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    15 February 2024 Volume 42 Issue 2
      
    Commentary
    The forty-three year development of newborn screening in china: starting with Chen Ruiguan
    ZHAO Zhengyan
    Journal of Clinical Pediatrics. 2024, 42(2):  89-92.  doi:10.12372/jcp.2024.24e0027
    Abstract ( 76 )   HTML ( 92 )   PDF (1275KB) ( 44 )  
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    After forty-three years of development, China’s newborn screening program has achieved remarkable success. Professor Chen Ruiguan, not only a pioneer in the field of newborn screening in China but also the founder of this discipline. This article comprehensively reviews the development of newborn screening in China, including the expansion of screened diseases and technological innovations, the promulgation of relevant national policies, the significant achievements of newborn screening, and its impact on families and society. It also looks ahead to future directions, commemorating Professor Chen’s outstanding contributions.

    Development history of food for special medical purpose in China
    FENG Yi, CAI Wei
    Journal of Clinical Pediatrics. 2024, 42(2):  93-95.  doi:10.12372/jcp.2024.24e0002
    Abstract ( 107 )   HTML ( 82 )   PDF (1304KB) ( 75 )  
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    Food for special medical purpose (FSMP) has undergone significant development in China. This paper provides an overview of the evolution of China’s special medical food industry, including its journey from its inception to independent research and development. Furthermore, it discusses the progress made in clinical application, product types, research and development capabilities, as well as regulation and standard management. The challenges and opportunities faced by the special medical food industry in China are also explored. As the domestic and international markets continue to expand and technology advances, FSMP will increasingly play a crucial role in the field of clinical nutrition therapy.

    New trends in the diagnosis and treatment of rare diseases in the digital medical era
    WANG Jian, LI Niu
    Journal of Clinical Pediatrics. 2024, 42(2):  96-101.  doi:10.12372/jcp.2024.23e1260
    Abstract ( 90 )   HTML ( 18 )   PDF (1287KB) ( 61 )  
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    The high-throughput sequencing technology of genomic DNA has greatly improved the diagnostic efficiency of rare diseases, but currently there are still some patients who have not been diagnosed. In recent years, various detection techniques such as transcriptome, proteomics, metabolomics and lipidomics, and epigenetics have gradually been applied in clinical practice, making it possible to comprehensively diagnose rare disease patients based on these multiomics methods. On the other hand, with the increase of confirmed cases, how to effectively integrate patient clinical data and build rare disease databases to meet the construction needs of high-quality research-oriented patient cohorts has become an increasingly important issue for governments around the world. More importantly, the development of big data models that integrate multiomics information can promote the application of artificial intelligence and machine learning in rare disease research. This will contribute to the clinical evaluation and precise classification of rare disease patients, and effectively improve the research and development efficiency of innovative diagnostic and therapeutic technologies such as gene therapy. Rare disease research has entered the era of digital medicine, which is also a practical need to meet the precise diagnosis and personalized treatment of patients at a higher level.

    Construction of the Shanghai children's rare disease registration database and summary of phased data
    LI Niu, LI Lei, CHEN Huiwen, WANG Jian, ZHANG Hao
    Journal of Clinical Pediatrics. 2024, 42(2):  102-109.  doi:10.12372/jcp.2024.23e0769
    Abstract ( 101 )   HTML ( 15 )   PDF (1402KB) ( 57 )  
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    Objective To summarize the construction plan of the Shanghai Children Rare Diseases Registry Database, and to retrospectively analyze the demographic characteristics and disease spectrum of the patients included in the database. We aim to clarify the distribution characteristics of rare diseases in children, and to provide data support for the construction of a high-level research-based patient cohort and the systematic management of patients with rare disease. Methods Based on the disease catalog from National Rare Diseases Registry System, we build a regional rare disease registration database that can connect to the hospital information system. Descriptive studies were conducted to analyze patient data in the database. Results A total of 6341 cases of rare disease patients diagnosed from 2008 to 2021 were included in the database, covering 109 kinds of diseases. The proportion of outpatients and inpatients was 59.4% (3764 cases) and 40.6% (2577 cases), respectively. The male to female ratio was 1.36∶1. Langerhans cell histiocytosis (11.3%), familial dilated cardiomyopathy (7.9%), hemophilia (5.5%), and neurofibroma (5.4%) accounted for the most cases. With the wide application of high-throughput sequencing technology, the number of pediatric rare disease patients with definite diagnosis has increased year by year, and more than 80% of children can get a clear diagnosis before the ten-year old. Conclusions The present study established a rare disease registry database that includes both outpatients and inpatients. We have described the disease spectrum and demographic characteristics of children with rare diseases, and also reflected the progress in the field of diagnosis of children’s rare diseases in recent years. This study will provide basic data support for further inclusion of more rare diseases and building a higher level database of children's rare diseases in multiple centers.

