95%CI: 0.1-1.7) and Ptrend<0.001. Boys had a higher level of NAFLD rate than that of girls (6.3% vs 3.7%). The NAFLD rate in normal weight population was 1.9%, and the elevated trend was still observed in normal weight (Ptrend<0.001) among the 7-year survey. After adjusting BMI and waist, the NAFLD prevalence was still had an increasing trend over year (Ptrend<0.001). Conclusion：NAFLD prevalence of children and adolescents in Shanghai increased nearly 1.0% per year. The increasing trend of NAFLD prevalence remains even after adjustment for BMI and waist. This trend calls for attention on the modifiable risk factors in addition to obesity in this population.
WANG Yingwen, SU Ling, GUI Yonghao, ZHANG Chongfan, LU Quan, HONG Jianguo, SHEN Bing, FENG Rui, FANG Jinwu, WANG Weibing, GU Ying, DONG Xiaoyan, WANG Ying, LU Guoping, YU Hui, YE Yingzi, TANG Liangfeng, GE Xiaoling, HUANG Min, YU Songxuan, XU Hong, ZHANG Xiaobo
Background：Automatic capture of real-world data from hospital medical information system for clinical research and management has always been paid much attention.
Objective：To construct an electronic case report form (eCRF) data collecting platform, and to apply the real-world data to clinical research and disease management.
Design：Data modeling.
Methods：Variables for pediatric pneumonia were extracted from the literature sought by a systematic search in databases to form a variable pool. Experts for reviewing were required to identify core variables from the pool for the development of eCRF following the rule of Clinical Data Interchange Standards Consortium (CDISC). After variable verification and correction, data collection test model was built and improved by testing the data collection ability, and the timeliness and system security were analyzed in parallel.
Main outcome measures：Response rate of eCRF for pediatric pneumonia data. Results：Based on the selected 7 guidelines, 4 articles on diagnosis and treatment recommendations, 10 papers of expert consensus and 9 classic monographs as the original source of variables, experts for reviewing identified 18 domains and 335 pediatric pneumonia variables for automatic collection. The results were refined after 5 rounds of testing and evaluation. The module of demographic information (8 variables) was 100% up to the standard in round 1 to 5. The module of structured information (175 variables) was 89.7% up to the standard in the first round, and 100% in the second to fifth rounds. The module of text data (152 variables) was 50.0% up to the standard in round 1 with 21 variables failing to meet the standard and 70 variables failing to be captured and in round 5, the rate was 90.1%, and the number of variables failing to meet the standard and to appear decreased to 7 and 8, respectively. The overall compliance rate was 95.5%(320/335). The detected variables could be automatically collected within 24 hours of data generation. Data verification and locking could also be done at the same time.
Conclusion：The eCRF data collection platform can automatically capture realworld data from hospital medical information system to facilitate clinical research and disease management.
LU Chunmei, JI Futing, LV Tianchan, YUAN Hao, YANG Tongling, HU Xiaojing, Investigation Group of Neonatal Iatrogenic Skin Injury of Society of Neonatal Nursing of China Medicine Education Association
Background：Iatrogenic skin injury is a common problem in neonates admitted to NICU.
Objective：To investigate the incidence of neonatal iatrogenic skin injury in NICUs in China.
Design：Cross-sectional survey.
Methods：Children's Hospital of Fudan University took the lead in establishing the NICU clinical data database of neonatal iatrogenic skin injury, which included 22 tertiary hospitals in 15 provinces, autonomous regions and municipalities directly under the central government. The causes of iatrogenic skin injury were related to diapers, viscose, pressure (including medical devices), surgery, vascular access, and physical or chemical factors. The continuous cases reported by NICUs of the cooperative hospitals were sent to the database, and the data were from the electronic medical record system or paper medical document records. The reported data included demographic data, medical devices use, iatrogenic skin injury events, the age, weight and length of hospital stay of the infant at the time of each iatrogenic skin injury, the location, size, type, color, treatment measures and prognosis of skin injury. The leading hospital trained the cooperating hospitals according to the indicators in the database and started data collection after passing the examination. The leading hospital was responsible for reviewing the data.
