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The life course health development model: a new approach to understanding human health
KE Yuye,CHAI Xiaoyun
J Zhejiang Univ (Med Sci), 2021, 50(4): 411-419.   https://doi.org/10.3724/zdxbyxb-2021-0155
Abstract( 279 )   HTML( 34 )     PDF(2336KB)( 87 )

The life course health development (LCHD) model is a cutting-edge theoretical model for the health science, which moves beyond the previous biomedical and biopsychosocial model. From the perspectives of “process, relationship and system”, it recognizes health as a dynamic ability to change over the course of life, and highlights the importance of optimizing individual health trajectories and health promotion. According to LCHD model, we should understand health from the perspective of development, which is characterized by unfolding, complexity, timing, plasticity, thriving and harmony. Health research and practice, therefore, should change ideas from the focus on accurate diagnosis, treatment and etiology previously to full using the relative plasticity of human development to enhance health development ability, enrich health resources and promote the healthy development of physiology, psychology, behavior and culture system; and to achieve a harmonious balance in the different stages of the life course. Based on the LCHD model, it is suggested for our country’s health service system (1) to strengthen the health education across the life-span and construct the health promotion model based on the social system; (2) to pay more attention to health promotion and disease prevention in early life; (3) to increase government spending on health promotion and prevention, not just on disease treatment.

Eye diseases burden in China in the past 30 years
CHEN Binbin,LOU Lixia,YE Juan
J Zhejiang Univ (Med Sci), 2021, 50(4): 420-428.   https://doi.org/10.3724/zdxbyxb-2021-0246
Abstract( 252 )   HTML( 14 )     PDF(2907KB)( 71 )

Objective: To investigate the national burden of eye diseases in China from 1990 to 2019. Methods: The national burden of eye diseases in China, including case numbers, prevalence rate, age-standardized prevalence rate (ASR), disability-adjusted life year (DALY), DALY rate and age-standardized DALY rate (ASD) were calculated and stratified by sex and age. The trends of eye diseases burden from 1990 to 2019 and the correlation between eye diseases burden and human development index (HDI) were analyzed. Results: In 2019, the total case number of eye diseases in China was 0.21 billion, the ASR was 9511/105, the total number of DALY was 4.72 million, and the ASD was 247.4/105. Near vision loss caused the greatest burden, followed by refraction disorders and cataract, with ASD being 73.8/105, 70.3/105 and 59.2/105, respectively. Men had lower risks of eye diseases than women. People aged 50– <70?years old and ≥70?years old had the greatest burden of eye diseases. Compared with the year 1990, the total case number increased by 134.6% and DALY by 113.0% in 2019. The ASD of all decreased by 7.5%, and was negatively correlated with national HDI. Conclusions: Near vision loss, refraction disorders and cataract are of heavy disease burden in China. Although the ASD of eye diseases is decreased with the development of the national socioeconomic status, the eye diseases burden in China still increased with population growth and aging.

Genetic screening techniques and diseases for neonatal genetic diseases
HAN Lianshu
J Zhejiang Univ (Med Sci), 2021, 50(4): 429-435.   https://doi.org/10.3724/zdxbyxb-2021-0288
Abstract( 411 )   HTML( 11 )     PDF(2229KB)( 81 )

Neonatal genetic disease is currently screened mainly based on metabolite biochemical technology. The false positive rate of biochemical screening technology is relatively high, and there are certain false negatives, and only few types of diseases can be screened. The genetic techniques have been gradually used for neonatal genetic disease screening in recent years. Gene detection technology includes quantitative PCR (qPCR) and high-throughput sequencing. High-throughput sequencing includes gene panel sequencing, whole-exome sequencing and whole-genome sequencing. At present, qPCR and gene panel sequencing are the main technologies to be used for newborn genetic disease screening. Genetic screening diseases range from single disease such as hearing loss, spinal muscular atrophy and severe combined immunodeficiency to multiple diseases. Besides standards and guidelines for the interpretation of sequence variants proposed by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology in 2015, the interpretation of genetic screening results should also consider biochemical results and other results. The development of newborn genetic screening needs to follow ethical principles, including the ethics of newborn genetic screening as a public health project, the privacy ethics of newborns and their family members, and the ethics of bioinformatics. The development of newborn genetic screening will enable more patients with inherited diseases to receive early diagnosis and treatment and improve their prognosis, which is a milestone in the field of neonatal screening.

