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ENGLISH ABSTRACT
TGFβ2基因新突变致4型Loeys-Dietz综合征伴显著骨骼畸形表现一家系研究
单慈
魏哲
章振林
作者及单位信息
·
DOI： 10.3760/cma.j.cn112138-20210908-00624
A pedigree study of Loeys-Dietz syndrome type 4 with skeletal deformity related to a novel TGFβ2 mutation
Shan Ci
Wei Zhe
Zhang Zhenlin
Authors Info & Affiliations
Shan Ci
Shanghai Clinical Research Center of Bone Disease, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People′s Hospital, Shanghai 200233, China
Wei Zhe
Shanghai Clinical Research Center of Bone Disease, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People′s Hospital, Shanghai 200233, China
Zhang Zhenlin
Shanghai Clinical Research Center of Bone Disease, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People′s Hospital, Shanghai 200233, China
·
DOI： 10.3760/cma.j.cn112138-20210908-00624
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摘要

目的Loeys-Dietz综合征为罕见的遗传性结缔组织疾病。分析伴显著骨骼畸形表现的Loeys-Dietz综合征一个家系的临床特征，并鉴定其致病基因突变。

方法收集先证者及家庭成员的临床资料，进行实验室及影像学相关辅助检查，采集家系成员外周血提取DNA，对先证者进行全外显子组测序，确定突变位点，对其他家系成员进行Sanger测序以验证突变位点。

结果先证者男，34岁。双下肢弯曲畸形30余年，体格检查示四肢细长伴扁平足、韧带松弛、脊柱侧弯，超声心动图示主动脉窦部扩张。先证者外周血基因组DNA中TGFβ2基因第1号外显子第220位核苷酸发生杂合错义突变（c. 220A>C，p.Thr74Pro）。先证者的姐姐及其1个女儿均存在双下肢弯曲畸形及扁平足等类似临床表现，并检出同一突变基因。该基因突变为新发突变，在ExAC和1000G中均未见报道，致病性预测为有害突变。据此，该家系可诊断为4型Loeys-Dietz综合征。

结论4型Loeys-Dietz综合征由TGFβ2基因突变导致，骨骼畸形是本病的显著特征之一，基因检测有助于早期诊断并与其他结缔组织疾病鉴别诊断。

结缔组织疾病;遗传性;4型Loeys-Dietz综合征;突变;TGFβ2基因
ABSTRACT

ObjectiveLoeys-Dietz syndrome is a rare type of hereditary connective tissue disease. This study was aimed to analyze the clinical characteristics and gene mutations in a family of Loeys-Dietz syndrome with skeletal deformity.

MethodsClinical data of the proband and family members were collected and biochemical measurements and radiological examinations were conducted. Genomic DNA was extracted from peripheral blood of the family members. Whole-exome sequencing was performed to determine the mutation sites in the proband, and Sanger sequencing was applied to verify the candidate mutation in the other family members.

ResultsThe proband is a 34-year-old man with deformities of lower extremities for more than 30 years. Physical examinations showed dolichostenomelia, pes planus, joint laxity and scoliosis. Echocardiography revealed the dilatation of aortic root at the level of the sinuses of Valsalva. A heterozygous missense mutation (c. 220A>C, p.Thr74Pro) in exon 1 of TGFβ2 gene was identified in the proband. The same mutation was detected in his sister and niece with similar clinical features such as deformities of lower extremities and pes planus. This novel mutation has not been reported in ExAC or 1000G and was predicted to be deleterious, supporting a diagnosis of Loeys-Dietz syndrome type 4.

ConclusionsLoeys-Dietz syndrome type 4 is caused by TGFβ2 mutations. Skeletal deformity is one of the distinctive features. Genetic testing is helpful for the early diagnosis and differential diagnosis from other connective tissue diseases.

Connective tissue diseases;Hereditary;Loeys-Dietz syndrome type 4;Mutation;TGFβ2 gene
Zhang Zhenlin, Email: nc.defudabe.utjslzgnahz
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引用本文

单慈,魏哲,章振林. TGFβ2基因新突变致4型Loeys-Dietz综合征伴显著骨骼畸形表现一家系研究[J]. 中华内科杂志,2022,61(05)：552-558.

DOI:10.3760/cma.j.cn112138-20210908-00624

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Loeys-Dietz综合征（Loeys-Dietz syndrome，LDS；OMIM #609192）是一种罕见的常染色体显性遗传性结缔组织疾病（heritable connective tissue disorder，HCTD），该综合征的典型临床表现为宽眼距、腭裂或悬雍垂异常、广泛头颈部动脉迂曲及与其他HCTD重叠的主动脉根部扩张、关节松弛和长骨骨骼过度生长等心血管及骨骼特征 ［ 1 ］ 。LDS根据涉及的基因分为5型，由编码转化生长因子β（transforming growth factor β，TGF β）信号通路相关组成部分基因突变导致，包括TGFBR1/2、SMAD3和TGFβ2/3。其中TGFBR2基因突变致LDS2病例数较多，TGFβ2基因突变致LDS4型（LDS4）仅占5%~10% ［ 2 ］ 。国外对LDS4仅有73例报道 ［ 3 ］ ，国内仅在一个胸主动脉瘤/夹层患者队列中检测到4例散发LDS4病例 ［ 4 ］ ，未见相关家系报告。本研究对一以显著骨骼畸形为主要临床表现的家系进行基因检测，结合临床表现确诊为LDS4，同时复习相关文献，总结LDS4的发病机制、临床特征，以提高临床医师对本病的认识。
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备注信息
A
章振林，Email： nc.defudabe.utjslzgnahz
B

单慈完成数据总结与分析，文章初稿的写作；魏哲完成数据采集，参与结果分析；章振林指导研究设计、数据分析，并对文章作批评性审阅

C

单慈, 魏哲, 章振林. TGFβ2基因新突变致4型Loeys-Dietz综合征伴显著骨骼畸形表现一家系研究[J]. 中华内科杂志, 2022, 61(5): 552-558. DOI: 10.3760/cma.j.cn112138-20210908-00624.

D
所有作者声明不存在利益冲突
E
国家重点研发计划 (2018YFA0800801)
国家自然科学基金 (81974123)
上海申康医院发展中心临床科技创新项目 (SHDC12018120)
上海市临床重点专科建设项目——内分泌代谢科（“振龙头”类）
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