Optical Genome Mapping Identifies a Novel Unbalanced Translocation Between Chromosomes 4q and 6q Leading to Feeding Difficulties and Hypotonia in a Neonate: A Case Report.

Optical Genome Mapping (OGM) technology has garnered growing interest for the identification of chromosomal structural variations (SVs), particularly complex ones that are implicated in genetic diseases in humans. In this study, we performed genetic diagnostics on a neonatal patient who presented with feeding difficulties, hypotonia, and an atrial septal defect. We utilized a combination of trio-whole exome sequencing and OGM for our analysis. The results revealed an unbalanced translocation between maternal chromosomes 4 and 6 in the proband, ogm[GRch38]t(4:6)(q35.2;q25.3), resulting in a 2.8 Mb deletion at the 4q35 terminal and a 10.2 Mb duplication at the 6q25 terminal. In summary, this study highlights how OGM, in conjunction with other genetic approaches, can unveil the genetic etiology of complex clinical syndromes. Neonatal patients often exhibit low specific phenotypes, underlining the significance of SV detection.

Auriculocondylar syndrome 2 caused by a novel PLCB4 variant in a male Chinese neonate: A case report and review of the literature.

BACKGROUND: Auriculocondylar syndrome (ARCND) is a rare congenital craniofacial developmental malformation syndrome of the first and second pharyngeal arches with external ear malformation at the junction between the lobe and helix, micromaxillary malformation, and mandibular condylar hypoplasia. Four subtypes of ARCND have been described so far, that is, ARCND1 (OMIM # 602483), ARCND2 (ARCND2A, OMIM # 614669; ARCND2B, OMIM # 620458), ARCND3 (OMIM # 615706), and ARCND4 (OMIM # 620457). METHODS: This study reports a case of ARCND2 resulting from a novel pathogenic variant in the PLCB4 gene, and summarizes PLCB4 gene mutation sites and phenotypes of ARCND2. RESULTS: The proband, a 5-day-old male neonate, was referred to our hospital for respiratory distress. Micrognathia, microstomia, distinctive question mark ears, as well as mandibular condyle hypoplasia were identified. Trio-based whole-exome sequencing identified a novel missense variant of NM_001377142.1:c.1928C>T (NP_001364071.1:p.Ser643Phe) in the PLCB4 gene, which was predicted to impair the local structural stability with a result that the protein function might be affected. From a review of the literature, only 36 patients with PLCB4 gene mutations were retrieved. CONCLUSION: As with other studies examining familial cases of ARCND2, incomplete penetrance and variable expressivity were observed within different families' heterozygous mutations in PLCB4 gene. Although, motor and intellectual development are in the normal range in the vast majority of patients with ARCND2, long-term follow-up and assessment are still required.

Differences in the amplitude of low-frequency fluctuations of spontaneous brain activity between preterm and term infants.

Objectives: To date, the majority of research on resting-state functional magnetic resonance imaging (rs-fMRI) in the developing brain has primarily centered on adolescents and adults, leaving a gap in understanding variations in spontaneous brain activity at rest in preterm infants. This study aimed to uncover and comprehend the distinctions in spontaneous brain activity between preterm and term infants, with the goal of establishing a foundation for assessing the condition of preterm infants. Methods: In this study, 14 term infants and 15 preterm infants with equivalent gestational age were carefully chosen from the neonatal unit of Anhui Provincial Children's Hospital. The amplitude of low-frequency fluctuations (ALFF) intensity was assessed using resting-state functional magnetic resonance imaging (rs-fMRI) to examine brain activity in both groups. Subsequently, the differences between the term and preterm infants were statistically analyzed using a two-sample t-test. A p-value of <0.05, corrected for the REST Gaussian Random Fields, was deemed to be statistically significant. Results: In comparison to the term infant group, the preterm infant group exhibited a significant increase in the ALFF value in the left precuneus, left frontal superior orbital gyrus, and left calcarine cortex. Conclusion: Significant variances in spontaneous brain activity have been observed in various regions between term infants and preterm infants of equivalent gestational age. These variations could potentially impact the emotional and cognitive development of preterm infants in the long term.

Clinical report and genetic analysis of rare premature infant nephronophthisis caused by biallelic TTC21B variants.

