TCIRG1基因突变致婴儿恶性石骨症1例并文献复习

A case report of infantile malignant osteopetrosis caused by TCIRG1 mutation and literature review

目的探讨婴儿恶性石骨症(IMO)的临床特点、致病基因、治疗及预后。方法总结1例IMO的临床资料,对患儿及其父母行二代高通量基因测序,并行相关文献复习,总结IMO的临床特点及致病基因。结果女,8月龄,因"咳嗽10 d,病程中发热1次"就诊。X线摄片示患儿全身骨骼密度增高,考虑IMO可能,为明确诊断,行高通量测序基因检测,结果显示患儿TCIRG1基因存在无义突变c.1360C>T(p.R454X)和移码缺失c.722delC(p.T241fs),故临床诊断IMO。文献复习共报道IMO 238例,其中国内128例(包括本文1例),国外110例。临床症状包括贫血(65.1%)、肝脾肿大(48.3%)、视力障碍(47.9%)、生长发育迟缓(40%)、血小板下降(26.5%)、合并感染(22.3%)、颅骨异常(17.2%)、低血钙(14.3%)、脑积水(10.5%)和惊厥(5.2%)。77例(国外58例,国内19例)基因测序发现6种致病基因,包括TCIRG1(50.6%)、RANK和RANKL(18.2%)、SNXIO(18.2%)、OSTMl(7.8%)和CNCL7(5.2%),国内报道的19例全部为TCIRG1基因突变。64例行造血干细胞移植,移植后死亡16例。结论 IMO临床症状主要有贫血、肝脾肿大、视力障碍和生长发育迟缓,最常见致病基因为TCIRG1基因。本文发现1例TCIRG1基因新的组合杂合突变所致IMO,丰富了TCIRG1基因突变谱。

Objective To explore the clinical characteristics,pathogenicity gene,treatment and prognosis of infantile malignant osteopetrosis(IMO).Methods The clinical data of one case with IMO was analyzed,and the second-generation high-throughput gene sequencing was applied for the infant and their parents to identify the causative mutation.To summarize the clinical features of the disease and the causative genes,the relevant literature was reviewed.Results The X-ray showed the bone density of the child was increased.The high-throughput gene sequencing showed two compound heterozygous mutations of TCIRG1 gene in the child.One was nonsense mutation c.1360C>T(p.R454X),and the other was frame shift mutation c.722delC(p.T241fs).The clinical diagnosis of IMO was established.A total of 238 cases with IMO were reported up to now,128 cases from China(including one case of this study),and 110 cases abroad.The clinical characteristics were anemia(65.1%),hepatosplenomegaly(48.3%),visual impairment(47.9%),growth retardation(40%),thromboeytopenia(26.5%),infection(22.3%),skull abnormalities(17.2%),hypocalcemia(14.3%),hydrocephalus(10.5%)and seizures(5.2%).Gene sequencing of 77(58 cases from abroad and 19 cases from China)showed six pathogenic genes,including TCIRG1(50.6%),RANK and RANKL(18.2%),SNXIO(18.2%),OSTMl(7.8%)and CNCL7(5.2%),and all 19 cases from China showed TCIRG1 gene mutation.Hematopoietic stem cell transplantation was carried out in 64 cases,however,16 patients died after transplantation.Conclusion Anemia,hepatosplenomegaly and visual impairment are the main clinical symptoms of IMO.TCIRG1 mutation is the leading cause of IMO.We reported an novel heterozygous mutation of TCIRG1 gene causing IMO.Above results may enrich the mutation spectrum of TCIRG1 gene and provide new evidence for the molecular basis of IMO.