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Advances in Clinical Medicine
Vol. 13  No. 11 ( 2023 ), Article ID: 75032 , 6 pages
10.12677/ACM.2023.13112451

一例ANK1基因突变型遗传性球形红细胞增多症病例报告并文献复习

耿静芝1，史航宇2*

1西安医学院研究生院，陕西 西安

2西安市儿童医院儿外科，陕西 西安

收稿日期：2023年10月11日；录用日期：2023年11月6日；发布日期：2023年11月9日

摘要

目的：总结分析遗传性球形红细胞增多症(Hereditary spherocytosis, HS)的临床特点及基因表型，进一步探讨其诊治策略。方法：对1例ANK1基因c.3604delG (缺失鸟嘌呤)，导致氨基酸改变p.D1202Tfs*28 (移码突变)，从而引发患儿HS的临床资料进行回顾性分析并文献复习，探讨诊治策略。结果：患儿男性，5岁4月，反复面色苍白、黄疸5年余，根据入院各项检查和既往基因检测结果，明确诊断为HS、脾功能亢进、溶血性贫血。遂行腹腔镜脾脏切除术，术后予抗凝处理，并动态复查相关指标，患儿术后恢复顺利。结论：基因检测在HS的诊疗中占据重要位置，我们在HS患儿中发现的ANK1基因新突变，进一步扩大了HS患儿基因突变谱，同时对分析不同基因表型下该疾病的相关表现形式提供依据，针对HS患儿脾切除仍是其治疗的有效方法。

关键词

遗传性球形红细胞增多症，ANK1基因，移码突变，脾切除

A Case Report of Hereditary Spherical with ANK1 Gene Mutation and Literature Review

Jingzhi Geng1, Hangyu Shi2*

1Graduate College of Xi’an Medical University, Xi’an Shaanxi

2Pediatric Surgery Department, Xi’an Children’s Hospital, Xi’an Shaanxi

Received: Oct. 11th, 2023; accepted: Nov. 6th, 2023; published: Nov. 9th, 2023

ABSTRACT

Objective: To summarize the clinical characteristics and genetic phenotype of hereditary spherocytosis (HS), and further explore the diagnosis and treatment strategies. Methods: The clinical data of a child with HS caused by ANK1 gene c.3604delG (Guanine is missing) and p.D1202Tfs*28 (Frameshift mutation), was retrospectively analyzed, and the related literatures were reviewed to explore the diagnosis and treatment strategies. Results: A boy, aged 5 years and 4 months, had recurrent pallor and jaundice for more than 5 years. He was diagnosed with HS, hypersplenism, and hemolytic anemia according to the results of admission examinations and previous genetic testing. Laparoscopic splenectomy was performed, anticoagulation treatment was given after operation, and the relevant indicators were dynamically reviewed. The patient recovered smoothly after operation. Conclusion: In HS, genetic testing occupies the important position. We found that children with HS new ANK1 gene mutationfurther expand the gene mutation spectrum of HS. At the same time, it provides the basis for analyzing the related manifestations of the disease under different genetic phenotypes. Splenectomy is still an effective treatment for children with HS.

Keywords:Hereditary Spherocytosis, ANK1 Genes, Frameshift Mutations, Splenectomy

Copyright © 2023 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

遗传性球形红细胞增多症(hereditary spherocytosis, HS)是一种遗传性红细胞膜缺陷导致的溶血性疾病，临床表现为贫血、间歇性黄疸和脾大 [1] 。绝大多数为常染色体显性遗传，少部分为常染色体隐性遗传，无家族史的散发病例可能是新发生的基因突变所导致 [2] 。任何年龄均可发病。发病机制为红细胞膜蛋白基因异常，膜骨架蛋白缺陷，细胞膜脂质丢失，细胞表面积减少，细胞球形变 [3] 。球形红细胞通过脾脏时遭受脾脏巨噬细胞的破坏而致血管外溶血和脾肿大 [4] 。HS患者中，可见ANK1突变、SPTB突变、SLC4A1突变、SPTA1及EPB42突变几种类型，据报道其中最常见的是ANK1突变 [5] 。红细胞膜蛋白基因突变类型中错义突变最常见 [6] ，而本例为罕见型移码突变，在HGMD专业版数据库中未见报道。现对本例ANK1基因突变导致遗传性球形红细胞增多症的患儿临床表现、基因特点和外科治疗进行分析，并复习相关文献。

