常染色体显性及隐性遗传高免疫球蛋白E综合征临床特征及基因分析

王珊; 刘盈; 徐子刚; 王召阳; 焦磊; 梁源; 徐哲; 马琳

doi:10.12376/j.issn.2097-0501.2022.03.007

常染色体显性及隐性遗传高免疫球蛋白E综合征临床特征及基因分析

doi: 10.12376/j.issn.2097-0501.2022.03.007

国家儿童医学中心首都医科大学附属北京儿童医院皮肤科，北京 100045

基金项目:

北京市医院管理局儿科学科协同发展中心专项经费 XTZD20180502

详细信息

通信作者:
马琳，E-mail：bch_maleen@aliyun.com

中图分类号: R593.3;R725.9
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出版历程
- 收稿日期: 2022-05-21
- 录用日期: 2022-06-09
- 网络出版日期: 2022-09-06

Clinical Features and Genetic Analysis of Autosomal Dominant and Recessive Hyperimmunoglobulin E Syndrome

Department of Dermatology, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China

Funding:

Special Fund of The Pediatric Medical Coordinated Development Center of Beijing Municipal Administration XTZD20180502

More Information

Corresponding author: MA Lin, E-mail: bch_maleen@aliyun.com

摘要

摘要: 目的总结常染色体显性及隐性遗传高免疫球蛋白E综合征(HIES)患儿的临床特征及基因分析。方法收集于2013年1月至2021年12月在首都医科大学附属北京儿童医院皮肤科收治的经临床及基因共同确诊为HIES患儿，归纳一般资料并分析其临床特征和基因型特点，比较常染色体显性遗传HIES(AD-HIES)和常染色体隐性遗传HIES(AR-HIES)临床特点的异同。结果共收集确诊HIES患儿7例，其中AD-HIES 3例，AR-HIES 4例。男4例，女3例。所有患儿均存在反复发作的顽固性湿疹样皮疹、反复皮肤及肺部感染，以及血清IgE和嗜酸性粒细胞水平升高。AD-HIES与AR-HIES的不同点主要包括：3例AD-HIES患儿皮肤感染均以细菌感染为主要表现(如脓肿、脓疱疮)，而4例AR-HIES患儿皮肤均以严重的病毒感染为主要表现(如寻常疣、传染性软疣)；3例AD-HIES患儿均存在不同种类的肺部实质改变(如肺大疱、肺囊肿、肺不张)，而4例AR-HIES患儿肺部均无类似改变；AR-HIES患儿中3/4存在过敏性疾病(包括哮喘、食物过敏等)，而AD-HIES患儿均无过敏性疾病报道；免疫系统外表现方面，AD-HIES更易见鼻梁扁平、高腭弓等特殊面容，AR-HIES中有肿瘤发生情况而AD-HIES尚未见。AD-HIES主要由STAT3基因突变引起，AR-HIES主要由DOCK8基因突变引起，其中两例患儿分别存在DOCK8基因的c.1798-2A＞T和c.874G＞A为新发突变位点。结论对于临床表现为顽固性湿疹样皮疹、反复感染，伴血清IgE水平显著升高的患儿，需寻找早期HIES疑诊线索，尽早进行基因检测明确诊断及分类，以更好地长期管理，改善生存预后。
- 高免疫球蛋白E综合征 /
- STAT3基因 /
- DOCK8基因 /
- 湿疹 /
- 原发性免疫缺陷病
Abstract: Objective To summarize the clinical and genetic features of children with autosomal dominant and recessive hyperimmunoglobulin E syndrome (HIES). Methods HIES patients were studied at the dermatology department of Beijing Children's Hospital, Capital Medical University were collected, from January 2013 to December 2021, diagnosed by both clinical manifestation and genetic assessment. The general data