Common variable immunodeficiency due to a novel variant in NFKB1 with a neonatal presentation of parechovirus meningitis and sepsis-like illness
Main Article Content
Keywords
common variable immune deficiency, human parechovirus, inborn error of immunity, inflammation, meningitis, NF-κB1
Abstract
Monoallelic variants in the nuclear factor kappa B 1 (NFKB1) gene reinforce the functional haploinsufficiency causing immunodeficiency with marked individual and intrafamilial variability in genotype-phenotype correlations. The leading clinical manifestations of NF-κB1 deficiency are recurrent infections and immune dysregulation disorders with autoinflammatory and lymphoproliferative disease. The reported patient initially presented with a neonatal sepsis-like illness with meningitis because of a parechovirus infection. The diagnosis of an inborn error of immunity, common variable immunodeficiency (CVID), was established based on hypogammaglobulinemia, impaired antibody response to vaccines, IgG subclass deficiency, and low numbers of switched memory B cells. Molecular genetic testing using trio whole exome sequencing was done to define the background of the presenting phenotype, and it revealed a novel heterozygous variant of NFKB1. Viral meningitis and sepsis-like illness are unusual, previously unreported, infectious complications in NF-κB1 deficiency. The transcriptional NF-κB1 regulatory effect on different target gene repertoires and numerous processes including immune and inflammatory responses may indiacte the vulnerability of deficient patients to severe viral infections. This case report exemplifies the advancement of immunogenetics paving the way for the transition from the initial era of clinical recognition to the era of molecular diagnosis of the pediatric CVID.
References
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25 Tuovinen EA, Kuismin O, Soikkonen L, Martelius T, Kaustio M, Hamalainen S, et al. Long-term follow up of families with pathogenic NFKB1 variants reveals incomplete penetrance and frequent inflammatory sequelae. Clin. Immunol. 2023 Jan;246:109181. 10.1016/j.clim.2022.109181
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27 Baxter SK, Walsh T, Casadei S, Eckert MM, Allenspach EJ, Hagin D, et al. Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy, and implications for clinical management. J. Allergy Clin. Immunol. 2022 Jan 149(1):327–339. 10.1016/j.jaci.2021.04.005
28 Staels F, De Keukeleere K, Kinnunen M, Keskitalo S, Lorenzetti F, Vanmeert M, et al. Common variable immunodeficiency in two kindreds with heterogeneous phenotypes caused by novel heterozygous NFKB1 mutations. Front. Immunol. 2022 Sep;13:973543. 10.3389/fimmu.2022.973543
29 Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human inborn errors of immunity: 2022 Update on the classification from the International Union of Immunological Societies Expert Committee. J. Clin. Immunol. 2022 Oct 42(7):1473–1507. 10.1007/s10875-022-01289-3
30 Ramirez NJ, Posadas-Cantera S, Caballero-Oteyza A, Camacho-Ordonez N, Grimbacher B. There is no gene for CVID–novel monogenetic causes for primary antibody deficiency. Curr. Opin. Immunol. 2021 Oct;72:176–185. 10.1016/j.coi.2021.05.010
