异基因造血干细胞移植治疗儿童先天性角化不良3例并文献复习

doi:10.12372/jcp.2024.23e0266

摘要/Abstract

摘要：

目的初步探讨异基因造血干细胞移植（HSCT）治疗儿童先天性角化不良（DKC）的疗效，为探索优化移植方案提供依据。方法回顾性分析自2019年6月至2022年6月在医院行HSCT的3例DKC患儿的临床资料并复习相关文献。结果 3例患儿预处理方案为以氟达拉滨(Flu)为主的减低剂量预处理。回输单个核细胞（MNC）中位计数为13.7（8.3~17.3）×10⁸/kg，CD34⁺细胞中位计数为8.2（6.3~13.1）×10⁶/kg。采用甲氨蝶呤、环孢素和吗替麦考酚酯联合预防移植物抗宿主病（GVHD）。HSCT预处理过程中3例患儿均能耐受；中性粒细胞植入中位时间11（10~11）d，血小板植入中位时间11（10~13）d，未发生原发性植入失败；2例发生不同程度急性GVHD，1例发展为慢性GVHD，1例移植后出现可逆性后部脑白质综合征（RPLS）。随访至2023年1月，随访中位时间19（11~42）个月，3例均存活，1例存在慢性GVHD，目前3例患儿均脱离输血，移植后血细胞未再检测出DKC相关基因突变，生长发育同正常同龄儿童，目前尚未发现合并实体肿瘤。结论 DKC患者HSCT治疗采用“Flu+低剂量环磷酰胺（CTX）+抗人胸腺淋巴细胞球蛋白（ATG）”预处理方案耐受性尚可，无原发性植入失败发生；GVHD仍是影响患儿生存主要因素，探索个体化方案治疗DKC的临床研究非常必要。

关键词: 先天性角化不良, 造血干细胞移植, 移植物抗宿主病, 减剂量预处理, 儿童

Abstract:

Objective To investigate the efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) in the treatment of children with dyskeratosis congenita (DKC), and to provide a basis for exploring the optimal transplantation program. Methods The clinical data of 3 children with DKC treated by HSCT in our hospital from June 2019 to June 2022 were retrospectively analyzed and the related literatures were reviewed. Results Three patients all underwent HSCT with a fludarabine-based reduced-intensity conditioning (RIC) regimen. The median count of mononuclear cells (MNC) and CD34⁺ cells was 13.7(8.3-17.3)×10⁸/kg and 8.2(6.3-13.1)×10⁶/kg respectively. A combination of methotrexate, cyclosporin A and mycophenolate mofetil was used to prevent graft-versus-host disease (GVHD). All 3 patients were able to tolerate the HSCT pretreatment. The median time of neutrophil implantation was 11(10-11) days, and the median time of platelet implantation was 11(10-13) days, and no primary implantation failure occurred. Two patients developed acute GVHD of different severity, 1 developed chronic GVHD, and 1 developed reversible posterior leukoencephalopathy syndrome (RPLS) after transplantation. The follow-up was completed in January 2023 and the median follow-up time was 19(11-42) months. All 3 patients survived, and 1 had chronic GVHD. At present, all 3 children were free from blood transfusion, and no DKC-related gene mutation was detected in blood cells after transplantation. The growth and development of the patients was similar to that of normal children of the same age, and no combined solid tumor has been found. Conclusions The pretreatment regimen of " Flu+low-dose cyclophosphamide (CTX) + anti-thymocyte globulin (ATG)" for HSCT treatment in DKC patients was tolerable, and no primary implantation failure occurred. GVHD is still the main factor affecting the survival of children, and it is necessary to explore the clinical study of individualized treatment for DKC.

Key words: dyskeratosis congenita, hematopoietic stem cell transplantation, graft versus host disease, low intensity conditional regimen, child

王英洁, 陈志伟, 买钰淼, 孙盼, 景沼贺, 董芃芃, 刘健. 异基因造血干细胞移植治疗儿童先天性角化不良3例并文献复习[J]. 临床儿科杂志, 2024, 42(3): 243-248.

WANG Yingjie, CHEN Zhiwei, MAI Yumiao, SUN Pan, JING Zhaohe, DONG Pengpeng, LIU Jian. Allogeneic hematopoietic stem cell transplantation for treatment of dyskeratosis congenita: a report of 3 cases and literature review[J]. Journal of Clinical Pediatrics, 2024, 42(3): 243-248.

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项目	例1	例2	例3
入院日期	2017年11月	2017年10月	2019年3月
确诊时年龄/岁	3.2	4.8	8.7
性别	男	女	男
首发症状	面色苍白	出血点	间断鼻衄
皮肤黏膜异常	指甲萎缩、结膜炎	指甲萎缩，皮肤网状灰棕色色素沉着、龋齿，双眼周边视网膜血管异常、双下泪小点闭锁、双眼结膜充血	无
血常规	WBC 1.14×10⁹/L，Hb 31.6g/L，PLT 2×10⁹/L，ANC 0.24×10⁹/L	WBC 2.94×10⁹/L，Hb 83g/L，PLT 1×10⁹/L，ANC 0.94×10⁹/L	WBC 2.06×10⁹/L，Hb 61g/L，PLT 21×10⁹/L，ANC 0.82×10⁹/L
骨髓细胞学	骨髓增生重度减低，粒系占5％；红系占0％，比值缺如，成熟红细胞大小不等，色素充盈欠佳；淋巴细胞比值增高；全片未见巨核细胞，可见成堆及散在血小板；全片易见网状细胞及网状细胞团	骨髓增生减低，粒系比例减低；红系比例大致正常，成熟红细胞大小不一；全片共见巨核细胞6个，血小板少见。骨髓小粒细胞面积10-20％，以非造血细胞为主，可见浆细胞。	骨髓增生减低，脂肪组织广泛增生，粒系比例减低；红系比例大致正常，成熟红细胞大小不一；全片未见巨核细胞，可见散在血小板。
基因变异	TINF2: c.845G>A:p.R282H	TINF2: c.845G>A:p.R282H	RTEL1: c.1489G>A:p.A497T
移植前用药（时间）	CsA、司坦唑醇（18个月）	司坦唑醇（4个月）	CsA（33个月）
移植前1月输血史RBC/PLT（U/治疗量）	3/8	1/7	7/4

患者	移植时年龄/岁	供体，HLA配型	供受者血型	MNC×10⁸/kg	CD34⁺×10⁶/kg	预处理方案	GVHD预防方案
1	4.8	MUD10/10	O供O	13.7	8.22	Flu+CTX+ATG	CsA+MMF+小剂量MTX
2	9.0	MMUD 9/10	AB供B	17.32	13.05	Flu+CTX+ATG	CsA+MMF+小剂量MTX
3	11.4	MSD10/10	A供B	8.3	6.3	Flu+CTX+ATG	CsA+MMF+小剂量MTX