Shwachman-Diamond 综合征7例患儿临床特点和基因变异分析

doi:10.12372/jcp.2024.23e1219

摘要/Abstract

摘要：

目的探讨Shwachman-Diamond 综合征（SDS）患儿的临床表型和基因变异特点。方法选取2018年1月至2023年9月于儿内分泌遗传科长期随访的7例SDS患儿，收集其临床资料，采集外周血样进行外显子组测序（ES）分析，并通过Sanger 测序对变异位点进行家系验证。结果 7例SDS患儿中男3例、女4例，初诊中位年龄为3.0（0.9~4.0）岁，6例为SBDS基因缺陷，1例为EFL1基因缺陷。6例SBDS缺陷的患儿中，5例携带复合杂合突变，2例为c.258+2T>C/c.183_184delinsCT，1例为c.258+2T>C/c.40A>G，1例为c.258+2T>C/c.184A>T，1例为c.258+2T>C/第3外显子杂合缺失；余1例携带c.258+2T>C纯合突变。SBDS缺陷患儿以矮小（6/6，100%）伴慢性腹泻（3/6，50%）和反复呼吸道感染（1/6，16.7%）就诊，经检查发现6例（100%）均存在中性粒细胞减少和肝酶升高，4例有骨骼发育异常表现，3例有胰腺外分泌功能不全表现。1例EFL1缺陷患儿携带复合杂合突变（c.2260C>T/c.316G>A），表现为矮小和骨骼发育异常，但无胰腺和血液系统受累。结论 SBDS缺陷患儿具有异质性的临床表型，以上发现丰富了中国SDS的表型谱和变异谱，并首次在中国人群中报道了1例EFL1变异患儿的临床特征。对矮小合并中性粒细胞减少、胰腺外分泌功能障碍、骨骼畸形等症状的患儿，应完善基因检测以免漏诊SDS。

关键词: Shwachman-Diamond综合征, SBDS基因, EFL1基因, 基因变异

Abstract:

Objective To investigate the clinical phenotype and genetic variant characteristics of children with Shwachman-Diamond syndrome (SDS). Methods From January 2018 to September 2023, seven children with SDS under long-term follow-up in the Department of Pediatric Endocrine and Genetics were selected as the research objects. The clinical data of children were gathered and peripheral blood samples were collected for exome sequencing (ES), and lineage validation of the variants was performed by Sanger sequencing. Results Among the 7 children with SDS, 3 were boys and 4 were girls. The median age at first diagnosis was 3.0 (0.9-4.0) years. Six patients carried SBDS defects and one case carried EFL1 defect. Among the six patients with SBDS deficiency, five of them carried compound heterozygous variants (two cases with the variants of c.258+2T>C/c.183_184delinsCT, one case with c.258+2T>C/c.40A>G, one case with c.258+2T>C/c.184A>T, one case with c.258+2T>C/ heterozygous deletion of exon 3), and the remaining one patient carried SBDS homozygous variation (c.258+2T>C). Patients with SBDS deficiency were initially diagnosed with short stature (6/6, 100%), and combined with chronic diarrhea (3/6, 50%) and recurrent respiratory infections (1/6, 16.7%). Through examination, all the six patients with SBDS deficiency (100%) were found to have neutropenia and elevated liver enzymes. Four cases had skeletal dysplasia and 3 cases had exocrine pancreatic dysfunction. One SDS patient was confirmed to carry compound heterozygous variants of EFL1 (c.2260C>T/c.316G>A). The main clinical manifestations included short stature and abnormal skeletal development, without pancreatic and blood system involvement. Conclusions Children with SBDS deficiency presented clinical phenotypic heterogeneity. The phenotypic spectrum and variation spectrum of SDS in China were enriched, and an SDS patient with EFL1 variant was reported for the first time in the Chinese population. For children with short stature and symptoms such as neutropenia, exocrine pancreatic dysfunction, and skeletal deformities, genetic testing should be completed to avoid missing the diagnosis of SDS.

Key words: Shwachman-Diamond syndrome, SBDS gene, EFL1 gene, genetic variation

王瑞芳, 梁黎黎, 张开创, 杨奕, 孙宇宁, 孙曼青, 肖冰, 韩连书, 张惠文, 顾学范, 余永国, 邱文娟. Shwachman-Diamond 综合征7例患儿临床特点和基因变异分析[J]. 临床儿科杂志, 2024, 42(3): 230-237.

WANG Ruifang, LIANG Lili, ZHANG Kaichuang, YANG Yi, SUN Yuning, SUN Manqing, XIAO Bing, HAN Lianshu, ZHANG Huiwen, GU Xuefan, YU Yongguo, QIU Wenjuan. Clinical characteristics and genetic variation analysis of Shwachman-Diamond syndrome in seven children[J]. Journal of Clinical Pediatrics, 2024, 42(3): 230-237.