BACKGROUND: Nephronophthisis (NPHP) is a genetically heterogeneous disease that can lead to end-stage renal disease (ESRD) in children. The TTC21B variant is associated with NPHP12 and mainly characterized by cystic kidney disease, skeletal malformation, liver fibrosis, and retinopathy. Affected patients range from children to adults. Some patients experience ESRD in infancy or early childhood, but clinical reports on neonatal patients are rare. We report a case of NPHP12 in a premature infant and analyze its genetic etiology. METHODS: Trio-whole exome sequencing analysis was performed on the patient and her parents; bioinformatics software was used to predict and analyze the hazards of the variants. Sanger sequencing was performed to verify variants. We calculated the free energy between mutant IFT139 and the IFT121-IFT122-IFT43 complex structure using molecular dynamics (MD). Finally, the clinical and genetic characteristics of patients with hotspot variant Cys518Arg were reviewed. RESULTS: Genetic analysis revealed compound-heterozyous TTC21B variants in the patient, c.497delA (p.Lys166fs*36) and c.1552T>C (p.Cys518Arg). Her father and mother had heterozygous c.497delA (p.Lys166fs*36) and heterozygous c.1552T>C (p.Cys518Arg), respectively. Cys518Arg represents a hotspot variant, and the MD calculation results show that this can reduce the structural stability of the IFT121-IFT122-IFT139-IFT43 complex structure. A literature review showed that Cys518Arg might lead to the early occurrence of ESRD. CONCLUSIONS: Compound-heterozygous TTC21B variants underlie the phenotype in this patient. Thus, Cys518Arg may be a hotspot variant in the Chinese population. Genetic testing should be recommended for NPHP in neonates and early infants.

Case Report: Mutation in TNNI3(c. 544G>A): a novel likely pathogenic mechanism of neonatal dilated cardiomyopathy.

Background: Dilated cardiomyopathy (DCM) is a rare disease that causes heart failure due to malfunction of the heart muscle characterized by left ventricular dilation and poor systolic function. Genetic screening leads to advantages in early diagnosis and prognostic assessment of patients with suspected inherited cardiomyopathies. Here, we report a case of neonatal dilated cardiomyopathy due to a mutation of the TNNI3 gene, which has not been published in neonatal dilated cardiomyopathy before. Case presentation: The patient was a 22-day-old newborn boy with poor ability to respond to stimuli, presenting with shortness of breath over 11 days. He presented with irregular fever, tachypnea, difficulty in ventilator withdrawal, and mild edema of both lower limbs, and III/6SM could be heard in the precardiac area. He presented repeated weaning difficulties during hospitalization with intractable low EF heart insufficiency. Doppler echocardiography showed refractory low ejection fraction, cardiac enlargement, cardiac insufficiency, mild pulmonary hypertension, and mitral and tricuspid insufficiency with mild valve regurgitation. Whole-exome sequencing showed a mutation in the TNNI3 gene, c. 544G>A (p.Glu182Lys). Thus, he was diagnosed with neonatal DCM. There was no mutation in the parents, the child died 2 weeks after discharge. Conclusions: TNNI3 mutation is a novel likely pathogenic mechanism of neonatal dilated cardiomyopathy. Therefore, systematic use of diagnostic tools, advanced risk models, and a deeper understanding of the mechanism are required to reduce morbidity and mortality in this disease.

Effect of different ventilation methods combined with pulmonary surfactant on neonatal acute respiratory distress syndrome.

