Novel heterozygous NFKB1 mutation in a pediatric patient with cytopenias, splenomegaly, and lymphadenopathy
Abstract
Background: The nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) signaling pathway is a critical regulator of many important adaptive and innate immune responses. The NF-κB transcription factor family consists of 5 structurally related core proteins, one of which is NFKB1. Mutations in the NFKB1 gene has been reported in patients with common variable immune deficiency (CVID) as well as with a large spectrum of clinical features including recurrent viral, bacterial, and fungal infections, autoimmunity, inflammation, and malignancy.
Aim: We describe the clinical characteristics of a pediatric patient with a novel mutation in NFKB1.
Methods: Patient informed consent was obtained in accordance with approved protocols from the Research Ethics Board at the Hospital for Sick Children. Gene panel testing was employed to identify the immune aberration.
Results: Our patient, a previously well 18-month-old boy of Philippines descent, presented with multi-lineage cytopenias (thrombocytopenia, hemolytic anemia, neutropenia), splenomegaly, and lymphadenopathy. He did not have prior history of recurrent infections. Immunological work-up showed normal numbers of T and B cells, normal quantitative immunoglobulins, and adequate vaccination titres. Gene panel testing revealed a novel heterozygous missense variant c.425T>C (p. Ile142Thr) in the NFKB1 gene. Due to persistent cytopenias unresponsive to steroids and IVIG, he was started on Sirolimus with improvement in symptoms.
Conclusion: NFKB1 encodes for p105, which is processed to generate the active p50 transcription factor that can interact with different proteins to activate or inhibit downstream signaling. Our patient was found to have a missense mutation in the Rel homology domain (RHD) of p50, which has distinct functions including DNA binding, protein dimerization, and inhibitory protein binding. The clinical presentation described here broadens the scope of characteristics associated with heterozygous NFKB1 mutations.
Statement of novelty: We report a novel heterozygous missense variant c.425T>C (p. Ile142Thr) in the NFKB1 gene in a pediatric patient with cytopenias, lymphadenopathy, and splenomegaly. To the best of our knowledge, this variant has not been previously reported.
Formats available
You can view the full content in the following formats:
REFERENCES
Boztug H., Hirschmugl T., Holter W., Lakatos K., Kager L., Trapin D., Pickl W., Förster-Waldl E., and Boztug K. 2016. NF-κB1 haploinsufficiency causing immunodeficiency and EBV-driven lymphoproliferation. J. Clin. Immunol. 36:533–540.
de Valle E., Grigoriadis G., O’Reilly L.A., Willis S.N., Maxwell M.J., Corcoran L.M., Tsantikos E., Cornish J.K.S., Fairfax K.A., Vasanthakumar A., Febbraio M.A., Hibbs M.L., Pellegrini M., Banerjee A., Hodgkin P.D., Kallies A., Mackay F., Strasser A., Gerondakis S., and Gugasyan R. 2016. NFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells. J. Exp. Med. 213:621–641.
Dieli-Crimi R., Martínez-Gallo M., Franco-Jarava C., Antolin M., Blasco L., Paramonov I., Semidey M.E., Fernández A.Á., Molero X., Velásquez J., Martín-Nalda A., Pujol-Borrell R., and Colobran R. 2018. Th1-skewed profile and excessive production of proinflammatory cytokines in a NFKB1-deficient patient with CVID and severe gastrointestinal manifestations. Clin. Immunol. 195:49–58.
Fliegauf M. and Grimbacher B. 2018. Nuclear factor κB mutations in human subjects: The devil is in the details. J. Allergy Clin. Immunol. 142:1062–1065.
Gilmore T.D. 2006. Introduction to NF-κB: Players, pathways, perspectives. Oncogene. 25:6680–6684.
Hayden M.S. and Ghosh S. 2008. Shared principles in NF-κB signaling. Cell. 132:344–362.
Hayden M.S. and Ghosh S. 2012. NF-κB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev. 26:203–234.
Karin M. and Lin A. 2002. NF-κB at the crossroads of life and death. Nat. Immunol. 3:221–227.
Kaustio M., Haapaniemi E., Göös H., Hautala T., Park G., Syrjänen J., Einarsdottir E., Sahu B., Kilpinen S., Rounioja S., Fogarty C.L., Glumoff V., Kulmala P., Katayama S., Tamene F., Trotta L., Morgunova E., Krjutškov K., Nurmi K., Eklund K., Lagerstedt A., Helminen M., Martelius T., Mustjoki S., Taipale J., Saarela J., Kere J., Varjosalo M., and Seppänen M. 2017. Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes. J. Allergy Clin. Immunol. 140:782–796.
