八例先天性角化不良伴骨髓衰竭患儿的临床特征及基因分析

Clinical and genetic features of dyskeratosis congenital with bone marrow failure in eight patients

目的加深对先天性角化不良（dyskeratosis congenital，DC）伴骨髓衰竭的认识。方法收集2010年9月30日至2015年9月30日8例伴骨髓衰竭DC患儿的临床资料，利用二代测序技术对DKC1、TERC、TERT、NOP10、NHP2、TINF2等16种端粒相关基因进行全外显子及剪接位点测序分析。结果8例DC患儿中男6例、女2例，中位发病月龄为42（15-60）个月。初诊血常规：中位WBC 3.99 （1.26-5.44）×109/L，中位中性粒细胞计数1.11（0.38-2.15）×109/L，中位RBC 2.45（0.37-3.56）×1012/L，中位HGB 82.5（15-127） g/L，中位PLT 27 （2-112）×109/L。8例患儿中6例骨髓增生减低或重度减低。3例患儿检出DKC1基因突变：c.961C〉A 1例，c.1058C〉T 2例；4例患儿检出TINF2基因突变：c.849delC、 c.844C〉T、c.811C〉T、c.862T〉A合并c.871delA各1例；1例患儿检出TINF2基因突变（c.848C〉A）合并TERT基因突变（c.1138C〉T）。其中DKC c.961C〉A、TINF2 c.849delC、TINF2 c.871delA突变为首次报道。7例患儿口服雄激素治疗，其中5例血常规指标改善。1例患儿死于重症感染，其余7例患儿维持治疗。结论DC伴骨髓衰竭以TINF2突变和DKC1突变为主。雄激素治疗对部分病例有效。

ObjectiveTo summary clinical and genetic features of childhood dyskeratosis congenital （DC） patients with bone marrow failure.MethodsThe clinical data of 8 DC patients with bone marrow failure diagnosed between September 2010 and September 2015 were collected. Whole exons with flanking regions of the 16 telomere-related genes, including DKC1, TERC, TERT, NOP10, NHP2, TINF2 and so on, were analyzed by next generation sequence.ResultsSix males and two females were included, with a median age of 42（15-60） months. The median blood cell count at onset were as follow： WBC 3.99 （1.26-5.44） × 109/L, ANC 1.11 （0.38-2.15） × 109/L, RBC 2.45 （0.37-3.56） × 1012/L, HGB 82.5（15-127） g/L, PLT 27 （2-112） ×109/L. Hypoplastic or marked hypoplastic bone marrow were seen in 6 patients. DKC1 mutiaton were indentified in 3 patients： one c.961C〉A mutation, and two c.1058C〉T mutation. TINF2 mutations were identified in 4 patients： c.849delC, c.844C〉T, c.811C〉T, c.862T〉A combined c.871delA. One patient had TINF2 mutation c.848C〉A combined TERT mutation c.1138C〉T. DKC1 c.961C〉A mutation, TINF2 c.849delC mutation and TINF2 c.871delA mutaion were not reported so far. 5 of 7 patients got better after androgen administration. During follow-up, one patient died of serious infection, the other seven patients continued the treatment.ConclusionsTINF2 and DKC1 mutations were the main genetic phenotypes in childhood DC with marrow failure patients. Androgen is effetive in some cases.