    Clinical characteristics of 20 rare diseases in children based on specific disease data
    ZHAO Shuai, MA Ang, LUO Shuying, XIA Songchen, HAO Chanjuan, LI Wei, WEI Haiyan, ZHANG Yaodong
    Journal of Clinical Pediatrics. 2024, 42(2):  110-115.  doi:10.12372/jcp.2024.23e0781
    Abstract ( 116 )   HTML ( 19 )   PDF (1371KB) ( 51 )  
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    Objective The purpose of this study is to explore and evaluate the clinical characteristics of children with different rare diseases by using the database of children's rare diseases in our hospital, so as to provide a basis for promoting the prevention, diagnosis and treatment of children with rare diseases. Methods The data of children in our rare disease database (Phase I) were analysed from 16th May 2011 to 29th January 2023 by child admission. The International Classification of Diseases (ICD-10) was used to classify and count the number of cases mined, gender, geography, age, genetic tests, repeat visits and hospitalisations. Results A total of 3491 children were included in the database, covering 20 rare diseases, representing 9.7% (20/207) of the rare disease catalogue. The ratio of male to female patients was 1.30:1 (1975 males/1516 females). Methylmalonic acidemia (1024 cases, 29.33%), congenital adrenocortical hyperplasia (944 cases, 27.04%) and phenylketonuria (191 cases, 5.47%) were the top three rare diseases. Genetic testing data were included in 220 cases, accounting for 6.30% of the total number of diseases. Hospitalised cases covered 16 provinces, with Henan province accounting for 96.60% of cases (1988/2058). Rare diseases in infancy accounted for 42.36% (1479/3491) of the total number of cases. Multiple osteofibrous dysplasia with precocious puberty syndrome was the highest percentage of repeat hospitalisation for rare diseases at 24.24% (8/33), while children with Kalman syndrome had the highest rate of repeat outpatient visits at 51.85% (14/27). Conclusion Based on the database of special diseases, we analyzed the clinical characteristics of 20 rare diseases in children, which provided a reference for promoting the prevention, control, detection and research of rare diseases in children in our province.

    Clinical characteristics and genotype analysis of adenosine deaminase 2 (ADA2) deficiency in China: a report of three cases
    ZHOU Yang, WU Yali, DING Yan
    Journal of Clinical Pediatrics. 2024, 42(2):  116-120.  doi:10.12372/jcp.2024.22e0958
    Abstract ( 88 )   HTML ( 12 )   PDF (2659KB) ( 50 )  
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    Objective To summarise the clinical features and genotypic characteristics of three children with adenosine deaminase 2 (ADA2) deficiency and to improve understanding of the disease. Methods The clinical features of three children with ADA2 deficiency were retrospectively analysed and genetically analysed using exome sequencing (ES). The activity of ADA2 enzyme in the plasma of the patients was measured using a kit. The clinical and genotypic features of the disease were summarised. Results All three children in our group had ADA2 gene variants. Case 1 had recurrent fever, rash, and convulsions as the main clinical manifestations, combined with stroke, accompanied by markedly elevated inflammatory indexes, and there were compound heterozygous variants in the ADA2 gene: c.139G>T and c.484T>C variants. Case 2 had recurrent fever and rash as the main clinical manifestations, combined with gastrointestinal perforation and stroke during the course of the disease, with markedly elevated inflammatory indexes. ES identified compound heterozygous variants of c.916C>T and c.1069G>A in the ADA2 gene. In Case 3, the patient had recurrent fever and cough as the main clinical manifestations, combined with myocarditis, accompanied by markedly reduced immune function. ES identified c.849T>G homozygous variants in ADA2 gene; Plasma ADA2 enzyme activity was found to be significantly reduced in case 1 and 2. Conclusion ADA2 deficiency is rare in China, with variable clinical features, and mastering its clinical features and genetic characteristics can help improve the diagnosis level.

