Objective:To explore the diagnostic value of fetal echocardiography (ECHO) for ventricular septal defect (VSD) and the causes of missed diagnosis and misdiagnosis by analyzing the standard of ECHO sections and image quality.Methods:A retrospective analysis was conducted on 94 VSD fetuses diagnosed by ECHO at Xiangtan Maternal and Child Health Care Hospital from January 2022 to June 2024. Clinical data including the anatomic subtypes, associated anomalies, chromosomal karyotype results, pregnancy outcomes, and neonatal ECHO results were collected and analyzed. Besides, by reviewing the ultrasound images from the institution's ultrasound workstation, a descriptive analysis was conducted on the ECHO section criteria and image quality in the missed and misdiagnosed cases.Results:Among 10 984 fetuses undergoing ECHO, a total of 94 cases of fetal VSD were detected (0.7%), including 45 (48%) isolated VSD and 49 (52%) non-isolated VSD cases. Anatomic distribution revealed perimembranous type predominance (67, 71%), followed by muscular (24, 26%), subarterial types (2, 2%), and perimembranous+muscular type (1, 1%). Among 29 missed diagnosis cases (fetal ECHO-negative but neonatal ECHO-confirmed VSDs), all were isolated VSD, muscular types accounted for 19 (66%), perimembranous types for 8 (27%), and subarterial types for 2 (7%). The causes of missed diagnosis include: technical limitation in 14 cases (48%), restricted cardiac acoustic window in 11 cases (38%), and operator-dependent factors in four cases (14%). All 18 misdiagnosed cases occurred in isolated VSD, with 15 cases of perimembranous and three cases of muscular types. The causes of misdiagnosis include: nine cases due to non-perpendicular beam alignment to perimembranous septum, six cases due to excessively high color flow gain,and three cases due to the misinterpretation of the right ventricular outflow tract flow above the aortic valve as VSD septal perforation blood flow. The sensitivity and specificity of fetal ECHO for diagnosing VSD were 76.42% and 99.83%. Among the 94 cases of fetal VSD, 38 cases (40%) underwent chromosomal karyotype analysis and chromosomal microarray analysis, which identified chromosomal karyotype abnormalities or pathogenic gene variants in 4/16 non-isolated VSDs (all perimembranous), while no anomalies were detected in 22 isolated VSDs. Pregnancy outcomes showed 31 terminations due to associated structural or chromosomal abnormalities versus 63 live births. In the live births, who underwent echocardiography in the neonatal period, 19 cases (30%) showed no VSD and were considered to have undergone spontaneous in utero closure, and persistent defects were found in 44 (70%).Conclusions:Fetal ECHO demonstrates high sensitivity and specificity in the diagnosis of fetal VSD. Critical quality control measures include individualized parameter adjustment and systematic multiplanar continuous scanning to minimize diagnostic errors. Isolated small and medium-sized muscular and perimembranous VSD usually have a good prognosis.

Objective:To explore the diagnostic value of fetal echocardiography (ECHO) for ventricular septal defect (VSD) and the causes of missed diagnosis and misdiagnosis by analyzing the standard of ECHO sections and image quality.Methods:A retrospective analysis was conducted on 94 VSD fetuses diagnosed by ECHO at Xiangtan Maternal and Child Health Care Hospital from January 2022 to June 2024. Clinical data including the anatomic subtypes, associated anomalies, chromosomal karyotype results, pregnancy outcomes, and neonatal ECHO results were collected and analyzed. Besides, by reviewing the ultrasound images from the institution's ultrasound workstation, a descriptive analysis was conducted on the ECHO section criteria and image quality in the missed and misdiagnosed cases.Results:Among 10 984 fetuses undergoing ECHO, a total of 94 cases of fetal VSD were detected (0.7%), including 45 (48%) isolated VSD and 49 (52%) non-isolated VSD cases. Anatomic distribution revealed perimembranous type predominance (67, 71%), followed by muscular (24, 26%), subarterial types (2, 2%), and perimembranous+muscular type (1, 1%). Among 29 missed diagnosis cases (fetal ECHO-negative but neonatal ECHO-confirmed VSDs), all were isolated VSD, muscular types accounted for 19 (66%), perimembranous types for 8 (27%), and subarterial types for 2 (7%). The causes of missed diagnosis include: technical limitation in 14 cases (48%), restricted cardiac acoustic window in 11 cases (38%), and operator-dependent factors in four cases (14%). All 18 misdiagnosed cases occurred in isolated VSD, with 15 cases of perimembranous and three cases of muscular types. The causes of misdiagnosis include: nine cases due to non-perpendicular beam alignment to perimembranous septum, six cases due to excessively high color flow gain,and three cases due to the misinterpretation of the right ventricular outflow tract flow above the aortic valve as VSD septal perforation blood flow. The sensitivity and specificity of fetal ECHO for diagnosing VSD were 76.42% and 99.83%. Among the 94 cases of fetal VSD, 38 cases (40%) underwent chromosomal karyotype analysis and chromosomal microarray analysis, which identified chromosomal karyotype abnormalities or pathogenic gene variants in 4/16 non-isolated VSDs (all perimembranous), while no anomalies were detected in 22 isolated VSDs. Pregnancy outcomes showed 31 terminations due to associated structural or chromosomal abnormalities versus 63 live births. In the live births, who underwent echocardiography in the neonatal period, 19 cases (30%) showed no VSD and were considered to have undergone spontaneous in utero closure, and persistent defects were found in 44 (70%).Conclusions:Fetal ECHO demonstrates high sensitivity and specificity in the diagnosis of fetal VSD. Critical quality control measures include individualized parameter adjustment and systematic multiplanar continuous scanning to minimize diagnostic errors. Isolated small and medium-sized muscular and perimembranous VSD usually have a good prognosis.

