Takeuchi Yusuke, Shigemura Tomonari, Kobayashi Norimoto, Kaneko Naoe, Iwasaki Tomoyuki, Minami Kisei, Kobayashi Keiko, Masumoto Junya, Agematsu Kazunaga
Department of Pediatrics, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto, 390-8621, Japan.
Department of Pathology, Ehime University Proteo-Science Center and Graduate School of Medicine, Ehime, Japan.
Clin Rheumatol. 2017 May;36(5):1189-1196. doi: 10.1007/s10067-017-3544-6. Epub 2017 Jan 27.
This study examined the pathogenesis of early-onset sarcoidosis (EOS) in a patient with a rare NOD2 mutation and surveyed the literature to identify the hallmark features for early diagnosis. An infant girl suffering from prolonged fever and skin rash of multiple pinkish papules and subsequent erythema nodosum was referred to our institution. Skin biopsy and DNA sequencing were performed along with cytokine profiling of the patient's serum and stimulated mononuclear cells. NF-κB activation was analyzed using transfected cells. Multiple non-caseating granuloma inclusions were recognized in biopsy specimens obtained from the patient's rash. DNA sequencing revealed a very rare heterozygous Met513Thr (M513T) mutation in NOD2. Mononuclear cells produced a low amount of IL-1β upon stimulation as compared with normal control cells. Mutated NOD2 transfection enhanced NF-κB activation. We suspected that the M513T mutation in NOD2 decreased IL-1β production and enhanced NF-κB activation, which was likely responsible for the patient's granuloma involvement. A comprehensive review of the literature on 30 cases of sporadic type of EOS revealed that all patients had cutaneous manifestations, with all but one displaying granulation. A majority of EOS patients have R334W/Q. But about half of sporadic EOS had NOD2 mutations other than R334W/Q, as in the present case. Accordingly, skin rash with granuloma formation and specific NOD2 mutations may represent early diagnostic hallmarks of EOS in infants with persistent inflammation.
本研究检测了一名患有罕见NOD2突变的早发型结节病（EOS）患者的发病机制，并查阅文献以确定早期诊断的标志性特征。一名患有持续发热和多处粉红色丘疹及随后结节性红斑皮疹的女婴被转诊至我院。进行了皮肤活检和DNA测序，并对患者血清和刺激后的单核细胞进行了细胞因子分析。使用转染细胞分析NF-κB激活情况。在从患者皮疹处获取的活检标本中发现了多个非干酪样肉芽肿包涵体。DNA测序显示NOD2存在一种非常罕见的杂合Met513Thr（M513T）突变。与正常对照细胞相比，单核细胞在刺激后产生的IL-1β量较低。突变的NOD2转染增强了NF-κB激活。我们怀疑NOD2中的M513T突变降低了IL-1β的产生并增强了NF-κB激活，这可能是导致患者肉芽肿病变的原因。对30例散发性EOS病例的文献进行全面综述发现，所有患者均有皮肤表现，除1例外在所有患者中均出现肉芽组织。大多数EOS患者有R334W/Q突变。但约一半的散发性EOS患者有R334W/Q以外其他的NOD2突变，如本病例。因此，伴有肉芽肿形成的皮疹和特定NOD2突变可能代表持续性炎症婴儿EOS的早期诊断标志。
