Orange JS, Jain A, Ballas ZK, Schneider LC, Geha RS, Bonilla FA. J Allergy Clin Immunol. 2004;113:725–733
Purpose of the Study.
To describe the clinical and immunologic natural history of patients with immunodeficiency associated with mutation in nuclear factor κB modulator (NEMO).
Seven boys who presented to Children’s Hospital Boston (Boston, MA) for immunodeficiency evaluation between 1984 and 2002 and were diagnosed to have a NEMO mutation with immunodeficiency (NEMO-ID).
Patients with recurrent bacterial infection and ectodermal dysplasia (ED) or atypical mycobacterial infection were evaluated by sequence analysis for NEMO mutation. Functional analyses of these mutations have been described previously. Genomic and complementary DNA from patient leukocytes were sequenced and compared with 40 healthy individuals. Serum immunoglobulin concentrations, leukocyte enumeration, lymphocyte subset numbers and function, nitroblue tetrazolium reduction, total hemolytic complement, and natural killer cell cytotoxicity were measured by using standard assays. Data were obtained both retrospectively and prospectively. NEMO-ID incidence rates were approximated by using US census data for the catchment area of Children’s Hospital Boston. Immunologic measurements were compared with laboratory-specific age-related norms, and significance of differences was assessed by Student’s t test.
The estimated incidence of NEMO-ID is 1 in 250 000 live male births. Four of the 6 independent mutations described (2 patients were half-siblings) affected the C-terminal zinc-finger domain encoded by exon 10. Six of 7 patients presented with ED. All patients had serious pyogenic bacterial infections early in life (median age at first infection: 8.1 months; range: 0.1–60.9 months). Immunodeficiency was diagnosed before ED in all patients. Five of 7 patients had infection with atypical mycobacteria (median: 84 months old; range: 14–168 months old). The most severe clinical phenotype was seen in the 2 sibling patients with a mutation resulting in truncation of >50% of the final exon. That mutation was also associated with a pattern of immunoglobulin dysregulation consisting of hyper-IgM and hypo-IgA. All but 1 patient (patient 5) was hypogammaglobulinemic, and all were deficient in specific antibody production. However, 5 of 6 mutations were associated with hyper-IgA. Patient 5, who has an unusual mutation causing deletion of exon 9, was also uniquely unaffected by ED. Lymphocyte subsets and in vitro function were variable, although natural killer cell cytolysis was markedly depressed in all patients tested (n = 5).
NEMO-ID is an X-linked combined immunodeficiency characterized by early susceptibility to pyogenic bacteria and later susceptibility to mycobacterial infection.
The majority of reported mutations in NEMO affect exon 10. This report extends our knowledge of NEMO-ID and suggests genotype-phenotype correlations, including for the first time a description of NEMO-ID without ED. The striking incidence of early pyogenic infections deserves emphasis and suggests defects in innate immunity. Severe pyogenic bacterial infection should prompt consideration of nuclear factor κB–activation disorders, especially when accompanied by hyper-IgA.