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.

Keywords: CD40LG; histoplasmosis; hyper-IgM syndrome; primary immunodeficiency diseases; whole exome sequencing.

Figure 1

(A,B) Disseminated vesicular or dry erythematous and ulcerous lesions over the body and scalp of the proband. (C) Histological analysis of the dermis showed intense edema, necrosis of the dermal fibers, and pseudo-granulomatous tissue. A few giant cells and a polymorphonuclear infiltrate are observed. Macrophages are present, loaded with oval-shaped parasites, between 2 and 4 µm in size, positive for periodic acid–Schiff staining (intense red-violet), consistent with Histoplasma capsulatum. (D) Pedigree of the family sequenced in this study. The arrow indicates the proband. The maternal uncles died of unspecified infections before they reached two years of age. The lower panel shows the Sanger sequencing results and familial segregation for the mutation in CD40LG in the affected proband and both unaffected parents. The mutation is inherited from the mother. (E) Normal CD4 and CD8 percentages and ratio within the CD3⁺ population. (F) Complete absence of CD40L upregulation in patient CD3⁺ population when stimulated for 6 h with SEB as compared to healthy paternal sample.