Boys with NEMO: Brandon - Cameron - Conner - Cooper
- Gavin -
- Jackson - Jackson -
Contact email: andy [at] andy.org.mx
Voice: 1 617 8483958
Postal: 423 Brookline Ave. 149, Boston, Ma. 02215, USA
NEMO is a complicated disease caused by a genetic mutations in the IKBKG gene. The official name of this gene is “inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma.” NEMO can involve many different cells of the body, and it often manifests in different ways in different individuals depending on the location of the mutation inside the gene. The most common clinical finding are skin and dental issues and susceptibility to specific bacterial, viral infections It’s considered an immunodeficiency that affects multiple facets of the immune system. Patients often have severe infections that can affect virtually any part of the body.
Definition of NEMO
NEMO originated as a clinical association between ectodermal dysplasia (ED) and susceptibility to infections. Such patients had the constellation of findings consistent with ectodermal dysplasia (thickened skin, conical teeth, absence of sweat glands, as well as thin and sparse hair). In addition to the dry, flaky skin of ectodermal dysplasia, patients had a range of infections with pyogenic organisms (S. pneumoniae and S. aureus) being the most prevalent. Infections were found in a range of tissues including the lungs, skin, central nervous system, liver, abdomen, urinary tract, bones, and gastrointestinal tract. Almost all cases occur in boys.
The early description of these patients indicated a range of severity and infections. Many patients exhibited B cell problems with a complete lack of response against bacteria such as S. pneumoniae. Other patients exhibited defects in other arms of the immune system with susceptibility to mycobacteria and skin infections.
In 2001, research uncovered the genetics of the large majority of these cases, and in these patients, the disease was renamed NEMO to reflect the genetic mutation. NEMO is a protein, it stands for the NF-κB Essential Modulator and is also known as the Inhibitor of Kappa Kinase γ (IKKγ). The protein acts as a scaffold for two other proteins to form a protein kinase complex. This complex is required for the downstream activation of the NF-κB family of transcription factors, which further regulate gene expression. This family of proteins regulates the development of a number of organ systems, including the immune system. Indeed, in the complete absence of NEMO activity, the effects cause embryonic lethality.
In patients with NEMO, the NEMO protein retains residual activity, but the activity is blunted. These “hypomorphic” proteins allow an embryo to develop, but many organ systems fail to develop normally, including the immune system. In the NEMO syndrome, B cells, T cells, neutrophils, macrophages, and dendritic cells respond poorly to bacterial and fungal invasion. This leads to problems in the engagement of the innate immune system as well as the formation of protective antibodies against microbes. The discovery of the genetics helped explain why patients showed such a wide-range of infectious susceptibilities.
There is at least one additional genetic cause of NEMO with defects in a similar pathway. While this form can affect both males and females, the disease is extremely rare.
Clinical Presentation of NEMO
NEMO can be a difficult diagnosis because of the wide range of presentations. Three typical presentations include: 1) Susceptibility to pyogenic infections, 2) Ectodermal Dysplasia, and 3) Susceptibility to Mycobacterial infection.
In the developed world, patients tend to present with susceptibility to pyogenic infections. Most commonly, patients tend to present with severe infections with the bacterium, S. pneumoniae, despite universal vaccination. Meningitis during the first year of life is a common presentation. Patients can also have deep tissue infections with S. aureus in the skin, liver, abdomen, bones, and lungs.
Ectodermal dysplasia is difficult to recognize early in life. As infants often have eczematous rashes and thin, sparse hair, infants with ectodermal dysplasia may go undetected. The eruption of conical teeth, however, is an important sign that should be examined closely.
In developing countries, particularly those that use the Bacillus Calmette- Guérin (BCG) live vaccine, patients with the NEMO syndrome may present with disseminated BCG-osis with the vaccine strain of the mycobacteria often invading a number of organ systems.
While meningitis or other deep tissue infection raises the immediate concern for a primary immunodeficiency, the presentation of the NEMO syndrome can also be more subtle with a history of recurrent skin infections or an infectious history similar to the presentation of common variable immunodeficiency. Fungal infections have also been noted in these patients.
Diagnosis of NEMO
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.
Therapy for NEMO
Therapy for NEMO is aimed at preventing infectious complications. Patients receive immunoglobulin replacement for the humoral immunodeficiency. While a cornerstone of therapy, this is insufficient to control infections given the broad-based immune defects in these patients. Therefore, patients also receive a series of antibiotics as part of their preventive regimen. These antibiotics are aimed at protecting the patients against S. pneumoniae, S. aureus, and mycobacterial infections.
Patients with NEMO should see their primary care physician and immunologist regularly as complications both infectious and otherwise are frequent. Patients with NEMO should also be monitored for bone health as NEMO syndrome patients may be less able to make strong bones (though recurrent fractures have not been a common theme amongst these patients).
Expectations for the NEMO patient
Patients with NEMO have a number of issues that make prognostication of their clinical course difficult. First, the relatively recent recognition of the disease and rarity mean that little data exist to give any concrete guidance with regard to long-term outcomes. Second, we do know that amongst patients with the diagnosis, there is wide variability in the severity of the immune deficiency. While some patients can expect relatively normal life expectancy, many patients have severe forms of the disease with both infectious and non-infectious complications. These non-infectious complications have been particularly difficult to understand as these entities often mimic infection during presentation. Further research is needed to fully understand both the immune defects and immune dysregulation observed in both NEMO in general as well as with individual genotypes. Hematopoietic stem cell transplantation has been used for NEMO patients with varying outcomes.