Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.
Ann Rheum Dis. 2013 Mar;72(3):410-3. doi: 10.1136/annrheumdis-2012-201818. Epub 2012 Oct 20.
Majeed syndrome is an autosomal recessive disorder characterised by the triad of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anaemia and a neutrophilic dermatosis that is caused by mutations in LPIN2. Long-term outcome is poor. This is the first report detailing the treatment of Majeed syndrome with biological agents and demonstrates clinical improvement with IL-1blockade.
We describe the clinical presentation, genetic analysis, cytokine profiles and response to biological therapy in two brothers with Majeed syndrome.
Both boys were homozygous for a novel 2-base pair deletion in LPIN2 (c.1312_1313delCT; p.Leu438fs+16X), confirming the diagnosis. Their bone disease and anaemia were refractory to treatment with corticosteroids. Both siblings had elevated proinflammatory cytokines in their serum, including tumour necrosis factor α (TNF-α), however a trial of the TNF inhibitor etanercept resulted in no improvement. IL-1 inhibition with either a recombinant IL-1 receptor antagonist (anakinra) or an anti-IL-1β antibody (canakinumab) resulted in dramatic clinical and laboratory improvement.
The differential response to treatment with TNF-α or IL-1 blocking agents sheds light into disease pathogenesis; it supports the hypothesis that Majeed syndrome is an IL-1β dependent autoinflammatory disorder, and further underscores the importance of IL-1 in sterile bone inflammation.
Majeed 综合征是一种常染色体隐性遗传病，其特征为三联征，即慢性复发性多灶性骨炎、先天性红细胞生成异常性贫血和中性粒细胞皮肤病，其病因是 LPIN2 基因突变。长期预后较差。这是首例详细报告 Majeed 综合征采用生物制剂治疗的病例，并证明 IL-1 阻断治疗具有临床改善作用。
我们描述了两例 Majeed 综合征兄弟的临床表现、基因分析、细胞因子谱和对生物治疗的反应。
两个男孩均为 LPIN2 中 2 个碱基缺失的纯合子（c.1312_1313delCT；p.Leu438fs+16X），从而确诊。他们的骨骼疾病和贫血对皮质类固醇治疗有抗药性。两个兄弟的血清中均存在升高的促炎细胞因子，包括肿瘤坏死因子-α（TNF-α），然而 TNF 抑制剂依那西普的试验并未改善病情。用重组 IL-1 受体拮抗剂（anakinra）或抗 IL-1β 抗体（canakinumab）进行 IL-1 抑制治疗，可显著改善临床和实验室指标。
对 TNF-α或 IL-1 阻断剂治疗的不同反应揭示了发病机制；这支持了 Majeed 综合征是一种依赖于 IL-1β的自身炎症性疾病的假说，并进一步强调了 IL-1 在无菌性骨炎症中的重要性。
