A Heterozygous Nonsense Variant of NFKBIA Leading to Gain-of-Function

Abstract

The NFKBIA gene encodes the protein IκBα, an important regulatory protein that interacts with nuclear factor kappa B family of transcription factors required for innate and adaptive immune responses and normal ectodermal development. Heterozygous nonsense and missense variants of the NFKBIA gene have been reported in a total of 19 individuals with autosomal dominant ectodermal dysplasia with immunodeficiency (EDA-ID) since 2003. Here, we report a patient with a novel de novo heterozygous nonsense variant in the N-terminal of NFKBIA. This patient initially presented to Immunology due to an abnormal presentation of IgA nephropathy (IgAN) with solely kappa staining and a notable history of recurrent AOM, PNA and viral infections including septic shock, diffuse watershed ischemic injury and new seizure onset due to influenza A. Immunologic assessment revealed lymphocytosis of T- and B-cells, particularly CD4+ and CD8+ memory, and CD27-IgD+ cells. In contrast, class-switched, non-class-switched memory B-cells, CD21lo, and plasmablasts were low. A distinct B-cell population expressing less CD19 with negative surface IgD, IgG, and IgM was also observed. Roughly 50% of these cells had IgM expression without surface IgD and were CD24 and CD27 negative, CD21 lo, and CD28 mid. Functionally, T-cells had poor response and proliferation to PHA as well as soluble anti-CD3, anti-CD3+anti-CD28, and anti-CD3+IL-2. Vaccine response was diminished, particularly to polysaccharides. Furthermore, TLR function of PBMCs were assessed revealing decreased cytokine response to soluble ligand exposure. Physical exam findings consistent with EDA-ID included several absent and conical teeth, xerosis, and sparse hair with a history notable for heat intolerance. In line with prior reports of patients with early truncating variants in NFKBIA, the infectious manifestations in these patients have been mild, particularly in comparison to those with missense variants that affect serine 32. In this patient, HSCT was not undertaken, but rather IgG replacement therapy was initiated resulting in absence of any further serious infections. Additionally, glucocorticoid therapy was initiated for IgAN with subsequent sustained remission. With an increase in published data, this may help broaden our scope of what phenotypical presentation can be expected, which may help increase the rate of diagnosis and early identification.