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

Frontiers in Pediatrics

article

Alejandra Aird¹  Felipe Cavagnaro¹  Lisa R. Forbes²  Ivan K. Chinn²  James R. Lupski³  Jordan S. Orange⁵  Maria Cecilia Poli¹  Macarena Lagos⁶  Alexander Vargas-Hernández²  Jennifer E. Posey³  Zeynep Coban-Akdemir³  Shalini Jhangiani³  Emily M. Mace⁵  Anaid Reyes²  Alejandra King¹ 

[1] Facultad de Medicina Clínica Alemana-Universidad del Desarrollo;Section of Immunology, Department of Pediatrics, Center for Human Immunobiology, Baylor College of Medicine, Texas Children's Hospital, United States;Department of Molecular and Human Genetics, Baylor College of Medicine, United States;Human Genome Sequencing Center, Baylor College of Medicine, United States;Division of Immunogenetics, Department of Pediatrics, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University Irving Medical Center, United States;Clínica Las Condes;Hospital Padre Hurtado

关键词: primary immunodeficiency;    NF-κB2;    common variable immunodeficiency (CVID);    nephrotic syndrome;    systemic cytomegalovirus;    pituitary deficiency;    NK cell deficiency;   

DOI  :  10.3389/fped.2019.00303

学科分类：社会科学、人文和艺术（综合）

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

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