TRNT1基因突变致SIFD 2例临床特征分析及文献复习.pdf

Med J Chin PLA,Vol.48,No.7,July 28,2023823TRNT1基因突变致SIFD 2例临床特征分析及文献复习陈香元1，符芳2，莫小兰3，李茹2，张松1，程苏云1，曾华松1*1广州医科大学附属妇女儿童医疗中心过敏免疫风湿科/广东省儿童健康与疾病临床医学研究中心，广东广州510623；2广州医科大学附属妇女儿童医疗中心优生围产研究所/广东省儿童健康与疾病临床医学研究中心，广东广州510623；3广州医科大学附属妇女儿童医疗中心药学部/广东省儿童健康与疾病临床医学研究中心，广东广州510623临床研究基金项目广州市卫生健康科技一般引导项目(20211A011024)作者简介陈香元，医学硕士，主治医师，主要从事免疫性疾病及风湿性疾病方面的研究通信作者曾华松，E-mail：论著中图分类号R725.9文献标志码ADOI10.11855/j.issn.0577-7402.0845.2022.1229声明本文所有作者声明无利益冲突引用本文陈香元,符芳,莫小兰,等.TRNT1基因突变致SIFD 2例临床特征分析及文献复习J.解放军医学杂志,2023,48(7):823-827.收稿日期2022-04-18录用日期2022-10-06上线日期2022-12-29摘要目的分析2例父母无亲缘关系的同胞TRNT1基因突变致铁粒幼细胞贫血、B细胞免疫缺陷、周期性发热和发育迟缓(SIFD)的临床特征及基因表型，为临床医师对SIFD的认识提供参考。方法收集广州市妇女儿童医疗中心过敏免疫风湿科确诊的2例姐弟SIFD患儿的临床资料，抽取患儿及其父母外周血进行全基因组测序分析。检索PubMed、中国知网及万方数据库，总结55例患者的临床特征及基因分析结果。结果先证者，女，15岁，自生后8个月起出现反复发热、炎性标志物升高；1岁以后渐出现右膝关节肿痛继发屈曲畸形、双眼白内障并失明，发育迟缓，生长停滞，至今不会说话，不能行走，无月经来潮。先证者同胞弟弟，男，7岁，生后3个月左右体检发现低免疫球蛋白血症，B细胞计数正常；4个月起出现腹泻，8个月左右因发热、支气管肺炎、腹泻住院，此后易反复发热、腹泻；生后19个月时出现双膝关节炎，2岁出现双眼白内障，复查免疫球蛋白A低于正常，B淋巴细胞计数正常，自27个月起不定期输注免疫球蛋白，关节肿痛渐有好转，发热次数减少；发育迟缓，生长停滞，能说简单的37字的短句，发音欠清晰，能理解并执行父母的命令；能独走，稳定性欠佳。对患儿及其父母外周血进行全基因组测序发现，两例患儿均携带TNRT1基因c.1056+1GA及c.1246AG(p.K416E)复合杂合突变。文献共报道病例55例，男21例，女30例，另4例文献中未提及性别；临床表现为反复发热、不同程度的铁粒幼细胞贫血和免疫学异常、关节炎、发育迟缓、听力异常、白内障、反复感染、皮疹等；静脉输注免疫球蛋白、肿瘤坏死因子-拮抗剂、造血干细胞移植及积极的对症处理可改善预后。结论TRNT1基因突变致SIFD为常染色体隐性遗传性疾病，其临床表现多样；临床诊断依据为基因检测，明确TRNT1基因致病性突变；临床医师应提高对该病的认识，早期诊断及干预治疗可提高患儿的生活质量。关键词SIFD；基因，TRNT1；免疫缺陷综合征；白内障；发育障碍Clinical characteristics and literature review of 2 cases of SIFD due to TRNT1 mutationChen Xiang-Yuan1,Fu Fang2,Mo Xiao-Lan3,Li Ru2,Zhang Song1,Cheng Su-Yun1,Zeng Hua-Song1*1Department of Allergy,Immunology and Rheumatology,2Institute of Birth Health and Perinatal Medicine,3Department of Pharmacy,Guangzhou Women and Childrens Medical Center,Guangzhou Medical University/Guangdong Provincial Clinical Research Center for Child Health,Guangzhou,Guangdong 510623,China*Corresponding author,E-mail:This work was supported by the General Guidance Project of Guangzhou Health Science and Technology(20211A011024)AbstractObjectiveTo analyze the clinical features and gene phenotype of sideroblastic anemia,B-cell immunodeficiency,periodic fevers,and developmental delay(SIFD)due to TRNT1 mutation in two siblings from non-consanguineous parents.MethodsThe clinical data of the siblings with SIFD that were diagnosed in the department of allergy,immunology and rheumatology of Guangzhou Women and Childrens Medical Center were collected.Then we detected the whole genome sequencing analysis with the peripheral blood samples of the patients and their parent.We summarize the clinical 解放军医学杂志2023年7月28日第48卷第7期824characteristics and gene analysis of 55 patients with SIFD that were concluded from the PubMed,China national knowledge internet