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.

Objectives: 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.

Keywords: Autoantibody; B-cell tolerance; Chromosome 17p11.2 deletion; FLCN; Immune deficiency; Smith-Magenis syndrome; TNFRSF13B; TOM1L2.

Figure 1

Most SMS caregivers perceive acute infections to worsen SMS-associated sleep disturbances, maladaptive behaviors and seizures.

Figure 2

SMS sera are less reactive than control sera to pathogen-associated and self-antigens. The heat map displays sera reactivities to 4 pathogen-associated antigens (upper panel) and 3 self-antigens (lower panel) lower in 18 SMS serum samples than 17 healthy-related and unrelated control samples. Colorimetric differences corresponding to array MFIs are indicated.