{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T11:56:06Z","timestamp":1790250966049,"version":"4.1.0"},"reference-count":16,"publisher":"American Academy of Pediatrics (AAP)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2004,7,1]]},"abstract":"<jats:p>The clinical features, the underlying CIAS1 mutation, and the results of cytokine analyses are described for a 10-year-old German boy with neonatal-onset multisystem inflammatory disease, whose condition improved with age. Disease onset occurred at 26 months of age with predominantly cutaneous (urticarial rash) and neurologic (headache, chronic meningitis) symptoms including early bilateral optic nerve atrophy, whereas articular manifestations were mild. Sequence analysis of exon 3 of the CIAS1 gene revealed heterozygosity for a novel missense mutation. A T515C transition led to the replacement of isoleucine by threonine at amino acid position 172 (I172T) in a region of cryopyrin flanking the PYRIN and NACHT domains. This mutation was not present in the parents or in 11 controls and therefore was considered to be a de novo mutation. Enzyme-linked immunosorbent assays were performed to determine interleukin-6 and soluble tumor necrosis factor receptor superfamily 1B levels in the patient's serum and cerebrospinal fluid (CSF). Concentrations were highly elevated in the CSF, whereas corresponding serum levels remained low. The strong cytokine activation in the CSF corresponded with the neurologic symptoms. Local activation of intrathecal macrophages may therefore be an important pathogenetic mechanism. CSF cytokine levels decreased to normal under corticosteroid and intrathecal methotrexate therapy. When the boy reached the age of 5.5 years, treatment was stopped, and he has remained relapse-free.<\/jats:p>","DOI":"10.1542\/peds.114.1.e124","type":"journal-article","created":{"date-parts":[[2004,8,14]],"date-time":"2004-08-14T00:53:04Z","timestamp":1092444784000},"page":"e124-e127","source":"Crossref","is-referenced-by-count":22,"title":["A Novel <i>CIAS1<\/i> Mutation and Plasma\/Cerebrospinal Fluid Cytokine Profile in a German Patient With Neonatal-Onset Multisystem Inflammatory Disease Responsive to Methotrexate Therapy"],"prefix":"10.1542","volume":"114","author":[{"given":"Silvia","family":"Stojanov","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases and Immunology, Children's Hospital, University of Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Weiss","sequence":"additional","affiliation":[{"name":"Children's Hospital, City of Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Lohse","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry- Grosshadern, University of Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd H.","family":"Belohradsky","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunology, Children's Hospital, University of Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"417","published-online":{"date-parts":[[2004,7,1]]},"reference":[{"key":"2021121006521062100_R1","doi-asserted-by":"crossref","unstructured":"Hassink SG, Goldsmith DP. Neonatal onset multisystem inflammatory disease. Arthritis Rheum.\u20081983;26:6368\u20136373","DOI":"10.1002\/art.1780260515"},{"key":"2021121006521062100_R2","doi-asserted-by":"crossref","unstructured":"Prieur A-M, Griscelli C, Lampert F, et al. A chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome. A specific entity analysed in 30 patients. Scand J Rheumatol Suppl.\u20081987;66:57\u201368","DOI":"10.3109\/03009748709102523"},{"key":"2021121006521062100_R3","unstructured":"Prieur A-M. A recently recognised chronic inflammatory disease of early onset characterised by the triad of rash, central nervous system involvement and arthropathy. Clin Exp Rheumatol.\u20082001;19:103\u2013106"},{"key":"2021121006521062100_R4","doi-asserted-by":"crossref","unstructured":"Dollfus H, Ha\u0308fner R, Hofmann HM, et al. Chronic infantile neurological cutaneous and articular\/Neonatal onset multisystem inflammatory syndrome. Ocular manifestations in a recently recognized chronic inflammatory disease of childhood. Arch Ophthalmol.\u20082000;118:1386\u20131392","DOI":"10.1001\/archopht.118.10.1386"},{"key":"2021121006521062100_R5","doi-asserted-by":"crossref","unstructured":"Galon J, Aksentijevich I, McDermott MF, O'Shea JJ, Kastner DL. TNFRSF1A mutations and autoinflammatory syndromes. Curr Opin Immunol.\u20082000;12:479\u2013486","DOI":"10.1016\/S0952-7915(00)00124-2"},{"key":"2021121006521062100_R6","doi-asserted-by":"crossref","unstructured":"Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells Syndrome. Nat Genet.\u20082001;29:301\u2013305","DOI":"10.1038\/ng756"},{"key":"2021121006521062100_R7","doi-asserted-by":"crossref","unstructured":"Feldmann J, Prieur A-M, Quartier P, et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet.\u20082002;71:198\u2013203","DOI":"10.1086\/341357"},{"key":"2021121006521062100_R8","doi-asserted-by":"crossref","unstructured":"Aksentijevich I, Nowak M, Mallah M, et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID). Arthritis Rheum.\u20082002;46:3340\u20133348","DOI":"10.1002\/art.10688"},{"key":"2021121006521062100_R9","doi-asserted-by":"crossref","unstructured":"Masumoto J, Taniguchi S, Sagara J. Pyrin N-terminal homology domain- and caspase recruitment domain-dependent oligomerization of ASC. 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