D2.377 - Severe Eosinophilia as an Atypical Initial Presentation of X-Linked Hyper-IgM Syndrome Due to CD40LG Deficiency

X-linked Hyper-IgM syndrome (XHIGM), caused by mutations in the CD40LG gene, is a rare primary combined immunodeficiency characterized by defective immunoglobulin class-switch recombination and severe, recurrent infections. Unusual inflammatory presentations may obscure early diagnosis. Marked eosinophilia is rarely reported as an initial manifestation and represents a significant diagnostic pitfall.

Case Description

We report a 1 year old male infant, born at 37 weeks of gestation (third pregnancy, third delivery; birth weight 2900 g, length 50 cm), with a history of recurrent respiratory infections. He was admitted with acute onset of vomiting, diarrhea, high-grade fever (39°C), rapidly progressing to severe respiratory distress, cyanosis, and altered consciousness. On admission, oxygen saturation was 68%, requiring invasive mechanical ventilation (FiO₂ 70%, PEEP 5 cmH₂O).

Laboratory investigations revealed extreme leukocytosis (up to 27.48 ×10⁹/L) with marked eosinophilia (36.4%, ~10 ×10⁹/L). Immunological work-up showed profound hypogammaglobulinemia: IgA 0.02 mg/ml (N 0.04–0.80), IgG 0.34 mg/ml, with relatively preserved IgM (0.56 mg/ml). Inflammatory and coagulation markers were markedly elevated (CRP >200 µg/ml, procalcitonin 0.97 ng/ml, D-dimer 2.05 mg/L).

Microbiological investigations identified severe polymicrobial infection, including Pseudomonas aeruginosa, Klebsiella pneumoniae, Candida albicans, Staphylococcus epidermidis bacteremia, and Human Rhinovirus/Enterovirus. Was tested for P. jirovecii infection, but it was not confirmed. Chest computed tomography demonstrated bilateral subtotal pneumonia with extensive ground-glass opacities and acute respiratory distress syndrome.

Genetic analysis confirmed X-linked combined immunodeficiency due to a CD40LG mutation (Xq26.3), establishing the diagnosis of XHIGM.

Conclusion

This case highlights severe eosinophilia as a misleading initial feature of XHIGM, emphasizing the need to consider primary immunodeficiencies in infants presenting with unexplained eosinophilia and life-threatening infections. Early recognition of atypical phenotypes is critical to improve outcomes.