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Vol 19, No 7
Vol 19, No 7 July 2023 ISSN 1708-8569
Review articles
Original articles
Review articles:
Inherited Fanconi syndrome
  Anna Luiza Braga Albuquerque, Rafael dos Santos Borges, Ana Fl芍via Conegundes, Erika Emmylaine dos Santos, Frederico Moreira Man Fu, Clara Tavares Araujo, Pedro Alves Soares Vaz de Castro, Ana Cristina Simões e Silva
Background: Fanconi-Debr谷-de Toni syndrome (also known as Fanconi renotubular syndrome, or FRST) profoundly increased the understanding of the functions of the proximal convoluted tubule (PCT) and provided important insights into the pathophysiology of several kidney diseases and drug toxicities.
Data sources: We searched Pubmed and Scopus databases to find relevant articles about FRST. This review article focuses on the physiology of the PCT, as well as on the physiopathology of FRST in children, its diagnosis, and treatment.
Results: FRST encompasses a wide variety of inherited and acquired PCT alterations that lead to impairment of PCT reabsorption. In children, FRST often presents as a secondary feature of systemic disorders that impair energy supply, such as Lowe*s syndrome, Dent's disease, cystinosis, hereditary fructose intolerance, galactosemia, tyrosinemia, Alport syndrome, and Wilson*s disease. Although rare, congenital causes of FRST greatly impact the morbidity and mortality of patients and impose diagnostic challenges. Furthermore, its treatment is diverse and considers the ability of the clinician to identify the correct etiology of the disease.
Conclusions: The early diagnosis and treatment of pediatric patients with FRST improve the prognosis and the quality of life.
  [Abstract] [Full Text] [PDF]  
Clinical spectrum and currently available treatment of type I interferonopathy Aicardi每Gouti豕res syndrome
  Giovanni Battista Dell*Isola, Gianluca Dini, Kaleb Logan Culpepper, Katherin Elizabeth Portwood, Pietro Ferrara, Giuseppe Di Cara, Alberto Verrotti, Mauro Lodolo
Background: Aicardi每Gouti豕res syndrome (AGS) is a genetically determined disorder with a variable phenotype. Since the original description of AGS, advances in gene sequencing techniques have resulted in a significant broadening of the phenotypic spectrum associated with AGS genes, and new clinical pictures have emerged beyond the classic presentation. The aim of this review is to provide a comprehensive analysis of the clinical spectrum of AGS and report currently available treatments and new immunosuppressive strategies.
Data sources: Literature reviews and original research articles were collected from databases, including PubMed and ClinicalTrials.gov. Relevant articles about AGS were included.
Results: The involvement of the nervous system certainly represents the major cause of mortality and morbidity in AGS patients. However, other clinical manifestations, such as chilblains, hepatosplenomegaly, and hematological disturbances, may lead to the diagnosis and considerably impact the prognosis and overall quality of life of these patients. Therapeutic approaches of AGS are limited to interventions aimed at specific symptoms and the management of multiple comorbidities. However, advances in understanding the pathogenesis of AGS could open new and more effective therapies.
Conclusions: The over-activation of innate immunity due to upregulated interferon production plays a critical role in AGS, leading to multi-organ damage with the main involvement of the central nervous system. To date, there is no specific and effective treatment for AGS. New drugs specifically targeting the interferon pathway may bring new hope to AGS patients.
  [Abstract] [Full Text] [PDF]  
Comprehensive characterization of the genetic landscape of familial Hirschsprung*s disease
  Jun Xiao, Lu-Wen Hao, Jing Wang, Xiao-Si Yu, Jing-Yi You, Ze-Jian Li, Han-Dan Mao, Xin-Yao Meng, Jie-Xiong Feng
Background: Hirschsprung*s disease (HSCR) is one of the most common congenital digestive tract malformations and can cause stubborn constipation or gastrointestinal obstruction after birth, causing great physical and mental pain to patients and their families. Studies have shown that more than 20 genes are involved in HSCR, and most cases of HSCR are sporadic. However, the overall rate of familial recurrence in 4331 cases of HSCR is about 7.6%. Furthermore, familial HSCR patients show incomplete dominance. We still do not know the penetrance and genetic characteristics of these known risk genes due to the rarity of HSCR families.
