Co-Segregation of Pyoderma Gangrenosum and a Heterozygous NFKB1 Variant in a Large Kindred: An Autoinflammatory CVID-Like Phenotype

BackgroundPyoderma gangrenosum (PG) is a rare ulcerative neutrophilic dermatosis that can be associated with primary immunodeficiencies. Its pathogenesis is incompletely understood, but it has been increasingly reported in a broad range of monogenic combined immunodeficiencies. NFKB1 variants are the most common genetic cause of common variable immunodeficiency (CVID), including in patients with prominent immune dysregulation, and some individuals can manifest significant autoinflammatory disease, including PG. The pathomechanism of PG in the context of NFKB1 deficiency remains poorly understood.ObjectiveTo characterize an immunophenotype of a kindred with a known history of PG and a recent diagnosis of a likely pathogenic NFKB1 variant.MethodsWe performed standardized clinical and immune phenotyping, including unique subsets of immune dysregulation such as T follicular helper (Tfh) cells, CD19^high21^low B cells, and monocyte subsets; targeted genetic testing; and pedigree analysis with cascade testing of at-risk relatives.ResultsThe proband is a 33-year-old woman with childhood-onset refractory PG, recurrent sinopulmonary infections, and arthritis. She had hypogammaglobulinemia with absent pneumococcal vaccine responses. Following PPSV23, she mounted hyper-reactive titers, consistent with immune dysregulation rather than classic vaccine failure. Flow cytometry demonstrated CD19^high21^low expansion, low switched-memory B cells, Tfh expansion, and marked skewing toward atypical/nonclassical monocytes. A heterozygous likely pathogenic intronic NFKB1 variant was identified (c.1752+2T>C). Pedigree analysis revealed PG and immune dysregulation co-segregating with the familial NFKB1 variant. Among the seven family members with recurrent PG, the proband’s mother and maternal uncle were confirmed to have the same variant. Genetic testing is pending in five additional family members. The proband’s 3-year-old daughter is asymptomatic and carries the same variant.ConclusionsIn our family, the co-segregation of PG with NFKB1 variants underscores the importance of early recognition of immune dysregulation and timely genetic testing to refine diagnosis and anticipate complications. Both adaptive and innate immune compartments are dysregulated in this context. Further pathomechanistic studies are needed to improve treatment options for refractory cases, such as those described in this family.