BACKGROUND: Acute respiratory distress syndrome precipitates is widespread pulmonary injury in impacted individuals, the neonatal respiratory distress syndrome (NRDS), primarily observed in preterm infants, represents a prevalent critical condition in neonatal clinical settings. AIM: To investigate the clinical efficacy of various ventilation strategies combined with pulmonary surfactant (PS) therapy in the treatment of NRDS. METHODS: A total of 20 neonates diagnosed with respiratory distress syndrome, admitted between May 2021 and June 2022, were randomly assigned to either a research group or a control group. Neonates in the research group received treatment involving high-frequency oscillatory ventilation (HFOV) in conjunction with PS. In contrast, neonates in the control group were administered either controlled mechanical ventilation or synchronous intermittent mandatory ventilation, combined with PS. Arterial blood samples from the neonates in both groups were collected before treatment, as well as 6 h, 12 h, 24 h, and 48 h post-treatment. These samples underwent blood gas analysis, with measurements taken for pH value, partial pressures of oxygen (O2) and carbon dioxide. Concurrently, data was collected on the duration of ventilator use, length of hospitalization time, O2 treatment time, treatment outcomes, and complications of the ventilator. RESULTS: From 6-48 h post-treatment, both groups demonstrated significant improvements in arterial blood pH and oxygen partial pressure, along with a significant decrease in carbon dioxide partial pressure compared to pre-treatment values (P < 0.05). Although these changes progressed over time, there were no significant differences between the two groups (P > 0.05). However, the research group had significantly lower X-ray scores, shorter hospitalization time, and less time on O2 therapy compared to the control group (P < 0.05). Mortality rates were similar between the two groups (P > 0.05), but the research group had a significantly lower incidence of complications (P < 0.05). CONCLUSION: The integration of HFOV combine with PS has proven to effectively expedite the treatment duration, decrease the occurrence of complications, and secure the therapeutic efficacy in managing NRDS.

Clinical report and genetic analysis of a Chinese neonate with craniofacial microsomia caused by a splicing variant of the splicing factor 3b subunit 2 gene.

BACKGROUND: Craniofacial microsomia (CFM) is a common congenital malformation with unknown pathogenesis. Although few cases have been reported, it is suggested that variants of the SF3B2 gene may lead to CFM. We herein report the case of a neonate with CFM exhibiting rare features of airway obstruction. METHODS: Trio whole-exome sequencing and Sanger validation were performed on the proband and her parents. Candidate gene mutations were analyzed using the Genome Aggregation Database (gnomAD) for normal frequency distributions. The Human Splicing Finder (HSF) and Rare Disease Data Center (RDDC) RNA splicer algorithms predicted the variant's harmfulness, verified by a Minigene assay. RESULTS: The proband had a heterozygous SF3B2 variant, NM_006842.3:c.777+1G>A. The patient's father also carried this variant and exhibited facial abnormalities. The variant was not in gnomAD, and HSF and RDDC RNA splicers indicated donor site disruption. The minigene assay suggested that two mRNA products were produced, leading to a premature termination codon. CONCLUSION: For this family, the pathogenesis of CFM may have been caused by an SF3B2 splicing variant. Affected family members exhibited varying degrees of malformation, indicating that CFM has phenotypic heterogeneity. This finding expands the phenotype and variant spectrum of SF3B2, enriches neonatal CFM research, and provides a possible guide to genetic counseling.

Primary care Adherence To Heart Failure guidelines IN Diagnosis, Evaluation and Routine management (PATHFINDER): a randomised controlled trial protocol.

INTRODUCTION: General practitioners (GPs) routinely provide care for patients with heart failure (HF); however, adherence to management guidelines, including titrating medication to optimal dose, can be challenging in this setting. This study will evaluate the effectiveness of a multifaceted intervention to support adherence to HF management guidelines in primary care. METHODS AND ANALYSIS: We will undertake a multicentre, parallel-group, randomised controlled trial of 200 participants with HF with reduced ejection fraction. Participants will be recruited during a hospital admission due to HF. Following hospital discharge, the intervention group will have follow-up with their GP scheduled at 1 week, 4 weeks and 3 months with the provision of a medication titration plan approved by a specialist HF cardiologist. The control group will receive usual care. The primary endpoint, assessed at 6 months, will be the difference between groups in the proportion of participants being prescribed five guideline-recommended treatments; (1) ACE inhibitor/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitor at least 50% of target dose, (2) beta-blocker at least 50% of target dose, (3) mineralocorticoid receptor antagonist at any dose, (4) anticoagulation for patients diagnosed with atrial fibrillation, (5) referral to cardiac rehabilitation. Secondary outcomes will include functional capacity (6-minute walk test); quality of life (Kansas City Cardiomyopathy Questionnaire); depressive symptoms (Patient Health Questionnaire-2); self-care behaviour (Self-Care of Heart Failure Index). Resource utilisation will also be assessed. ETHICS AND DISSEMINATION: Ethical approval was granted by the South Metropolitan Health Service Ethics Committee (RGS3531), with reciprocal approval at Curtin University (HRE2020-0322). Results will be disseminated via peer-reviewed publications and conferences. TRIAL REGISTRATION NUMBER: ACTRN12620001069943.

