18例Barth综合征患儿的临床和遗传学特征分析

doi:10.3969/j.issn.1674-8115.2024.11.007

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (11): 1406-1413.doi: 10.3969/j.issn.1674-8115.2024.11.007

• 论著 · 临床研究 • 上一篇

18例Barth综合征患儿的临床和遗传学特征分析

詹湉柳(), 严子航, 吴近近, 陈浩, 陈丽君, 陈轶维, 傅立军()

上海交通大学医学院附属上海儿童医学中心心内科，上海 200127

收稿日期:2024-06-02 接受日期:2024-07-05 出版日期:2024-11-28 发布日期:2024-11-28
通讯作者: 傅立军 E-mail:1961534943@qq.com;fulijun@scmc.com.cn
作者简介:詹湉柳（1994—），女，硕士生；电子信箱：1961534943@qq.com。
基金资助:
国家重点研发计划(2023YFC2706201);国家自然科学基金(81770380);上海市科学技术委员会项目(20MC1920400)

Analysis of clinical and genetic characteristics of 18 pediatric patients with Barth syndrome

ZHAN Tianliu(), YAN Zihang, WU Jinjin, CHEN Hao, CHEN Lijun, CHEN Yiwei, FU Lijun()

Department of Cardiology, Shanghai Children′s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China

Received:2024-06-02 Accepted:2024-07-05 Online:2024-11-28 Published:2024-11-28
Contact: FU Lijun E-mail:1961534943@qq.com;fulijun@scmc.com.cn
Supported by:
National Key Research and Development Program of China(2023YFC2706201);National Natural Science Foundation of China(81770380);Project of Shanghai Municipal Science and Technology Commission(20MC1920400)

摘要/Abstract

摘要：

目的·分析18例Barth综合征（Barth syndrome，BTHS）患儿的临床特征和遗传学特点，为BTHS的防治提供依据。方法·纳入2010年1月—2023年11月上海交通大学医学院附属上海儿童医学中心确诊为BTHS的18例患儿。收集患儿的临床资料，包括年龄、出生体质量、家族史、心电图、超声心动图，尿串联质谱检测报告，血常规、血生化检查以及基因检测结果，分析患儿的临床特征、基因检测结果以及预后。结果·18例BTHS患儿均为男性（包括2例同卵双胞胎），1例为彝族，17例为汉族。18例患儿的中位诊断年龄为3.0（1.0，5.6）个月；15例患儿发病时出现心功能下降，左室射血分数（left ventricular ejection fraction，LVEF）低于50%；15例患儿发病时出现扩张型心肌病（dilated cardiomyopathy，DCM），12例患儿出现左室致密化不全（left ventricular non-compaction，LVNC），9例患儿出现室壁肥厚。在就诊和随访期间，9例患儿出现QTc间期延长，2例患儿出现室性心律失常，9例患儿出现中性粒细胞缺乏症，10例患儿出现单核细胞增多症。13例患儿的尿串联质谱检测结果中，有8例出现3-甲基戊烯二酸尿症（3-methylglutaconic aciduria，3-MGCA）。18例患儿中共检测到15种TAZ基因突变，包含5种新发现的突变；16例患儿父母的基因检测结果发现，15例患儿的基因突变来源于母亲。中位随访时间为8.5（2.6，29.3）个月，其中12例患儿死亡，死亡的中位年龄为7.5（6.0，12.8）个月。7例死于心力衰竭（其中4例合并感染），3例猝死，1例死于心室颤动，1例患儿因意外死亡。结论·BTHS是一种罕见的累及全身多系统的遗传病，主要临床特征包括心肌病、中性粒细胞缺乏症等，该病发病早，病情重，预后差。临床上应做到早发现、早诊断、早治疗。

关键词: Barth综合征（BTHS）, TAZ基因突变, 心肌病, 中性粒细胞缺乏症

Abstract:

Objective ·To analyze the clinical and genetic characteristics of Chinese pediatric patients with Barth syndrome (BTHS) and provide data to support the prevention and treatment of BTHS. Methods ·Eighteen pediatric patients diagnosed with BTHS at Shanghai Children′s Medical Center, Shanghai Jiao Tong University School of Medicine, from January 2010 to November 2023, were included. Clinical data (age, birth weight, family history, electrocardiogram, echocardiogram, urine tandem mass spectrometry, complete blood count, blood biochemistry, and genetic test results) were collected to analyze the clinical characteristics, genetic findings, and prognoses of the patients. Results ·The study included 18 male patients with BTHS (including 2 monozygotic twins), consisting of one Yi ethnic and 17 Han Chinese patients. The median age at diagnosis was 3.0 (1.0, 5.6) months. Fifteen patients experienced decreased cardiac function at disease onset, with a left ventricular ejection fraction (LVEF) below 50%. Dilated cardiomyopathy (DCM) was observed in 15 patients, left ventricular non-compaction (LVNC) in 12 patients, and myocardial hypertrophy in 9 patients. During the diagnosis and follow-up, QTc interval prolongation occurred in 9 patients, ventricular arrhythmias in 2 patients, neutropenia in 9 patients, and monocytosis in 10 patients. Urine tandem mass spectrometry revealed 3-methylglutaconic aciduria (3-MGCA) in 8 of 13 tested patients. Fifteen types of TAZ gene mutation were identified in the 18 patients, including 5 novel mutations. Genetic testing of the parents of 16 patients indicated maternal inheritance in 15 cases. The median follow-up period was 8.5 (2.6, 29.3) months, during which 12 patients died. The median age at death was 7.5 (6.0, 12.8) months. Causes of death included heart failure (7 cases, with 4 concurrent infections), sudden death (3 cases), ventricular fibrillation (1 case), and accidental death (1 case). Conclusion ·BTHS is a rare genetic disorder with multisystem involvement. Its primary clinical manifestations include cardiomyopathy and neutropenia. The condition typically presents early in life, with severe progression and poor prognosis. Prompt recognition, accurate diagnosis, and early intervention are essential for managing this disease.

