CARD9 deficiency is a rare, inherited primary immunodeficiency disorder caused by a genetic mutation. This condition severely compromises the body’s ability to mount an effective defense against certain fungi by failing the immune system’s signaling pathways. This defect leaves affected individuals highly susceptible to recurrent and severe fungal infections that are typically harmless to people with a functioning immune system.
The Role of the CARD9 Protein
The CARD9 protein functions as an adaptor molecule within various immune cells, including macrophages and dendritic cells. It acts downstream of Pattern Recognition Receptors (PRRs), such as C-type lectin receptors, which sense fungal structures. When a fungal pathogen is detected, CARD9 relays the signal inside the cell to initiate a protective inflammatory response.
Mutations in the CARD9 gene prevent this signaling cascade from operating correctly. This signaling failure profoundly impairs the development of T-helper 17 (Th17) cells, specialized white blood cells that produce the cytokines Interleukin-17 (IL-17) and Interleukin-22 (IL-22). The IL-17 pathway is paramount for driving inflammation, recruiting other infection-fighting cells like neutrophils, and producing antimicrobial peptides specifically to combat fungal threats. Consequently, an individual with a non-functional CARD9 protein cannot generate the robust Th17 response needed to clear a fungal infection.
Signs and Symptoms of the Deficiency
The clinical presentation of CARD9 deficiency is dominated by extreme susceptibility to fungal infections, with the majority of patients developing the disorder during childhood or adolescence. The most frequent infections involve Candida species, leading to a condition known as chronic mucocutaneous candidiasis (CMCC). CMCC typically manifests as persistent, difficult-to-treat infections of the skin, nails, and mucous membranes, such as the mouth and genital area.
A more dangerous manifestation is invasive or systemic fungal infection, which can be life-threatening. The deficiency is particularly associated with deep-seated infections of the central nervous system (CNS), including the brain and spinal cord, which can result in severe meningitis. Other pathogens beyond Candida are also common, including dermatophytes like Trichophyton and dematiaceous fungi, which cause infections in the lymph nodes or viscera.
Identifying the Condition
Diagnosis of CARD9 deficiency is often first suspected when a patient presents with recurrent, severe, or unusually localized fungal infections that do not respond to standard antifungal treatments. Healthcare providers maintain a high index of suspicion in individuals with persistent CMCC or those with systemic fungal infections of the CNS, which are rare in otherwise healthy people. A definitive diagnosis relies on genetic testing to identify the specific mutation within the CARD9 gene.
Since the condition is an autosomal recessive disorder, the diagnosis is confirmed by finding disease-causing mutations on both copies of the patient’s CARD9 gene. Supporting laboratory tests, such as immunological assays, can also be performed to demonstrate the functional immune defect. These assays show that the patient’s immune cells, when stimulated with fungal antigens, are impaired in their ability to produce the protective cytokines like IL-17 and IL-22. This combination of clinical observation, genetic confirmation, and functional testing allows for a firm diagnosis.
Treatment and Long-Term Care
The primary goal of treatment for CARD9 deficiency is to manage and prevent fungal infections through continuous antifungal therapy. This often involves long-term, high-dose administration of antifungal medications to suppress fungal growth and prevent life-threatening systemic spread. Continuous prophylactic antifungal medication is a common component of long-term care to prevent relapse, especially against Candida.
The management of deep-seated infections, particularly those involving the CNS, requires prolonged courses of systemic antifungal drugs and careful neurological monitoring. For patients with severe, refractory infections, Hematopoietic Stem Cell Transplantation (HSCT) has emerged as a potential curative option. HSCT aims to replace the defective immune system with healthy, functioning immune cells that can produce the necessary CARD9 protein and restore antifungal immunity.