Main outcome measures：Incidence of iatrogenic skin injury in NICU hospitalized neonates.
Results：From December 1, 2019 to January 31, 2020, the data of NICU consecutive cases (n=8,126) collected by 22 cooperative hospitals were all qualified and included in this analysis. There were 521 cases of iatrogenic skin injury (6.4%), and the incidence of iatrogenic skin injury in NICU in children's specialized hospitals, general hospitals and maternal and child health hospitals were 7.4%(280/3,783), 6.4% (153/2,387) and 4.5%(88/1,956), respectively. There were 566 times of iatrogenic skin injury in 521 neonates, and 45 cases (8.6%) had two times of iatrogenic skin injury. The median age of neonates with iatrogenic skin injury was 6 (3, 17) days, those within 1 week after birth accounting for 57.4%(n=299). The median corrected gestational age of neonates with iatrogenic skin injury was 37.2% (32.7, 40.0) weeks, those with the corrected gestational age≥40 weeks accounting for 57.4%(n=294). The median weight of neonates with iatrogenic skin injury was 2,800 (1,9123,450) g, those with the weight≥2,500 g accounting for 59.1%(n=308). There were 250 cases of diaperrelated skin injury (48.0%), 81 cases of pressurerelated (including medical devicerelated) (15.5%), 69 cases of viscoserelated (13.2%), 70 cases of various physical and chemical factorsrelated (13.4%), 22 cases of vascular accessrelated (4.2%), 14 cases of surgeryrelated (2.7%), and 15 cases of other types (2.9%). The proportion of all kinds of iatrogenic skin injury in neonates aged 17 days was the highest. Except that pressurerelated skin injury was easy to occur in very low birth weight infants and iatrogenic viscoserelated skin injury was easy to occur in all body recombination, other types of skin injury mostly occurred in neonates weighing≥2,500 g. Pressure-related and viscose-related skin injuries mostly occurred in neonates with the corrected gestational age of 28-32 weeks. Vascular access-related skin injuries accounted for a relatively even proportion in each corrected gestational age group, and other skin injuries were more likely to occur in neonates with the corrected gestational age >32 weeks. Most iatrogenic skin injuries(78.9%) occurred within one-week hospitalization stay of <1 week. The incidence rate decreased week by week.
Conclusion：The incidence of iatrogenic skin injury in NICU neonates in China was 6.4%. Diaper-related dermatitis, the application of medical devices, and the use of medical tape were the three main factors of iatrogenic skin injury in neonates. Iatrogenic skin injury was affected by many factors, such as gestational age, birth weight, and the use of various catheters.
Background：Many previous studies have been conducted on risk genes for bronchopulmonary dysplasia (BPD), but the phenotypic variation among studies is large, making it difficult to be used as a genetic risk for BPD in respiratory distress syndrome (RDS).
Objective：To identify genetic risk factors for RDS complicated by BPD and to clarify the impact of genetic factors on the prognosis of children with RDS. Design：A retrospective nested casecontrol study.
Methods：Children with clinically confirmed RDS who were hospitalized at the Children's Hospital of Fudan University from January 1, 2016, to August 1, 2021, were included and divided into BPD and nonBPD groups based on whether they had concomitant BPD. A propensity scoring strategy was used to balance the gestational age of the two groups, and rarevariant association analysis and functional enrichment analysis were used to explore the biological process of rare variant gene enrichment and to screen for candidate risk genes with significantly more damaging variants in the BPD group. Gene expression data were retrieved from the GEO database, and time series analysis of gene expression patterns was performed to verify the expression characteristics of the high variant burden genes in this paper.
Main outcome measures：Genetic risk factors for RDS complicated by BPD.