Objective:To analyze the clinical features of anti-neurofascin-155 (NF155) antibody positive autoimmune nodopathy in children.Methods:This was a case series study. A total of 6 children who were diagnosed accurately as anti-NF155 antibody positive autoimmune nodopathy by cell immunofluorescence assay at the Children′s Hospital of Fudan University from January 2020 to December 2023 were collected. This study retrospectively analyzed 6 pediatric children′s clinical manifestations, laboratory and electrophysiological examination results, and treatment outcomes.Results:Among 6 children with anti-NF155 antibody positive autoimmune nodopathy, there were 4 boys and 2 girls. The onset age of 6 children ranged from 3 years and 8 months to 12 years. All 6 children had extremity weakness (more severe in the distal and the lower extremities than in the upper extremities), 5 children had sensory deficits such as numbness or pain in the extremities, 4 children had tremors and ataxia, 3 children had cranial nerve involvement. Among the 6 children, 4 children had protein-cell separation in cerebrospinal fluid examinations. Among the 6 children, 1 child had central nervous system demyelination, the brain magnetic resonance imaging showed multiple abnormal signals in the bilateral cerebral hemispheres. Four children showed motor and sensory nerve damage in electrophysiological examination, and 2 children only showed motor nerve damage. Three children showed myelin and axonal damage, and 3 children only showed axonal damage. Among the 6 children, 5 children were treated with intravenous immunoglobulin and steroids. Among them, 2 children underwent plasma exchange due to poor efficacy, and subsequently, rituximab was added. There was 1 child changed the treatment with olfatomumab since the symptoms did not significantly improve after using rituximab. After treatment for 4-15 months, 2 children had no clinical symptoms, 1 child had improvement in clinical symptoms, 2 children had no significant improvement in clinical symptoms, and 1 child who did not receive the immunotherapy had no significant change in clinical symptoms.Conclusions:Anti-NF155 antibody positive autoimmune nodopathy in children presents with varying degrees of clinical manifestations. It is mainly characterized by extremity weakness, numbness and pain, often accompanied bytremorsand ataxia. Some pediatric patients may also have central nervous system demyelination. Cerebrospinal fluid and electrophysiological examination are important auxiliary examination methods. If steroid therapy is not effective, plasma exchange and rituximab treatment should be used as soon as possible.

OBJECTIVE: To explore the clinical features and genetic variant in a child with Cerebral creatine deficiency syndrome (CCDS). METHODS: A child who had presented at the Affiliated Children's Hospital of Fudan University on March 5, 2021 was selected as the study subject. Whole exome sequencing (WES) was carried out for the child, and candidate variant was verified by Sanger sequencing. The level of creatine in the brain was determined by magnetic resonance spectroscopy. RESULTS: The patient, a 1-year-and-10-month male, had presented with developmental delay and epilepsy. Both his mother and grandmother had a history of convulsions. MRS showed reduced cerebral creatine in bilateral basal ganglia and thalamus. The child was found to harbor a hemizygous splicing variant of the SLC6A8 gene, namely c.1767+1_1767+2insA, which may lead to protein truncation. The variant was not found in the public databases. Both his mother and grandmother were heterozygous carriers for the same variant. CONCLUSION The hemizygous c.1767+1_1767+2insA variant of the SLC6A8 gene probably underlay the CCDS in this child. Discovery of the novel variant has also expanded the mutational spectrum of the SLC6A8 gene.
Humans ; Male ; Amino Acid Metabolism, Inborn Errors ; Brain ; Creatine/genetics* ; Heterozygote ; Mothers ; Nerve Tissue Proteins ; Plasma Membrane Neurotransmitter Transport Proteins/genetics* ; Infant

