title: Early diagnosis of early-onset sarcoidosis: a case report with functional analysis and review of the literature.
abstract: 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.
authors.affiliation: Department of Pediatrics, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto, 390-8621, Japan. takeuchiyu@shinshu-u.ac.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takeuchi
authors.affiliation: Department of Pediatrics, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto, 390-8621, Japan.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Shigemura
authors.affiliation: Department of Pediatrics, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto, 390-8621, Japan.
authors.forename: Norimoto
authors.initials: N
authors.lastname: Kobayashi
authors.affiliation: Department of Pathology, Ehime University Proteo-Science Center and Graduate School of Medicine, Ehime, Japan.
authors.forename: Naoe
authors.initials: N
authors.lastname: Kaneko
authors.affiliation: Department of Pathology, Ehime University Proteo-Science Center and Graduate School of Medicine, Ehime, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Iwasaki
authors.affiliation: Nagano Children's Hospital, Azumino, Japan.
authors.forename: Kisei
authors.initials: K
authors.lastname: Minami
authors.affiliation: Department of Infection and Host Defense, Graduate School of Medicine, Shinshu University, Matsumoto, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Pathology, Ehime University Proteo-Science Center and Graduate School of Medicine, Ehime, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Masumoto
authors.affiliation: Department of Infection and Host Defense, Graduate School of Medicine, Shinshu University, Matsumoto, Japan.
authors.forename: Kazunaga
authors.initials: K
authors.lastname: Agematsu
mesh_terms: D001168:Arthritis; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D007223:Infant; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000378:metabolism; D012507:Sarcoidosis / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D012867:Skin / Q000473:pathology*; D013585:Synovitis; D014605:Uveitis; D056660:Hereditary Autoinflammatory Diseases
chemical_list: D015415:Biomarkers; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D004247:DNA
keywords: Early-onset sarcoidosis; IL-1β; NF-κB activation; NOD2/CARD15