先天性心脏病患儿的免疫和甲状旁腺功能状态
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摘要
背景：先天性心脏病(congenital heart disease，CHD)患儿易伴发感染，传统观点认为其感染与血液动力学改变和机械因素有关，然而近期的文献显示：CHD可能是Digeorge综合征(Digeorge syndrome，DGS)的一部分，CHD患儿对感染的易感性与其存在不同程度的免疫功能缺陷有关。
目的：探讨CHD患儿有无免疫功能缺陷，观察CHD新生儿胸腺影改变，了解CHD患儿是否存在甲状旁腺功能低下。结合文献探讨CHD与DGS的关系。
方法：
（一） 检测28例单纯性CHD患儿和20例对照组儿童（门诊体检的正常儿童）外周血部分免疫学指标：
1 用单克隆抗体和流式细胞仪(FCM)检测淋巴细胞亚群的变化。
用逆转录聚合酶链反应（reverse transcription and polymerase chain reaction，RT-PCR）半定量测定外周血单个核细胞（peripheral blood monoeuclear cell，PBMC）经植物血凝素（phytohaemagglutinin，PHA）诱导的白细胞介素4（interleukin-4，
2 IL-4）和γ-干扰素（interferon-gamma，IFN-γ）mRNA表达，以单克隆抗体酶联免疫吸附法（enzyme-linked immuno-sorbent assay，ELISA）测定培养上清中IL-4和IFN-γ含量。
3 用3H胸腺嘧啶核苷（3H-thymidine，3H-TdR）掺入法测定PBMC经PHA和脂多糖（lipopolysaccharide，LPS）诱导的增殖功能。
4 用免疫散射比浊法（immuno-scatter turbidmetry，ISTM）测定血清免疫球蛋白和C3水平。
（二）用胸部X光片回顾性测定72例单纯性心脏畸形CHD、34例复杂性心脏畸形CHD新生儿及50例对照组新生儿（同日龄肺炎新生儿）胸腺影的大小。
（三）检测18例单纯性CHD患儿和17例对照组儿童（门诊体检的健康儿童）外周血清甲状旁腺素（parathyroid hormone，PTH）水平及离子Ca2+、Mg2+浓度。PTH用放射免疫法(immunoradiometric assay，IRMA)测定，离子Ca2+用离子选择电极法（ion selective electrode，ISE）测定，Mg2+用甲基麝香草酚蓝比色法(methyl thyme camphor blue，MTB)测定。
结果：
与对照组儿童比较，CHD患儿外周血总T细胞和CD8+T细胞数稍增高，CD4/CD8比值、NK细胞和B细胞数略降低，但无统计学意义，CD4+T细胞数与对照组儿童无差别。两组儿童的
1 淋巴细胞亚群均随年龄的增加而有轻度改变，但各年龄段之间比较无统计学意义。各年龄段CHD患儿与同年龄段对照组患儿比较以上指标均无显著性差异。
2 CHD患儿PBMC增殖功能正常，3H-TdR每分钟放射脉冲数（counts of per minut impulse，cpm值）和增殖指数（proliferative index，PI）与对照组儿童比较均无显著性差异。两组儿童的cpm值和PI均随年龄的增长略有改变，但各年龄段之间比较无统计学意义。各年龄段CHD患儿与同年龄段对照组儿童比较cpm值和PI均无显著性差异。
3 与对照组儿童比较，CHD患儿PBMC IL-4mRNA表达稍低，IFN-γmRNA表达稍高，培养上清中IL-4水平稍低，IFN-γ水平稍高，但无统计学意义。两组儿童的IL-4mRNA表达和IL-4水平均随年龄增长略有降低，而IFN-γmRNA表达和IFN-γ水平均随年龄增长略有增高，但无统计学意义。各年龄段CHD患儿与同年龄段对照组儿童比较以上四个指标均无显著性差异。
4 CHD患儿血清IgG和IgA水平较对照组略高，而IgM和C3较对照组略低，但无统计学意义。两组儿童的IgG水平随年龄的增加略有升高，IgM、IgA和C3水平随年龄变化亦略有改变，但同年龄段之间比较无统计学意义。各年龄段CHD患儿血清IgG、IgA、IgM及C3水平与同年龄段对照组儿童比较均无显著性差异。
5 所有新生儿的X光片上均可见到胸腺影，目测结果形状多变，大小有异。单纯性心脏畸形CHD新生儿和复杂性心脏畸形CHD新生儿的胸腺影大小与同日龄肺炎新生儿比较均无显著性差异。
6 CHD患儿血清PTH水平较对照组明显降低，二者比较有显著性差异(p<0.05)，CHD患儿有8例（44.4%）PTH<10ng/L，而对照组无一例<10ng/L；CHD患儿血清Ca2+和Mg2+较对照组稍低，但无统计学意义。
结论：
1 并非所有的CHD患儿均并发免疫功能缺陷。
2 单纯的CHD可能不是DGS的一个部分，即使是DGS也可能属于部分性DGS(partial DGS，pDGS)而非完全性DGS(complete DGS，cDGS)，其免疫功能低下不明显。
3 CHD患儿易感染不一定是先天性免疫功能低下的表现。
4 CHD新生儿无胸腺的先天性发育不全。
5 CHD患儿PTH分泌的储备不足，存在亚临床甲状旁腺功能低下。
6 CHD患儿甲状旁腺功能低下可能是因合并部分的先天性甲状旁腺发育不良所致。
Background：Children with congenital heart disease(CHD) are vulnerable for infections. The alteration of blood kinetic and mechanic factors are traditionally thought to be the cause，but literatures in the last years show that CHD may be a part of Digeorge syndrome(DGS) and that the susceptibility to infection in children with CHD may be related to partial primary immunodeficiency.
