Published online June 12, 2006
PEDIATRICS Vol. 118 No. 1 July 2006, pp. e205-e211 (doi:10.1542/peds.2005-2661)
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EXPERIENCE AND REASON

Successful Allogeneic Hemopoietic Stem Cell Transplantation in a Child Who Had Anhidrotic Ectodermal Dysplasia With Immunodeficiency

Sophie Dupuis-Girod, MDa,b, Caterina Cancrini, MD, PhDc, Françoise Le Deist, MD, PhDd, Paolo Palma, MDc, Christine Bodemer, MDe, Anne Puel, PhDf, Susanna Livadiotti, MDc, Capucine Picard, MDa, Xavier Bossuyt, MD, PhDg, Paolo Rossi, MD, PhDc, Alain Fischer, MD, PhDa,h and Jean-Laurent Casanova, MD, PhDa,f

a Unité d'Immunologie et d'Hématologie Pédiatriques
d Centre d'études des Déficits Immunitaires
e Service de Dermatologie
h Développement Normal et Pathologique du Système Immunitaire, Institut National de la Santé et de la Recherche Médicale U429, Hôpital Necker-Enfants Malades, Paris, France
b Service de Génétique, Hospices Civils de Lyon, Hôpital de l'Hotel Dieu, Lyon, France
c Division of Immunology and Infectious Disease, Bambino Gesù Children's Hospital, University of Rome Tor Vergata, Rome, Italy
f Laboratoire de Génétique Humaine des Maladies Infectieuses, Université René Descartes-Institut National de la Santé et de la Recherche Médicale U550, Faculté de Médecine Necker-Enfants Malades, Paris, France
g Laboratory of Experimental Medicine, University Hospital Leuven, Leuven, Belgium


   ABSTRACT
TOP
 ABSTRACT
CASE REPORT
 DISCUSSION
 REFERENCES
 
Anhidrotic ectodermal dysplasia with immunodeficiency is associated with multiple infections and a poor clinical outcome. Hypomorphic mutations in nuclear factor {kappa}B essential modulator (NEMO)/I{kappa}B kinase complex and a hypermorphic mutation in inhibitor {alpha} of nuclear factor {kappa}B (I{kappa}B{alpha}) both result in impaired nuclear factor {kappa}B activation and are associated with X-recessive and autosomal-dominant forms of anhidrotic ectodermal dysplasia with immunodeficiency, respectively. Autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency is also associated with a severe T-cell phenotype. It is not known whether hematopoietic stem cell transplantation can cure immune deficiency in children with anhidrotic ectodermal dysplasia with immunodeficiency. A boy with autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency and a severe T-cell immunodeficiency underwent transplantation at 1 year of age with haploidentical T-cell–depleted bone marrow after myeloablative conditioning. Engraftment occurred, with full hematopoietic chimerism. Seven years after transplantation, clinical outcome is favorable, with normal T-cell development. As expected, the developmental features of the anhidrotic ectodermal dysplasia syndrome have appeared and persisted. This is the first report of successful hematopoietic stem cell transplantation in a child with anhidrotic ectodermal dysplasia with immunodeficiency. Hematopoietic stem cell transplantation is well tolerated and efficiently cures the profound immunodeficiency associated with autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency.

Key Words: anhidrotic ectodermal dysplasia • hematopoietic stem cell transplantation • NF-{kappa}B • primary immunodeficiency

Abbreviations: EDA, anhidrotic ectodermal dysplasia • EDA-ID, anhidrotic ectodermal dysplasia with immunodeficiency • NF-{kappa}B, nuclear factor {kappa}B • NEMO, nuclear factor {kappa}B essential modulator • OL-EDA-ID, osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency • XR, X-recessive • AD, autosomal dominant • HSCT, hematopoietic stem cell transplantation • I{kappa}B{alpha}, inhibitor {alpha} of NF-{kappa}B • IgG, immunoglobulin G • GVHD, graft-versus-host disease • BMT, bone marrow transplant • TNF-{alpha}, tumor necrosis factor {alpha} • IL, interleukin • TLR, Toll-like receptor

