反复发热、前囟隆起、血白细胞异常

Recurrent fever, bulging fontanelle and elevated white blood cell

患儿6月龄起病，以发热、抽搐、前囟隆起为主要临床表现，外周血白细胞、红细胞沉降率、C－反应蛋白显著增高，血、脑脊液均培养出肺炎链球菌，诊断为细菌性脑膜炎、侵袭性肺炎链球菌感染、脓毒症。经过联合、敏感、足量、足疗程抗生素治疗后，仍反复高热，各项炎性指标仍高。考虑存在原发性免疫缺陷病，送医学外显子基因包检查（二代测序），未发现致病性突变。加用激素及诊断性抗结核治疗后体温及炎性指标逐步恢复正常。于1岁1个月时，在维持抗结核治疗及激素减量期间，患儿再次发生肺炎链球菌脑膜炎。重新评估临床特征，发现患儿有毛发稀疏，肤色偏白、出汗少、牙齿发育不佳等外胚层发育不良的表现，结合其反复严重感染的特点，符合少汗型外胚层发育不良伴免疫缺陷病的表型。该病的主要致病基因为NEMO，位于X染色体，在其下游存在一个假基因IKBKGP，与NEMO的3～10号外显子具有99.8%的同源性，在二代测序中假基因可以掩盖NEMO基因同源序列的突变。对NEMO基因进行一代测序，发现该患儿在NEMO基因4号外显子上存在新生错义突变c.505G〉C（p.A169 P），为已报道的少汗型外胚层发育不良伴免疫缺陷病的致病性突变，最终为该患儿的确诊提供了理论依据。

This patient presented with fever, seizure and bulging fontanelle when he was 6-month-old.According to the investigations, white blood cell （WBC）, erythrocyte sedimentation rate （ESR） and C-reactive protein （CRP） increased significantly, and Streptococcus Pneumonia grew in both blood and cerebrospinal fluid （CSF）. He responded to standard antibiotic treatment poorly even it lasted long enough.At the same time, the inflammation seemed to be over-activated, the WBC level was still elevated, high fever continued.Thus they thought of primary immunodeficiency and sent blood sample for gene panel testing （Sanger sequencing） but got negative result.At last, they added steroid together with anti-tuberculosis drug therapy, his temperature as well as the intracranial pressure became better ever since.At the age of 1 year and 1 month, he got another Streptococcus Pneumonia meningitis, while he was still on anti-tuberculosis drug therapy and tapering off steroid.At this time, he presented with coarse hair, hypohidrosis and delayed eruption of teeth, which strongly indicated Anhidrotic Ectodermal Dysplasia with Immunodeficiency （EDA-ID）. NEMO is the most common gene responsible for EDA-ID and locates on X chromosome.It has a pseudogene named IKBKGP which locates downstream of NEMO. IKBKGP and NEMO share 3-10 exons with the homology of 99.8%, which makes it difficult to find out most real mutations within NEMO with Sanger sequencing.Then they performed PCR with the primer starting upstream of the shared exons.Finally, they found out the pathogenic mutation [c.505G〉C（p.A169P）] of NEMO, which has been reported.This finding led us to make the right diagnosis as well as the proper treatment and the prognosis for this patient.