目的 总结分析囊性纤维化（cystic fibrosis，CF）患儿的临床及基因突变位点，以提高对CF的认识，减少误诊、漏诊。 方法 回顾性分析河北省儿童医院2018~2021年确诊的8例CF患儿的病历资料。 结果 8例患儿（男5例，女3例），诊断年龄为3~48个月（中位年龄8个月），发病年龄为0~24个月（中位年龄2.5个月）。临床表现为反复呼吸道感染7例，鼻窦炎3例，支气管扩张4例，腹泻8例，脂肪泻3例，可疑胰腺功能不全6例，胰腺CF 1例，营养不良5例，假性Bartter综合征4例。最常见的呼吸道病原为铜绿假单胞菌（4例）。经高通量测序、多重连接探针扩增技术和Sanger测序验证共发现16个变异位点，包括移码突变5个，无义突变4个，错义突变4个，外显子缺失2个，剪接突变1个。8例患儿均检出CFTR基因突变。最常见的基因突变类型是p.G970D（3例），观察到1例F508del基因突变。检出4个新发现的变异：deletion exon15、c.3796_3797dupGA(p.I1267Kfs*12)、c.2328dupA(p.V777Sfs*2)、c.2950G>A(p.D984N)。 结论 p.G970D为CF患儿最常见的突变类型。对于临床上反复呼吸道感染，合并或不合并消化系统表现和假性Bartter综合征，以及呼吸道病原学检测示铜绿假单胞菌阳性的患儿，需警惕CF。
Abstract
Objective To study the clinical features and gene mutation sites of children with cystic fibrosis (CF), in order to improve the understanding of CF to reduce misdiagnosis and missed diagnosis. Methods A retrospective analysis was performed on the medical records of 8 children with CF who were diagnosed in Hebei Children's Hospital from 2018 to 2021. Results Among the 8 children with CF, there were 5 boys and 3 girls, with an age of 3-48 months (median 8 months) at diagnosis, and the age of onset ranged from 0 to 24 months (median 2.5 months). Clinical manifestations included recurrent respiratory infection in 7 children, sinusitis in 3 children, bronchiectasis in 4 children, diarrhea in 8 children, fatty diarrhea in 3 children, suspected pancreatic insufficiency in 6 children, pancreatic cystic fibrosis in 1 child, malnutrition in 5 children, and pseudo-Bartter syndrome in 4 children. The most common respiratory pathogens were Pseudomonas aeruginosa (4 children). A total of 16 mutation sites were identified by high-throughput sequencing, multiplex ligation-dependent probe amplification, and Sanger sequencing, including 5 frameshift mutations, 4 nonsense mutations, 4 missense mutations, 2 exon deletions, and 1 splice mutation. CFTR mutations were found in all 8 children. p.G970D was the most common mutation (3 children), and F508del mutation was observed in one child. Four novel mutations were noted: deletion exon15, c.3796_3797dupGA(p.I1267Kfs*12), c.2328dupA(p.V777Sfs*2), and c.2950G>A(p.D984N). Conclusions p.G970D is the most common mutation type in children with CF. CF should be considered for children who have recurrent respiratory infection or test positive for Pseudomonas aeruginosa, with or without digestive manifestations or pseudo-Bartter syndrome.
关键词
囊性纤维化 /
基因突变 /
反复呼吸道感染 /
胰腺功能不全 /
儿童
Key words
Cystic fibrosis /
Gene mutation /
Recurrent respiratory infection /
Pancreatic insufficiency /
Child
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
1 Elborn JS. Cystic fibrosis[J]. Lancet, 2016, 388(10059): 2519-2531. PMID: 27140670. DOI: 10.1016/S0140-6736(16)00576-6.
2 Cystic Fibrosis Foundation. 2019 Patient registry annual data report[EB/OL]. [2021-10-20]. https://www.cff.org/sites/default/files/2021-10/2019-Patient-Registry-Annual-Data-Report.pdf.
3 Cystic Fibrosis Trust. UK cystic fibrosis registry annual data report 2019[EB/OL]. [2021-10-20]. https://www.cysticfibrosis.org.uk/sites/default/files/2020-12/2019%20Registry%20Annual%20Data%20report_Sep%202020.pdf.
4 Izumikawa K, Tomiyama Y, Ishimoto H, et al. Unique mutations of the cystic fibrosis transmembrane conductance regulator gene of three cases of cystic fibrosis in Nagasaki, Japan[J]. Intern Med, 2009, 48(15): 1327-1331. PMID: 19652440. DOI: 10.2169/internalmedicine.48.2078.
5 Farrell PM, White TB, Ren CL, et al. Diagnosis of cystic fibrosis: consensus guidelines from the cystic fibrosis foundation[J]. J Pediatr, 2017, 181S: S4-S15.e1. PMID: 28129811. DOI: 10.1016/j.jpeds.2016.09.064.
6 王国丽, 赵春娜, 周锦, 等. 儿童胰腺囊性纤维化11例临床分析[J]. 中华儿科杂志, 2017, 55(5): 373-376. PMID: 28482390. DOI: 10.3760/cma.j.issn.0578-1310.2017.05.013.
7 中国医师协会胰腺病专业委员会慢性胰腺炎专委会. 胰腺外分泌功能不全诊治规范(2018, 广州)[J]. 中华消化内镜杂志, 2018, 35(12): 871-875. DOI: 10.3760/cma.j.issn.1007-5232.2018.12.002.
8 王兴兰, 尹子福, 申月琳, 等. 汗液电导率检测对儿童囊性纤维化的诊断价值分析[J]. 中华儿科杂志, 2019, 57(7): 548-552. PMID: 31269556. DOI: 10.3760/cma.j.issn.0578‐1310.2019.07.011.