Relationship of plasma MBP and 8-oxo-dG with brain damage in preterm.

Preterm infants face a significant risk of brain injury in the perinatal period, as well as potential long-term neurodevelopmental disabilities. However, preterm children with brain injury lack specific clinical manifestations in the early days. Therefore, timely and accurate diagnosis of brain injury is of vital importance. This study was to explore the diagnostic efficiency of myelin basic protein (MBP) and 8-oxo-deoxyguanosine (8-oxo-dG) serum levels in brain injury of premature infants. A total of 75 preterm infants with gestational age between 28 and 32 weeks and birth weight higher than 1,000 g were prospectively included. MBP serum levels were significantly higher in premature infants with white matter injury (WMI). 8-oxo-dG serum levels were significantly increased in both WMI and periventricular-intraventricular hemorrhages (PIVH). MBP and 8-oxo-dG were significantly correlated. The area under the curve was 0.811 [95% confidence interval (CI) 0.667-0.955; p = 0.002] in MBP and 0.729 (95% CI 0.562-0.897; p = 0.020) in 8-oxo-dG. Therefore, the results showed that high MBP levels indicated a possibility of WMI in the premature brain during the early postnatal period, while high 8-oxo-dG levels were closely related to both WMI and PIVH, thus suggesting that MBP and 8-oxo-dG could be used as potential neuro-markers of preterm brain injury.

[Value of intestinal regional oxygen saturation and C-reactive protein in the diagnosis of necrotizing enterocolitis in preterm infants]. / è‚ é“å±€éƒ¨ç»„ç»‡æ°§é¥±å’Œåº¦å’ŒC-ååº”è›‹ç™½åœ¨è¯Šæ–­æ—©äº§å„¿åæ­»æ€§å°è‚ ç»“è‚ ç‚Žä¸­çš„ä»·å€¼.

OBJECTIVES: To study the clinical value of intestinal regional oxygen saturation (rSO2) and C-reactive protein (CRP) in the diagnosis of necrotizing enterocolitis (NEC) in preterm infants. METHODS: A prospective observational study was conducted among the preterm infants who were hospitalized in Children's Hospital Affiliated to Anhui Medical University, from October 2020 to December 2021, with 22 infants in the NEC group and 35 infants in the non-NEC group. Intestinal rSO2 was monitored 24 hours after a confirmed diagnosis of NEC in the NEC group, and serum CRP levels were measured before anti-infection therapy. In the non-NEC group, intestinal rSO2 monitoring and serum CRP level measurement were performed at the corrospording time points. The two groups were compared in terms of intestinal rSO2 and serum CRP level. The receiver operating characteristic (ROC) curve was used to analyze the value of intestinal rSO2 alone, serum CRP alone, and intestinal rSO2 combined with CRP in the diagnosis of NEC in preterm infants. RESULTS: Compared with the non-NEC group, the NEC group had a significantly lower level of intestinal rSO2 (P<0.05) and a higher serum CRP level (P<0.05). The ROC curve analysis showed that intestinal rSO2 had an optimal cut-off value of 50.75% in the diagnosis of NEC in preterm infants, with a sensitivity of 81.8%, a specificity of 85.7%, and an area under the ROC curve (AUC) of 89.4%; CRP had an optimal cut-off value of 12.05 mg/L in the diagnosis of NEC in preterm infant, with a sensitivity of 72.7%, a specificity of 74.3%, and an AUC of 74.8%; intestinal rSO2 combined with CRP had a sensitivity of 90.9%, a specificity of 77.1%, and an AUC of 91.9% in the diagnosis of NEC. The AUC of intestinal rSO2 alone in the diagnosis NEC was higher than that of CRP (P<0.05). There was no significant difference in the AUC between intestinal rSO2 alone and intestinal rSO2 combined with CRP (P>0.05). CONCLUSIONS: The value of intestinal rSO2 in the diagnosis NEC is higher than that of CRP, and is equivalent to that of the combination of intestinal rSO2 and CRP in preterm infants.

The Value of Macrogene Second-Generation Sequencing in the Diagnosis, Guidance of Drug Use, and Efficacy Monitoring of Infectious Pneumonia in Premature Infants.