Results：There were 111 cases in the BPD group and 157 cases in the nonBPD group, and the differences of gestational age in the two groups were not statistically significant. Based on 1,558 biological processes of 2 742 significantly enriched background genes (P<0.01), the most significantly enriched gene set for proteintruncating variants was associated with regulation of protein kinase activity (P=0.011), and the largest total number of genes carrying proteintruncating variants in the BPD group was for cation transmembrane transportrelated genes (P=0.027). The set of most significantly enriched genes for missense or nonsynonymous variants was associated with the developmental growth (P=0.001). Twenty-six genes in the BPD group had a significantly higher burden of missense or nonsynonymous variants than that of the nonBPD group (P<0.05), with three genes (ARSB, B9D2 and UVSSA) having high statistical significance (P<0.01). ARSB was significantly downexpressed in severe BPD as verified by GEO database data (P<0.001), and time series analysis revealed a significantly different expression pattern of ARSB genes in neonates with severe BPD compared to neonates without BPD or with mild BPD (P<0.01). Conclusion：ARSB is a risk genetic factor for RDS complicated by BPD.
Background：Pulmonary nodules are increasingly detected in healthy children while the relevant research are limited. There are still problems and challenges in diagnosis and treatment.
Objective：To retrospectively review the clinical characteristics, imaging features, and prognosis of pulmonary nodules in children, and to provide a reference for the clinical diagnosis and treatment.
Design：A case series report.
Methods：Consecutive cases of children aged <18 years old, diagnosed with pulmonary nodules, and followed up for ≥6 months in the Department of Respiratory Medicine from January 1, 2015, to December 30, 2021, at Children's Hospital of Fudan University, were retrospectively collected. Children with malignancy, immunodeficiency disease, tuberculosis, and congenital pulmonary airway malformation were excluded. Data were extracted from outpatient medical records, including gender, age at the first identification, visit date, indication for imaging, the type of imaging leading to the diagnosis, combining or accompanying diseases, final diagnosis, and changes of repeated chest imaging.
Main outcome measures：The detection rate of pulmonary nodules and followup outcomes.
Results：A total of 74 children with pulmonary nodules were included in the analysis. The average age was (8.7±3.9) years old, 44 cases (59.5%) were older than 8 years, 49 cases (66.2%) were male, and 67 cases (90.5%) were detected by chest CT. Fiftyone patients had complete image data. Nodule size was <5 mm in 32 patients, 510 mm in 10 patients, and >10mm in 9 patients. Eighteen cases had bilaterally distributed nodules and 33 cases had unilaterally distributed nodules. There were 24 cases with a single nodule, 22 cases with 2 to 10 nodules, and 5 cases with over 10 nodules. Nodule shapes were mainly round/quasi round (29 cases) and mixed shaped (16 cases), and the edge was mainly smooth (41 cases). Solid nodules were found in 37 cases, mixed in 7 cases, ground glass in 5 cases, and partially solid in 2 cases. A total of 39 cases were followedup with CT. The median time of the first followup was 3.3 (1, 6) months. The nodules were shrunk or decreased in 14 cases (35.9%), remained unchanged in 9 cases (23.1%), disappeared in 8 cases (20.5%), and enlarged or increased in 8 cases (20.5%). For the 8 patients with enlarged or increased nodules, the mean age at the first identification was (8.1±3.0) years old, with the median nodule size of 5 (2.5, 15) mm. In 7 cases with image data in our hospital, 3 cases with a single nodule, 1 case with 2 to 10 nodules, 1 case with 10 to 20 nodules, and 2 cases with >20 nodules. Three had round/quasi round nodules, and 4 had mixedshaped nodules. Nodules with smooth margin were seen in 4 cases, with poorly defined, halo sign, and spiculated margin were seen in one case each. Nodules were solid in 6 cases and mixed in one case. Five patients underwent lung biopsies (all nodules size >10 mm). Eight patients were finally diagnosed, 4 cases were confirmed by lung biopsy (2 pulmonary sarcoidosis, 1 anaerobic infection, and 1 inflammatory myofibroblastic tumor), and the other 4 cases were clinically diagnosed (3 pulmonary infection, 1 caused by trauma). Sixtysix patients were undiagnosed, 8 of which had a clinical proposed diagnosis including pulmonary infection in 4 cases, granulomatous disease, pulmonary spaceoccupying lesions, connective tissue disease, and vascular disease each in one case. Fiftyeight cases did not have a definitive diagnosis. Conclusion：The potential detection rate of pulmonary nodules in children deserves attention. The overall diagnosis rate is low, and dynamic imaging followup is required. Biopsy should be considered in patients whose nodules are >10mm and without a definitive diagnosis by routine investigation.
