To the Editor: Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. To date, over 2000 CFTR mutations have been identified. CF mostly occurs in the Caucasian population, and its incidence is approximately 1/25,000 to 1/1800.However, the number of CF cases in China is small. To discover the gene mutations and clinical characteristics of Chinese children with CF, as well as their correlation, the clinical data of 10 children with CF or CFTR-related disorders (CFTR-RD) were retrospectively analyzed in this study. Children with newly diagnosed CF or CFTR-RD were hospitalized at the Children's Hospital Affiliated to the Capital Institute of Pediatrics from June 2015 to August 2021 were enrolled. This study was approved by the Ethics Committee of the Capital Institute of Pediatrics (No. SHERLL2021013), and all patients have signed informed consent forms. The diagnostic criteria were as follows:(1) Sweat chloride values ≥60 mmol/L; or (2) Sweat chloride values in the intermediate range (30–59 mmol/L) in the presence of CF-causing CFTR mutations or CFTR dysfunction approved by CFTR physiologic testing. However, individuals with clinical features that might be consistent with CF who had a sweat chloride <30 mmol/L were less likely to have CF.[1] The children's basic data were collected from the electronic medical record system at our hospital. The blood samples of children and their parents were sent to testing institutions (Beijing MyGenostics Co., Ltd, China and Shanghai Hanyao Biomedical Technology Co., Ltd, China) for genetic tests and analysis. The mutated gene was identified by high-throughput sequencing and confirmed by Sanger sequencing. The test results classified the pathogenicity of the genetic variation according to the guidelines issued by the American College of Medical Genetics and Genomics (ACMG) in 2015. The CFTR2 (https//www.cftr2.org/), ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), and CFTR-France (https://cftr.iurc.montp.inserm.fr/cftr/) databases were used to interpret the pathogenicity of CFTR variants. Sweat was collected for the quantitative detection of chloride ions. Among the 10 children, nine children were diagnosed with CF and one child was diagnosed with CFTR-RD, and all the parents and siblings had no clear history of CF. The age of onset was 29 days to 10 years, with a median age of four months. The age at diagnosis ranged from 10 months to 12.5 years, with a median age of 6.2 years. One children was Uyghur, and the rest were Han Chinese. The main manifestations were repeated cough, and wheezing and pulmonary infection in eight cases, two cases had low sodium, hypochloremia, and hypokalemia with mild cough, three cases had allergic bronchopulmonary aspergillosis (ABPA), and four cases had fatty diarrhea. In addition, there were two cases had intestinal obstruction, liver cirrhosis, diabetes, and pancreatitis [Supplementary Table 1, https://links.lww.com/CM9/B705]. The average value of the sweat chloride tests in nine children with CF was over 60 mmol/L. The sweat chloride test value of the child with CFTR-RD was 28 mmol/L. Sputum bacterial culture and next-generation sequencing were applied to find the etiology. The pathogenic examination of the nine CF children when first diagnosed revealed one case without infection and eight cases with Pseudomonas aeruginosa infection, among which four patients had additional bacterial infections. Pseudomonas aeruginosa was the most common infectious pathogen reported in China.[2] Spirometry and airway resistance tests with impulse oscillation were performed on nine of the 10 children, and seven cases had obstructive ventilation dysfunction to varying degrees. One of the remaining two patients had diffusion dysfunction, and the others had normal pulmonary function. Abdominal ultrasound was performed on all 10 children, including four with diffuse liver enlargement, three with abnormal pancreatic echo genicity, one with chronic inflammation of the intestinal wall, and two with normal tissue. All children with abnormal pancreatic echogenicity had clinical manifestations of fatty diarrhea. All 10 children underwent pulmonary computed tomography (CT) examination, and eight had bronchiectasis with varying degrees of "tree bud sign" and "signet ring sign". Thickening of the bronchial wall was seen in the other two patients. Nine children underwent sinus CT, which revealed sinusitis, mainly bilateral maxillary sinusitis, manifesting as thickening of the maxillary sinus mucosa or blockage of the sinus cavity. Electronic bronchoscopy was performed on nine children, all of whom had bronchitis changes. One patient had suppurative changes in the bronchial intima, and one patient had extensive squamous metaplasia of the bronchial mucosal epithelium. All 10 children underwent genetic testing (records were lost for case 7), a total of 16 mutations were found in this study. The homozygous CFTR variants were p. phe508del (phenylalanine deletion at position 508) (case 8) and p.Y325X (the