Familial candidiasis is an inherited tendency to develop infections caused by a type of fungus called Candida. Affected individuals typically have infections of the skin, the nails, and the moist lining of body cavities (mucous membranes). These infections are recurrent and persistent, which means they come back repeatedly and can last a long time. This pattern of infection is called chronic mucocutaneous candidiasis.

Candida is commonly present on the skin and on the mucous membranes, and in most people usually causes no health problems. However, certain medications (such as antibiotics and corticosteroids) and other factors can lead to occasional overgrowth of Candida (candidiasis) in the mouth (where it is known as thrush) or in the vagina. These episodes, commonly called yeast infections, usually last only a short time before being cleared by a healthy immune system.

Most people with familial candidiasis have chronic or recurrent yeast infections that begin in early childhood. Skin infections lead to a rash with crusty, thickened patches; when these patches occur on the scalp, they can cause loss of hair in the affected area (scarring alopecia). Candidiasis of the nails can result in thick, cracked, and discolored nails and swelling and redness of the surrounding skin. Thrush and gastrointestinal symptoms such as bloating, constipation, or diarrhea are common in affected individuals. Women with familial candidiasis can develop frequent vaginal yeast infections, and infants can have yeast infections on the skin that cause persistent diaper rash.

Depending on the genetic change involved in this condition, some affected individuals are at risk for developing systemic candidiasis, a more severe condition in which the infection spreads through the bloodstream to various organs including the brain and the meninges, which are the membranes covering the brain and spinal cord. Systemic candidiasis can be life-threatening.

Chronic or recurrent yeast infections can occur in people without familial candidiasis. Some individuals experience recurrent candidiasis as part of a general susceptibility to infections because their immune systems are impaired by a disease such as acquired immune deficiency syndrome (AIDS) or severe combined immunodeficiency (SCID), medications, or other factors. Other individuals have syndromes such as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or autosomal dominant hyper-IgE syndrome (AD-HIES) that include a tendency to develop candidiasis along with other signs and symptoms affecting various organs and systems of the body.

Candidiasis is a fungal infection caused by a yeast (a type of fungus) called Candida. Some species of Candida can cause infection in people; the most common is Candida albicans. Candida normally lives on the skin and inside the body, in places such as the mouth, throat, gut, and vagina, without causing any problems. Candida can cause infections if it grows out of control or if it enters deep into the body (for example, the bloodstream or internal organs like the kidney, heart, or brain). Some types of Candida are resistant to the antifungals used to treat them.

Candidiasis that develops in the mouth or throat is called thrush or oropharyngeal candidiasis. Candidiasis in the vagina is commonly referred to as a yeast infection. Invasive candidiasis occurs when Candida species enter the bloodstream or affect internal organs like the kidney, heart, or brain.

CARD9 deficiency is a genetic immune disorder characterized by susceptibility to fungal infections like candidiasis, which is caused by the yeast fungus Candida. Typically, Candida does not cause severe problems in healthy people, but it can take advantage of those with a weakened immune system.

NIAID researchers are exploring how mutations that cause Candida susceptibility impact the function of immune cells by studying people with genetic disorders such as CARD9 deficiency; SCID; and deficiencies in STAT1, STAT3 and DOCK8. NIAID researchers also are studying chronic mucocutaneous candidiasis (CMC) and systemic candidiasis—two types of Candida infection—in mouse models of these genetic disorders. By identifying the genetic defects responsible for a person’s immunodeficiency, researchers may be able to develop targeted therapies to prevent these opportunistic infections.

CARD9 deficiency, an autosomal recessive disorder, differs from many other genetic immune disorders that cause fungal infections. Most genetic immune disorders cause either CMC or systemic candidiasis, but people with CARD9 deficiency experience both CMC and systemic candidiasis. CMC is a localized Candida infection that causes lesions and scaling on the skin and nails. The infection also occurs in areas where the skin transitions to other tissues, such as the genital area, eyelids and mouth, and may progress along the throat. Normally, cells of the adaptive immune system, like T cells, stop this infection from taking hold. Systemic candidiasis is an invasive infection that involves the bloodstream and deep-seated organs such as the kidneys, brain, liver and/or spleen, and requires innate immune cells to prevent. CARD9 is required for anti-fungal responses in both innate and adaptive immune cells, explaining why people with this deficiency experience both conditions.

Systemic candidiasis may lead to life-threatening sepsis or meningitis, an infection of the brain and its linings. Many people with CARD9 deficiency develop systemic candidiasis that targets the central nervous system, or CNS. NIAID researchers have described the crucial role of CARD9 in recruiting infection-fighting neutrophils to the CNS during fungal infection, helping explain why people with CARD9 deficiency are highly susceptible to fungal CNS infections.

Fungal infections are diagnosed by physical examination of the infected sites and by using laboratory tests to confirm the presence of Candida or other fungi. If warranted, genetic testing can confirm the presence of mutations associated with these infections, like CARD9 deficiency.

Patients with fungal infections may be prescribed antifungal medications.