Background：SLC6A1 encodes the gammaaminobutyric acid (GABA) transporter protein 1 (GAT1), which is responsible for the reuptake of GABA from the synapse. It plays an important role in the pathogenesis of neurological disorders such as epilepsy, intellectual disability and autism.
Objective：To summarize the clinical phenotypes and results of genetic testing in children with SLC6A1 mutations.
Design：Case series report.
Methods：Patients with SLC6A1 mutations treated in the Department of Neurology, Children's Hospital of Fudan University from December 2007 to October 2021 were enrolled. The clinical data of patients were collected to summarize the clinical manifestations, therapeutic effects and genetic results. The relationship between reported gene variants and clinical phenotypes was summarized through searching databases.
Main outcome measures：Mutation sites of SLC6A1 gene and clinical phenotypes. Results：Five children were included in the study, including 4 males and 1 female. They experienced seizure onset from 1 to 3 years old. Among them, 4 had myoclonic seizures，3 cases had absence seizures, 2 cases had myoclonicatonic seizures, and 1 had generalized tonicclonic seizures. Developmental delay was present in all patients. Delayed language development was prominent. Four of the 5 patients became seizure free. Two patients received valproic acid monotherapy, and the other two received valproic acid in combination with levetiracetam. De novo heterozygous SLC6A1 gene mutations were identified in these patients, including 3 missense mutations, 1 splicing mutation and 1 nonsense mutation. Two mutations including c.1379T>G (p.L460R), and c.1485G>A (p.W495X) have not been previously reported in public. Alteration of amino acids of GAT1 caused by pathogenic or likely pathogenic missense variants are largely clustered around the extracellular domain of EC34 and the seventh transmembrane domain. Conclusion：Most of the patients associated with SLC6A1 gene mutations experienced seizure onset in early childhood. The patients presented with various types of seizures. Valproic acid was effective to control seizures. Most of the patients had developmental delays. The discovery of new variants has enriched the spectrum of SLC6A1 gene variants.
Background：The clinical spectrum of 16p11.2 microdeletion syndrome is highly heterogeneous, and most studies are case reports.
Objective：To summarize the clinical features of 16p11.2 microdeletion syndrome with epilepsy as the main phenotype, so as to improve the clinical understanding of this disease.
Design：Case series report.
Methods：From July, 2017 to October, 2021, children with epilepsy diagnosed as 16p11.2 microdeletion syndrome in the Department of Neurology, Shenzhen Children's Hospital were included. The clinical manifestations, laboratory examination results, EEG and neuropsychological evaluation results, imaging examination reports, treatment and follow-up of children were intercepted from the medical record system. Peripheral venous blood was collected from patients and their parents for the genetic testing.
