Journal of Clinical Pediatrics

Detection technology and application selection of genetic metabolic diseases

HAN Lianshu

Journal of Clinical Pediatrics. 2023, 41(2): 81-85. doi:10.12372/jcp.2023.22e1461

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Inherited metabolic diseases among rare diseases, also known as inborn errors of metabolism, refer to the enzymes, receptors, and cell membrane dysfunctions involved in and caused by genetic defects. These diseases lead to the blockage of metabolic pathways, and an accumulation of intermediate, bypass products, or a lack of terminal products, resulting in a variety of clinical symptoms. In recent years, the advances in detection techniques have enabled a larger number of patients to be diagnosed and treated timelier, shortening the time from disease onset to treatment and improving the quality of outcomes. This article focuses on fluorescence immunoassay techniques, tandem mass spectrometry, gas chromatography-mass spectrometry, gene sequencing, chromosome detection techniques and options of techniques above for inherited metabolic diseases to improve clinicians' understanding.

Genetic diagnosis and management of TRPV4 disorders

HU Xuyun, HAO Chanjuan

Journal of Clinical Pediatrics. 2023, 41(2): 86-91. doi:10.12372/jcp.2023.22e1621

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TRPV4 disorders are a group of disorders with the same disease-causing gene but highly heterogeneous phenotypes. TRPV4 disorders can be divided into two different subgroups: neuromuscular disorders and skeletal dysplasia. TRPV4 disorders were clinically classified as multiple independent disorders before their molecular basis was discovered. Therefore, genetic testing is of great significance for the diagnosis and management of TRPV4 disorders. This paper reviews the characteristics of TRPV4 and each disorder, genetic testing methods, genotype-phenotype correlation information and management after diagnosis, providing ideas for the diagnosis and treatment of TRPV4 disorders.

Genetic classification, diagnosis, and treatment of hyperphenylalaninemia

LIANG Lili

Journal of Clinical Pediatrics. 2023, 41(2): 92-97. doi:10.12372/jcp.2023.22e1525

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Hyperphenylalaninemia is a group of autosomal recessive amino acid metabolic disorders, caused by defects in phenylalanine hydroxylase and its coenzyme tetrahydrobiopterin. If left untreated, severe neurological damage will occur. Treatment is based on low-phenylalanine diet therapy and neurotransmitter drug supplementation. Newborn screening for hyperphenylalaninemia began in China in 1982, more and more patients are being diagnosed during the screening. The diagnosis of hyperphenylalaninemia has shifted from the diagnosis of clinical symptoms to biochemical and genetic diagnosis in asymptomatic period. The early differential diagnosis and proper treatment for patients with hyperphenylalaninemia has become a new challenge for clinicians. Therefore, the article focuses on the genetic background, diagnosis, differential diagnosis and treatment of hyperphenylalaninemia, to raise the awareness for the disease among clinicians.

Screening of newborns with hyperphenylalaninemia and analysis of PAH gene mutation and deletion

MA Cuixia, Feng Lulu, Ma Qianqian, Li Yang, Feng Jizhen

Journal of Clinical Pediatrics. 2023, 41(2): 98-102. doi:10.12372/jcp.2023.21e1659

