FOXP3基因突变致X连锁多内分泌腺病肠病伴免疫失调综合征二例

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome in two cases

目的分析两例X连锁多内分泌腺病肠病伴免疫失调综合征（immune dysregulation，polyendocrinopathy，enteropathy，X-linked，IPEX综合征）患儿的临床特点及FOXP3基因的突变类型。方法收集患儿的临床资料，抽提患儿及其父母的外周血DNA，对FOXP3基因进行测序，对新发现的突变位点以100名无亲缘关系的健康儿童为对照进行验证，并用生物信息学软件对突变的进行功能预测。结果两例患儿均于新生儿期起病，表现为高血糖、腹泻、湿疹、营养不良，反复感染致症状加重，其家长放弃治疗。两例患儿分别于6月龄和2月龄死亡。患儿1基因检测结果示FOXP3基因存在第9内含子C．967＋3A〉T剪切突变（患儿为半合子，母亲为杂合子，父亲为野生型），该突变既往未见报道。患儿2基因检测结果提示FOXP3基因第11外显子C．1150G〉A错义突变（患儿为半合子，母亲携带杂合错义突变，父亲为野生型）。对100名对照进行FOXP3基因C．967＋3A〉T剪切位点测序，未发现相同的突变。HumanSplicingFinder软件预测c．967＋3A〉T可影响mRNA的剪接，从而影响蛋白质的功能。结论两例患儿均有较为典型IPEX综合征的临床表现，且经基因分析明确了诊断。IPEX综合征起病早，临床表现多样，死亡率高。对于新生儿糖尿病的患儿，建议尽早进行基因检测，以明确诊断。

Objective To report on two cases affected with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome （IPEX）. Methods Two unrelated Chinese infants affected with IPEX were investigated. Case 1 was a 4-month-old boy with neonatal diabetes and severe enteropathy. Case 2 was a 6-day newborn boy with neonatal diabetes and ketoacidosis. DNA samples of the two infants and their parents were sequenced for FOXP3 gene mutations. Suspected mutations were verified among 100 unrelated healthy controls. The function of mutations was predicted with bioinformatics software. Results Both infants had onset of the disease during neonatal period, and manifested insulin- dependent diabetes mellitus, persistent diarrhea, eczema and malnutrition. In case 1, a novel splice site mutation was identified in intron 9 （c. 967＋3A〉T） of the FOXP3 gene, for which his mother was a carrier. For case 2, a missense mutation （c. 1150G〉A） was detected in exon 11 of the FOXP3 gene, for whieh his mother was also a carrier. The IVS9 c. 967＋3A mutation was not detected among the 100 healthy controls. As predicted with Human Splicing Finder software, the c. 967＋3A〉T mutation may influence the splicing of mRNA and affect the function of protein. Conclusion Both cases had typical clinical manifestation of the IPEX syndrome, among whom a novel splice site mutation （IVS9 c. 967＋3A〉T） and a missense mutation （c. 1150G〉A） of the FOXP3 gene were identified. The clinical manifestation of the IPEX syndrome may be variable and the mortality is high. FOXP3 gene sequencing is recommended when insulin-dependent diabetes mellitus is diagnosed during the neonatal period.