and Wanfang databases.ResultsThe proband was a 15-year-old girl,she presented with recurrent fever and elevated inflammatory markers since she was 8 months of age.After 1 year-old of age,she gradually developed swelling and arthralgia of the right knee,flexion deformity of arthritis,bilateral cataract,developmental delay and growth retardation.She cant talk with others,cant walk by herself and had no menstruation until now.The probands sibling brother was 7 years old,presented with hypoimmunoglobulinemia and normal B cell counts at 3 months,which showed low immunoglobulin A but with normal immunoglobulin G and M and normal B cell counts at 2 years old.Diarrhea appeared at 4 months of age.He was hospitalized with fever,bronchopneumonia and diarrhea at 8 months of age.Since then,he was prone to recurrent fever and diarrhea.At 19 months,he developed arthritis of both knees and presented bilateral cataract at the age of 2 years.Irregular infusion of immunoglobulin was performed,swelling and pain of the knee gradually improved and the frequency of fever decreased.Now,he still presents with developmental delay and growth retardation.He can talk with people by 3-7 words short sentences,but the pronunciation is not clear.He can understand and carry out the orders of his parent.He can walk alone but with poor stability.Whole genome sequencing of the blood revealed biallelic TRNT1 heterozygous mutations,c.1056+1GA/c.1246AG(p.K416E).A total of 55 cases were reported in the literatures,including 21 males and 30 females,and 4 cases were not mentioned in the references.The clinical manifestations presented with repeated fever,different levels of sideroblastic anemia and immunologic abnormalities,arthritis,growth retardation,hearing abnormalities,cataracts,repeated infections,skin rashes and so on.Intravenous infusion of immunoglobulin and tumor necrosis factor-antagonists,hematopoietic stem cell transplantation and positive symptomatic treatments may improve the prognosis.ConclusionsSIFD caused by TRNT1 gene mutation is an autosomal recessive inherited disease with diverse clinical manifestations.Genetic testing of TRNT1 gene mutationis is the basis of clinical diagnosis.Clinicians should recognize the complex disease,early diagnosis and intervention can improve the quality of life for patients.Key wordsSIFD;genes,TRNT1;immunodeficiency syndrome;cataract;developmental delay铁粒幼细胞性贫血、B细胞免疫缺陷、周期性发热和发育迟缓(sideroblastic anemia,B cell immunodeficiency,periodic fevers,and developmental delay，SIFD)是2013年由Wiseman团队通过对12例患者进行分析后提出并命名的一组综合征1，随 后 在 2 0 1 4 年 对 该 组 患 者 进 行 了 致 病 基 因CCA加1转移RNA核苷酸转移酶(transfer RNA nucleotidyltransferase，CCA-adding 1，TRNT1)的分子鉴定2。TRNT1的双等位基因功能缺失突变可导致不同程度的小细胞低色素性贫血、低免疫球蛋白血症、B细胞数量减少、反复发热、发育迟缓，部分患者还可表现为生长停滞、感音性耳聋、癫痫、心肌病、色素性视网膜炎及白内障等。