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Objective To understand the incidence, clinical typing, and variant characteristics of related genes in neonates with hyperphenylalaninemia (HPA) in Shijiazhuang. Methods 487,380 newborns underwent HPA screening in Shijiazhuang Disease Screening and Diagnosis Center from March 2017 to May 2021 were selected. The phenylalanine concentration in heel blood samples was detected by immunofluorescence, the phenylalanine hydroxylase (PAH) related genes of suspected positive children were detected by gene sequencing, and the target gene variants were verified by the Sanger sequencing in the parents of the children, and the results of gene sequencing were further compared with the normal people to fragment deletion regions. Results Among the 487,380 neonates, 191 were screened positive and 104 were diagnosed as HPA, all with PAH deficiency, with a prevalence of 1/4686. A total of 62 genetic variations were detected in 104 children, including 37 missense mutations, 10 splice mutations, 7 nonsense mutations, 2 synonymous mutations, 1 full code mutation and 5 heterozygous deletions. The most common variants of PAH gene are c.158G>A (18.7%), c.728G>A (10.5%), c.611A>G (6.7%), c.331C>T (4.8%) and c.721C>T (4.8%), and unreported gene fragment deletions (exon 6 heterozygous deletion) and gene variants (c.630T>G, c.61-1G>A, c.912+5G>A) were found. Conclusions The prevalence of HPA in Shijiazhuang was high at 1/4686; 62 PAH gene variants, including 5 fragment deletions, were identified; in addition, 5 unreported gene variants were found, which enriches the gene database.

Gene mutation analysis and long-term follow-up of 6-pyruvoyltetrahydropterin synthase deficiency in Qingdao

ZHONG Yaoyao, ZHANG Liqin, DU Wei, LU Weibing, LIU Tingting

Journal of Clinical Pediatrics. 2023, 41(2): 103-107. doi:10.12372/jcp.2023.22e1473

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Objective To investigate the screening, clinical manifestations, genetic variants and long-term follow-up results of 6-pyruvoyltetrahydropterin synthase deficiency (PTPSD) in Qingdao. Methods Two hundred and fifty-one children with hyperphenylalaninemia (HPA) in Qingdao Women and Children's Hospital from November 1998 to December 2021 were included, and urinary pterin profile test, erythrocyte dihydropteroate reductase activity test, tetrahydrobiopterin (BH4) loading test, and genetic test were performed to confirm the diagnosis of PTPSD. The incidence, gene mutations and long-term follow-up of PTPSD were analyzed. Results Twenty-six children were diagnosed as tetrahydrobioptenin deficiency (BH4D), all PTPSD, and the incidence of PTPSD among newborns in Qingdao was 12.7 per million. 19 children (from 17 families) underwent genetic testing, and 10 variants were detected among 34 alleles of PTS, with the higher frequency of variants being c.259C>T (29.4%, 10/34), and the rest were c.286G>A (14.7%, 5/34), c.272A>G (14.7%, 5/34), c.84-291A>G (8.8%, 3/34), c.166G>A (8.8%, 3/34), c.276T>A (8.8%, 3/34 ), and the variant sites were mainly concentrated in exon 5 (67.6%, 23/34). Among them, c.200C>T, c.259C>T and c.286G>A may be associated with severe PTPSD. Conclusion The incidence of PTPSD in Qingdao is 12.7/ million in 1996-2021, and the hotspot variants of PTS gene are c.259C>T, c.286G>A, c.272A>G. Establishment of a complete integrated management system of newborn disease screening-diagnosis-treatment-long-term follow-up-assistance is a powerful measure to achieve a tertiary prevention of birth defects and reduce the occurrence of disabled children.

Two cases of hydrocephalus due to methylenetetrahydrofolate reductase deficiency and MTHFR gene variants

DONG Hui, CHEN Zhehui, MA Xue, ZHANG Yao, SONG Jinqing, JIN Ying, LI Mengqiu, ZHANG Hongwu, YAO Hongxin, YANG Yanling

Journal of Clinical Pediatrics. 2023, 41(2): 108-112. doi:10.12372/jcp.2023.22e1574