Anhidrotic ectodermal dysplasia (EDA) is a rare syndrome that is characterized by the aberrant development of skin appendages, including hair (hypotrichosis or atrichosis), teeth (hypodontia or anodontia, with conical incisors), and eccrine sweat glands (hypohidrosis or anhidrosis), resulting in characteristic facial features and heat intolerance.1 Some children with EDA also experience severe infections that are caused by a variety of microorganisms.2–16 The term EDA with immunodeficiency (EDA-ID) was coined by Abinun7,8 to describe the latter group of patients, after identification of an impaired antibody response to polysaccharides in 1 of them. After the identification of amorphic mutations in the X-linked NEMO gene, encoding nuclear factor {kappa}B (NF-{kappa}B) essential modulator (NEMO)/I{kappa}B kinase complex, an essential component of the NF-{kappa}B signaling pathway, in male fetuses who died in utero of the X-dominant syndrome of incontinentia pigmenti,15,17 2 boys with EDA-ID, osteopetrosis, and lymphedema (OL-EDA-ID) were found to carry a hypomorphic mutation in NEMO.13,15–17 Both patients with OL-EDA-ID were hemizygous for the same mutation of the stop codon (X420W).

Patients with X-recessive EDA-ID (XR-EDA-ID) without osteopetrosis and lymphedema have been shown to bear various hypomorphic mutations in the coding region of NEMO.9,12–14,18–20 The spectrum of disorders that are associated with mutations in NEMO expands beyond "classical" EDA-ID, to patients with an immunodeficiency and conical teeth,21 and even a pure immunodeficiency.22,23 We also recently reported a child with an autosomal dominant form of EDA-ID (AD-EDA-ID), heterozygous for a hypermorphic mutation in IKBA, which encodes the inhibitor {alpha} of NF-{kappa}B (I{kappa}B{alpha}). This mutation prevents I{kappa}B{alpha} phosphorylation and its subsequent degradation, enhancing the inhibitory capacity of I{kappa}B{alpha} and impairing NF-{kappa}B activation.24 The same mutation was documented recently in another, unrelated patient with AD-EDA-ID.25 In patients with XL-EDA-ID or AD-EDA-ID, the clinical features of EDA result from impaired signaling via the EDA receptor, as shown by the similar developmental phenotype of children with mutations in EDA receptor or its ligand ectodysplasin.26

The infections that are associated with XL-EDA-ID vary from patient to patient, but the overall prognosis is poor. Approximately half of the patients reported have died of overwhelming infection in childhood.3,5,7–16,18,20,27 The pathogens involved mostly were pyogenic bacteria, notably Streptococcus pneumoniae, and poorly virulent mycobacteria, such as Mycobacterium avium. In routine immunologic workup, impaired antibody response to polysaccharides is the phenotype that most consistently is observed in patients.8,13 The multiplicity and the severity of infections in these patients reflect the large number of receptors, including members of the tumor necrosis factor (TNF) receptor, interleukin (IL)-1R, and Toll-like receptor (TLR) superfamilies, which are known to signal via NF-{kappa}B.22,28,29 The clinical features of AD-EDA-ID are even more severe, consistent with the broader and more severe immunologic abnormalities detected, with a lack of memory T cells in vivo and an impaired T-cell response to CD3 and antigens in vitro.24 It is interesting that a child with a mutation in NEMO was reported recently to have a distinct but related T-cell phenotype,19 indicating that both AD-EDA-ID and XR-EDA-ID may be associated with profound T-cell deficiency.

