First Description of Late‐Onset Autoinflammatory Disease Due to Somatic NLRC4 Mosaicism

Abstract

Objective Autoinflammatory diseases are inherited disorders of innate immunity that usually start during childhood. However, several recent reports have described an increasing number of patients with autoinflammatory disease starting in adulthood. This study was undertaken to investigate the underlying cause of a case of late‐onset uncharacterized autoinflammatory disease. Methods Genetics studies were performed using Sanger sequencing and next‐generation sequencing (NGS) methods. In silico, in vitro, and ex vivo analyses were performed to determine the functional consequences of the detected variant. Results We studied a 57‐year‐old woman who at the age of 47 years began to have recurrent episodes of fever, myalgias, arthralgias, diffuse abdominal pain, diarrhea, adenopathies, and systemic inflammation, which were relatively well controlled with anti–interleukin‐1 (anti‐IL‐1) drugs. NGS analyses did not detect germline variants in any of the known autoinflammatory disease–associated genes, but they identified the p.Ser171Phe NLRC4 variant in unfractionated blood, with an allele fraction (2–4%) compatible with gene mosaicism. Structural modeling analyses suggested that this missense variant might favor the open, active conformation of the NLRC4 protein, and in vitro and ex vivo analyses confirmed its propensity to oligomerize and activate the NLRC4 inflammasome, with subsequent overproduction of IL‐18. Conclusion Our findings indicate that the postzygotic p.Ser171Phe NLRC4 variant is a plausible cause of the disease in the enrolled patient. Functional and structural studies clearly support, for the first time, its gain‐of‐function behavior, consistent with previously reported NLRC4 pathogenic variants. These novel findings should be considered in the diagnostic evaluation of patients with adult‐onset uncharacterized autoinflammatory disease.

Case report: Schnitzler-like syndrome without monoclonal gammopathy

“…However, a genetic analysis failed to establish an association of Schnitzler`s syndrome with germline or somatic mutations in the NLRP3 gene locus except in rare individual cases ( 15 , 18 , 25 – 28 ). Nevertheless, it is probable that Schnitzler’s syndrome is caused by an acquired mutation, like in VEXAS syndrome ( 29 , 30 ), or in acquired Familial Mediterranean Fever ( 31 ) and acquired NLRC4-associated CAPS ( 32 ). Interestingly, a somatic NLRP3 mutation (NLRP3: c.1709A>G (p.Tyr570Cys)) identical to that reported in a Neonatal Onset Multisystem Inflammatory Disease (NOMID, or Chronic Infantile Neurological, Cutaneous and Articular Syndrome, CINCA) case was also found in a patient with a clinical picture closely resembling Schnitzler’s syndrome, and without gammopathy and without bone pain like in our patient ( 22 ).…”

Early‐onset recurrent panniculitis as a phenotype of NLRC4‐associated autoinflammatory syndrome: Characterization of pathogenicity of the p.Ser445ProNLRC4 variant

“…3,5,8,11 The elucidation of the major role of IL-18 in the disease pathogenesis has allowed the application of targeted therapies. 8,15,16 As IL-18 activity is controlled by the endogenous inhibitor IL-18 binding protein (IL-18BP), the administration of the recombinant human IL-18BP (tadekinig alfa) resulted in a very successful response in a patient with refractory AIFEC. 3,16 These promising results have led to different clinical trials in NLRC4-AID using different strategies including rhIL-18BP (NCT03512314 and NCT03113760) or monoclonal antibodies (MAS825; NCT04641442).…”

“…Patients with NLRC4‐AID show variable responses to conventional treatments (NSAIDs, corticosteroids, colchicine, anti‐TNF, anti‐IL‐1 drugs) 3,5,8,11 . The elucidation of the major role of IL‐18 in the disease pathogenesis has allowed the application of targeted therapies 8,15,16 . As IL‐18 activity is controlled by the endogenous inhibitor IL‐18 binding protein (IL‐18BP), the administration of the recombinant human IL‐18BP (tadekinig alfa) resulted in a very successful response in a patient with refractory AIFEC 3,16 .…”

Genetic Approaches to Study Rheumatic Diseases and Its Implications in Clinical Practice

“…46 The reported mutant variant allele fraction (VAF) varies among patients, but in some instances, it can be less than 5% in peripheral blood, which requires different diagnostic approaches from those used for detecting germline variants. 47 Limited data are available on the stability of somatic mutations over time in blood and whether targeted therapies modulate VAF. 48 Notably, the identification of somatic mutations has immediately led to highly effective cytokine-blocking therapies in numerous patients who have not received a CAPS diagnosis for decades.…”