小头畸形-癫痫-发育迟缓综合征1家系遗传学分析并文献复习

Microcephaly-seizures-development delay syndrome in a pedigree:genetic analysis and literature review

目的探讨小头畸形-癫痫-发育迟缓(microcephaly-seizures-development delay,MCSZ)综合征的临床表现和遗传学病因。方法对2018年6月在本院就诊的1个MCSZ家系中患儿及其父母行全基因外显子组测序和生物信息学分析,将所得的致病性变异用Sanger测序法验证。明确患儿的分子诊断后,对该家系2020年再妊娠胎儿行产前基因诊断。并通过文献复习,总结和分析国内外已报道的MCSZ综合征病例的临床特征及遗传学特点。结果(1)本病例:患儿女性,8月龄,因“头围小,反复抽搐”收入院,临床表现为小头畸形、多发性癫痫、精神发育迟缓。听觉诱发电位示左侧耳神经通路中度损害,全外显子组测序发现患儿存在PNKP基因复合杂合变异。其中致病性c.199-10_203delinsTCTGAGGGGT变异遗传自父亲,可能致病性c.1505C>T(p.P502>L)变异遗传自母亲,两变异均为文献未报道的变异。结合临床表现考虑遗传学病因为PNKP基因复合杂合变异。该家系再孕胎儿未遗传来自父母的PNKP基因变异,夫妇选择继续妊娠。随访至2021年12月,再孕胎儿为女性,现13月龄,枕额围测值、语言、运动发育正常。(2)文献复习:共检索到相关文献12篇、MCSZ综合征患者38例,合并本例共39例。39例患儿的临床表型包括:小头畸形(91.7%,33/36)、癫痫(88.2%,30/34)、发育迟缓(96.4%,27/28)、多动症(25.6%,10/39)、胃食管反流(10.3%,4/39)和听力丧失(7.7%,3/39)。其中癫痫首发年龄集中在婴幼儿期(96.3%,26/27),头颅MRI检查异常比例为91.2%(31/34)。结论对于产前发现胎儿头围偏小,且进行性缩小表现,出生后伴有小头畸形、癫痫、发育迟缓、多动症、胃食管反流和听力丧失等临床特征的患者,应当考虑MCSZ综合征可能。此类患儿临床预后差异大,基因检测有助于早期诊断和遗传咨询。

Objective To analyze the phenotypes and genetic etiology of microcephaly-seizures-development delay(MCSZ)syndrome.Methods The patient was diagnosed with MCSZ syndrome in June 2018 at Shenzhen Maternity and Child Healthcare Hospital.She was the couple's first child,and the mother conceived a second child in 2020.The clinical data of the proband were retrospectively analyzed,and the bioinformatics analysis and whole-exome sequencing(WES)were performed on the proband and her parents to identify the pathogenic variants,which were further validated using Sanger sequencing.The prenatal genetic diagnosis of the second fetus was performed following the molecular diagnosis of the proband was confirmed.The clinical manifestations and pathogenesis of MCSZ syndrome were summarized by reviewing related literature.Results(1)Case report:The patient,an eight-month-old girl,was admitted to our hospital due to microcephaly and repeated seizures.Another clinical characteristic was mental retardation.Auditory evoked potential detected moderate impairment of the left auditory nerve pathway.WES showed a compound heterozygous variation in the PNKP gene of the proband.Moreover,the pathogenic variation,c.199-10_203delinsTCTGAGGGGT,was inherited from the father,and the likely pathogenic variation,c.1505C>T(p.P502>L),was inherited from the mother,which was both de novo mutations.The compound heterozygous variation in the PNKP gene was considered genetic etiology based on the genetic testing and clinical features.Prenatal diagnosis showed that the second fetus did not inherit the PNKP gene variants from the parents and the couples chose to continue the pregnancy.A girl was born,and her psychomotor development and occipitofrontal size circumference were normal at 13 months old.(2)Literature review:39 MCSZ syndrome cases were retrieved,including the present case and 38 cases from 12 relevant literature.The clinical characteristics were microcephaly(91.7%,33/36),seizures(88.2%,30/34),development delay(96.4%,27/28),hyperactivity(25.6%,9/39),gastroesophageal reflux(10.3%,4/39),and hearing loss(7.7%,3/39).Most patients'first onset of epilepsy was in infancy(96.3%,26/27).Cranial MRI examination showed brain dysplasia in 31 cases(91.2%,31/34).Conclusions When the fetal head circumference is smaller than normal and is progressively reduced combined with postnatal microcephaly,epilepsy,developmental retardation,hyperactivity disorder,gastroesophageal reflux,and hearing loss,MCSZ syndrome should be considered.The prognosis varies widely,and genetic testing facilitates the early diagnosis and genetic counseling of MCSZ syndrome.