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Objective To investigate the clinical characteristics, treatment, and prognosis of hydrocephalus due to methylenetetrahydrofolate reductase (MTHFR) deficiency caused by MTHFR gene variations. Methods Two boys admitted to the Department of Pediatrics of Peking University First Hospital with hydrocephalus were diagnosed by serum total homocysteine, blood amino acid and acylcarnitine profile, urinary organic acid, and genetic analysis. The clinical manifestations, biochemical features, MTHFR gene variants, diagnosis, therapy, and prognosis were retrospectively analyzed. Results Two children presented with hydrocephalus and seizures at 2 and 4 months of age, respectively, with significantly increased serum total homocysteine, reduced or low normal blood methionine, normal urinary organic acids, and severe hydrocephalus on cranial imaging. Serum total homocysteine decreased after treatment with betaine, calcium folinic acid, and cobalamin in both children, and intracranial pressure improved after lateral ventriculoperitoneal shunt surgery, but intellectual and motor development was delayed and seizures were still present. The diagnosis of homocysteinemia type 2 due to MTHFR deficiency was confirmed by the presence of compound heterozygous variants in the MTHFR gene in both children. One of the 4 variants was a known pathogenic variant and 3 were unreported novel variants. Conclusion Children with MTHFR deficiency may develop severe neurological symptoms such as hydrocephalus and epilepsy in early infancy, and serum total homocysteine and gene analysis are keys for the diagnosis.

Clinical features of three patients with ZTTK syndrome caused by SON gene mutation

ZHAO Peiwei, BI Bo, ZHANG Lei, HUANG Yufeng, TAN Li, HE Xuelian, ZHU Hongmin

Journal of Clinical Pediatrics. 2023, 41(2): 113-116. doi:10.12372/jcp.2023.22e0180

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Objective To investigate the clinical features and gene mutation of patients diagnosed with ZTTK syndrome (Zhu-Tokita-Takenouchi-Kim syndrome). Method The clinical data of three cases of ZTTK syndrome were retrospectively analyzed. Whole exome sequencing was applied to analyze the patients' genetic variants, and Sanger sequencing was used to verify the variant loci. Results In this study, 3 patients, aged from 10 months to 3 years and 8 months, had clinical phenotypes of facial dysmorphism, developmental delay, intellectual disability, microcephaly and abnormal muscle tone, abnormal hand joint or foot valgus, pyelonephritis, cryptorchidism and premature closure of cranial suture. In two cases, sulcus widening and cerebral dysplasia were observed on brain MRI. We found de novo variation in SON gene in all three children, c.3020G>A (p.R1007H), c.1195delG (p.V399fsTer1) and c.5753_5756delTTAG (p.V1918EfsTer87). Conclusion This study reports three cases of ZTTK syndrome due to SON gene abnormalities, which expands the mutation spectrum of SON gene. In this paper, we report three cases of ZTTK syndrome, extending the spectrum of mutations in this gene. The clinical manifestations of ZTTK syndrome are of multisystem involvement; whole exome sequencing may help to make a clear clinical diagnosis.

Comparison of the ratio method drug susceptibility test, micropore-plate method and whole-genome sequencing of anti-tuberculosis drugs in children

ZHANG Ying, REN Qiaoli, ZHAO Ruiqiu, XU Hongmei, LONG Xiaoru

Journal of Clinical Pediatrics. 2023, 41(2): 117-124. doi:10.12372/jcp.2023.22e0083