SIFD是一种罕见病，本研究报道一家系姐弟两人TRNT1双等位基因复合杂合突变所致SIFD的临床特征及基因分析结果，旨在提高临床医师对该病的认识，扩充中国人群的SIFD临床资料及基因数据。1病例资料1.1一般资料收集2016年5月就诊于广州医科大学附属妇女儿童医疗中心过敏免疫风湿科的2例确诊为SIFD患者的临床资料，经广州市妇女儿童医疗中心伦理委员会审核批准(2016021645)，且家属签署知情同意书后，抽取患儿及其父母外周血并于我中心优生围产研究所行全基因组测序分析。1.2先证者P1的临床资料先证者P1，女，2006年10月出生，父母体健，非近亲结婚。为第一胎第一产(G1P1)，母孕39周顺产娩出，出生体重2.8 kg，双耳听力筛查正常。否认母孕期异常及出生后抢救史。患儿24个月发热一次，对症处理持续35 d热退。患儿因家庭原因未定期返院复诊。自生后8个月左右开始反复发热，炎性指标升高，12个月发作一次，未能找到明确病原，对症处理后缓解。生后16个月左右出现右膝关节肿胀伴疼痛，MRI提示右膝滑膜炎及骨髓水肿，后呈屈曲畸形，无肌张力低下，不能下地行走，可屈膝扶站片刻。生后19个月左右出现双眼视物不清，眼科就诊确诊为双眼白内障，查心脏彩超未见异常。生后7岁头颅MRI提示双侧大脑半球轻度萎缩样改变，双侧额叶发育欠饱满。患儿曾因发热多次于我中心门诊就诊，多次查血常规提示轻度小细胞低色素性贫血，外周血铁代谢检测正常。因贫血不需要输血治疗家属不同意行骨髓穿刺检查，未能明确有无环状铁粒幼红细胞。12岁时外周血免疫球蛋白检查提示免疫球蛋白A水平较低，免疫球蛋白G、免疫球蛋白M、免疫球蛋白E、补体C3及补体C4在正常参考值范围。淋巴细胞计数提示B淋巴细胞及T淋巴细胞比例与计数均正常。随访至今，生长发育落后，现15岁，体重12 kg(3SD)，身高102 cm(3SD)，头围48 cm，会咿呀发音，不能清楚表达词句，能理解部分语句及执行简单动作。1.3先证者弟弟P2的临床资料患儿P2，2014年5月出生，为G2P2，孕38+5周顺产娩出，出生体重3 kg。因其姐姐有上述病变，患儿生后3个月于本Med J Chin PLA,Vol.48,No.7,July 28,2023825中心常规体检，双耳听力筛查正常，发现患儿存在轻度小细胞低色素性贫血，中性粒细胞吞噬功能正常，B、T淋巴细胞计数正常，免疫球蛋白检测提示免疫球蛋白G 2.33 g/L(3.227.18 g/L)，免疫球蛋白A0.07 g/L(0.130.35 g/L)，头颅B超提示外围性脑积水。生后4个月出现第一次腹泻，未找到致病原。生后8个月因发热及咳嗽诊断为支气管肺炎住院，期间再次出现腹泻，咽拭子病原学提示呼吸道合胞病毒感染。此后反复发热，每个月12次，每次持续37 d，经对症处理后缓解。生后19个月出现双膝关节肿胀疼痛，不愿下地行走，发热时明显，B超提示膝关节腔内积液。生后24个月出现视物不清，眼科确诊为双眼白内障，复查免疫球蛋白A低于正常参考值范围，免疫球蛋白G、免疫球蛋白M、免疫球蛋白E均正常，B、T淋巴细胞计数正常。生后27个月起不定期静脉输注免疫球蛋白，发热次数减少，但仍有反复。37个月时再次因发热、腹泻住院，5岁因支气管肺炎、流行性感冒病毒A型感染住院，肝脾无肿大，查心脏彩超、泌尿系B超、头颅MRI等未见异常。患儿于5岁余在我中心行眼科白内障囊外摘除术+后囊膜切开+前玻璃体切除术+人工晶体植入术，视力有所恢复。随访至今，生长发育落后，现7岁，体重11 kg(3SD)，身高98 cm(A/c.1246AG(p.K416E)。其中，c.1246AG(p.K416E)已有相关文献报道2-3，来源于父亲，c.1056+1GA暂无文献报道，来源于母亲。c.1056+1GA变异位于mRNA剪接区域，为经典剪切位点突变，经生物信息学软件AutoPVS1(http:/ 对接受TNF-拮抗剂(依那西普)治疗的2例SIFD患儿进行11年随访发现，该药可使患儿的炎性指标下降并转为正常，贫血缓解，且发热无复发，肌肉、骨骼症状消失，但仍然存在发育迟缓、双侧感音神经性听力丧失和生长停滞。异体骨髓移植通常被认为是干预性治疗，目的是恢复正常的免疫功能和红细胞生成23。Barton等20报道1例患儿在5个月时进行了匹配的同胞骨髓移植，但在38周后死于显著的神经系统并发症。另1例患儿在9个月时接受了清髓异体骨髓移植治疗，发热得到缓解，生长发育正常，但移植后32个月出现色素性视网膜炎，其他一般状态保持良好超过3年1。还有1例患者在骨髓移植后无反复发热，生长改善，发育也取得了一些进展，但仍存在中度听力损失和视网膜病变5。由此可见，骨髓移植治疗并不能完全缓解SIFD患者的症状，而针对TRNT1基因突变基因型的特异性治疗还在不断探索中。综上所述，SIFD是临床上非常罕见的一组常染色体隐性遗传性疾病，临床表现形式多样，早期诊断可使患者得到及时治疗，提高其生活质量。本研究中的姐弟经基因检测明确诊断为SIFD，临床主要表现为反复发热、轻度贫血、关节炎、白内障、生长发育迟缓、身材矮小及免疫球蛋白异常等。病例中的弟弟不定期静脉输注人免疫球蛋白治疗后在一定程度上降低了发热的频率。此外，本研究病例行基因检测发现了TRNT1基因的一种新的剪接突变，丰富了TRNT1基因的突变位点队列，为临床医师提供了更多参考。但不足之处在于因患儿家庭原因，未能对其进行定期复诊，也未能选择和尝试其他的治疗方式，因而未能观察到SIFD经积极治疗后的效果及其预后。在今后的工作中，我们期待更多临床病例能纳入研究，进行更深层次的分子致病机制及临床表型探讨，积极选择有效的治疗措施，以便更好地为患者服务。【参考文献】1 Wiseman DH,May A,Jolles S,et al.A novel syndrome of congenital sideroblastic anemia,B-cell immunodeficiency,periodic fevers,and developmental delay(SIFD)J.Blood,2013,122(1):112-123.2 Chakraborty PK,Schmitz-Abe K,Kennedy EK,et al.Mutations in TRNT1 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