Published online April 24, 2006
PEDIATRICS Vol. 117 No. 5 May 2006, pp. e1049-e1056 (doi:10.1542/peds.2005-2062)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schmid, J. M. P.
Right arrow Articles by Gungor, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schmid, J. M. P.
Right arrow Articles by Gungor, T.
Related Collections
Right arrow Infectious Disease & Immunity
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

EXPERIENCE & REASON

Transient Hemophagocytosis With Deficient Cellular Cytotoxicity, Monoclonal Immunoglobulin M Gammopathy, Increased T-Cell Numbers, and Hypomorphic NEMO Mutation

Jana M. Pachlopnik Schmid, MD, PhDa, Sonja A. Junge, MD, PhDa, Johann Peter Hossle, PhDa, E. Marion Schneider, PhDb, Eddy Roosnek, PhDc, Reinhard A. Seger, MDa and Tayfun Gungor, MDa

a Division of Immunology/Hematology/BMT, University Children's Hospital, Zurich, Switzerland
b Section of Experimental Anesthesiology, University of Ulm, Ulm, Germany
c Division of Immunology and Allergology, University Hospital, Geneva, Switzerland

ABSTRACT

X-linked osteopetrosis, anhydrotic ectodermal dysplasia, and immunodeficiency (XL-O-EDA-ID) is a disorder that is caused by hypomorphic mutations in the nuclear factor {kappa}B essential modulator (NEMO). These mutations lead to an impaired NF-{kappa}B activation. In vitro analyses and studies in animal models show that inhibition of NF-{kappa}B leads to a decrease of cytokine production and T-cell proliferation. Patients classically display poor or delayed inflammatory response to infections. We describe a boy with XL-O-EDA-ID, 1167-1168insC NEMO mutation, and recurrent infections. In early infancy, he experienced hemophagocytosis with transient deficiency of natural killer activity. Increased immunoglobulin M levels in blood resulted from a monoclonal immunoglobulin M gammopathy. Blood T-cell numbers were constantly increased, most probably resulting from a peripheral T-cell expansion. Our observations suggest that patients with hypomorphic NEMO mutations and repeated infections may experience inflammatory dysregulation.

Key Words: NEMO • immunodeficiency • hemophagocytic disease • monoclonal gammopathy • T-cell receptor excision circles

Abbreviations: NF-{kappa}B, nuclear factor {kappa}B • NEMO, NF-{kappa}B essential modulator • EDA, anhydrotic ectodermal dysplasia • TNF, tumor necrosis factor • IL, interleukin • IgM, immunoglobulin M • CMV, cytomegalovirus • Ig, immunoglobulin • NK, natural killer • XL-O-EDA-ID, X chromosome–linked anhydrotic ectodermal dysplasia with immunodeficiency and osteopetrosis • TCR, T-cell receptor • TREC, T-cell receptor excision circles • PBMC, peripheral blood mononuclear cell • IVIg, intravenous immunoglobulin • PCR, polymerase chain reaction

Loss-of-function mutations of the nuclear factor {kappa}B (NF-{kappa}B) essential modulator (NEMO) cause X-linked dominant incontinentia pigmenti in affected girls, whereas in boys, they usually are lethal in utero. Hypomorphic mutations that impair but do not abolish the function of NEMO are associated with a broad spectrum of clinical phenotypes in affected boys. Despite the pivotal role of NEMO, male patients with NEMO mutations are difficult to diagnose early in infancy. All of the patients described so far experience immunodeficiency, and most of them have an anhydrotic ectodermal dysplasia (EDA), whereas osteopetrosis, lymphedema, and hemangioma are optional.1–6 Immunodeficiency results from impaired NF-{kappa}B activation upon stimulation by various receptors such as members of the Toll-like receptor, interleukin-1 (IL-1) receptor, and tumor necrosis factor (TNF) receptor superfamilies and T/B-cell receptors.7 Some patients have a hyper-immunoglobulin M (IgM) phenotype. Furthermore, deficient natural killer (NK) cell cytotoxicity has been described in male patients with NEMO mutations.8 Although impaired NK cell cytotoxicity has been proposed to play a role in the pathogenesis of hemophagocytic disease,9 no patient with NEMO and this disease has been described so far.

NEMO might be critical in T-cell development in humans. This is supported by the findings in a patient who had X-linked EDA and immunodeficiency with reversion mosaicism of NEMO mutation and who had peripheral T cells that mainly showed reverted NEMO.10 It therefore is surprising that most patients with NEMO mutations have normal T-cell numbers.3,5,6 Analyses of recent thymic emigrants and T-cell repertoires have not been published in these patients so far.

