周期性发热-阿弗他口炎-咽炎-淋巴结炎11例临床表型及基因特点分析

Clinical and genetic analysis of 11 cases with periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome

目的探讨周期性发热-阿弗他口炎-咽炎-淋巴结炎（PFAPA）患儿的临床特征、血浆细胞因子变化及基因变异特点。方法回顾性分析2015年6月至2017年5月深圳市儿童医院诊断的11例PFAPA患儿的临床资料及基因变异特点，选择15名健康体检的儿童为健康对照组，检测患儿及健康对照组血浆细胞因子白细胞介素（IL）1β、IL-6、IL-17、肿瘤坏死因子α （TNF-α）、γ干扰素（IFN-γ）、粒细胞集落刺激因子（G-CSF），比较患儿发热期与发热间歇期外周血炎症指标[白细胞（WBC）、C反应蛋白（CRP）、血浆淀粉样蛋白（SAA）]及发热期、间歇期与健康对照组血浆细胞因子，组间比较采用t检验；患儿及父母外周血行免疫基因组外显子检测。结果11例患儿中男7例，女4例，中位起病年龄24（3-60）月龄，中位诊断年龄69（11-151）月龄，中位发热时长4（1-8）d，发热间歇期1-8周。11例患儿均有周期性发热及咽炎或扁桃体炎，7例有淋巴结炎，5例有口腔溃疡。发热期与间歇期外周血炎症指标： WBC[（14.7±4.1）×109/L比（8.4±1.9）×109/L,t=4.645,P〈0.001]，CRP[（24.2±21.1）比（3.3±2.1）mg/L,t=3.286,P=0.040]，SAA[（136.4±47.7）比（7.1±1.1）mg/L,t=7.172,P〈0.001]，组间比较差异均有统计学意义。血浆细胞因子检测显示，发热期分别与发热间歇期、健康对照组两两比较，IL-6[（38±10）比（8±4）、（8±5）ng/L，t=6.514、6.830]、IFN-γ[（132±43）比（49±21）、（53±21）ng/L, t=4.069、4.276]、G-CSF[（403±12）比（175±90）、（121±49）ng/L, t=4.219、9.047]升高，差异有统计学意义（P均〈0.05）。免疫基因组外显子测序显示8例PFAPA患儿存在MEFV基因杂合变异。结论PFAPA临床特征包括周期性发热、咽炎或扁桃体炎、阿弗他口炎及淋巴结炎，当患儿表现为周期性发热伴上述临床症状时需警惕PFAPA，基因测序分析、外周血炎症指标及细胞因子检测有助于诊断此病。

ObjectiveTo investigate the clinical, inflammatory and genetic characteristics of cases with periodic fever, aphthous stomatitis, pharyngitis and adenitis （PFAPA） syndrome.MethodsClinical and inflammatory manifestations and gene sequencing of 11 cases with PFAPA were retrospectively analyzed. Inflammatory markers including white blood cell （WBC） , C reactive protein （CRP） , and serum amyloid A （SAA） were compared between febrile period and intermittent period. Fifteen normal children were taken as healthy controls. The levels of plasma inflammatory cytokines including interleukin（IL）1β, IL-6, IL-17, tumor necrosis factor（TNF）-α, interferon （IFN）-γ, and granulocyte-colony stimulating factor（G-CSF） were compared between febrile period and intermittent period with paired-sample t test, and compared between febrile cases and healthy controls with independent t test.ResultsA total of 11 cases （7 females and 4 males） were included. The median onset age was 24 （3-60） months, and the median age of diagnosis was 69 （11-151） months. The median febrile duration was 4 （1-8） days, and the intermittent period lasted 1 to 8 weeks. All the cases had periodic fever and pharyngitis/tonsillitis, 7 of whom had combined lymphadenitis, and 5 of whom suffered from oral ulcers. Compared to intermittent-period-status,WBC （（14.7±4.1） ×109/L vs. （8.4±1.9） ×109/L, P〈0.05）, CRP（（24.2±21.1） vs. （3.3±2.1）mg/L, P〈0.05）, SAA （（136.4±47.7） vs. （7.1±1.1）mg/L, P〈0.05） were significantly elevated in febrile period. Compared to intermittent-period-status and healthy controls, plasma levels of IL-6 （（38±10） vs. （8±4） and （8±5）ng/L, t=6.514 and 6.830 respectively, P〈0.05）, IFN-γ （（132±43） vs.（49±21） and （53±21）ng/L, t=4.069 and 4.276 respectively, P〈0.05）, G-CSF （（403±12） vs. （175±90） and （121±49）ng/L, t=4.219 and 9.047 respectively, P〈0.05） were significantly higher in febrile period, while no differences were found in levels of IL-1β, IL-17 and TNF-α. Gene sequencing found MEFV gene heterozygous variation in 8 cases.ConclusionsPFAPA often manifests as periodic fever, pharyngitis, tonsillitis, aphthous stomatitis and adenitis. Gene sequencing analysis, detection of inflammation markers and cytokines could help with the diagnose of this disease.