31 Szczawińska-Popłonyk A, Ciesielska W, Konarczak M, Opanowski J, Orska A, Julia Wróblewska, et al. Immunogenetic landscape in pediatric common variable immunodeficiency. Int J Mol Sci. 2024 Sep;25(18):9999. 10.3390/ijms25189999
32 Fliegauf M, Bryant VL, Frede N, Slade C, Woon ST, Lehnert K, et al. Haploinsufficiency of the NF-κB1 subunit p50 in common variable immunodeficiency. Am. J. Hum. Genet. 2015 Sep 97(3):389–403. 10.1016/j.ajhg.2015.07.008
33 Fekrvand S, Khanmohammadi S, Abolhassani H, Yazdani R. B- and T-cell subset abnormalities in monogenic common variable immunodeficiency. Front. Immunol. 2022 Jun;13:912826. 10.3389/fimmu.2022.912826
34 Rojas-Restrepo J, Caballero-Oteyza A, Huebscher K, Haberstroh H, Fliegauf M, Keller B, et al. Establishing the molecular diagnoses in a cohort of 291 patients with predominantly antibody deficiency by targeted next-generation sequencing: experience from a monocentric study. Front. Immunol. 2021 Dec;12:786516. 10.3389/fimmu.2021.786516
35 Mauracher AA, Gujer E, Bachmann LM, Gusewell S, Pachlopnik Schmid J. Patterns of immune dysregulation in primary immunodeficiencies: A systematic review. J. Allergy Clin. Immunol. Pract. 2021 Feb 9(2):792–802. 10.1016/j.jaip.2020.10.057
36 Fathi N, Mojtahedi H, Nasiri M, Abolhassani H, Marzbali MY, Esmaeili M, et al. How do nuclear factor kappa B (NF-κB)1 and NF-κB2 defects lead to the incidence of clinical and immunological manifestations of inborn errors of immunity? Expert Rev. Clin. Immunol. 2023 Mar 19(3):329–339. 10.1080/1744666X.2023.2174105
37 De Jong EP, van den Beuken MGA, van Elzakker EPM, Wolthers KC, Sprij AJ, Lopriore E, et al. Epidemiology of sepsis-like illness in young infants: Major role of enterovirus and human parechovirus. Pediatr. Infect. Dis. 2018 Feb 37(2):113–118. 10.1097/INF.0000000000001718
38 Autore G, Bernardi L, Perrone S, Esposito S. Update on viral infections involving the central nervous system in pediatric patients. Children. 2021 Sep;8(9):782. 10.3390/children8090782
39 Fortuna D, Cardenas AM, Graf EH, Harshyne LA, Hooper DC, Prosniak M, et al. Human parechovirus initiate distinct CNS innate immune responses: Pathogenic and diagnostic implications. J. Clin. Virol. 2017 Jan;86:39–45. 10.1016/j.jcv.2016.11.007
40 Joseph L, May M, Thomas M, Smerdon C, Tozen S, Bialasiewicz S, et al. Human parechovirus 3 in infants: Expanding our knowledge of adverse outcomes. Pediatr. Infect. Dis. 2019 Jan 38(1):1–5. 10.1097/INF.0000000000002136
41 Song K and Li S. The role of ubiquitination in NF-κB signaling during virus infection. Viruses. 2021 Jan;13(2):145. 10.3390/v13020145
42 Zheng Y and Gao C. Fine tuning of antiviral innate immunity by ubiquitination. Adv. Immunol. 2020 Dec;145:95–128. 10.1016/bs.ai.2019.11.004
43 Chawla S, Barman P, Tyagi R, Jindal AK, Sharma S, Rawat A, et al. Autoimmune cytopenias in common variable immunodeficiency are a diagnostic and therapeutic conundrum: an update. Front Immunol. 2022 Jun;13:869466. 10.3389/fimmu.2022.869466
44 Danandeh K, Jabbari P, Rayzan E, Zoghi S, Shahkarami S, Heredia RJ, et al. Case report of a novel NFκB mutation in a lymphoproliferative disorder patient. Endocr. Metab. Immune. Disord. Drug Targets. 2022;22(10):1040–1046. 10.2174/1871530322666220407091356