Objective:To analyze the clinical characteristics and genetic features of SMC1A gene related disorders. Methods:The data of 5 children with SMC1A gene variants were collected from Children′s Hospital of Fudan University from February 2018 to January 2022. The clinical features, electroencephalogram (EEG), brain imaging and gene testing results were summarized. Results:Among the 5 patients, 4 are females and 1 is male. Two female cases are siblings. One boy had dysmorphic features, consisting of bilateral ptosis, synophrys, a short nose and upturned nasal tip. He also had patent foramen ovale plus atrial septal defect, unilateral cryptorchidism and microcephaly. Three cases had microcephaly. Two girls had patent foramen ovale, and 2 girls had microcephaly. Four cases had epilepsy, and age at seizure onset ranged from 2 to 52 months. Multiple seizure types were observed, including bilateral tonic clonic seizures in 2 patients, and focal seizures in 3 patients. The seizures in 3 cases were in cluster. All patients had developmental delay, including 1 patient with mild and 4 patients with moderate to severe developmental delay. Three patients had slow background activity in EEG. Interictal EEG showed abnormal discharges in 4 patients, including focal discharges in 3 cases and generalized discharges in 1 case. Brain magnetic resonance imaging was normal in 3 patients and showed mild cortical thickening in 1 case. All cases harbored 4 SMC1A gene variants, including 2 missense variants and 2 frameshift variants (c.580_587del, c.2699delG, c.3362G>A, c.1486C>T). Three cases harbored heterozygous SMC1A variants and 2 cases carried somatic mosaic SMC1A variants with 17.5% and 88.1% mosaicism in peripheral blood. The follow-up lasted for 3 months to 4 years. The epilepsy was refractory in 2 cases. During the follow-up, all cases had very slow developmental progress or developmental retardation. All cases had different levels of growth retardation. The scores of Cornelia de Lange syndrome (CdLS) phenotypes in 5 cases were 2-6. One case had the combined phenotypes of atypical CdLS and developmental epileptic encephalopathy (DEE). The phenotype was atypical CdLS in 1 case and DEE in 1 case. The phenotypes of 2 cases with SMC1A missense variants were mild, manifesting as non-refractory epilepsy and moderate to severe developmental delay. Conclusions:All of cases with SMC1A gene variants have developmental delay. Most of the patients have clusters of seizures and some dysmorphisms. The phenotypes of SMC1A gene related disorders are diverse. Except CdLS and DEE, there are some patients with mild phenotype due to missense variants of SMC1A gene.

Objective:To analyze the clinical phenotype, copy number variation, treatment and follow-up characteristics of children with typical 16p11.2 deletion syndrome.Methods:The clinical data of 10 children with typical 16p11.2 deletion syndrome who were treated in the Department of Neurology, Children′s Hospital of Fudan University from August 2011 to December 2021 were retrospectively collected, and their clinical phenotype, copy number variation, treatment and follow-up were summarized.Results:Among the 10 children, 4 are female and 6 are male, all with epilepsy. Nine patients had epilepsy in infancy, and the age of onset was 6.0 (4.0, 8.5) months. Four cases had focal seizures (1 with fever), 4 had generalized tonic-clonic seizures, and 2 had focal seizures with generalized tonic-clonic seizures. Eight cases had cluster seizures (more than 2 to 10 seizures within 24 hours), and 1 case had 1 status epilepticus. Nine children did not show obvious developmental delay at the onset of epilepsy, and 1 child had developmental delay at the onset of epilepsy at 14 months of age. One child had parallel toes at left foot, and 1 had macrocephaly and low limb muscle tone. Genetic testing found that 10 children carried typical 16p11.2 heterozygous deletion, the starting position of the deletion fragment was Chr16:29478119-29675016, the ending position was Chr16:30125670-30206112, and the deletion length was 525-712 kb, all of which were considered pathogenic variants. In the antiepileptic drug treatment, 4 children were treated with oxcarbazepine, 2 with sodium valproate, 2 was switched to oxcarbazepine after levetiracetam was ineffective, 1 with levetiracetam combined with sodium valproate, and 1 with levetiracetam in combination with sodium valproate and ketogenic diet, and all 10 children had no seizures. One patient developed episodic exercise-induced dyskinesia at school age, and the seizures decreased after treatment with oxcarbazepine. Follow-up of 10 children found that 9 children had different degrees of developmental delay (language was significantly affected), 3 cases were combined with autism-like manifestations, and 1 case had poor comprehension, learning difficulties, and repeated grades after entering regular primary schools.Conclusion:The typical 16p11.2 microdeletion syndrome has the deletion of gene fragments in the proximal region of 16p11.2, characterized by drug-responsive cluster seizures with onset in infancy, which may be accompanied by language delay, autism spectrum disorder and nonspecific malformations.