Objective：To explore whether there is immunodeficiency in children with CHD in terms of measurement of thymus shadow on X-ray film during neonate stage，the immunologic and parathroid functions in the early childhood were observed and to clarify the relationship between CHD and DGS by reviewing literatures.
Methods：
1 Partial immunologic laboratory data from peripheral blood were observed in 28 children with simple CHD and 20 age matched healthy children servered as a control.
1.1 Classification of lymphocytic subsets measured by monoclone
antibodies and flow cytometer.
1.2 The mRNA expression of IL-4 and IFN-γin peripheral blood monoeuclear cell（PBMC） stimulated with phytohaemagglutinin(PHA)and the levels of IL-4 and IFN-γin supernatant were measured by reverse transcription and polymerase chain reaction(RT-PCR) and enzyme-linked immuno-sorbent assay(ELISA) respectively.
1.3 The proliferative response of PBMC stimulated with PHA and lipopolysaccharide(LPS) were measured by intake of 3H-thymidine(3H-TdR) technique.
1.4 Serum IgG、IgA、IgM and C3 levels were estimated by immune scatter turbidimetry.
2 The size of thymus shadow of chest X ray films in 106 neonates including 74 simple and 34 complex CHD were measured retrospectively.50 neonates with pneumonia enrolled in the control.
3 The serum parathyrin(PTH)、Ca2+ and Mg2 in 18 children with simple CHD and 17 age matched healthy children were estimated by immunoradiometric assay(IRMA),ion selective electrode(ISE) and methyl thyme camphor blue(MTB) respectively.
Results：
1 The amount of total T and CD8+T lymphocytes was higher and the ratio of CD4/CD8, the amount of NK cells and total B cells were lower in children with CHD as compared with control，but no significant statistic difference was found. The number of CD4+T lymphocytes in both CHD and control was the same. The peripheral blood lymphocytic subsets in children with CHD and control were changed along with age increasing，but no significant statistic difference.
2 Comparing with normal control, proliferative response of PBMC stimulated with PHA and LPS in children with CHD was normal.
3 The IL-4mRNA expression in PBMC and the levels of IL-4 in supernatants of PBMC were lower gently，IFN-γmRNA expression in PBMC and the levels of IFN-γ in supernatants of PBMC were higher gently in children with CHD as compared with controls，but there were no significant statistic differences.
4 The serum levels of IgG and IgA in CHD children were higher，and IgM and complement C3 were lower than those in controls，.but no significant differences were found. The levels of IgG rised gently as their age increased in both groups，but no significant statistic difference were found.
5 The thymus shadow of X-ray film was found in all neonates both CHD and controls with variance in shape and size. The sizes of thumus shadow for simple and complex CHD were no different.
6 The serum levels of PTH in children with CHD were significantly lower as compared with controls. The level of PTH below 10ng/L was found in 8 cases in CHD group，but none of the controls.The serum concentration of Ca2+ and Mg2+ was mildly decreased in CHD group in comparation with controls，but there were no statistic significance.
Conclusion：
1 Immunodeficiency does not exist in children with CHD enrolled in this study.
2 Simple CHD probably is not a part of DGS. Even if it belongs to DGS，it would not be complete DGS(cDGS), may be partial DGS(pDGS)，without significant immunodeficiency.
