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

¹ Immunology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK
² Regional Molecular Genetics, Great Ormond Street Hospital for Children

Correspondence to:
Dr K C Gilmour, Immunology, Level 4 CBL, Great Ormond Street Hospital, London WC1N 3JH, UK;
gilmok{at}gosh.nhs.uk

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.

Keywords: CD40 ligand; X linked hyper-IgM; immunodeficiency; diagnostic strategy; TNFSF5

Abbreviations: CD40L, CD40 ligand; CVID, common variable immunodeficiency; f, forward; FITC, fluorescein isothiocyanate; PCP, Pneumocystis carinii pneumonia; r, reverse; SSCP, single strand conformation polymorphism; WAS, Wiskott-Aldrich syndrome; XHIM, X linked hyper-IgM; XLP, X linked lymphoproliferative disease