Disease variability is a result, at least in part, of the hypomorphic nature of the NEMO mutations and the resulting degree of impairment of protein function. Severe clinical courses have been observed in patients with the 1167-1168insC mutation. There are 6 previously described male patients with this mutation. Immunodeficiency in these patients resulted in pneumococcal,3 mycobacterial, and pseudomonal infections,5,10 Pneumocystis jiroveci infections,3,5,11 and, in 1 case, in cytomegalovirus (CMV) infection.5,11 Two of these 6 previously reported patients had osteopetrosis,5 whereas lymphedema, as it can occur in male patients with other NEMO mutations, was not found in patients with the 1167-1168insC mutation. Extramedullary hematopoiesis was reported in 1 patient's cranial dura.12

Here we report on a patient with the 1167-1168insC mutation of the NEMO gene, X chromosome–linked anhydrotic ectodermal dysplasia, immunodeficiency, and osteopetrosis (XL-O-EDA-ID). Because the patient experienced hemophagocytic disease in early infancy, NK activity was measured at that time and later in his life. The hyper-IgM phenotype in this patient resulted, at least in part, from a monoclonal IgM gammopathy. Because of constantly increased T-cell numbers, the content of T-cell receptor (TCR) excision circles (TREC) in peripheral blood mononuclear cells (PBMCs), naive (CD45RA+) CD4+ T cells that coexpress CD31, and memory (CD45RO+) CD4+ T cells were measured. TCR ß-chain diversity was assessed by spectratype analysis.

CASE REPORT

Clinical Description
A now 5.5-year-old boy, son of nonconsanguineous Swiss parents, is reported (Fig 1 A and B). Five brothers of his mother died in early infancy for unclear reasons; 1 brother of his mother is healthy. His mother and 1 of her 3 sisters have typical skin signs of incontinentia pigmenti (Fig 1 C). The son of this aunt died at the age of 6 months; histologic signs of a disseminated CMV infection were detected in autopsy. His mother had bacterial meningitis at the age of 6 years and facial cellulitis at the age of 40 years.


Figure 1
View larger version (68K):
[in this window]
[in a new window]
  		FIGURE 1 The patient (A and B) and the patient's mother (C). A, Teeth are reduced in number, are widely spaced, and have a conical form. B, The patient at the age of 5 years. There is a mild facial dysmorphy with relative frontal bossing. Periorbital skin is wrinkled and darkened. Jawbones are not well developed, probably as a result of the missing teeth, leading to a progeric appearance of the face. C, Reticular hyperpigmented lesions (consistent with incontinentia pigmenti stage III) on the forearm of the patient's mother.

 
At 2 months of age, the patient became clinically apparent with Klebsiella pneumoniae sepsis. Signs of hemophagocytosis were present with fever, bicytopenia (hemoglobin: 62 g/L; thrombocytes: 12 x 109/L), hyperferritinemia (27750 µg/L), hypofibrinogenemia (1.0 g/L), erythrophagocytosis in bone marrow smear (Fig 2), and low cellular cytotoxic activity (Fig 3). Leukocyte numbers remained within the reference range; however, they decreased from initially 36.6 x 109/L to 18.1 x 109/L within the first week during the course of the disease. Triglycerides remained normal, and the spleen was only slightly enlarged. After introduction of antibiotical and high-dose intravenous immunoglobulin (IVIg) therapy, the patient recovered from sepsis and signs of hemophagocytosis.


Figure 2
View larger version (119K):
[in this window]
[in a new window]
  		FIGURE 2 Bone marrow aspirate smear at the age of 2 months during K pneumoniae sepsis (activated macrophage engaged in phagocytosis of erythrocytes; May-Grünwald Giemsa stain was used).

 

Figure 3
View larger version (13K):
[in this window]
[in a new window]
  		FIGURE 3 Cytotoxic activity. NK activity was measured by lysis of Fas-deficient target cells at the age of 4 months (A), 10 months (B), and 5 years (C). The effector-to-target cell ratio reflects the ratio of the patient's PBMCs to K562 target cells. Results are expressed as percentage of lysis. {blacktriangleup}, patient; {circ}, control. Cytotoxic activity was measured by NKTEST as described by the supplier (Orpegen Pharma, Heidelberg, Germany). Alternatively, the standard 51-chromium (Cr) release assay (4-hour)16 was applied. The HLA antigen classes I–and II–negative K562 leukemic cell line was applied as a sensitive target cell throughout. Lysed target cells were labeled with a DNA dye and analyzed by a flow cytometer (FACScan; Becton Dickinson, Basel, Switzerland).

