同患两种罕见遗传病患儿9例的临床与遗传学特点  

Clinical and genetic characteristics of 9 rare cases with coexistence of dual genetic diagnoses

作　　者：谈丹丹[1] 刘艺丹 范燕彬 魏翠洁[1] 宋丹羽 杨海坡[1] 潘虹[2] 崔伟丽 毛姗姗[4] 徐向平[5] 于晓莉[6] 崔博 熊晖[1] Tan Dandan;Liu Yidan;Fan Yanbin;Wei Cuijie;Song Danyu;Yang Haipo;Pan Hong;Cui Weili;Mao Shanshan;Xu Xiangping;Yu Xiaoli;Cui Bo;Xiong Hui(Department of Pediatrics,Peking University First Hospital,Beijing 100034,China;Department of Central Laboratory,Peking University First Hospital,Beijing 100034,China;Department of Rehabilitation,Children′s Hospital Affiliated to Zhengzhou University,Henan Children′s Hospital,Zhengzhou Children′s Hospital,Zhengzhou 450053,China;Department of Neurology,the Children′s Hospital,Zhejiang University School of Medicine,National Clinical Research Center for Child Health,Hangzhou 310052,China;Department of Pediatrics,the First Affiliated Hospital of Harbin Medical University,Harbin 150001,China;Department of Neurology,Tianjin Children′s Hospital,Tianjin 300134,China;Department of Rehabilitation Medicine,Third Affiliated Hospital of Zhengzhou University,Henan Maternal and Child Health Care Hospital,Zhengzhou 450052,China)

机构地区：[1]北京大学第一医院儿科,北京100034 [2]北京大学第一医院实验中心,北京100034 [3]郑州大学附属儿童医院、河南省儿童医院、郑州儿童医院康复医学科,郑州450053 [4]浙江大学医学院附属儿童医院神经内科、国家儿童健康与疾病临床医学研究中心,杭州310052 [5]哈尔滨医科大学附属第一医院儿科,哈尔滨150001 [6]天津市儿童医院神经内科,天津300134 [7]郑州大学第三附属医院、河南省妇幼保健院康复科,郑州450052

出　　处：《中华儿科杂志》2023年第4期345-350,共6页Chinese Journal of Pediatrics

基　　金：国家自然科学基金(82171393,81571220);国家重点研发计划(2016YFC0901505);北京市自然科学基金(7212116);中央高水平医院临床科研业务费(北京大学第一医院高质量临床研究专项)(2022CR69)。

摘　　要：目的:分析同患两种罕见遗传病患儿的临床特征。方法:回顾性分析2021年1月至2022年2月北京大学第一医院确诊的同患两种罕见遗传病的患儿病例资料,总结其临床及遗传学特征。结果:9例患儿中男6例、女3例,末次就诊或随访年龄为5.0(2.7,6.8)岁,主要临床表现包括运动发育落后、智力发育落后、表观畸形、骨骼异常等。例1~4均为男性,表现为步态异常、跑跳差,血清肌酸激酶明显增高,遗传学分析证实为DMD基因致病性变异所致的Duchenne型或Becker型肌营养不良,同患另1种遗传病,分别为原发性肥大性骨关节病、脊髓性肌萎缩症、脆性X综合征、脑海绵状血管瘤3型。例5~9分别为COL9A1基因相关多发性骨骺发育不良6型和NF1基因相关神经纤维瘤病Ⅰ型,COL6A3基因相关Bethlem肌病和WNT1基因相关成骨不全症ⅩⅤ型,Turner综合征(45,X0/46,XX嵌合体)和TH基因相关Segawa综合征,22q11.2微重复综合征和DYNC1H1基因相关常染色体显性遗传下肢受累脊髓性肌萎缩症1型,ANKRD11基因相关KBG综合征与IRF2BPL基因相关神经发育障碍伴倒退、运动异常、语言丧失和癫痫。Duchenne型肌营养不良最多见,6种常染色体显性遗传病为新生杂合致病性变异所致。结论:存在两种罕见遗传病的患儿临床表型复杂,当患儿临床特征及病情变化不能用一种罕见遗传病解释时,需考虑可能同时存在其他罕见遗传病,并注意新生致病性变异所致的常染色体显性遗传病。基于核心家系的全外显子组测序联合多种分子遗传学检测有助于遗传病的精准诊断。Objective To analyze the clinical and genetic characteristics of pediatric patients with dual genetic diagnoses(DGD).Methods Clinical and genetic data of pediatric patients with DGD from January 2021 to February 2022 in Peking University First Hospital were collected and analyzed retrospectively.Results Among the 9 children,6 were boys and 3 were girls.The age of last visit or follow-up was 5.0(2.7,6.8)years.The main clinical manifestations included motor retardation,mental retardation,multiple malformations,and skeletal deformity.Cases 1-4 were all all boys,showed myopathic gait,poor running and jumping,and significantly increased level of serum creatine kinase.Disease-causing variations in Duchenne muscular dystrophy(DMD)gene were confirmed by genetic testing.The 4 children were diagnosed with DMD or Becker muscular dystrophy combined with a second genetic disease,including hypertrophic osteoarthropathy,spinal muscular atrophy,fragile X syndrome,and cerebral cavernous malformations type 3,respectively.Cases 5-9 were clinically and genetically diagnosed as COL9A1 gene-related multiple epiphyseal dysplasia type 6 combined with NF1 gene-related neurofibromatosis type 1,COL6A3 gene-related Bethlem myopathy with WNT1 gene-related osteogenesis imperfecta type XV,Turner syndrome(45,X0/46,XX chimera)with TH gene-related Segawa syndrome,Chromosome 22q11.2 microduplication syndrome with DYNC1H1 gene-related autosomal dominant lower extremity-predominant spinal muscular atrophy-1,and ANKRD11 gene-related KBG syndrome combined with IRF2BPL gene-related neurodevelopmental disorder with regression,abnormal movement,language loss and epilepsy.DMD was the most common,and there were 6 autosomal dominant diseases caused by de novo heterozygous pathogenic variations.Conclusions Pediatric patients with coexistence of double genetic diagnoses show complex phenotypes.When the clinical manifestations and progression are not fully consistent with the diagnosed rare genetic disease,a second rare genetic disease should be considered,and

关 键 词：诊断 表型 遗传性疾病 基因检测 DUCHENNE型肌营养不良 

分 类 号：R725.9[医药卫生—儿科]