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Objective To explore the value of drug susceptibility test (DST) by micropore-plate method and whole-genome sequencing (WGS) in detecting the drug resistance of anti-tuberculosis drugs in children. Methods Sixty-one partially preserved strains with positive culture of Mycobacterium tuberculosis (MTB) were collected. The drug resistance of isoniazid, rifampicin, ethambutol, and streptomycin were detected by proportional method, micropore-plate method DST and WGS. The variants of four drug resistance related genes in WGS were summarized, and the clinical data, treatment plan and recovery of the affected children were collected. The reasons for the differences of drug resistance detected by the three methods were analyzed. Results Among 61 MTB strains, 78.69% (n=48) were pan-susceptible strains, 1.64% (n=1) was isoniazid-resistant strain, 1.64% (n=1) was streptomycin resistant strain, 6.56% (n=4) were isoniazid and streptomycin resistant strains, 3.28% (n=2) were isoniazid, rifampicin, and ethambutol resistant strains, 3.28% (n=2) were isoniazid, rifampicin and streptomycin resistant strains, and 4.92% (n=3) were resistant to the four drugs. The sensitivity, specificity, positive predictive value, negative predictive value, and the Kappa value of micropore-plate method for predicting isoniazid resistance were 100%, 92.0%, 73.3%, 100% and 0.81, for rifampicin were 85.7%, 98.2%, 85.7%, 98.2% and 0.84, for ethambutol were 0.0%, 100%, 0.0%, 91.8% and 0.0, for streptomycin were 80.0%, 98.0%, 88.9%, 96.2% and 0.81, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and the Kappa value of WGS for predicting isoniazid resistance were 90.9%, 94.0%, 76.9%, 97.9% and 0.79, for rifampicin were 100%, 98.2%, 87.5%, 100% and 0.92, for ethambutol were 60.0%, 94.6%, 50.0%, 96.4% and 0.50, for streptomycin were 80.0%, 98.0%, 88.9%, 96.2% and 0.81, respectively. Conclusion Highly consistent with ratio method, micropore-plate method and WGS have higher sensitivity to predict isoniazid, rifampin, and streptomycin resistant tuberculosis in children, which can replace traditional proportional method in clinical practice. However, it is suggested to use proportional method combined with WGS to comprehensively evaluate the ethambutol resistance of MTB, as the consistency of micropore-plate and ratio methods is poor.

Genotypes and clinical phenotypes of Noonan syndrome in children with hypertrophic cardiomyopathy

ZHU Xiaoli, YANG Qianli, WANG Bo, TA Shengjun, ZHAO Xueli, LI Jing, CHENG Shengquan, LIU Liwen

Journal of Clinical Pediatrics. 2023, 41(2): 125-129. doi:10.12372/jcp.2023.21e1258

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Objective To retrospectively summarize the genetic variants and clinical characteristics of Noonan syndrome in children with hypertrophic cardiomyopathy (HCM). Methods A total of 123 children with HCM were enrolled in this study. Second generation sequencing and bioinformatic analysis of 96 genes associated with hypertrophic cardiomyopathy were performed in 123 probands. Eleven patients with diagnosed with Noonan syndrome, and their clinical data and echocardiographic findings were collected. Results The median age of diagnosis of HCM was 2 years and 7 months (5 months to 10 years), and the median age of diagnosis of Noonan syndrome was 6 years and 9 months (7 months to 16 years). 10 of 11 children had variants in RAF1 gene on chromosome 3, one had variant in PTPN11 gene on chromosome 12, and 7 had other novel variants. One of the patients with RAF1 was also found carrying variant in MYBPC3 which is associated with HCM. Nine out of 11 patients with HCM had typical facial features of Noonan syndrome. All 11 children had hypertrophic cardiomyopathy, 9 with obstructive hypertrophic cardiomyopathy, 2 with right ventricular outflow tract obstruction, and 7 with congenital heart disease. Conclusion RFA1 mutation is commonly seen in children with HCM in Noonan syndrome. Those patients carried with RFA1 mutation are more likely to have left ventricular outflow track obstruction and congenital heart diseases.

Analysis of perioperative nutritional status of children with digestive system diseases

SHENG Jinye, MAO Xiaomeng, NIU Yang, ZOU Jing, LU Lina, WANG Ying, TANG Qingya, FENG Yi, CAI Wei

Journal of Clinical Pediatrics. 2023, 41(2): 130-133. doi:10.12372/jcp.2023.22e0552