 
At 3 months of age, he developed pneumonia caused by P jiroveci. He recovered completely after antibiotic therapy and was put on antibiotic prophylaxis and regular IVIg substitutions thereafter. At 4 months of age, a retinitis as a result of CMV infection was diagnosed; CMV pp65 antigen in blood was positive (16/100000 granulocytes). Connatal CMV infection was excluded by negative CMV polymerase chain reaction (PCR) that was performed with DNA extracted from an archived blood spot on his newborn screening ("Guthrie") card. CMV PCR and bacterial cultures from cerebrospinal fluid were negative. MRI of the neurocranium revealed 2 new subependymal calcifications in the forebrain. The patient recovered after an antiviral therapy without relapse of retinal disease. Between 3 and 5 years of age, being under regular IVIg and cotrimoxazole prophylaxis, he experienced recurrent, moderately severe bacterial infections with Staphylococcus aureus and Streptococcus pneumoniae that were treated successfully with antibiotics. At 5 years and 4 months of age, he experienced chronic fatigue and diarrhea as a result of a disseminated Mycobacterium avium infection, which is currently being treated with clarithromycin, ciprofloxacin, ethambutol, and rifabutin. Amikacin was added during the first 2 weeks of treatment.

Since early infancy, he has had a pruritic eczematous skin rash that has been indistinguishable from atopic dermatitis except that the distribution of the rash has not changed with age. The neck and intertriginous areas have been most severely affected, the trunk and scalp to a lesser extent. Because he had received a nonirradiated blood transfusion, a skin graft-versus-host disease was ruled out by skin biopsy. Histopathologic changes were nonspecific; a mild epidermal hyperplasia, intercellular edema of the epidermis (spongiosis), and infiltration of lymphocytes and macrophages along the venous plexus in the dermis were found. The chronic skin disease responded to systemic and topical steroids. Scalp hair has been sparse. Repeatedly performed sweat tests did not yield enough sweat for interpretation and thereby confirmed insufficient production. Dentition was abnormal. At 2 years of age, the patient had only 2 upper conical teeth (Fig 1 A). Nutrition has always been a serious problem because the patient has not been able to chew sufficiently and refused fluid nutrition. A nasogastric feeding tube has been installed. Bone radiographs showed signs of osteopetrosis, but no hematologic, visual, or auditory abnormalities were noted. A bone biopsy that was taken from the iliac spine revealed the absence of osteoclasts.

At present, 5.5 years of age (Fig 1 B), he has a developmental delay of 10 months. IVIg is administered every 2 to 4 weeks. Antimycobacterial therapy and P jiroveci pneumonia prophylaxis is continued. The skin is treated with ascomycin and tacrolimus ointments to avoid chronic steroid application.

Laboratory Findings
Informed consent was obtained from the patient's parents, and the work was approved by the internal review board of the University Children's Hospital Zurich. Mutation analysis of the NEMO gene revealed insertion of a cytosine (1167-1168insC) within a wild-type run of 7 cytosines (C1161–C1167) in exon 10, resulting in a premature stop at amino acid 394. The sequencing pattern of the patient was heterogeneous from position C1168 onward as a result of the known presence of a NEMO pseudogene.12 PCR amplification of individual NEMO exons was performed with DNA that was extracted from PBMCs and conducted with the forward primer in intron 9 and the reverse primer at the end of exon 10 as published previously.12 The patient's mother was identified as a carrier of this mutation. Immunodeficiency, centromere instability, facial anomalies syndrome was ruled out by cytogenetic analyses.

At 2 months of age, hemophagocytic disease was diagnosed. NK function tests revealed depressed cytolysis of K562 target cells during hemophagocytic disease (Fig 3 A). With increasing age, the cellular cytotoxicity ameliorated to almost normal levels (Fig 3 B and C). Results of a fluorescence release assay were comparable to those of standard chromium release assays. Intracellular Perforin expression that was measured by flow cytometry was not reduced.

TNF-{alpha} production on lipopolysaccharide stimulation was abnormally low, with a slight increase after addition of interferon-{gamma} (data not shown). Lymphocyte proliferation in response to mitogens (phytohemagglutinin, staphylococcal enterotoxin B, phorbol 12-myristate 13-acetate + ionomycin) initially was low but subsequently normalized. However, proliferation in response to stimulation with anti-CD3 remained constantly poor. Mitogen stimulation induced normal CD40 ligand (and CD69) expression. Lymphocyte proliferation in response to antigens (Candida, CMV) also initially was low and subsequently normalized. IL-2 production after phytohemagglutinin stimulation was absent. Mixed leukocyte cultures were abnormal, with moderate increase after addition of exogenous IL-2 (data not shown).

