CREBBP基因末端外显子截断变异致Rubinstein-Taybi综合征：临床表型特征与比较分析

doi:10.12372/jcp.2026.26e0297

临床儿科杂志 ›› 2026, Vol. 44 ›› Issue (6): 524-531.doi: 10.12372/jcp.2026.26e0297

CREBBP基因末端外显子截断变异致Rubinstein-Taybi综合征：临床表型特征与比较分析

王艳蕊¹, 石伊洁¹, 张开创², 王晓强³, 肖冰¹, 孙昱¹()

¹ 上海交通大学医学院附属新华医院上海市儿科医学研究所（上海 200092）
² 上海交通大学医学院附属新华医院儿内分泌遗传科（上海 200092）
³ 上海交通大学医学院附属新华医院儿神经外科（上海 200092）

收稿日期:2026-01-17 修回日期:2026-04-01 录用日期:2026-04-22 出版日期:2026-06-15 发布日期:2026-06-04
通讯作者: 孙昱 E-mail:sunyu@xinhuamed.com.cn
作者简介:第一联系人：作者贡献（Authors’ Contributions）
王艳蕊负责数据分析、研究设计及论文初稿撰写。石伊洁负责资料收集。张开创、王晓强、肖冰负责提供临床专业指导，并对研究的临床内容进行审阅。孙昱负责研究设计、论文指导和审阅。所有作者对要发布的版本给予最终批准，并同意对本论文负责。
基金资助:
科技部国家重点研发计划“生育健康与妇女儿童健康保障”重点专项(2025YFC2708200)

Rubinstein-Taybi syndrome caused by truncating variants in the last exon of CREBBP gene: clinical phenotypic characteristics and comparative analysis

WANG Yanrui¹, SHI Yijie¹, ZHANG Kaichuang², WANG Xiaoqiang³, XIAO Bing¹, SUN Yu¹()

¹ Shanghai Institute for Pediatric Research, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
² Department of Neurology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
³ Department of Pediatric Neurosurgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China

Received:2026-01-17 Revised:2026-04-01 Accepted:2026-04-22 Published:2026-06-15 Online:2026-06-04
Contact: SUN Yu E-mail:sunyu@xinhuamed.com.cn

摘要/Abstract

摘要：

目的分析携带CREBBP末端外显子截断变异患儿的临床特征，并探讨其与经典Rubinstein-Taybi综合征（RSTS）表型的关系。方法回顾性分析3例携带CREBBP（NM_004380.3）末端外显子截断变异患儿临床及遗传学资料，并结合既往文献报道的相关病例及经典RSTS表型进行比较分析。结果 3例患儿在CREBBP基因中检测到杂合无义变异，均位于末端外显子区域，3例均为新发变异。2例变异既往已有报道，1例为未报道变异。根据美国医学遗传学与基因组学学会和分子病理学学会指南，相关变异被判定为致病或可能致病。3例患儿均表现出不同程度的RSTS相关特征，但在核心特征的表现上存在差异。其中1例可见宽拇指/趾及特殊面容等多项典型特征，其余2例仅表现部分RSTS相关体征，整体临床表现不完全符合经典RSTS表型。既往文献分析显示，CREBBP末端外显子变异相关患者部分不表现为典型RSTS的核心体征。结论 CREBBP末端外显子变异患者临床表现及疾病严重程度方面存在异质性。临床诊断及遗传咨询时应结合系统表型评估与分子检测结果进行综合判断。

关键词: CREBBP, Rubinstein-Taybi综合征, 无义变异, 末端外显子, 表型异质性

Abstract:

Objective To analyze the clinical characteristics of children carrying truncating variants in the last exon of CREBBP and to explore their phenotypic features in comparison with the classical Rubinstein-Taybi syndrome (RSTS). Methods The clinical and genetic data of three patients carrying truncating variants in the last exon of CREBBP (NM_004380.3) were retrospectively reviewed. Their phenotypic features were compared with previously reported cases involving last exon variants and with the classical RSTS phenotype. Results All three patients harbored heterozygous nonsense variants in the last exon of CREBBP. All three variants arose de novo. Two variants had been previously reported, and one was novel. According to ACMG/AMP guidelines, the variants were classified as pathogenic or likely pathogenic. All patients exhibited features within the RSTS spectrum, while the core manifestations varied. One patient showed broad thumbs/halluces and several characteristic facial features of RSTS, whereas the other two displayed only partial RSTS-related features and did not fully meet the classical phenotype. A review of the literature indicated that patients with CREBBP last exon variants demonstrated heterogeneity in the expression of core features and disease severity. Conclusions Patients with nonsense variants in the last exon of CREBBP generally fall within the RSTS phenotypic spectrum, although their clinical manifestations may be atypical or incomplete. Comprehensive evaluation integrating detailed phenotypic assessment with molecular findings is important for accurate diagnosis and genetic counseling.