Methods: To find published references, we used the title/abstract terms ※Hirschsprung§ and ※familial§ in the PubMed database and the MeSH terms ※Hirschsprung§ and ※familial§ in Web of Science. Finally, we summarized 129 HSCR families over the last 40 years.
Results: The male-to-female ratio and the percentage of short segment-HSCR in familial HSCR are much lower than in sporadic HSCR. The primary gene factors in the syndromic families are ret proto-oncogene (RET) and endothelin B receptor gene (EDNRB). Most families show incomplete dominance and are relevant to RET, and the RET mutation has 56% penetrance in familial HSCR. When one of the parents is a RET mutation carrier in an HSCR family, the off spring*s recurrence risk is 28%, and the incidence of the off spring does not depend on whether the parent suffers from HSCR.
Conclusion: Our findings will help HSCR patients obtain better genetic counseling, calculate the risk of recurrence, and provide new insights for future pedigree studies.
  [Abstract] [Full Text] [PDF]  
Original articles:
Poly-hydroxylated bile acids and their prognostic roles in Alagille syndrome
  Meng-Xuan Wang, Jun Han, Teng Liu, Ren-Xue Wang, Li-Ting Li, Zhong-Die Li, Jun-Cong Yang, Lang-Li Liu, Yi Lu, Xin-Bao Xie, Jing-Yu Gong, Shi-Yu Li, Lei Zhang, Victor Ling, Jian-She Wang
Background: The liver manifestations of Alagille syndrome (ALGS) are highly variable, and factors affecting its prognosis are poorly understood. We asked whether the composition of bile acids in ALGS patients with good clinical outcomes differs from that in patients with poor outcomes and whether bile acids could be used as prognostic biomarkers.
Methods: Blood for bile acid profiling was collected from genetically confirmed JAG1-associated ALGS patients before one year of age. A good prognosis was defined as survival with native liver and total bilirubin (TB) < 85.5 米mol/L, while a poor prognosis was defined as either liver transplantation, death from liver failure, or TB ≡ 85.5 米mol/L at the last follow-up.
Results: We found that the concentrations of two poly-hydroxylated bile acids, tauro-2汕,3汐,7汐,12汐-tetrahydroxylated bile acid (THBA) and glyco-hyocholic acid (GHCA), were significantly increased in patients with good prognosis compared to those with poor prognosis [area under curve (AUC) = 0.836 and 0.782, respectively] in the discovery cohort. The same trend was also observed in the molar ratios of GHCA to glyco-chenodeoxycholic acid (GCDCA) and tetrahydroxylated bile acid (THCA) to tauro-chenodeoxycholic acid (TCDCA) (both AUC = 0.836). A validation cohort confirmed these findings. Notably, tauro-2汕,3汐,7汐,12汐-THBA achieved the highest prediction accuracy of 88.00% (92.31% sensitivity and 83.33% specificity); GHCA at > 607.69 nmol/L was associated with native liver survival [hazard ratio: 13.03, 95% confidence interval (CI): (2.662每63.753), P = 0.002].
Conclusions: We identified two poly-hydroxylated bile acids as liver prognostic biomarkers of ALGS patients. Enhanced hydroxylation of bile acids may result in better clinical outcomes.
  [Abstract] [Full Text] [PDF]  
A multicenter prospective study of next-generation sequencing-based newborn screening for monogenic genetic diseases in China
  Ru-Lai Yang, Gu-Ling Qian, Ding-Wen Wu, Jing-Kun Miao, Xue Yang, Ben-Qing Wu, Ya-Qiong Yan, Hai-Bo Li, Xin-Mei Mao, Jun He, Huan Shen, Hui Zou, Shu-Yuan Xue, Xiao-Ze Li, Ting-Ting Niu, Rui Xiao, Zheng-Yan Zhao
Background: Newborn screening (NBS) is an important and successful public health program that helps improve the long-term clinical outcomes of newborns by providing early diagnosis and treatment of certain inborn diseases. The development of next-generation sequencing (NGS) technology provides new opportunities to expand current newborn screening methodologies.