3 It is unlikely that children with CHD tending to pulmonary infection is caused by primary immunode
目的：探讨CHD患儿有无免疫功能缺陷，观察CHD新生儿胸腺影改变，了解CHD患儿是否存在甲状旁腺功能低下。结合文献探讨CHD与DGS的关系。
方法：
（一） 检测28例单纯性CHD患儿和20例对照组儿童（门诊体检的正常儿童）外周血部分免疫学指标：
1 用单克隆抗体和流式细胞仪(FCM)检测淋巴细胞亚群的变化。
用逆转录聚合酶链反应（reverse transcription and polymerase chain reaction，RT-PCR）半定量测定外周血单个核细胞（peripheral blood monoeuclear cell，PBMC）经植物血凝素（phytohaemagglutinin，PHA）诱导的白细胞介素4（interleukin-4，
2 IL-4）和γ-干扰素（interferon-gamma，IFN-γ）mRNA表达，以单克隆抗体酶联免疫吸附法（enzyme-linked immuno-sorbent assay，ELISA）测定培养上清中IL-4和IFN-γ含量。
3 用3H胸腺嘧啶核苷（3H-thymidine，3H-TdR）掺入法测定PBMC经PHA和脂多糖（lipopolysaccharide，LPS）诱导的增殖功能。
4 用免疫散射比浊法（immuno-scatter turbidmetry，ISTM）测定血清免疫球蛋白和C3水平。
（二）用胸部X光片回顾性测定72例单纯性心脏畸形CHD、34例复杂性心脏畸形CHD新生儿及50例对照组新生儿（同日龄肺炎新生儿）胸腺影的大小。
（三）检测18例单纯性CHD患儿和17例对照组儿童（门诊体检的健康儿童）外周血清甲状旁腺素（parathyroid hormone，PTH）水平及离子Ca2+、Mg2+浓度。PTH用放射免疫法(immunoradiometric assay，IRMA)测定，离子Ca2+用离子选择电极法（ion selective electrode，ISE）测定，Mg2+用甲基麝香草酚蓝比色法(methyl thyme camphor blue，MTB)测定。
结果：
与对照组儿童比较，CHD患儿外周血总T细胞和CD8+T细胞数稍增高，CD4/CD8比值、NK细胞和B细胞数略降低，但无统计学意义，CD4+T细胞数与对照组儿童无差别。两组儿童的
1 淋巴细胞亚群均随年龄的增加而有轻度改变，但各年龄段之间比较无统计学意义。各年龄段CHD患儿与同年龄段对照组患儿比较以上指标均无显著性差异。
2 CHD患儿PBMC增殖功能正常，3H-TdR每分钟放射脉冲数（counts of per minut impulse，cpm值）和增殖指数（proliferative index，PI）与对照组儿童比较均无显著性差异。两组儿童的cpm值和PI均随年龄的增长略有改变，但各年龄段之间比较无统计学意义。各年龄段CHD患儿与同年龄段对照组儿童比较cpm值和PI均无显著性差异。
3 与对照组儿童比较，CHD患儿PBMC IL-4mRNA表达稍低，IFN-γmRNA表达稍高，培养上清中IL-4水平稍低，IFN-γ水平稍高，但无统计学意义。两组儿童的IL-4mRNA表达和IL-4水平均随年龄增长略有降低，而IFN-γmRNA表达和IFN-γ水平均随年龄增长略有增高，但无统计学意义。各年龄段CHD患儿与同年龄段对照组儿童比较以上四个指标均无显著性差异。
4 CHD患儿血清IgG和IgA水平较对照组略高，而IgM和C3较对照组略低，但无统计学意义。两组儿童的IgG水平随年龄的增加略有升高，IgM、IgA和C3水平随年龄变化亦略有改变，但同年龄段之间比较无统计学意义。各年龄段CHD患儿血清IgG、IgA、IgM及C3水平与同年龄段对照组儿童比较均无显著性差异。
5 所有新生儿的X光片上均可见到胸腺影，目测结果形状多变，大小有异。单纯性心脏畸形CHD新生儿和复杂性心脏畸形CHD新生儿的胸腺影大小与同日龄肺炎新生儿比较均无显著性差异。
6 CHD患儿血清PTH水平较对照组明显降低，二者比较有显著性差异(p<0.05)，CHD患儿有8例（44.4%）PTH<10ng/L，而对照组无一例<10ng/L；CHD患儿血清Ca2+和Mg2+较对照组稍低，但无统计学意义。
结论：
1 并非所有的CHD患儿均并发免疫功能缺陷。
2 单纯的CHD可能不是DGS的一个部分，即使是DGS也可能属于部分性DGS(partial DGS，pDGS)而非完全性DGS(complete DGS，cDGS)，其免疫功能低下不明显。
3 CHD患儿易感染不一定是先天性免疫功能低下的表现。
4 CHD新生儿无胸腺的先天性发育不全。
5 CHD患儿PTH分泌的储备不足，存在亚临床甲状旁腺功能低下。
6 CHD患儿甲状旁腺功能低下可能是因合并部分的先天性甲状旁腺发育不良所致。
Background：Children with congenital heart disease(CHD) are vulnerable for infections. The alteration of blood kinetic and mechanic factors are traditionally thought to be the cause，but literatures in the last years show that CHD may be a part of Digeorge syndrome(DGS) and that the susceptibility to infection in children with CHD may be related to partial primary immunodeficiency.
Objective：To explore whether there is immunodeficiency in children with CHD in terms of measurement of thymus shadow on X-ray film during neonate stage，the immunologic and parathroid functions in the early childhood were observed and to clarify the relationship between CHD and DGS by reviewing literatures.