Clinical features and outcomes of patients with cblC type methylmalonic acidemia carrying MMACHC gene c.609G>A mutation
YU Yue,LING Shiying,SHUAI Ruixue,QIU Wenjuan,ZHANG Huiwen,LIANG Lili,JI Wenjun,LIU Yuchao,GU Xuefan,HAN Lianshu
J Zhejiang Univ (Med Sci), 2021, 50(4): 436-443.   https://doi.org/10.3724/zdxbyxb-2021-0276
Abstract( 262 )   HTML( 10 )     PDF(2311KB)( 81 )

Objective:To explore the clinical features and long-term outcomes of patients with cblC type methylmalonic acidemia (MMA) carrying c.609G>A (p.W203X) mutation ofMMACHC gene. Methods: The clinical and laboratory findings of 720 patients with MMA carrying the c.609G>A mutation were retrospectively analyzed. There were 172 cases carrying homozygous mutations of c.609G>A (group A), 169 cases carrying compound heterozygous mutations of c.609G>A with c.482G>A (p.R161Q), c.80A>G (p.Q27R) or c.394C>T (p.R132X) (group B), and 379 cases carrying compound heterozygous mutations of c.609G>A with c.658_660delAAG(p.K220del), c.315A>T(p.Y105X) or c.567dupT(p.I190fs*13)(group C).The clinical manifestations, the level of blood acylcarnitine, homocysteine and urinary organic acid, and the therapeutic efficacy were compared among groups. Logistic regression was used to analyze the factors influencing the prognosis of patients. Results:There were 306 patients (42.5%) detected from newborn screening, including 156 cases with disease onset; and 414 patients were not detected from the screening, among whom 10 cases were diagnosed by testing after the sibling confirmed, and the remaining 404 were clinical cases. In 560 patients with disease onset, the median onset age is 1.2?months (3 days to 20?years). The onset age of patients in group B was later than that in group A and group C (P<0.01). Patients aged <1?year mostly manifested as vomiting, diarrhea, feeding difficulties and convulsions, while those aged >1?year mostly manifested as movement disorders and mental retardation. Patients with renal disease all carried mutations of c.80A>G or c.482G>A, and patients with pulmonary hypertension all carried c.80A>G mutations. A total of 621 cases had long-term follow-up, 156 cases (25.1%) developed well, 433 cases (69.7%) had development delay and 32 cases (5.2%) died. The available data of 559 cases were analyzed by logistic regression, and the results showed that the neonatal screening, disease onset, age of onset and gene mutation site were significantly associated with the prognosis of patients (P<0.05 orP<0.01).Conclusions:The c.609G>A mutation inMMACHC gene is associated with early-onset MMA, and most patients, clinical onset occurred within 1?month after birth. The neonatal screening and early treatment can improve the prognosis of patients,whereas clinical onset is unfavorable for prognosis. Patients with c.609G>A homozygous mutation have a worse prognosis than those with the compound heterozygous mutation of c.609G>A with other mutations.

Follow-up of two newborns with c.158G>A (p.Arg53His) mutation inPAH gene and assessment of the site function
WANG Jie,ZHU Bo,ZHANG Lichun,ZHAO Yitong,WANG Xiaohua,JIA Yueqi
J Zhejiang Univ (Med Sci), 2021, 50(4): 444-453.   https://doi.org/10.3724/zdxbyxb-2021-0256
Abstract( 165 )   HTML( 6 )     PDF(5388KB)( 62 )

Objective: To investigate the clinical significance of PAHc.158G>A (p.Arg53His) mutation.Methods: The blood phenylalanine (Phe) was continuously monitored in 2 unrelated newborns with suspected hyperphenylalaninimia (HPA) carrying PAH c.158G>A mutation. The cross-species conservation of the mutant amino acid was analyzed using T-Coffee. Swiss-Model software was used to construct a 3D protein structure and the impact of candidate mutations on the secondary structure of the protein product was analyzed. The population carrying rate of the p.Arg53His mutation was analyzed by literature searching. Allelic phenotype values (APV) and genotypic phenotype values (GPV) were used to predict the phenotype associated with the mutation.Results:Two mutations of PAHgene were detected in each newborn: c.611A>G(p.Tyr204Cys), c.158G>A(p.Arg53His) and c.1238G>C(p.Arg413Pro), c.158G>A(p.Arg53His). Two children tolerated normal diet and plasma Phe levels were within the normal range during follow-up. The mother of case 2 was homozygous with p.Arg53His mutation under the condition of long-term normal diet, and the blood Phe concentration and Phe/Tyr were all within the normal range. The mutant amino acids were not highly conserved among the 13 different species. The 3D structural model showed that p.Arg53His mutation reduced the hydrogen bond from 2 to 1 between the 53rd and 49th amino acids of PAH. The allele frequency of p.Arg53His was 0.015?08 in HPA patients and 0.001?621 in normal population, while the prevalence of p.Arg53His allele was highest in the East Asian normal population (0.013?73). The APV and GPV system predicted that the mutation was related to mild HPA(MHP) type.Conclusion: The different compound heterozygous mutations of p.Arg53His lead to clinical phenotype varieties. The reduction of enzyme activity caused by the mutation of p.Arg53His is not sufficient to cause symptoms of phenylketonuria, so the mutation may be “likely benign”.

