Suspected STAT3-Related Hyper-IgE Syndrome in a Toddler with a Novel STAT3 Variant of Uncertain Significance

Background Dominant-negative (DN) STAT3 defects (STAT3-DN) result in >75% loss of STAT3 function and lead to autosomal-dominant hyper-IgE syndrome (HIES) characterized by severe eczema, recurrent bacterial and fungal infections, elevated IgE, eosinophilia, and skeletal and connective-tissue abnormalities. More recently, STAT3 haploinsufficiency (STAT3-HI), typically due to truncating or splice-site variants with partial preservation of STAT3 activity (>25%), has been associated with atopy, impaired Th17 differentiation, and possible increased susceptibility to fungal infections. When a STAT3 variant of uncertain significance (VUS) is identified, diagnosis of STAT3-related HIES in early childhood can be challenging without additional functional testing. Case Presentation A 22-month-old male presented with complex congenital and atopic disease. Congenital findings include a solitary kidney with cross-fused renal ectopia, Chiari malformation, vertebral anomalies, and gross motor delay. Atopic manifestations included early-onset eczema, multiple IgE-mediated food allergies, and recurrent wheezing. He experienced multiple respiratory illnesses, including status asthmaticus, recurrent croup, pneumonia, and bronchiolitis. Family history is notable for a sibling with specific antibody deficiency, intrauterine fetal demise of another sibling with bilateral renal agenesis, and a father with recurrent infections, bronchiectasis, and possible pneumatocele attributed to allergic bronchopulmonary aspergillosis (ABPA), treated with dupilumab. Immunologic evaluation demonstrated elevated IgE (569 IU/mL), otherwise normal quantitative immunoglobulins, and poor pneumococcal titers (4/14 protective), with repeat titers pending. A previously undescribed paternally inherited heterozygous STAT3 intronic VUS (c.1233+1_1233+3delinsCTTp.?) was identified on whole-genome sequencing. In silico analysis predicts a deleterious effect on splicing. His National Institutes of Health HIES score was 22, within the “possible” range for his age. Functional studies (RNA-sequencing testing) and Th17 enumeration are being pursued to clarify variant pathogenicity. Discussion Diagnostic uncertainty stems from his young age, incomplete evolution of classic HIES features, and lack of functional STAT3 testing. Nonetheless, primary diagnosis of STAT3-related HIES is suspected, with consideration of both classic STAT3-DN and emerging STAT3-HI as mechanistic possibilities. Further immunophenotyping and functional studies can facilitate diagnosis. Conclusion In young patients with complex congenital anomalies, atopic disease, and relevant family history, identification of a STAT3 VUS warrants comprehensive functional evaluation. Distinguishing STAT3-DN from STAT3-HI will have meaningful implications for prognosis and clinical management.