Early canakinumab therapy for the sensorineural deafness in a family with Muckle-Wells syndrome due to a novel mutation of NLRP3 gene
Cryopyrin-associated periodic syndrome (CAPS) is one of the autoinflammatory disorders caused by mutations in NLRP3 gene. The over-production of interleukin (IL)-1β induced by NLRP3 gene mutations plays an important role in the pathophysiology of CAPS. We diagnosed 3 patients with CAPS, who were lineal family members having a novel mutation of NLRP3 gene. The objective of this report is to compare the characteristics of symptoms and differences in the therapeutic responses of them, who had the same mutation. In addition, we aimed to examine the usefulness of cytokine measurement for diagnosis or determination of treatment effect of CAPS. A 5-year-old Japanese boy (proband) came to our hospital because of short stature, reached the diagnosis of Muckle-Wells syndrome (MWS) due to a mutation in NLRP3 gene, which had not been reported so far (p.G328E, c.G983A). His mother and grandmother harbored the same mutation of NLRP3. We measured serum concentrations of cytokines in the proband assessed by flow-cytometric bead array. All of them had episodic skin eruptions with conjunctivitis, hearing loss, and arthralgia, but not periodic fever, cold-triggered episodes, and chronic aseptic meningitis. Only the proband had short stature. Canakinumab therapy led to a prompt relief of symptoms and normalized laboratory data in all patients. Audiograms demonstrated an improved hearing level in the proband, but not two others despite of the same mutation. All cytokines did not show any characteristic findings. Sensorineural hearing loss and itchless rash but not serum cytokine profile deserved attention to the diagnosis and treatment start of CAPS. The early intervention of IL-1β blockade may reduce the chance of complete deafness in patients with CAPS.
KeywordsCAPS G328E G983A Hearing loss IL-1β
We thank the patients and their family for their cooperation.
Compliance with ethical standards
- 6.Cuisset L, Jeru I, Dumont B, Fabre A, Cochet E, Le Bozec J, French CAPS Study Group et al (2011) Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France. Ann Rheum Dis 70:495–499CrossRefGoogle Scholar
- 13.Levy R, Gérard L, Kuemmerle-Deschner J, Lachmann HJ, Koné-Paut I, Cantarini L, for PRINTO and Eurofever et al (2015) Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry. Ann Rheum Dis 74:2043–2049CrossRefGoogle Scholar
- 17.Goldbach-Mansky R, Shroff SD, Wilson M, Snyder C, Plehn S, Barham B, Pham TH, Pucino F, Wesley RA, Papadopoulos JH, Weinstein SP, Mellis SJ, Kastner DL (2008) A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 trap) in patients with familial cold autoinflammatory syndrome. Arthritis Rheum 58:2432–2442CrossRefGoogle Scholar
- 18.Rodriguez-Smith J, Lin YC, Tsai WL, Kim H, Montealegre-Sanchez G, Chapelle D et al (2017) Cerebrospinal fluid cytokines correlate with aseptic meningitis and blood-brain barrier function in neonatal-onset multisystem inflammatory disease: central nervous system biomarkers in neonatal-onset multisystem inflammatory disease correlate with central nervous system inflammation. Arthritis Rheum 69:1325–1336CrossRefGoogle Scholar
- 19.Marchetti C, Swartzwelter B, Gamboni F, Neff CP, Richter K, Azam T, Carta S, Tengesdal I, Nemkov T, D’Alessandro A, Henry C, Jones GS, Goodrich SA, St. Laurent JP, Jones TM, Scribner CL, Barrow RB, Altman RD, Skouras DB, Gattorno M, Grau V, Janciauskiene S, Rubartelli A, Joosten LAB, Dinarello CA (2018) OLT1177, a beta-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc Natl Acad Sci U S A 115:E1530–E1539CrossRefGoogle Scholar
- 20.Kuemmerle-Deschner JB, Ozen S, Tyrrell PN, Kone-Paut I, Goldbach-Mansky R, Lachmann H, Blank N, Hoffman HM, Weissbarth-Riedel E, Hugle B, Kallinich T, Gattorno M, Gul A, ter Haar N, Oswald M, Dedeoglu F, Cantarini L, Benseler SM (2017) Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS). Ann Rheum Dis 76:942–947CrossRefGoogle Scholar