Clinical data of two patients with congenital myasthenia syndrome type 22 (CMS22) treated at the Children′s Hospital of Fudan University from February 2019 to November 2021 were retrospectively analyzed, and relevant literatures were reviewed.Both patients were female, aged 3 months 18 days and 3 months 26 days, respectively, with typical clinical features of CMS (postnatal onset, skeletal muscle weakness, feeding difficulties, and delayed motor development). Genetic testing revealed that one patient had a homozygous frameshift mutation of the PREPL gene from maternal uniparental disomy c. 1282_1285del(p.F428fs*18), and the other one had a compound heterozygous mutation, including the paternal homozygous frameshift mutation of the PREPL gene and maternal monoallelic nonsense mutation and splicing mutation c. [1501G>T; 2020+ 1G>T], p.[G501*; -]. Two patients were treated with Pyridostigmine bromide at the age of 6 months old and 4 months old, respectively, and the medication last for 15 months and 3 months (still under treatment), respectively.The treatment was effective.Through literature review, 7 English language articles were retrieved, involving 13 cases (2 cases in the presented study were included). The main clinical symptoms of CMS22 included neonatal onset with feeding difficulties and motor development delay, accompanied by cognitive impairment, growth hormone deficiency, and obesity.Genetic testing is favorable to the early diagnosis, early treatment, and symptom relief.

Anti-seizure medications (ASMs) are the main therapy for epilepsy.There are many kinds of ASMs with complex mechanism of action, so it is difficult for pharmacists to examine prescriptions.This paper put forward some suggestions on the indications, dosage forms/routes of administration, appropriateness of usage and dosage, combined medication and drug interaction, long-term prescription review, individual differences in pathophysiology of children, and drug selection when complicated with common epilepsy, for the reference of doctors and pharmacists.

Christianson syndrome is a rare X-linked disease caused by mutations in the SLC9A6 gene. The clinical manifestations are male developmental delay, language disorder, seizures, mental retardation, ataxia, microcephaly and so on. Two cases of male children with Christianson syndrome were reported. The proband was 1 year and 11 months old. Clinical manifestations include microcephaly, global developmental delay, and seizures. The electroencephalogram showed that the central midline region of spikes and slow waves were emitted, and all exons sequencing detected a mutation in the SLC9A6 gene chrX: 135084373 [c.803+1(IVS6)G>A]. The proband′s brother was 4 years and 8 months old. The clinical manifestations were similar. The electroencephalogram showed spikes and spines in the Rolandic area on both sides. Slow waves and spiny slow waves were emitted. Magnetic resonance imaging suggested brain atrophy. The genetic verification results were consistent with the proband. The SLC9A6 gene c.803+1(IVS6) G>A splicing mutation was a pathogenic mutation in this family.

Objective:To summarize the clinical features of childhood opsoclonus-myoclonus syndrome (OMS), evaluate severity degree and prognosis using OMS Symptom Severity Standard Rating Scale.Methods:The clinical features,diagnosis, therapeutic regimen and follow-up of 9 children with OMS in Department of Neurology and Oncology Department of Children's Hospital of Fudan University between 2011 and 2019 were retrospectively reviewed. Severity degree and prognosis were evaluated using OMS Symptom Severity Standard Rating Scale.Results:Among the 9 children with OMS, 4 were males and 5 were females. The onset age ranged from 14 months to 5 years, with a median of 17 months. Main symptoms were opsoclonus, myoclonus, ataxia, motor function regression, behavior and mood changes and sleep disorders. Eghit patients were combined with tumor. Seven of them with neuroblastoma were confirmed by surgical pathology, the other one showed spontaneous regression and symptom remission without treatment. Eight patients received hormone combined with intravenous immunoglobulin, of which 3 cases received adrenocorticotropic hormone, while 5 cases received methylprednisolone pulse therapy, with prednisone sequential therapy, decreasing dose gradually. Rituximab was administrated in 3 patients whose annual recurrent time was≥2. Nine patients were divided into 3 groups according to OMS Symptom Severity Standard Rating Scale, 1 of mild degree, 3 of moderate degree, 5 of severe degree. There was no recurrence and sequelae in the mild-degree patient after 3 years follow-up. There was no recurrence and sequelae in 2 of the moderate-degree patients after 1-2 years follow-up. Different degrees of motor, cognitive sequelae were found in 1 of moderate-degree patients and all of severe-degree patients after 1-8 years follow-up.Conclusions:Childhood OMS patients have early onset age. Bad symptom severity before treatment and multiphase course are associated with poor prognosis. OMS Symptom Severity Standard Rating Scale is suitable for estimations of long-term prognosis.