Challenges of Diagnostic Approach in a Hyper-IgE Syndrome Family

Abstract

Introduction: Hyper IgE syndrome (HIES), formerly known as Job’s syndrome, is an inborn error of immunity (IEI) with variable clinical presentations of infection, allergies, and high IgE levels. HIES has recently become better defined by genetic defects in STAT3, DOCK8, IL6R, and IL6ST, among others. Identifying defects in these genes can serve as a diagnostic method alongside scoring reports such as the NIH HIES scoring system. However, some patients may present with clinical manifestations that are unaccompanied by an identified pathogenic variant. Here, we highlight challenges in the diagnostic approach of HIES in an affected family. MethodsA retrospective data collection of the clinical history, symptoms, demographics, and treatment outcomes of the proband and his affected father was performed. Extensive immune subset phenotyping and functional assays on the signaling pathways were also conducted. Genetic evaluation was also completed and included 207-gene panel testing and whole exome sequencing. ResultsThe 15-year-old proband’s clinical history included significantly elevated IgE levels, eczema, lymphadenopathy, and severe, treatmentresistant herpes infections that led to two hospitalizations within the last year. His NIH HIES score was determined to be 45. His father experienced frequent herpes infections and recurrent abscesses and is also in remission for non-Hodgkin’s lymphoma. A 207 Invitae testing panel showed that neither individual had a pathogenic variant observed in STAT3 or DOCK8. Flow cytometric analysis revealed reduced memory and expanded CD19hi CD21lo B-cell populations in both the proband and father. Th2 skewing was seen in the CD4+ memory T cells of both individuals, along with increased fractions of CD4+ recent thymic emigrants and exhausted T cells. Notably, functional assays also revealed elevated phosphorylation of ERK, JNK, and AKT, while the phosphorylation of STAT5 in the naive compartment was lowered. Although these findings are not normally observed in STAT3 loss of function, they may be indicative of IL-2 signaling defects. ConclusionsDespite both the proband and the father exhibiting many clinical manifestations of HIES and scoring highly in the NIH HIES scoring system, the underlying IEI remains unidentified. Functional studies and extensive genetic analysis are vital for making clinical decisions and determining targeted therapies.