ELECTRONIC ARTICLE |




* Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale U550, Necker Medical School, Paris, France
Pediatric Hematology-Immunology, Debrousse Hospital, Lyon, France
Pediatric Pneumology and Immunology, Charite-Campus Virchow Klinikum, Berlin, Germany
|| Stomatology, Necker Hospital, Paris, France
¶ Dermatology, Necker Hospital, Paris, France
# Laboratory of Experimental Medicine, University Hospital Leuven, Leuven, Belgium
** Pediatric Hematology-Immunology, Necker Hospital, Paris, France
| ABSTRACT |
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B essential modulator (NEMO), which is essential for nuclear factor-
B activation. Early in life, affected boys present a typical appearance, with hypotrichosis or atrichosis, hypohidrosis or anhidrosis, and hypodontia or anodontia with conical incisors. They are also susceptible to various microorganisms, mostly pyogenic bacteria and mycobacteria. Here we report 2 unrelated boys, aged 6 and 11 years, who have novel mutations in NEMO and present conical incisors and hypodontia as their sole and long-unrecognized developmental anomaly. One child had isolated recurrent pneumococcal disease, whereas the other had multiple infections. Our observations indicate that conical incisors should prompt the search for NEMO mutations in boys with unusual infectious diseases.
Key Words: NEMO ectodermal dysplasia conical teeth immunodeficiency NF-
B
Abbreviations: XL-EDA-ID, X-linked anhidrotic ectodermal dysplasia with immunodeficiency NF-
B, nuclear factor-
B NEMO, nuclear factor-
B essential modulator TNF, tumor necrosis factor IL, interleukin Ig, immunoglobulin Hib, Haemophilus influenzae type b
X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is a rare congenital disease, characterized by abnormal development of ectoderm-derived skin appendages and susceptibility to infectious diseases.112 Most affected individuals are male. In early childhood, they generally present multiple overt developmental anomalies, such as hypohidrosis or anhidrosis resulting in intolerance to heat, hypotrichosis or atrichosis, and hypodontia or anodontia with conical incisors, resulting in a typical facial appearance. A small number of patients also present with osteopetrosis and lymphedema. More than half of the known patients died from severe infections, generally caused by pyogenic bacteria and poorly pathogenic mycobacteria. Paradoxically, the only anomaly that is found consistently during routine immunologic tests is an impaired antibody response to polysaccharide antigens. Various hypomorphic mutations have been found in nuclear factor-
B (NF-
B) essential modulator (NEMO), which encodes a critical component of the NF-
B signaling pathway. The EDA phenotype results from impaired NF-
B activation by the single ectodysplasin receptor. In contrast, immunodeficiency results from impaired NF-
B activation by multiple immune receptors, such as members of the Toll-like receptor, interleukin (IL)-1 receptor, and tumor necrosis factor (TNF) receptor superfamilies and T/B-cell receptors. We report 2 unrelated boys who bear mutations in NEMO. Both experienced severe infectious diseases. Abnormal teeth were their sole developmental anomaly.
| CASE REPORTS |
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Patient 1 had a functional spleen and normal complement levels. The lymphocyte subsets were normally distributed, and in vitro T-lymphocyte proliferation in response to both mitogens and antigens was normal (Table 1). At 5 years, patient 1 had normal immunoglobulin (Ig) M and IgA and high IgG serum levels. IgG subclasses were normal. At this age, serum antibodies to the tetanus toxoid recall antigen were within the normal range, but antibodies against S pneumoniae were undetectable despite 3 episodes of pneumococcal arthritis (titer of antibodies to a pool of 23 serotypes <0.15 mg/L and no detectable specific antibodies to serotypes 3, 4, and 9). He then was vaccinated with a pneumococcal polysaccharidic vaccine (Pneumovax 23), and 1 month later, no adequate antibody response was detected against serotypes 3, 4, 9N, 18C, and 23F despite an antibody titer of 0.8 µg/mL against a mixture of the 23 serotypes. Antibodies against H influenzae type b (Hib) were also detectable after vaccination with a conjugated Hib capsule (46% inhibition, normal value >20%). Anti-B allohemagglutinins were barely detectable in serum at the age of 5 years (titer: 1/4; blood group A).
