Variable Clinical Presentation, Diagnostic and Treatment Challenges in a family with a novel variant of NFKB1

Abstract

Introduction: Nuclear factor kappa B subunit 1 (NFKB1) gene plays an essential role in immune cell signaling. Heterozygous NFKB1 variants are the most common cause of Common Variable Deficiency (CVID). Patients are susceptible to recurrent infections and non-infectious complications often requiring immune modulation. Intrafamilial variability of clinical phenotypes causes challenges in diagnosis and determining personalized treatment strategies. We describe a family with a novel NFKB1 variant and challenges in diagnostic and treatment approaches. MethodsA retrospective chart review was performed to include demographics, clinical manifestations, laboratory findings, and genetic evaluation. We performed extensive immune cell subsets by flow cytometry. Microbiome analysis was performed by 16 s sequencing from stool samples, complemented by lifestyle questionnaires. ResultsThe index case is a 41-year-old female with lifelong recurrent bacterial and viral infections. She was not diagnosed with CVID until 36 years of age. Non-infectious complications included GLILD, chronic diarrhea, persistent splenomegaly and arthritis. Genetic testing with a targeted 409 gene panel revealed heterozygosity for a novel, likelypathogenic NFKB1 c.2419+1 dup variant affecting splice site for intron 21. Extensive immune phenotyping showed a decrease in both T- and B-cell counts. Expansion of the exhausted CD4 and T-follicular helper cell subsets was also observed. In the B-cell compartment, memory class-switched B-cells were significantly decreased while there was a skew towards CD38lo “atypical” naive B-cells. Besides immunoglobulin replacement therapy (IgRT), the patient was considered for CTLA4-Ig treatment for immune dysregulation. Genetic findings prompted testing of her children for the same variant. Two of her three sons shared the same NFKB1 variant with distinctive phenotypic expressions. The 13-year-old son was symptomatic with recurrent nasal herpes, diarrhea, low weight, and chronic cough. Immune evaluation revealed specific antibody deficiency inducing inadequate streptococcus pneumoniae titers. The 11-year-old son had mild arthralgia with laboratory findings of specific antibody deficiency. In both cases, the mild immune phenotype did not provide clarity on treatment outcomes when using IgRT versus immune modulators. ConclusionGenetic findings in an index case led to the screening of family members for pathogenic mutations. Close immunological monitoring and early initiation of therapy is vital to prevent the progression of complications.