ANK1和SPTB基因突变致遗传性球形红细胞增多症的临床特点及遗传学分析

龚军; 贺湘玲; 邹润英; 陈可可; 游亚兰; 邹惠; 田鑫; 朱呈光

doi:10.7499/j.issn.1008-8830.2019.04.013

PDF(2015 KB)

HTML

中国当代儿科杂志 ›› 2019, Vol. 21 ›› Issue (4) : 370-374. DOI: 10.7499/j.issn.1008-8830.2019.04.013

论著·临床研究

ANK1和SPTB基因突变致遗传性球形红细胞增多症的临床特点及遗传学分析

龚军, 贺湘玲, 邹润英, 陈可可, 游亚兰, 邹惠, 田鑫, 朱呈光

作者信息 +

Clinical characteristics and genetic analysis of hereditary spherocytosis caused by mutations of ANK1 and SPTB genes

GONG Jun, HE Xiang-Ling, ZOU Run-Ying, CHEN Ke-Ke, YOU Ya-Lan, ZOU Hui, TIAN Xin, ZHU Cheng-Guang

Author information +

文章历史 +

摘要

该研究对5例遗传性球形红细胞增多症（HS）患儿的临床特点及ANK1和SPTB基因突变特征进行分析。5例患儿均通过外周血基因检测确诊。5例患儿均表现为贫血、黄疸、脾肿大。红细胞渗透脆性试验显示3例增高；Coombs试验、葡萄糖6磷酸脱氢酶测定、蔗糖溶血试验、酸化血清溶血试验、地中海贫血基因检测均为阴性；外周血涂片球形红细胞计数仅1例增加。高通量测序发现病例1~3存在ANK1基因突变，分别为c.3398（exon29）delA、c.4306C > T以及c.957（exon9）_c.961（exon9）delAATCT，其中c.3398（exon29）delA未见报道；病例4的SPTB基因存在C.318delGExon3突变；病例5存在SPTB基因合并SLC4A1基因突变，其中SPTB基因c.3484delC为自发突变，SLCA4A1基因的突变位点来自父亲，为非致病基因。该研究提示，贫血、黄疸、脾肿大是HS患儿主要的临床表现；多数HS患儿外周血球形红细胞计数无明显异常；基因检测有助于HS的精准诊断。

Abstract

This study analyzed the clinical features of 5 children with hereditary spherocytosis (HS) and the characteristics of ANK1 and SPTB gene mutations. All 5 children were confirmed with HS by peripheral blood genetic detection. Anemia, jaundice and splenomegaly were observed in all 5 children. Three children had an increase in erythrocyte osmotic fragility. All 5 children had negative results of the Coombs test, glucose 6 phosphate dehydrogenase test, sucrose hemolysis test, acidified-serum hemolysis test and thalassemia gene test. Peripheral blood smear showed an increase in spherocyte count in one child. High-throughput sequencing revealed ANK1 gene mutations in patients 1 to 3, namely c.3398(exon29)delA, c.4306C > T and c.957(exon9)_c.961(exon9)delAATCT, among which c.3398(exon29)delA had not been reported before. Patient 4 had c.318delGExon3 mutation in the SPTB gene. Patient 5 had mutations in the SPTB and SLC4A1 genes, among which c.3484delC in the SPTB gene was a spontaneous mutation; the mutation site of the SLCA4A1 gene was inherited from the father and was a non-pathogenic gene. This study suggests that anemia, jaundice and splenomegaly are major clinical manifestations of HS children. Most children with HS do not have the typical spherocytic changes. Genetic detection may help with the accurate diagnosis of HS.

导出引用

龚军, 贺湘玲, 邹润英, 陈可可, 游亚兰, 邹惠, 田鑫, 朱呈光. ANK1和SPTB基因突变致遗传性球形红细胞增多症的临床特点及遗传学分析[J]. 中国当代儿科杂志. 2019, 21(4): 370-374 https://doi.org/10.7499/j.issn.1008-8830.2019.04.013

GONG Jun, HE Xiang-Ling, ZOU Run-Ying, CHEN Ke-Ke, YOU Ya-Lan, ZOU Hui, TIAN Xin, ZHU Cheng-Guang. Clinical characteristics and genetic analysis of hereditary spherocytosis caused by mutations of ANK1 and SPTB genes[J]. Chinese Journal of Contemporary Pediatrics. 2019, 21(4): 370-374 https://doi.org/10.7499/j.issn.1008-8830.2019.04.013