9 Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA[J]. Science, 1989, 245(4922): 1066-1073. PMID: 2475911. DOI: 10.1126/science.2475911.
10 Bell SC, Mall MA, Gutierrez H, et al. The future of cystic fibrosis care: a global perspective[J]. Lancet Respir Med, 2020, 8(1): 65-124. PMID: 31570318. PMCID: PMC8862661. DOI: 10.1016/S2213-2600(19)30337-6.
11 Widdicombe JH. Regulation of the depth and composition of airway surface liquid[J]. J Anat, 2002, 201(4): 313-318. PMID: 12430955. PMCID: PMC1570918. DOI: 10.1046/j.1469-7580.2002.00098.x.
12 Wielpütz MO, Eichinger M, Biederer J, et al. Imaging of cystic fibrosis lung disease and clinical interpretation[J]. Rofo, 2016, 188(9): 834-845. PMID: 27074425. DOI: 10.1055/s-0042-104936.
13 Baker RD. Assessing exocrine pancreatic function: when the best test is not possible[J]. J Pediatr Gastroenterol Nutr, 2013, 56(2): 116-117. PMID: 23201709. DOI: 10.1097/MPG.0b013e31827e2293.
14 Guo X, Liu K, Liu Y, et al. Clinical and genetic characteristics of cystic fibrosis in Chinese patients: a systemic review of reported cases[J]. Orphanet J Rare Dis, 2018, 13(1): 224. PMID: 30558651. PMCID: PMC6296146. DOI: 10.1186/s13023-018-0968-2.
15 Sherwood JS, Ullal J, Kutney K, et al. Cystic fibrosis related liver disease and endocrine considerations[J]. J Clin Transl Endocrinol, 2022, 27: 100283. PMID: 35024343. PMCID: PMC8724940. DOI: 10.1016/j.jcte.2021.100283.
16 Flass T, Narkewicz MR. Cirrhosis and other liver disease in cystic fibrosis[J]. J Cyst Fibros, 2013, 12(2): 116-124. PMID: 23266093. PMCID: PMC3883947. DOI: 10.1016/j.jcf.2012.11.010.
17 Bartlett JR, Friedman KJ, Ling SC, et al. Genetic modifiers of liver disease in cystic fibrosis[J]. JAMA, 2009, 302(10): 1076-1083. PMID: 19738092. PMCID: PMC3711243. DOI: 10.1001/jama.2009.1295.
18 Shen Y, Tang X, Liu J, et al. Pseudo-Bartter syndrome in Chinese children with cystic fibrosis: clinical features and genotypic findings[J]. Pediatr Pulmonol, 2020, 55(11): 3021-3029. PMID: 32761997. DOI: 10.1002/ppul.25012.
19 Mantoo MR, Kabra M, Kabra SK. Cystic fibrosis presenting as Pseudo-Bartter syndrome: an important diagnosis that is missed![J]. Indian J Pediatr, 2020, 87(9): 726-732. PMID: 32504456. DOI: 10.1007/s12098-020-03342-8.
20 Reynolds D, Kollef M. The epidemiology and pathogenesis and treatment of Pseudomonas aeruginosa infections: an update[J]. Drugs, 2021, 81(18): 2117-2131. PMID: 34743315. PMCID: PMC8572145. DOI: 10.1007/s40265-021-01635-6.
21 Mogayzel PJ, Naureckas ET, Robinson KA, et al. Cystic fibrosis foundation pulmonary guideline. pharmacologic approaches to prevention and eradication of initial Pseudomonas aeruginosa infection[J]. Ann Am Thorac Soc, 2014, 11(10): 1640-1650. PMID: 25549030. DOI: 10.1513/AnnalsATS.201404-166OC.
22 Rabeh WM, Bossard F, Xu H, et al. Correction of both NBD1 energetics and domain interface is required to restore ΔF508 CFTR folding and function[J]. Cell, 2012, 148(1-2): 150-163. PMID: 22265408. PMCID: PMC3431169. DOI: 10.1016/j.cell.2011.11.024.
23 张金花. 1例囊性纤维化患者应用替加环素诱发急性胰腺炎[J]. 药学与临床研究, 2017, 25(1): 75-76. DOI: 10.13664/j.cnki.pcr.2017.01.022.
24 申月琳, 陈琼华, 唐晓蕾, 等. 儿童囊性纤维化相关变应性支气管肺曲霉菌病22例临床分析[J]. 中华儿科杂志, 2020, 58(8): 646-652. PMID: 32842385. DOI: 10.3760/cma.j.cn112140-20200426-00435.
25 Tian X, Liu Y, Yang J, et al. p.G970D is the most frequent CFTR mutation in Chinese patients with cystic fibrosis[J]. Hum Genome Var, 2016, 3: 15063. PMID: 27081564. PMCID: PMC4785583. DOI: 10.1038/hgv.2015.63.
26 Shi R, Wang X, Lu X, et al. A systematic review of the clinical and genetic characteristics of Chinese patients with cystic fibrosis[J]. Pediatr Pulmonol, 2020, 55(11): 3005-3011. PMID: 32716133. DOI: 10.1002/ppul.24980.
27 Grody WW, Cutting GR, Klinger KW, et al. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening[J]. Genet Med, 2001, 3(2): 149-154. PMID: 11280952. DOI: 10.1097/00125817-200103000-00010.
28 Marshall B, Faro A, Elbert A, et al. 2018 patient registry annual data report[EB/OL]. [2021-10-20]. https://www.cff.org/medical-professionals/patient-registry.
PDF(806 KB)
