title: Congenital alterations of NEMO glutamic acid 223 result in hypohidrotic ectodermal dysplasia and immunodeficiency with normal serum IgG levels.
abstract: BACKGROUND
  Hypomorphic mutations in the nuclear factor-κB (NF-κB) essential modulator (NEMO) gene result in a variable syndrome of somatic and immunologic abnormalities. Clinically relevant genotype-phenotype associations are essential to understanding this complex disease.
  
  
  OBJECTIVE
  To study 2 unrelated boys with novel NEMO mutations altering codon 223 for similarity in phenotype in consideration of potential genotype-phenotype associations.
  
  
  METHODS
  Clinical and laboratory features, including cell counts, immunoglobulin quantity and quality, natural killer cell cytotoxicity, and Toll-like and tumor necrosis factor receptor signaling, were evaluated. Because both mutations affected NEMO codon 223 and were novel, consideration was given to new potential genotype-phenotype associations.
  
  
  RESULTS
  Both patients were diagnosed as having hypohidrotic ectodermal dysplasia and had severe or recurrent infections. One had recurrent sinopulmonary infections and the other necrotizing soft tissue methicillin-resistant Staphylococcus aureus infection and Streptococcus anginosus subdural empyema with bacteremia. NEMO gene sequence demonstrated a 3-nucleotide deletion (c.667_669delGAG) in one patient and a substitution (667G>A) in the other. These findings predict either the deletion of NEMO glutamic acid 223 or it being replaced with lysine, respectively. Both patients had normal serum IgG levels but poor specific antibodies. Natural killer cell cytotoxicity and Toll-like and tumor necrosis factor receptor signaling were also impaired. Serious bacterial infection did not occur in both patients after immunoglobulin replacement therapy.
  
  
  CONCLUSIONS
  Two different novel mutations affecting NEMO glutamic acid 223 resulted in clinically relevant similar phenotypes, providing further evidence to support genotype-phenotype correlations in this disease. They suggest NEMO residue 223 is required for ectodermal development and immunity and is apparently dispensable for quantitative IgG production but may be required for specific antibody production.
authors.affiliation: Health Science Center, Louisiana State University, New Orleans, LA, USA.
authors.forename: Gital
authors.initials: G
authors.lastname: Karamchandani-Patel
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hanson
authors.forename: Rushani
authors.initials: R
authors.lastname: Saltzman
authors.forename: C Eve
authors.initials: CE
authors.lastname: Kimball
authors.forename: Ricardo U
authors.initials: RU
authors.lastname: Sorensen
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
mesh_terms: D000918:Antibody Specificity / Q000276:immunology; D002675:Child, Preschool; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000276:immunology; D053358:Ectodermal Dysplasia 1, Anhidrotic; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics* / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood*; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D009154:Mutation; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: C491731:IKBKG protein, human; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D018124:Receptors, Tumor Necrosis Factor; D051193:Toll-Like Receptors; D051550:I-kappa B Kinase