Screening of multiple acyl-CoA dehydrogenase deficiency in newborns and follow-up of patients
ZHOU Duo,YE Meiling,HU Zhenzhen,ZHANG Yu,ZHU Lin,YANG Rulai,HUANG Xinwen
J Zhejiang Univ (Med Sci), 2021, 50(4): 454-462.   https://doi.org/10.3724/zdxbyxb-2021-0261
Abstract( 146 )   HTML( 10 )     PDF(2346KB)( 75 )

Objective:To investigate the incidence rate, clinical and gene mutation characteristics of multiple acyl-CoA dehydrogenase deficiency (MADD) in newborns in Zhejiang province. Methods:A total of 3 896 789 newborns were screened for MADD using tandem mass spectrometry in Zhejiang Neonatal Screening Center during January 2009 and December 2020. Patients of MADD were confirmed by urine organic acid and electron transferring flavoprotein (ETF)or electron transferring flavoprotein dehydrogenase (ETFDH) gene detection. MADD patients were given diet and life management, supplemented with L-carnitine, riboflavin and coenzyme Q 10 treatment, and their growth and intellectual development were evaluated during the followed up.Results:Thirteen patients with MADD were diagnosed, with an incidence of 1/299 753. One patient was type Ⅱ, and the rest were type Ⅲ. Patients were followed up for 3–45?months, 1 case died, 4 cases had acute metabolic disorders with hypoglycemia as the main manifestation due to infection, 1 case had hypotonia, and the rest 7 cases developed well. Patients had raised levels of C4–C18:1 acylcarnitines in the initial screening. Thirteen children were genetically tested, 1 case with compound heterozygous mutation in the ETFA gene, 1 case with homozygous mutation in theETFA gene, 1 case with compound heterozygous mutation in the ETFB gene, 8 cases with compound heterozygous mutation and 1 case with homozygous mutation in the ETFDH gene, 1 case that only 1 locus of ETFDH gene was detected. The c.250G>A was the hotspot mutation in this study.Conclusion:The clinical manifestations of MADD are highly heterogeneous. The neonatal-onset form is serious, and late onset form usually has no obvious clinical symptoms. C4–C18:1 acylcarnitines usually increased in the initial screening, and the hotspot gene mutation is c.250G>A.

Screening for neonatal inherited metabolic disorders by tandem mass spectrometry in Guangzhou
TANG Chengfang,TAN Minyi,XIE Ting,TANG Fang,LIU Sichi,WEI Qingxiu,LIU Jilian,HUANG Yonglan
J Zhejiang Univ (Med Sci), 2021, 50(4): 463-471.   https://doi.org/10.3724/zdxbyxb-2021-0260
Abstract( 280 )   HTML( 2 )     PDF(2261KB)( 49 )