Methods：
1 Partial immunologic laboratory data from peripheral blood were observed in 28 children with simple CHD and 20 age matched healthy children servered as a control.
1.1 Classification of lymphocytic subsets measured by monoclone
antibodies and flow cytometer.
1.2 The mRNA expression of IL-4 and IFN-γin peripheral blood monoeuclear cell（PBMC） stimulated with phytohaemagglutinin(PHA)and the levels of IL-4 and IFN-γin supernatant were measured by reverse transcription and polymerase chain reaction(RT-PCR) and enzyme-linked immuno-sorbent assay(ELISA) respectively.
1.3 The proliferative response of PBMC stimulated with PHA and lipopolysaccharide(LPS) were measured by intake of 3H-thymidine(3H-TdR) technique.
1.4 Serum IgG、IgA、IgM and C3 levels were estimated by immune scatter turbidimetry.
2 The size of thymus shadow of chest X ray films in 106 neonates including 74 simple and 34 complex CHD were measured retrospectively.50 neonates with pneumonia enrolled in the control.
3 The serum parathyrin(PTH)、Ca2+ and Mg2 in 18 children with simple CHD and 17 age matched healthy children were estimated by immunoradiometric assay(IRMA),ion selective electrode(ISE) and methyl thyme camphor blue(MTB) respectively.
Results：
1 The amount of total T and CD8+T lymphocytes was higher and the ratio of CD4/CD8, the amount of NK cells and total B cells were lower in children with CHD as compared with control，but no significant statistic difference was found. The number of CD4+T lymphocytes in both CHD and control was the same. The peripheral blood lymphocytic subsets in children with CHD and control were changed along with age increasing，but no significant statistic difference.
2 Comparing with normal control, proliferative response of PBMC stimulated with PHA and LPS in children with CHD was normal.
3 The IL-4mRNA expression in PBMC and the levels of IL-4 in supernatants of PBMC were lower gently，IFN-γmRNA expression in PBMC and the levels of IFN-γ in supernatants of PBMC were higher gently in children with CHD as compared with controls，but there were no significant statistic differences.
4 The serum levels of IgG and IgA in CHD children were higher，and IgM and complement C3 were lower than those in controls，.but no significant differences were found. The levels of IgG rised gently as their age increased in both groups，but no significant statistic difference were found.
5 The thymus shadow of X-ray film was found in all neonates both CHD and controls with variance in shape and size. The sizes of thumus shadow for simple and complex CHD were no different.
6 The serum levels of PTH in children with CHD were significantly lower as compared with controls. The level of PTH below 10ng/L was found in 8 cases in CHD group，but none of the controls.The serum concentration of Ca2+ and Mg2+ was mildly decreased in CHD group in comparation with controls，but there were no statistic significance.
Conclusion：
1 Immunodeficiency does not exist in children with CHD enrolled in this study.
2 Simple CHD probably is not a part of DGS. Even if it belongs to DGS，it would not be complete DGS(cDGS), may be partial DGS(pDGS)，without significant immunodeficiency.
3 It is unlikely that children with CHD tending to pulmonary infection is caused by primary immunode
引文
1. 谢进生综述，孙衍庆审校．先天性心脏病的分子生物学研究进展．国外医学．心血管疾病分册1997，24(4)：3-6
2. 刘微廷，周世瑜，华帮杰，等．上海市扬浦区先天性心脏病发病率及流行病学调查．中华儿科杂志1989，27：262
3. 刘宝琴，冯 平，王小稳．新生儿先天性心脏病临床特点分析．河南医学信息 1998，7(3)：247-248
