NF- ?B Essential Modulator Deficiency Leading to Disseminated Cutaneous Atypical Mycobacteria
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Keywords
Immunodeficiency, NEMO, rare diseases, mycobacterial Infections
Abstract
NF- ?B essential modulator (NEMO) is a kinase integral to the macrophage TNF-? pathway, which leads to the intracellular destruction of Mycobacteria species. Defects in the NEMO pathway lead to a spectrum of diseases, including but not limited to ectodermal dysplasia, Mendelian susceptibility to mycobacterial diseases, and incontinentia pigmenti. In addition, paucity of NEMO can lead to the inability to mount a proper immune response against opportunistic pyogenic and mycobacterial infections, leading to dissemination to various organ systems. This manuscript will discuss the numerous clinical manifestations of NEMO deficiency, the differential diagnosis for atypical mycobacterial infections in immunocompetent adults, and feature a case report of rare isolated susceptibility to disseminated atypical mycobacteria due to a mutation in the first exon of the NEMO gene.
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References
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Incontinentia pigmenti or Bloch-Sulzberger syndrome: a rare X-linked genodermatosis. An Bras Dermatol. 2014; 89(3): 486-489.
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24. Chi CY, Chu CC, Liu JP, et al. Anti-IFN-y autoantibodies in adults with disseminated non tuberculous mycobacterial infections are associated with HLA-DRB1*16:02 and HLA-DQB1*05:02 and the reactivation of latent varicella-zoster virus infection. Blood. 2013 Feb 21;121(8):1357-66.
25. Lee WI, Huang JL, Wu TS, et al. Patients with inhibitory and neutralizing auto-antibodies to interferon –y resemble the sporadic adult onset phenotype of Mendelian susceptibility to Mycobacterial Disease (MSMD) lacking Bacille Calmette-Guerin (BCG) induced diseases. Immunobiology. 2013 May; 218(5):762-71.
26. Bustamante J, Arias AA, Vogt G, et al. Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked presisposition to tuberculous mycobacterial disease. Nat Immunol. 2011 Mar;12(3):213-21.
27. Lee W, Huang JL, Yeh KW, et al. Immune defects in active mycobacterial diseases in patients with primary immunodeficiency diseases (PIDs). Journal of the Formosan Medical Association. 2011; 110(12): 750-758.
28. Chapgier A, Boisson-Dupuis S. Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease. PLoS Genet. 2006 Aug 18;2(8):e131.
2. Frucht DM, Holland SM. Defective monocyte costimulation for IFN-gamma production in familial disseminated Mycobacterium avium complex infection: abnormal IL-12 regulation. J Immunol.1996 Jul 1;157(1):411-6.
3. Newport MJ, CM Huxley, Huston S, et al. 1996. A mutation in the interferon-?-receptor gene and susceptibility to mycobacterial infection. N. Engl. J. Med. 335:1941–1949.
4. Filipe-Santos O, Bustamante J, Haverkamp MH, et al. X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production. JEM. 2006; 203(7):1745-1749.
5. Tarantino N, Tinevez JY, Crowell EF, et al. TNF and IL-1 exhibit distinct ubiquitin requirements for inducing NEMO-IKK supramolecular structures. J Cell Biol. 2014; 204(2):231-45.
6. Schmidt-Supprian M, Bloch W, Courtois G, et al.
NEMO/IKK?-Deficient Mice Model Incontinentia Pigmenti. Mol Cell. 2000; 5(6):981-992.
7. Makris C, Godfrey VL, Krahn-Senftleben, et al. Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol Cell. 2000 Jun;5(6):969-79.
8. Zonana J, Elder ME, Schneider LC, et al. A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am J Hum Genet. 2000;67:1555.
9. Orange JS, Jain A, Ballas ZK, Schneider LC, Geha RS, Bonilla FA. The presentation and natural history of immunodeficiency caused by nuclear factor kappaB essential modulator mutation. J Allergy Clin Immunol. 2004 Apr;113(4):725-33.
