title: Smith-Magenis Syndrome Patients Often Display Antibody Deficiency but Not Other Immune Pathologies.
abstract: BACKGROUND
  Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder associated with recurrent otitis. Most SMS cases result from heterozygous interstitial chromosome 17p11.2 deletions that encompass not only the intellectual disability gene retinoic acid-induced 1 but also other genes associated with immunodeficiency, autoimmunity, and/or malignancy.
  
  
  OBJECTIVE
  The goals of this study were to describe the immunological consequence of 17p11.2 deletions by determining the prevalence of immunological diseases in subjects with SMS and by assessing their immune systems via laboratory methods.
  
  
  METHODS
  We assessed clinical histories of 76 subjects with SMS with heterozygous 17p11.2 deletions and performed in-depth immunological testing on 25 representative cohort members. Laboratory testing included determination of serum antibody concentrations, vaccine titers, and lymphocyte subset frequencies. Detailed reactivity profiles of SMS serum antibodies were performed using custom-made antigen microarrays.
  
  
  RESULTS
  Of 76 subjects with SMS, 74 reported recurrent infections including otitis (88%), pneumonia (47%), sinusitis (42%), and gastroenteritis (34%). Infections were associated with worsening SMS-related neurobehavioral symptoms. The prevalence of autoimmune and atopic diseases was not increased. Malignancy was not reported. Laboratory evaluation revealed most subjects with SMS to be deficient of isotype-switched memory B cells and many to lack protective antipneumococcal antibodies. SMS antibodies were not more reactive than control antibodies to self-antigens.
  
  
  CONCLUSIONS
  Patients with SMS with heterozygous 17p.11.2 deletions display an increased susceptibility to sinopulmonary infections, but not to autoimmune, allergic, or malignant diseases. SMS sera display an antibody reactivity profile favoring neither recognition of pathogen-associated antigens nor self-antigens. Prophylactic strategies to prevent infections may also provide neurobehavioral benefits to selected patients with SMS.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Conn.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Perkins
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rosenberg
authors.affiliation: Division of Allergy Immunology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Penn.
authors.forename: Carole
authors.initials: C
authors.lastname: Le Coz
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Alaimo
authors.affiliation: Division of Allergy Immunology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Penn.
authors.forename: Melissa
authors.initials: M
authors.lastname: Trofa
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors.forename: Sureni V
authors.initials: SV
authors.lastname: Mullegama
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Conn; Department of Dermatology, Yale University School of Medicine, New Haven, Conn.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Antaya
authors.affiliation: Division of Allergy Immunology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Penn.
authors.forename: Soma
authors.initials: S
authors.lastname: Jyonouchi
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Elsea
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, Calif; Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Conn; Department of Internal Medicine, Yale University School of Medicine, New Haven, Conn.
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
authors.affiliation: Division of Allergy Immunology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Penn. Electronic address: rombergn@email.chop.edu.
authors.forename: Neil
authors.initials: N
authors.lastname: Romberg
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D000071457:DEAD Box Protein 58 / Q000235:genetics; D005260:Female; D006801:Humans; D017578:Immunoglobulin Class Switching; D007153:Immunologic Deficiency Syndromes / Q000453:epidemiology*; D007156:Immunologic Memory; D007223:Infant; D008607:Intellectual Disability; D008297:Male; D009154:Mutation / Q000235:genetics; D010031:Otitis; D011014:Pneumonia; D015995:Prevalence; D011971:Receptors, Immunologic; D012852:Sinusitis; D058496:Smith-Magenis Syndrome / Q000453:epidemiology* / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: D011971:Receptors, Immunologic; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58
keywords: Autoantibody; B-cell tolerance; Chromosome 17p11.2 deletion; FLCN; Immune deficiency; Smith-Magenis syndrome; TNFRSF13B; TOM1L2