The patient had high IgM, absent IgE, and low IgA levels in serum. At 2 months of age, before the first administration of IVIg, serum IgG was normal (4 g/L). Because he has been under regular IVIg substitutions thereafter, specific antibody responses to vaccines were not analyzed. Immune electrophoresis repeatedly revealed monoclonal gammopathy of IgM type. Bence Jones proteinuria of {kappa} type was detected. Concentration of monoclonal IgM was moderate (<20 g/L). Serum calcium and phosphorus as well as renal parameters in blood were normal. Plasma cell numbers have been below 10% in bone marrow smears until present. Cytogenetic examination of the bone marrow was normal and not compatible with multiple myeloma. Southern blot analyses of the IgH locus did not show any monoclonal rearrangement products. Because of these findings, the diagnosis of monoclonal gammopathy of undetermined significance13 was made.

T-cell numbers in peripheral blood were elevated (Table 1). To analyze the source of this T-cell expansion, we measured various markers of naive and memory T cells: the frequency of CD31+ T helper cells among the CD4+CD45RA+ T cells was low (62%) at 5 years of age (frequency for children <15 years: 85%–90%14), whereas the absolute numbers of CD4+ and CD8+ T cells were elevated. The content of TREC in mononuclear cells was abnormally low. The percentage of CD57+ lymphocytes was elevated at the age of 5 years. However, from the age of 1 year onward, CMV pp65 antigen and CMV PCR remained negative. EBV, HIV, and human herpes virus 6, 7, and 8 PCR analyses also repeatedly were negative. Southern blot analyses of the TCR-{alpha} locus did not show any monoclonal rearrangement products. However, a high relative content of V{alpha}24-positive NK T cells (>3% of the lymphocyte fraction) was documented on 2 occasions at the age of 5 years (data not shown). TCR Vß diversity was assessed by spectratyping, measuring the size heterogeneity of the TCR hypervariable CDR3 region. Figure 4 shows 5 representative Vß spectratypes of the patient and the corresponding Vß spectratypes of cord blood from a healthy control subject representing a naive T-cell repertoire. Vß11 consisted of 1 dominant band, whereas distribution patterns of Vß12 and Vß24, which were representative for more than half of the 21 Vß tested, were irregular.


View this table:
[in this window]
[in a new window]
  		TABLE 1 Lymphocyte Subsets by Fluorescence-Activated Cell-Sorting Analysis and Content of TREC

 

Figure 4
View larger version (21K):
[in this window]
[in a new window]
  		FIGURE 4 TCR Vß diversity. CDR3 length distribution patterns of TCR Vß in PBMCs were assessed by spectratyping. Procedures and sequences of oligonucleotides that correspond to the 21 variable segments of the TCR ß-chain used in this study have been published previously.29 Spectratypes of 5 representative Vß families of the patient (A) and cord blood from a healthy control subject (B). Data analysis was performed by using Genescan (Applied Biosystems; Rotkreuz, Switzerland) analysis software.

 

DISCUSSION

The transcription factor NF-{kappa}B regulates genes that are involved in inflammatory and immune responses, tumorigenesis, and apoptosis. Hypomorphic mutations in NEMO of male patients impair the activation of NF-{kappa}B. We describe a male patient with the typical clinical signs of hypomorphic NEMO mutation: immunodeficiency, EDA, and osteopetrosis. In addition, he had infection-associated hemophagocytosis with transient deficiency of NK activity, monoclonal IgM gammopathy, and increased T-cell counts with reduced TREC content and limited TCR diversity.

