Once suspected, a patient must have a thorough immunologic screen to evaluate NEMO though genetic testing is the only means to definitively make the diagnosis. Unfortunately, patients with NEMO can have a varied presentation, but in general, the patients will have a “signature” of test results.
Most NEMO patients will have an elevated IgM, though it is not usually as high as is seen in classic hyper IgM syndrome. Patients also tend to have low IgG, IgA, and IgE. However, it is important to note that patients may also have normal levels of all immunoglobulins early in life. Patients may also tend to have normal
to high total leukocyte counts. They may have a slight neutrophilic predominance. Lymphocyte subsets are often normal with normal to subtly diminished findings in lymphocyte proliferative analyses.
One key (and nearly universal) feature of NEMO is absence of anti-pneumococcal responses following pneumococcal vaccination with either the conjugated (Prevnar or Prevnar 13) or polysaccharide pneumonia vaccine (Pneumovax). This finding is even found in patients with otherwise normal total immunoglobulin levels.
Research-based testing is more revealing. Innate immune cells from patients with NEMO demonstrate poor responses after stimulation with molecules derived from microbes. Though such findings do not make the diagnosis of NEMO , these tests offer valuable insights into host defense defects.
Genetic testing for the NEMO gene (IKBKG gene) is commercially available. NEMO follows an X-linked inheritance pattern. The genetic variants are considered hypomorphic mutations rather than a complete loss of NEMO protein activity.