Unraveling CARD9 Mutations in Deep Dermatophytosis: A Genetic Gateway to Fungal Invasion and Immune Dysfunction

Deep dermatophytosis is a rare, life-threatening fungal infection characterised by the invasion of dermatophytes beyond the superficial layers of keratinised tissue into the dermis and subcutaneous tissues. The present review aimed to identify the current knowledge on the role of Caspase Recruitment Domain-containing protein 9 (CARD9) deficiency in the pathogenesis, clinical spectrum, diagnosis, and management of deep dermatophytosis. For innate immune activation, CARD9 acts as an adaptor molecule. Basically, CARD9 helps mediate the connection between the fungal pattern recognition receptor (Dectin-1) and the NF-κB and MAPK signalling pathways, and it mediates cytokine production, thereby activating phagocytic activities. Thereby, any change or mutation in the CARD9 gene may disrupt these pathways, leading to dysfunctional neutrophils and impaired Th17-mediated antifungal immunity. Clinically, patients with CARD9 deficiency are immunocompetent but susceptible to recurrent and/or severe fungal infections [Candida, dermatophytes (Trichophyton spp.), and phaeohyphomycetes]. Deep dermatophytosis in these patients is usually chronic, treatment-resistant, and characterized by erythematous papules, nodules, plaques, ulcers, or necrotic lesions, most of which occur on the lower limbs. It usually occurs in adulthood and is more common in males. There have been instances of geographic clustering of CARD9 deficiency in Asia, North Africa, and the Middle East. Early recognition and genetic diagnosis of CARD9 mutations in patients with recurrent or atypical deep dermatophytosis. Although antifungal therapy is essential, hematopoietic stem cell transplantation can be a definitive treatment for selected patients with CARD9 deficiency. Thus, CARD9 deficiency is a critical factor in the better management of patients but remains an underrecognized cause of severe, treatment-resistant deep dermatophytosis, and early genetic diagnosis is essential for guiding targeted management and improving patient outcomes. This review emphasises the importance of CARD9 in antifungal immunity and underscores the need for greater clinical awareness and the incorporation of genetic evaluation into the management of deep dermatophytosis.