Patients with caspase-associated recruitment domain-9 (CARD9) deficiency are more likely to develop invasive fungal disease that affect CNS. However, the understanding of how Candida invades and persists in CNS is still limited. We here reported a 24-year-old woman who were previously immunocompetent and diagnosed with CNS candidiasis. A novel autosomal recessive homozygous CARD9 mutation (c.184 + 5G > T) from this patient was identified using whole genomic sequencing. Furthermore, we extensively characterized the impact of this CARD9 mutation on the host immune response in monocytes, neutrophils and CD4 + T cells, using single cell sequencing and in vitro experiments. Decreased pro-inflammatory cytokine productions of CD14 + monocyte, impaired Th17 cell differentiation, and defective neutrophil accumulation in CNS were found in this patient. In conclusion, this study proposed a novel mechanism of CNS candidiasis development. Patients with CNS candidiasis in absence of known immunodeficiencies should be analyzed for CARD9 gene mutation as the cause of invasive fungal infection predisposition.

Autosomal recessive CARD9 deficiency can underly deep and superficial fungal diseases. We identified two Japanese patients, suffering from superficial and invasive Candida albicans diseases, carrying biallelic variants of CARD9. Both patients, in addition to another Japanese and two Korean patients who were previously reported, carried the c.820dup CARD9 variant, either in the homozygous (two patients) or heterozygous (three patients) state. The other CARD9 alleles were c.104G > A, c.1534C > T and c.1558del. The c.820dup CARD9 variant has thus been reported, in the homozygous or heterozygous state, in patients originating from China, Japan, or South Korea. The Japanese, Korean, and Chinese patients share a 10 Kb haplotype encompassing the c.820dup CARD9 variant. This variant thus originates from a common ancestor, estimated to have lived less than 4,000 years ago. While phaeohyphomycosis caused by Phialophora spp. was common in the Chinese patients, none of the five patients in our study displayed Phialophora spp.-induced disease. This difference between Chinese and our patients probably results from environmental factors. (161/250).

Autosomal recessive deficiency in the caspase recruitment domain-containing protein 9 (CARD9) is a congenital immunological condition that leads to susceptibility to mucocutaneous and invasive fungal infections. There is growing incidence of fungal infections in patients with CARD9 deficiency, a phenomenon that is increasingly recognised. This study aimed to assess the frequency, geographic distribution and nature of mutations in patients with CARD9 deficiency, based on published papers in the literature until March 2023. We swiftly conducted a study to pinpoint every documented instance of fungal infections arising from CARD9 deficiency. We selected case reports from the databases of PubMed, Embase, Scopus and Google Scholar spanning the period from October 2009 to March 2023. We analysed 90 cases of fungal infections and identified 32 mutations in the CARD9 gene. Notably, the homozygous (HMZ) p.Q295X (c.883C > T) mutation was associated with an increased risk of candidiasis. In contrast, the HMZ p.Q289X (c.865C > T) mutation is linked to a higher risk of dermatophytosis. We observed differences in the geographical distribution of these mutations. The primary mutations found in African patients differ from those in Asian patients. Specifically, Asian patients exhibit a broader spectrum of CARD9 mutations than African patients. The diversity of mutations observed in the 90 cases revealed 32 distinct variations, emphasising the unique genetic alterations in the CARD9 gene associated with specific geographical areas and the corresponding prevalence of fungal infections.

Exophiala dermatitidis is a relatively common environmental black yeast with a worldwide distribution that rarely causes fungal infection. Here, we report a case of a 6-year-old girl with central nervous system (CNS) encephalitis caused by E. dermatitidis and Angiostrongylus cantonensis. E. dermatitidis was identified by both cerebrospinal fluid culture and metagenomic next-generation sequencing (mNGS). Angiostrongylus cantonensis infection was confirmed by an enzyme linked immunosorbent assay (ELISA). Whole exome sequencing showed that this previously healthy girl carried a homozygous CARD9 mutation for c.820dupG (p.D274Gfs*61) that underlies invasive fungal and parasite infections. We chose glucocortieoid pulse therapy and anti-infective therapy based on the initial results of laboratory examination and cranial MRI images. With the aggravation of the disease and the evidence of the subsequent etiologic test, the combination of antifungal antiparasitic treatments (voriconazole, fluorocytosine and amphotericin B) were actively used. Unfortunately, the girl finally died due to severe systemic infection. mNGS performs a potential value for diagnosing rare CNS infections, and autosomal recessive CARD9 deficiency should be considered in patient with fatal invasive fungal infections.

Deep dermatophytosis is an invasive and sometimes life-threatening fungal infection mainly reported in immunocompromised patients. However, a caspase recruitment domain-containing protein 9 (CARD9) deficiency has recently been reported to cause deep dermatophytosis. Herein, we report the first Japanese case of deep dermatophytosis associated with CARD9 deficiency. An 80-year-old Japanese man with tinea corporis presented with subcutaneous nodules on his left sole. Histopathological findings revealed marked epithelioid cell granulomas with filamentous fungal structures in the deep dermis and subcutis, and the patient was diagnosed with deep dermatophytosis. Despite antifungal therapy, the subcutaneous nodule on his left sole gradually enlarged, his left calcaneal bone was invaded, and the patient finally underwent amputation of his left leg. Genetic analysis revealed a homozygous CARD9 c.586 A > G (p. Lys196Glu) variant, suggesting a CARD9 deficiency. Here, we discuss the clinical features of CARD9 deficiency-associated deep dermatophytosis with a case report and review of the literature.