Phenotypic heterogeneity in a family with a CD40 ligand intracellular domain mutation

We describe a family with the rare mutation R11X that leads to a truncated CD40 ligand (CD40L) missing the intracellular domain. The index case had detectable CD40L expression and presented at the age of 41 years with cerebral toxoplasmosis. A brother and two nephews were also identified as having the same mutation but exhibited milder and variable phenotypes. The older affected nephew had a moderately depressed immunoglobulin G level and a history of pneumonia at 4 months of age. The younger nephew suffered from sinusitis with normal immunoglobulin levels. Both nephews had absent antibody responses to a protein antigen with conserved responses to polysaccharide antigens. The two sisters of the index case are carriers who had elevated levels of IgM but remain well. This mutation may affect CD40 ligand function by reducing cell surface levels, diminishing CD40 interaction or disrupting CD40L intracellular signalling in T cells. The variable phenotype in members of this family offers an opportunity to further understand the CD40-CD40L signalling pathway in human immune responses.