The severity of the prognosis of children with EDA-ID raises the question as to whether hematopoietic stem cell transplantation (HSCT) would be beneficial in these patients. The activation of NF-{kappa}B in leukocytes during protective immunity suggests that this may be the case.30 However, the NEMO and IKBA genes are ubiquitously expressed, and NF-{kappa}B activation controls a number of fundamental biological processes.31,32 HSCT in patients with EDA-ID therefore raises several concerns. First, known (EDA, OL) and currently unknown developmental phenotypes that may appear later in life are unlikely to be caused by impaired NF-{kappa}B activation in hematopoietic cells. Second, vulnerability to infections may result from the impairment of NF-{kappa}B activation in cells that are derived from both the hematopoietic and nonhematopoietic lineages. Third, myeloablative conditioning regimens may be particularly toxic in these patients, as suggested by the death of our patient with XR-OL-EDA-ID from veno-occlusive disease shortly after HSCT.16 We describe here the clinical features of a boy with life-threatening AD-EDA-ID and his favorable outcome 7 years after HSCT.


   CASE REPORT
TOP
 ABSTRACT
 CASE REPORT
DISCUSSION
 REFERENCES
 
A male infant was born by cesarean section to unrelated Italian parents at 36 weeks of gestation. At birth, he weighed 2240 g (10th–25th percentile) and was 47 cm long (50th percentile). He was hospitalized in Rieti, Italy, at 2 months of age for chronic diarrhea (4–6 stools per day, 100 mL/day) and fever and later was discharged with a diagnosis of rotavirus infection and a lactose-free diet. He presented recurrent upper respiratory infections in subsequent months. He failed to thrive, and growth retardation was observed, reaching –2 SD for weight and –2 SD for length at 4 months of age and –3.5 SD for weight and –2.5 SD for length at 5 months of age. At 5 months of age, he was admitted to Bambino Gesu Children's Hospital in Rome. Clinical examination revealed poor general condition, severe malnutrition, anemia, and hepatosplenomegaly. Chest radiograph showed interstitial pneumonia. The patient experienced another bout of severe chronic diarrhea while in the hospital. Bone marrow examination was normal. Blood cytomegalovirus and Epstein-Barr virus polymerase chain reaction tests were negative. Pseudomonas, Klebsiella, and Serratia were isolated from bronchoalveolar lavage. The results of metabolic investigations were normal. Duodenoscopy and rectosigmoidoscopy with biopsies showed intestinal atrophy with inflammatory infiltration (data not shown). No infectious agents were found in the stools or biopsy samples. The patient underwent blood transfusion and was treated parenterally with trimethoprim-sulfamethoxazole, ceftriaxone, and netilmicin. Total parenteral nutrition was initiated at 6 months of age. Immunologic investigations are summarized in Tables 1 and 2: white blood cell counts were high, at 35390/mm3, and the patient presented neutrophilia and polyclonal lymphocytosis (22%–29% of polymorphonuclear neutrophils, 76%–50% of lymphocytes), with severe anemia (hemoglobin: 5.5 mg/dL; hematocrit: 18%; red blood cells: 3090000).


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  		TABLE 1 Immunologic Data Before and After HSCT

 

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  		TABLE 2 Serology Data Before and After HSCT

 
At the age of 9 months, the patient was transferred to Necker Enfants-Malades Hospital, Paris, for persistent severe diarrhea (5–6 stools per day), cutaneous candidiasis, and recurrent bronchopneumonitis. Bronchoalveolar lavage identified Pseudomonas aeruginosa and Staphylococcus aureus, which were treated with parenteral antibiotics. Immunologic investigations revealed an unusual combined immunodeficiency (detailed by Courtois et al24). Peripheral blood leukocyte counts repeatedly were high, with polyclonal lymphocytosis and a normal distribution of T, B, and NK lymphocytes (Tables 1 and 2). Serum immunoglobulin G (IgG) levels were low, and the patient was treated with intravenous immunoglobulins. Titers of antibodies that were directed against recall antigens were negative after vaccination, and the patient's T cells did not proliferate in vitro in response to tetanus toxoid, poliovirus, tuberculin, and candidin. No {gamma}/{delta} T cells were detected, and all of the {alpha}/ß T cells had the naive CD45RA phenotype, with no CD45RO memory T cells detected. These findings are consistent with a complete lack of proliferation in response to CD3-specific antibodies and the recovery of proliferation after the addition of recombinant IL-2- or CD28-specific antibody. Conversely, phorbol 12-myristate 13-acetate plus ionomycin induced a normal proliferative response, with a normal expression of activation markers HLA-DR, CD40L, and CD25. The T-cell receptor repertoire of the CD4 and CD8 subsets, as analyzed by fluorescence-activated cell sorting, was normal. NK cells were present (CD3–, CD16+, and CD56+ lymphocytes), and NK activity was normal. The whole-blood response to lipopolysaccharide, IL-1ß, and TNF-{alpha} was impaired, in terms of IL-6, IL-1ß, and IL-10 secretion, respectively, as measured by enzyme-linked immunosorbent assay. As reported by Courtois et al,24 the presence of a hypermorphic heterozygous mutation of I{kappa}B{alpha} has impaired the phosphorylation of I{kappa}B{alpha} by IKK.