Objective:To analyze the screening results for inherited metabolic disorders (IMD) in newborns by tandem mass spectrometry (MS/MS) in Guangzhou.Methods:A total of 272?117 newborns in Guangzhou from Jan 2015 to Dec 2020 were screened for IMD by MS/MS in Guangzhou Newborn Screening Center. When the primary screening was positive, the newborns and their mothers were recalled. For those with positive in re-examination, the biochemical and related genetic analysis were required for confirmation. The screening results, clinical characteristics and outcomes of the confirmed cases were retrospectively analyzed and the performance was optimized. Results:Among 272?117 neonates, 1808 (0.66%) cases were positive in primary screening, and 1738 cases (96.13%) were recalled for review. The median clinical diagnosis time was 15 d after birth. A total of 79 cases of IMD were diagnosed, including 23 with aminoacidopathy, 17 with disorder of organic acid metabolism and 39 with fatty acid oxidation disorders, involving 21 diseases. The incidence rate was 1/3444 in newborns, and the positive predictive value of 4.5%. Four false negative cases were found, all of them were citrin deficiency. The common diseases were primary carnitine deficiency (26.6%), methylmalonic aciduria (12.7%) and phenylalanine hydroxylase deficiency (11.4%). The mothers of 32 cases were confirmed, including 30 cases of primary carnitine deficiency, 1 case of isobutyl-coenzyme A dehydrogenase deficiency and 1 case of 3-methylcromaryl coenzyme A carboxylase deficiency. The detection rate was 1/2451 in total population. During the follow-up, most patients remain asymptomatic, except for 5 severe cases who died early (1 case of maple syrup urine disease, 2 cases of isolated methylmalonic acidurmia, and 2 cases of carnitine-acylcarnitine translocase deficiency); and 10 cases of organic acid metabolism disorders developed mild psychomotor developmental retardation. After optimizing the screening indicators, the number of initial screening positives dropped to 903, and the positive predictive value increased to 9.1%, and no confirmed cases were missed. Conclusion:The incidence rate of fatty acid oxidation disorders is high in Guangzhou. A variety of IMD can be effectively screened out by MS/MS, and the screening performance can be improved by optimizing screening indicators.

Screening and follow-up results of fatty acid oxidative metabolism disorders in 608 818 newborns in Jining, Shandong province
YANG Chiju,SHI Caihong,ZHOU Cheng,WAN Qiuhua,ZHOU Yanbin,CHEN Xigui,JIN Xianlian,HUANG Chenggang,XU Peng
J Zhejiang Univ (Med Sci), 2021, 50(4): 472-480.   https://doi.org/10.3724/zdxbyxb-2021-0259
Abstract( 235 )   HTML( 3 )     PDF(2289KB)( 59 )

Objective:To investigate the incidence and gene mutation characteristics of fatty acid oxidative metabolism disorders in Jining area of Shandong province , and to evaluate the therapeutic effect.Methods: Blood samples of newborns were collected in Jining of Shandong province between July 14, 2014 and December 31, 2019. Tandem mass spectrometry was used to determine the levels of carnitine and acylcarnitine in the blood to screen for fatty acid oxidative metabolism disorder. For newborns with positive screening result, blood DNA was analyzed by MassARRAY and high-throughput sequencing, then verified by Sanger sequencing. The diagnosed children were given early intervention and treatment, and followed up. Results:Forty-two children with fatty acid oxidative metabolism disorders were screened out of 608 818 newborns, with an incidence rate of 1/14 496. Primary carnitine deficiency (16 cases, 38.10%) and short-chain acyl-CoA dehydrogenase deficiency (16 cases, 38.10%) were the most common, followed by very long-chain acyl-CoA dehydrogenase deficiency (6 cases, 14.29%), medium-chain acyl-CoA dehydrogenase deficiency (4 cases, 9.53%). In children with primary carnitine deficiency, c.1400C>G (p.S467C) and c.51C>G (p.F17L) were the most common inSLC22A5 mutations; and c.278C>T (p.S93L), c.1049T >C (p.L350P), c.572A>G (p.K191R), c.431T>C (p.L144P) were newly discovered mutations. Ten children with carnitine replacement therapy showed normal development during the follow-up. In 6 children without carnitine replacement treatment, hypoglycemia developed during the neonatal period in 1 case, in whom the creatine kinase was increased, and the intellectual and language development delayed in the later period; the other 5 children developed normally during the follow-up period. TheACADS gene mutations c.1031A>G (p.E344G) and c.164C>T (p.P55L) were common in children with short-chain acyl-CoA dehydrogenase deficiency, and the children developed normally during the follow-up. In children with very long-chain acyl-CoA dehydrogenase deficiency, the c.1349G>A (p.R450H) was common inACADVL gene mutations; and c.488T>A (p.L163*), c.1228G>T (p.D410Y), c.1276G>A (p.A426T), c.1522C>T (p.Q508*), c.1226C>T (p.T409M) were newly discovered mutations. Three children treated with milk powder rich in medium-chain fatty acids had normal development during the follow-up. The other 3 cases with combined carnitine reduction were treated with levocarnitine and milk powder enriched of medium-chain fatty acids, 1 case developed normally during the follow-up, 1 case died of acute illness at the age of 3?months, and 1 case had acute illness and recovered after treatment, and developed normally during the follow-up. c.449_452del (p.T150Rfs*4) was the most commonACADM gene mutation in children with medium-chain acyl-CoA dehydrogenase deficiency, and c. 718A>G (p.M240V) was a newly discovered mutation. All children received low-fat diet, and hunger and fatigue were avoided; 1 child was supplemented with L-carnitine, and the other 3 children were not treated with drugs, and all of them developed normal during the follow-up.Conclusions:Primary carnitine deficiency and short-chain acyl-CoA dehydrogenase deficiency are the most common fatty acid oxidative metabolism disorders in Jining area. There are gene hotspot mutations and new discovered gene mutations in patients. Patients with early diagnosis and treatment through neonatal screening have a good prognosis.

