Immune Chaos in a Child with Takenouchi–Kosaki Syndrome: A Case of Dual Dysregulation and Multisystem Involvement

Introduction Takenouchi–Kosaki syndrome (TKS) is a rare multisystem disorder caused by a heterozygous mutation in the CDC42 gene, often presenting with immune dysregulation, developmental anomalies, and inflammatory features. We report a complex case of TKS manifesting with combined immunodeficiency and autoinflammatory symptoms. Case Report Brazilian female, born to non-consanguineous parents, presented at birth with multiple congenital anomalies, including a single umbilical artery, hypoplasia of the corpus callosum, and congenital heart disease. At 4 months of age, she was hospitalized due to a severe systemic infection and hemolytic anemia. Immunophenotyping revealed CD3 1,969 cells/µL, CD4 275 cells/µL (83 naïve), and CD8 1,500 cells/µL (144 naïve), with a markedly inverted CD4/CD8 ratio of 0.2. During her hospitalization, she experienced recurrent infections, most notably a persistent cytomegalovirus (CMV) infection with high and refractory viral load. She also exhibited fever, diarrhea, and seizure episodes. At one year of age, hypogammaglobulinemia was confirmed (IgA 1 mg/dL, IgM 27.8 mg/dL, IgG 379 mg/dL), along with a pericardial effusion unresponsive to high-dose intravenous immunoglobulin (IVIG). Genetic analysis identified a heterozygous mutation in CDC42 (specific variant: c.242G>T;p.(Cys81Phe). Now two years old, the patient is maintained on immunoglobulin replacement therapy and prophylactic antibiotics. Her CMV load remains controlled under valganciclovir therapy. For autoimmune cytopenias, she is being treated with sirolimus and erythropoietin, with partial hematologic improvement. She continues to experience systemic inflammatory flares resembling sepsis, and her chronic pericardial effusion is currently managed with colchicine. Discussion This case illustrates an early-onset, non-SCID (severe combined immunodeficiency) lymphopenia with pronounced autoinflammatory features, reflecting the dual immune dysfunction characteristic of TKS. The underlying CDC42 mutation leads to impaired lymphocyte development and antibody production, alongside constitutive NF-κB pathway activation, contributing to the inflammatory phenotype. Management remains complex and largely supportive; however, emerging data suggest that anti–IL-1 therapy may offer clinical benefit in patients with similar presentations.