45 Szczawińska-Popłonyk A, Tąpolska-Jóźwiak K, Schwartzmann E, Popłonyk N. Immune dysregulation in pediatric common variable immunodeficiency: Implications for the diagnostic approach. Front Pediatr. 2022 Mar;10:855200. 10.3389/fped.2022.855200
46 Walter JE, Ayala IA, Milojevic D. Autoimmunity as a continuum in primary immunodeficiency. Curr Opin Pediatr. 2019 Dec;31(6):851–862. Doi: 10.1097/MOP.0000000000000833
47 Yin J, Hayes KM, Ong M, Mizgerd JP, Cunningham-Rundles C, Dominguez I, et al. Common variable immunodeficiency clinical manifestations are shaped by presence and type of heterozygous NFKB1 variants. J Allergy Clin Immunol Pract. 2024 Dec;s2213–2198(24)01242-X. 10.1016/j.jaip.2024.12.002
48 Principi N and Esposito S. Vaccine use in primary immunodeficiency disorders. Vaccine. 2014 Jun;32(30):3725–3731. 10.1016/j.vaccine.2014.05.022
49 Milito C, Soccodato V, Collalti G, Lanciarotta A, Bertozzi I, Rattazzi M, et al. Vaccination in PADs. Vaccines. 2021 Jun;9(6):626. 10.3390/vaccines9060626
50 Szczawińska-Popłonyk A, Bręborowicz A, Samara M, Ossowska L, Dworacki G. Impaired antigen-specific immune response to vaccines in children with antibody production defects. Clin. Vaccine Immunol. 2015;22:875–882. 10.1128/CVI.00148-15
2 Schnappauf O and Aksentijevich I. Mendelian diseases of dysregulated canonical NF-κB signaling: From immunodeficiency to inflammation. J. Leukoc. Biol. 2020 Aug;108(2):573–589. 10.1002/JLB.2MR0520-166R
3 Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transd. Target Ther. 2017 Jul;2:17023. 10.1038/sigtrans.2017.23
4 Sun SC. The non-canonical NF-κB pathway in immunity and inflammation. Nat. Rev. Immunol. 2017 Sep;17(9):545–558. 10.1038/nri.2017.52
5 Napetschnig J and Wu H. Molecular basis of NF-κB signaling. Ann. Rev. Biophys. 2013 Mar;42:443–468. 10.1146/annurev-biophys-083012-130338
6 Gaspar Pereira S and Oakley F. Nuclear factor-kappaB1: Regulation and function. Int. J. Biochem. Cell Biol. 2008 May 40(8):1425–1430. 10.1016/j.biocel.2007.05.004
7 Liu P, Li Y, Wang W, Bai Y, Jia H, Yuan Z, et al. Role and mechanisms of the NF-κB signaling pathway in various developmental processes. Biomed. Biopharm. 2022 Sep;153:113513. 10.1016/j.biopha.2022.113513
8 Hayden MS and Ghosh S. NF-kappaB in immunobiology. Cell Res. 2011 Feb;21(2):223–244. 10.1038/cr.2011.13
9 Boztug H, Hirschmugl T, Holter W, Lakatos K, Kager L, Trapin D, et al. NF-κB1 haploinsufficiency causing immunodeficiency and EBV-driven lymphoproliferation. J. Clin. Immunol. 2016 Aug 36(6):533–540. 10.1007/s10875-016-0306-1
10 Guldenpfennig C, Teixeiro E, Daniels M. NF-kB’s contribution to B cell fate decisions. Front Immunol. 2023 Jul;14:1214095. 10.3389/fimmu.2023.1214095
11 Durkee-Shock J, Zhang A, Liang H, Wright H, Magnusson J, Garabedian E, et al. Morbidity, mortality, and therapeutics in combined immunodeficiency: data from the USIDNET Registry. J. Allergy Clin. Immunol. Pract. 2022 May 10(5):1334–1341. 10.1016/j.jaip.2022.01.042
12 Dabbah-Krancher G and Snow AL. Mistuned NF-κB signaling in lymphocytes: Lessons from relevant inborn errors of immunity. Clin. Exp. Immunol. 2023 Apr 212(2):117–128. 10.1093/cei/uxad006