Objective: A group-controlled trial was conducted to explore the value of macrogene second-generation sequencing in the diagnosis, drug use, and efficacy monitoring of infectious pneumonia in premature infants. Methods: One hundred and thirty-eight premature infants with suspected infectious pneumonia treated in our hospital from March 2019 to June 2022 were selected as subjects. All patients underwent deep phlegm extraction and were randomly divided into two groups. 69 cases of control group were treated with general bacterial and fungal culture. The lavage fluid of the remaining 69 cases of observation group were detected by metagenomic next-generation sequencing (mNGS). The number of diagnosed preterm infants with infectious pneumonia was compared between the two groups, and the diagnostic value of the two methods was analyzed by the receiver operator characteristic (ROC) curve. Then, the differences in clinical efficacy, antimicrobial neonatal intensive care unit (NICU) use time, antimicrobial adjustment frequency, NICU stay time, hospital stay, and serum inflammatory factors were compared between the two groups. Results: The positive rate of mNGS pathogen detection in the lavage fluid of the observation group was 92.75% (64/69). The positive rate of the culture of the lavage fluid of the control group was 52.17% (36/69). The ROC curve analysis showed that the ROC AUC of traditional culture was 0.752 (95%CI = 0.610-0.894), and that of mNCS was 0.934 (95%CI = 0.854-0.999). In the observation group, there were 35 cases of bacterial infection, 20 cases of fungi, 4 cases of virus, and 5 cases of Chlamydia psittaci. In the control group, 26 cases of bacterial infection and 9 cases of fungi were detected; but viruses and other mycoplasmas could not be detected. After 2 weeks of treatment, the effective rate of the observation group was 95.31%, while that of the control group was 69.44%. The NICU use time, adjustment frequency, NICU stay time, and hospitalization time of antibiotics in the observation group were significantly less than those in the control group, and the difference was statistically significant (P < 0.05). After treatment, the levels of serum interleukin-6 (IL-6), procalcitonin (PCT), and hypersensitivity-C-reactive protein (hs-CRP) in observation group were significantly higher than those in control group, and the difference was statistically significant (P < 0.05). Conclusion: mNGS can improve the efficiency of clinical diagnosis of infectious pneumonia in premature infants, effectively improve the detection rate of pathogens and the clinical efficacy of premature infants. At the same time, it can also assist the clinical efficacy monitoring and adjust the treatment plan at any time.

Noonan syndrome caused by RIT1 gene mutation: A case report and literature review.

Objective: Noonan syndrome (NS), an autosomal dominant disease known as a RASopathy, is caused by germline mutations in mitogen-activated protein kinase pathway genes. A RIT1 gene mutation has been found to cause NS. The present study summarizes RIT1 gene mutation sites and associated clinical phenotypes. Methods: We retrospectively analyzed the clinical characteristics of a case of NS caused by RIT1 mutation in our hospital, and searched the PubMed database, China National Knowledge Infrastructure (CNKI) database and Wanfang database with the keywords Noonan syndrome and RIT1. Studies published between May 1, 2014 and July 1, 2021 were retrieved. By reviewing the abstracts and full text of the studies, we screened NS cases associated with RIT1 mutation in children 0-18 years of age. The clinical characteristics of these cases were summarized. Results: A total of 41 cases were analyzed, including 13 boys and 28 girls. There were 14 premature cases. The age at diagnosis was 4 days to 18 years, and 10 cases were diagnosed at 0-1 years of age. Common amino acid substitution positions included 57 (13/41), 95 (7/41), 82 (8/41), and 90 (4/41). A total of 63.63% cases had abnormal prenatal examination results, manifesting mainly as fetal neck edema, polyhydramnios and cardiac malformation. With respect to abnormal conditions after birth, 70-80% of patients had typical developmental malformations of the face, neck and thorax; 19/35 patients had abnormal lymphatic development; and a portion of patients had short stature and motor development disorders. A total of 87.80% (36/41) patients had cardiac dysplasia, among which hypertrophic cardiomyopathy (HCM) accounted for 58.53%. A total of 84.62% of patients carrying the p.A57G mutation had HCM, but no HCM was found in patients with the p.G95A mutation. A total of 34.15% of patients had pulmonary artery or pulmonary valve stenosis (PVS). In patients with the p.M90I mutation, 75% had PVS. Patients with concurrent HCM and PVS accounted for 19.51 and 48.78% of patients had supraventricular tachycardia. Conclusion: A RIT1 gene mutation causing NS was associated with a high rate of abnormal prenatal examination findings. Most patients had typical NS craniofacial deformities, and some have short stature and motor development disorders. The cardiac deformity rate was high, and HCM was common. Some patients had supraventricular arrhythmias. Heart abnormalities showed high heterogeneity, given the various mutation loci.