Very long chain acylcarnitines and lysophosphatidylcholines in screening of peroxisomal disease in children by tandem mass spectrometry
WANG Yanmin,TIAN Guoli,JI Wei,WANG Simei,ZHANG Xiaofen
J Zhejiang Univ (Med Sci), 2021, 50(4): 481-486.   https://doi.org/10.3724/zdxbyxb-2021-0254
Abstract( 131 )   HTML( 3 )     PDF(2404KB)( 55 )

Objective:To investigate the value of very long chain acylcarnitine (VLCAC) and lysophosphatidylcholine (LPC) in screening of peroxisomal disease in children. Methods:Eighteen children with peroxisomal disease, including 14 cases of X-linked adrenoleukodystrophy (X-ALD group) and 4 cases of Zellweger syndrome (ZS group) diagnosed based on clinical symptoms, MRI and genetic tests were enrolled in the study; and 200 healthy children were selected as control group. Samples of dried blood spots were collected from all subjects, VLCAC and LPC in dried blood spots were extracted by solvent containing internal isotopic standards hexacosanoylcarnitine (2H3-C26) and C26:0 lysophosphatidylcholine (2H4-C26:0-LPC). The eicosanoylcarnitine (C20), docosanoylcarnitine (C22), tetracosanoylcarnitine (C24), hexacosanoylcarnitine (C26), C20:0 lysophosphatidylcholine (C20:0-LPC), C22:0 lysophosphatidylcholine (C22:0-LPC), C24:0 lysophosphatidylcholine (C24:0-LPC) and C26:0 lysophosphatidylcholine (C26:0-LPC) were detected by tandem mass spectrometry (MS/MS). The above 8 indicators and the ratios were compared among the groups using Kruskal-WallisH test and Mann-Whitney U test; the contribution of each index to the disease were analyzed by partial least square method. Results:Except C24:0-LPC/C20:0-LPC, there were significant differences in all indicators and ratios among all groups (P<0.05 orP<0.01). There were differences in most indicators and ratios between X-ALD group and the control group, as well as between ZS group and the control group, but there was no difference between the X-ALD group and the ZS group. PLS-DA analysis showed that the peroxisome disease group (including X-ALD group and ZS group) and the control group were able to be completely separated, and C26 had the highest variable importance for the projection (VIP) value.Conclusion:MS/MS detection of VLCAC and LPC can be used as a screening method for peroxisomal disease, and C26 may be a sensitive indicator for diagnosis.

Application of genetic screening processor in screening neonatal glucose-6-phosphate dehydrogenase deficiency
MIAO Haixia,ZHANG Yu,FANG Kexin,SHI Yezhen,ZHANG Ting,CHEN Rongqing,WU Dingwen,YANG Rulai,HUANG Xinwen
J Zhejiang Univ (Med Sci), 2021, 50(4): 487-493.   https://doi.org/10.3724/zdxbyxb-2021-0275
Abstract( 124 )   HTML( 1 )     PDF(2392KB)( 83 )