The patient underwent HSCT at the age of 12 months because of his poor clinical condition and the severity of his immunologic abnormalities. The bone marrow donor was his haploidentical mother (HLA A 32/11, B 35/35, and DRB1 15/11 for the mother and HLA A 32/11, B 35/61, and DRB1 15/15 for the patient). The conditioning regimen consisted of 5 mg/kg per day busulfan, from day –10 (with the day of HSCT taken as day 0) to day –7 (20 mg/kg total dose), and 50 mg/kg per day cyclophosphamide from day –5 to day –2 (200 mg/kg total dose). The patient's bone marrow was depleted of T cells by means of CD34+ stem cell enrichment (Miltenyi Biotec, Bergisch Gladback, Germany). The patients received 7.5 x 106 CD34+ cells per kg and 3.5 x 105 CD3+ cells per kg. He also received an infusion of anti-CD2 (BE-2, mouse IgG2b; Diaclone, Besançon, France; 0.2 mg/kg per day from day –2 to day 10) anti–leukocyte function antigen-1 (25.3, mouse IgG1; Pasteur Mérieux, Paris, France; 0.2 mg/kg per day from day –3 to day 9) antibodies to prevent graft failure and graft-versus-host disease (GVHD).33 There was no additional GVH prophylaxis. Infections were prevented by hospitalization in a sterile isolator, oral nonabsorbable antibiotics, and intravenous acyclovir treatment (1600 mg/m2 per day) starting 11 days before transplantation until day 60 and weekly treatment with intravenously administered immunoglobulins (400 mg/kg) for 6 months. The blood products that were used tested negative for cytomegalovirus and were irradiated.

Seven days after transplantation, the patient developed seizures that required 2 days of intensive care and phenobarbital treatment. MRI scans were normal. CSF contained large numbers of white blood cells (92/mm3) and a high concentration of interferon {alpha} (75 IU/mL), consistent with a viral disease. However, bacteriologic and virologic CSF cultures were negative. Two months after HSCT, the patient developed progressive interstitial pneumonia while hospitalized in the sterile isolator. Bronchoalveolar lavage was performed, and a Pneumocystis jiroveci infection was identified. This infection resolved favorably after intravenous trimethoprim-sulfamethoxazole treatment. Persistent diarrhea was observed before HSCT and continued for 3 months after HSCT, improving thereafter. Gastric, duodenal, and colonic biopsy results then were normal (data not shown). Total parenteral nutrition was continued for 5 months after HSCT and then was stopped definitively. The patient did not develop GVHD.

The patient reached an absolute blood neutrophil count of 500/mm3 on day 25 and a CD3+ lymphocyte count of 350/mm3 on day 102 and of 870/mm3 on day 110, with a CD4+ lymphocyte count of 307/mm3. T cells from the patient proliferated in vitro after stimulation with phytohemagglutinin on day 110 and after stimulation with tetanus toxoid, poliovirus after immunization, and candidin on day 210. CD4 CD45 RO memory T cells were present on day 145. Chimerism was assessed 3 months and 3, 5, and 7 years after gender-mismatched bone marrow transplant (BMT), by fluorescence in situ hybridization. We observed 100% heterologous chimerism in T cells, B cells, and monocytes.

