Lamb-Shaffer综合征表现为矮小症伴语言、运动发育迟缓一例及文献复习

doi:10.16150/j.1671-2870.2022.03.008

摘要/Abstract

摘要：

目的：分析1例以矮小伴语言运动发育迟缓为主要表现的Lamb-Shaffer综合征（Lamb-Shaffer syndrome,LAMSHF）患者的临床资料和基因检测结果,以提高临床医师对本病的认识。方法：分析本院收治的1例表现为严重身材矮小和语言运动发育迟缓的LAMSHF男性患儿,收集其临床资料,并抽取患儿及父母全血,提取基因组DNA进行全外显子测序及DNA Sanger测序。同时,在国内外数据库中检索相关文献,分析LAMSHF病例的临床特征、诊治方法及预后。结果：本例患儿9岁2个月,身高108.7 cm [-4.82个标准差（standard deviation,SD）],体重17.1 kg（<-2.1 SD）,体质量指数14.5 kg/m²（-1.1 SD）,大运动及语言发育延迟1年,实验室检查示胰岛素样生长因子水平为74 ng/mL（-2.14 SD）,生长激素激发试验提示非生长激素缺乏,其他检查无异常。全外显子测序提示,患儿第12号染色体p12.1到p11.1位置（p12.1s;p11.1）,存在至少10.4 Mb的拷贝数缺失,涉及SOX5等多个已知致病基因,发现该杂合变异来源于父源染色体,父母验证基因正常,提示该拷贝数变异为新发突变。遗传变异分类标准与指南指南评估该突变为可能致病[强致病证据（strong piece of evidence for pathogenicity,PS2）+中等致病证据（moderate piece of evidence for pathogenicity,PM1）],故诊断患儿为LAMSHF。收集分析11项研究共75例LAMSHF患者,LAMSHF的诊断依赖基因检测,且尚无明确的基因型-表型相关性,患者的智力障碍改善依赖于康复治疗。由于本病患者发生癫痫、眼征、肌张力减退风险较高,且有肿瘤倾向,预后不佳,对于矮小症状应避免使用生长激素。结论：LAMSHF的诊断依赖包括SOX5基因在内的基因检测。本例LAMSHF患儿携带目前已知的最大12p12.1缺失片段,且矮小程度最严重。临床上,对于合并智力异常的矮小症患儿,需进行SOX5突变及拷贝数变异筛查,同时治疗时应避免盲目使用生长激素带来的潜在危害。

关键词: 矮小症, 语言发育迟缓, 运动发育迟缓, Lamb-Shaffer综合征

Abstract:

Objective: To analyze a case of Lamb-Shaffer syndrome(LAMSHF) with short stature and delayed language and motor development as the main manifestation,and summerize data of the disease in data bank for improving the understanding of this disease. Methods: A male child aged 9 year and 3 months with severe short stature and delayed language and motor development admitted to our hospital was analyzed. Their clinical data were collected, and the genomic DNA was extracted from whole blood of the children and their parents for whole exome sequencing and DNA Sanger sequencing verification. Meanwhile, relevant literature was reviewed to analyze the pathogenesis, clinical characteri-stics, diagnosis and therapy and prognosis of LAMSHF. Results: The height of the boy was 108.7 cm [-4.82 standard deviation (SD)], weight was 17.1 kg (<-2.1 SD), body mass index was 14.5 kg/m² (-1.1 SD), and gross motor and language development 1-year delay. Laboratory test showed the insulin-like growth factor was 74 ng/mL (-2.14 SD), growth hormone challenge test suggested growth hormone and the remaining tests were all normal. Whole exome sequencing revealed that Seq[GRCh37]del(12)(p12.1s; p11.1) involved multiple known pathogenic genes including SOX5, with a copy number deletion of at least 10.4 Mb, and which were not detected before, so the copy number variant was a novel mutation. The mutation was assessed by ACMG guidelines as probable pathogenic (PS2+PM1). Therefore Lamb-Shaffer syndrome was diagnosed. Literature reviewing indicated that 11 LAMSHF-related studies included 1 domestic study and 10 foreign studies, with a total of 75 patients. The diagnosis of LAMSHF depended on genetic testing, and there is no clear genotype-phenotype correlation. The improvement of the patient's intellectual disability depended on rehabilitation treatment. Due to the high risk of epilepsy, ocular signs, and hypotonia in this disease, and the tendency to have tumors, growth hormone should be avoided for treatment of short stature. Patients with this disease currently had a poor prognosis. Conclusions: The boy with LAMSHF carried 12p12.1 deletion, which is the largest deletion and is never reported, presenting severe short stature. Short stature children with abnormal intelligence need to be screened for gene mutation and copy number variation of SOX5, and growth hormone therapy should be avoided due to potential risk of tumorigenesis.

