From the Division of Pediatric Rheumatology, Department of Pediatrics, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.
J Clin Rheumatol. 2023 Jun 1;29(4):207-213. doi: 10.1097/RHU.0000000000001953. Epub 2023 Mar 6.
The aim of this study was to investigate the clinical associations of the second allele mutations and the effect of genotype and presenting features on colchicine resistance in children with familial Mediterranean fever (FMF), carrying at least one M694V variant.
The medical records of the patients diagnosed with FMF, in whom at least one allele M694V mutation was detected, were reviewed. Patients were grouped according to the genotype as M694V homozygotes, compound heterozygote M694V with an exon 10 mutation, compound heterozygote M694V with a variant of unknown significance (VUS), and M694V heterozygotes. Disease severity was assessed with the International Severity Scoring System for FMF.
Among the 141 patients included, homozygote M694V (43.3%) was the most frequent MEFV genotype. Clinical manifestations of FMF at diagnosis were not significantly different according to genotypic alterations except homozygote M694V. Besides, homozygous M694V was associated with a more severe disease, with more frequent comorbidities and colchicine-resistant disease. A lower disease severity score was observed in compound heterozygotes with VUS than in M694V heterozygotes (median 1 vs 2, p = 0.006). Regression analysis revealed that homozygous M694V, arthritis, and frequency of attacks were associated with an increased risk of colchicine-resistant disease.
Clinical manifestations of FMF at diagnosis with a M694V allele were predominantly influenced by the M694V rather than the second allele mutations. Although homozygous M694V was associated with the most severe form, the presence of compound heterozygosity with a VUS did not affect disease severity or clinical features. Homozygous M694V confers the highest risk of colchicine-resistant disease.
本研究旨在探讨携带至少一个 M694V 变异的家族性地中海热（FMF）患者中第二等位基因突变的临床关联，以及基因型和表现特征对秋水仙碱耐药的影响。
回顾性分析了诊断为 FMF 的患者的病历，这些患者至少有一个 M694V 等位基因突变。根据基因型将患者分为 M694V 纯合子、M694V 与外显子 10 突变的复合杂合子、M694V 与意义不明的变异（VUS）的复合杂合子和 M694V 杂合子。采用国际 FMF 严重程度评分系统评估疾病严重程度。
在纳入的 141 例患者中，M694V 纯合子（43.3%）是最常见的 MEFV 基因型。除 M694V 纯合子外，FMF 的临床表现在不同基因型改变时无显著差异。此外，M694V 纯合子与更严重的疾病、更多的合并症和秋水仙碱耐药疾病相关。与 M694V 杂合子相比，VUS 复合杂合子的疾病严重程度评分较低（中位数 1 比 2，p=0.006）。回归分析显示，M694V 纯合子、关节炎和发作频率与秋水仙碱耐药疾病的风险增加相关。
M694V 等位基因引起的 FMF 诊断时的临床表现主要受 M694V 而非第二等位基因突变的影响。虽然 M694V 纯合子与最严重的形式相关，但存在 VUS 的复合杂合子并不影响疾病严重程度或临床特征。M694V 纯合子导致秋水仙碱耐药疾病的风险最高。