4. Gong L， Liu M， Jen J，etc．GNB1L，a gene deleted in the critical region for DiGeorge syndrome on 22q11，encodes a G-protein beta-subunit-like polypeptide．Biochim Biophys Acta 2000，1494(1-2)：185-8
5. Shah SS，Lai SY，Ruchelli E，etc．Retropharyngeal aberrant thymus．Pediatrics 2001，108(5)：94
6. 徐 让综述，陈树宝审校．心脏发生的分子调控，国外医学．心血管疾病分册1998，25(2)：67-70
7. Cuneo BF．22q11.2 deletion syndrome：DiGeorge，velocardiofacial，and conotruncal anomaly face syndromes．Curr Opin Pediatr 2001，13(5)：465-72
8. Sabry MA，Ismail EA，al-Naggar RL，etc．Unusal traits associated with Robinow syndrome．J Med Genet 1997，34（9）：736-740
9. Wang JK，Hsieh KH．Immunologic study of the asplenia syndrome，Pediatr Infect Dis J 1991，10(11)：819-22
10. 杨锡强主编．儿童免疫学．北京：人民卫生出版社，2001，327
11. 梁业民，杨兴季．先天性心脏病的免疫功能缺陷．国外医学心血管疾病分册 1997，24(1)：18-20
12. Kiel EA，Drummond WH，Barrett DJ．Prevalence of T-lymphocyte abnormalities in infants with congenital heart disease．Am J Dis Child 1984，138(2)：143-6
13. 朱微琴，黄希勇，刘 浩．先天性心脏病患儿外周血免疫功能的变化．实用儿科临床杂志 1996，11(6)：333-334
14. 黄宏琳，郭芹梅，郭玉掌，先天性心脏病患儿OKT免疫系统分布情况的探讨，中国优生与遗传杂志，1996，4(1)：97-98
15. 陈元萍，郭芹梅，黄宏琳，先天性心脏病患儿免疫功能和微量元素测定及分析，中国实用儿科杂志，1997，12(5)：283-284
16. 杨林海，姚建宏，苗翠萍．先天性心脏病免疫功能变化及临床意义．山西医药杂志 2001，30(2)：102-103
17. 陈晓波，张 弛，李树林，等．先天性心脏病的免疫学初步研究．哈尔滨医科大学学报 1996，30(6)：577-578
18. 梁业民，杨兴季，张孝中，等．先天性心脏病患儿T细胞和红细胞等免疫功能的变化．上海免疫学杂志 1996，16(4)：197,205
19. 饶智国，黄显湘，李佩玲，等．33例先天性心脏病患儿T细胞亚群、B细胞和免疫球蛋白的检测．新医学 2000，31(1)，28-29
20. Slade HB，Greenwood JH，Beekman RH，etc．Flow cytometric analysis of lymphocyte subpopulations in infants with congenital heart disease．J Clin Lab Anal 1989 3(1)：14-20
21. Khalil A，Trehan R，Tiwari A，etc．Immunological profile in congenital heart disease，Indian Pediatr 1994，31(3)：295-300
22. Dmitrieva VA，Samuilova DSh，Putiato NA，etc．The role of immunological studies in the diagnosis of bacterial endocarditis in patients with congenital heart defects．Vestn Khir Im I I Grek 1992，149(9-10)：147-51
23. Hong R．The DiGeorge anomaly(CATCH 22，DiGeorge/velocardiofacial syndrome)．Semin Hematol 1998，35(4)：282-90
Hasegawa T，Hasegawa Y，Yokoyama T，etc．Unmasking of latent hypoparathyroidism in a child with partial DiGeorge syndrome by
24. ethylenediaminetetraacetic acid infusion．Eur J Pediatr 1993，152(4)：316-8
25. Cuneo BF，Langman CB，Ilbawi MN，etc．Latent hypoparathyroidism in children with conotruncal cardiac defects．Circulation 1996，93(9)：1702-8
26. Martin Mateos MA，Perez Duenas BP，Iriondo M，etc．Clinical and immunological spectrum of partial DiGeorge syndrome．J Investig Allergol Clin Immunol 2000，10(6)：352-60
27. Epstein JA，Buck CA．Transcriptional regulation of cardiac development: implications for congenital heart disease and DiGeorge syndrome．Pediatr Res 2000，48(6)：717-24
28. Hirotani A，Morimoto S，Koh E，etc．Partial DiGeorge syndrome at the age of thirty-four．Intern Med 1994，33(7)：418-21
29. Nonoyama M，Fujino S，Takemura T，etc．[A report of successful surgical management of ASD，VSD and PDA associated with partial DiGeorge syndrome in infant]．Nippon Kyobu Geka Gakkai Zasshi 1993，41(9)：1590-4
30. Cuneo BF．22q11.2 deletion syndrome: DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes．Curr Opin Pediatr 2001，13(5)：465-72
31. Radford DJ，Thong YH．The association between immunodeficiency and congenital heart disease．Pediatr Cardiol 1988，9(2)：103-8
32. Radford DJ，Perkins L，Lachman R，etc．Spectrum of Di George syndrome in patients with truncus arteriosus: expanded Di George syndrome．Pediatr Cardiol 1988，9(2)：95-101
33. Levy-Mozziconacci A，Lacombe D，Leheup B，etc．Microdeletion of the chromosome 22q11 in children: apropos of a series of 49 patients．Arch Pediatr 1996，3(8)：761-8