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Objective To understand the incidence of malnutrition and the application of nutritional support in children hospitalized during the perioperative period for digestive system diseases.Methods Children who underwent surgery at Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine related to digestive system diseases with preoperative risk of malnutrition from April 2018 to December 2020 were selected as the studied population. Children were divided into well-nourished, moderately, and severely malnourished groups according to the results of the subjective holistic child nutrition assessment tool (SGNA), and the perioperative nutritional support of children with different nutritional status was compared. Results Three-hundred and ten (310) children were included, 191 males and 119 females, with a median age of 20.7 (6.1-80.6) months. Of the 310 children 124 (40.0%), were malnourished, 99 were moderately malnourished, and 25 were severely malnourished. The difference in age and disease distribution between the well-nourished and malnourished groups was statistically significant (P<0.05), with a higher proportion of the malnourished group correcting for 1 month to 3 years of age and a higher proportion of short bowel syndrome and esophageal hiatal hernia. Among 124 malnourished children, 95 (76.6%) received nutritional support. In the moderately malnourished group, 73 cases received nutritional support; in the severely malnourished group, 22 cases received nutritional support, and the difference in the distribution of nutritional support modalities between the two groups was statistically significant (P<0.05). Compared with children in the well-nourished group, children in the preoperative malnutrition group had longer hospital days and increased total hospital costs (P<0.05). Conclusion The detection rate of malnutrition in children with perioperative digestive system diseases is high, especially in children <3 years old. The rate of nutritional support was higher in children with malnutrition, but there were still cases of non-support.

Risk factors of 90-day readmission after liver transplantation in children with biliary atresia

WAN Shuangshuang, XU Renying, QIAN Yongbing, HONG Li, FENG Yi

Journal of Clinical Pediatrics. 2023, 41(2): 134-139. doi:10.12372/jcp.2023.22e0452

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Objective To investigate the 90-day readmission rate and risk factors of children with biliary atresia (BA) after liver transplantation (LT). Methods This retrospective cohort study was conducted in Xinhua Hospital, Renji Hospital and Shanghai Children's Medical Center affiliated to Shanghai Jiao Tong University School of Medicine from January 1 to December 31, 2019. Data of children with BA who received LT for the first time were retrospectively analyzed. Patients were divided into readmission group and non-readmission group according to whether they were readmitted within 90 days after LT. The differences between the two groups were compared. Logistic regression was used to analyze the risk factors of 90-day readmission. Results A total of 264 children (female 53.0%) were included, with a median age of 6.9 (5.6-9.4) months. The 90-day readmission rate was 22.0% (58 / 264). Compared with the non-readmission group, the readmission group had higher pediatric end-stage liver disease (PELD) score, higher serum total bile acid level (TBA), higher international normalized ratio (INR), longer length of hospital stays (LOS), lower platelet count and lower psoas muscle area (PMA), and all the difference were statistically significant (P<0.05). Binary logistic regression analysis showed that thrombocytopenia (OR =2.347, 95%CI: 1.154-4.776), TBA (OR =1.058, 95% CI: 1.011-1.106), PMA (OR = 0.615, 95% CI: 0.301-0.989), and LOS (OR= 1.069, 95% CI: 1.031-1.109) were the influencing factors of 90-day readmission after pediatric LT, with statistical significance (P<0.05).Conclusions Children with thrombocytopenia, elevated TBA, lower PMA and long LOS had a higher risk of 90-day readmission after LT.

Successful treatment of a case of premature IPEX syndrome with umbilical cord blood stem cell transplantation and literature review

XU Pu, QIAN Xiaowen, ZHAI Xiaowen, WANG Laishuan

Journal of Clinical Pediatrics. 2023, 41(2): 140-145. doi:10.12372/jcp.2023.22e0712

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The X-linked polyendocrine adenopathy enteropathy with immune disorder syndrome (IPEX ) is a primary immunodeficiency disease caused by a variant of the FOXP3 gene, typically presenting with a triad of severe enteropathy, type 1 diabetes mellitus and eczema. The child, a male, started with diabetes, intractable diarrhea, eczema, and recurrent infections, and was diagnosed with IPEX syndrome caused by FOXP3 gene variant by genetic testing, and was eventually treated with umbilical cord blood stem cell transplantation, which improved the child's autoimmune symptoms. In infants with early onset diabetes, intractable diarrhea and eczema, IPEX syndrome should be considered, and genetic testing should be performed. Early hematopoietic stem cell transplantation can prevent disease progression and complications in most children and improve their survival rate.

