KMT2A基因变异致Wiedemann-Steiner综合征3例临床及遗传学分析

Clinical and genetic analysis of Wiedemann-Steiner syndrome caused by KMT2A gene mutation in three cases

目的报告3例KMT 2 A基因变异所致的Wiedemann-Steiner综合征(Wiedemann-Steiner syndrome,WDSTS)的临床和遗传特点,提高对该疾病的认识及临床诊治效率。方法回顾三个家系的3例KMT 2 A基因变异导致的WDSTS患儿的临床资料,并复习总结文献。结果3例患儿均为婴儿期诊断,最小诊断年龄2个月,就诊原因分别为生长迟缓和食欲不振。与以往文献相似的临床表现为特殊面容、营养不良(3/3),喂养困难、睡眠障碍、多毛(2/3),发育迟缓(1/3),既往无报道的临床表现为脐疝、腹股沟疝。3例均是新发移码变异,变异分别发生于热点变异区的外显子3和27以及非热点变异区的外显子11。结论对于营养不良、喂养困难及发育迟缓的患儿,结合特殊面容和特异性多毛的临床表现,应考虑Wiedemann-Steiner综合征,需要做高通量全外显子基因分析确诊,有助于患儿尽早诊断;KMT2A基因以新生移码变异常见,变异热点是外显子27和3,本研究未经报道的3个移码变异丰富了该基因的变异谱,KMT 2 A基因含CXXC区变异的患者临床表型可能更重。

Objective To report the clinical and genetic characteristics of three cases of Wiedemann-Steiner syndrome(WDSTS)caused by KMT2A gene mutation,and improve the understanding of the disease and the efficiency of diagnosis and treatment.Methods The clinical data of three cases of WDSTS caused by KMT2A gene mutation in three families diagnosed in Shengjing Hospital of China Medical University from December 2019 to September 2021 were reviewed,and the clinical and genetic characteristics of WDSTS patients reported in the literature were reviewed and summarized.Results All three cases were diagnosed in infancy,with the youngest age of diagnosis of two months old,and the reasons for consultation were growth retardation and anorexia,respectively.Similar to those in previous literature,the clinical manifestations were special facial features,malnutrition(3/3),feeding difficulties,sleep disorders,hirsutism(2/3),and developmental delay(1/3).The clinical manifestations that had not been reported before were umbilical hernia and inguinal hernia.All three cases were de novo frameshift variants,which occurred in exon 3 and 27 in hot spot variants region and exon 11 in non-hot spot variants region,respectively.Conclusions Wiedemann-Steiner syndrome should be considered in children with malnutrition,feeding difficulty and developmental delay,combined with special facial features and specific hirsute.High-throughput exome sequencing should be used to facilitate early diagnosis.De novo frameshift variants of KMT2A gene are common,with hot spots in exon 27 and 3.The three unreported frameshift variants in this study enrich the mutation spectrum of this gene.In addition,patients with variants in the CXXC region of the KMT2A gene may have a more severe clinical phenotype.