Persistent nodal histoplasmosis in nuclear factor kappa B essential modulator deficiency: Report of a case and review of infection in primary immunodeficiencies

Multiple cell surface receptors converge on the induction of NF-κB activation, including CD40, the Toll-like receptors, TNF-α receptor, IL-1 receptor, and the receptor for ectoderm formation, ectodysplasin.2 Amorphic mutations in the X-linked gene for NEMO (IKBKG) are lethal prenatally in males, but cause incontinentia pigmenti in females.3 Lyonization allows cells with normal NEMO expression to survive; however, those cells with completely absent expression die with inflammatory consequences.3 Hypomorphic NEMO mutations resulting in reduced activation of NF-κB permit male survival and cause a spectrum of conditions, including ectodermal dysplasia, invasive pneumococcal diseases, and mycobacterial disease.3,4 Reduced natural killer cell function, variable hypogammaglobulinemia, and impaired function of the receptors of innate immunity predispose to viral, pyogenic bacterial, and mycobacterial infections.5 NEMO mutations can also impair CD40 signaling in monocytes, leading to diminished IL-12 secretion and therefore impaired IFN-γ production and increased susceptibility to mycobacterial infections, suggesting that activation of NF-κB by NEMO is essential for the destruction of intracellular pathogens.4 A 52-year-old man with NEMO deficiency presented to our institution with 1 year of mildly worsening dyspnea and intermittent night sweats. STAT3 deficiency (5 patients),E7-E11 CD40L deficiency (1 patient),E12 and GATA2 deficiency (3 patients), a disorder characterized by impaired phagocytic activity.E13,E14 Additional cases of disseminated histoplasmosis were reported in patients with PIDs diagnosed on the basis of clinical history and/or immunoglobulin levels: ICL (4 patients),E15-E18 common variable immunodeficiency (CVID) (3 patients),E19-E21 chronic mucocutaneous candidiasis (CMC) (3 patients),E22-E24 hyper-IgM syndrome (2 patients),E25,E26 hyper-IgE syndrome (1 patient),E27 and a clinically suspected case of Warts, Hypogammaglobulinemia, Infections, Myelokathexis syndrome (1 patient).\n Although our patient represents the only case yet identified of histoplasmosis in NEMO deficiency, susceptibility to disseminated histoplasmosis in CD40L deficiency also confirms the importance of intact activation of NF-κB. These observations suggest that the administration of IFN-γ might be therapeutic, as reported in a patient with autosomal- dominant IFN-γ receptor 1 deficiency and recurrent Histoplasma osteomyelitis who progressively cleared all bone lesions