Methods: We designed a newborn genetic screening (NBGS) panel targeting 135 genes associated with 75 inborn disorders by multiplex PCR combined with NGS. With this panel, a large-scale, multicenter, prospective multidisease analysis was conducted on dried blood spot (DBS) profiles from 21,442 neonates nationwide.
Results: We presented the positive detection rate and carrier frequency of diseases and related variants in different regions; and 168 (0.78%) positive cases were detected. Glucose-6-Phosphate Dehydrogenase deficiency (G6PDD) and phenylketonuria (PKU) had higher prevalence rates, which were significantly different in different regions. The positive detection of G6PD variants was quite common in south China, whereas PAH variants were most commonly identified in north China. In addition, NBGS identified 3 cases with DUOX2 variants and one with SLC25A13 variants, which were normal in conventional NBS, but were confirmed later as abnormal in repeated biochemical testing after recall. Eighty percent of high-frequency gene carriers and 60% of high-frequency variant carriers had obvious regional differences. On the premise that there was no significant difference in birth weight and gestational age, the biochemical indicators of SLC22A5 c.1400C > G and ACADSB c.1165A > G carriers were significantly different from those of non-carriers.
Conclusions: We demonstrated that NBGS is an effective strategy to identify neonates affected with treatable diseases as a supplement to current NBS methods. Our data also showed that the prevalence of diseases has significant regional characteristics, which provides a theoretical basis for screening diseases in different regions.
  [Abstract] [Full Text] [PDF]  
Unique mutation spectrum of progressive pseudorheumatoid dysplasia in the Chinese population: a retrospective genotype每phenotype analysis of 105 patients
  Wei Wang, Si-Hao Gao, Min Wei, Lin-Qing Zhong, Wei Liu, Shan Jian, Juan Xiao, Cai-Hui Zhang, Jian-Guo Zhang, Xiao-Feng Zeng, Wei-Bo Xia, Zheng-Qing Qiu, Hong-Mei Song
Background: Progressive pseudorheumatoid dysplasia (PPRD) is a rare genetic disease with autosomal recessive inheritance. There was a lack of genotype每phenotype correlation data from the Chinese population. This study aimed to identify the genotype and phenotype characteristics of Chinese PPRD patients and to conduct a genotype每phenotype analysis of Chinese PPRD patients.
Methods: Genetic analysis was performed for suspected PPRD patients from Peking Union Medical College Hospital. Medical records were collected from the electronic medical record system and patient-held portable health records. Published Chinese PPRD cases were gathered from both international and Chinese local databases. We collected demographic information, genetic variants, clinical manifestations, and imaging characteristics for further analysis.
Results: We included 105 Chinese PPRD patients in the current study. Thirty-three variants, including nine novels and five hotspot variants, were identified, with 26/33 (79%) variants exclusively seen in the Chinese population. Chinese PPRD patients share a phenotype similar to that in international reports. Joint involvement may progress with age (R2 = 0.2541). Long bone shortening and severe deformities occur in three patients with biallelic null variants, of which at least one variant is located in exon 2. Among hotspot variants, c.624dupA (p.C209Mfs*21) were associated with later onset and more involved joints. Elbow joints were more likely to be affected in patients carrying c.624dupA (p.C209Mfs*21) and c.866dupA (p.S209Efs*13). Shoulder joints are more likely to be involved in patients with biallelic null variants (P = 0.027).
Conclusions: Chinese PPRD patients share a unique mutation spectrum. Among the five hotspot variants, c.624dupA is associated with later onset of disease, more extensive joint involvement, and a tendency to affect elbow joints. Biallelic null variants with at least one variant in exon 2 could be a likely cause of long bone shortening and severe deformities.
  [Abstract] [Full Text] [PDF]  
Delayed-onset adenosine deaminase deficiency with a novel synonymous mutation and a case series from China
  Yue Zhang, Wei Liu, Zhou Shu, Yan Li, Fei Sun, Zhi-Gang Li, Tong-Xin Han, Hua-Wei Mao, Tian-You Wang
Background: Adenosine deaminase (ADA) is a key enzyme in the purine salvage pathway. Genetic defects of the ADA gene can cause a subtype of severe combined immunodeficiency. To date, few Chinese cases have been reported.