13 Tuijnenburg P, Lango Allen H, Burns SO, Greene D, Jansen MH, Staples E, et al. Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans. J. Allergy Clin. Immunol. 2018 Oct 142(4):1285–1296. 10.1016/j.jaci.2018.01.039
14 Schroder C, Sogkas G, Fliegauf M, Dork T, Liu D, Hanitsch LG, et al. Late-onset antibody deficiency due to monoallelic alterations in NFKB1. Front. Immunol. 2019 Nov;10:2618. 10.3389/fimmu.2019.02618
15 Li J, Lei WT, Zhang P, Rapaport F, Seeleuthner Y, Lyu B, et al. Biochemically deleterious human NFKB1 variants underlie an autosomal dominant form of common variable immunodeficiency. J. Exp. Med. 2021 Nov 218(11):20210566. 10.1084/jem.20210566
16 Fliegauf M, Kruger R, Steiner S, Hanitsch LG, Buchel S, Wahn V, et al. A pathogenic missense variant in NFKB1 causes common variable immunodeficiency due to detrimental protein damage. Front. Immunol. 2021 Apr;12:621503. 10.3389/fimmu.2021.621503
17 Kaustio M, Haapaniemi E, Goos H, Hautala T, Park G, Syrjanen J, et al. Damaging heterozygous mutations in NFKB1 lead to diverse clinical phenotypes. J. Allergy Clin. Immunol. 2017 Sep 140(3):782–796. 10.1016/j.jaci.2016.10.054
18 Shen Y, Boulton APR, Yellon RL, Cook MC. Skin manifestations of inborn errors of NF-κB. Front. Pediatr. 2023 Jan;10:1098426. 10.3389/fped.2022.1098426
19 Ameratunga R, Lehnert K, Woon ST. All patients with common variable immunodeficiency disorders (CVID) should be routinely offered diagnostic genetic testing. Front. Immunol. 2019 Nov;10:2678. 10.3389/fimmu.2019.02678
20 Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) Registry working definitions for the clinical diagnosis of inborn errors of immunity. J. Allergy Immunol. Pract. 2019 Jul–Aug;7(6):1763–1770. 10.1016/j.jaip.2019.02.004
21 Bogaert DJA, Dullaers M, Lambrecht BN, Vermaelen KY, De Baere E, Haerynck F. Genes associated with common variable immunodeficiency: One diagnosis to rule them all? J. Med. Genet. 2016 Sep 53(9):575–590. 10.1136/jmedgenet-2015-103690
22 Cunningham-Rundles C, Casanova JL, Boisson B. Genetics and clinical phenotypes in common variable immunodeficiency. Front. Genet. 2024 Jan;14:1272912. 10.3389/fgene.2023.1272912
23 Lorenzini T, Fliegauf M, Klammer N, Frede N, Proietti M, Bulashevska A, et al. Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations. J. Allergy Clin. Immunol. 2020 Oct 146(4):901–911. 10.1016/j.jaci.2019.11.051
24 Szczawińska-Popłonyk A, Schwartzmann E, Bukowska-Olech E, Biernat M, Gattner S, Korobacz S, et al. The pediatric common variable immunodeficiency-from genetics to therapy: A review. Eur. J. Pediatr. 2022 Apr 181(4):1371–1383. 10.1007/s00431-021-04287-6
25 Tuovinen EA, Kuismin O, Soikkonen L, Martelius T, Kaustio M, Hamalainen S, et al. Long-term follow up of families with pathogenic NFKB1 variants reveals incomplete penetrance and frequent inflammatory sequelae. Clin. Immunol. 2023 Jan;246:109181. 10.1016/j.clim.2022.109181
26 Fathi N, Nirouei M, Rizi ZS, Fekrvand S, Abolhassani H, Salami F, et al. Clinical, immunological, and genetic features in patients wit NFKB1 and NFKB2 mutations: A systematic review. J. Clin. Immunol. 2024 Jul 44(7):160. 10.1007/s10875-024-01763-0
27 Baxter SK, Walsh T, Casadei S, Eckert MM, Allenspach EJ, Hagin D, et al. Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy, and implications for clinical management. J. Allergy Clin. Immunol. 2022 Jan 149(1):327–339. 10.1016/j.jaci.2021.04.005
