Patient Vignette - part 2
Discussion
The assays show similar patterns: low CD40L expression at baseline and essentially no upregulation after stimulation (with normal ICOS and CD69 expression), while the healthy control exhibits the typical pattern of CD40L up-regulation on activated T-cells.
Despite a similar lack of CD40L upregulation, only one of the patient samples was obtained from a patient with HIGM1. The other CD40L assay, illustrated in the middle histogram, was obtained in the context of a broad-based immunologic workup in a patient with autoimmune cytopenias. The patient is a previously healthy 14-year old male, who presented with a transient episode of autoimmune hemolytic anemia, followed by chronic/relapsing immunemediated thrombocytopenia (ITP), requiring escalating therapeutic interventions (including the use of rituximab). The clinical history was negative for recurrent and/or chronic infections, including opportunistic infections. The patient showed widespread lymphadenopathy, as well as a mild splenomegaly, both predating the occurrence of ITP. The immunological workup revealed normal levels of isotype-switched immunoglobulins (IgG, IgA and IgE) and a low IgM level. Responses to antibody titers could not be measured due to prior infusions of IVIG and rituximab; no B cells were present in peripheral blood. T-cell and NK-cell function were normal. Genetic evaluation of CD40L showed a sequence variation, characterized by a non-conservative substitution of glycine to arginine in amino acid 219 (G219R). A polymorphism at this position has previously been reported (see side box, #5). Genetic evaluation of the patient's mother showed that she is a carrier of this sequence variation. Given the fact that her CD40L assay showed the characteristic bimodal distribution seen in carriers of HIGM1 would indicate that this sequence variant may not merely be a polymorphism. A second male patient with recalcitrant ITP (requiring splenectomy), showing absent CD40L upregulation, as well as the CD40L-G219R sequence variant was recently identified. His evaluation, so far, is similarly not consistent with HIGM1.
Despite an abnormal CD40L assay, no evidence of Hyper IgM syndrome: A case of mistaken immunologic identity?