were summarized, the clinical and genetic characteristics were analyzed, and the similarities and differences between autosomal dominant HIES (AD-HIES) and autosomal recessive HIES (AR-HIES) were compared. Results A total of 7 children with HIES were studied, including 3 cases of AD-HIES and 4 cases of AR-HIES. There were 4 males and 3 females. All children had recurrent eczema-like lesions, recurrent skin and pulmonary infections, and elevated serum IgE and eosinophil levels. The differences between AD-HIES and AR-HIES mainly include: the main cutaneous infection in 3 children with AD-HIES were bacterial infections (such as abscess and impetigo), while in 4 children with AR-HIES, cutaneous infections were mostly severe viral infection (such as verruca vulgaris and molluscum contagiosum). There were pulmonary parenchymal changes (such as pneumatoceles, cyst and atelectasis) in 3 children with AD-HIES, whilst there were no similar changes in the lungs of 4 children with AR-HIES; 75% of children with AR-HIES had allergic diseases (including asthma and food allergy), while there were no reports of allergic diseases in children with AD-HIES. As for manifestations outside of immune system, AD-HIES was more likely to appear facial dysmorphism(such a broad nasal bridge and a high-arched palate). Furthermore, the incidence of tumor in AR-HIES was higher than that in AD-HIES. AD-HIES was mainly caused by the mutation of STAT3 gene, and AR-HIES was mainly caused by the mutation of DOCK8 gene. We reported two new mutation sites of DOCK8 gene c.1798-2A > T and c.874G > A in two cases, respectively. Conclusions For children with clinical manifestations of recurrent eczema-like lesions, repeated infection and significant increase in serum IgE levels, HIES should be suspected, and genetic screening should be carried out to make definite diagnosis and classification, to achieve better long-term management and improve prognosis.
- hyperimmunoglobulin E syndrome /
- STAT3 gene /
- DOCK8 gene /
- eczema /
- primary immunodeficiency diseases
注释:

作者贡献：王珊、刘盈、王召阳、焦磊负责临床资料收集；梁源、徐哲、徐子刚、马琳指导研究设计；王珊资料汇总和论文撰写；马琳、徐子刚修改论文。

利益冲突：所有作者均声明不存在利益冲突。

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图 1 AR-HIES的严重病毒感染

A.P4患儿(8岁时)前胸部大量传染性软疣；B.P4患儿(8岁时)腹股沟皮损及大量传染性软疣

Figure 1. Severe viral infection of AR-HIES

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图 2 AD-HIES患儿面部特殊面容

A.P1患儿(3岁时)面部皮肤粗糙、凹陷性痘疮样瘢痕、前额突出、鼻梁扁平；B.P2患儿(11岁时)前额突出、眼距宽、鼻梁扁平

Figure 2. Facial dysmorphism of AD-HIES children

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图 3 后颈部不典型湿疹样皮损

A.P2患儿(11岁时)后颈部肥厚及渗出皮损的叠加；B.P2患儿(15岁时)后颈部肥厚增生性斑块

Figure 3. Atypical eczema-like lesions of the posterior neck

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表 1 3例AD-HIES患儿临床及基因特点

Table 1. Clinical and genetic features of 3 children with AD-HIES

项目	AD-HIES
项目	P1	P2	P3
一般信息
性别	女	男	女
确诊年龄	1岁7个月	11岁	2岁
目前年龄^*	8岁	15岁	11岁
皮肤情况
反复湿疹样皮疹	有	有	有
新生儿期皮疹	UK	UK	面部湿疹
皮肤感染	软组织感染面部蜂窝织炎	金黄色葡萄球菌“冷脓肿”	脓疱疮反复脓肿头部毛囊炎
其他免疫相关表现
肺部感染(次/年)	3~5 合并胸腔积液重症坏死性肺炎	2~3 (四年级后频率减少)	1~2
肺实质异常	肺大疱肺不张	肺囊肿	间实质病变
真菌感染	鹅口疮	无	鹅口疮甲癣
其他感染	无	无	肾脓肿肾周脓肿
合并过敏性疾病	无	无	无
免疫系统外表现
特殊面容	有(皮肤粗糙、凹陷性痘疮样瘢痕、前额突出、鼻梁扁平)	有(前额突出、眼距宽、鼻梁扁平、高腭弓)	有(皮肤粗糙、前额突出、宽鼻梁、舟状头)
骨骼牙齿异常	下肢跛行膝外翻	小腿骨折	无
中枢神经系统异常	癫痫髓鞘化不良？脱髓鞘病变？双侧脑室、脑沟增宽	无	无
并发肿瘤	无	无	无
其他异常	左侧面神经瘫痪	阑尾炎术后	无
HIES的临床疑诊线索	反复多次皮肤软组织感染	不典型湿疹样皮疹(后颈部肥厚及渗出皮损的叠加、腰骶部斑块、结节) 特殊面容	反复皮肤脓肿病史脓疱疮及毛囊炎表现
实验室检查
IgE(最高)(IU/mL)	2830↑(≤60)^#	382↑(≤200)	＞3000
IgG(g/L)	22.80↑(4.82~12.00)	17.3↑(7.0~14.0)	20.2↑(7.0~14.0)
IgA(g/L)	0.46(0.22~1.18)	1.09(0.7~2.3)	1.46(0.44~3.95)
IgM(g/L)	1.34(0.54~2.09)	1.53↑(0.4~1.5)	2.660↑(0.4~1.5)
T(CD3⁺)(%)	73.4(55.0~82.0)	90.1↑(55.0~82.0)	83.2↑(55.0~82.0)
CD4⁺	42.9(33.0~46.0)	39.8(25.0~57.0)	48.9(25.0~57.0)
CD8⁺	22.1(14.0~33.0)	35.3↑(9.0~35.0)	27.4(14.0~34.0)
B(%)	20.9(11.0~45.0)	5.8↓(9.0~29.0)	11.8(9.0~29.0)
NK(%)	4.1↓(7.0~40.0)	2.2↓(7.0~40.0)	3.3↓(7.0~40.0)
嗜酸细胞绝对值(最高)(×10⁹/L) (参考范围均0.05~0.50)	0.80↑	1.05↑	1.11↑
嗜酸细胞百分比(最高)(%) (参考范围均0.5~5.0)	13.1↑	120↑	14.7↑
临床评分
NIH评分(分)	45	48	48
遗传学检查
基因	STAT3	STAT3	STAT3
核苷酸变化	c.1144G＞A	c.1144C＞T	c.1145G＞A
	杂合	杂合	杂合
氨基酸变化	p.R382W	p.R382W	p.R382Q
HIES：高免疫球蛋白E综合征；AD-HIES：常染色体显性遗传高免疫球蛋白E综合征；UK：未知；NIH：美国国立卫生研究院；STAT3：信号转导与转录活化因子3基因；DOCK8：胞质分裂专一物8基因；^*2021年12月为截至文章完成的末次随访时间；^#括号中为该项目正常儿童参考区间，不同年龄有所区别

