What is CARD9 deficiency?

CARD9 deficiency is a rare inherited immune disorder caused by mutations in the CARD9 gene which has a key role in signalling inside the immune cells.¹ This gene provides instructions for making a protein that plays a crucial role in the immune systems response to fungal infections hence the mutation affects the body’s ability to fight off fungal infections making them more susceptible to them particularly those caused by candida (yeast) or certain dermatophytes.² CARD9 deficiency is an autosomal recessive pattern meaning that both parents require the recessive gene for an offspring to display this mutation.

Why is an early diagnosis important?

Early detection of this disorder is critical as untreated infections can spread to the brain, bones and other organs, harming their function and can lead to meningitis or brain abscesses.¹ Early diagnosis allows for targeted treatment through infection monitoring and family counselling. 

This article will allow you to explore the ins and outs of such a rare disease and provide you with the knowledge of when to suspect CARD9 and the steps to confirm the diagnosis. 

When to suspect CARD9 deficiency?

Common signs to look out for when someone has a CARD9 deficiency include…

• Patients develop serious fungal infections 
• Recurrent or unusual fungal infections
• Infections that affect the brain, bones, or skin in usually healthy people
• Siblings or cousins with a similar infection (as inherited)¹

The following conditions can be caused by CARD9 deficiency:¹ Invasive fungal disease-yeast infections that spread to the bloodstream or organs.

• mycosis
• Candida infection (candidiasis)
• chronic mucocutaneous candidiasis (CMC)- persistent yeast infections of the skin, nails, and mucous membranes.
• invasive candidiasis
• Spontaneous central nervous system candidiasis (brain candidiasis)
• Candidal endophthalmitis (eye candidiasis)
• Candidal osteomyelitis (bone candidiasis)
• deep dermatophytosis
• chronic invasive dermatophyte infection (tinea profunda)
• Phyomycosis (black mould disease)

Bacterial and viral infections are often ruled out and are not considered an effect of the CARD9 mutation. 

Who is affected by CARD9 deficiency? 

CARD9 deficiencies mainly affect adults, as found in reported cases and affect males and females in equal numbers, although the exact frequency is still unknown. It is said that the disease is found in certain populations due to the founder effect, where the mutation originates before being spread.³ 

Diagnostic approach

1. Medical history
   • Looking at family history and inspecting parents' genetic code⁴
2. Physical exam
   • Review infections, durations and responses to antifungals
   • Detect signs of systemic illness or syndromic features
3. Lab work
   • Complete blood count is done alongside immunoglobulin levels to rule out other illnesses such as HIV or diabetes 
4. Specialised immune testing
   • Neutrophil oxidative burst test…
   • Lymphocyte function test…
5. Histopathology
   • Cultures from infected tissues are used to identify fungal species after a biopsy of infected areas
6. Genetic testing⁵
   • Targeted CARD9 sequencing to identify mutations affecting the protein structure, including single-nucleotide changes and smaller insertions/deletions to the bases
   • Sanger sequencing is used for confirmation and further family testing

Management after diagnosis

One option for management once CARD9 deficiency is diagnosed is long-term antifungal therapy. This is especially crucial as individuals are vulnerable to deep and persistent fungal infections and cannot remove these infections on their own. Treatment can last for several months, depending on the severity and location of the infection.⁶ Some examples of commonly used antifungal medications include amphotericin B, itraconazole, and voriconazole. As these drugs can have side effects in individuals, regular monitoring of liver toxicity, kidney issues, and signs of resistance to medications is required when used over long periods. 

Another management method is immune-boosting therapies in addition to the antifungal medications. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a useful way to resolve invasive fungal infections in individuals. One reported case described a patient with recurring Candida meningitis who got completely better after being treated with GM-CSF. This suggests that GM-CSF can help make up for the weak immune response seen in people with CARD9 deficiency. Another group of cases showed that specific immune cells (phagocytes) were unresponsive to GM-CSF, further supporting why this treatment might help.⁷

Genetic counselling is also offered to families, as this deficiency is autosomal recessive, meaning each offspring has a 25% chance of being affected and 50% carrier. Genetic counselling identifies carrier relatives through testing and provides family planning guidance for those at risk. 

Future directions of CARD9 research

As we know, CARD9 is a key part of the body’s defence system against fungal infections. It helps to send signals from the receptors that detect fungi to trigger the release of immune substances like cytokines and chemokines. These chemicals aid white blood cells in fighting off infections; hence, CARD9 is important in both animals and humans in coordinating the immune response. 

Currently, clinicians may use imaging tools such as MRI or CT scans to locate and track an infection over time. However, future research shows that biomarkers and studying patterns in immune signalling, such as low levels of cytokines, can help monitor how active the disease is to determine if treatment is working.⁸

Another future path to tackle CAR9 deficiency is gene therapy, which aims to fix the mutated CAR9 gene. This can offer a long-term solution, decreasing the chances of passing the gene on to offspring, although this is still in its early stages of research. Furthermore, scientists are looking at preventive antifungal treatments that can be given to those who are known to carry the mutation before they exhibit negative symptoms, reducing the impact of having the deficiency.⁸ 

Overall, CARD9 deficiency requires careful management involving long-term antifungals and comprehensive genetic screening. On the research front, ongoing studies of CARD9 immune signalling, imaging biomarkers, and gene-based therapies promise to expand therapeutic options for this rare but serious condition.

Summary

CARD9 deficiency is a rare inherited immune disorder that makes people more vulnerable to serious fungal infections, particularly those caused by Candida and certain fungi that affect skin, nails, bones, and even the brain. Early diagnosis is important to prevent severe complications and allow proper treatment. Signs include recurrent or unusual fungal infections, often in otherwise healthy individuals, sometimes running in families. Diagnosis involves reviewing medical and family history, lab tests, and genetic testing. Management focuses on long-term antifungal therapy, immune-boosting treatments, and genetic counselling for families. Ongoing research aims to improve monitoring, develop gene therapies, and explore preventive strategies to better protect those with this condition.