Twenty Year Follow up of a Patient with a New De-Novo NLRP3 Mutation (S595G) and CINCA Syndrome

Abstract

We report on a 22-year-old girl with a history of recurrent febrile episodes, chronic arthritis, urticarial rash, and neurological symptoms including right hemiparesis, internal hydrocephalus, mental retardation, progressive deafness, and visual impairment. Treatment starting at age 20 months, including different combinations of immunosuppressive and antiinflammatory drugs such as corticosteroids and anti-TNFα antibody, was unsuccessful. Four years ago, we found a heterozygous S595G mutation in the NLRP3 gene of this patient. This prompted us to introduce anakinra, which resulted in considerable improvement of the patient's complaints.

Zusammenfassung

Die 22-jährige Patientin hat eine Anamnese mit rezidivierenden Fieberschüben, chronischer Arthritis, urtikariellen Exanthemen und neurologischen Symptomen wie rechtsseitige Hemiparese, interner Hydrozephalus, mentale Retardierung, zunehmende Schwerhörigkeit und Sehstörung. Keine der im Alter von 20 Monaten begonnenen und unterschiedlichen immunsuppressiven und antientzündlichen war erfolgreich. Vor vier Jahren fanden wir eine heterozygote S595G Mutation im NLRP3 Gen dieser Patientin. Auf die dann folgende Behandlung mit Anakinra reagierte die Patientin mit einer dramatischen Besserung ihrer Symptome.

Key words

autoinflammation - amyloidosis - urticarial rash - hydrocephalus

Schlüsselwörter

Autoinflammation - Amyloidose - Urtikaria - Hydrozephalus

Literatur

• 1 Aksentijevich I. et al . De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): A new member of the expanding family of pyrin-associated autoinflammatory diseases.  Arthritis Rheum. 2002;  46 3340-3348
• 2 Aksentijevich I. et al . An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.  N Engl J Med. 2009;  360 2426-2437
• 3 Ansell MB. et al . Familial arthropathy with rash, uveitis and mental retardation.  Proc R Soc Med. 1975;  68 584-585
• 4 Brydges SD. et al . Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity.  Immunity. 2009;  30 875-887
• 5 Callejas JL. et al . Anakinra in mutation-negative CINCA syndrome.  Clin Rheumatol. 2007;  26 576-577
• 6 Feldmann J. 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. 2002;  71 198-203
• 7 Hedrich CM. et al . Good response to IL-1beta blockade by anakinra in a 23-year-old CINCA/NOMID patient without mutations in the CIAS1 gene. Cytokine profiles and functional studies.  Scand J Rheumatol. 2008;  37 385-389
• 8 Honey K. Inflammation: Cytokine ignition complex characterized.  Nature Reviews Immunology. 2004;  4 320
• 9 Ilowite NT. Update on biologics in juvenile idiopathic arthritis.  Curr Opin Rheumatol. 2008;  20 613-618
• 10 Joly S. et al . Cutting Edge: Candida albicans Hyphae Formation Triggers Activation of the Nlrp3 Inflammasome.  J Immunol. 2009;  183 (doi 10.4049) 
• 11 Kashiwagi Y. et al . Extreme efficiency of anti-interleukin 1 agent (anakinra) in a Japanese case of CINCA syndrome.  Clin Rheumatol. 2008;  27 277-279
• 12 Li H. et al . Cutting edge: Necrosis activates the NLRP3 inflammasome.  J Immunol. 2009;  183 1528-1532
• 13 Lorber J. Syndrome for diagnosis: dwarfing, persistently open fontanelle; recurrent meningitis; recurrent subdural effusions with temporary alternate-sided hemiplegia; high-tone deafness; visual defect with pseudopapilloedema; slowing intellectual development; recurrent acute polyarthritis; erythema marginatum, splenomegaly and iron-resistant hypochromic anaemia.  Proc R Soc Med. 1973;  66 1070-1071
• 14 Lovell DJ. et al . Interleukin-1 blockade by anakinra improves clinical symptoms in patients with neonatal-onset multisystem inflammatory disease.  Arthritis Rheum. 2005;  52 1283-1286
• 15 Masters SL. et al . Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease.  Annu Rev Immunol. 2009;  27 621-668
• 16 Matsubara T. et al . A severe case of chronic infantile neurologic, cutaneous, articular syndrome treated with biologic agents.  Arthritis Rheum. 2006;  54 2314-2320
• 17 Matsubayashi T. et al . Anakinra therapy for CINCA syndrome with a novel mutation in exon 4 of the CIAS1 gene.  Acta Paediatr. 2006;  95 246-249
• 18 Meng G. et al . A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses.  Immunity. 2009;  30 860-874
• 19 Prieur AM. A recently recognised chronic inflammatory disease of early onset characterised by the triad of rash, central nervous system involvement and arthropathy.  Clin Exp Rheumatol. 2001;  19 103-106
• 20 Prieur AM, Griscelli C. Arthropathy with rash, chronic meningitis, eye lesions, and mental retardation.  J Pediatr. 1981;  99 79-83
• 21 Winterhalter S, Niehues T. TNFalpha-blocking agents or conventional immuno-suppressive drugs in the therapy of children with uveitis? – an evidence based approach.  Klin Padiatr. 2008;  220 342-347
• 22 Yarom A. et al . Infantile multisystem inflammatory disease: A specific syndrome?.  J Pediatr. 1985;  106 390-396

Correspondence