CARD9

CARD9 (Caspase-Recruitment Domain 9) deficiency is a rare condition that weakens the immune system, making it harder for the body to defend itself against fungal infections.¹ It is an important protein in the immune system to help it detect and respond to harmful fungi and bacteria, acting as a frontline defence against microbial threats. In simple terms, CARD9 helps kickstart the body’s immune response when it encounters fungal pathogens. When someone lacks functional CARD9, their immune system struggles to fight off these infections effectively.² 

Fungi include organisms like yeasts and molds, which can be identified through lab tests. People with CARD9 deficiency are particularly vulnerable to certain fungi, especially Candida and molds such as dermatophytes (which cause conditions like ringworm and athlete’s foot), and black molds. Interestingly, individuals with this deficiency typically develop infections from only one type of fungus at a time and don’t appear to be at higher risk for infections caused by bacteria, viruses, or parasites.³ 

Understanding infection risks

Types of infections

Candida

The most common fungal infection seen in people with CARD9 deficiency is caused by Candida, a type of yeast that can lead to conditions such as thrush (also known as candidiasis). CARD9 deficiency itself is extremely rare, and because many cases likely go undiagnosed, its exact prevalence is not known. Since the disorder was first identified, only 58 cases have been reported worldwide, each involving different mutations in the CARD9 gene.⁴ Most people with this condition develop invasive fungal diseases (IFD), which are serious and potentially life-threatening infections that affect internal organs. These infections usually involve only one type of fungus at a time, most commonly from a group called Ascomycota, which includes Candida, Aspergillus, and Trichophyton. Among them, Candida is the most frequently identified fungus in these cases.⁴ 

A review of published cases showed that since 1989, CARD9-related fungal infections have been reported in just 14 countries, with most cases coming from Algeria and several countries in Asia, especially Iran. T.⁵he review also found that candidiasis made up 40% of these infections, and those with Candida, 41% had infections involving the nervous system.⁵ This is significant because Candida usually causes only mild problems in healthy individuals, but for those with a weakened immune system, it can cause far more serious complications.⁶ 

People with CARD9 deficiency can experience two main types of Candida infections:

• Chronic Mucocutaneous Candidiasis (CMC): This causes long-lasting fungal infections on the nails, skin, as well as areas where skin transitions to other tissues like the mouth, throat, eyelids, and genitals
• Systemic candidiasis: A much more severe infection where Candida invades the bloodstream or internal organs like the brain and kidney, which can lead to sepsis

CARD9 plays a vital role in both the body’s first and second lines of defense regarding immune responses, helping to activate immune cells and initiate infection-fighting neutrophils. Without this function, individuals with CARD9 deficiency are especially vulnerable to fungal infections, including those that affect the central nervous system, which explains the high number of neurological infections seen in these patients.⁶ 

Deep dermatophytosis

Another serious fungal infection linked to CARD9 deficiency is deep dermatophytosis. Unlike common skin infections that stay on the skin's surface, this type of infection invades the deeper layers of skin and underlying tissues. It can spread to the lymph nodes and even the central nervous system, causing more damage and being much harder to treat. Because topical medications cannot reach deep tissue infections effectively, treatment often requires systemic antifungal drugs and, in some cases, even surgery. If left untreated, it can lead to permanent tissue damage or long-term complications. Interestingly, a study found that every patient diagnosed with deep dermatophytosis (but without any known immunodeficiency) actually had CARD9 deficiency, suggesting that this form of infection is a clear clinical sign of the condition.⁷ 

Risk factors

Genetic mutations

CARD9 deficiency tends to occur more often in certain areas and populations, especially in North Africa, Asia, and the Middle East. For example:

• In North Africa, a mutation called ‘c.865C>T’ has been found in multiple patients, and four people from Algeria shared the same genetic background, pointing to a ‘founder effect’, which refers to where a gene mutation is passed down through generations from a common ancestor
• In Turkey, another common mutation is ‘c.208C>T’, also thought to come from a shared ancestor
• In China, a different mutation was found in 0.067% of people who were tested, and three of those patients in China shared similar genetic profiles

This shows how ancestry and geography play a major role in how CARD9 deficiency appears in different parts of the world. The founder effect explains why the same mutation shows up repeatedly in some regions. It begins in a small group of people and spreads over time within that population. In contrast, countries like Japan and Korea have reported only three cases each, suggesting that CARD9 deficiency is very rare in these populations, or perhaps the lack of awareness of this deficiency causes people to live undiagnosed or go without testing. Overall, this highlights the importance of genetic testing, especially in regions where the condition is less recognised. Identifying these mutations can help doctors diagnose the disease earlier and improve treatment for people who may otherwise be overlooked.⁸ 

Medical management

Antifungal therapy

For most people with fungal infections, antifungal medications are the go-to treatment and usually work well. But when someone has a CARD9 deficiency, their immune system does not respond properly, so standard antifungal drugs might not be enough. Depending on how serious the infection is, they may need additional therapies to recover fully.