nucleotide 975 in the coding region changed from thymine to guanine, resulting in the amino acid change of p.Y325X, which is a nonsense mutation)(case 10), the main clinical manifestation of the patient with p. phe508del was recurrent lung infections and steatorrhea, similar to the symptoms observed in the Caucasian population. The p.Y325X mutation was rarely reported, and the clinical manifestation of this patient was repeated fatty diarrhea, intestinal obstruction, and cough. The Sudan III dye test of fecal matter was positive. The chest high resoluation CT confirmed the presence of central bronchiectasis. The paranasal CT showed nasosinusitis. Abdominal CT showed that the pancreas had a high fat density. Nine new mutant nucleotides that were not previously included in the CFTR 2 database were found in this study. Two children with the p.phe508del mutation, rarely reported in China, were identified. One homozygous mutation and one heterozygous mutation were found, the homozygous mutation was found in a Uyghur child and the heterozygous mutation in a Han Chinese child [Supplementary Table 1, https://links.lww.com/CM9/B705]. Two children (case 1 and case 7) underwent double lung transplantation due to the continuous deterioration of lung function. The two children were girls aged 14 years and 13 years at the time of transplantation. At present, they are 3 years and 2 years after lung transplantation, respectively. Their pulmonary function and quality of life after lung transplantation improved. Studies have shown that the 5-year survival rate after lung transplantation could reach 60–70%, and 45% of CF patients could survive for 10 years after lung transplantation.[3] A boy died from recurrent intestinal obstruction at the age of 10. Children with fatty diarrhea were given pancreatin enteric-coated capsules orally. One child had CF-related diabetes and was treated with insulin. Three children with ABPA were treated with oral corticosteroids, and their cough and wheezing symptoms were improved. The other two cases mainly manifested as repeated electrolyte disorders, and pulmonary symptoms, such as cough and expectoration, were not obvious. Oral rehydration salt was administered to correct the electrolyte disorders. The median age at CF diagnosis is 8.7 years in Chinese patients, 0.5 month in European patients[5] and 3 months in American patients according to the 2017 Patient Registry Annual Data Report, indicating a significant delay in diagnosis in China. In our study, the median age at diagnosis was 6.2 years. The CFTR mutations are mainly divided into six classes. The gene mutation in two children in this study was p.phe508del, which was not commonly reported in China. Two children in this study had the p.G970D mutation, which is the most common mutation type in Chinese CF patients but is rare or absent in Caucasias.[4] In this report, there were two cases (cases 4 and case 5) with no obvious respiratory involvement who mainly presented with irreversible hyponatremia, hypochloremia, and hypokalemia after vomiting. At onset, the disease was first considered "Bartter syndrome", but there was no renal tubular damage. The patients were finally diagnosed with CF by the sweat chloride test and gene sequencing studies. Retrospective case studies by Shen et al[5] have also revealed that pseudo-Bartter syndrome can be the only or first manifestation of CF and p.G970D was the most frequent variant in cystic fibrosis-associated pseudo-Bartter syndrome (CF-PBS), with a significant ethnic association with the Chinese population, in which the genotypes differ from those observed in Caucasians. Case 9 had recurrent coughing, wheezing, and lung infections. The genetic test results revealed two variants, c.1405A >G and c.2977G >T. According to the ACMG guidelines, the mutation site c.1405A >G and c.2977G >T were determined to be unknown clinically significant mutations. However, the sweat chloride test was negative, and the disorder could not be diagnosed as CF, but as CFTR-RD. CFTR-RD is a disease with relevant clinical manifestations of CFTR dysfunction, but involving only one system, the detection of sweat chloride ion concentration is in the suspicious interval or normal, does not carry two clear CF pathogenic genes, and cannot meet the diagnostic criteria of CF.[6] Compared with CF patients, the clinical symptoms of CFTR-RD patients are often relatively mild, and the prognosis is relatively good. In contrast to other countries, CFTR mutations in China demonstrate substantial heterogeneity, and many previously unreported CFTR mutant genes are being found. Sweat chloride tests and genetic analysis are actively carried out to enrich the CFTR mutation spectrum, which is of great significance to the individualized diagnosis and treatment of children with CF in the future. Funding This work was supported by a grant from the Special Fund of Pediatric Coordinated Development Center of Beijing Hospitals Authority (No. XTCX2018021). Conflicts of interest None.