Mutations in any of several genes have been identified in people with familial candidiasis. These genes include CARD9, IL17RC, STAT1, and others. The genes associated with familial candidiasis provide instructions for making proteins that are involved in immune system function.

When the immune system recognizes Candida, it generates cells called Th17 cells. These cells produce signaling molecules (cytokines) called the interleukin-17 (IL-17) family as part of an immune process called the IL-17 pathway. The IL-17 pathway creates inflammation, sending other cytokines and white blood cells that fight foreign invaders and promote tissue repair. In addition, the IL-17 pathway promotes the production of certain antimicrobial protein segments (peptides) that control growth of Candida on the surface of mucous membranes.

The gene mutations associated with familial candidiasis interfere with the IL-17 pathway in various ways. Mutations in several genes, including IL17RC, impair signaling in the IL-17 pathway. Mutations in other genes, including STAT1 and CARD9, are thought to block (inhibit) the activity of the pathway. Impairment of the IL-17 pathway diminishes the body's immune response to Candida, leading to the chronic or recurrent yeast infections that occur in people with familial candidiasis. Mutations in most of the genes associated with familial candidiasis cause chronic mucocutaneous candidiasis; only CARD9 gene mutations have also been known to lead to systemic candidiasis in some affected individuals.

Normal Function

The CARD9 gene provides instructions for making an immune system protein that is involved in the body's defense against fungal infections and is particularly important for fighting infection by a fungus called Candida. When the immune system recognizes Candida, it generates cells called Th17 cells. These cells produce signaling molecules (cytokines) called the interleukin-17 (IL-17) family as part of an immune process called the IL-17 pathway. The IL-17 pathway creates inflammation, sending other cytokines and white blood cells that fight foreign invaders and promote tissue repair. In addition, the IL-17 pathway promotes the production of certain antimicrobial protein segments (peptides) that control growth of Candida on the surface of mucous membranes.

In its role in defending against Candida on the mucous membranes and skin, the CARD9 protein passes along signals from other types of immune system proteins. Each of these proteins recognizes a different component of the Candida cell wall to trigger the production of Th17 cells and launch the immune response.

In addition to its role in protecting mucous membranes from fungal infection, the CARD9 protein is also important in recruiting neutrophils (immune cells that have strong anti-fungal activity) from the blood to protect the brain and other organs from fungal infection.

Health Conditions Related to Genetic Changes

Familial candidiasis

At least 15 CARD9 gene mutations have been identified in people with familial candidiasis, an inherited tendency to develop infections caused by the Candida fungus (commonly called yeast infections). Most people with familial candidiasis have chronic yeast infections of the skin, nails, and mucous membranes. This pattern of signs and symptoms, which is called chronic mucocutaneous candidiasis, typically begins in early childhood. People with familial candidiasis caused by CARD9 gene mutations can also develop systemic candidiasis, a potentially life-threatening condition in which Candida invades the blood and vital organs, especially the brain. Infections caused by additional types of fungi have also been identified in some people with this form of the disorder, which is sometimes called CARD9 deficiency.

Mutations in the CARD9 gene impair multiple signaling pathways that normally help recognize Candida and are thought to block (inhibit) the activity of the IL-17 pathway. Impairment of this pathway diminishes the body's immune response to Candida, leading to the chronic or recurrent yeast infections that occur in people with familial candidiasis. The mutations are also thought to impair the recruitment of neutrophils to fight Candida infection in the brain and other organs, which can lead to systemic candidiasis.

Other Names for This Gene

• caspase recruitment domain family, member 9
• hCARD9

Genomic Location

Normal Function

The IL17RC gene provides instructions for making a protein that is involved in immune system function, specifically in the body's defense against a fungus called Candida. When the immune system recognizes Candida, it generates cells called Th17 cells. These cells produce signaling molecules (cytokines) called the interleukin-17 (IL-17) family as part of an immune process called the IL-17 pathway. The IL-17 pathway creates inflammation, sending other cytokines and white blood cells that fight foreign invaders and promote tissue repair. In addition, the IL-17 pathway promotes the production of certain antimicrobial protein segments (peptides) that control growth of Candida on the surface of mucous membranes.

The protein produced from the IL17RC gene is present in many tissue types in the body, and is involved in cell signaling as part of the IL-17 pathway. Together with the protein produced from the IL17RA gene, it forms one of several receptors for IL-17 cytokines. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. Certain IL-17 cytokines attach to receptors containing the IL17RC and IL17RA proteins, triggering signals that promote inflammation and the defense against Candida infection.

Health Conditions Related to Genetic Changes

Familial candidiasis

At least three mutations in the IL17RC gene have been identified in people with familial candidiasis, an inherited tendency to develop infections caused by the Candida fungus (commonly known as yeast infections). Most people with familial candidiasis have chronic yeast infections of the skin, nails, and mucous membranes (collectively called chronic mucocutaneous candidiasis) beginning in early childhood.

