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This is a Case Report study (also classified as: In Vitro Study).

August 25, 2025Open Access

Adult onset cryopyrin-associated periodic syndrome due to germline missense mutation in NLRP3 in a previously healthy middle-aged woman

SCSinyoung ChoSeoul National University SKSheehyun KimSeoul National University Hospital JKJu Yeon KimJaseng Hospital of Korean Medicine

Key Points

A 47-year-old woman experienced recurrent symptoms, linked to a missense mutation in the NLRP3 gene.
Genetic analysis identified a heterozygous mutation that elevated interleukin-1β and tumor necrosis factor α levels.
Whole-exome sequencing enabled the discovery of the mutation causing her adult-onset cryopyrin-associated periodic syndrome.
Treatment with anakinra successfully reduced symptoms and normalized cytokine production during inflammation.

Abstract

Background Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory disease caused by a gain-of-function mutation in the NLRP3 gene, which regulates inflammasome-mediated interleukin-1β (IL-1β) production. This leads to recurrent episodes of fever, rash, and arthritis, typically beginning in childhood. Objective To demonstrate the role of a missense mutation, c. 386AG, in NLRP3 in adult-onset CAPS in a previously healthy middle-aged woman. Methods Whole-exome sequencing was performed. Serum levels of IL-1β, interleukin-1 receptor antagonist (IL-1RA), and tumor necrosis factor α (TNF-α) were measured. CD14-positive monocytes, isolated from the patient before and during IL-1 inhibition therapy, were stimulated with lipopolysaccharide (LPS), and cytokine production was assessed. Results A 47-year-old woman presented with recurrent periorbital swelling and inflammatory symptoms, along with elevated IL-1RA and IL-6 levels. Genetic analysis revealed a heterozygous missense mutation in the NLRP3 gene (NM₀01243133, c. 386AG, p. Lys129Arg). Serum IL-1RA levels were significantly elevated during active disease. Monocytes from the patient produced high levels of IL-1β and TNF-α upon LPS stimulation. Treatment with anakinra ameliorated all symptoms and normalized inflammatory cytokine overproduction in the monocytes. Conclusion We report a case of adult-onset CAPS in a previously healthy woman, caused by a missense mutation (c. 386AG) in the NLRP3 gene, who exhibited a remarkable response to anakinra treatment. Autoinflammatory diseases should be considered in patients presenting with fever, skin rashes, and systemic symptoms, regardless of age.

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