Key words: CREBBP, Rubinstein-Taybi syndrome, nonsense variant, last exon, phenotypic heterogeneity

中图分类号:

王艳蕊, 石伊洁, 张开创, 王晓强, 肖冰, 孙昱. CREBBP基因末端外显子截断变异致Rubinstein-Taybi综合征：临床表型特征与比较分析[J]. 临床儿科杂志, 2026, 44(6): 524-531.

WANG Yanrui, SHI Yijie, ZHANG Kaichuang, WANG Xiaoqiang, XIAO Bing, SUN Yu. Rubinstein-Taybi syndrome caused by truncating variants in the last exon of CREBBP gene: clinical phenotypic characteristics and comparative analysis[J]. Journal of Clinical Pediatrics, 2026, 44(6): 524-531.

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参考文献 37

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类型	类别	评分	项目	例1	例2	例3
核心特征	面部特征	6项中≥3项阳性，若存在d或f为4分；否则为3分	a)高拱眉
			b)眼裂下斜	√
			c)鼻梁凸起	√
			d)鼻小柱低于鼻翼
			e)高腭弓	√		√
			f)典型“微笑样表情”
		面部特征得分		3	0	0
	骨骼异常	若存在a为4分；若仅存在b或c为3分	a)拇指或拇趾成角畸形
			b)宽拇指	√
			c)宽拇趾	√
		骨骼异常得分		3	0	0
	生长异常	任一存在为2分	a)小头畸形	√	√
		任一存在为2分	b)出生后发育迟缓	√	√	√
		生长异常得分		2	2	2
	发育异常	2分	发育迟缓/智力障碍	√	√	√
	发育异常	发育异常得分		2	2	2
支持特征		仅c为1分； a或b(可伴或不伴c)为3分	a)母体子痫前期
			b)瘢痕疙瘩
			c)多毛
		支持特征得分		0	0	0
总得分				10	4	4

患儿	基因	核苷酸变异 (c.)	蛋白变异 (p.)	外显子	变异类型	新发变异	GnomAD 频率	文献已报道	ACMG评级
例1	CREBBP	c.5905C>T	p.(Gln1969Ter)	31	无义变异	是	未见收录	是^[16-18]	P(PVS1_Moderate+PM2_Supporting+ PS4_Supporting+PP4+PS2)
例2	CREBBP	c.5686C>T	p.(Gln1896Ter)	31	无义变异	是	未见收录	否	LP(PVS1_Moderate+PM2_Supporting+ PS2_Moderate)
例3	CREBBP	c.6010C>T	p.(Arg2004Ter)	31	无义变异	是	未见收录	是^[23]	LP(PVS1_Moderate+PM2_Supporting+ PS2_Moderate)

项目	末端截断变异	经典型RSTS^[32]
例数	22	308
生长发育
宫内生长受限	4/10(40%)	49%
出生后生长迟缓	9/18(50%)	75%
肥胖	1/11(9%)	29%
小头畸形	15/16(94%)	54%
颅面部特征
高拱眉	8/13(62%)	85%
长睫毛	1/1(100%)	89%
内眦赘皮	N/A	44%
斜视	2/11(18%)	71%
近视	1/5(20%)	56%
眼裂下斜	13/15(87%)	79%
鼻梁凸起(喙鼻)	13/15(87%)	81%
鼻小柱低于鼻翼	7/8(88%)	88%
典型“诡秘微笑”	8/10(80%)	94%
高拱腭	6/7(86%)	77%
爪形切牙	0/4(0%)	73%
小下颌	10/13(77%)	61%
低位耳	6/12(50%)	44%
躯干及四肢特征
宽拇指	15/17(88%)	96%
拇指偏斜(桡侧偏斜)	6/12(50%)	49%
指端增宽	9/10(90%)	87%
宽大脚趾	15/17(88%)	95%
多毛	1/7(14%)	76%
瘢痕疙瘩	0/7(0%)	23%
脊柱侧弯	4/8(50%)	18%
心血管异常	9/16(56%)	35%
便秘	1/3(33%)	76%
泌尿系统异常	3/5(60%)	28%
神经肌肉系统
癫痫	1/9(11%)	25%
认知与行为
智力障碍	16/16(100%)	99%
孤独症谱系障碍	2/6(33%)	49%

CREBBP基因末端外显子截断变异致Rubinstein-Taybi综合征：临床表型特征与比较分析

Rubinstein-Taybi syndrome caused by truncating variants in the last exon of CREBBP gene: clinical phenotypic characteristics and comparative analysis

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