Novel Heterozygous Mutation in NFKB2 Is Associated With Early Onset CVID and a Functional Defect in NK Cells Complicated by Disseminated CMV Infection and Severe Nephrotic Syndrome.

Alejandra Aird,Jordan S Orange,Alexander Vargas-Hernández,Ivan K Chinn,Shalini Jhangiani,Lisa R Forbes,James R Lupski,Felipe Cavagnaro,Maria Cecilia Poli,Emily M Mace,Jennifer E Posey,Macarena Lagos,Zeynep Coban-Akdemir,Alejandra King,Anaid Reyes

doi:10.3389/fped.2019.00303

Abstract

Nuclear factor kappa-B subunit 2 (NF-κB2/p100/p52), encoded by NFKB2 (MIM: 164012) belongs to the NF-κB family of transcription factors that play a critical role in inflammation, immunity, cell proliferation, differentiation and survival. Heterozygous C-terminal mutations in NFKB2 have been associated with early-onset common variable immunodeficiency (CVID), central adrenal insufficiency and ectodermal dysplasia. Only two previously reported cases have documented decreased natural killer (NK) cell cytotoxicity, and little is known about the role of NF-κB2 in NK cell maturation and function. Here we report a 13-year-old female that presented at 6 years of age with a history of early onset recurrent sinopulmonary infections, progressive hair loss, and hypogamaglobulinemia consistent with a clinical diagnosis of CVID. At 9 years of age she had cytomegalovirus (CMV) pneumonia that responded to ganciclovir treatment. Functional NK cell testing demonstrated decreased NK cell cytotoxicity despite normal NK cell numbers, consistent with a greater susceptibility to systemic CMV infection. Research exome sequencing (ES) was performed and revealed a novel de novo heterozygous nonsense mutation in NFKB2 (c.2611C>T, p.Gln871*) that was not carried by either of her parents. The variant was Sanger sequenced and confirmed to be de novo in the patient. At age 12, she presented with a reactivation of the systemic CMV infection that was associated with severe and progressive nephrotic syndrome with histologic evidence of pedicellar effacement and negative immunofluorescence. To our knowledge, this is the third NF-κB2 deficient patient in which an abnormal NK cell function has been observed, suggesting a role for non-canonical NF-κB2 signaling in NK cell cytotoxicity. NK cell function should be assessed in patients with mutations in the non-canonical NF-κB pathway to explore the risk for systemic viral infections that may lead to severe complications and impact patient survival. Similarly NF-κB2 should be considered in patients with combined immunodeficiency who have aberrant NK cell function. Further studies are needed to characterize the role of NF-κB2 in NK cell cytotoxic function.

Highlights

Common variable immunodeficiency (CVID) is one of the most frequently diagnosed symptomatic primary immunodeficiencies
In the non-canonical pathway, the NFKB2 transcripts are first translated into a p100 precursor protein that undergoes activation-dependent cytoplasmic proteolytic processing through NF-κB-inducing kinase (NIK) into the smaller active transcription factor p52
Mutations at the 3’end of the NFKB2 gene, encoding the C-terminal region of the protein, both perturb immune and endocrine function resulting in central adrenocorticotropic hormone deficiency and CVID [10,11,12,13]

Summary

BACKGROUND

Common variable immunodeficiency (CVID) is one of the most frequently diagnosed symptomatic primary immunodeficiencies. Heterozygous C-terminal mutations in NFKB2 (MIM 164012) were determined to cause early onset CVID with variable association with central adrenal insufficiency, ectodermal dysplasia, and autoimmunity [10,11,12,13,14,15,16]. We describe a female patient with a novel heterozygous nonsense mutation in NFKB2 presenting with early onset CVID, ectodermal dysplasia, subclinical adrenal insufficiency and functional NK cell deficiency with overwhelming systemic CMV infection, uniquely associated with severe nephrotic syndrome. This case report highlights the relevance of NK cell function in prognosis and suggests that functional NK cell evaluation could impact treatment strategies in these patients.

Borderline low

DISCUSSION