One year after BMT, at the age of 2 years, the patient displayed better growth and normal nutrition. During the next 6 years of follow-up, the patient's growth gradually improved in weight (–1 SD) and height (–1 SD). Distinctive mild facial dysmorphy became evident by the age of 4 years: frontal bossing; saddle nose; and fine, lightly pigmented, sparse hair. These facial features were not specific, but their association with conical milk teeth and dry skin suggested a diagnosis of ectodermal dysplasia. Orthopanoramic radiograph showed severe hypodontia, with the absence of 5 permanent teeth (15, 25, 35, 44, and 45; Fig 1). Clinical lymphedema was not observed, and skeletal radiograph was normal, with no evidence of osteopetrosis.


Figure 1
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  		FIGURE 1 Orthopantomography, showing severe hypodontia, with 5 permanent teeth (15, 25, 35, 44, and 45) absent. This photograph was taken when the patient was 4.5 years old.

 
At his most recent follow-up visit, 7 years after HSCT, the patient, now 8 years of age, was found to have experienced no other severe opportunistic infections. He however presented recurrent upper respiratory tract infections with chronic sinusitis. The patient's lymph nodes did not enlarge during infections, and no palatine tonsils were visible. Computed tomography of the chest showed persistent mild interstitial infiltration. The patient also presented 2 episodes of local zoster infection on the thorax, at the ages of 5 and 7 years. Finally, since the age of 2 years, he has presented recurrent planar warts on the face. These infections have resulted in the patient's continuing to receive intravenous immunoglobulin infusions (400 mg/kg every 4 weeks) and oral trimethoprim-sulfamethoxazole prophylaxis (20 mg/kg per day). In October 2004, immunoglobulin treatment was stopped to assess the patient's antibody response and clinical status in the absence of this substitution treatment. During this period, the patient developed Klebsiella pneumoniae bacteremia, which responded well to ad hoc parenteral antibiotic treatment.

Serum IgG levels remained normal 6 months after the last immunoglobulin infusion (Tables 1 and 2). Moreover, the patient's specific antibody response to both protein (tetanus toxoid, poliovirus) and polysaccharide (Haemophilus influenzae b) antigens was normal but low for S pneumoniae antigens (Tables 1 and 2). There were no detectable antibodies to varicella zoster virus, however, and the percentage of memory (CD27) B cells was low (2%). Immune reconstitution otherwise was excellent, with a lymphocyte count of 12730/mm3, normal lymphocyte distribution (73% CD3+ T cells, 39% CD4+ T cells, 27% CD8+ T cells) and the presence of memory T cells, as shown by assessment of CD45RO expression. T-cell proliferation in response to CD3-specific antibody and to the tetanus toxoid and poliovirus recall antigens was normal (Tables 1 and 2). The patient's whole blood also responded normally to lipopolysaccharide, IL-1ß, and TNF-{alpha}, in terms of IL-1ß, IL-6, and IL-10 secretion, respectively (data not shown). However, lymphocytosis (median: 11580/mm3; mean: 12402; range: 6280-18140) persisted. The last assessment of chimerism, 7 years after BMT, was based on the analysis of fluorescence in situ hybridization and showed 100% heterologous chimerism in T cells, B cells, and monocytes. Immunoglobulin substitution nevertheless was reinstituted on clinical and immunologic grounds.


