ALPK3基因缺陷相关心肌病伴颅面-骨骼畸形一例并文献复习

ALPK3 gene-related pediatric cardiomyopathy with craniofacial-skeletal features:a report and literature review

目的:探讨ALPK3基因缺陷相关心肌病伴颅面-骨骼畸形患儿的临床特征及基因突变的特点。方法:回顾性分析1例ALPK3基因相关心肌病伴颅面-骨骼畸形患儿随诊11年的临床资料。总结患儿临床特征、超声心动图、心电图、心脏磁共振成像、基因检测的特点,并以“ALPK3基因”或“ALPK3 gene”作为检索词在中文数据库(中国知网数据库、万方数据库)和PubMed数据库中检索截至2020年11月的相关文献,总结ALPK3基因缺陷相关心肌病伴颅面-骨骼畸形的临床特点及基因突变信息。结果:患儿女,10月龄,因“发现心脏扩大2个月”入院,超声心动图示左心室扩大、左心收缩功能减低,体检示耳低位,胸骨左缘可闻及2/6级柔和收缩期杂音,双侧通贯掌,诊断为“心内膜弹力纤维增生症”,经治疗,1岁1月龄时心脏大小及心功能恢复正常,但室间隔及左心室壁较正常同龄儿增厚,修正诊断为“肥厚型心肌病(HCM)、先天畸形综合征待诊”。8岁前心肌肥厚进展缓慢,之后明显加速。9岁完善全外显子组测序发现染色体15q25.2的ALPK3基因存在外显子1 c.721dup(p.Y241Lfs*42)移码突变和外显子10 c.4840C>T(p.R1614*)无义突变,分别遗传自其母亲和父亲,符合常染色体隐性遗传模式,最终诊断为“ALPK3基因缺陷相关心肌病伴颅面-骨骼畸形”。随访至11岁,定期复查超声心动图示心室肌进行性肥厚;11岁完善心电图示左心室肥厚、多导联ST-T改变、T波倒置,QT间期延长;心脏磁共振成像示双心室心肌肥厚,心肌钆对比剂延迟强化示左右心室壁心肌弥漫性不均匀高信号影。文献检索共检索到文献7篇,其中中文0篇,英文7篇,共报道27例ALPK3基因突变致病病例,结合本例患儿,共28例,包含24个基因突变位点,其中18例为纯合突变,10例为复合杂合突变。11例患儿病初表现为扩张型心肌病(DCM),10例之后发展为HCM,且以疾病进展后的HCM为主;8例起病即为HCM;9例病初为DCM和HCM混合表型,其中6例进展为HCM。心电图表现为QT间期延长;心外表现包括矮身材、特殊面容、腭裂、颈蹼、关节挛缩和脊柱侧弯等。结论:ALPK3基因缺陷相关心肌病伴颅面-骨骼畸形以进行性心肌肥厚为主要临床特点,精确诊断依赖分子遗传学检测,需积累更多病例进一步分析基因型-表型关系和预后评估。

Objective To explore the clinical characteristics and mutation spectrum of ALPK3-related pediatric cardiomyopathy and craniofacial-skeletal abnormalities in children.Methods The clinical data during a follow-up of 11 years including clinical features,echocardiogram,electrocardiogram,cardiac magnetic resonance,genetic testing,and other data of a child firstly diagnosed with ALPK3 gene-related cardiomyopathy and craniofacial-skeletal abnormalities in China were collected retrospectively.The literatures containing the keyword of"ALPK3 gene"published in the China National Knowledge Infrastructure,Wanfang database and PubMed were collected up to November 2020.Then,the clinical features and gene mutations of ALPK3 gene-related pediatric cardiomyopathy with craniofacial-skeletal features were summarized.Results A female patient aged 10 months who presented with an enlarged heart for 2 months,was admitted to the hospital and initially diagnosed with endocardial elastic fibrosis.The echocardiography showed features of dilated left ventricle(LV)and LV systolic dysfunction.Low-set ears,webbed neck,a grade 2/6 systolic murmur at lower left sternal area and bilateral absent flexion creases of dig were observed.After treatment,the size and function of the heart recovered to normal at age 13 months.However,the ventricular septum and LV wall were thicker than normal values.Then,the diagnosis was revised to hypertrophic cardiomyopathy(HCM)and suspected congenital malformation syndrome.LV hypertrophy(LVH)progressed slowly before the age of 8 years and then progressed rapidly.At age 9 years,compound heterozygous ALPK3 mutations(c.721dup,p.Y241Lfs*42(exon 1)and c.4840C>T,p.R1614*(exon 10))were detected in the proband and the mutations had not been reported previously.Then,the final diagnosis of ALPK3 gene-related pediatric cardiomyopathy with craniofacial-skeletal features was made.During the follow up of 11 years,regular follow-up echocardiographic images showed progressive LVH.At age 11 years,electrocardiogram showed LVH,ST-T changes in multiple-lead,T wave inversion,and prolonged QT intervals.Cardiac magnetic resonance showed biventricular hypertrophy and late gadolinium enhancement showed non-uniform enhancement of left and right ventricular myocardium.A total of 7 articles published in English were retrieved,and no Chinese literature was found.Twenty-eight cases were reported in the articles plus the patient in this study.Twenty-four mutations were reported worldwide,18 patients carried homozygous mutations and 10 patients compound heterozygous mutations.Eleven patients showed dilated cardiomyopathy(DCM)at early stage of disease,and 10 of them transitioned to HCM at the disease progression stage.Eight patients presented with HCM at early stage of disease.Nine patients initially exhibited a mixed phenotype of DCM and HCM,and 6 of them eventually progressed to HCM.Electrocardiogram showed prolonged QT interval.Extracardiac features included short stature,special face,cleft palate,webbed neck,joint contracture,and scoliosis,etc.Conclusions Progressive myocardial hypertrophy is a major feature of ALPK3 gene-related cardiomyopathy with craniofacial-skeletal malformations.Precise diagnosis depends on molecular genetic techniques.More cases should be accumulated for further analysis on the genotype-phenotype correlation and prognosis assessment.