Development and Validation of a Nomogram for Predicting the Risk of Bell's Stage II/III Necrotizing Enterocolitis in Neonates Compared to Bell's Stage I.

Background: Patients with Bell's Stage II/III necrotizing enterocolitis (NEC) may have more severe presentations, higher rates of death, and more long-term complications than those with Bell's Stage I NEC, so the purpose of this article was to construct a nomogram model to distinguish Bell's stage II/III NEC early from Bell's Stage I NEC, which is critical in the clinical management of NEC. Patients and Methods: A total of 730 NEC newborns diagnosed from January 2015 to January 2021 were retrospectively studied. They were randomly divided into training and validation groups at the ratio of 7:3. A nomogram model for predicting NEC was developed based on all the independent risk factors by multivariate regression analysis. The model's performance was mainly evaluated through three aspects: the area under the curve (AUC) to verify discrimination, the Hosmer-Lemeshow test and calibration curve to validate the consistency, and decision curve analysis (DCA) to determine the clinical effectiveness. Results: Predictors included in the prediction model were gestational age (GA), birth weight (BW), asphyxia, septicemia, hypoglycemia, and patent ductus arteriosus (PDA). This nomogram model containing the above-mentioned six risk factors had good discrimination ability in both groups, and the AUCs were 0.853 (95% CI, 0.82-0.89) and 0.846 (95% CI, 0.79-0.90), respectively. The calibration curve and DCA confirmed that the nomogram had good consistency and clinical usefulness. Conclusions: This individual prediction nomogram based on GA, BW, asphyxia, septicemia, hypoglycemia, and PDA served as a useful tool to risk-stratify patients with NEC, and can help neonatologists early distinguish Bell's stage II/III NEC early from Bell's Stage I NEC.

[Clinical characteristics and genetic analysis of a neonate with Smith-Magenis syndrome].

OBJECTIVE: To explore the clinical features and genetic etiology for a neonate with Smith-Magenis syndrome (SMS). METHODS: Copy number variation sequencing (CNV-seq) was applied to the neonate and his parents, and the genotype-phenotype correlation was analyzed. RESULTS: On the second day after birth, the neonate had presented with pathological jaundice and immunodeficiency. Cranial MRI revealed ventricular enlargement and enlargement of cisterna magna. At 3 months, the infant has presented with square face, prominent forehead, deep-set eyes, hypertelorism, palpebral fissure upward and button noses. Genetic testing showed that he had carried a 2.9 Mb deletion in 17p11.2 region, seq[GRCh37] del(17)(p11.2)(chr17:16 836 379-19 880 992). The same deletion was not found in either parent. CONCLUSION: SMS is mostly diagnosed in child and adulthood, but rarely in neonates. For neonates with SMS, the neurological and behavioral abnormalities have not been shown, but pathological jaundice, CNS abnormalities and immune deficiency may be the characteristics, which require attention of neonatal physicians.

Chronic granulomatous disease associated with Duchenne muscular dystrophy caused by Xp21.1 contiguous gene deletion syndrome: Case report and literature review.

Chronic granulomatous disease (CGD) and Duchenne muscular dystrophy (DMD) are X-linked recessive disorders whose genes are 4.47 Mb apart within Xp21.1. A combination of both diseases is rare with only five cases reported in the literature where it is known as Xp21.1 "contiguous gene deletion syndrome". We describe a male neonate who presented with sepsis at 19 days of age. The diagnosis of CGD with DMD was established through copy number variation sequencing (CNV-seq) with an extensive 7.5 Mb deletion of Xp21.2-Xp11.4 of the proband. One of his elder sisters and his mother are carriers. The deletion includes six known genes: glycerol kinase (GK), dystrophin (DMD), cilia- and flagella-associated protein 47 (CFAP47), gp91 (CYBB), Kell antigen (XK), and retinitis pigmentosa GTPase regulator (RPGR). Laboratory assays revealed an increased creatine kinase (CK) level, decreased gp91 expression, and a positive nitroblue tetrazolium test. Due to the extensive gene deletion and the poor prognosis, the family determined to pursue conservative management without further laboratory workup. The patient passed away from a fulminant infection at the age of three-month at a local medical facility. To the best of our knowledge, this case of Xp21.1 contiguous gene deletion syndrome represents the most extensive deletion of genes in this region ever reported. A literature review of similar cases is presented.

