A Novel de Novo Mutation in the CD40 Ligand Gene in a Patient With a Mild X-Linked Hyper-IgM Phenotype Initially Diagnosed as CVID: New Aspects of Old Diseases

Abstract

Mutations in the CD40 ligand (CD40L) gene (CD40LG) lead to X-linked hyper-IgM syndrome (X-HIGM), which is a primary immunodeficiency (PID) characterized by decreased serum levels of IgG and IgA and normal or elevated IgM levels. Although most X-HIGM patients become symptomatic during the first or second year of life, during which they exhibit recurrent infections, some patients exhibit mild phenotypes, which are usually associated with hypomorphic mutations that do not abrogate protein expression or function. Here, we describe a 28-year-old man who initially presented with recurrent infections since the age of 7 years, when he exhibited meningitis caused by Cryptococcus neoformans. The patient had no family history of immunodeficiency, and based on clinical and laboratory presentation, he was initially diagnosed with common variable immunodeficiency (CVID). In subsequent years, he displayed several sporadic episodes of infection, including pneumonia, pharyngotonsillitis, acute otitis media, rhinosinusitis, fungal dermatosis, and intestinal helminthiasis. The evaluation of CD40L expression on the surface of activated CD3+CD4+ T cells from the patient showed decreased expression of CD40L. Genetic analysis revealed a novel de novo mutation consisting of a 6-nucleotide insertion in exon 1 of CD40LG, which confirmed the diagnosis of X-HIGM. In this report, we describe a novel mutation in the CD40L gene and highlight the complexities of PID diagnosis in light of atypical phenotypes and hypomorphic mutations as well as the importance of the differential diagnosis of PIDs.

Case Report: Hyper IgM Syndrome Identified by Whole Genome Sequencing in a Young Syrian Man Presenting With Atypical, Severe and Recurrent Mucosal Leishmaniasis

“…This case illustrates and supports the growing potential for exome or whole genome sequencing in accurate PID diagnostics. We speculate that HIGM may be under-or misdiagnosed, and clinically milder phenotypes in particular could be misdiagnosed as other immunodeficiencies such as CVID, as occurred with our patient and has been reported previously (15). Genetic investigation is becoming increasingly available and utilized, thus potentially enabling better understanding of genotypes and phenotypes, and consequently improved care and genetic counseling for patients and family members.…”

“…HIGM variants typically affect the extracellular domain, thus resulting in inability of CD40-CD40L binding. Variants in exon 1 decrease the expression of CD40L (15). In this case, we found a nonsense variant in exon 1, and the pathogenicity was illustrated by impaired upregulation of CD40L on activated CD4 cells, as assessed by flowcytometry (Figure 3).…”

“…However, heterogeneity in the clinical presentations of HIGM has been reported. Previous reports include patients with mild phenotypes and late presenters ( 15 , 20 , 30 – 32 ). A family of patients with the same genetic variant as that found in our case patient (p.Arg11 ∗ ) has been described by ( 30 ), in which the index patient presented at the age of 41 with cerebral toxoplasmosis.…”

Associations between Cryptococcus Genotypes, Phenotypes, and Clinical Parameters of Human Disease: A Review

“…The balance of immunoglobulins, IgM, IgG, and IgA are involved in cryptococcal immune response. X-linked hyper-IgM immunodeficiency syndrome is caused by mutations that occur in the CD40 ligand gene which results in decreased levels of IgG and IgA and elevated IgM has been shown to increase susceptibility to infections including invasive and cutaneous cryptococcosis particularly observed in pediatric male patients [ 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 ]. In addition, in vitro assays using C. neoformans found that IgM but not IgG inhibited Titan cell formation, reduced capsule thickness, and decreased the expression of chitin synthetase genes ( CHS1 , CHS2 , CHS8 , α-1–3-glucan synthetase ( AGS1 ), and β-1,3-glucan synthetase ( FKS1 ) [ 156 ].…”

In Silico Analysis and Modeling of Novel Pathogenic Single Nucleotide Polymorphisms (SNPs) in HumanCD40LGGene

“…[20] CD40LG acts as an immune modulator in activated T cells [21] Inactivation of CD40LG gene resulted from the insertion of an AluYb8 element in exon 1 responsible for a total deficiency of CD40 ligand expression by T lymphocytes [22] Interestingly, some study shows that, not all mutations occur in CD40LG gene may cause XHIGM [23] Different mutations have been reported. [23][24][25][26][27][28][29][30][31][32] As far as we know there are two options for treatment, either hematopoietic stem cell transplantation or intravenous immunoglobulin replacement therapy. [33] but it is sometimes completely ignored because of low recognition and limited knowledge of this rare disease.…”