Analysis of the results of the combined hearing and deafness genetic screening of newborns in Tianjin

LIU Hongyan, LIU Huikun, LENG Junhong

Journal of Clinical Pediatrics. 2023, 41(2): 146-149. doi:10.12372/jcp.2023.22e0703

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To analyze clinical results of newborn hearing combined with genetic screening in Tianjin. Methods Newborns born in all midwifery institutions in Tianjin from January 1 to December 31, 2018, were selected as the study population, and combined newborn hearing and deafness gene screening was performed under the premise of informed and voluntary screening. Results Among the 102,570 newborns, 210 (0.2%) had different degrees of hearing impairment, including 114 cases of bilateral hearing loss and 96 cases of unilateral hearing loss. 72,866 cases were screened for deafness genes, and 3924 (5.4%) newborns were detected with genetic variants, including 146 single gene homogeneous variants, 14 single gene compound heterozygous variants, 68 multi-gene compound heterozygous and 3696 single gene heterozygous variants. The detection rates of GJB2, SLC26A4, GJB3 and mitochondrial 12SrRNA gene variants were 4.8%, 4.5%, 0.4% and 0.2%, respectively. Among the 423 children who underwent audiological diagnosis, the deafness gene variation rate was higher in the hearing impaired group than in the normal group; among the 210 hearing impaired children, the deafness gene variation rate was higher in the binaural deafness group than in the unilateral deafness group; among the 114 binaural deaf children, the deafness gene variation rate was higher in the severe to profound deafness group than in the mild to moderate deafness group, and the differences were statistically significant (P<0.05). Conclusion This study reports the incidence of hearing impairment and the detection of common deafness genes in newborns in Tianjin, and provides a reference for healthcare consultation in this region.

Research progress of biomarkers for early diagnosis of fetal growth restriction

WANG Shiming, WANG Yiweng, ZHANG Yongjun

Journal of Clinical Pediatrics. 2023, 41(2): 150-155. doi:10.12372/jcp.2023.22e1429

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Fetal growth restriction (FGR) is a common pregnancy complication and a major cause of neonatal morbidity and mortality. The adverse effects of FGR persist throughout the entire lifespan would increase the risk of delayed neurological development, chronic metabolic diseases, and mortality. At present, in clinic, the detection rate of prenatal diagnosis of FGR fetuses is low. Improving detection and effective monitoring of progression is critical, and there is an urgent need to find better diagnostic methods for early identifying pregnancies at high-risk, guiding management and intervention. As a relatively non-invasive detection method, biomarkers have shown great potential in early prediction of FGR, and increasing biomarkers have been found. This review summarizes the research progress of maternal peripheral blood molecular biomarkers (proteins, metabolites or ribonucleic acid) in early diagnosing FGR, and elaborates the possible mechanism of their involvement in the occurrence and development of FGR, in order to provide evidence for clinicians to identify and evaluate the prognosis of FGR.

Advances in the gene therapy for Fanconi anemia

XI Bixin, HU Qun, LIU Aiguo

Journal of Clinical Pediatrics. 2023, 41(2): 156-160. doi:10.12372/jcp.2023.21e1465

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Fanconi anemia is a rare monogenic disease with the hallmark of bone marrow failure. Although allogeneic hematopoietic stem cell transplantation constitutes the preferred therapy for bone marrow failure in Fanconi anemia patients, the increased incidence and mortality of transplant-related complications have seriously affected their quality of life. As medical science advances in recent 30 years, gene therapy may emerge as an innovative low-toxicity therapeutic option for this life-threatening disorder. In this paper, attention is focused on the advances in gene therapy for Fanconi anemia in children.

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