Novel variants of NEK9 associated with neonatal arthrogryposis: Two case reports and a literature review.

Objective: Pathogenic variants in NEK9 (MIM: 609798) have been identified in patients with lethal congenital contracture syndrome 10 (OMIM: 617022) and arthrogryposis, Perthes disease, and upward gaze palsy (APUG and OMIM: 614262). The shared core phenotype is multiple joint contractures or arthrogryposis. In the present study, three novel variants of NEK9 associated with neonatal arthrogryposis were reported. Methods: The clinical data of two premature infants and their parents were collected. The genomic DNA was extracted from their peripheral blood samples and subjected to trio-whole-exome sequencing (trio-WES) and copy number variation analysis. Results: Using trio-WES, a total of three novel pathogenic variants of NEK9 were detected in the two families. Patient 1 carried compound heterozygous variations of c.717C > A (p. C239*741) and c.2824delA (p.M942Cfs*21), which were inherited from his father and mother, respectively. Patient 2 also carried compound heterozygous variations of c.61G > T (p. E21*959) and c. 2824delA (p. M942Cfs*21), which were inherited from his father and mother, respectively. These variants have not been previously reported in the ClinVar, HGMD, or gnomAD databases. Conclusion: This is the first report about NEK9-related arthrogryposis in neonatal patients. The findings from this study suggest that different types of mutations in NEK9 lead to different phenotypes. Our study expanded the clinical phenotype spectrum and gene spectrum of NEK9-associated arthrogryposis.

Transarterial Embolization in Neonatal Kasabach-Merritt Syndrome.

Background: Kasabach-Merritt syndrome (KMS) is characterized by large hemangiomas and persistent thrombocytopenia, which may result in visceral hemorrhage and disseminated intravascular coagulation. This study aimed to evaluate the value of transarterial embolization (TAE) in neonatal KMS patients. Patients and Methods: The clinical course of 11 neonates with KMS who underwent TAE in the Department of Neonatology, Anhui Provincal Children's Hospital, Anhui Medical University, China, were reviewed retrospectively. Results: Eleven neonates with KMS (nine male and two female) were admitted to our hospital between the age of 1 h and 6 days. All were born with progressively enlarged hemangiomas and persistent thrombocytopenia. The largest lesion had its maximum size reached at 15 × 8 × 8 cm. Eight patients had cutaneous hemangiomas (1 right face, one oropharynx, one left upper arm, two back, one left lumbar, one right lower leg, and one right thigh), and three patients had liver hemangiomas. All 11 patients underwent TAE. Nine patients underwent two TAEs, and two patients underwent only one embolization procedure. They all obtained >80% devascularization of their lesions without a major complication. The platelet count increased at 2-5 days after treatment and reached normal count and coagulation profile at 18-28 days after the TAE. Conclusions: TAE is a safe and effective alternative therapy for neonatal KMS patients.

Angiopoietin-2 silence alleviates lipopolysaccharide-induced inflammation, barrier dysfunction and endoplasmic reticulum stress of intestinal epithelial cells by blocking Notch signaling pathway.

Necrotizing enterocolitis, a devastating gastrointestinal disease with high mortality, poses great threats to global health. Therefore, we conducted this study to explore the role of ANGPT2, as well as the potential mechanism, in necrotizing enterocolitis. IEC-6 cells were stimulated with lipopolysaccharide (LPS) to induce necrotizing enterocolitis model in vitro. The expression of ANGPT2 was measured by RT-qPCR. The cell viability was detected using CCK-8. Besides, the expressions of endoplasmic reticulum (ER) stress-related proteins, Notch signaling pathway-related proteins and tight junction proteins were checked by western blot. The apoptosis and inflammatory response were detected by TUNEL and ELISA, respectively. Moreover, with the adoption of TEER, the cell monolayer permeability was detected. The results showed that ANGPT2 expression was greatly increased after LPS induction. In addition, ANGPT2 knockdown significantly decreased the apoptosis, inflammatory response, barrier dysfunction and endoplasmic reticulum stress of LPS-induced IEC-6 cells. What is more, ANGPT2 knockdown could block Notch signaling pathway. Additionally, with the treatment of Jagged-1, the protective effect of ANGPT2 knockdown on LPS-induced intestinal injury was partly abolished. To sum up, silencing ANGPT2 could improve LPS-induced inflammation, barrier dysfunction and ER stress of intestinal epithelial cells via blocking Notch signaling pathway.