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The patient had a functional spleen and normal complement levels. In vitro T-lymphocyte proliferation in response to both mitogens and antigens was low (Table 1). At the age of 9 years, patient 2 had low IgM and normal IgG and IgA serum levels. IgG subclasses were normal at the age of 3 years. He displayed normal levels of serum antibodies against tetanus toxoid after vaccination. He was not vaccinated against S pneumoniae, but no serum antibodies against S pneumoniae could be detected at 2 or 6 years despite multiple episodes of pneumococcal disease. At 5 years of age, his antibody response to Hib conjugate vaccine was normal (0.89 mg/L; for protective values: >0.15 mg/L). He had neither anti-A nor anti-B serum allohemagglutinins at the ages of 5 and 7.5 years (blood group O).
These 2 children display no developmental signs of EDA syndrome other than hypodontia and conical incisors (Fig 1). Their eye brows, eye lashes, and hair are normal, and there is no facial dysmorphy. Both patients sweat normally, with no heat intolerance. Patient 1 had all of his lacteal teeth but with 4 conical-shaped mandibular incisors (teeth 71, 72, 81, and 82; Fig 1A). Mandibular radiography revealed hypodontia with agenesis of 1 adult premolar (tooth 35). The mother of patient 1 presents no immunodeficiency or incontinentia pigmenti. However, her teeth are also sparse and some incisors are conical (not shown). Patient 2 also has hypodontia of adult teeth, and some of his lacteal incisors were conical (Fig 1B). Deciduous incisor 81 is conical shaped, and there is agenesis of adult teeth 12, 22, 31, 32, 41, and 42. The mother of patient 2 displays no clinical abnormalities.
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By Western blot, NEMO was detected in cellular extract from patient 1 and patient 2 (Fig 2B). However, fibroblasts from patient 1 and patient 2 responded weakly to TNF-
and IL-1ß in terms of IL-6 production, when compared with a healthy control subject (Fig 2B). Fibroblasts bearing an amorphic NEMO mutation did not respond to these stimulations. These data validated the pathogenic impact of the 2 mutations identified, despite the presence of detectable NEMO protein.
| DISCUSSION |
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Our observations thus indicate that impaired tooth development and defective antipolysaccharide antibody response to unconjugated polysaccharides (allohemagglutinins and antipneumococcal antibodies) are the 2 most consistent clinical indicators of NEMO mutations. Our 2 patients extend our description of the clinical phenotype associated with hypomorphic NEMO mutations, as not only the immunologic but also the developmental phenotype varies considerably from case to case. The mutations 811_828del (patient 1) and L80P (patient 2) both are associated with a mild developmental impact in vivo in hemizygous male individuals, yet only the heterozygous mother of patient 1 shows abnormal teeth. Paradoxically, the heterozygous mother of patient 2, unlike that of patient 1, shows a skewed X-inactivation in her blood cells. Biochemical studies now are required to understand how the different mutations in NEMO112 (this article) result in such different clinical phenotypes. In clinical practice, all boys with unusually severe infections and conical incisors or hypodontia should be investigated for NEMO mutations, even if they do not display the canonical EDA phenotype. Moreover, neither an apparently normal antibody response to conjugated polysaccharides nor a random X-inactivation in blood cells from their symptomatic or asymptomatic mothers or a detectable NEMO protein by Western Blot should delay the sequencing of the coding region of the NEMO gene.
| ACKNOWLEDGMENTS |
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| FOOTNOTES |
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Reprint requests to (J.-L.C.) Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes-INSERM U550, Faculté de Médecine Necker, 156 Rue de Vaugirard, 75015 Paris, France. E-mail casanova{at}necker.fr
No conflict of interest declared.
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