   DISCUSSION
TOP
 ABSTRACT
 CASE REPORT
 DISCUSSION
REFERENCES
 
We report here the first successful HSCT in a child with EDA-ID. In our patient, HSCT with total donor chimerism restored both innate and adaptive immune responses, resulting in a considerable clinical improvement. Diarrhea and other digestive signs were dramatically improved by HSCT, and parenteral nutrition was stopped 5 months after HSCT. HSCT also was successful immunologically, as shown by the normal maturation of memory T cells in vivo and normal antigen-induced T-cell proliferation in vitro. Moreover, the blood response to lipopolysaccharide, IL-1ß, and TNF-{alpha}, which bind to TLR-4, IL-1R, and TNF-{alpha} receptors, respectively, was shown to be normal in terms of IL-1ß, IL-6, and IL-10 production, respectively. This immunologic phenotype, like the chimerism, remained stable during the 7 years after transplantation. The child therefore grew and developed normally. These data clearly indicate that the most severe immunologic abnormalities that are associated with AD-EDA-ID can be controlled by HSCT, suggesting that the extrahematopoietic activation of NF-{kappa}B is not required for the development of mature T cells and responses to most agonists of the TLR, IL-1R, and TNF receptor superfamilies. Our patient with AD-EDA-ID underwent HSCT before we knew that he was carrying a mutation in IKBA, as it is difficult to detect signs of EDA in young children. HSCT clearly did not prevent known EDA developmental abnormalities. Unlike these developmental defects, the clinical consequences of the immunodeficiency that are observed in AD-EDA-ID can be cured by HSCT.

The patient did not present GVHD and experienced no life-threatening infections in the 7 years after transplantation. He has experienced recurrent planar warts in the past 2 years, however, as reported in a few other NEMO-deficient patients.34 Recurrent bacterial infections of the respiratory tract were not correlated with any major abnormality in antibody response but required continuous immunoglobulin substitution. Similarly, the 2 episodes of zoster infections were not correlated with any detectable T-cell phenotype. These relatively benign infections may reflect imperfect immune reconstitution after haploidentical HSCT. Furthermore, as for severe combined immunodeficient patients, response to pneumococcal polysaccharide was low.35 Alternatively, impaired NF-{kappa}B signaling in nonhematopoietic cells may have had an undetectable effect on hematopoietic immune responses, accounting for these infections. Impaired NF-{kappa}B signaling in nonhematopoietic cells also may have impaired host defenses directly. For example, the persistent alteration of the NF-{kappa}B pathway in keratinocytes may have been responsible for the patient's warts.29,36 This situation is reminiscent of the recurrent papilloma virus infections that are observed in certain severe combined immunodeficient patients after transplantation, possibly as a result of a deficiency of {gamma}c-dependent molecule expression in keratinocytes.37

Finally, the conditioning regimen was well tolerated by our patient. Another patient who had XR-OL-EDA-ID and severe immunodeficiency and underwent HSCT16 died of veno-occlusive disease 11 days after transplantation, as a result of the toxicity of the conditioning regimen, perhaps, at least in part, because of an increase in apoptosis, as observed in male patients with incontinentia pigmenti and male NEMO knockout mice, which die in utero.38–41 However, this child with a NEMO mutation was in very poor clinical condition at the time of transplantation, and the patient herein reported did not experience any major conditioning toxicity. Therefore, despite the minor complications that were observed and unknown long-term outcome, our positive experience is consistent with the indication of HSCT in patients with AD-EDA-ID associated with mutations in IKBA. Seven years of follow-up in a child with a good quality of life is encouraging. HSCT should be considered the optimal treatment not only for AD-EDA-ID but also possibly for selected cases of XR-EDA-ID with a severe immunodeficiency. Subtle biochemical differences between patients with NEMO and I{kappa}B{alpha} deficiencies may render HSCT in patients with NEMO more difficult. Pilot studies therefore should be conducted to determine whether patients with severe mutations in NEMO can be treated by HSCT. Potentially life-saving HSCT should be offered to patients with NEMO and IKBA mutations and severe immunodeficiency.


   ACKNOWLEDGMENTS
 
We thank M. Cavazzana-Calvo, N. Brousse, N. Jabado, S. Blanche, M. Luisa Romiti, and S. Di Cesare for helpful discussions and technical help.


   FOOTNOTES
 
Accepted Jan 17, 2005.

Address correspondence to Jean-Laurent Casanova, MD, PhD, Laboratoire de Génétique Humaine des Maladies Infectieuses, Université René Descartes-INSERM U550, Faculté de Médecine Necker-Enfants Malades, 75015 Paris, France. E-mail: casanova{at}necker.fr

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

Dr Le Deist's current address is Département de Microbiologie et d'Immunologie, Hôpital Sainte Justine, Montréal, Québec, Canada H3T 1C5.