Main outcome measures：Clinical phenotype and genetic abnormality analysis. Results：Totally 11 patients (age range: 336 months; median age: 7 months; male:6, female: 5), were enrolled. All 11 patients presented focal seizure as the early symptom. There are 8 cases of language retardation and 2 cases of motor retardation (including 1 case of paroxysmal motorinduced dyskinesia). By EGG, 8 patients were found having intermittent discharge while the other 3 patients had normal EGG backgrounds, and by brain MR imaging, 1 case of abnormal white matter signal was observed. The 11 cases of 16p11.2 microdeletion showed a deletion of 524908 kb and 8 of them were de novo mutations. The overlapping region chr16:2967499130199601 contains 27 proteincoding genes and 6 of them are diseaserelated OMIM genes. Only PRRT2 was well evidenced to be haploinsufficient, which causes benign infantile epilepsy. Epilepsy was easy to control in all these patients. Nine cases were treated with antiepileptic drugs, including monotherapy of oxcarbazepine, sodium valproate or topiramate (n=8) and combination therapy of phenobarbital and levetiracetam (n=1). Paroxysmal motorinduced dyskinesia occurred after the combination therapy cure the disease and was stopped, but it did not happen again after the oxcarbazepine treatment.
Conclusion：16p11.2 microdeletion syndrome is one of the potential causes of epilepsy, which should be paid attention to in genetic evaluation. For children with 16p11. 2 microdeletion syndrome, dynamic neuropsychological evaluation is needed and attention should be paid to PKD symptoms so as to make timely diagnosis and treatment.
Background：Foreign literature has reported that children with primary ciliary dyskinesia (PCD) were prone to anxiety and depression. Until now, there were no reports on anxiety and depression of Chinese PCD children and their parents. Objective：To investigate the occurrence and influencing factors for anxiety and depression of PCD children and their parents.
Design：Casecontrol study.
Methods：Children with PCD over 7 years old and their parents were selected as the PCD children group and the PCD parents group. Children with asthma and their parents were selected as the asthma children group and asthma parents group, and healthy children and their parents were selected as the control children group and control parents group. Children's anxiety and depression were evaluated by the scale of Screen for Child Anxiety Related Emotional Disorders (SCARED) and Children's Depression Inventory (CDI). Parents' anxiety and depression were evaluated by SelfRating Anxiety Scale (SAS) and Center for Epidemiological Survey Depression Scale (CESD). The care burden on parents of children with PCD was evaluated by Zarit Caregiver Burden Scale. Influencing factors of anxiety and depression in children with PCD and their parents were analyzed. Main outcome measures：Incidence and influencing factors of anxiety and depression in children with PCD and their parents.
Results：There were 38 cases in PCD children group, 76 cases in each of the asthma children group and control children group. There were 82 parents in each group including PCD group, asthma group and control group. The incidence of anxiety and the score of SCARED in PCD children group were higher than those in asthma children group and control group (P<0.05). There were no significant difference in the score of CDI and incidence of depression among the three children groups (P≥0.05). The incidence of anxiety and depression and the score of CESD in parents of children with PCD were higher than those in asthma group and control group (P<0.05). There were no significant difference in incidence of anxiety and depression and the score of CESD between parents of asthma group and control group (P≥0.05). There was no significant difference in the score of SAS between parents of PCD group and asthma group (P≥0.05). The incidence of anxiety and depression and the score of CESD, SAS and Zarit Caregiver Burden Scale in mothers of children with PCD were higher than those in fathers (P<0.05). Multivariate binary logistic regression analysis showed that, for the children with PCD aged 717, the boys were more prone to anxiety than the girls, and regular airway nursing was a protective factor to avoid anxiety and depression. For parents of children with PCD aged 417, high level of education, stable occupation and regular exercise of children were the protective factors to avoid anxiety, and high level of education, hospitalization frequency of children less than once in recent one year and regular exercise of children were the protective factors to avoid depression. The high score of Zarit Burden Scale was the risk factor for anxiety and depression in parents of children with PCD.
Conclusion：The incidence of anxiety in children with PCD was higher, which was affected by gender and the situation of airway nursing. The incidence of anxiety and depression in parents of children with PCD were higher, which were affected by their occupation, level of education, care burden, children's exercise situation and hospitalization frequency of children in recent one year.