Key words: Barth syndrome (BTHS), TAZ gene mutation, cardiomyopathy, neutropenia

中图分类号:

R725.4

詹湉柳, 严子航, 吴近近, 陈浩, 陈丽君, 陈轶维, 傅立军. 18例Barth综合征患儿的临床和遗传学特征分析[J]. 上海交通大学学报（医学版）, 2024, 44(11): 1406-1413.

ZHAN Tianliu, YAN Zihang, WU Jinjin, CHEN Hao, CHEN Lijun, CHEN Yiwei, FU Lijun. Analysis of clinical and genetic characteristics of 18 pediatric patients with Barth syndrome[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(11): 1406-1413.

图/表 4

参考文献 26

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Sample	Age of onset /month	Age at diagnosis /month	Birth weight/g	Age at death /month	Cause of death	First presentation	Genotype	LVEF/LVFS /%	LVEDd Z score	LVPWd Z score	NC/C	Prolonged QTc	Neutropenia
BTHS 1	2.5	3	2 000	7	Heart failure with fever	Pneumonia	c.527A>G	45.6/22.1	5.7	0.45	1.58	-	-
BTHS 2	2.5	3	2 400	7.5	Heart failure with fever	Heart failure	c.527A>G	36.2/16.7	3.8	-0.12	2.2	-	-
BTHS 3	6	20	2 850	77	Accidental asphyxiation in a vegetative state	Muscle weakness	c.367C>T	40.1/19.1	3.3	1.96	2.11	-	+
BTHS 4	6.5	6.5	2 300	7.5	Ventricular fibrillation	Pneumonia	c.710_711delTG	36.8/17.3	5.3	2.18	2.75	-	+
BTHS 5	1	1	2 650	12	Heart failure and respiratory infection	Heart failure	c.134_136delinsCC	40.1/18.9	5.7	0.9	4	+	+
BTHS 6	0	6	3 620	Alive	-	Cardiomyopathy	c.324_325insCACTCC	62/31	0.24	1.54	2.19	+	+
BTHS 7	4	6	2 500	6	Sudden death	Growth delay	del TAZ	48.1/23.2	2.24	4.24	2.09	-	+
BTHS 8	0	1	3 100	Alive	-	Cardiomyopathy	c.718G>A	46.2/21.5	1.51	1.84	2.68	+	+
BTHS 9	1	1	3 250	13	Heart failure and respiratory infection	Diarrhea	c.589G>A	41.1/19.2	3.56	NA	1.95	+	-
BTHS 10	In utero	2	2 550	Alive	-	Cardiomyopathy	c.193A>G	35/15	4.46	-0.65	2.85	+	+
BTHS 11	4	4	2 400	5	Heart failure	Heart failure	c.226C>T	47.5/23.2	5.38	3.57	2.47	-	-
BTHS 12	5.5	5.5	2 500	Alive	-	Pneumonia	c.207C>A	44/21	4.65	2.27	2.4	+	-
BTHS 13	2	2	3 550	alive	-	Heart failure	c.85G>A	32.6/15	5.93	3.09	1.9	+	-
BTHS 14	1	1	3 050	7.5	Sudden death	Cardiomyopathy	Del exon 3‒5	50.8/24.9	2.64	2.17	2	-	-
BTHS 15	5	5	3 210	17	Sudden death	Diarrhea	c.777+1G>A	20/8.6	5.22	2.84	1.63	+	-
BTHS 16	In utero	0	2 315	0.1	Heart failure	Cardiomyopathy	c.699+1G>A	26.4/11.7	6.28	0.92	2	-	-
BTHS 17	3	3	2 800	Alive	-	Cardiomyopathy	c.589G>A	61.4/31.3	-0.02	4.41	1.94	NA	+
BTHS 18	4	4	4 150	6	Heart failure	Feeding difficulties	c.367C>T	41/19	4.93	4.22	1.5	+	+