2. 资料与方法

一般资料

患儿男性，5岁4月，因“反复面色苍白、黄疸5年余”于2021年10月12日入院。5年余前患儿出生后家属发现其面色苍白，辗转于多家医院未明确诊断。4年10月前就诊于北京儿童医院，采全血送于北京迈基诺医学检验所行基因检测回示ANK1基因移码突变，结合临床表现及其他检查考虑诊断为遗传性球形红细胞增多症，建议6岁后行脾脏切除术。

入院体格检查：发育正常，营养中等，意识清楚，精神可，皮肤及巩膜轻度黄染，口唇稍苍白。双肺呼吸音粗，未闻及干湿性啰音，心率100次/分，心音清，心律齐，各瓣膜区未闻及病理性杂音。腹平软，无压痛反跳痛，肝肋下未触及肿大，脾肋下3 cm触及，质软，边缘钝，无触痛。

3. 入院检验及检查

一般检查

Table 1. General laboratory examination

表1. 一般实验室检查

(a) (b) (c)

Figure 1. (a) Family analysis of the mutation gene in the patient; (b) Color Doppler ultrasonography: abdomen (liver, gallbladder, pancreas and spleen): spleen outline regular, the parenchyma echo is even, intercostal thickness 36 mm, long diameter 116 mm, subcostal 36 mm; (c) CT scan: upper abdomen (plain scan): left upper abdomen slightly bulging appearance. The spleen volume increases, the inner edge reaches the midline, the lower edge reaches the level of the lower edge of the lumbar 4 vertebral body, the spleen edge is smooth, the density is even, the CT value is about 56 HU

图1. (a) 该患儿突变基因家系分析；(b) 彩超检查：腹部(肝胆胰脾)：脾脏轮廓规则，实质回声均匀，肋间厚36 mm，长径116 mm，肋下36 mm；(c) CT检查：上腹部(平扫)：左上腹外形稍膨隆。脾脏体积增大，内缘达中线，下缘达腰4椎体下缘水平，脾脏边缘光滑，密度均匀，CT值约56 HU

血细胞分析 + 五分类：见表1，网织红细胞百分率8.56%，肝功能：总胆红素46.8 μmol/L，直接胆红素16.8 μmol/L，间接胆红素30.0 μmol/L，谷丙转氨酶8.0 U/L，谷草转氨酶20 U/L；肾功能、电解质、凝血四项正常；彩超检查：腹部(肝胆胰脾)：脾脏轮廓规则，实质回声均匀，肋间厚36 mm，长径116 mm，肋下36 mm；肝、胆、胰未见异常。CT检查：上腹部(平扫)：左上腹外形稍膨隆。脾脏体积增大，内缘达中线，下缘达腰4椎体下缘水平，脾脏边缘光滑，密度均匀，CT值约56 HU (图1(b)~(c))。

1) 基因测序结果经基因测序在患儿ANK1基因发现c.3604delG，导致氨基酸改变p.D1202Tfs*28。患儿父母该位点均未见异常(图1(a)、表2)。

Table 2. Family DNA mutation information in children

表2. 患儿家族DNA变异信息

注：hom/het/hemi：hom表示此突变位点为纯合突变；het表示此突变位点为杂合突变；hemi表示此突变位点为半合子突变。遗传方式：AR表示常染色体隐性遗传；AD表示常染色体显性遗传；XR表示X染色体隐性遗传；XD表示X染色体显性遗传。

2) 治疗根据患儿病史、查体并完善各项检查后行腹腔镜脾脏切除术，切除的巨脾送病理检查。病理结果提示：脾索充血，脾窦见大量红细胞影，窦内皮细胞肥胖，红索内见散在分布的脾小体及脾小梁。符合遗传性球形红细胞增多症致脾肿大的病理改变。

术后第1天给与患儿皮下注射低分子量肝素钙注射液0.3 ml，此后给与患儿口服阿司匹林肠溶片25 mg 2次/天，并于术后第1、3、5、7天复查血常规、凝血及腹部血管彩超。血常规及凝血见表3，彩超均提示腹部大血管彩色血流未见明显异常。患儿恢复顺利并于术后8天出院。