Key words: Short stature, Language retardation, Motor retardation, Lamb-Shaffer syndrome

中图分类号:

R541.7

张娟娟, 何亲羽, 杨媛艳, 董治亚, 肖园, 陈立芬, 张彩萍. Lamb-Shaffer综合征表现为矮小症伴语言、运动发育迟缓一例及文献复习[J]. 诊断学理论与实践, 2022, 21(03): 336-342.

ZHANG Juanjuan, HE Qinyu, YANG Yuanyan, DONG Zhiya, XIAO Yuan, CHEN Lifen, ZHANG Caiping. Lamb-Shaffer syndrome presenting as short stature with delays in motor and language acquisition: a case report and literature review[J]. Journal of Diagnostics Concepts & Practice, 2022, 21(03): 336-342.

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项目	结果
体格检查
身高	108.7 cm
体重	17.1 kg
体块指数	14.5 kg/m²
实验室检验
血尿常规、肝肾功能、电解质、心肌酶谱、血脂	正常
空腹血糖	5.67 mmol/L
糖化血红蛋白	6%
空腹胰岛素	6.42 μIU/mL
内分泌
生长激素激发	生长激素峰 10.383 ng/mL
IGF-1	74 ng/mL
甲状腺功能	三碘甲腺原氨酸1.65 nmol/L,甲状腺素 127.18 nmol/L,游离三碘甲腺原氨酸 4.55 pmol/L,游离甲状腺素17.38 pmol/L, 促甲状腺素3.568 4 μIU/mL
促肾上腺皮质激素	19.92 pg/mL
皮质醇（8 Am）	7.56 μg/dL
硫酸脱氢表雄酮	50.70 μg/dL
肿瘤标志物
甲胎蛋白	0.48 ng/mL
癌胚抗原	1.42 ng/mL
影像学检查
腹部B超	胆囊底部中等回声灶,胆泥可能;肝胰体脾肾肾上腺区未见明显异常
垂体MRI增强	垂体形态略偏小,高度2.9 mm左右, 蝶窦炎
骨龄	8岁

文献	病例数	SOX5突变	遗传方式	身高SD分数	智力障碍	骨骼畸形	其他表型
Schanze I, et al^[4]	3	基因内缺失 12p12.1缺失 120 Kb~4.9 Mb	新发	-1.8~0	轻中度	胸廓畸形, 短指趾, 扁平足	特殊面容, 行为障碍
Lamb AN, et al^[5]	16	基因内缺失 12p12.1缺失相互易位	新发、父系遗传	<-2~1.3	轻中重	短指趾, 趾弯曲, 扁平足, 高弓足	特殊面容, 行为障碍, 眼征, 癫痫
Fukushi D, et al^[6]	1	相互易位	新发	-3.0	轻度	指趾前倾	行为障碍
Lee RW, et al^[7]	2	基因内缺失 12p12.1缺失 53 Kb~3.2 Mb	新发	-1.6~0.9	中重度	多趾	特殊面容
Quintela I, et al^[8]	1	基因内缺失 493.94 Kb	新发	正常	中度	无	特殊面容, 行为障碍, 眼征
Zawerton A, et al^[1]	41	基因内缺失 12p12.1缺失 43.7 Kb~1.7 Mb 错义突变截短突变	新发、母系遗传、嵌合体	正常	轻中重	小头畸形, 脊椎骨畸形, 胸廓畸形, 并指, 髋关节发育不良	特殊面容, 行为障碍, 眼征, 癫痫, 肌张力减退
Nesbitt A, et al^[9]	1	截短突变	新发	0.65	中度	脊椎骨畸形, 胸廓畸形, 并趾	特殊面容, 行为障碍, 眼征
Zech M, et al^[10]	2	截短突变	新发	未报道	无	无	行为障碍, 肌张力减退
Gkirgkinoudis A, et al^[11]	1	意义未明变异	新发	-2.1	无	椎骨畸形, 指趾弯曲	无
Innella G, et al^[12]	6	基因内缺失 50~300 Kb 错义突变	新发、嵌合体	-2.3~正常	轻中重度	小头畸形, 脊柱畸形	特殊面容, 行为障碍, 眼征, 癫痫
Cao JH, et al^[13]	1	截短突变	新发	未报道	轻度	指弯曲	特殊面容