Sample	Age of onset /month	Age at diagnosis /month	Birth weight/g	Age at death /month	Cause of death	First presentation	Genotype	LVEF/LVFS /%	LVEDd Z score	LVPWd Z score	NC/C	Prolonged QTc	Neutropenia
BTHS 1	2.5	3	2 000	7	Heart failure with fever	Pneumonia	c.527A>G	45.6/22.1	5.7	0.45	1.58	-	-
BTHS 2	2.5	3	2 400	7.5	Heart failure with fever	Heart failure	c.527A>G	36.2/16.7	3.8	-0.12	2.2	-	-
BTHS 3	6	20	2 850	77	Accidental asphyxiation in a vegetative state	Muscle weakness	c.367C>T	40.1/19.1	3.3	1.96	2.11	-	+
BTHS 4	6.5	6.5	2 300	7.5	Ventricular fibrillation	Pneumonia	c.710_711delTG	36.8/17.3	5.3	2.18	2.75	-	+
BTHS 5	1	1	2 650	12	Heart failure and respiratory infection	Heart failure	c.134_136delinsCC	40.1/18.9	5.7	0.9	4	+	+
BTHS 6	0	6	3 620	Alive	-	Cardiomyopathy	c.324_325insCACTCC	62/31	0.24	1.54	2.19	+	+
BTHS 7	4	6	2 500	6	Sudden death	Growth delay	del TAZ	48.1/23.2	2.24	4.24	2.09	-	+
BTHS 8	0	1	3 100	Alive	-	Cardiomyopathy	c.718G>A	46.2/21.5	1.51	1.84	2.68	+	+
BTHS 9	1	1	3 250	13	Heart failure and respiratory infection	Diarrhea	c.589G>A	41.1/19.2	3.56	NA	1.95	+	-
BTHS 10	In utero	2	2 550	Alive	-	Cardiomyopathy	c.193A>G	35/15	4.46	-0.65	2.85	+	+
BTHS 11	4	4	2 400	5	Heart failure	Heart failure	c.226C>T	47.5/23.2	5.38	3.57	2.47	-	-
BTHS 12	5.5	5.5	2 500	Alive	-	Pneumonia	c.207C>A	44/21	4.65	2.27	2.4	+	-
BTHS 13	2	2	3 550	alive	-	Heart failure	c.85G>A	32.6/15	5.93	3.09	1.9	+	-
BTHS 14	1	1	3 050	7.5	Sudden death	Cardiomyopathy	Del exon 3‒5	50.8/24.9	2.64	2.17	2	-	-
BTHS 15	5	5	3 210	17	Sudden death	Diarrhea	c.777+1G>A	20/8.6	5.22	2.84	1.63	+	-
BTHS 16	In utero	0	2 315	0.1	Heart failure	Cardiomyopathy	c.699+1G>A	26.4/11.7	6.28	0.92	2	-	-
BTHS 17	3	3	2 800	Alive	-	Cardiomyopathy	c.589G>A	61.4/31.3	-0.02	4.41	1.94	NA	+
BTHS 18	4	4	4 150	6	Heart failure	Feeding difficulties	c.367C>T	41/19	4.93	4.22	1.5	+	+

Item	M (Q₁, Q₃)
LVEF/%	41.1 (35.9, 47.7)
LVFS/%	19.2 (16.3, 23.2)
LVEDd Z score	4.56 (2.54, 5.46)
LVPWd Z score	2.17 (0.91, 3.33)
NC/C	2.10 (1.93, 2.52)

Item	M (Q₁, Q₃)
LVEF/%	41.1 (35.9, 47.7)
LVFS/%	19.2 (16.3, 23.2)
LVEDd Z score	4.56 (2.54, 5.46)
LVPWd Z score	2.17 (0.91, 3.33)
NC/C	2.10 (1.93, 2.52)

Location	Nucleotide change	Amino acid change	Type of mutation	Number of pedigree	Mother with proven TAZ mutation
Exon 1	c.85G>A	p.G29S	Missense mutation	1	Yes
Exon 2	c.134_136delinsCC	p.H45PfsX38	Frameshift mutation	1	Yes
Exon 2	c.193A>G	p.T65A	Missense mutation	1	Yes
Exon 2	c.207C>A	p.H69Q	Missense mutation	1	Yes
Exon 2	c.226C>T	p.P76S	Missense mutation	1	Yes
Exon 3‒5	Del exon 3‒5		Exon deletions	1	Yes
Exon 4	c.324_325insCACTCC	p.111_112insSH	Inframe mutation	1	Not mutated
Exon 4	c.367C>T	p.R123X	Nonsense mutation	2	Yes
Exon 6	c.527A>G	p.H176R	Missense mutation	2	Yes
Exon 8	c.589G>A	p.G197R	Missense mutation	2	Yes
Exon 10	c.710_711delTG	p.V237AfsX73	Frameshift mutation	1	Yes
Exon 10	c.718G>A	p.G240R	Missense mutation	1	Yes
Intron 9	c.699+1G>A	p.?	Splicing defect	1	Not available
Intron 10	c.777+1G>A	p.?	Splicing defect	1	Yes
TAZ gene	Del TAZ gene		Gene deletion	1	Not available

18例Barth综合征患儿的临床和遗传学特征分析

Analysis of clinical and genetic characteristics of 18 pediatric patients with Barth syndrome

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