Methods: We retrospectively reviewed the medical records of patients diagnosed with ADA deficiency in Beijing Children*s Hospital and summarized the previously published ADA deficiency cases from China in the literature.
Results: Nine patients were identified with two novel mutations (W272X and Q202 =). Early-onset infection, thymic abnormalities and failure to thrive were the most common manifestations of Chinese ADA-deficient patients. The ADA genotype has a major effect on the clinical phenotype. Notably, a novel synonymous mutation (c.606G>A, p.Q202=) was identified in a delayed-onset patient, which affected pre-mRNA splicing leading to a frameshift and premature truncation of the protein. Furthermore, the patient showed 污汛T cells expansion with an increased effect or phenotype, which may be associated with the delayed onset of disease. In addition, we reported cerebral aneurysm and intracranial artery stenosis for the first time in ADA deficiency. Five patients died with a median age of four months, while two patients received stem cell transplantation and are alive.
Conclusions: This study described the first case series of Chinese ADA-deficient patients. Early-onset infection, thymic abnormalities and failure to thrive were the most common manifestations in our patients. We identified a synonymous mutation that affected pre-mRNA splicing in the ADA gene, which had never been reported in ADA deficiency. Furthermore, we reported cerebral aneurysm in a delayed-onset patient for the first time. Further study is warranted to investigate the underlying mechanisms.
  [Abstract] [Full Text] [PDF]  
Australian children living with rare diseases: health service use and barriers to accessing care
  Suzy Teutsch, Yvonne Zurynski, Guy D. Eslick, Marie Deverell, John Christodoulou, Helen Leonard, Troy Dalkeith, Sandra L. J. Johnson, Elizabeth J. Elliott
Background: Children with rare diseases experience challenges at home and school and frequently require multi-disciplinary healthcare. We aimed to determine health service utilization by Australian children with rare diseases and barriers to accessing healthcare.
Methods: Parents completed an online survey on health professional and emergency department (ED) presentations, hospitalization, and barriers to accessing services. Potential barriers to service access included residential location (city, regional, remote) and child health-related functioning, determined using a validated, parent-completed measure-of-function tool.
Results: Parents of 462 children with over 240 rare diseases completed the survey. Compared with the general population, these children were more likely to be hospitalized [odds ratio (OR) = 17.25, 95% confidence interval (CI) = 15.50每19.20] and present to the ED (OR = 4.15, 95% CI = 3.68每4.68) or a family physician (OR = 4.14, 95% CI = 3.72每4.60). Child functional impairment was nil/mild (31%), moderate (48%) or severe (22%). Compared to children with nil/mild impairment, those with severe impairment were more likely to be hospitalized (OR = 13.39, 95% CI = 7.65每23.44) and present to the ED (OR = 11.16, 95% CI = 6.46每19.27). Most children (75%) lived in major cities, but children from regional (OR = 2.78, 95% CI = 1.72每4.55) and remote areas (OR = 9.09, 95% CI = 3.03每25.00) experienced significantly more barriers to healthcare access than children from major cities. Barriers included distance to travel, out-of-pocket costs, and lack of specialist medical and other health services.
Conclusions: Children with rare diseases, especially those with severe functional impairment have an enormous impact on health services, and better integrated multidisciplinary services with patient-centered care are needed. Access must be improved for children living in rural and remote settings.
  [Abstract] [Full Text] [PDF]  
Incidence and severity of pediatric appendicitis during the COVID-19 pandemic
  Paula Rosanna Quaglietta, Reto M. Baertschiger
  [Abstract] [Full Text] [PDF]  
Response to ※Incidence and severity of pediatric appendicitis during the COVID-19 pandemic§
  Francesca del Giorgio, Jocelyn Gravel, Nelson Pich谷, Olivier Drouin
  [Abstract] [Full Text] [PDF]  
World Journal of Pediatric Surgery
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