Immunological and genetic analysis of 65 patients with a clinical suspicion of X linked hyper-IgM

Abstract

Background: X linked hyper-IgM (XHIM) is a primary immunodeficiency caused by mutations in the tumour necrosis factor superfamily 5 gene, TNFSF5, also known as the CD40 ligand (CD40L) gene. Patients often present with recurrent infections, and confirmation of a diagnosis of XHIM enables appropriate therapeutic interventions, including replacement immunoglobulin, antibiotics, and bone marrow transplantation. Aim: To review and optimise the institution's diagnostic strategy for XHIM. Method: Samples from 65 boys were referred to this centre for further investigation of suspected XHIM. The results, which included a flow cytometric whole blood assay for CD40L expression followed by mutation analysis in selected patients, were reviewed. Results: Twenty one patients failed to express CD40L and TNFSF5 mutations were found in 20 of these patients. In contrast, no TNFSF5 mutations were found in 16 patients with weak expression of CD40L. Interestingly, one quarter of patients with confirmed XHIM who had TNFSF5 mutations had low concentrations of IgG, IgA, and IgM. Most of the remaining patients with XHIM had the classic pattern of normal or raised IgM with low concentrations of IgA and IgG. Conclusions: This study demonstrates the usefulness of the whole blood staining method as a rapid screen to select patients for subsequent TNFSF5 mutation analysis, and shows the benefits of a unified protein/genetic diagnostic strategy.

Cerebral toxoplasmosis in a middle-aged man as first presentation of primary immunodeficiency due to a hypomorphic mutation in the CD40 ligand gene

“…In our patient, activation-induced CD40L surface upregulation was within the range of normality,5 albeit slightly less than the control. Perceived differences in the upregulation of surface CD40L between laboratories could be due to technical reasons, such as different affinities of monoclonal antibodies or the use of other reagents for CD40L detection (eg, CD40 Ig).…”

“…This was performed as previously described 5. Briefly, blood was collected from the patient and a control subject into tubes containing lithium heparin anticoagulant.…”

Class-Switch Recombination Defects

“…However, a few patients have low IgM levels, 45 indicating that this feature does not rule out a diagnosis of CD40L deficiency. Conversely, normal or even elevated IgA levels and (more rarely) IgG levels can sometimes be observed; this suggests the presence of a CD40-independent CSR pathway, which may operate upon stimulation of B cells through their BAFF or TACI receptors in the intestinal lamina propria 46 or Toll-like receptors in the marginal zone.…”

Pitfalls of “hyper”-IgM syndrome: a new CD40 ligand mutation in the presence of low IgM levels. A case report and a critical review of the literature

“…The numbers of cases with low IgM differ strikingly between the studies. For example, Katz et al [14] and Levy et al [2] reported no cases with low IgM (n = 0/16 and n = 0/55, respectively), whereas Winkelstein et al [20] reported eight cases and Gilmour et al [21] reported four cases with low IgM (n = 8/56 and n = 4/17, respectively). Our global analysis of all of the results of Table 2 using two-tailed Fisher's exact test revealed that the IgM serum levels reported by the studies differ significantly (P = 0.004).…”