中国成人自身炎症性疾病临床和基因型特点:成人自身炎症性疾病单中心报道

Clinical and Genetic Phenotypes of Chinese Patients with Adult Autoinflammatory Diseases:Report from an Adult Reference Center

目的探讨中国汉族成人自身炎症性疾病(autoinflammatory diseases,AUID)的临床特点和基因型。方法2015年4月至2016年5月北京协和医院风湿免疫科成人AUID中心前瞻性纳入拟诊单基因AUID的成人患者(≥16岁),收集其临床资料,并对其进行包含单基因AUID致病基因在内的全基因组二代测序。AUID诊断需结合临床表型和基因型。结果本研究中心1年时间共对37例临床拟诊单基因AUID的成人患者进行了基因检测。其中16例(43.2%)确诊单基因AUID,2例诊断周期性发热-阿弗它口炎-咽炎-淋巴结炎(periodic fever,aphthous stomatitis,pharyngitis and adenitis,PFAPA)综合征。最终,共18例成人AUID患者在本中心获得确诊并随访,其中包括家族性地中海热7例(38.9%),肿瘤坏死因子受体相关周期性综合征2例(11.1%),冷炎素相关周期性综合征3例(16.7%),核苷酸结合寡聚化结构域样受体12(NLR family,pyrindomaincontaining12,NLRP12)自身炎症性疾病(autoinflammatory disease,AD)(NLRP12-AD)3例(16.7%),Blau综合征1例(5.6%)以及PFAPA综合征2例(11.1%)。18例患者中成年起病者15例(83.3%),从起病至最终确诊时间平均长达10年。成人AUID的基因型常常为低外显基因变异,均为杂合突变或复合杂合突变。结论成人AUID并不少见,其中以家族性地中海热、冷炎素相关周期性综合征和NLRP12-AD相对常见。由于成人AUID患者基因型多为低外显基因变异,临床表现轻微或不典型,易导致诊断延误。成人拟诊AUID患者的基因检测结果需慎重解读,建议转诊至成人AUID中心专病门诊。

Objective We aimed to characterize the clinical and genetic phenotypes of Chinese adult patients with AUID. Methods We prospectively evaluated the clinical and genetic features of adult patients （ ≥ 16 years） who were suspected to have monogenic AUID during April 2015 to May 2016, at the adult AUID center, Department of Rheumatology of Peking Union Medical College Hospital. The diagnosis of each disease was confirmed if both clinical phenotypes and genetic confirmation＇criteria were met.Results During the study period, a total of 37 adult patients with suspicious clinical phenotypes mono- genic AUID were tested for a genetic study. The final diagnosis of monogenic AUID was confirmed in 16 patients （43.2% of patients tested）. Two additional patients were diagnosed with periodic fever, aph- thous stomatitis, pharyngitis and adenitis （PFAPA） syndrome. Finally, a total of 18 patients with AUID were diagnosed and were followed in our center, including 7 （38. 9% ） familial Mediterranean fever （ FMF）, 2 （ 11.1% ） tumor necrosis factor-receptor associated periodic syndrome （TRAPS）, 3 （ 16. 7% ） cryopyrin-associated periodic syndrome （ CAPS ）, 3 （ 16. 7% ） NLRP12-autoinflammtory disease （ NL- RP12-AD）, 1 （5.6%）Blau syndrome （BS）, and 2 （11.1%）PFAPA. Disease onset during adulthood was observed in 15 （83.3%） patients, and the final diagnosis was delayed with an average of 10 years. Adult AUID patients usually carried low-penetrance mutations and all gene variants were presented as heter- ozygosis or compound heterozygosis. Conclusion Adult AUID is not uncommon. FMF, CAPS, and NL- RP12-AD are relatively common monogenic AUID in adults. Adult-onset AUID may be related to the pres- ence of low-penetrance mutations, being characterized by nonspecific, incomplete or atypical disease pat- terns, leading to a delay of diagnosis. The interpretation of gene analysis in adult suspected AUID should be performed with caution, and if possible, should be referred to expert physicians in adult AUID center.