Objective: To evaluate the performance of genetic screening processor (GSP analyzer) in neonatal screening for glucose-6-phosphate dehydrogenase (G6PD)deficiency. Methods:The accuracy and precision of GSP analyzer was evaluated with the control materials from National Center for Clinical Laboratories and the low and high quality G6PD control kit (fluorescence analysis). GSP analyzer and semi-automatic fluorescence immunoanalyzer (1420 analyzer) were simultaneously used to detect 2622 neonatal screening samples and 41 confirmed samples to analyze the correlation and consistency of the test results; 78 floating samples and 78 non-floating samples were detected to compare the result. A total of 1?100?384 neonatal screening samples from January 2017 to December 2018 and 855?856 neonatal screening samples from January 2019 to December 2020 were detected with 1420 analyzer and GSP analyzer, respectively. Referring to the percentile method and the expert consensus, the new cut-off value of GSP analyzer for G6PD deficiency in screening was established. Results: The relative bias of GSP analyzer in detecting G6PD was 0.71%–4.23%; the intra assay precision was 4.34%–4.91%, the inter assay precision was 0.85%–2.12%, and the total coefficient of variation was 5.44%–5.72%. There was a significant positive correlation between G6PD activity detected by GSP analyzer and 1420 analyzer (r=0.740, P<0.01). Forty-one clinical confirmed patients were identified by both 1420 analyzer and GSP analyzer (Kappa=0.945). The G6PD activity in floating dry blood spots detected by 1420 analyzer was significantly lower than that in non-floating dry blood spots (P<0.05), but there was no significant difference in G6PD activity between floating and non-floating dry blood spots detected by GSP analyzer (P>0.05). The sensitivities of GSP analyzer and 1420 analyzer in screening G6PD deficiency were both 100.00%, and the specificities were both more than 99.80%. Compared with 1420 analyzer, the positive predictive value, positive rate and prevalence of G6PD deficiency detected by GSP analyzer were increased, and the false positive rate was decreased (allP<0.01). The new cut-off value was 26.1 U/dL for male and 29.1 U/dL for female according to the 99.1% percentile of the population.Conclusion: GSP analyzer has better detection performance with high automation, efficiency and throughput, which can be used in large-scale screening for neonatal G6PD deficiency.

Clinical and genetic characteristics of Keishi-Bukuryo-Gan syndrome: an analysis of 5 cases
WANG Shiqi,WEI Haiyan,FU Dongxia,LIU Xiaojing,SHEN Linghua,WU Shengnan,CHEN Yongxing
J Zhejiang Univ (Med Sci), 2021, 50(4): 494-499.   https://doi.org/10.3724/zdxbyxb-2021-0268
Abstract( 143 )   HTML( 3 )     PDF(6925KB)( 16 )

Objective: To analyze the clinical and genetic characteristics of children with Keishi-Bukuryo-Gan (KBG) syndrome. Methods:The clinical and genetic data of 5 children with KBG syndrome admitted in Children’s Hospital Affiliated of Zhengzhou University from November 2018 to September 2020 were retrospectively analyzed. Results:Five children were all males who came from four different families. All children presented triangular face, bushy eyebrows, thin upper lip, large or delayed closure of anterior fontanel, and abnormal bone development. Four cases had growth retardation, large ears, thick ear lips; 3 cases had large central incisors; 2 cases had congenital heart disease; 2 cases had abnormal skin changes; 2 cases had genital changes; and 2 cases became grumpy. Liver and kidney function,thyroid function, blood gas analysis and electrolyte of the children were all in the normal range. Three children received bone age examination, and all showed bone age lag. Two cases showed backward myelination of white matter in MRI. Whole exome sequencing revealed that all 5 children had heterozygous mutations in theANKRD11 gene, among which c.6836_6837delTG, c.5866C>T, and c.6270delT were newly discovered mutation sites. None of the parents of probands were found to carry the mutations inANKRD11 gene. Two cases achieved height catch-up and cognitive improvement after treatment with recombinant human growth hormone. Conclusion: KBG syndrome is characterized by a wide spectrum of phenotypes, and large or delayed closure of the anterior fontanel, large ears and thick ear lips may be the main manifestations of the disease in infants and young children. ANKRD11 gene mostly presents spontaneous mutations, and early application of growth hormone therapy can achieve height catch-up and cognitive improvement without obvious adverse reactions.

Clinical features, genetic detection and therapeutic response to rhGH of children with Noonan syndrome: an analysis of 12 cases
SHANGGUAN Huakun,XU Yuanbin,CHEN Ruimin
J Zhejiang Univ (Med Sci), 2021, 50(4): 500-505.   https://doi.org/10.3724/zdxbyxb-2021-0263
Abstract( 274 )   HTML( 0 )     PDF(2227KB)( 45 )

