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

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.386A>G, 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 (NM_001243133, c.386A>G, 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.386A>G) 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.

Keywords: IL-1β; adult onset; anakinra; autoinflammatory diseases; cryopyrin-associated periodic syndrome (CAPS); mutation.

Figure 1

Recurrent periorbital swelling. (A) Recurrent and alternating swelling of the patient’s eyelids. (B) CT image of the orbital area showing soft tissue infiltration in the preseptal region, lacrimal gland, and left orbit (arrow). (C) Lacrimal gland biopsy showing multifocal lymphoplasmacytic infiltration (upper panel) and a few IgG4-positive cells (lower panel). (D) Temperature graph showing the patient’s fever pattern during the first 5 days of admission. (E) Maculopapular eruption. (F) PET scan showing increased metabolic activity in lymph nodes and spleen (arrows).

Figure 2

C-reactive protein levels in response to treatment. (A) C-reactive protein (CRP) levels over the first 6 months of treatment. (B) CRP changes with and without anakinra. ANA, anakinra; CRP, C-reactive protein; CS, corticosteroids; MTX, methotrexate; TAC, tacrolimus.

Figure 3

Genetic analysis. (A) Whole-exome sequencing identified a non-synonymous single-nucleotide variant in the NLRP3 gene. The variant was detected in 41 sequencing reads, with a variant allele frequency of 45.6%. (B) The NLRP3 variant results in the substitution of the 129th amino acid from lysine (K) to arginine (R) in exon 3 of transcript NM_001243133. The UCSC Genome Browser (https://genome.ucsc.edu/) was used to visualize the variant.

Figure 4

Elevated proinflammatory cytokine levels and hyperinflammatory response upon stimulation. (A) Cytokine concentrations in the plasma of healthy controls (n = 3) and the patient, before and after anakinra treatment, measured using ELISA. The dotted line represents the detection limit. (B) Purified CD14⁺ monocytes were stimulated with lipopolysaccharide (LPS, 10 ng/mL) for 24 h, and cytokine levels in the supernatant were quantified by ELISA. LPS, lipopolysaccharide; ND, not detected; Pt, patient.