Drs Dupuis-Girod and Cancrini contributed equally to this study.


   REFERENCES
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 DISCUSSION
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  1. Clarke A, Phillips DI, Brown R, Harper PS. Clinical aspects of X-linked hypohidrotic ectodermal dysplasia. Arch Dis Child. 1987;62 :989 –996[Abstract/Free Full Text]
  2. Franken E. Anhidrotic form of ectodermal dysplasia with hypogammaglobulinemia and properdin deficiency [in German]. Dermatol Wochenschr. 1966;152 :841 –845[Medline]
  3. Frix CD 3rd, Bronson DM. Acute miliary tuberculosis in a child with anhidrotic ectodermal dysplasia. Pediatr Dermatol. 1986;3 :464 –467[Medline]
  4. Davis JR, Solomon LM. Cellular immunodeficiency in anhidrotic ectodermal dysplasia. Acta Derm Venereol. 1976;56 :115 –120[Web of Science][Medline]
  5. Sitton JE, Reimund EL. Extramedullary hematopoiesis of the cranial dura and anhidrotic ectodermal dysplasia. Neuropediatrics. 1992;23 :108 –110[Web of Science][Medline]
  6. Brooks EG, Klimpel GR, Vaidya SE, et al. Thymic hypoplasia and T-cell deficiency in ectodermal dysplasia: case report and review of the literature. Clin Immunol Immunopathol. 1994;71 :44 –52[CrossRef][Web of Science][Medline]
  7. Abinun M. Ectodermal dysplasia and immunodeficiency. Arch Dis Child. 1995;73 :185[Free Full Text]
  8. 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]
  9. Carrol ED, Gennery AR, Flood TJ, Spickett GP, Abinun M. Anhidrotic ectodermal dysplasia and immunodeficiency: the role of NEMO. Arch Dis Child. 2003;88 :340 –341[Abstract/Free Full Text]
  10. 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 [in German]. Klin Padiatr. 1999;211 :459 –461[Web of Science][Medline]
  11. Smythe WR, Bridges ND, Gaynor JW, Nicolson S, Clark BJ, Spray TL. Bilateral sequential lung transplant for ectodermal dysplasia. Ann Thorac Surg. 2000;70 :654 –656[Abstract/Free Full Text]
  12. 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]
  13. 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]
  14. Jain A, Ma CA, Liu S, Brown M, Cohen J, Strober W. Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol. 2001;2 :223 –228[CrossRef][Web of Science][Medline]
  15. 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]
  16. Dupuis-Girod S, Corradini N, Hadj-Rabia S, et al. Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pigmenti in his mother. Pediatrics. 2002;109(6) . Available at: www.pediatrics.org/cgi/content/full/109/6/e97
  17. 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]
  18. 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]
  19. 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]
  20. 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]
  21. Ku CL, Dupuis-Girod S, Dittrich AM, et al. NEMO mutations in 2 unrelated boys with severe infections and conical teeth. Pediatrics. 2005;115(5) . Available at: www.pediatrics.org/cgi/content/full/115/5/e615
  22. 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]
  23. Orange JS, Levy O, Brodeur SR, et al. Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia. J Allergy Clin Immunol. 2004;114 :650 –656[CrossRef][Web of Science][Medline]
  24. Courtois G, Smahi A, Reichenbach J, et al. A hypermorphic I{kappa}B{alpha} mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J Clin Invest. 2003;112 :1108 –1115[CrossRef][Web of Science][Medline]
  25. Janssen R, van Wengen A, Hoeve MA, et al. The same I{kappa}B{alpha} mutation in two related individuals leads to completely different clinical syndromes. J Exp Med. 2004;200 :559 –568[Abstract/Free Full Text]