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表 2 4例AR-HIES患儿临床及基因特点

Table 2. Clinical and genetic features of 4 children with AR-HIES

项目	AR-HIES
项目	P4	P5	P6	P7
一般信息
性别	男	男	女	男
确诊年龄	8岁	5岁	11岁	14岁
目前年龄^*	10岁病故	10岁	14岁	23岁
皮肤情况
反复湿疹样皮疹	有	有	有	有
新生儿期皮疹	UK	UK	湿疹样	面颈躯干湿疹样表现
皮肤感染	传染性软疣(大量) 寻常疣(大量)	传染性软疣(大量)	口周、鼻周、颈部感染HSV1、HPV16感染	寻常疣(大量)
其他免疫相关表现
肺部感染(次/年)	1~2	1~2	既往共2次	1~2
肺实质异常	无	无	无	无
真菌感染	无	无	无	牙龈继发真菌感染
其他感染	中耳炎	中耳炎	中耳炎、副鼻窦炎、腮腺炎、牙髓炎	无
合并过敏性疾病	哮喘	无	反复过敏性皮炎	哮喘食物过敏(鸡蛋、花生、豆类、牛奶)
免疫系统外表现
特殊面容	无	无	无	有(宽鼻梁、眼距宽)
骨骼牙齿异常	无	无	胸椎部分椎体略扁	下肢跛行
中枢神经系统异常	反复癫痫额顶叶、颞叶、枕叶异常信号因脑梗死病故	无	无	脑软化脑梗死抽搐
并发肿瘤	无	无	无	颌下巨大淋巴结增生症(Castleman病)
其他异常	肥胖	肥胖	颈部巨大肿物(鳞状上皮疣状增生伴感染性肉芽肿) 鼻腔肿物(重度慢性炎伴溃疡形成及小脓肿伴假上皮瘤样增生)	口腔、外阴溃疡牙龈感染、牙龈增生牙龈切除术
HIES的临床疑诊线索	大量传染性软疣	大量传染性软疣哥哥病史	间擦部位及鼻腔周围不典型湿疹样皮疹(炎性增生明显)	大量寻常疣间擦部位及颈后不典型湿疹样皮疹(肥厚及渗出皮损的叠加)
实验室检查
IgE(最高)(IU/mL)	8788.8↑(≤155)	8878.4↑(≤60)	8830↑(≤200)	3000(≤200)
IgG(g/L)	21.8↑(6.46~14.51)	13.20↑(4.82~12)	8.75(7.0~14.0)	6.39↓(7.0~14.0)
IgA(g/L)	3.35↑(0.28~2.22)	2.94(0.22~1.18)	1.05(0.7~2.3)	1.03(0.7~2.3)
IgM(g/L)	0.63(0.55~2.32)	0.52↓(0.54~2.09)	0.161↓(0.4~1.5)	0.1↓(0.4~1.5)
T(CD3⁺)(%)	64.3(55.0~82.0)	78.5(55.0~82.0)	54.6↓(62.06~76.54)	56.8(55.0~82.0)
CD4⁺	24.1↓(27.0~57.0)	22.5↓(27.0~57.0)	19.9↓(28.47~41.39)	12.0↓(25.0~57.0)
CD8⁺	27.1(19.0~34.0)	40.8↑(14.0~33.0)	26.4(22.5~32.37)	34.8↑(9.0~35.0)
B(%)	15.4(9.0~29.0)	15.6(9.0~29.0)	17.2(9.23~18.15)	14.9(9.0~29.0)
NK(%)	19.5(7.0~40.0)	4.9↓(7.0~40.0)	26.2↑(7.75~23.47)	5.0↓(7.0~40.0)
嗜酸细胞绝对值(最高)(×10⁹/L) (参考范围均0.05~0.50)	11.86↑	67.97↑	3.47↑	10.29↑
嗜酸细胞百分比(最高)(%) (参考范围均0.5~5.0)	66.7↑	86.3↑	22.6↑	47.0↑
临床评分
NIH评分(分)	34	32	33	32
遗传学检查
基因	DOCK8	DOCK8	DOCK8	DOCK8
核苷酸变化	c.646-647delCT DOCK8外显子1~48及KANK大片段杂合缺失	c.646-647delCT DOCK8外显子1~48及KANK大片段杂合缺失	c.1798-2A＞T DOCK8外显子25~48大片段杂合缺失	c.874G＞A DOCK8外显子11纯合缺失；12~33大片段杂合缺失
	复合杂合	复合杂合	复合杂合	复合杂合
氨基酸变化	p.L216Vfs10	p.L216Vfs10	splicing剪接突变	p.D292N
AR-HIES：常染色体隐性遗传高免疫球蛋白E综合征；^*2021年12月为截至文章完成的末次随访时间；^#括号中为该项目正常儿童参考区间，不同年龄有所区别

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