囊性纤维化是由囊性纤维化跨膜传递调节因子基因突变所致的一种常染色体隐性遗传病.因囊性纤维化跨膜传递调节因子基因突变导致其编码蛋白的功能出现不同程度的缺陷,进而引起外分泌腺功能紊乱,可累及呼吸、消化、生殖等多个系统.随着当前分子生物学技术及精准医学的进步与发展,基因诊断和治疗逐步成为当下医学研究的热点.

Objective To investigate the therapeutic effect of low molecular weight heparin on adjuvant treat-ment of Mycoplasma pneumoniae pneumonia (MPP)with elevated D-dimer in children,and to summarize the clinical features of MPP with elevated D-dimer in children. Methods Ninety-three cases of MPP with elevated D-dimer in the Affiliated Children′s Hospital of Capital Institute of Pediatrics from January 2015 to October 2016 were randomly di-vided into the high dose group,the low dose group and the non-heparin group. All patients in 3 groups were given ac-tive anti-infection and other conventional treatment. High dose group was given subcutaneous injection of low molecu-lar weight heparin 100 IU/ kg,q12h,treatment for 5 days or D-dimer returned to normal;Low dose group was given subcutaneous injection of low molecular weight heparin 50 IU/ kg,q12h for 5 days,and then D-dimer returned to nor-mal;non-heparin group was given anti-infection and other conventional treatment. Contrast observation was performed among 3 groups for clinical symptoms and chest imaging changes before and after treatment. Also,the hospitalization days and financial costs among 3 groups were compared and the adverse reactions were observed. Another 31 patients of MPP with normal D-dimer were randomly selected for comparison with non-heparin group,including C-reactive protein(CRP),erythrocyte sedimentation rate(ESR)and other inflammatory markers,clinical symptoms,chest imaging changes,hospitalization days and the costs. Results (1)The inflammatory indicators such as CRP [(33. 49 ± 31. 75)g/ L],ESR [(34. 59 ± 16. 25)mm/ 1h],cough improvement time [(7. 77 ± 2. 85)d],heat back time [(5. 87 ± 2. 88)d],hospitalization days[(10. 87 ± 3. 50)d],hospital costs[(15455. 91 ± 4086. 95)yuan],and chest imaging severity[the ratio of large-area shadowing to small-area shadowing in terms of chest image severity was (13 / 16 cases)]of MPP with elevated D-dimer group were higher than those of MPP with normal D-dimer group [(14. 83 ± 18. 97)g/ L,(25. 33 ± 20. 35)mm/ 1 h,(3. 90 ± 1. 08)d,(2. 81 ± 1. 99)d,(5. 26 ± 1. 84)d, (7659. 85 ± 2216. 69)yuan,5 / 23 cases],and the differences were statistically significant(Z =-2. 99,- 2. 06,- 5. 82,- 5. 21,- 6. 20,t = 12. 73,χ2 = 4. 80,all P < 0. 05). (2)The time of improvement of cough,chest imaging im-provement time and the hospitalization days in the heparin-treated group[those in the low dose heparin group were (5. 48 ± 1. 95)d,(13. 84 ± 9. 18)d,(9. 19 ± 5. 10)d,and those in the high dose heparin group were(5. 35 ± 1. 91)d,(12. 88 ± 10. 81)d,(8. 58 ± 2. 81)d]were lower than those in the non-heparin group[(7. 77 ± 2. 85)d, (18. 54 ± 10. 13)d,(10. 87 ± 3. 50)d],and the differences were statistically significant(all P < 0. 05),but no signi-ficant difference was found in different doses of heparin (all P > 0. 05). D-dimer and fibrinogen degradation product (FDP)after treatment in the high dose heparin-treated group [(258. 00 ± 516. 00)ng/ L,(2. 25 ± 7. 45)mg/ L] were significantly lower than those in the non-heparin group[(1. 00 ± 691. 00)ng/ L,(0. 70 ± 3. 10)mg/ L],and the diffe-rences were statistically significant(Z = 6. 41,6. 54,all P < 0. 05). Conclusions (1)Compared with the children with MPP with elevated D-dimer,MPP children with normal D-dimer in children have more severe clinical symp-toms,higher inflammatory indicators and more serious chest imaging performance. (2)Low molecular weight heparin on adjuvant treatment of elevated D-dimer children with MPP can significantly improve the clinical symptoms and pro-mote absorption of lung disease,shorten hospitalization days,reduce hospital costs. There is no adverse reaction with short-term application. It is worthy of further promotion.