First Case of CD40LG Deficiency in Ecuador, Diagnosed after Whole Exome Sequencing in a Patient with Severe Cutaneous Histoplasmosis

Abstract

Severe infections with Histoplasma capsulatum are commonly observed in patient with secondary immunodeficiency disorders. We report a two and a half years old boy previously healthy with disseminated cutaneous histoplasmosis. Using whole exome sequencing, we found an indel mutation at the CD40LG gene, suggesting a diagnosis of hyper-IgM (HIGM) syndrome, even in the absence of the usual features for the disease. Interestingly, the patient lives in a region endemic for histoplasmosis. The unusual infections in our case suggest that in children with severe histoplasmosis and resident in endemic areas, HIGM syndrome should be considered as a diagnosis.

Of Mycelium and Men: Inherent Human Susceptibility to Fungal Diseases

“…While MSMDs were initially recognized for their distinct susceptibility to mycobacteria (particularly non-tuberculous (NTM) and occasionally M. tuberculosis ) and Salmonella (predisposing victims to extra-intestinal salmonellosis) [ 38 , 39 , 150 , 151 , 152 , 153 , 154 ], they were also subsequently found in patients with otherwise unexplained disseminated TDEF infection, including histoplasmosis (IL12RB1 [ 153 , 155 , 156 , 157 ]; IFNGR1 [ 158 ]), coccidioidomycosis (IFNGR1 [ 159 ] and IL12RB1 [ 160 ]), and paracoccidioidomycosis (IL12RB1 [ 161 ]). These findings provided the framework of human immunity to TDEF, which was followed by the identification of other IEI congruent with defective IFN-γ-mediated immunity, including CD40L deficiency [ 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 ] (discussed further in the section on “Pneumocystis”), GATA2 deficiency [ 171 ], and STAT1 GOF [ 168 , 169 , 172 , 173 ].…”

Cellular and Molecular Defects Underlying Invasive Fungal Infections—Revelations from Endemic Mycoses

“…Disseminated and cutaneous forms of histoplasmosis have been reported in eight patients in patients with X-linked hyper-IgM disorder (Table 4 ). Five cases had disseminated histoplasmosis, while two had lymphadenitis and one had cutaneous involvement only ( 86 , 110 – 115 ). All of them responded well to antifungal therapy, and only two patients had recurrent histoplasmosis ( 86 , 111 ).…”

Inborn Errors of Immunity Causing Pediatric Susceptibility to Fungal Diseases

“…However, CD40L also binds CD40 on macrophages and dendritic cells, and loss of this interaction causes defective cell-mediated immunity, resulting in a combined immunodeficiency clinical phenotype [ 150 , 151 , 152 , 153 ]. XL-HIGM increases susceptibility to various TDEF, including Histoplasma , Talaromyces marneffei , and Paraccoidioides [ 154 , 155 , 156 , 157 ]. All cases have been disseminated.…”