One case from China involved a patient with an invasive Candida infection that had spread to his central nervous system and abdomen. After genetic testing confirmed he had a CARD9 mutation, he was treated with a combination of antifungal medication and G-CSF (a drug that helps stimulate the immune system). This approach worked very well, as his symptoms went away, and he stayed healthy for over a year during follow-up. This case suggests that combining C-CSF with antifungal medication can be highly effective in treating serious fungal infections linked to CARD9 deficiency.⁹ 

In another case, a patient from Egypt had a widespread skin and nail infection caused by Trichophyton rubrum, a type of fungus. This patient also had an autosomal recessive CARD9 deficiency. He was treated with posaconazole, an antifungal medication, which he tolerated well. His symptoms completely cleared up within three months, and he stayed infection-free for at least eight months afterward.¹⁰ 

A third case involved a patient with a newly identified CARD9 mutation who suffered from recurrent brain and spinal infections due to Candida (meningoencephalitis). The patient was treated with GM-CSF, a medication that helps boost immune responses. The treatment led to a full recovery.¹¹ 

Takeaway

Treating fungal infections in people with a CARD9 deficiency may require more than just the typical antifungal medication. Therapies like G-CSF and GM-CSF, which help the immune system fight back, can be very crucial, especially in more serious or stubborn infection cases. The right treatment depends on how severe the infection is and what kind of fungus is involved, and sometimes a combination of treatments is the most effective approach in tackling the infection.

Routine monitoring

If you have a CARD9 deficiency, regular medical checkups and testing are incredibly important. This condition weakens the immune system’s ability to fight off fungal infections, making people more vulnerable to them. Since the body can’t defend itself as effectively, routine monitoring helps catch infections early, before they become serious or life-threatening. For those already receiving treatment, ongoing check-ups help doctors see how well the body is responding. These visits allow healthcare professionals to track progress, spot any potential complications, and adjust treatment plans if needed to get the best results. Regular monitoring also includes helpful advice and guidance on how to prevent infections, like advice on maintaining good hygiene, keeping infection wounds or vulnerable areas clean, and taking other simple steps to reduce exposure to fungi. In short, staying on top of your health through routine care is one of the most effective ways to manage CARD9 deficiency and stay protected.

Personal hygiene and daily habits

Hygiene practices 

For people with CARD9 deficiency, maintaining good personal hygiene is essential to reduce the risk of fungal infections. Since this condition weakens the immune system’s ability to fight off fungi, especially on the skin and nails, it is important to take extra care of vulnerable areas.

Make sure to keep affected skin clean and dry, as moisture can help fungi grow. Wash the areas gently every day, pat them dry (do not rub), and try not to touch them too much to avoid spreading the infection. Wearing breathable fabrics, like cotton, can help reduce irritation, especially around infected areas. It is also helpful to change into clean clothes daily, wash your bedding regularly, and always use clean towels to prevent infections from worsening. Also, using antifungal soaps or topical creams, which you can get from the GP or a pharmacy, is also effective. These can help manage skin-level fungal infections. However, for those with CARD9 deficiency, creams and soaps may only offer partial relief. In most cases, they will need to be used alongside oral antifungal medications for the best effect.¹²

What to watch out for

When living with CARD9 deficiency, it is especially important to monitor fungal infections closely, particularly during treatment. If an infection isn’t improving, or it keeps coming back, you should speak to your GP. It could mean that the fungus is resistant to the treatment, the medications aren’t working properly, or there’s another underlying issue. Your doctor might need to run further tests or change your treatment plan.

Here are some signs that something might be wrong:

• Changes in how the infection looks, such as spreading or worsening
• Unusual symptoms elsewhere on your body
• Feeling fatigue or feverish, which could mean the infection is spreading, or possible symptoms of sepsis
• Slow healing wounds that take longer than normal to recover
• Frequent infections that keep returning, despite treatment

These are all the warning signs that need medical attention. That is why regular checkups and monitoring are so important for people with a CARD9 deficiency; they allow doctors to catch infections early and prevent serious complications.

Summary

People with CARD9 deficiency need to monitor fungal infections very carefully, as untreated or recurring infections can lead to serious complications. If an infection does not improve, continues to return, or causes unusual symptoms, it is important to see a doctor. Warning signs include infections that spread or worsen, unusual symptoms in other parts of the body, fatigue, fever, slow-healing wounds, or frequent recurrences despite treatment. These issues may signal that the fungus is resistant to medication, the treatment is not effective, or another problem is present. Regular medical checkups are essential because they allow doctors to detect infections early and adjust treatment to prevent further complications.