Pulmonary alveolar proteinosis and Pneumocystis jirovecii infection in an infant with hyper-IgM syndrome caused by a novel CD40LG variant: a case report.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease. While autoimmunity is the leading cause of PAP in adults, the majority of pediatric cases occur secondary to immunodeficiency and opportunistic infections. Secondary PAP associated with CD40 ligand (CD40L) deficiency is extremely rare, and the underlying pathophysiology remains poorly understood. CASE PRESENTATION: We report the case of a 4-month-old boy admitted due to failure to thrive and severe hypoxemic respiratory failure. Chest computed tomography demonstrated diffuse ground-glass opacities with interlobular septal thickening. Bronchoalveolar lavage yielded clear fluid containing Periodic acid-Schiff-positive material consistent with PAP, and polymerase chain reaction was positive for Pneumocystis jirovecii. An immunologic evaluation showed hypogammaglobulinemia (IgG and IgA), a normal IgM level for his age, an absence of class-switched memory B cells, and significantly reduced CD40L expression on activated T lymphocytes. Targeted genetic testing identified a previously unreported hemizygous CD40LG missense variant [c.137T>C, p.(Leu46Pro)]. Integration of the patient's immunophenotype, an in silico variant evaluation, and segregation data permitted classification of this variant as likely pathogenic, confirming X-linked hyper-IgM syndrome. The patient improved with ventilatory support, high-dose trimethoprim-sulfamethoxazole, and immunoglobulin replacement therapy. CONCLUSIONS: Early-onset PAP associated with P. jirovecii infection may reveal CD40L deficiency and should prompt evaluation for primary immunodeficiency. An integrated clinico-immunologic assessment coupled with genetic testing is essential to provide a molecular diagnosis, guide management, and prognostication, and to support timely consideration of curative hematopoietic stem cell transplantation.