28 Staels F, De Keukeleere K, Kinnunen M, Keskitalo S, Lorenzetti F, Vanmeert M, et al. Common variable immunodeficiency in two kindreds with heterogeneous phenotypes caused by novel heterozygous NFKB1 mutations. Front. Immunol. 2022 Sep;13:973543. 10.3389/fimmu.2022.973543
29 Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human inborn errors of immunity: 2022 Update on the classification from the International Union of Immunological Societies Expert Committee. J. Clin. Immunol. 2022 Oct 42(7):1473–1507. 10.1007/s10875-022-01289-3
30 Ramirez NJ, Posadas-Cantera S, Caballero-Oteyza A, Camacho-Ordonez N, Grimbacher B. There is no gene for CVID–novel monogenetic causes for primary antibody deficiency. Curr. Opin. Immunol. 2021 Oct;72:176–185. 10.1016/j.coi.2021.05.010
31 Szczawińska-Popłonyk A, Ciesielska W, Konarczak M, Opanowski J, Orska A, Julia Wróblewska, et al. Immunogenetic landscape in pediatric common variable immunodeficiency. Int J Mol Sci. 2024 Sep;25(18):9999. 10.3390/ijms25189999
32 Fliegauf M, Bryant VL, Frede N, Slade C, Woon ST, Lehnert K, et al. Haploinsufficiency of the NF-κB1 subunit p50 in common variable immunodeficiency. Am. J. Hum. Genet. 2015 Sep 97(3):389–403. 10.1016/j.ajhg.2015.07.008
33 Fekrvand S, Khanmohammadi S, Abolhassani H, Yazdani R. B- and T-cell subset abnormalities in monogenic common variable immunodeficiency. Front. Immunol. 2022 Jun;13:912826. 10.3389/fimmu.2022.912826
34 Rojas-Restrepo J, Caballero-Oteyza A, Huebscher K, Haberstroh H, Fliegauf M, Keller B, et al. Establishing the molecular diagnoses in a cohort of 291 patients with predominantly antibody deficiency by targeted next-generation sequencing: experience from a monocentric study. Front. Immunol. 2021 Dec;12:786516. 10.3389/fimmu.2021.786516
35 Mauracher AA, Gujer E, Bachmann LM, Gusewell S, Pachlopnik Schmid J. Patterns of immune dysregulation in primary immunodeficiencies: A systematic review. J. Allergy Clin. Immunol. Pract. 2021 Feb 9(2):792–802. 10.1016/j.jaip.2020.10.057
36 Fathi N, Mojtahedi H, Nasiri M, Abolhassani H, Marzbali MY, Esmaeili M, et al. How do nuclear factor kappa B (NF-κB)1 and NF-κB2 defects lead to the incidence of clinical and immunological manifestations of inborn errors of immunity? Expert Rev. Clin. Immunol. 2023 Mar 19(3):329–339. 10.1080/1744666X.2023.2174105
37 De Jong EP, van den Beuken MGA, van Elzakker EPM, Wolthers KC, Sprij AJ, Lopriore E, et al. Epidemiology of sepsis-like illness in young infants: Major role of enterovirus and human parechovirus. Pediatr. Infect. Dis. 2018 Feb 37(2):113–118. 10.1097/INF.0000000000001718
38 Autore G, Bernardi L, Perrone S, Esposito S. Update on viral infections involving the central nervous system in pediatric patients. Children. 2021 Sep;8(9):782. 10.3390/children8090782
39 Fortuna D, Cardenas AM, Graf EH, Harshyne LA, Hooper DC, Prosniak M, et al. Human parechovirus initiate distinct CNS innate immune responses: Pathogenic and diagnostic implications. J. Clin. Virol. 2017 Jan;86:39–45. 10.1016/j.jcv.2016.11.007