Familial hemophagocytic lymphohistiocytosis type 2 in a female Chinese neonate: A case report and review of the literature.

BACKGROUND: Familial hemophagocytic lymphohistiocytosis type 2 (FHL2) is a rare genetic disorder presenting with fever, hepatosplenomegaly, and pancytopenia secondary to perforin-1 (PRF1) mutation. FLH2 has been described in Chinese but usually presents after 1 year old. We describe a female Chinese neonate with FHL2 secondary to compound heterozygous PRF1 mutation with symptom onset before 1 mo old. We review Chinese FHL2 patients in the literature for comparison. CASE SUMMARY: A 15-d-old female neonate was referred to our hospital for persistent fever and thrombocytopenia with diffuse petechiae. She was born to a G5P3 mother at 39 wk and 4 d via cesarean section secondary to breech presentation. No resuscitation was required at birth. She was described to be very sleepy with poor appetite since birth. She developed a fever up to 39.5°C at 7 d of life. Leukocytosis, anemia, and thrombocytopenia were detected at a local medical facility. CONCLUSION: A literature review identified 75 Chinese FHL2 patients, with only five presenting in the first year of life. Missense and frameshift mutations are the most common PRF1 mutations in Chinese, with 24.8% having c.1349C>T followed by 11.6% having c.65delC. The c.658G>C mutation has only been reported once in the literature and our case suggests it can be pathogenic, at least in the presence of another pathogenic mutation such as c.1066C>T.

[Clinical features of Kasabach-Merritt syndrome: an analysis of 16 neonates].

OBJECTIVE: To study the clinical features, treatment, and prognosis of neonates with Kasabach-Merritt syndrome (KMS), and to provide a reference for optimizing the diagnosis and treatment of this disease. METHODS: A retrospective analysis was performed for the clinical and follow-up data of 16 neonates with KMS who were admitted to the Anhui Children's Hospital, Anhui Medical University, from January 2016 to December 2020. RESULTS: Of the 16 neonates, there were 13 boys (81%) and 3 girls (19%), with an age of 1 hour to 10 days on admission. Among these neonates, 13 (81%) had cutaneous hemangioma (2 in the head and face, 5 in the trunk, and 6 in the extremities) and 3 (19%) had liver hemangioma. The main clinical manifestations of bleeding tendency and scattered petechiae and ecchymosis were observed in 10 neonates (62%). All the 16 neonates had varying degrees of thrombocytopenia and coagulation disorders. They all received glucocorticoid treatment after admission and 7 (44%) of them had response, among whom 4 experienced recurrence. Among the neonates with no response to glucocorticoid treatment, 3 received sirolimus treatment, among whom 1 had the tumor volume reduced by 58.8% after 4 weeks of treatment, with platelet count and coagulation function returning to normal, while 2 had no significant reduction in tumor volume or significant increase in platelet count and achieved a tumor volume reduced by (43.7±0.4)% after 4 weeks of combined treatment with bleomycin arterial embolization, with platelet count and coagulation function returning to normal. After 4 weeks of bleomycin arterial embolization alone for 4 neonates, tumor volume was reduced by (52.0±3.4)%, and platelet count and coagulation function returned to normal. Blunt and sharp dissection was performed for 2 neonates. The tumor was removed completely during surgery in the 2 neonates, with no infection or recurrence after surgery, and platelet count and coagulation function returned to normal. The postoperative pathological examination showed Kaposiform hemangioendothelioma in 1 out of the 2 neonates. CONCLUSIONS: KMS has characteristic clinical manifestations, histopathological features, and laboratory examination results. The KMS neonates who are not sensitive to glucocorticoids can achieve a good curative effect through arterial embolization and sirolimus treatment.