Simon J. Tavernier, Belgium
University Hospital Ghent Department of Internal Diseases and PediatricsPresenter of 1 Presentation
EXPANDING THE SPECTRUM OF HYPER IGE SYNDROMES: DESCRIPTION OF A KINDRED WITH A NOVEL VARIANT IN IL6ST
Abstract
Background and Aims
Historically, hyper IgE syndromes (HIES) are characterized by a clinical triad of relapsing skin abscesses, recurrent pneumonias complicated by pneumatocoele and elevated serum levels of IgE. HIES is a multi-system disease; aside of the abovementioned triad, recurrent viral infections, eosinophilia, eczema and connective tissue abnormalities (such as retained teeth and craniosynostosis) further complicate the phenotype. With the advent of next generation sequencing, the genetic landscape of HIES is ever-expanding, providing unique opportunities to understand this complex immunodeficiency syndrome.
Methods
Here we present a Bulgarian 8-year-old girl suffering from atopic eczema, severe asthma and recurrent respiratory infections. Her father has a similar phenotype characterized by relapsing staphylococcal skin infections and severe airway infections complicated by pneumatocele and mucormycosis. Both daughter and father present with frontal bossing and supernumerary teeth, due to absent shedding. In both cases, immunological investigations reveal eosinophilia and increased levels of IgE. The father’s phenotype is additionally complicated by hypogammaglobulinemia.
Results
Genetic analysis revealed a heterozygous frameshift mutation in the gene IL6ST resulting in a premature stop (I719NfsTer2). IL6ST encodes GP130, a transmembrane protein that acts as a signal transducer for many cytokines, including IL-6 and IL-27. In two recent reports, homozygous IL6ST missense variants were identified in patients suffering from HIES with defective STAT3 signaling. Indeed, STAT3 phosphorylation is impaired in I719NfsTer2 PBMCs upon stimulation, providing first prove of the pathogenic nature of this variant.
Conclusions
In summary, the discovery of this novel variant highlights the role of IL6ST in human immunity and expands the spectrum of hyper IgE-like syndromes.