Zegarska Jolanta, Wiesik-Szewczyk Ewa, Hryniewiecka Ewa, Wolska-Kusnierz Beata, Soldacki Dariusz, Kacprzak Magdalena, Sobczynska-Tomaszewska Agnieszka, Czerska Kamila, Siedlecki Pawel, Jahnz-Rozyk Karina, Bernatowska Ewa, Zagozdzon Radoslaw, Paczek Leszek
Department of Immunology, Transplant Medicine and Internal Diseases, Medical University of Warsaw, 59 Nowogrodzka St., 02-006 Warsaw, Poland.
Department of Internal Medicine, Pulmonology, Allergy and Clinical Immunology, Central Clinical Hospital of the Ministry of National Defense, Military Institute of Medicine in Warsaw, 128 Szaserów St., 04-141 Warsaw, Poland.
J Clin Med. 2021 Jan 26;10(3):465. doi: 10.3390/jcm10030465.
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) belongs to systemic autoinflammatory diseases (AIDs). Many of these syndromes are genetically conditioned and can be inherited. Diagnosis relies on clinical symptoms and should be confirmed by genetic testing. One of the most serious complications is AA amyloidosis. We present the diagnostic route of a 33-year-old male with AA amyloidosis and his children, leading to diagnosis of monogenic autoinflammatory syndrome, confirmed by genetic analysis. A novel variant of the in-frame insertion type in one allele of gene was found by whole exome sequencing and confirmed by Sanger sequencing, which allowed a diagnosis of TRAPS. Three-dimensional modeling was used to assess the structural changes introduced into TNFR1 molecule by the insertion. The analysis of the 3D model revealed that accommodation of the 4AA insert induces misalignment of three cysteine bridges (especially the C70-C96 bridge) in the extracellular domain, leading to putatively misfolded and improperly functioning TNFR1. Three of the patient's daughters inherited the same variant of the gene and presented TRAPS symptoms. TRAPS is a very rare disease, but in the presence of suggestive symptoms the genetic diagnostic workout should be undertaken. Early diagnosis followed by appropriate clinical management can prevent irreversible complications.
肿瘤坏死因子受体相关周期性综合征（TRAPS）属于系统性自身炎症性疾病（AIDs）。这些综合征中的许多是由基因决定的，并且可以遗传。诊断依赖于临床症状，应通过基因检测来确诊。最严重的并发症之一是AA淀粉样变性。我们介绍了一名患有AA淀粉样变性的33岁男性及其子女的诊断过程，最终通过基因分析确诊为单基因自身炎症性综合征。通过全外显子测序在一个等位基因中发现了一种新的框内插入型变异，并通过桑格测序得到证实，这使得能够诊断出TRAPS。利用三维建模来评估插入对TNFR1分子引入的结构变化。三维模型分析表明，4个氨基酸插入的容纳导致细胞外结构域中三个半胱氨酸桥（尤其是C70-C96桥）错位，导致TNFR1可能错误折叠且功能异常。患者的三个女儿遗传了相同的基因变异并出现了TRAPS症状。TRAPS是一种非常罕见的疾病，但在出现提示性症状时应进行基因诊断检查。早期诊断并随后进行适当的临床管理可以预防不可逆的并发症。