    Clinical Features And Genetic Characteristics Of Epilepsy Associated With CHD2 Gene Variants
    ZHANG Xiaoli, WANG Mengyue, ZHANG Chenyu, LI Jialin, MA Yichao, WANG Junling, LI Xiaoli, HAN Rui, XU Dan, JIA Tianming
    Journal of Clinical Pediatrics. 2024, 42(2):  121-126.  doi:10.12372/jcp.2024.22e1638
    Abstract ( 98 )   HTML ( 16 )   PDF (2854KB) ( 46 )  
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    Objective To analyze the clinical features and genetic characteristics of patients with epilepsy associated with CHD2 gene variants. Methods The clinical features, electroencephalogram (EEG), genotypes and responses to the anti-seizure medications (ASM) of 6 patients with CHD2 gene variants were retrospectively analyzed. Results The onset age of seizures in the 6 patients (5 males and 1 female) ranged from 20 months to 12 years. Multiple seizure types were observed, including focal seizures in 3 cases, generalized tonic-clonic seizures in 3 cases, eyelid myoclonus with or without absence seizures in 2 cases, atypical absence seizures in 1 case, epileptic spasms in 1 case, myoclonic seizures in 1 case and tonic seizures in 1 case. Three patients were diagnosed with epilepsy syndrome, of which 2 were Jeavons syndrome and 1 was Lennox-Gastaut syndrome. Two cases were photosensitive. All 6 patients had comorbidities, including 6 patients 6 were intellectual disability, 3 attention deficit hyperactivity disorder, 2 autism spectrum disorders, and 1 mental disorder. 4 patients carried de novo mutations and the other 2 were maternal origin in the CHD2 gene. Of these, 3 were nonsense variants, 2 were missense variants and 1 was 3.58-Mb deletion including CHD2. Within the follow-up of 5 years to 15 years, 4 of the 5 patients were effective with regular ASM. Two patients achieved seizure-free more than 2 years, 1 patients achieved seizure-free more than 1 year and 8 months. Conclusion Epileptic seizures are common clinical phenotype of patients with CHD2 gene variants. The common seizure types include focal and generalized tonic-clonic seizures, and the age of onset of epilepsy varies widely. Patients with Jeavons syndrome have poor prognosis. Valproate may show a positive effect on epilepsy with CHD2 gene variation. Mental disorder is a rare clinical phenotype.

