The Broad Clinical Heterogeneity of TRNT1-Related Autoinflammatory Syndrome: A Comprehensive Review

Mutations in the tRNA Nucleotidyl Transferase 1 (TRNT1) gene have been associated with a systemic autoinflammatory disease (SAID) that presents with a wide clinical spectrum, ranging from severe and fatal forms to milder disorders. We conducted a literature review to provide a comprehensive analysis of the clinical characteristics of patients diagnosed with TRNT1-associated SAID and to explore therapeutic approaches to this condition, with particular attention to the follow-up outcomes of patients treated with TNF-α inhibitors. Sixty-six patients were included in this narrative review: more than 70% presented with fever and immunodeficiency. Developmental delay was very common, reported in 65.2% of patients. Ocular signs were reported in 36.4%, hearing loss in 27.3%, musculoskeletal symptoms in 24.2%, cutaneous manifestations in 37.9%, and other less common features, including gastrointestinal symptoms in 24.2%, cardiac involvement in 9.1%, and growth hormone deficiency in 9.1%. A total of 83.3% of patients underwent genetic assessment, which identified two mutations affecting TRNT1 function in 53 patients, while in two patients, despite identification of only a single mutation in the TRNT1 gene, a broad clinical phenotype resembling a systemic autoinflammatory disease was described. Among the different therapeutic strategies, etanercept was used in 13 patients. The median age at etanercept initiation was 24 months (IQR 21–60). Etanercept was effective in controlling systemic inflammation by suppressing fever and inflammatory markers. Additionally, it helped manage cutaneous symptoms in a few patients. Based on current knowledge, etanercept seems to be the most promising therapy in TRNT1-related SAID.