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Successful hematopoietic cell transplantation in patients with unique NF-κB essential modulator (NEMO) mutations

Bone Marrow Transplantation volume 49, pages 1446–1447 (2014)Cite this article

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The use of allo-HSCT in NF-κB essential modulator (NEMO) deficiency caused by hypomorphic IKBKG mutations remains a controversial topic. Initial observations led to widespread concerns that allo-HSCT preparative regimens were poorly tolerated;1 and, in those who escaped chemotherapy-associated toxicity, there were additional concerns that the underlying somatic tissue defects were exacerbated.2,3 In particular, it was proposed that introducing a competent immune system into a NEMO-deficient host results in severe, chronic intestinal inflammation and infection as a response to increased translocation of enteric bacteria.4 As more patients have been identified, it has become apparent that the somatic features that result from hypomorphic IKBKG mutations are quite variable. This phenotypic variability supports the notion that the effect of introducing a competent immune system into NEMO-deficient patients may also be variable. We report allo-HSCT in two patients with hypomorphic IKBKG mutations with successful outcomes, including full immune reconstitution.

Allo-HSCT was carried out in patient 1, a 2-year-old boy with Pneumocystis jirovecii pneumonia and CMV viremia, who was found to have a novel mutation in the first coiled-coil domain of IKBKG, c.337G>A (p.Asp113Asn). Clinical and laboratory features were previously reviewed and were significant for the absence of the somatic problems of oligodontia, ectodermal dysplasia or chronic gastrointestinal (GI) disease.5 Despite both impaired natural killer (NK) cell function and impaired T-cell receptor (TCR) signaling, Toll-like receptor (TLR) signaling appeared to be intact.5 The patient received a myeloablative conditioning regimen consisting of BU, CY and equine antithymocyte globulin (ATG) followed by 10/10-matched, unrelated umbilical cord blood allo-HSCT. Post transplant, the patient developed allergies to sulfa and walnuts but did not develop chronic GI symptoms. Complete donor chimerism was achieved and T- and B-cell reconstitution was complete. He was able to discontinue replacement IgG therapy, and he responded appropriately to both conjugate and live virus vaccines. He remains well, 6 years post allo-HSCT.

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References

  1. Dupuis-Girod S, Corradini N, Hadj-Rabia S, Fournet J-C, Faivre L, Le Deist F et al. Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pigmenti in his mother. Pediatrics 2002; 109: e97.

    Article  Google Scholar 

  2. Fish JD, Duerst RE, Gelfand EW, Orange JS, Bunin N . Challenges in the use of allogeneic hematopoietic SCT for ectodermal dysplasia with immune deficiency. Bone Marrow Transplant 2008; 43: 217–221.

    Article  Google Scholar 

  3. Pai S-Y, Levy O, Jabara HH, Glickman JN, Stoler-Barak L, Sachs J et al. Allogeneic transplantation successfully corrects immune defects, but not susceptibility to colitis, in a patient with nuclear factor-kappaB essential modulator deficiency. J Allergy Clin Immunol 2008; 122: 1113–1118 e1.

    Article  CAS  Google Scholar 

  4. Nenci A, Becker C, Wullaert A, Gareus R, van Loo G, Danese S et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 2007; 446: 557–561.

    Article  CAS  Google Scholar 

  5. Salt BH, Niemela JE, Pandey R, Hanson EP, Deering RP, Quinones R et al. IKBKG (nuclear factor-κB essential modulator) mutation can be associated with opportunistic infection without impairing Toll-like receptor function. J Allergy Clin Immunol 2008; 121: 976–982.

    Article  CAS  Google Scholar 

  6. Devora GA, Sun L, Chen Z, van Oers NSC, Hanson EP, Orange JS et al. A novel missense mutation in the nuclear factor-κB essential modulator (NEMO) gene resulting in impaired activation of the NF-κB pathway and a unique clinical phenotype presenting as MRSA subdural empyema. J Clin Immunol 2010; 30: 881–885.

    Article  Google Scholar 

  7. Permaul P, Narla A, Hornick JL, Pai S-Y . Allogeneic hematopoietic stem cell transplantation for X-linked ectodermal dysplasia and immunodeficiency: case report and review of outcomes. Immunol Res 2009; 44: 89–98.

    Article  Google Scholar 

  8. Tono C, Takahashi Y, Terui K, Sasaki S, Kamio T, Tandai S et al. Correction of immunodeficiency associated with NEMO mutation by umbilical cord blood transplantation using a reduced-intensity conditioning regimen. Bone Marrow Transplant 2007; 39: 801–804.

    Article  CAS  Google Scholar 

  9. Mancini AJ, Lawley LP, Uzel G . X-linked ectodermal dysplasia with immunodeficiency caused by NEMO mutation: early recognition and diagnosis. Arch Dermatol 2008; 144: 342–346.

    Article  Google Scholar 

  10. Imamura M, Kawai T, Okada S, Izawa K, Takachi T, Iwabuchi H et al. Disseminated BCG infection mimicking metastatic nasopharyngeal carcinoma in an immunodeficient child with a novel hypomorphic NEMO mutation. J Clin Immunol 2011; 31: 802–810.

    Article  Google Scholar 

  11. Kawai T, Nishikomori R, Izawa K, Murata Y, Tanaka N, Sakai H et al. Frequent somatic mosaicism of NEMO in T cells of patients with X-linked anhidrotic ectodermal dysplasia with immunodeficiency. Blood 2012; 119: 5458–5566.

    Article  CAS  Google Scholar 

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Acknowledgements

JKA is the recipient of a fellowship grant from CSL Behring.

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Authors and Affiliations

  1. Division of Allergy and Immunology, Department of Pediatrics, National Jewish Health, Denver, CO, USA

    J K Abbott & E W Gelfand

  2. Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplant, Children’s Hospital Colorado, Aurora, CO, USA

    R R Quinones

  3. Division of Allergy and Immunology, University of Texas Southwestern Medical Center in Dallas and Children’s Medical Center, Dallas, TX, USA

    M T de la Morena

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  1. J K Abbott
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  2. R R Quinones
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  4. E W Gelfand
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Correspondence to E W Gelfand.

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Abbott, J., Quinones, R., de la Morena, M. et al. Successful hematopoietic cell transplantation in patients with unique NF-κB essential modulator (NEMO) mutations. Bone Marrow Transplant 49, 1446–1447 (2014). https://doi.org/10.1038/bmt.2014.157

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