10. Gilmore TD. Introduction to NF-[kappa]B: Players, Pathways, Perspectives. Oncogene. 2006. Oct 30;25(51):6680-4.
11. Hanson EP, Monaco-Shawver L, Solt LA, et al. Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. J Allergy Clin Immunol. 2008 Dec;122(6):1169-1177.
12. Orange JS, Geha RS. Finding NEMO: genetic disorders of NF- kappa B activation. J Clin Invest. 2003; 112:983.
13. Puel A, Picard C, Ku CL, Smahi A, Casanova JL. Inherited disorders of NF-kappaB-mediated immunity in man. Curr Opin Immunol. 2004; 16:34.
14. Huttner K. Future Developments in XLHED Treatment Approaches. Am J Med Genet. Part A. 9999:1–4.
15. Clarke A, Phillips DI, Brown R, Harper PS. Clinical aspects of X-linked hypohidrotic ectodermal dysplasia. Arch Dis Child. 1987; 62:989–996.
16. Temmerman ST, Ma CA, Zhao Y, et al. Defective nuclear IKK? function in patients with ectodermal dysplasia with immune deficiency. J Clin Invest. 2012; 122(1): 315–326.
17. Mooster JL, Cancrini C, Simonetti A, et al. Immune deficiency caused by impaired expression of nuclear factor-?B essential modifier (NEMO) because of a mutation in the 5? untranslated region of the NEMO gene. J Allergy Clin Immunol. 2010; 126(1): 127-32.e7.
18. Fete T. Respiratory problems in patients with ectodermal dysplasia syndromes. Am J Med Genet. 2014. Part A 9999:1–4.
19. Ku CL, Picard C, Erd?s M, et al. IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J Med Genet. Jan 2007; 44(1): 16–23.
20. Marques GF, Tonello CS, Martins J, Sousa P.
Incontinentia pigmenti or Bloch-Sulzberger syndrome: a rare X-linked genodermatosis. An Bras Dermatol. 2014; 89(3): 486-489.
21. Mini?, S., Trpinac, D, Obradovi?, M. Incontinentia pigmenti diagnostic criteria update. Clinical Genetics. 2014; 85: 536–542.
22. Camargo JF, Lobo SA, Hsu AP, Zerbe CS, Wormser GP, Holland SM. MonoMAC Syndrome in a patient with a GATA2 mutation: Case report and review of literature. Clin Infect Dis. 2013 Sep;57(5):697-9.
23. Beaussant CS, Fenneteau O, Plouvier E, et al. Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry. Orphanet J Rare Dis. Sep 2012 25;7:71.
24. Chi CY, Chu CC, Liu JP, et al. Anti-IFN-y autoantibodies in adults with disseminated non tuberculous mycobacterial infections are associated with HLA-DRB1*16:02 and HLA-DQB1*05:02 and the reactivation of latent varicella-zoster virus infection. Blood. 2013 Feb 21;121(8):1357-66.
25. Lee WI, Huang JL, Wu TS, et al. Patients with inhibitory and neutralizing auto-antibodies to interferon –y resemble the sporadic adult onset phenotype of Mendelian susceptibility to Mycobacterial Disease (MSMD) lacking Bacille Calmette-Guerin (BCG) induced diseases. Immunobiology. 2013 May; 218(5):762-71.
26. Bustamante J, Arias AA, Vogt G, et al. Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked presisposition to tuberculous mycobacterial disease. Nat Immunol. 2011 Mar;12(3):213-21.
27. Lee W, Huang JL, Yeh KW, et al. Immune defects in active mycobacterial diseases in patients with primary immunodeficiency diseases (PIDs). Journal of the Formosan Medical Association. 2011; 110(12): 750-758.
28. Chapgier A, Boisson-Dupuis S. Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease. PLoS Genet. 2006 Aug 18;2(8):e131.