Hoffmann MH，Vadstrup S．DiGeorge syndrome Velocardiofacial syndrome/chromosome 22q11 deletion syndrome．Ugeskr Laeger 2000，162(19)：
34. 2736-9
35. Greenberg F，DiGeorge syndrome: an historical review of clinical and cytogenetic features．J Med Genet 1993，30(10)：803-806
36. Hou JW，Wang JK，Tsai WY，etc．CATCH 22: deletion of locus 22q11 in velocardiofacial syndrome，DiGeorge anomaly，and nonsyndromic conotruncal defects．J Formos Med Assoc 1997，96(6)：419-23
37. Radford DJ，Perkins L，Lachman R，etc．Spectrum of Di George syndrome in patients with truncus arteriosus: expanded Di George syndrome．Pediatr Cardiol 1988，9(2)：95-101
38. 余传霖，叶天星，陆德源，等．现代医学免疫学．上海：上海医科大学出版社，1998，756
39. Widhe M，Ekerfelt C，Forsberg P，etc．IgG subclasses in Lyme borreliosis: a study of specific IgG subclass distribution in an interferon-gamma-predominated disease．Scand J Immunol 1998，47(6)：575-81
40. 孙 鹂，刘雅明．先天性心脏病患儿细胞因子水平的变化．浙江医学 1999，21(6)：326-327
41. Kornfeld SJ，Zeffren B，Christodoulou CS，etc．DiGeorge anomaly: a comparative study of the clinical and immunologic characteristics of patients positive and negative by fluorescence in situ hybridization．J Allergy Clin Immunol 2000，105(5)：983-7
42. Morgan BP，Walport MJ．Complement deficiency and disease．Immunol Today 1991，12(9)：301-6
43. Matsuoka R，Takao A，Kimura M，etc．Confirmation that the conotruncal anomaly face syndrome is associated with a deletion within 22q11.2．Am J Med Genet 1994，53(3)：285-9
Neubert R，Delgado I，Abraham K，etc．Evaluation of the age-dependent
44. development of lymphocyte surface receptors in children．Life Sci 1998，62(12)：1099-110
45. Comans-Bitter WM，de Groot R，van den Beemd R，etc．Immunophenotyping of blood lymphocytes in childhood. Reference values for lymphocyte subpopulations．J Pediatr 1997，130(3)：:388-93
46. Barrett DJ，Ammann AJ，Wara DW，etc．Clinical and immunologic spectrum of the DiGeorge syndrome．J Clin Lab Immunol 1981，6(1)：1-6
47. Junker AK，Driscoll DA．Humoral immunity in DiGeorge syndrome，J Pediatr，1995 127(2)：231-7
48. Borgmann S, Luhmer I, Arslan-Kirchner M,etc．A search for chromosome 22q11.2 deletions in a series of 176 consecutively catheterized patients with congenital heart disease: no evidence for deletions in non-syndromic patients．Eur J Pediatr 1999，158(12)：958-63
49. 黄开伟，董宗祈综述．胸腺肥大婴幼儿的诊断、伴发畸形、神经功能障碍和预防接种．临床儿科杂志1992，10（6）：422-423
50. HenriquesUV，Dybdahl H．The thymus in congenital heart disease．Acta Pathol Microbiol Immunol Scand [A] 1985，93(2)：89-92
51. Hong R．The DiGeorge anomaly．Clin Rev Allergy Immunol 2001，20(1)：43-60
52. Wadey R， Daw S， Taylor C，etc．Isolation of a gene encoding an integral membrane protein from the vicinity of a balanced translocation breakpoint associated with DiGeorge syndrome．Hum Mol Genet 1995，4(6)：1027-33
53. Hoffmann MH，Vadstrup S．DiGeorge syndrome Velocardiofacial syndrome/chromosome 22q11 deletion syndrome．Ugeskr Laeger 2000，162(19)：2736-9
Iserin L， de Lonlay P， Viot G，etc．Prevalence of the microdeletion 22q11 in newborn infants with congenital conotruncal cardiac anomalies．Eur J Pediatr
54. 1998，157(11)：881-4
55. Lindsay EA， Botta A， Jurecic V，etc．Congenital heart disease in mice deficient for the DiGeorge syndrome region．Nature 1999，401(6751)：379-83
56. 徐赛英主编．实用儿科放射诊断学．北京：北京出版社，1998，338
57. Hong R．The DiGeorge anomaly(CATCH 22，DiGeorge/velocardiofacial syndrome)．Semin Hematol 1998，35(4)：282-90
58. Lynch BJ，Rust RS．Natural history and outcome of neonatal hypocalcemic and hypomagnesemic seizures．Pediatr Neurol 1994，11(1)：23-7
59. 史轶繁主编．协和内分泌和代谢学．北京：人民卫生出版社，1998，1478
2. 刘微廷，周世瑜，华帮杰，等．上海市扬浦区先天性心脏病发病率及流行病学调查．中华儿科杂志1989，27：262
3. 刘宝琴，冯 平，王小稳．新生儿先天性心脏病临床特点分析．河南医学信息 1998，7(3)：247-248