Lougaris V., Moratto D., Baronio M., Tampella G., Meer J.W.M., van der Badolato R., Fliegauf M., and Plebani A. 2017. Early and late B-cell developmental impairment in nuclear factor kappa B, subunit 1-mutated common variable immunodeficiency disease. J. Allergy Clin. Immunol. 139:349–352.e1.
Maffucci P., Filion C.A., Boisson B., Itan Y., Shang L., Casanova J.-L., and Cunningham-Rundles C. 2016. Genetic diagnosis using whole exome sequencing in common variable immunodeficiency. Front. Immunol. 7:220.
Oeckinghaus A., Hayden M.S., and Ghosh S. 2011. Crosstalk in NF-κB signaling pathways. Nat. Immunol. 12:695–708.
Schipp C., Nabhani S., Bienemann K., Simanovsky N., Kfir-Erenfeld S., Assayag-Asherie N., Oommen P.T., Revel-Vilk S., Hönscheid A., Gombert M., Ginzel S., Schäfer D., Laws H.-J., Yefenof E., Fleckenstein B., Borkhardt A., Stepensky P., and Fischer U. 2016. Specific antibody deficiency and autoinflammatory disease extend the clinical and immunological spectrum of heterozygous NFKB1 loss-of-function mutations in humans. Haematologica. 101:e392–e396.
Scott O. and Roifman C.M. 2019. NF-κB pathway and the Goldilocks principle: Lessons from human disorders of immunity and inflammation. J. Allergy Clin. Immunol. 143:1688–1701.
Sehgal S.N. 2003. Sirolimus: Its discovery, biological properties, and mechanism of action. Transplant. Proc. 35:S7–S14.
Shih V.F.-S., Tsui R., Caldwell A., and Hoffmann A. 2011. A single NFκB system for both canonical and non-canonical signaling. Cell Res. 21:86–102.
Siebenlist U., Franzoso G., and Brown K. 1994. Structure, regulation and function of NF-κB. Annu. Rev. Cell Biol. 10:405–455.
Stanic A.K., Bezbradica J.S., Park J.-J., Matsuki N., Mora A.L., Van Kaer L., Boothby M.R., and Joyce S. 2004. NF-κB controls cell fate specification, survival, and molecular differentiation of immunoregulatory natural T lymphocytes. J. Immunol. 172:2265–2273.
Tuijnenburg P., Lango Allen H., Burns S.O., Greene D., Jansen M.H., Staples E., Stephens J., Carss K.J., Biasci D., Baxendale H., Thomas M., Chandra A., Kiani-Alikhan S., Longhurst H.J., Seneviratne S.L., Oksenhendler E., Simeoni I., de Bree G.J., Tool A.T.J., van Leeuwen E.M.M., Ebberink E.H.T.M., Meijer A.B., Tuna S., Whitehorn D., Brown M., Turro E., Thrasher A.J., Smith K.G.C., Thaventhiran J.E., Kuijpers T.W., and NIHR BioResource—Rare Diseases Consortium. 2018. 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. 142:1285–1296.
Vallabhapurapu S. and Karin M. 2009. Regulation and function of NF-κB transcription factors in the immune system. Annu. Rev. Immunol. 27:693–733.
Zhang Q., Lenardo M.J., and Baltimore D. 2017. 30 years of NF-κB: A blossoming of relevance to human pathobiology. Cell. 168:37–57.
Information & Authors
Information
Published In
LymphoSign Journal
Volume 6 • Number 2 • June 2019
Pages: 61 - 67
History
Received: 8 April 2019
Accepted: 22 May 2019
Accepted manuscript online: 24 May 2019
Copyright
© 2019.
Authors
Metrics & Citations
Metrics
Other Metrics
Citations
Cite As
LucyDuan and StephenFeanny. 2019. Novel heterozygous NFKB1 mutation in a pediatric patient with cytopenias, splenomegaly, and lymphadenopathy. LymphoSign Journal.
6(2): 61-67. https://doi.org/10.14785/lymphosign-2019-0006
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
There are no citations for this item
View Options
Login options
Check if you access through your login credentials or your institution to get full access on this article.