Objective:To analyze the clinical manifestations, genetic features and therapeutic efficacy of patients with Noonan syndrome (NS). Methods:The clinical data of 12 NS children treated in Fuzhou Children’ Hospital of Fujian Medical University from September 2015 to April 2021 were analyzed. Among them, 7 patients with height lower than two standard deviations of the mean (or below the third percentile) were treated with recombinant human growth hormone (rhGH), and were followed up every 3?months.Results:The clinical characteristics were as following: facial anomalies (n=12), short stature (n=11), congenital heart diseases (n=5), facial freckles (n=4), coffee spots on the skin (n=3), intelligence disability (n=3),cryptorchidism (n=3), feeding difficulties (n=2), scoliosis (n=2), pectus carinatum (n=2), pectus excavatum (n=1), rib dysplasia companied with short finger (n=1), hyperopia (n=1), myopia (n=1) and early puberty (n=1). ThePTPN11 mutation was detected in 10 cases, RIT1 mutation was detected in 1 case, and RAF1 mutation was detected in 1 case. In 7 patients treated with rhGH, the mean height velocity increased from (2.8±1.0)?cm/year before treatment to (8.3±1.6)?cm/year after treatment for (1.5±0.8)?years (P<0.01); the height velocity was the fastest during 3 to 6?months of treatment, and then gradually went slower. The serum levels of insulin-like growth factor 1 (IGF-1) remained within the normal range.Conclusions:The clinical manifestations of NS are diverse, and the disease can be diagnosed through genetic testing. For NS patients with short stature, rhGH treatment can increase the height velocity and no obvious adverse reactions were found.

Clinical characteristics and genetic analysis of neonatal intrahepatic cholestasis caused by citrin deficiency in comparison with idiopathic neonatal cholestasis
LIU Hao,LI Chun,LI Xiaowen,YU Chaowen,HE Xiaoyan,MIAO Jingkun
J Zhejiang Univ (Med Sci), 2021, 50(4): 506-513.   https://doi.org/10.3724/zdxbyxb-2021-0264
Abstract( 168 )   HTML( 8 )     PDF(2307KB)( 71 )

Objective:To compare the clinical and genetic characteristics of patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and idiopathic neonatal cholestasis (INC). Methods: The clinical data of 30 patients with NICCD and 30 patients with INC admitted in Children’s Hospital of Chongqing Medical University during September 2012 and December 2017 were retrospectively analyzed. The clinical manifestations, biochemical indicators and genetic characteristics were compared between two groups. Results:Patients in both groups presented similar clinical manifestations, however the chubby face and clay-colored stool were more common in NICCD patients (both P<0.01). Comparing with INC group, NICCD group showed significantly decreased blood levels of glucose, prealbumin, albumin, total protein, fibrinogen, and aminotransferases (P<0.05 orP<0.01), while significantly increased blood levels of indirect bilirubin, total bile acid, alkaline phosphatase, lactic dehydrogenase, ammonium, alpha fetoprotein, and markers of coagulation function (P<0.05 orP<0.01). In addition, NICCD patients showed remarkably increased blood levels of citrulline, methionine, tyrosine, arginine, and threonine; as well as significantly increased urine levels of 4-hydroxyphenyllactic acid, 4-hydroxyphenylpyruvic acid and phenyllactic acid, while those indicators in INC patients were normal (allP<0.01). All the patients with NICCD hadSLC25A13 mutation including 8 homozygotes, 9 compound heterozygotes, and 13 single heterozygotes. Among all mutations, c.851_854del was most common (53.19%), c.1196T>A and c.919G>T were two novel mutations.Conclusions:The manifestations of chubby face and clay-colored stool may provide clue for early diagnosis of NICCD along with the elevated biochemical parameters, such as ammonium, alpha-fetal protein, citrulline in blood and 4-hydroxyphenyllactic acid, 4-hydroxyphenylpyruvic acid, phenyllactic acid in urine. Target gene trapping and high-throughput sequencing have the key values in diagnosis and differential diagnosis of NICCD.

Hereditary tyrosinemia type Ⅰ: newborn screening, diagnosis and treatment
TANG Yue,KONG Yuanyuan
J Zhejiang Univ (Med Sci), 2021, 50(4): 514-523.   https://doi.org/10.3724/zdxbyxb-2021-0255
Abstract( 218 )   HTML( 6 )     PDF(2700KB)( 71 )

Hereditary tyrosinemia type Ⅰ (HT-1) is a severe autosomal recessive inherited metabolic disease. Due to the deficiency of fumarylacetoacetase hydrolase (FAH), the toxic metabolites are accumulated in the body, resulting in severe liver dysfunction, renal tubular dysfunctions, neurological crises, and the increased risk of hepatocellular carcinoma. Clinical symptoms typically begin at 1?year after the birth; the prognosis of patients is poor if they are not treated timely. Succinylacetone is a specific and sensitive marker for HT-1, and the screening in newborns can make early diagnosis of HT-1 at the asymptomatic stage. The diagnosis of HT-1 can be confirmed based on the characteristic biochemical findings and molecular testing of mutations in both alleles of FAHgene. Combined treatment with nitisinone and a low tyrosine diet may significantly improve outcomes for patients. Liver transplantation is an effective treatment in cases where nitisinone is not available. Some novel HT-1 treatments are in clinical trials, including enzyme replacement therapy, hepatocyte transplantation and gene-targeted therapy.