Table 3. Postoperative blood routine and coagulation

表3. 患儿术后血常规及凝血

4. 讨论

遗传性球形红细胞增多症(HS)是一种常见的遗传性疾病。临床表现为贫血、黄疸和脾肿大，任何年龄段皆可发病。地域上，HS尤其在北欧和北美人群更为常见，发病率分别为1/5000和1/2000 [7] ，据报道国人的发病率为男性1.27:10万，女性1.49:10万 [8] 。患者临床症状有很大差异性，从无症状到严重溶血均可出现 [5] [9] 。仅通过血常规、网织红细胞计数、外周血涂片、骨髓细胞学检查、红细胞渗透脆性试验等一般检查，鉴别遗传性球细胞增多症、红细胞葡萄糖-6-磷酸脱氢酶缺乏症、自身免疫性溶血性贫血等溶血性疾病较为困难，易造成漏诊、误诊 [10] 。

研究发现ANK1、SPTB、SLC4A1、EPB42和SPTA1基因突变，将导致它们编码的锚蛋白、β-膜收缩蛋白、带3蛋白、蛋白4.2和α-膜收缩蛋白缺失 [11] 。当上述红细胞膜骨架蛋白缺陷时，细胞膜双分子层丢失，细胞表面积减少，细胞球形变。球形红细胞变形能力降低，通过脾脏时受到脾脏巨噬细胞的破坏而发生溶血性贫血 [12] 。此发病机制为HS诊断提供了重要的基因学检测依据。

据统计，目前在ANK1中至少发现60余种突变 [13] ，其中以错义突变最为常见，本例患儿基因检测发现ANK1基因c.3604delG (第3604位缺失鸟嘌呤)的杂合核苷酸变异，该变异(p.D1202Tfs*28)导致产生截短蛋白，ANK1基因编码的锚蛋白缺失，红细胞球形改变，患儿出现一系列相关临床症状。对于确诊HS的患儿，脾切除术疗效显著 [14] ，现已作为外科治疗中、重度遗传性球形红细胞增多症的方法(表4) [15] [16] 。脾切除后红细胞在体内的破坏明显减少，患儿的贫血、黄疸及网织红细胞增多可得到明显改善。

Table 4. The severity of hereditary spherocytosis and the indication of splenectomy

表4. 遗传性球细胞增多症严重程度及脾切除指征

*患儿需要定期输血。

临床上必须关注脾切除术后两类并发症。一是脾切除后凶险性感染(OPSI)，发生率约为每年0.23%~0.42%，终生风险为5% [17] 。过早进行脾切除患儿发生OPSI的概率会大大增加，通过将脾切除术延迟到6岁后，加上疫苗接种和抗生素预防，能降低风险，也有文献指出脾切除术可视情况于更小年龄进行 [16] [18] 。二是静脉血栓栓塞 [19] ，其主要是因为脾脏是血小板破坏最为重要的场所，脾切除术后血小板反应性增多，血小板计数可于术后2~10天开始增加，在1~3周内达到高峰 [20] ，需术后早期抗凝预防。虽然越来越多的文献增加了对脾切除术后并发症的认识，也有诸多预防措施，但是脾切除术后并发症死亡率依然很高 [21] [22] ，如何降低死亡率这一问题亟待解决。

综上所述，遗传性球形红细胞增多症(HS)是一种常见的遗传性疾病，临床表现差异较大，易发生误诊、误诊，基因检查可为HS的诊断提供重要参考并指导遗传咨询。本例发现的ANK1基因新突变，进一步扩大了HS患儿基因突变谱，同时对分析不同基因表型下该疾病的相关表现形式提供依据。目前脾切除术是HS最有效的治疗手段，但脾切除术后并发症治疗仍无有效方法。

文章引用

耿静芝,史航宇. 一例ANK1基因突变型遗传性球形红细胞增多症病例报告并文献复习
A Case Report of Hereditary Spherical with ANK1 Gene Mutation and Literature Review[J]. 临床医学进展, 2023, 13(11): 17496-17501. https://doi.org/10.12677/ACM.2023.13112451

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    23. NOTES

    *通讯作者。

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