IL17RC gene mutations result in an absence of IL17RC receptor protein. Loss of this protein impairs binding of IL-17 cytokines and IL-17 signaling. This impaired signaling decreases production of the antimicrobial peptides and inflammatory molecules that are critical for defense against Candida, and results in the chronic infection that occurs in familial candidiasis.

Other Names for This Gene

• IL-17 receptor C
• IL-17RL
• IL17F receptor
• interleukin-17 receptor homolog
• interleukin-17 receptor-like protein

Genomic Location

Normal Function

The STAT1 gene provides instructions for making a protein that is involved in multiple immune system functions, including the body's defense against a fungus called Candida. When the immune system recognizes Candida, it generates cells called Th17 cells. These cells produce signaling molecules (cytokines) called the interleukin-17 (IL-17) family as part of an immune process called the IL-17 pathway. The IL-17 pathway creates inflammation, sending other cytokines and white blood cells that fight foreign invaders and promote tissue repair. In addition, the IL-17 pathway promotes the production of certain antimicrobial protein segments (peptides) that control growth of Candida on the surface of mucous membranes.

The STAT1 protein helps keep the immune system in balance by controlling the IL-17 pathway. When the STAT1 protein is turned on (activated), it blocks (inhibits) this pathway.

In contrast to its inhibitory role in the IL-17 pathway, the STAT1 protein helps promote other immune processes called the interferon-alpha/beta (IFNA/B) and interferon-gamma (IFNG) signaling pathways. The IFNA/B pathway is important in defense against viruses, and the IFNG pathway helps fight a type of bacteria called mycobacteria, which includes the bacterium that causes tuberculosis.

Health Conditions Related to Genetic Changes

Familial candidiasis

At least 35 STAT1 gene mutations have been identified in people with familial candidiasis, an inherited tendency to develop infections caused by the Candida fungus (commonly called yeast infections). Most people with familial candidiasis have chronic infections of the skin, nails, and mucous membranes such as the lining of the mouth, collectively called chronic mucocutaneous candidiasis, beginning in early childhood.

Some people with STAT1 gene mutations have additional features such as increased susceptibility to other infections and an increased risk of autoimmune disorders, in which the immune system attacks the body's own tissues or organs. This combination of signs and symptoms caused by STAT1 gene mutations is sometimes called immunodeficiency 31C.

The STAT1 gene mutations that have been identified in people with familial candidiasis are described as "gain of function" because they increase the amount of activated STAT1 protein in cells. By increasing STAT1's inhibitory effect on the IL-17 pathway, the mutations impair the body's ability to fight Candida and result in the chronic infection that occurs in familial candidiasis. The effects of the increase in activated STAT1 protein on other signaling pathways are thought to underlie the variety of features that can occur in immunodeficiency 31C, but the specific mechanisms are not well understood.

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Other disorders

STAT1 gene mutations can also cause other immune system problems called immunodeficiency 31A and immunodeficiency 31B. In contrast with the gain-of-function mutations associated with familial candidiasis (described above), these STAT1 gene mutations are described as "loss-of-function" mutations because they impair or eliminate the protein's normal action.

The STAT1 gene mutations that cause immunodeficiency 31A impair the STAT1 protein's function in the IFNG pathway, resulting in an increased susceptibility to mycobacteria. In the more severe disorder immunodeficiency 31B, the STAT1 gene mutations impair both the IFNG pathway and the IFNA/B pathway, resulting in susceptibility to both viral infections such as herpes simplex and viral encephalitis, and mycobacterial infections such as tuberculosis.

Other Names for This Gene

• IMD31A
• IMD31B
• IMD31C
• ISGF-3
• signal transducer and activator of transcription 1, 91kDa
• signal transducer and activator of transcription-1
• STAT91
• transcription factor ISGF-3 components p91/p84

Genomic Location

Familial candidiasis can be inherited in different patterns. People with this disorder inherit a tendency to develop recurrent or chronic Candida infections, not the infections themselves. Familial candidiasis caused by mutations in some genes, including STAT1, is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Familial candidiasis caused by mutations other genes, such as CARD9 or IL17RC, is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How is invasive candidiasis treated?

The specific type and dose of antifungal medication used to treat invasive candidiasis usually depends on the patient’s age, immune status, and location and severity of the infection. For most adults, the initial recommended antifungal treatment is an echinocandin (caspofungin, micafungin, or anidulafungin) given through the vein (intravenous or IV). Fluconazole, amphotericin B, and other antifungal medications may also be appropriate in certain situations.

How long does the treatment last?

For candidemia, treatment should continue for 2 weeks after signs and symptoms have resolved and Candida yeasts are no longer in the bloodstream. Other forms of invasive candidiasis, such as infections in the bones, joints, heart, or central nervous system, usually need to be treated for a longer period of time.

Candida is present on the skin and mucous membranes of up to half the population at any given time, normally without creating health problems. The prevalence of the inherited susceptibility to Candida infections that characterizes familial candidiasis is unknown, but the condition is thought to be rare.