一例组织非特异性碱性磷酸酶基因突变所致的围生期致死型低磷酸酶症病例

One patient with perinatal hypophosphatasia due to mutations in the tissue-nonspecific alkaline phosphatase gene

目的对1例围生期致死型(新生儿型)低磷酸酶症(HPP)患者及其父母进行临床分析及基因突变检测,以期能更好地认识该病。方法对l例罕见的围生期致死型低磷酸酶症患者的临床表现、实验室及影像学检查结果进行总结。提取患儿及其亲属外周血基因组DNA,采用针对组织非特异性碱性磷酸酶(ALPL)基因调控区及编码区的特异性引物进行PCR扩增,直接对产物进行测序分析。结果患儿血碱性磷酸酶水平显著降低,血钙增高;骨骼显示骨软骨发育障碍类疾病样改变。ALPL基因测序结果显示患儿为复合杂合突变,同时携带位于第5外显子及第10外显子上c.346G>A(p.A116T)和c.1171C>T(p.R391C)的错义突变。临床表现正常的父亲、母亲为杂合子,分别携带c.346G>A(p.A116T)和c.1171C>T(p.R391C)的错义突变。该家系符合常染色体隐性遗传。结论围生期致死型HPP死亡率很高,骨骼发育异常、高血钙、血清低碱性磷酸酶在其鉴别诊断中非常重要。

Objective To explore the clinical and genetic characteristics of a Chinese baby with perinatal hypophosphatasia(HPP)and his parents for better understanding of the disease.Methods The clinical data of the patient with HPP was carefully collected.The laboratory and radiographic examination data were taken for this baby patient.Sequencing for all the twelve tissue-nonspecific alkaline phosphatase(ALPL)exons and the flanking exon-intron junctions were performed in the proband and his parents with their genomic DNA from peripheral blood.Results The blood level of alkaline phosphatase was decreased in this patient while serum calcium level was increased.His bone revealed chondrodysplasia-like change.Compound heterozygous mutations were found in the proband,with c.346G>A(p.A116T)in exon 5 and c.1171C>T(p.R391C)in exon 10.His father and mother were without clinical manifestation while respectively carried c.346G>A(p.A116T) and c.1171C>T(p.R391C)missense mutations,suggesting an autosomal recessive inheritance in this family.Conclusion Perinatal HPP has a high mortality rate.Skeletal deformities,hypercalcemia,and low level of ALP are important in the differential diagnosis of perinatal HPP.