Chronic and Invasive Fungal Infections in a Family with CARD9 Deficiency

Abstract

Chronic mucocutaneous or invasive fungal infections are generally the result of primary or secondary immune dysfunction. Patients with autosomal recessive CARD9 mutations are also predisposed to recurrent mucocutaneous and invasive fungal infections with Candida spp., dermatophytes (e.g., Trichophyton spp.) and phaeohyphomycetes (Exophiala spp., Phialophora verrucosa). We study a consanguineous family of Turkish origin in which three members present with distinct clinical phenotypes of chronic mucocutaneous and invasive fungal infections, ranging from chronic mucocutaneous candidiasis (CMC) in one patient, treatment-resistant cutaneous dermatophytosis and deep dermatophytosis in a second patient, to CMC with Candida encephalitis and endocrinopathy in a third patient. Two patients consented to genetic testing and were found to have a previously reported homozygous R70W CARD9 mutation. Circulating IL-17 and IL-22 producing T cells were decreased as was IL-6 and granulocyte/macrophage colony-stimulating factor (GM-CSF) secretion upon stimulation with Candida albicans. Patients with recurrent fungal infections in the absence of known immunodeficiencies should be analyzed for CARD9 gene mutations as the cause of fungal infection predisposition.

Inborn errors of immunity underlying fungal diseases in otherwise healthy individuals

“…This report identified AR CARD9 deficiency as a possible genetic etiology of CMC. However, CMC has since been described in only 20 of the 53 (37.7%) reported patients with CARD9 deficiency [22,52–58]. It therefore seems that a loss of CARD9 function confers a predisposition to CMC, but with incomplete penetrance.…”

“…Since the initial report, the most striking and consistent disease attributed to AR CARD9 deficiency is Candida disease of the central nervous system (CNS), affecting the brain parenchyma (abscess) and/or the meninges (meningitis). In the 16 cases of reported with probable or proven Candida CNS disease due to CARD9 deficiency [22,52,55,56,58–62], C. albicans was the primary agent (one case was due to the phylogenetically related C. dubliniensis [59]; another possibly due to C. glabrata [52]). The disease presented during childhood or adulthood (mean: 20.0 years; median 17.0 years; range [3.5 to 39 years]).…”

“…Three of the 16 patients died [22]. Relapses may occur despite appropriate antifungal therapy (based on in vitro antimicrobial susceptibility testing), even during suppressive (maintenance) treatment, in the absence of antifungal drug resistance [52,58,60,62]. Although C. albicans is not known to be neurotropic, invasive candidiasis in CARD9-deficient patients seems primarily to affect the CNS.…”

“…To date, 21 patients with AR CARD9 deficiency and extensive or deep dermatophytosis have been reported, mostly originating from North Africa: Algeria ( n=12 ), Morocco ( n=2 ), Tunisia ( n=4 ), Egypt ( n=1 ), but also from Turkey ( n =1) and one patient was a Brazilian born to Italian parents. The male:female ratio for this disease is 15:6 [53,54,58,67,68]. Based on published microbiological data, deep dermatophytosis in these patients was caused principally by Trichophyton spp.…”

Severe Chromoblastomycosis-Like Cutaneous Infection Caused by Chrysosporium keratinophilum

“…Recent studies of primary immunodeficiencies (PIDs), a group of hereditary immune disorders with increased susceptibility to infection, have led to significant breakthroughs in our understanding of cellular and molecular mechanisms that predispose to both invasive and mucocutaneous fungal infections. Given the severity of the case, the recurrence of the fungus over decades, and the occurrence of similar infections in family members, a rare inherited immune disorder such as homozygous mutations in the CARD9 gene involved in the C-type lectin pathway may be surmised (Alves de Medeiros et al, 2016; Wang and van de Veerdonk, 2016). Unfortunately, our patient was lost for follow-up before this was realized.…”