At 2 months of age, this patient had hemophagocytic disease. Despite the young age at disease onset, the patient had a transient hemophagocytic syndrome. The course was benign, was self-limiting, and did not relapse after initiation of IVIg therapy and antibiotic treatment of the preceding K pneumoniae infection. We observed a transient impairment of NK activity. Transient and permanent NK cell impairment has been described in patients with hemophagocytic diseases.9 Defects of the cytotoxic effector pathways of NK, NKT, and cytotoxic T cells are fundamental to the current understanding of pathogenesis of hemophagocytic disease.15 NF-{kappa}B transcription factors play a unique role in the differentiation of NK and NKT cells in mice.16,17 An impairment of NK cell cytotoxicity has been reported in male patients with NEMO mutations that could be corrected partially by addition of IL-2.8 However, no cases of hemophagocytic disease have been described so far in these patients. Patients with NEMO mutations might lack the hypercytokinemia that seems to play a central role in the pathogenesis of hemophagocytic diseases.18

An impaired TNF-{alpha} production on lipopolysaccharide stimulation has been shown in a patient with hypomorphic NEMO mutation5 and also was observed in our patient. Experiments in mouse models show that TNF-{alpha} plays an important role in the clearance of K pneumoniae.19 Persistence of the K pneumoniae infection, in addition to the impaired cellular cytotoxicity, might have contributed to the pathogenesis of the hemophagocytic disease in our patient. TNF-{alpha} furthermore plays a pivotal role in directing precursors toward the differentiation into dendritic cells with potency to stimulate T cells instead of a differentiation into macrophage-like cells.20 A lack of TNF-{alpha} hence could contribute to a preponderance of phagocytic dendritic cells.

Our patient has a developmental delay. Neurologic impairment is known in some patients with incontinentia pigmenti.21 Another explanation for the neurologic impairment of our patient could have been a central nervous system involvement as a result of hemophagocytic disease,22 but the MRI findings were not characteristic for hemophagocytic disease. Instead, characteristic retinal lesions together with suspicious MRI findings (acquired intracerebral calcifications) make a symptomatic, atypical, nonconnatally acquired CMV infection of the central nervous system probable.

Some male patients with hypomorphic NEMO mutations have a hyper-IgM phenotype. It has been shown that B-cell proliferation on CD40L stimulation5 and CD40-mediated c-Rel activation23 are impaired in some patients with NEMO mutations. These mechanisms may play an important role in class switch recombination in B cells and therefore contribute to the hyper-IgM phenotype. The elevation of IgM in our patient was attributable, at least in part, to a monoclonal gammopathy of IgM type, a finding that as yet has not been published in patients with NEMO mutations. Diagnostic criteria of monoclonal gammopathy of undetermined significance were fulfilled,13 and, so far, no multiple myeloma has developed. Individuals with primary immunodeficiencies are more susceptible to malignancies, presumably as a result of impaired immune surveillance. In male patients with NEMO mutations, no increased prevalence to malignancies has been described up to now. However, the number of male patients with NEMO mutations is small, and early death as a result of infections is common.

Recent studies have shown that inhibitors of NF-{kappa}B might even prevent tumorigenesis, because tumor suppressor gene products may negatively regulate NF-{kappa}B activation.24 Some tumor tissue cells, eg, tumor tissues derived from patients with multiple myeloma, constitutively express NF-{kappa}B. Therefore, inhibition of the NF-{kappa}B pathway is regarded as a promising strategy in the treatment of certain malignancies, including multiple myeloma.25 Therefore, development of monoclonal gammopathy into multiple myeloma could be blocked, at least theoretically, by an NF-{kappa}B–dependent mechanism in our patient. However, NF-{kappa}B seems to have a dual role in tumorigenesis. NF-{kappa}B also can have growth-inhibitory roles, and it has been postulated that suppression of NF-{kappa}B could be tumorigenic, but so far this has been the case only in skin cancer models.25

Analyses of TREC and of the TCR repertoire have not been published so far in male patients with NEMO mutations. We observed a reduced percentage of mononuclear cells that contained TREC in our patient. TRECs are stable DNA episomes that are formed during TCR recombinations. TRECs are not replicated during mitosis and are diluted out during cell division.26 In view of the findings in a patient who had XL-O-EDA-ID and reversion mosaicism of NEMO mutation and had peripheral T cells that mainly showed reverted NEMO,10 our data could be consistent with a reduced thymic output in our patient. However, a reduction in the TREC content in peripheral T cells does not necessarily result from a reduced thymic output; peripheral effects such as cell division or changes in the cellular lifespan also account for changes in the TREC content.26 Peripheral cell divisions include homeostatic cell division of naive CD4+ T cells and priming of recent thymic emigrants to become memory CD4+ T cells. TCR engagement leads not only to cell division but also to the loss of CD31 expression.27 The percentage of naive CD4+CD45RA+ T cells that coexpress CD31 was reduced in our patient, suggesting peripheral cell division on TCR engagement.

