BackgroundD40LG-associated X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis has rarely been reported, and its genotype-phenotypic correlation remains elusive.Case presentationWe describe a five-month-old boy withCD40LGmutation (c.516T > A, p.Tyr172Ter) X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis as the first manifestation. The patient completely recovered after immunotherapy and allogeneic hematopoietic stem cell transplantation. In addition, four previously reported patients withCD40LGmutation with pulmonary alveolar proteinosis were also analyzed. All of these patients presented with early onset of pulmonary infections and a good response to immunotherapy. The structural model ofCD40LGindicated that all mutations caused the X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis to be located within the tumor necrosis factor homology domain.ConclusionsA case was presented, and the characteristics of four cases ofCD40LG-associated X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis were summarized. The variant locations may explain the phenotypic heterogeneity of patients with theCD40LGmutation.