NLR family pyrin domain containing 3 (NLRP3)-associated autoinflammatory disease (NLRP3-AID), formerly known as cryopyrin-associated periodic syndrome, is a group of AIDs comprising neonatal-onset multisystem inflammatory disorder, Muckle-Wells syndrome, and familial cold autoinflammatory syndrome. Mutations in the NLRP3 gene are considered central to its pathogenesis. Here, we present a Chinese infant diagnosed with severe NLRP3-AID who carried a heterozygous variant in the NLRP3 gene. The patient exhibited recurrent episodes of fever, urticaria-like rashes, aseptic meningitis, and hearing loss. During hospitalization, elevated inflammatory markers and leukocytosis in body fluids were observed without evidence of infection. DNA sequencing identified a de novo heterozygous mutation, c.1006A > G (p.I336V), in the NLRP3 gene. We report an infant with NLRP3-AID and emphasize the importance of early diagnosis based on clinical manifestations.

The NLR family pyrin domain containing 3-associated autoinflammatory disease (NLRP3-AID) is a rare and heterogeneous hereditary inflammatory disorder caused by variants in the NLRP3 gene on chromosome 1q44. This condition encompasses a broad spectrum of clinical phenotypes, including urticarial rash, fever, ocular disorders, hearing loss, and musculoskeletal and central nervous system (CNS) involvement. This study reports the clinical features and newly identified NLRP3 gene variants in two Chinese Han patients with NLRP3-AID presenting with leukoencephalopathy. The study includes two adult male patients aged 25 and 24 years. Both patients experienced recurrent fevers with elevated C-reactive protein levels during febrile episodes, which normalized during asymptomatic intervals. Elevated cerebrospinal fluid protein levels and magnetic resonance imaging (MRI) findings of intracranial calcification and white matter damage were observed in both cases. Genetic testing revealed novel heterozygous NLRP3 variants: p.L798M in Patient 1 and p.K829T in Patient 2. Both patients received treatment with adalimumab and canakinumab, resulting in significant clinical improvement. The clinical and genetic features of two NLRP3-AID patients were characterized. Functional studies demonstrated overactivation of the NLRP3 inflammasome in these patients. Neurological involvement in NLRP3-AID patients is variable. This study expands the clinical spectrum of CNS damage in NLRP3-AID to include intracranial calcification and leukoencephalopathy. Additionally, two novel NLRP3 variants, L798M and K829T, were identified and associated with the disease.

To investigate the optic disc changes (ODC) in Chinese patients with NLRP3-associated autoinflammatory disease (NLRP3-AID). Patients who were diagnosed with NLRP3-AID at the Department of Rheumatology, Peking Union Medical College Hospital between April 2015 and December 2022 were retrospectively reviewed and analyzed. A total of 20 patients were enrolled in this retrospective study. All 20 patients had a moderate MWS NLRP3-AID phenotype. Thirteen patients (65%) had ocular involvements. The interval between symptoms onset and diagnosis was significantly longer in patients with ocular involvement than in patients without (p = 0.044). The incidence of hearing loss was significantly higher in patients with ocular involvement (p = 0.017), while the incidence of abdominal pain was significantly lower when compared to patients without ocular involvement (p = 0.007). Optic disc swelling (ODS) (50%) was the most common ODC. All of the four T348M mutation carriers within our cohort exhibited ODS with visual-field defects. There was a significant difference between patients with/without ODS regarding the number of patients carrying T348M mutation (p = 0.014). The occurrence of hearing loss and CNS involvement was significantly higher in the group with ODS compared to the group without (p = 0.0014, p = 0.0198). Of the eight patients who underwent lumbar puncture, five presented with intracranial hypertension (IH). ODS was observed in all patients with IH. The serum inflammatory markers were significantly higher in patients with ODS than in those without. Two patients receiving regular subcutaneous IL-1 inhibitor treatment showed improvements in ODC. ODC is common among Chinese patients with NLRP3-AID, with ODS being the most common manifestation. Hearing loss and CNS involvement often accompany the occurrence of ODS. The serum inflammatory markers are associated with ODS. The T348M mutation is more likely to lead to ODC with visual-field defects.

NLRP3-associated autoinflammatory disease is a heterogenous group of monogenic conditions caused by NLRP3 gain-of-function mutations. The poor functional characterization of most NLRP3 variants hinders diagnosis despite efficient anti-IL-1 treatments. Additionally, while NLRP3 is controlled by priming and activation signals, gain-of-functions have only been investigated in response to priming. Here, we characterize 34 NLRP3 variants in vitro, evaluating their activity upon induction, priming, and/or activation signals, and their sensitivity to four inhibitors. We highlight the functional diversity of the gain-of-function mutants and describe four groups based on the signals governing their activation, correlating partly with the symptom severity. We identify a new group of NLRP3 mutants responding to the activation signal without priming, associated with frequent misdiagnoses. Our results identify key NLRP3 residues controlling inflammasome activity and sensitivity to inhibitors, and antagonistic mechanisms with broader efficacy for therapeutic strategies. They provide new insights into NLRP3 activation, an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and drug development.

NLRP3-associated autoinflammatory disease (NLRP3-AID) is characterized by gain-of-function variants in the NLRP3 gene. Since there are little literature focusing on pediatric NLRP3-AID in China, we aimed to elucidate the phenotypic and genotypic profiles of Chinese patients with NLRP3-AID. Patients with NLRP3-AID at three rheumatology centers in China were genotyped through whole exome sequencing or gene panel sequencing. Sanger sequencing was performed on all patients and their parents. Clinical phenotype, treatment, and prognosis were analyzed. Nine patients with NLRP3-AID were enrolled between December 2014 and October 2022 with an average follow-up period exceeding 30 months. The median age of onset was 12 months, and 66.7% were younger than 3 years old. The diagnosis was significantly delayed and the median delay duration was 115 months. The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%). During acute attack, white blood cell, C-reactive protein, and/or erythrocyte sedimentation rate all increased in all cases, and inflammatory markers remained elevated beyond 7 days postfever resolution in 57.1% of patients (4/7). Two cases of chronic infantile neurological cutaneous articular syndrome (CINCA) had clubbed fingers, one with interstitial lung disease, a finding rarely reported. Treatment with glucocorticoids (77.8%) and biologic agents (33.3%) yielded 66% complete remission and 33% partial remission. Genetic analysis identified eight pathogenic NLRP3 missense mutations, including one novel mutation. Our study illuminated the distinct clinical and genetic features of Chinese NLRP3-AID patients, emphasizing the significance of early genetic screening. Despite delayed diagnosis, treatment primarily with glucocorticoids and biologic agents, led to favorable outcomes. Genetic heterogeneity, including a novel mutation, highlighted the complexity of NLRP3-AID in this population.