third autoimmune crisis; third autoimmune crisis; The patient developed a fever after receiving scheduled vaccinations at 2 months which led to a third autoimmune crisis; This is a literature report.  Homozygous null mutations of IKBKB encoding IKK2 are known to cause severe combined immunodeficiency (SCID) with normal peripheral T cell and B cell counts, and hypogammaglobulinemia. Heterozygous missense mutations in the same gene were described to cause an autosomal dominant combined immunodeficiency. To our knowledge, a phenotype of autoinflammation with organ-specific autoimmunity has not been described. A 6-week-old ex-full term male developed a self-limiting episode of rash, fever, and autoimmune hemolytic anemia (AIHA) - hemoglobin (hgb) 10.4 g/dL, platelets 407 k/mcL, and absolute neutrophil count (ANC) 3321/mcL at presentation. Symptoms recurred at 7 weeks (hgb 6.5 g/dL, platelets 702 k/mcL, ANC 8474/mcL) with serological testing being positive for anti-D antibodies and anti neutrophil antibodies, requiring packed red cell transfusion. His rash was clinically described as erythematous papules coalescing into plaques scattered on the arms, legs, trunk, and diagnosed by biopsy as Sweet syndrome. Serum immunoglobulins were not decreased (IgG 493 mg/dL, IgM 278 mg/dL and IgA 55.2 mg/dL). The patient developed a fever after receiving scheduled vaccinations at 2 months which led to a third autoimmune crisis. He had received the second dose of Hepatitis B, and first doses of diphtheria, Tetanus, Pertussis, Haemophilus influenzae type b, inactivated Polio vaccine, pneumococcal conjugate vaccine (PCV13), and Rotavirus. A targeted primary immunodeficiency gene panel identified two IKBKB variants in trans (IKBKB: c.1552G>A, p.D518K; c.1676 C>T, p.T559M). Variant c.1676 C>T, p.T559M had a low minor allele frequency of 5.24e-5 (Gnomad) while c.1552G>A, p.D518K was absent from major gene databases. Functional assays showed decrease in IkBalpha degradation in patient's PBMCs following TNFalpha stimulation, as well as elevation of baseline phospho-AKT. Our case is the first to demonstrate a clinical phenotype of autoinflammation with organ-specific autoimmunity due to novel compound heterozygous variants in IKBKB. Though the specific consequences of these individual IKBKB variants remains unknown, the phenotype could suggest dysfunctional signaling of the canonical NF-kappaB pathway affecting its interaction with NLRP3, TNFalpha, and IL-1beta. These findings suggest that a IKBKB mutations should be considered in the setting of disease manifesting with features of autoinflammation or autoimmune dysregulation.   Pfizer is a marketing authorization holder of Pneumococcal 13-Val Conj Vac (Dipht CRM197 Protein) vaccine in the country of incidence or the country where the product was purchased (if different). This may be a duplicate report if another marketing authorization holder of Pneumococcal 13-Val Conj Vac (Dipht CRM197 Protein) has submitted the same report to the regulatory authorities.; Sender's Comments: Based on the information available (the apparent time association), a possible contributory role of the vaccinations might not be fully excluded towards the onset of fever which subsequently triggered the third episode of underlying autoimmune disease.  The impact of this report on the benefit/risk profile of the Pfizer product is evaluated as part of Pfizer procedures for safety evaluation, including the review and analysis of aggregate data for adverse events. Any safety concern identified as part of this review, as well as any appropriate action in response, will be promptly notified to Regulatory Authorities, Ethics Committees and Investigators, as appropriate.