PDF(Pubmed)
Abstract：
Familial Mediterranean fever (FMF) is a hereditary, autoinflammatory disease that causes recurrent fever, arthritis, and serositis. The diagnosis of FMF is based on the presentation of typical clinical symptoms and the Mediterranean fever gene (MEFV) test. However, the challenge lies in diagnosing atypical cases. In this report, we have described a pediatric patient with complex FMF whose diagnosis required trio-whole exome sequencing (WES) and functional validation of a rare MEFV variant. A 3-year-old boy presented with recurrent episodes of elevated liver enzymes and arthralgia. He was diagnosed with autoimmune hepatitis (AIH), and his liver enzymes improved rapidly with steroid treatment. However, he exhibited recurrent arthralgia and severe abdominal attacks. Trio-WES identified compound heterozygous mutations in MEFV (V726A and I692del). Ex vivo functional assays of the patient\'s monocytes and macrophages, which had been pre-treated with Clostridium difficile toxin A (TcdA) and colchicine, were comparable to those of typical FMF patients, thereby confirming the diagnosis of FMF. Although he was intolerant to colchicine because of liver toxicity, subsequent administration of canakinumab successfully ameliorated his abdominal attacks. However, it was ineffective against liver injury, which recurred after steroid tapering. Therefore, in this case, the pathogenesis of AIH was probably interleukin-1β (IL-1β)-independent. In fact, AIH might have been a concurrent disease with FMF, rather than being one of its complications. Nevertheless, further studies are necessary to determine whether FMF-induced inflammasome activation contributes to AIH development. Moreover, we must consider the possibility of mixed phenotypes in such atypical patients who present distinct pathologies simultaneously.
摘要：
家族性地中海热（FMF）是一种遗传性，引起反复发热的自身炎症性疾病，关节炎,和浆膜炎。FMF的诊断基于典型临床症状的表现和地中海热基因（MEFV）测试。然而,挑战在于诊断非典型病例。在这份报告中,我们描述了1例复杂FMF的儿科患者,其诊断需要三全外显子组测序(WES)和一个罕见MEFV变异体的功能验证.一个3岁男孩反复出现肝酶升高和关节痛。他被诊断为自身免疫性肝炎(AIH),他的肝酶通过类固醇治疗迅速改善。然而,他表现出复发性关节痛和严重的腹部发作。Trio-WES鉴定了MEFV(V726A和I692del)中的复合杂合突变。患者单核细胞和巨噬细胞的离体功能测定，用艰难梭菌毒素A（TcdA）和秋水仙碱预处理，与典型的FMF患者相当，从而确认FMF的诊断。尽管由于肝毒性他对秋水仙碱不耐受，随后服用canakinumab成功缓解了他的腹部发作.然而,它对肝损伤无效，类固醇逐渐减少后复发。因此,在这种情况下,AIH的发病机制可能与白细胞介素-1β（IL-1β）无关。事实上,AIH可能是FMF的并发疾病，而不是它的并发症之一。然而，需要进一步的研究来确定FMF诱导的炎性小体激活是否有助于AIH的发展。此外，我们必须考虑在这些同时呈现不同病理的非典型患者中混合表型的可能性。