    Clinical phenotypes and gene mutations analysis of children with STXBP1 gene-related encephalopathy
    LI Xiaoli, ZHANG Xiaoli, LI Xiao, HAN Rui, XU Dan, GAN Ling, JIA Tianming
    Journal of Clinical Pediatrics. 2024, 42(2):  127-132.  doi:10.12372/jcp.2024.22e1145
    Abstract ( 87 )   HTML ( 12 )   PDF (1350KB) ( 67 )  
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    Objective To investigate the clinical phenotype and genetic characteristics of children with developmental and epileptic encephalopathy(DEE) caused by syntaxin-binding protein 1(STXBP1) gene mutation. Methods The clinical data of 11 patient with STXBP1 gene-related encephalopathy admitted to the Third Affiliated Hospital of Zhengzhou University from October 2015 to May 2022 were retrospectively reviewed, and their clinical phenotypes, gene outcomes, treatment and efficacy were analyzed. Results Of the 11 children, 4 were males and 7 were females, 10 had seizures with developmental delay and 1 showed only developmental delay. The age of onset of epilepsy was 3 days to 1.5 years, with 6 cases starting at less than 3 months, 3 at 3-12 months, and 1 at more than 1 year of age. The common seizure types are epileptic spasm and focal seizure. All the 11 patients had the abnormal interictal electroencephalograms (EEG) including background slowness, multifocal discharge, suppression-burst, and hypsarrhythmia. Two cases had Otahara syndrome in the early stages, which evolved into infantile spasms in the later stages, five cases had infantile spasms, and the rest had epileptic syndromes that could not be typed. Four children had non-specific abnormalities on cranial MRI, including poor development of myelination, and widening of the subarachnoid space in the frontotemporal region.frontotemporal. All children had STXBP1 gene variants, with a total of 11 variant types, including 7 missense variants, 1 frameshift variant, 1 splicing variant, and 2 deletion variants, and the variant loci of the 7 children have not been reported in the literature, which were c.1694T>A, c.1115T>G, C.133_135del, C.1543dupG, exons 6-17 heterozygous deletion, C.429+1G>C, C.855C>G and c.842_843insGGACGACGGCCTGTGGGATAGCACT. During follow-up, 11patients had different degrees of developmental delay, 2 patients had died, and 4 patients had autistic like features. Ten patients with epilepsy were treated with levetiracetam. One patient was seizure free with levetiracetam alone, 5 patients showed partial response, and 4 patients showed no response on multitherapy. 3 patients was seizure free, the remaining 7 patients were drug resistant epilepsy. Conclusion STXBP1 gene-related epilepsy usually occur to infant, and infantile spasm is the most common phenotype. There is significant heterogeneity in the therapeutic effect of epilepsy. Seven unreported mutation sites enriched the gene spectrum of STXBP1 encephalopathy.

    Analysis of the results of newborn screening for fatty acid oxidative metabolic diseases in ethnic minority areas of Hainan Province
    HUANG Cidan, XU Haizhu, WEN Yingmei, LIU Xiulian
    Journal of Clinical Pediatrics. 2024, 42(2):  133-138.  doi:10.12372/jcp.2024.22e1193
    Abstract ( 65 )   HTML ( 8 )   PDF (1388KB) ( 34 )  
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    Objective To investigate the incidence of fatty acid oxidative metabolism disorders (FAOD) in the neonatal population in ethnic minority areas of Hainan Province, and to analyse the clinical characteristics of the diagnosed children, so as to provide the basis for the prevention of birth defects in Hainan Province. Methods Tandem mass spectrometry screening data of newborns with inherited metabolic disorders from October 2016 to December 2021 were collected from ethnic minority areas in Hainan Province. Tandem mass spectrometry was used to detect the levels of free carnitine as well as 30 acylcarnitines in dried blood spots of newborns. Initial screen-positive neonates were recalled for review of blood tandem mass spectrometry, urinary organic acids were measured by gas-phase mass spectrometry, and peripheral blood was collected from neonates and their parents for gene sequencing. Results A total of 46285 newborn samples were screened, of which 513 were positive in the first screening, the positive rate of the first screening was 1/90, 501 cases were recalled, and 11 cases of fatty acid β -oxidation metabolic disease were diagnosed, the incidence rate was 1/4208, including 6 cases of primary carnitine deficiency, 1 case of short chain, medium chain and very long acyl-CoA dehydrogenase deficiency, and 1 case of carnitine palmitoyl transferase I and II deficiency. Conclusion The incidence of fatty acid β-oxidative metabolic disease is high among newborns in minority areas of Hainan province, and primary carnitine deficiency is more common. It is suggested that the screening of neonatal genetic metabolic diseases by tandem mass spectrometry should be included in the routine of newborn screening program.

