Early diagnosis of early-onset sarcoidosis: a case report with functional analysis and review of the literature
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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.
KeywordEarly-onset sarcoidosis IL-1β NF-κB activation NOD2/CARD15
We express our sincere appreciation to the doctors in the Department of Dermatology at Shinshu University Hospital for skin biopsy procedures and Dr. S. Ohara for performing DNA sequencing.
Compliance with ethical standards
This genetic analysis was approved by the institutional review board of Shinshu University and performed in accordance with the ethical tenets set forth in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from the patient’s parents for publication of this case report and its accompanying images.
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