Nuclear factor κB essential modulator–deficient child with immunodeficiency yet without anhidrotic ectodermal dysplasia

Niehues, Tim; Reichenbach, Janine; Neubert, Jennifer; Gudowius, Sonja; Puel, Anne; Horneff, Gerd; Lainka, Elke; Dirksen, Uta; Schroten, Horst; Döffinger, Rainer; Casanova, Jean Laurent; Wahn, Volker

doi:10.1016/j.jaci.2004.08.047

« Previous Next »The Journal of Allergy and Clinical Immunology
Volume 114, Issue 6 , Pages 1456-1462, December 2004

Nuclear factor κB essential modulator–deficient child with immunodeficiency yet without anhidrotic ectodermal dysplasia

Tim Niehues, MD
- From the Pediatric Immunology and Rheumatology Unit, Departments of Pediatric Oncology, Hematology, and Immunology, and General Pediatrics, Heinrich Heine Universität Duesseldorf
- These two authors contributed equally to this work.
- Reprint requests: Tim Niehues, MD, Pediatric Immunology and Rheumatology Unit, Department of Pediatric Oncology, Hematology and Immunology, Heinrich Heine Universität Düsseldorf, Moorenstr 5, 40225 Düsseldorf, Germany.
Janine Reichenbach, MD
- Unite d'Immunologie et d′Hematologie Pediatriques, Laboratoire de Genetique Humaine des Maladies Infectieuses, Universite de Paris Rene Descartes-INSERM U550, Faculte de Medecine Necker-Enfants Malades, Paris
- These two authors contributed equally to this work.
Jennifer Neubert, MD
- From the Pediatric Immunology and Rheumatology Unit, Departments of Pediatric Oncology, Hematology, and Immunology, and General Pediatrics, Heinrich Heine Universität Duesseldorf
Sonja Gudowius, MD
- From the Pediatric Immunology and Rheumatology Unit, Departments of Pediatric Oncology, Hematology, and Immunology, and General Pediatrics, Heinrich Heine Universität Duesseldorf
Anne Puel, MD
- Unite d'Immunologie et d′Hematologie Pediatriques, Laboratoire de Genetique Humaine des Maladies Infectieuses, Universite de Paris Rene Descartes-INSERM U550, Faculte de Medecine Necker-Enfants Malades, Paris
Gerd Horneff, MD
- Department of Pediatrics, Martin Luther University Halle-Wittenberg
Elke Lainka, MD
- From the Pediatric Immunology and Rheumatology Unit, Departments of Pediatric Oncology, Hematology, and Immunology, and General Pediatrics, Heinrich Heine Universität Duesseldorf
Uta Dirksen, MD
- From the Pediatric Immunology and Rheumatology Unit, Departments of Pediatric Oncology, Hematology, and Immunology, and General Pediatrics, Heinrich Heine Universität Duesseldorf
Horst Schroten, MD
- From the Pediatric Immunology and Rheumatology Unit, Departments of Pediatric Oncology, Hematology, and Immunology, and General Pediatrics, Heinrich Heine Universität Duesseldorf
Rainer Döffinger, MD
- Unite d'Immunologie et d′Hematologie Pediatriques, Laboratoire de Genetique Humaine des Maladies Infectieuses, Universite de Paris Rene Descartes-INSERM U550, Faculte de Medecine Necker-Enfants Malades, Paris
Jean Laurent Casanova, MD
- Unite d'Immunologie et d′Hematologie Pediatriques, Laboratoire de Genetique Humaine des Maladies Infectieuses, Universite de Paris Rene Descartes-INSERM U550, Faculte de Medecine Necker-Enfants Malades, Paris
Volker Wahn, MD
- Children's Hospital Schwedt/Oder

Received 24 July 2004; received in revised form 19 August 2004; accepted 20 August 2004. published online 28 October 2004.

Duesseldorf, Schwedt, Halle, and Wittenberg, Germany, and Paris, France

Background

Amorphic mutations in the X-linked nuclear factor κB essential modulator (NEMO) gene cause Incontinentia pigmenti, which is lethal in hemizygous male patients. Hypomorphic NEMO mutations in male patients lead to anhidrotic ectodermal dysplasia (EDA) with immunodeficiency.

Objective

To report the clinical features of a child bearing a NEMO mutation who displayed an immunodeficiency without EDA.

Methods

Documentation of clinical care, chart review, standard immunologic and microbiological laboratory techniques, mutation analysis of the NEMO gene.

Results

Since the age of 15 months, the patient had Mycobacterium avium disease, beginning with multiple adenitis, later followed by disseminated osteomyelitis and dermatitis. In addition, Haemophilus influenzae and Streptococcus pneumoniae infections led to bronchiectasis. An immunologic work-up revealed a low production of IFN-γ by PBMCs associated with a hyper-IgM phenotype. Despite treatment using repeated cycles of a 4-drug antimycobacterial regimen, continuous subcutaneous IFN-γ, repeated antibiotic treatment, and intravenous immunoglobulin substitution, the boy remained chronically ill. At the age of 12 years, the disease was complicated by severe autoimmune hemolytic anemia and eventually fatal herpes simplex virus 1 encephalitis despite high-dose acyclovir therapy. Although he did not present any sign of EDA, a novel type of disease-causing hypomorphic NEMO mutation (110-111insC in exon 2) was identified.

Conclusion

This case demonstrates that patients hemizygous for NEMO mutations can present with an immunodeficiency without EDA. An investigation of NEMO should thus be undertaken in selected children with immunodeficiency despite the lack of EDA.

Key words: Children, hyper-IgM, immunodeficiency, ectodermal dysplasia, mycobacteria

Abbreviations used: DTH, Delayed-type hypersensitivity, EDA, Ectodermal dysplasia, EDA-ID, Ectodermal dysplasia with immunodeficiency, EDAR, Receptor for ectodysplasin, HIGM, Hyper-IgM syndrome, HSV, Herpes simplex virus 1, MRI, Magnetic resonance imaging, NEMO, Nuclear factor κB essential modulator, NFκB, Nuclear factor κB, OL-EDA-ID, Ectodermal dysplasia with immunodeficiency, osteopetrosis, lymphedema, and hemangiomas, PPD, Purified protein D, RANK, Receptor activator of NFκB