参考文献

[1] Bolton-Maggs PH, Langer JC, Iolascon A,et al. Guidelines for the diagnosis and management of hereditary spherocytosis-2011 update[J]. Br J Haematol, 2012, 156(1):37-49.
[2] 张丹, 万伍卿. ANK1基因突变致遗传性球型红细胞增多症1例报告[J]. 临床儿科杂志, 2017, 35(9):691-693.
[3] 马亚南, 刘玉峰. 儿童遗传性球形红细胞增多症88例临床特点分析[J]. 河南医学研究, 2017, 26(6):992-993.
[4] 方潇倩, 徐酉华. 儿童遗传性球形细胞增多症35例[J]. 中国小儿血液与肿瘤杂志, 2013, 18(2):74-77.
[5] 张碧红, 陈纯, 岑丹阳, 等. 遗传性球形红细胞增多症26例[J]. 实用儿科临床杂志, 2008, 23(15):1162-1164.
[6] Ma S, Deng X, Liao L, et al. Analysis of the causes of the misdiagnosis of hereditary spherocytosis[J]. Oncol Rep, 2018, 40(3):1451-1458.
[7] Deng Z, Liao L, Yang W, et al. Misdiagnosis of two cases of hereditary spherocytosis in a family and review of published reports[J]. Clin Chim Acta, 2015, 441:6-9.
[8] Gallagher PG. Abnormalities of the erythrocyte membrane[J]. Pediatr Clin North Am, 2013, 60(6):1349-1362.
[9] Bolton-Maggs PH. Hereditary spherocytosis; new guidelines[J]. Arch Dis Child, 2004, 89(9):809-812.
[10] 张之南, 沈悌. 血液病诊断及疗效标准[M]. 北京:科学出版社, 2007:43-46.
[11] 周玲, 刘敏, 陈钟. 球形红细胞计数在遗传性球形红细胞增多症诊断中的意义[J]. 大理医学院学报, 2000, 9(2):9-10.
[12] Bianchi P, Fermo E, Vercellati C, et al. Diagnostic power of laboratory tests for hereditary spherocytosis:a comparison study in 150 patients grouped according to molecular and clinical characteristics[J]. Haematologica, 2012, 97(4):516-523.
[13] Hunt L, Greenwood D, Heimpel H, et al. Toward the harmonization of result presentation for the eosin-5'-maleimide binding test in the diagnosis of hereditary spherocytosis[J]. Cytometry B Clin Cytom, 2015, 88(1):50-57.
[14] Arora RD, Dass J, Maydeo S, et al. Flow cytometric osmotic fragility test and eosin-5'-maleimide dye-binding tests are better than conventional osmotic fragility tests for the diagnosis of hereditary spherocytosis[J]. Int J Lab Hematol, 2018, 40(3):335-342.
[15] Ma S, Deng X, Liao L, et al. Analysis of the causes of the misdiagnosis of hereditary spherocytosis[J]. Oncol Rep, 2018, 40(3):1451-1458.
[16] Chari PS, Prasad S. Flow cytometric eosin-5'-maleimide test is a sensitive screen for hereditary spherocytosis[J]. Indian J Hematol Blood Transfus, 2018, 34(3):491-494.
[17] Crisp RL, Solari L, Vota D, et al. A prospective study to assess the predictive value for hereditary spherocytosis using five laboratory tests (cryohemolysis test, eosin-5'-maleimide flow cytometry, osmotic fragility test, autohemolysis test, and SDSPAGE) on 50 hereditary spherocytosis families in Argentina[J]. Ann Hematol, 2011, 90(6):625-634.
[18] Russo R, Andolfo I, Manna F, et al. Multi-gene panel testing improves diagnosis and management of patients with hereditary anemias[J]. Am J Hemato, 2018, 93(5):672-682.
[19] Wang X, Yi B, Mu K, et al. Identification of a novel de novo ANK1 R1426^* nonsense mutation in a Chinese family with hereditary spherocytosis by NGS[J]. Oncotarget, 2017, 8(57):96791-96797.
[20] Chen J, Zhou Y, Gao Y, et al. A genetic features and gene interaction study for identifying the genes that cause hereditary spherocytosis[J]. Hematology, 2017, 22(4):240-247.
[21] Narla J, Mohandas N. Red cell membrane disorders[J]. Int J Lab Hematol, 2017, 39(Suppl 1):47-52.
[22] Delaunay J. The molecular basis of hereditary red cell membrane disorders[J]. Blood Rev, 2007, 21(1):1-20.
[23] He BJ, Liao L, Deng ZF, et al. Molecular genetic mechanisms of hereditary spherocytosis:current perspectives[J]. Acta Haematol, 2018, 139(1):60-66.
[24] Wang R, Yang S, Xu M, et al. Exome sequencing confirms molecular diagnoses in 38 Chinese families with hereditary spherocytosis[J]. Sci China Life Sci, 2018, 61(8):947-953.
[25] Luo Y, Li Z, Huang L, et al. Spectrum of ankyrin mutations in hereditary spherocytosis:a case report and review of the literature[J]. Acta Haematol, 2018, 140(2):77-86.
[26] Miraglia del Giudice E, Francese M, Nobili B, et al. High frequency of de novo mutations in ankyrin gene (ANK1) in children with hereditary spherocytosis[J]. J Pediatr, 1998, 132(1):117-120.
[27] Perrotta S, Gallagher PG, Mohandas N. Hereditary spherocytosis[J]. Lancet, 2008, 372(9647):1411-1426.
[28] Park J, Jeong DC, Yoo J, et al. Mutational characteristics of ANK1 and SPTB genes in hereditary spherocytosis[J]. Clin Genet, 2016, 90(1):69-78.
[29] Chong J, Jones P, Spelman D, et al. Overwhelming postsplenectomy sepsis in patients with asplenia and hyposplenia:a retrospective cohort study[J]. Epidemiol Infect, 2017, 145(2):397-400.
[30] Kimmig LM, Palevsky HI. Review of the association between splenectomy and chronic thromboembolic pulmonary hypertension[J]. Ann Am Thorac Soc, 2016, 13(6):945-954.
[31] Pugi J, Carcao M, Drury LJ, et al. Results after laparoscopic partial splenectomy for children with hereditary spherocytosis:are outcomes influenced by genetic mutation?[J]. J Pediatr Surg, 2018, 53(5):973-975.