title: NF-κB1 Haploinsufficiency Causing Immunodeficiency and EBV-Driven Lymphoproliferation.
abstract: NF-κB signaling is critically important for regulation of both innate and adaptive immune responses. While activation of NF-κB has been implicated in malignancies such as leukemia and lymphoma, loss-of-function mutations affecting different NF-κB pathway components have been shown to cause primary immunodeficiency disorders. Recently, haploinsufficiency of NF-κB1 has been described in three families with common variable immunodeficiency (CVID).
  
  
  
  We studied a patient with recurrent respiratory infections and bacterial parapharyngeal abscess. Immunological investigations revealed normal total B- cell numbers, but hypogammaglobulinemia, decreased frequencies of class-switched B cells and impaired T-cell proliferation. Targeted next-generation sequencing using a custom-designed panel comprising all known PID genes (IUIS 2014 classification) and novel candidate genes identified a novel heterozygous frameshift mutation in the NFKB1 gene leading to a premature stop codon (c.491delG; p.G165A*31). We could show that the mutation leads to reduced phosphorylation of p105 upon stimulation, resulting in decreased protein levels of p50. The further disease course was mainly characterized by two episodes of severe EBV-associated lymphoproliferative disease responsive to rituximab treatment. Due to disease severity, the patient is considered for allogeneic hematopoietic stem cell transplantation. Interestingly, the father carries the same heterozygous NFKB1 mutation and also shows decreased frequencies of memory B cells but has a much milder clinical phenotype, in line with a considerable phenotypic disease heterogeneity.
  
  
  
  Deficiency of NF-κB1 leads to immunodeficiency with a wider phenotypic spectrum of disease manifestation than previously appreciated, including EBV lymphoproliferative diseases as a hitherto unrecognized feature of the disease.
authors.affiliation: St. Anna Kinderspital, Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Boztug
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Lazarettgasse 14 AKH BT 25.3, Vienna, Austria.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Hirschmugl
authors.affiliation: St. Anna Kinderspital, Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Holter
authors.affiliation: St. Anna Kinderspital, Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Karoly
authors.initials: K
authors.lastname: Lakatos
authors.affiliation: St. Anna Kinderspital, Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Leo
authors.initials: L
authors.lastname: Kager
authors.affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Trapin
authors.affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Winfried
authors.initials: W
authors.lastname: Pickl
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Vienna, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Förster-Waldl
authors.affiliation: St. Anna Kinderspital, Department of Pediatrics, Medical University of Vienna, Vienna, Austria. kboztug@cemm.oeaw.ac.at.|CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Lazarettgasse 14 AKH BT 25.3, Vienna, Austria. kboztug@cemm.oeaw.ac.at.|Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Vienna, Austria. kboztug@cemm.oeaw.ac.at.|Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Lazarettgasse 14 AKH BT 25.3, Vienna, Austria. kboztug@cemm.oeaw.ac.at.
authors.forename: Kaan
authors.initials: K
authors.lastname: Boztug
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015415:Biomarkers; D001706:Biopsy; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000821:virology; D059472:Exome; D005260:Female; D057895:Haploinsufficiency; D004854:Herpesvirus 4, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000150:complications* / Q000235:genetics*; D016130:Immunophenotyping; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000175:diagnosis / Q000209:etiology*; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D016328:NF-kappa B
keywords: Combined immunodeficiency; EBV lymphoproliferative disease; NF-κB1; haploinsufficiency