This study aimed to describe a patient harboring a novel non-C-terminal CDC42 variant (c.128C>T, p.T43I) presenting with severe autoinflammation, and to systematically evaluate the phenotypic spectrum, frequency of inflammatory manifestations, and therapeutic responses associated with non-C-terminal variants through comprehensive literature analysis.

We performed comprehensive clinical, laboratory, and genetic characterization of the index patient, including whole-exome sequencing. A systematic literature review was conducted to identify reported cases of CDC42-related disorders up to December 2025. Extracted data included demographic features, variant location, clinical manifestations, and treatment outcomes. Patients were stratified into C-terminal and non-C-terminal groups for comparative analysis. In addition, ex vivo functional assays were performed using peripheral blood mononuclear cells (PBMCs) obtained from the patient before and after treatment, as well as from healthy controls. Cellular responses to inflammatory stimulation and the effects of interleukin-1 (IL-1) blockade were assessed.

The index patient presented with long-standing, multisystem autoinflammation that was refractory to conventional therapies but achieved sustained clinical and laboratory remission following IL-1 inhibition with canakinumab. A total of 56 cases were included in the literature review, comprising 25 patients with C-terminal variants and 31 with non-C-terminal variants. While autoinflammation was more prevalent in the C-terminal group (76%), a substantial proportion (38.7%) of patients with non-C-terminal variants also exhibited significant inflammatory manifestations. Functional analyses demonstrated that the p.Thr43Ile variant was associated with enhanced cellular responsiveness to inflammatory stimuli, indicating a hyperinflammatory state. This abnormal response was effectively normalized following IL-1 blockade, supporting the involvement of IL-1–mediated pathways in disease pathogenesis.

Non-C-terminal CDC42 variants represent an underrecognized but clinically relevant cause of autoinflammation. Our findings expand the phenotypic spectrum of CDC42-related disorders and highlight the importance of recognizing inflammatory manifestations beyond classical variant regions. IL-1 blockade appears to be an effective targeted therapeutic strategy for these patients. Integrating clinical phenotyping with functional validation may facilitate more precise diagnosis, risk stratification, and personalized treatment in rare immune dysregulation diseases.