New-onset and relapsing glomerular diseases related to COVID-19 vaccination
LIU Fei,FENG Chunyue,MAO Jianhua,FU Haidong
J Zhejiang Univ (Med Sci), 2021, 50(4): 524-528.   https://doi.org/10.3724/zdxbyxb-2021-0156
Abstract( 206 )   HTML( 10 )     PDF(1979KB)( 87 )

COVID-19 vaccine, as one of the critical measures to control the pandemic, has been administered in nearly all countries. However, the new-onset and relapsing glomerular diseases associated with COVID-19 vaccination have become a new concern. Both mRNA vaccine and inactivated vaccine may cause new-onset and relapsing glomerular diseases; these diseases would occur after the first dose vaccination or the second dose. New-onset glomerular disease is mainly minimal change glomerulopathy, which is mostly sensitive to steroid, while relapsing cases have good prognosis, and some cases can be spontaneously remitted. The pathogenesis of these vaccine-associated diseases is possibly due to the humoral and cellular immune responses. In this article, we provide a general review of the new-onset and relapsing glomerular diseases related to COVID-19 vaccination, and make suggestions for patients with kidney diseases to receive COVID-19 vaccination.

Simultaneous determination of related substances in entecavir film-coated tablet by high performance liquid chromatography
J Zhejiang Univ (Med Sci), 2021, 50(4): 529-536.   https://doi.org/10.3724/zdxbyxb-2021-0247
Abstract( 208 )   HTML( 13 )     PDF(4825KB)( 96 )

Objective: To establish a high performance liquid chromatography method to simultaneously quantify eight related substances in entecavir film-coated tablets.Methods:According to USP40 and YBH33292005 standards, a high performance liquid chromatography (HPLC) method for simultaneous determination of 8 related substance in entecavir film-coated tablets was established and validated. The column was WATERS C18 (250 mm×4.6?mm, 5?μm), the mobile phase A was water-acetonitrile-trifluoroacetic acid (990∶10∶1), the mobile phase B was water-acetonitrile-trifluoroacetic acid (700∶300∶1) with gradient elution and ultraviolet-visible light detector, detection wavelength at 254 nm and column temperature of 30?℃. Results: The resolution between entecavir and each impurity peak was more than 1.5, and each impurity had a good linear relationship with the peak area in the linear range. The limits of detection and quantification, precision, stability, durability, specificity, met the verification requirements. Conclusion:The HPLC method established in this study can be used for simultaneous determination of 8 related substance in entecavir film-coated tablets.

Research progress on neonatal Fc receptor and its application
HU Mangsha,WEI Shuli,ZHOU Wuyuan,WANG Pingli
J Zhejiang Univ (Med Sci), 2021, 50(4): 537-544.   https://doi.org/10.3724/zdxbyxb-2021-0252
Abstract( 226 )   HTML( 8 )     PDF(2829KB)( 79 )

Neonatal Fc receptor (FcRn) is a specific receptor for immunoglobulin G (IgG) and albumin, which binds to them in a pH-dependent manner and prevents them from lysosomal degradation to keep a long plasma half-life. In addition, FcRn plays an important role in transmembrane transport of IgG and albumin and in antigen presentation. In autoimmune diseases, anti-FcRn antibody can promote the degradation of pathogenic IgG by competitive binding to FcRn. In infectious diseases, the half-life of drugs can be prolonged by increasing the affinity between therapeutic antibody and FcRn, while the combination of viral antigen and Fc fragment of IgG can cause local immune response of mucosa for disease prevention and treatment. In cancer, albumin as a carrier of anticancer drugs can achieve efficient drug delivery, and FcRn itself may be used as a predictor of the prognosis of cancer patients. This review details the functions of FcRn, highlights its role in autoimmune diseases, infectious diseases and cancer, as well as the mechanism of drug development based on FcRn, to provide a reference for the clinical application and drug development of FcRn.

17 articles