title: Comèl-Netherton syndrome defined as primary immunodeficiency.
abstract: BACKGROUND
  Mutations in serine protease inhibitor Kazal-type 5 (SPINK5), encoding the serine protease inhibitor lympho-epithelial Kazal-type 5 related inhibitor (LEKTI), cause Comèl-Netherton syndrome, an autosomal-recessive disease characterized by congenital ichthyosis, bamboo hair, and atopic diathesis. Despite increased frequency of infections, the immunocompetence of patients with Comèl-Netherton syndrome has not been extensively investigated.
  
  
  OBJECTIVE
  To define Comèl-Netherton syndrome as a primary immunodeficiency disorder and to explore the benefit of intravenous immunoglobulin replacement therapy.
  
  
  METHODS
  We enrolled 9 patients with Comèl-Netherton syndrome, sequenced SPINK5, and analyzed LEKTI expression by immunohistochemistry. Immune function was assessed by measuring cognate immunity, serum cytokine levels, and natural killer cell cytotoxicity.
  
  
  RESULTS
  All patients presented with recurrent skin infections caused predominantly by Staphylococcus aureus. All but 1 reported recurrent respiratory tract infections; 78% had sepsis and/or pneumonia; 67% had recurrent gastrointestinal disease and failure to thrive. Mutations in SPINK5-including 6 novel mutations-were identified in 8 patients. LEKTI expression was decreased or absent in all patients. Immunologic evaluation revealed reduced memory B cells and defective responses to vaccination with Pneumovax and bacteriophage phiX174, characterized by impaired antibody amplification and class-switching. Immune dysregulation was suggested by a skewed T(h)1 phenotype and elevated proinflammatory cytokine levels, whereas serum concentrations of the chemokine (C-C motif) ligand 5 and natural killer cell cytotoxicity were decreased. Treatment with intravenous immunoglobulin resulted in remarkable clinical improvement and temporarily increased natural killer cell cytotoxicity.
  
  
  CONCLUSIONS
  These data provide new insights into the immunopathology of Comèl-Netherton syndrome and demonstrate that this multisystem disorder, characterized by lack of LEKTI expression in epithelial cells, is complicated by cognate and innate immunodeficiency that responds favorably to intravenous immunoglobulin therapy.
authors.affiliation: Dr v Haunersches Kinderspital, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Ellen D
authors.initials: ED
authors.lastname: Renner
authors.forename: Dominik
authors.initials: D
authors.lastname: Hartl
authors.forename: Stacey
authors.initials: S
authors.lastname: Rylaarsdam
authors.forename: Marguerite L
authors.initials: ML
authors.lastname: Young
authors.forename: Linda
authors.initials: L
authors.lastname: Monaco-Shawver
authors.forename: Gary
authors.initials: G
authors.lastname: Kleiner
authors.forename: M Louise
authors.initials: ML
authors.lastname: Markert
authors.forename: E Richard
authors.initials: ER
authors.lastname: Stiehm
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Belohradsky
authors.forename: Melissa P
authors.initials: MP
authors.lastname: Upton
authors.forename: Troy R
authors.initials: TR
authors.lastname: Torgerson
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007153:Immunologic Deficiency Syndromes / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D007155:Immunologic Factors / Q000627:therapeutic use; D008297:Male; D009154:Mutation; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D013207:Staphylococcal Skin Infections / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D013211:Staphylococcus aureus; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D053491:Proteinase Inhibitory Proteins, Secretory; C120650:SPINK5 protein, human; D000074163:Serine Peptidase Inhibitor Kazal-Type 5
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