Spectratypes from normal (naïve) TCR repertoires show a Gaussian distribution of 8 to 10 bands representing the different lengths of the respective TCR variable, diversity, and joining regions. Spectratypes from a T-cell compartment that is partially generated by peripheral expansion are not Gaussian, and some Vß families may consist, for the most part, of 1 to 2 dominant clones.28 In the patient reported here, most spectratype bands were present, indicating that a diverse T-cell repertoire had been generated. However, some clones had expanded to an extent that they dominated the Vß family. The dominant bands in our patient also could have been caused by a chronic infection, but this extreme oligo-(mono-)clonality rarely is seen. In acute mononucleosis, for example, the spectratypes are more Gaussian, and after the acute phase, during the chronic infections, the T cells are hardly detectable.29,30 However, the oligoclonal expansion in the patient reported here further supports the hypothesis of a peripheral T-cell expansion.

The absolute numbers of T cells were constantly elevated in our patient. Previously reported male patients with NEMO mutations mostly had normally distributed lymphocyte subsets by percentage ratio, whereas absolute numbers were decreased,31 normal,3,5,6 or slightly elevated.32 The lymphocyte subset distributions in our patient also essentially were normal by percentage ratio but elevated by absolute numbers. The patient had a CMV infection in early infancy. This could have been the cause for the T-cell expansion and relative increase of CD8+ T cells at that age. Induction of CD57 antigen has been associated with CMV virus infections.33 The percentage of CD57+ lymphocytes was elevated in our patient. However, no CMV or other herpes viruses could be detected anymore by PCR after the age of 1 year. It was shown previously that downregulation of NF-{kappa}B transcriptional activity is associated with an increase in cell death.34 However, our patient showed peripheral expansion of the T-cell pool instead. As shown previously, hypomorphic NEMO mutations that cause EDA-ID and OL-EDA-ID impair but do not abolish NF-{kappa}B signaling.5 Therefore, the remaining functional activity of NF-{kappa}B could have led to a sufficient inflammatory response with increase of T-cell divisions or prolonged lifespan of specific T cells that have been able to keep the CMV infection under control. Because IL-2 secretion and signaling seem to be affected in patients with NEMO mutations,8 one might also consider protective antibodies to play a role.

An impairment of the NF-{kappa}B activity has been shown to increase apoptosis and reduce inflammation in T-cell lineages.34 Paradoxically, the observations in our patient implicate an increased cell survival and an episode of uncontrolled inflammation instead. Peripheral T-cell numbers were elevated as a result of increased division or survival of peripheral T cells most probably maintained by chronic or repeated infections. This postulated impairment of cell survival control also may have contributed to monoclonal gammopathy. Increased susceptibility to infections and prolonged persistence of the infectious agents furthermore seemed to increase the risk for hemophagocytic disease in the presence of impaired NK activity.

CONCLUSIONS

Hypomorphic NEMO mutations may be associated with inflammatory dysregulation and expansion of certain cell subpopulations, probably as a result of the residual function of NEMO in combination with an infectious trigger. Our findings add new information to the clinical and immunologic picture of male patients who are affected by hypomorphic NEMO mutations while indicating a role of NEMO and impaired NF-{kappa}B production in immune homeostasis and cell surveillance.

ACKNOWLEDGMENTS

Dr Schmid received research grants from Octapharma (Lachen, Switzerland), the Swiss National Foundation (grant PASMA-110658/1), and the Swiss Foundation for Grants in Medicine and Biology (grant 1211).

We thank the patient and his family for cooperation, the nurses for the care of the patient, and Dr R. Guggenheim for the documentation of the patient's history. The excellent technical assistance of Susanne Loeliger, Jannie Nievergelt, Cynthia Noetzli, Maja Rutishauser, and Corinne Wenk is greatly appreciated.

FOOTNOTES

Accepted Nov 14, 2005.

Address correspondence to Tayfun Gungor, MD, University Children's Hospital, Steinwiesstrasse 75, 8032 Zurich, Switzerland. E-mail: tayfun.guengoer{at}kispi.unizh.ch

The authors have indicated they have no financial relationships relevant to this article to disclose.