40 Joseph L, May M, Thomas M, Smerdon C, Tozen S, Bialasiewicz S, et al. Human parechovirus 3 in infants: Expanding our knowledge of adverse outcomes. Pediatr. Infect. Dis. 2019 Jan 38(1):1–5. 10.1097/INF.0000000000002136
41 Song K and Li S. The role of ubiquitination in NF-κB signaling during virus infection. Viruses. 2021 Jan;13(2):145. 10.3390/v13020145
42 Zheng Y and Gao C. Fine tuning of antiviral innate immunity by ubiquitination. Adv. Immunol. 2020 Dec;145:95–128. 10.1016/bs.ai.2019.11.004
43 Chawla S, Barman P, Tyagi R, Jindal AK, Sharma S, Rawat A, et al. Autoimmune cytopenias in common variable immunodeficiency are a diagnostic and therapeutic conundrum: an update. Front Immunol. 2022 Jun;13:869466. 10.3389/fimmu.2022.869466
44 Danandeh K, Jabbari P, Rayzan E, Zoghi S, Shahkarami S, Heredia RJ, et al. Case report of a novel NFκB mutation in a lymphoproliferative disorder patient. Endocr. Metab. Immune. Disord. Drug Targets. 2022;22(10):1040–1046. 10.2174/1871530322666220407091356
45 Szczawińska-Popłonyk A, Tąpolska-Jóźwiak K, Schwartzmann E, Popłonyk N. Immune dysregulation in pediatric common variable immunodeficiency: Implications for the diagnostic approach. Front Pediatr. 2022 Mar;10:855200. 10.3389/fped.2022.855200
46 Walter JE, Ayala IA, Milojevic D. Autoimmunity as a continuum in primary immunodeficiency. Curr Opin Pediatr. 2019 Dec;31(6):851–862. Doi: 10.1097/MOP.0000000000000833
47 Yin J, Hayes KM, Ong M, Mizgerd JP, Cunningham-Rundles C, Dominguez I, et al. Common variable immunodeficiency clinical manifestations are shaped by presence and type of heterozygous NFKB1 variants. J Allergy Clin Immunol Pract. 2024 Dec;s2213–2198(24)01242-X. 10.1016/j.jaip.2024.12.002
48 Principi N and Esposito S. Vaccine use in primary immunodeficiency disorders. Vaccine. 2014 Jun;32(30):3725–3731. 10.1016/j.vaccine.2014.05.022
49 Milito C, Soccodato V, Collalti G, Lanciarotta A, Bertozzi I, Rattazzi M, et al. Vaccination in PADs. Vaccines. 2021 Jun;9(6):626. 10.3390/vaccines9060626
50 Szczawińska-Popłonyk A, Bręborowicz A, Samara M, Ossowska L, Dworacki G. Impaired antigen-specific immune response to vaccines in children with antibody production defects. Clin. Vaccine Immunol. 2015;22:875–882. 10.1128/CVI.00148-15
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May 1, 2025
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Szczawińska-Popłonyk, A., Popłonyk, N., Bernat-Sitarz, K., Jończyk-Potoczna, K., & Pollak, A. (2025). Common variable immunodeficiency due to a novel variant in NFKB1 with a neonatal presentation of parechovirus meningitis and sepsis-like illness. Allergologia Et Immunopathologia, 53(3), 31-40. https://doi.org/10.15586/aei.v53i3.1307
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Author Biography
Aleksandra Szczawińska-Popłonyk, Poznań University of Medical Sciences, Institute of Pediatrics, Department of Pediatric Pneumonology, Allergy and Clinical Immunology, Szpitalna Poznań, Poland.
How to Cite
Szczawińska-Popłonyk, A., Popłonyk, N., Bernat-Sitarz, K., Jończyk-Potoczna, K., & Pollak, A. (2025). Common variable immunodeficiency due to a novel variant in NFKB1 with a neonatal presentation of parechovirus meningitis and sepsis-like illness. Allergologia Et Immunopathologia, 53(3), 31-40. https://doi.org/10.15586/aei.v53i3.1307