  26. Kumar A, Eby MT, Sinha S, Jasmin A, Chaudhary PM. The ectodermal dysplasia receptor activates the nuclear factor-{kappa}B, JNK, and cell death pathways and binds to ectodysplasin A. J Biol Chem. 2001;276 :2668 –2677[Abstract/Free Full Text]
  27. Aradhya S, Courtois G, Rajkovic A, et al. Atypical forms of incontinentia pigmenti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKK-gamma). Am J Hum Genet. 2001;68 :765 –771[CrossRef][Web of Science][Medline]
  28. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21 :335 –376[CrossRef][Web of Science][Medline]
  29. Kouba DJ, Nakano H, Nishiyama T, Kang J, Uitto J, Mauviel A. Tumor necrosis factor-alpha induces distinctive NF-kappa B signaling within human dermal fibroblasts. J Biol Chem. 2001;276 :6214 –6224[Abstract/Free Full Text]
  30. Li Q, Verma IM. NF-{kappa}B regulation in the immune system. Nat Rev Immunol. 2002;2 :725 –734[CrossRef][Web of Science][Medline]
  31. Karin M, Lin A. NF-{kappa}B at the crossroads of life and death. Nat Immunol. 2002;3 :221 –227[CrossRef][Web of Science][Medline]
  32. Reuther JY, Baldwin AS Jr. Apoptosis promotes a caspase-induced amino-terminal truncation of I{kappa}B{alpha} that functions as a stable inhibitor of NF-{kappa}B. J Biol Chem. 1999;274 :20664 –20670[Abstract/Free Full Text]
  33. Jabado N, Le Deist F, Cant A, et al. Bone marrow transplantation from genetically HLA-nonidentical donors in children with fatal inherited disorders excluding severe combined immunodeficiencies: use of two monoclonal antibodies to prevent graft rejection. Pediatrics. 1996;98 :420 –428[Abstract/Free Full Text]
  34. Orange JS. Congenital immunodeficiencies and sepsis. Pediatr Crit Care Med. 2005;6(suppl) :S99 –S107[CrossRef][Medline]
  35. Slatter MA, Bhattacharya A, Flood TJ, et al. Polysaccharide antibody responses are impaired post bone marrow transplantation for severe combined immunodeficiency, but not other primary immunodeficiencies. Bone Marrow Transplant. 2003;32 :225 –229[CrossRef][Web of Science][Medline]
  36. Nees M, Geoghegan JM, Hyman T, Frank S, Miller L, Woodworth CD. Papillomavirus type 16 oncogenes downregulate expression of interferon-responsive genes and upregulate proliferation-associated and NF-{kappa}B-responsive genes in cervical keratinocytes. J Virol. 2001;75 :4283 –4296[Abstract/Free Full Text]
  37. Laffort C, Le Deist F, Favre M, et al. Severe cutaneous papillomavirus disease after haemopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common gammac cytokine receptor subunit or JAK-3 deficiency. Lancet. 2004;363 :2051 –2054[CrossRef][Web of Science][Medline]
  38. Rudolph D, Yeh WC, Wakeham A, et al. Severe liver degeneration and lack of NF-{kappa}B activation in NEMO/IKK{gamma}-deficient mice. Genes Dev. 2000;14 :854 –862[Abstract/Free Full Text]
  39. Kenwrick S, Woffendin H, Jakins T, et al. Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome. Am J Hum Genet. 2001;69 :1210 –1217[CrossRef][Web of Science][Medline]
  40. Makris C, Godfrey VL, Krahn-Senftleben G, et al. Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol Cell. 2000;5 :969 –979[CrossRef][Web of Science][Medline]
  41. Schmidt-Supprian M, Bloch W, Courtois G, et al. NEMO/IKK gamma-deficient mice model incontinentia pigmenti. Mol Cell. 2000;5 :981 –992[CrossRef][Web of Science][Medline]
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

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M. Luengo-Blanco, C. Prando, J. Bustamante, W. C. Aragao-Filho, P. V. S. Pereira, J. Rehder, C. Padden, J.-L. Casanova, P. E. Newburger, and A. Condino-Neto
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