图/表 1

表1

SDS 7例患儿的临床表型和基因型特征总结"

项目		例1		例2	例3
变异基因		SBDS		SBDS	SBDS
变异位点1（母源）		c.258+2T>C		c.40A>G(p.Asn14Asp)	c.258+2T>C
变异位点2（父源）		c.183_184delinsCT(p.Lys62*)		c.258+2T>C	c.183_184delTAinsCT（p.Lys62*）
临床特征
性别		男		女	女
出生史		G1P1，足月，出生体重2.6kg		G1P1，足月，出生体重2kg	G1P1，足月，出生体重3.2kg
家族史		无		无	无
父、母亲身高/cm		173、158		170、158	172、157
初诊年龄/岁		0.8		0.9	3.3
初诊时身高/cm(SD)		67.1(-2.2SD)		67.0(-2.1SD)	83.4(-3.9SD)
初诊时体重/kg(SD)		7.1(-2.5SD)		5.7(-3.9SD)	12.0(-2SD)
体质指数/kg·m^-2(SD)		15.8(-1SD)		12.7(-3.2SD)	17.3(1.3SD)
感染		反复湿疹；反复呼吸道感染、肺炎		反复湿疹	无
消化系统		肝肿大；慢性腹泻		慢性腹泻	无
发育情况		运动发育迟缓		运动发育迟缓	正常
骨骼异常及其他畸形		喉软骨软化；前胸部血管瘤		双膝轻度内翻	无
辅助检查（初诊时）
丙氨酸氨基转移酶/U·L^-1		566.0		316.0	85.0
天冬氨酸氨基转移酶/U·L^-1		375.8		293.0	120.0
血淀粉酶/U·L^-1		53.0		31.0	-
血脂肪酶/U·L^-1		<10		<10	-
胰淀粉酶/U·L^-1		0.6		4.9	-
大便常规		少量脂肪滴		少量脂肪滴	正常
中性粒细胞绝对值×10⁹·L^-1		0.5		0.6	0.6
血红蛋白/g·L^-1		80.0		125.0	117.0
血小板计数×10⁹·L^-1		222.0		279.0	185.0
IGF-1/μg·mL^-1		-		-	75.3
生长激素激发试验（GH峰值/ng·mL^-1）		-		-	21.0
25-羟维生素D/ng·mL^-1		25.0		36.1	27.8
消化系统超声及肝穿		肝活检：肝脂肪变50%，大小细胞混合型，可见小叶内点灶状坏死		正常	-
骨骼系统影像		-		双侧膝关节稍内翻；颈胸腰段部分椎体前缘稍圆顿	-
骨龄（左手正位片）		-		-	2.5岁
头颅磁共振		未见异常		未见异常	未见异常
骨髓穿刺检查		红系增生减低		-	-
治疗		脂溶性维生素；胰酶；护肝药物		脂溶性维生素；胰酶；护肝药物	-
项目	例4		例5	例6	例7
变异基因	SBDS		SBDS	SBDS	EFL1
变异位点1（母源）	c.258+2T>C		c.258+2T>C	c.258+2T>C	c.2260C>T(p.Arg754*)
变异位点2（父源）	c.258+2T>C		c.184A>T(p.Lys62*)	第3外显子杂合缺失	c.316G>A(p.Ala106Thr)
临床特征
性别	男		女	女	男
出生史	G1P1，足月，出生体重3.2kg		G2P2，足月，出生体重3.4kg	G1P1，足月，出生体重3.5kg	G2P2，足月，出生体重3.7kg
家族史	无		姐姐体健，无类似症状	无	哥哥体健，无类似症状
父、母亲身高/cm	169、160		165、165	170、160	165、160
初诊年龄/岁	4		5	1	3
初诊时身高/cm(SD)	94.0(-2.6SD)		97.0(-3.1SD)	63.0(-4.4SD)	86.0(-2.8SD)
初诊时体重/kg(SD)	11.9(-3SD)		15.5(-1.4SD)	6.0(-4.2SD)	12.6(-1.4SD)
体质指数/kg·m^-2(SD)	13.5(-1.6SD)		16.5(0.7SD)	15.1(-1SD)	17.0(1SD)
感染	无		无	无	无
消化系统	黄疸减退延迟		无	慢性腹泻	无
发育情况	运动发育迟缓		正常	正常	正常
骨骼异常及其他畸形	牙齿稀，轻度鸡胸		左侧拇指多指畸形；遗尿症	无	走路摇摆状，扁平足，O型腿，左眼内斜
辅助检查（初诊时）
丙氨酸氨基转移酶/U·L^-1	396.0		70.0	247.0	31.0
天冬氨酸氨基转移酶/U·L^-1	374.0		69.0	144.0	39.0
血淀粉酶/U·L^-1	-		-	44.0	-
血脂肪酶/U·L^-1	-		-	<10	519.0
胰淀粉酶/U·L^-1	-		-	-	-
大便常规	正常		正常	查见脂肪滴	正常
中性粒细胞绝对值×10⁹·L^-1	0.5		0.6	0.4	1.5
血红蛋白/g·L^-1	118.0		128.0	99.0	117.0
血小板计数×10⁹·L^-1	132.0		121.0	169.0	216.0
IGF-1/μg·mL^-1	35.7		39.5	34.6	59.0
生长激素激发试验（GH峰值/ng·mL^-1）	-		5.6	-	4.8
25-羟维生素D/ng·mL^-1	84.0		8.6	11.3	66
消化系统超声及肝穿	-		-	超声：胰腺形态饱满，内部回声增强，不均匀	正常
骨骼系统影像	-		-	关节周围骨质稍肿胀	脊柱、骨盆、双下肢多发骨质异常；多发性骨骺发育不良；骶1隐裂
骨龄（左手正位片）	3岁		4岁	-	2岁
头颅磁共振	未见异常		垂体上缘中份稍凹陷，局部高度变扁	小脑扁桃体下疝畸形，chiari畸形Ⅱ型	-
骨髓穿刺检查	-		-	-	-
治疗	护肝药物		生长激素	胰酶	生长激素

表1

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