Hyper-IgE syndrome (HIES) encompasses several distinct genetic entities with varying mechanisms and manifestations. Management depends on the specific immune deficiency type, making genetic confirmation essential for guiding therapeutic strategies. Through this case report, authors illustrate the diagnostic challenge of HIES.
ST, a 7-year-old boy born to non-consanguineous parents, has presented with severe manifestations since the neonatal period, including allergic symptoms (eczema, food allergy, asthma, urticaria), infectious symptoms (recurrent respiratory and skin infections, oral thrush, with Staphylococcus aureus isolated twice), and developmental delay (delayed language acquisition).
Laboratory findings showed eosinophilia (500-1500/mm3) and elevated IgE levels (1700-2750 IU/mL), while IgG, IgA, and IgM levels, lymphocyte subsets, lymphocyte proliferation assay, phosphorylated STAT3 expression, and vaccine response were all normal. Organ evaluation (abdominal, renal, and cardiac ultrasound, as well as brain MRI) was normal. Chest CT revealed multiple bilateral pulmonary micronodules. Whole-exome sequencing did not detect any phenotype-related variant, except for a heterozygous mutation in the CCDC39 gene (c.2190del p.Glu731Asnfs*31), which is known to cause primary ciliary dyskinesia in a homozygous state. Whole-genome sequencing identified a variant of uncertain significance (VUS) in the LZTR1 gene (c.651G>T p.Glu217Asp), which is associated with RASopathies, including Noonan syndrome and certain myeloid malignancies via RAS-MAPK pathway activation. The RAS-MAPK pathway may modulate STAT6 activity through increased phosphorylation by JAK1 via MEK/ERK → prolonged transcriptional activation and IL-4 production via ERK-mediated transcriptional activation.
This case illustrates the diagnostic challenges of HIES in the absence of a definitive genetic diagnosis and highlights the need for functional validation of VUS. Further research is needed to explore the relationship between RAS-MAPK signaling and immune dysregulation, which could enhance our understanding of hyper-IgE syndromes.
