Dominant-Negative Ikaros: First Reported Case Associated with Adverse Reaction to Bacillus Calmette–Guérin Vaccination

Introduction IKAROS deficiency is caused by a mutation in the IKZF1 gene, which plays a key role in the differentiation and development of lymphoid and myeloid cells, and negatively regulates cell proliferation. Mutations are classified according to protein expression as haploinsufficiency, dimerization defect, dominant-negative (DN), and gain-of-function; all are associated to varying degrees with susceptibility to infections, autoimmunity, allergy, and malignancy. Presentation of the Case Female infant received the Bacillus Calmette–Guérin (BCG) vaccine at 10 days of life. At 3 and 7 months of age, she presented with bronchiolitis and pneumonia, requiring hospitalization for 89 days, mechanical ventilation, broad-spectrum antibiotics, and treatment for severe viral, bacterial, and fungal infections. She developed swelling at the BCG injection site and ipsilateral axillary lymphadenopathy. Lymphocyte subpopulations showed B and T cell lymphopenia; CD20: 0.5%, hypogammaglobulinemia, normal dihydrorhodamine. Complete blood counts revealed monocytopenia, eosinopenia, and neutropenia. Genetic testing on 07/08/2024 revealed IKZF1 c.476A>G (p.Asn159Ser). Currently 20 months old, she is undergoing hematopoietic stem cell transplant evaluation (father 50% HLA compatible); she is receiving maintenance-phase anti-tuberculosis therapy, prophylactic antibiotics, and intravenous immunoglobulin. Discussion This case involves a DN IKAROS mutation with an early-onset, severe, and fully penetrant phenotype. Of the nine cases reported worldwide, one-third received BCG vaccination without documented adverse reactions; these patients show increased susceptibility to malignancy, with no reported associations with autoimmunity or atopy. Definitive treatment is hematopoietic stem cell transplantation. IKAROS mutations are associated with a broad spectrum of immunological phenotypes; reporting of such cases contributes to timely recognition and treatment of these conditions.