X-linked hyper-IgM syndrome (XHIM) due to CD40L deficiency typically presents in early childhood with recurrent sinopulmonary or opportunistic infections, and its initial manifestations can be misleading. We report a 9-month-old boy with eosinophilic lung disease and severe Pneumocystis jirovecii pneumonia (PJP), whose evaluation revealed XHIM.
To highlight the diagnostic process of an infant with XHIM syndrome including atypical presentation and CD40L variant of uncertain significance (VUS).
We performed a retrospective chart review, immunophenotyping, CD40L studies, and genetic testing.
Our patient was born with normal newborn screening (NBS) results. He had multiple emergency visits at 4 months for viral infections and bronchiolitis, including one pediatric intensive care unit (PICU) admission for presumed Mycoplasma pneumonia. No total IgG level was obtained. At 9 months, he was readmitted to the PICU for respiratory distress, presenting with leukocytosis and marked eosinophilia. Chest computed tomography (CT) showed diffuse ground-glass opacities with subpleural sparing. BD-glucan was elevated, and both plasma cell-free DNA (Karius) and bronchoalveolar lavage were positive for PJP. Serum immunoglobulins showed absent IgG, IgA, and IgE, with elevated IgM. Flow cytometry revealed nearly absent class-switched memory B cells. Genetic testing identified a CD40L c.524T>G (p.V175G) VUS inherited from his mother, and further testing confirmed absent CD40L expression on activated T cells. The patient required 6 weeks to recover after prolonged mechanical ventilation and complex therapy with high-dose trimethoprim-sulfamethoxazole, corticosteroids, antifungals, and intravenous immunoglobulin.
This case highlights that atypical pneumonias complicated by eosinophilia may represent an initial manifestation of XHIM. Infants older than 6 months of age may experience diagnostic delays if serum immunoglobulin levels, particularly IgG, are not measured at the time of admission. Because XHIM is characterized by profound T cell dysfunction, NBS with T cell receptor excision circles (TRECs) may be normal and does not exclude the diagnosis. Early recognition of XHIM enables timely initiation of immunoglobulin replacement, PJP prophylaxis, and evaluation for curative hematopoietic stem cell transplantation or gene therapy before irreversible complications occur.