REFERENCES

  1. Abinun M, Spickett G, Appleton AL, Flood T, Cant AJ. Anhidrotic ectodermal dysplasia associated with specific antibody deficiency. Eur J Pediatr. 1996;155 :146 –147[Web of Science][Medline]
  2. Schweizer P, Kalhoff H, Horneff G, Wahn V, Diekmann L. Polysaccharide specific humoral immunodeficiency in ectodermal dysplasia: case report of a boy with two affected brothers. Klin Padiatr. 1999;211 :459 –461[Web of Science][Medline]
  3. Zonana J, Elder ME, Schneider LC, et al. A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am J Hum Genet. 2000;67 :1555 –1562[CrossRef][Web of Science][Medline]
  4. Mansour S, Woffendin H, Mitton S, et al. Incontinentia pigmenti in a surviving male is accompanied by hypohidrotic ectodermal dysplasia and recurrent infection. Am J Med Genet. 2001;99 :172 –177[CrossRef][Web of Science][Medline]
  5. Doffinger R, Smahi A, Bessia C, et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-{kappa}B signaling. Nat Genet. 2001;27 :277 –285[CrossRef][Web of Science][Medline]
  6. Niehues T, Reichenbach J, Neubert J, et al. Nuclear factor {kappa}B essential modulator-deficient child with immunodeficiency yet without anhidrotic ectodermal dysplasia. J Allergy Clin Immunol. 2004;114 :1456 –1462[CrossRef][Web of Science][Medline]
  7. Puel A, Picard C, Ku CL, Smahi A, Casanova JL. Inherited disorders of NF-{kappa}B-mediated immunity in man. Curr Opin Immunol. 2004;16 :34 –41[CrossRef][Web of Science][Medline]
  8. Orange JS, Brodeur SR, Jain A, et al. Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations. J Clin Invest. 2002;109 :1501 –1509[CrossRef][Web of Science][Medline]
  9. Laroche C, Mouthon L. Pathogenesis of hemophagocytic syndrome. Autoimmun Rev. 2004;3 :69 –75[CrossRef][Medline]
  10. Nishikomori R, Akutagawa H, Maruyama K, et al. X-linked ectodermal dysplasia and immunodeficiency caused by reversion mosaicism of NEMO reveals a critical role for NEMO in human T cell development and/or survival. Blood. 2004;103 :4565 –4572[Abstract/Free Full Text]
  11. Sitton JE, Reimund EL. Extramedullary hematopoiesis of the cranial dura and anhidrotic ectodermal dysplasia. Neuropediatrics. 1992;23 :108 –110[Web of Science][Medline]
  12. Smahi A, Courtois G, Vabres P, et al. Genomic rearrangement in NEMO impairs NF-{kappa}B activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature. 2000;405 :466 –472[CrossRef][Medline]
  13. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346 :564 –569[Abstract/Free Full Text]
  14. Kimmig S, Przybylski GK, Schmidt CA, et al. Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood. J Exp Med. 2002;195 :789 –794[Abstract/Free Full Text]
  15. Schneider EM, Lorenz I, Muller-Rosenberger M, Steinbach G, Kron M, Janka-Schaub GE. Hemophagocytic lymphohistiocytosis is associated with deficiencies of cellular cytolysis but normal expression of transcripts relevant to killer-cell-induced apoptosis. Blood. 2002;100 :2891 –2898[Abstract/Free Full Text]
  16. Samson SI, Memet S, Vosshenrich CA, et al. Combined deficiency in I{kappa}B{alpha} and I{kappa}B{epsilon} reveals a critical window of NF-{kappa}B activity in natural killer cell differentiation. Blood. 2004;103 :4573 –4580[Abstract/Free Full Text]
  17. Sivakumar V, Hammond KJ, Howells N, Pfeffer K, Weih F. Differential requirement for Rel/nuclear factor kappa B family members in natural killer T cell development. J Exp Med. 2003;197 :1613 –1621[Abstract/Free Full Text]
  18. Henter JI, Elinder G, Soder O, Hansson M, Andersson B, Andersson U. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood. 1991;78 :2918 –2922[Abstract/Free Full Text]
  19. Moore TA, Lau HY, Cogen AL, Standiford TJ. Defective innate antibacterial host responses during murine Klebsiella pneumoniae bacteremia: tumor necrosis factor (TNF) receptor 1 deficiency versus therapy with anti-TNF-alpha. Clin Infect Dis. 2005;41 (suppl 3):213–217
  20. Caux C, Vanbervliet B, Massacrier C, et al. CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF alpha. J Exp Med. 1996;184 :695 –706[Abstract/Free Full Text]
  21. Mangano S, Barbagallo A. Incontinentia pigmenti: clinical and neuroradiologic features. Brain Dev. 1993;15 :362 –366[CrossRef][Web of Science][Medline]