    Factors related to bronchiolitis obliterans syndrome in pediatric patients survived longer than 100 days after hematopoietic stem cell transplantation
    SUN Ruonan, LI Bohan, ZHENG Defei, ZHAO Xiaying, LIN Ziyun, HU Yixin, GAO Li, GAO Jing, LI Jie, LU Jun, XIAO Peifang, PAN Jian, LING Jing, FANG Fang, HU Shaoyan
    Journal of Clinical Pediatrics. 2024, 42(2):  139-145.  doi:10.12372/jcp.2024.22e1533
    Abstract ( 88 )   HTML ( 15 )   PDF (1416KB) ( 59 )  
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    Objective To analyse the clinical characteristics and risk factors of occlusive bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children in order to further optimize the treatment protocol.Methods Clinical data of children who received allo-HSCT from October 2010 to December 2018 at Children's Hospital of Soochow University were retrospectively analysed. Results A total of 351 children were included, 213 males and 138 females. Until September 1, 2019, a total of 29 (8.3%) children developed BOS, 11 males and 18 females, with a median age of 92.0 (67.0-132.0) months. The median time from transplantation to the development of BOS was 10.0 (8.5-20.0) months. The cumulative incidence of BOS at 1, 2, and 3 years after transplantation was (6.0±1.3)%, (10.0±1.8)%, and (10.7±2.0)%, respectively. 28 of the 29 children with BOS had comorbidities with chronic graft-versus-host disease (cGVHD) in other target organs prior to the onset of BOS. The results of multifactorial logistic regression analysis showed that older age, female gender, respiratory disease within 100 days after transplantation, and comorbidities with other target organ cGVHD were independent risk factors for the development of BOS (P<0.05). Conclusion BOS is a serious complication after HSCT. Children who were female, older, had a combination of other target organ cGVHD, and had respiratory disease within 100 days of transplantation were at greater risk of developing BOS.

    Diagnosis of a child with Duchenne muscular dystrophy using optical genome mapping
    LIANG Huan, ZHANG Huiwen
    Journal of Clinical Pediatrics. 2024, 42(2):  146-150.  doi:10.12372/jcp.2024.22e1407
    Abstract ( 82 )   HTML ( 13 )   PDF (1494KB) ( 114 )  
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    Objective To explore the application of optical genome mapping (OGM) in the diagnosis of Duchenne muscular dystrophy (DMD). Methods An OGM analysis was performed in a child with suspected DMD with a view to discovering the molecular basis of the pathogenesis. Results A male child with significantly elevated creatine kinase at 7 months of age was clinically suspected of having DMD. No pathogenic gene variants were detected by multiplex ligation-dependent probe amplification analysis (MLPA) and exome sequencing. At 1 year and 9 months, the child was unstable and prone to falls, and bilateral gastrocnemius muscle hypertrophy and muscle weakness were detected on physical examination. At the age of 2 years, an intra-arm inversion of about 711kb involving 12 exons of the 44-55 region of the gene was identified by OGM, which enabled the molecular diagnosis of this child. Conclusions OGM technology can successfully detect the reverse mutation of the DMD gene, and is thus poised to become a supplementary diagnostic tool for this disease.

