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Hyper-IgM syndrome type 3 (HIGM3) is a rare autosomal recessive primary immunodeficiency manifesting in infancy. CD40, encoded by CD40, interacts with CD40 ligand to drive germinal center formation, immunoglobulin class switch recombination, and cell-mediated immunity. Loss-of-function CD40 variants abrogate CD40L-induced B cell activation and dendritic cell maturation. Patients typically present with recurrent respiratory and gastrointestinal infections, neutropenia, and elevated serum IgM with absent IgG and IgA. First reported cases involved two siblings with opportunistic infections and dendritic cells that failed to fully mature despite TNF-α or LPS plus IFN-γ stimulation (PMID:12893749). These observations established the essential role of CD40 in orchestrating adaptive immune responses.
Systematic literature review to August 2023 identified 40 unique HIGM3 patients with confirmed CD40 deficiency (PMID:38129705). In a cohort of 11 patients from 7 families, all affected individuals exhibited recurrent lower respiratory tract infections and neutropenia, with segregation of biallelic CD40 variants in pedigree analyses (PMID:24122029). An independent study reported 6 patients from 3 families who underwent successful HSCT, confirming autosomal recessive inheritance (PMID:29884852). The most frequent molecular lesions were splice-site variants (36%) and missense changes (32%), with recurrent mutations such as c.170C>T (p.Thr57Met). HSCT outcomes demonstrated 100% engraftment and immune reconstitution in this small series. Overall fatality rate across all cohorts was 21% with supportive management alone.
Variants in CD40 span the coding sequence and splice junctions. Identified pathogenic alleles include c.256+2T>C, yielding aberrant splicing, and missense substitutions such as c.170C>T (p.Thr57Met). Allelic heterogeneity is high, with no clear founder effect. Loss-of-function and hypomorphic alleles both contribute to disease severity. Population carrier frequencies are exceedingly low, reflecting the rarity of this AR disorder. Genetic testing of CD40 is therefore critical for accurate diagnosis.
Clinically, HIGM3 patients suffer recurrent bacterial and opportunistic infections, including Pneumocystis jirovecii pneumonia and cryptosporidiosis. Neutropenia is observed in the majority, contributing to severe sepsis risk. Sclerosing cholangitis due to Cryptosporidium has been reported in nearly one-third of patients (PMID:38129705). Immunoglobulin replacement and antimicrobial prophylaxis provide partial benefit but do not correct class switching. HSCT from HLA-matched siblings achieved full immunologic recovery in all 6 transplanted patients (PMID:29884852). This supports early transplant as a definitive therapy.
Functional assays demonstrate monocyte-derived DCs from CD40-deficient patients express CD83 and DC-LAMP but have reduced HLA-DR and costimulatory activity for naive T cells (PMID:12893749). These DCs secrete lower IL-12 and elevated IL-10, impairing Th1 polarization. Plasmacytoid DCs fail to secrete IFN-α upon HSV-1 challenge, compromising antiviral defense. Mouse Cd40-knockout models recapitulate defective antibody responses, validating in vivo relevance. In vitro characterization of missense mutants such as p.Cys83Arg reveals ER retention and variable degradation kinetics (PMID:20702779). Together, these studies implicate loss-of-function and misfolding as primary pathogenic mechanisms.
In summary, autosomal recessive biallelic CD40 variants cause HIGM3 by impairing CD40-mediated B cell and dendritic cell activation. The robust genetic and functional concordance across multiple independent studies supports a Strong clinical validity classification. Genetic evidence is Strong with 40 probands across 10 families and segregation confirmed (PMID:38129705; PMID:24122029). Functional evidence is Moderate based on consistent DC maturation defects and supportive murine models. Early molecular diagnosis enables definitive cure via HSCT.
Gene–Disease AssociationStrong40 probands across multiple studies, segregation in at least 10 families, and concordant functional data Genetic EvidenceStrong40 biallelic variants in probands with segregation demonstrated in 10 families Functional EvidenceModerateDefective DC maturation and cytokine imbalance in patient cells and supportive murine models |