  22. Henter JI, Elinder G. Cerebromeningeal hemophagocytic lymphohistiocytosis. Lancet. 1992;339 :104 –107[CrossRef][Web of Science][Medline]
  23. Jain A, Ma CA, Lopez-Granados E, et al. Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation. J Clin Invest. 2004;114 :1593 –1602[CrossRef][Web of Science][Medline]
  24. Kovalenko A, Chable-Bessia C, Cantarella G, Israel A, Wallach D, Courtois G. The tumour suppressor CYLD negatively regulates NF-{kappa}B signalling by deubiquitination. Nature. 2003;424 :801 –805[CrossRef][Medline]
  25. Aggarwal BB. Nuclear factor-{kappa}B: the enemy within. Cancer Cell. 2004;6 :203 –208[CrossRef][Web of Science][Medline]
  26. Hazenberg MD, Borghans JA, de Boer RJ, Miedema F. Thymic output: a bad TREC record. Nat Immunol. 2003;4 :97 –99[CrossRef][Web of Science][Medline]
  27. Demeure CE, Byun DG, Yang LP, Vezzio N, Delespesse G. CD31 (PECAM-1) is a differentiation antigen lost during human CD4 T-cell maturation into Th1 or Th2 effector cells. Immunology. 1996;88 :110 –115[CrossRef][Web of Science][Medline]
  28. Dumont-Girard F, Roux E, van Lier RA, et al. Reconstitution of the T cell compartment after bone marrow transplantation: restoration of the repertoire by thymic emigrants. Blood. 1998;92 :4464 –4471[Abstract/Free Full Text]
  29. Silins SL, Sherritt MA, Silleri JM, et al. Asymptomatic primary Epstein-Barr virus infection occurs in the absence of blood T-cell repertoire perturbations despite high levels of systemic viral load. Blood. 2001;98 :3739 –3744[Abstract/Free Full Text]
  30. Silins SL, Cross SM, Elliott SL, et al. Development of Epstein-Barr virus-specific memory T cell receptor clonotypes in acute infectious mononucleosis. J Exp Med. 1996;184 :1815 –1824[Abstract/Free Full Text]
  31. Orange JS, Jain A, Ballas ZK, Schneider LC, Geha RS, Bonilla FA. The presentation and natural history of immunodeficiency caused by nuclear factor {kappa}B essential modulator mutation. J Allergy Clin Immunol. 2004;113 :725 –733[CrossRef][Web of Science][Medline]
  32. Dupuis-Girod S, Corradini N, Smail H, et al. Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinential pigment in his mother. Pediatrics. 2002;109(6) . Available at: www.pediatrics.org/cgi/content/full/109/6/e97
  33. Rowbottom AW, Garland RJ, Lepper MW, et al. Functional analysis of the CD8+CD57+ cell population in normal healthy individuals and matched unrelated T-cell-depleted bone marrow transplant recipients. Br J Haematol. 2000;110 :315 –321[CrossRef][Web of Science][Medline]
  34. Ferreira V, Sidenius N, Tarantino N, et al. In vivo inhibition of NF-kappa B in T-lineage cells leads to a dramatic decrease in cell proliferation and cytokine production and to increased cell apoptosis in response to mitogenic stimuli, but not to abnormal thymopoiesis. J Immunol. 1999;162 :6442 –6450[Abstract/Free Full Text]
  35. Shearer WT, Rosenblatt HM, Gelman RS, et al. Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol. 2003;112 :973 –980[CrossRef][Web of Science][Medline]
  36. Hazenberg MD, Otto SA, Cohen Stuart JW, et al. Increased cell division but not thymic dysfunction rapidly affects the T cell receptor excision circle content of the naive T cell population in HIV-1 infection. Nat Med. 2000;6 :1036 –1042[CrossRef][Web of Science][Medline]
  37. Zhang L, Lewin SR, Markowitz M, et al. Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy. J Exp Med. 1999;190 :725 –732[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 BloodHome page
S. Kohler and A. Thiel
Life after the thymus: CD31+ and CD31- human naive CD4+ T-cell subsets
Blood, January 22, 2009; 113(4): 769 - 774.
[Abstract] [Full Text] [PDF]

Home page
 Arch DermatolHome page
A. J. Mancini, L. P. Lawley, and G. Uzel
X-Linked Ectodermal Dysplasia With Immunodeficiency Caused by NEMO Mutation: Early Recognition and Diagnosis
Arch Dermatol, March 1, 2008; 144(3): 342 - 346.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schmid, J. M. P.
Right arrow Articles by Gungor, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schmid, J. M. P.
Right arrow Articles by Gungor, T.
Related Collections
Right arrow Infectious Disease & Immunity
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?