    Clinical Report
    Acute Liver Failure of Preterm Infant
    ZHOU Lin, LIU Chengbo, LIU Ming, ZHU Yunkai, LU Yongjian, ZHANG Yongjun, XIA Hongping
    Journal of Clinical Pediatrics. 2024, 42(2):  151-156.  doi:10.12372/jcp.2024.22e1420
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    Objective To investigate the clinical features of gestational alloimmune liver disease-neonatal hemochromatosis (GALD-NH) and to provide differential diagnosis of neonatal liver failure.Method A preterm infant admitted in neonatal intensive care unit shortly after birth. He presented with persistent thrombocytopenia, severe coagulation disorder, hypoproteinemia, cholestasis and ascites. Specialists from Department of Radiology, Ultrasonography, and Stomatology were invited to discuss the case. The diagnosis and treatment were adjusted according to the result of discussion. Results The case was characterized by acute liver failure in the early life. After multi-disciplinary treatment, GALD-NH was considered as the most likely cause of liver failure. Although oral mucosa biopsy was negative, abdominal (liver, spleen, pancreas) MRI showed liver and spleen had hypointense on T2WI. Liver biopsy showed that pathologic siderosis in hepatocytes. The patient finally diagnosed as GALD-NH. Conclusion When neonate with liver failure, neonatal hemochromatosis should be considered in addition to infectious liver disease, obstructive liver disease and genetic metabolic disease.

    Literature Review
    Progress in diagnosis and treatment of Bardet Biedl syndrome
    LIN Jiao, XU Xinxing, WANG Chuankai, JIANG Liqiong, WANG Chunlin
    Journal of Clinical Pediatrics. 2024, 42(2):  157-163.  doi:10.12372/jcp.2024.22e1314
    Abstract ( 101 )   HTML ( 198 )   PDF (1353KB) ( 66 )  
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    The Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder affecting multiple systems, primarily manifesting as retinal lesions, polydactylism (or hyperdactylism), obesity, intellectual diminution, sexual duct development deficiency, and renal abnormalities. To date, 26 disease-causing genes have been identified, all of which are localised to the primary cilia, with the BBS1, BBS2 and BBS10 genes being the most common genetic causes. There is no curative therapy for this disease, and symptomatic supportive treatment is the main focus. This paper reviews the disease from the perspectives of clinical characteristics, diagnostic criteria, causative genes, the current situation of BBS patients in China, and treatment, with a view to providing reference for the clinical diagnosis and treatment of this disease.

    New advances in the study of cartilage extracellular matrix gene regulation and genetic defects
    JIN Yuyu, LUO Feihong
    Journal of Clinical Pediatrics. 2024, 42(2):  164-170.  doi:10.12372/jcp.2024.23e0827
    Abstract ( 78 )   HTML ( 193 )   PDF (1353KB) ( 43 )  
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    The formation and development of growth plate cartilage is a sophisticated biological phenomenon that is governed by a combination of extracellular matrix (ECM), intracellular signaling, paracrine signaling and endocrine signaling. The ECM plays a critical role in providing structural support to chondrocytes and acts as a mediator for the transport of growth factors and associated signaling molecules that control chondrocyte growth and development. This review provides a comprehensive examination of the composition and physiological role of the cartilage ECM, explores the impact of pathogenic variants in genes responsible for encoding the cartilage ECM on skeletal development, investigates the specific phenotypes associated with such defects and establishes a correlation between pathogenic gene variants and phenotypic outcomes aiming to provide novels insights for clinical diagnosis and managements.

    Continuing Medical Education
    Status and prospects of the children's digital research network
    WANG Bo, ZHOU Xin, SUN Jing, ZHAO Liudan, SUN Kun
    Journal of Clinical Pediatrics. 2024, 42(2):  171-176.  doi:10.12372/jcp.2024.23e0824
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    Due to the characteristics of children's growth and development, the diagnosis and treatment of pediatric diseases differ significantly from those of adults, and there is an urgent need to develop a series of diagnostic and treatment guidelines that are appropriate for pediatric diseases and populations. However, the prevalence of most childhood disorders is low, and single-center clinical investigations cannot provide sufficient empirical support. Big data research networks are interconnected research platforms made up of multiple medical institutions, disease-specific research networks, and data collaboration platforms. They can collect a large enough sample size to efficiently conduct pediatric clinical research, better understand pediatric diseases, and improve diagnostic and treatment protocols. This article reviews the clinical research and key technologies based on the pediatric research network, discusses the existing problems, and proposes future development ideas, in order to provide reference for the subsequent construction and development of the pediatric research network, and further enhance the level of pediatric clinical research in China.