4. Gong L， Liu M， Jen J，etc．GNB1L，a gene deleted in the critical region for DiGeorge syndrome on 22q11，encodes a G-protein beta-subunit-like polypeptide．Biochim Biophys Acta 2000，1494(1-2)：185-8
5. Shah SS，Lai SY，Ruchelli E，etc．Retropharyngeal aberrant thymus．Pediatrics 2001，108(5)：94
6. 徐 让综述，陈树宝审校．心脏发生的分子调控，国外医学．心血管疾病分册1998，25(2)：67-70
7. Cuneo BF．22q11.2 deletion syndrome：DiGeorge，velocardiofacial，and conotruncal anomaly face syndromes．Curr Opin Pediatr 2001，13(5)：465-72
8. Sabry MA，Ismail EA，al-Naggar RL，etc．Unusal traits associated with Robinow syndrome．J Med Genet 1997，34（9）：736-740
9. Wang JK，Hsieh KH．Immunologic study of the asplenia syndrome，Pediatr Infect Dis J 1991，10(11)：819-22
10. 杨锡强主编．儿童免疫学．北京：人民卫生出版社，2001，327
11. 梁业民，杨兴季．先天性心脏病的免疫功能缺陷．国外医学心血管疾病分册 1997，24(1)：18-20
12. Kiel EA，Drummond WH，Barrett DJ．Prevalence of T-lymphocyte abnormalities in infants with congenital heart disease．Am J Dis Child 1984，138(2)：143-6
13. 朱微琴，黄希勇，刘 浩．先天性心脏病患儿外周血免疫功能的变化．实用儿科临床杂志 1996，11(6)：333-334
14. 黄宏琳，郭芹梅，郭玉掌，先天性心脏病患儿OKT免疫系统分布情况的探讨，中国优生与遗传杂志，1996，4(1)：97-98
15. 陈元萍，郭芹梅，黄宏琳，先天性心脏病患儿免疫功能和微量元素测定及分析，中国实用儿科杂志，1997，12(5)：283-284
16. 杨林海，姚建宏，苗翠萍．先天性心脏病免疫功能变化及临床意义．山西医药杂志 2001，30(2)：102-103
17. 陈晓波，张 弛，李树林，等．先天性心脏病的免疫学初步研究．哈尔滨医科大学学报 1996，30(6)：577-578
18. 梁业民，杨兴季，张孝中，等．先天性心脏病患儿T细胞和红细胞等免疫功能的变化．上海免疫学杂志 1996，16(4)：197,205
19. 饶智国，黄显湘，李佩玲，等．33例先天性心脏病患儿T细胞亚群、B细胞和免疫球蛋白的检测．新医学 2000，31(1)，28-29
20. Slade HB，Greenwood JH，Beekman RH，etc．Flow cytometric analysis of lymphocyte subpopulations in infants with congenital heart disease．J Clin Lab Anal 1989 3(1)：14-20
21. Khalil A，Trehan R，Tiwari A，etc．Immunological profile in congenital heart disease，Indian Pediatr 1994，31(3)：295-300
22. Dmitrieva VA，Samuilova DSh，Putiato NA，etc．The role of immunological studies in the diagnosis of bacterial endocarditis in patients with congenital heart defects．Vestn Khir Im I I Grek 1992，149(9-10)：147-51
23. Hong R．The DiGeorge anomaly(CATCH 22，DiGeorge/velocardiofacial syndrome)．Semin Hematol 1998，35(4)：282-90
Hasegawa T，Hasegawa Y，Yokoyama T，etc．Unmasking of latent hypoparathyroidism in a child with partial DiGeorge syndrome by
24. ethylenediaminetetraacetic acid infusion．Eur J Pediatr 1993，152(4)：316-8
25. Cuneo BF，Langman CB，Ilbawi MN，etc．Latent hypoparathyroidism in children with conotruncal cardiac defects．Circulation 1996，93(9)：1702-8
26. Martin Mateos MA，Perez Duenas BP，Iriondo M，etc．Clinical and immunological spectrum of partial DiGeorge syndrome．J Investig Allergol Clin Immunol 2000，10(6)：352-60
27. Epstein JA，Buck CA．Transcriptional regulation of cardiac development: implications for congenital heart disease and DiGeorge syndrome．Pediatr Res 2000，48(6)：717-24
28. Hirotani A，Morimoto S，Koh E，etc．Partial DiGeorge syndrome at the age of thirty-four．Intern Med 1994，33(7)：418-21
29. Nonoyama M，Fujino S，Takemura T，etc．[A report of successful surgical management of ASD，VSD and PDA associated with partial DiGeorge syndrome in infant]．Nippon Kyobu Geka Gakkai Zasshi 1993，41(9)：1590-4
30. Cuneo BF．22q11.2 deletion syndrome: DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes．Curr Opin Pediatr 2001，13(5)：465-72
31. Radford DJ，Thong YH．The association between immunodeficiency and congenital heart disease．Pediatr Cardiol 1988，9(2)：103-8
32. Radford DJ，Perkins L，Lachman R，etc．Spectrum of Di George syndrome in patients with truncus arteriosus: expanded Di George syndrome．Pediatr Cardiol 1988，9(2)：95-101
33. Levy-Mozziconacci A，Lacombe D，Leheup B，etc．Microdeletion of the chromosome 22q11 in children: apropos of a series of 49 patients．Arch Pediatr 1996，3(8)：761-8
