Expanding the Clinical and Genetic Spectrum of Human CD40L Deficiency: The Occurrence of Paracoccidioidomycosis and Other Unusual Infections in Brazilian Patients

Abstract

CD40 ligand (CD40L) deficiency or X-linked hyper-IgM syndrome (X-HIGM) is a well-described primary immunodeficiency in which Pneumocystis jiroveci pneumonia is a common clinical feature. We have identified an unusual high incidence of fungal infections and other not yet described infections in a cohort of 11 X-HIGM patients from nine unrelated Brazilian families. Among these, we describe the first case of paracoccidioidomycosis (PCM) in X-HIGM. The molecular genetic analysis of CD40L was performed by gene sequencing and evaluation of CD40L protein expression. Nine of these 11 patients (82%) had fungal infections. These included fungal species common to CD40L deficiency (P. jiroveci and Candida albicans) as well as Paracoccidioides brasiliensis. One patient presented with PCM at age 11 years and is now doing well at 18 years of age. Additionally, one patient presented with a simultaneous infection with Klebsiella and Acinetobacter, and one with condyloma caused by human papilloma virus. Molecular analysis revealed four previously described CD40L mutations, two novel missense mutations (c.433 T > G and c.476 G > C) resulting in the absence of CD40L protein expression by activated CD4(+) cells and one novel insertion (c.484_485insAA) within the TNFH domain leading to a frame shift and premature stop codon. These observations demonstrated that the susceptibility to fungal infections in X-HIGM extends beyond those typically associated with X-HIGM (P. jiroveci and C. albicans) and that these patients need to be monitored for those pathogens.

Clinical Features and Genetic Analysis of 20 Chinese Patients with X-Linked Hyper-IgM Syndrome

“…Opportunistic infections, especially Cryptosporidium parvum and Pneumocystis jirovecii infections, are common and prominent clinical feature of XHIGM patients [16, 17, 23]. Besides, infections caused by tubercle bacillus were detected [16, 17, 19].…”

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

“…All of them responded well to antifungal therapy, and only two patients had recurrent histoplasmosis (86, 111). One case of PCM was reported in Brazil (116). It was shown that mature DCs from patients with CD40L deficiency exhibited markedly reduced IL-12 and increased IL-10 production in response to P. brasiliensis and C. albicans compared with normal controls, and T cells had significantly reduced IFN-γ production when cocultured with their DCs, whereas IL-4 and IL-5 production was increased.…”

Important aspects of oral paracoccidioidomycosis–a literature review

“…Paracoccidioidomycosis can be associated with comorbidities, such as Hodgkin disease, 5 leukaemia, lymphoma 52 and carcinomas, especially lung, oropharynx and larynx carcinomas 5,52 . The use of immunosuppressive drugs, including TNF‐α blockers, 56 as well as the occurrence of X‐linked hyper‐IgM syndrome (X‐HIGM), has been reported in association with paracoccidioidomycosis 57 . Still, regarding the role played by immunosuppressive drugs, it is notable that adrenal glands are highly susceptible to P. brasiliensis infection because of the local immunosuppression caused by their high steroid concentrations 58 .…”