Basic and clinical immunology
The presentation and natural history of immunodeficiency caused by nuclear factor κB essential modulator mutation

https://doi.org/10.1016/j.jaci.2004.01.762Get rights and content

Abstract

Background

An increasing number of rare genetic defects are associated with immunodeficiency and impaired ability to activate gene transcription through nuclear factor (NF) κB. Hypomorphic mutations in the NFκB essential modulator (NEMO) impair NFκB function and are linked to both immunodeficiency and ectodermal dysplasia (ED), as well as susceptibility to atypical mycobacterial infections.

Objective

We sought to investigate the clinical and immunologic natural history of patients with NEMO mutation with immunodeficiency (NEMO-ID).

Methods

Patients with severe bacterial infection and ED or unexplained mycobacterial sensitivity were evaluated for NEMO mutation. Laboratory investigations and clinical data were retrospectively and prospectively accumulated and reviewed.

Results

We have given a diagnosis of NEMO-ID to 7 boys; 6 had ED, and 5 had gene mutations in the 10th exon of NEMO. Our resulting estimated incidence of NEMO-ID is 1:250,000 live male births. All patients had serious pyogenic bacterial illnesses early in life, and the median age of first infection was 8.1 months. Most boys had mycobacterial disease (median age, 84 months), and a minority had herpesviral infections. Initial immunologic assessments showed hypogammaglobulinemia (median IgG, 170 mg/dL) with variable IgM (median, 41 mg/dL) and IgA (median, 143 mg/dL) levels. Two patients had increased IgM levels, and 5 had increased IgA levels. All patients evaluated had normal lymphocyte subsets with impaired proliferative responses, specific antibody production, and natural killer cell function. Two patients died from complications of mycobacterial disease (ages 21 and 33 months).

Conclusion

NEMO-ID is a combined immunodeficiency with early susceptibility to pyogenic bacteria and later susceptibility to mycobacterial infection. Specific features of particular NEMO mutations in these patients provide insight into the role of this gene in immune function.

Section snippets

Patients

Our patients all presented for evaluation of immunodeficiency to Children's Hospital Boston between 1984 and 2002. All studies were performed with informed parental consent–child assent and were approved by the Children's Hospital Committee on Clinical Investigation.

Brief clinical presentations, NEMO mutation, and some immunologic characteristics of patients 1 to 3 have been described in a previous publication and correspond to patients 1 to 3 in that report.21 Additional investigations of NFκB

Diagnosis of ED-ID or NEMO-ID

A diagnosis of NEMO-ID was considered on the basis of severe infection with characteristics of ED in patients 1 to 4, 6, and 7, or recurrent infection and atypical mycobacterial disease in patient 5. Before evaluation for a NEMO mutation, extensive immunologic investigations effectively excluded known genetic and acquired causes of immunodeficiency. The characteristics of ED for diagnosis are described11 and included the following: hypohidrosis; conical or peg-shaped teeth with oligodontia;

Discussion

Although patients having NEMO-ID were in part originally identified on the basis of their susceptibility to mycobacterial infections, a hallmark of the boys described here was severe pyogenic bacterial infections early in life. This feature highlights the underlying pathophysiology of the gene mutation. Aside from its role in adaptive immunoreceptor signaling, NFκB activation is essential for function of innate immunoreceptors. In particular, toll-like receptors (TLRs), which recognize

Note added in proof

After the acceptance of this manuscript, another protein, Bc110, has been shown to act on NEMO and require an intact NEMO zinc finger for function (Zhou et al. Nature 2004;427:167–71). It is likely that this interaction is impaired in certain NEMO-ID patients and participates in the mechanism underlying the immunodeficiency.

Acknowledgements

We thank the patients and families affected by NEMO-ID for their devotion to research. We also thank Ms Cathy Howlett, Mackenzie Dismore, and Wendy Rasmussen for technical assistance; Drs Marilyn Liang, Stephen Gellis, Samuel Nurko, Daniel Pietryga, Julia Kohler, Ofer Levy, Hans Oettgen, and Steven Holland for advice; and Drs Thomas Fleisher, Jonathan Zonana, Betsy Ferguson, and Narayanaswamy Ramesh for help with genetic analyses.

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    Dr Orange is currently affiliated with the Division of Immunology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pa.

    Supported by National Institutes of Health Grants AI-31541 and 31136 (to R.S.G) and AI-55602 (to J.S.O.), the Children's Hospital General Clinical Research Center grant MO1-RR02172 from the General Clinical Research Centers Program, the National Center for Research Resources, and the Jeffrey Modell Foundation.

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