Hoffmann MH，Vadstrup S．DiGeorge syndrome Velocardiofacial syndrome/chromosome 22q11 deletion syndrome．Ugeskr Laeger 2000，162(19)：
34. 2736-9
35. Greenberg F，DiGeorge syndrome: an historical review of clinical and cytogenetic features．J Med Genet 1993，30(10)：803-806
36. Hou JW，Wang JK，Tsai WY，etc．CATCH 22: deletion of locus 22q11 in velocardiofacial syndrome，DiGeorge anomaly，and nonsyndromic conotruncal defects．J Formos Med Assoc 1997，96(6)：419-23
37. Radford DJ，Perkins L，Lachman R，etc．Spectrum of Di George syndrome in patients with truncus arteriosus: expanded Di George syndrome．Pediatr Cardiol 1988，9(2)：95-101
38. 余传霖，叶天星，陆德源，等．现代医学免疫学．上海：上海医科大学出版社，1998，756
39. Widhe M，Ekerfelt C，Forsberg P，etc．IgG subclasses in Lyme borreliosis: a study of specific IgG subclass distribution in an interferon-gamma-predominated disease．Scand J Immunol 1998，47(6)：575-81
40. 孙 鹂，刘雅明．先天性心脏病患儿细胞因子水平的变化．浙江医学 1999，21(6)：326-327
41. Kornfeld SJ，Zeffren B，Christodoulou CS，etc．DiGeorge anomaly: a comparative study of the clinical and immunologic characteristics of patients positive and negative by fluorescence in situ hybridization．J Allergy Clin Immunol 2000，105(5)：983-7
42. Morgan BP，Walport MJ．Complement deficiency and disease．Immunol Today 1991，12(9)：301-6
43. Matsuoka R，Takao A，Kimura M，etc．Confirmation that the conotruncal anomaly face syndrome is associated with a deletion within 22q11.2．Am J Med Genet 1994，53(3)：285-9
Neubert R，Delgado I，Abraham K，etc．Evaluation of the age-dependent
44. development of lymphocyte surface receptors in children．Life Sci 1998，62(12)：1099-110
45. Comans-Bitter WM，de Groot R，van den Beemd R，etc．Immunophenotyping of blood lymphocytes in childhood. Reference values for lymphocyte subpopulations．J Pediatr 1997，130(3)：:388-93
46. Barrett DJ，Ammann AJ，Wara DW，etc．Clinical and immunologic spectrum of the DiGeorge syndrome．J Clin Lab Immunol 1981，6(1)：1-6
47. Junker AK，Driscoll DA．Humoral immunity in DiGeorge syndrome，J Pediatr，1995 127(2)：231-7
48. Borgmann S, Luhmer I, Arslan-Kirchner M,etc．A search for chromosome 22q11.2 deletions in a series of 176 consecutively catheterized patients with congenital heart disease: no evidence for deletions in non-syndromic patients．Eur J Pediatr 1999，158(12)：958-63
49. 黄开伟，董宗祈综述．胸腺肥大婴幼儿的诊断、伴发畸形、神经功能障碍和预防接种．临床儿科杂志1992，10（6）：422-423
50. HenriquesUV，Dybdahl H．The thymus in congenital heart disease．Acta Pathol Microbiol Immunol Scand [A] 1985，93(2)：89-92
51. Hong R．The DiGeorge anomaly．Clin Rev Allergy Immunol 2001，20(1)：43-60
52. Wadey R， Daw S， Taylor C，etc．Isolation of a gene encoding an integral membrane protein from the vicinity of a balanced translocation breakpoint associated with DiGeorge syndrome．Hum Mol Genet 1995，4(6)：1027-33
53. Hoffmann MH，Vadstrup S．DiGeorge syndrome Velocardiofacial syndrome/chromosome 22q11 deletion syndrome．Ugeskr Laeger 2000，162(19)：2736-9
Iserin L， de Lonlay P， Viot G，etc．Prevalence of the microdeletion 22q11 in newborn infants with congenital conotruncal cardiac anomalies．Eur J Pediatr
54. 1998，157(11)：881-4
55. Lindsay EA， Botta A， Jurecic V，etc．Congenital heart disease in mice deficient for the DiGeorge syndrome region．Nature 1999，401(6751)：379-83
56. 徐赛英主编．实用儿科放射诊断学．北京：北京出版社，1998，338
57. Hong R．The DiGeorge anomaly(CATCH 22，DiGeorge/velocardiofacial syndrome)．Semin Hematol 1998，35(4)：282-90
58. Lynch BJ，Rust RS．Natural history and outcome of neonatal hypocalcemic and hypomagnesemic seizures．Pediatr Neurol 1994，11(1)：23-7
59. 史轶繁主编．协和内分泌和代谢学．北京：人民卫生出版社，1998，1478