CARD9 Deficiency
NORD gratefully acknowledges Mélanie Langelier, RN, BSc(N), MSc(N), Clinical Manager: Medical Genetics, Neurophysiology, Cardiology and Hemodynamics Laboratory, McGill University Health Centre - Research Institute, and Donald C. Vinh, MD, FRCP(C) Director, Centre of Excellence for Genetic Research in Infection and Immunity, Associate Professor, FRQS Clinician-Scientist, Dept. of Medicine (Division of Infectious Diseases; Division of Allergy & Clinical Immunology), Dept. of Medical Microbiology; Dept. of Human Genetics, McGill University Health Centre - Research Institute, for the preparation of this report.
General Discussion
Summary
CARD9 deficiency is a rare disorder of the immune system caused by changes (mutations) in the gene calledcaspase recruitment domain family member 9(CARD9). CARD9 deficiency leads to increased susceptibility to certain fungal infections. Generally speaking, the term “fungi” includes two broad categories, yeasts and molds that can be accurately identified in a hospital diagnostic microbiology laboratory. CARD9 deficiency can render affected individuals susceptible particularly to the yeast called Candida (causing “candidiasis”), as well as to certain types of molds (those called “dermatophytes”, which usually cause infections like “ringworm” and “athlete’s foot”, as well as those called “black molds” or “pheohyphomycetes”). However, current knowledge suggests that people with CARD9 deficiency are at increased risk for disease with only one of these types of fungus. As well, people with CARD9 deficiency do not seem to be at increased risk for infections caused by other microbes, such as bacteria, viruses, or parasites.
Introduction
CARD9 deficiency is a type of primary immunodeficiency. Primary immunodeficiency diseases (also called “inborn errors of immunity”) are a group of more than 420 rare, chronic disorders in which part of the body’s immune system is missing or functions improperly. These diseases are caused by a mutation in a gene or genes, and, although some disorders present at birth or in early childhood, the disorders can affect anyone, regardless of age or gender. Some affect a single part of the immune system; others may affect one or more components of the system.
Signs & Symptoms
The signs and symptoms (or manifestations) of CARD9 deficiency appear quite varied.
As mentioned above, some persons develop infection only with Candida, while others develop infection only with dermatophytes, and others develop infection only with “black molds”.
The following conditions can be caused by CARD9 deficiency:
• invasive fungal disease
• mycosis
• Candida infection (candidiasis)
• chronic mucocutaneous candidiasis (CMC)
• 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)
• pheohyphomycosis (black mold disease)
Infections with Candida can be superficial and chronic (termed “chronic mucocutaneous candidiasis” or CMC). In distinction to the majority of other primary immunodeficiency disorders that cause CMC, CARD9 deficiency distinctly predisposes to invasive infection with Candida (termed “invasive candidiasis”), where the Candida can invade beyond the skin to go to other parts of the body. A very distinct manifestation is Candida involving the brain or the meninges (the protective layer of the brain, resulting in meningitis). In some cases of CARD9 deficiency where Candida infects the brain, the affected patients have radiologic brain imaging (for example, by CT or MRI) and are found to have mass(es) that resemble brain cancers; however, on biopsy, there is no cancer and only Candida infection is found. CARD9 deficiency can also lead to candida infection of the eye (leading to loss of vision) or of bone (leading to pain in the affected area). In all of these cases of invasive candidiasis, there is no risk factor for the fungus to reach these organs (the usual risk factors include things such as leukemia, chemotherapy, intravenous lines, all of which are absent in affected individuals).The invasive candidiasis may appear to be successfully treated with antifungal drugs that target Candida, although the infection may recur (relapse), when the antifungal drug is stopped; in some instances, it may recur even when the person is currently taking the right antifungal drug.
Infections with dermatophytes and “black molds” tend be chronic and difficult to treat, responding partially or poorly to antifungal drugs. They can be disfiguring and they can also spread from the skin to lymph nodes and deep organs, including the brain.
There has been a report of other fungal infections associated with CARD9 deficiency, although the evidence has been less conclusive.
Although CARD9 deficiency is a genetic disorder, the invasive fungal infection can occur at any age. In fact, most of the reported cases have been in adults. Males and females are equally affected.
Causes
CARD9 deficiency is caused by mutations in theCARD9gene. This gene is responsible for production of the CARD9 protein which is normally expressed by only two specific types of white blood cells: neutrophils and monocytes (monocytes in the blood become macrophages once they go into tissues). In CARD9 deficiency, the CARD9 protein is abnormal, and both of these types of cells (neutrophils and monocytes/macrophages) have difficulty responding to fungus, which allows one of the above fungal diseases to develop.
CARD9 deficiency is inherited in an autosomal recessive fashion, which means that both copies of the gene, one inherited from each parent, have to have a mutation in order for a person to develop this condition. If only one copy of the gene has a mutation, then the person is considered to be a “carrier”; to date, carriers are not thought to be at increased risk for fungal infections. However, the risk for two carrier parents to pass the gene mutation and, consequently, to have an affected child is 25 percent with each pregnancy.
Affected Populations
CARD9 deficiency affects males and females in apparently equal numbers and has been reported all over the world. However, the exact frequency of this condition in the general population is unknown. It may be relatively more frequently found in some parts of the world because of a local “founder effect”. A “founder effect” occurs in history when a new population is established by a very small number of individuals; over generations, carriers may become more common, allowing two carriers to have children, who are then affected.
Related Disorders
The invasive fungal disease that is seen in CARD9 deficiency can also occur in other primary immunodeficiencies. For example, in chronic granulomatous disease (CGD), where the ability of white blood cells to produce a “respiratory burst” does not work properly, those patients can get infections with certain fungi. Also, patients with genetic mutations in the pathway that control the interleukin(IL)-12/Interferon-gamma pathway can also get invasive infections with certain molds.
CARD9 deficiency can also predispose to chronic mucocutaneous candidiasis (CMC). CMC can be seen in many other primary immunodeficiencies, including those in which special subsets of lymphocytes (called T helper cells that produce IL-17 or Th17) do not function properly.
Diagnosis
A diagnosis of CARD9 deficiency is suspected based upon a thorough clinical evaluation, a detailed patient history, particularly one in which there is invasive fungal infection without any of the typical risk factors listed above, and a variety of blood tests.
A diagnosis of CARD9 deficiency can be confirmed through molecular genetic testing for mutations in theCARD9gene.
Standard Therapies
Treatment
As CARD9 deficiency presents with invasive fungal disease, the treatment is directed toward the fungus causing the infection, with anti-fungal drugs. There are many different types of antifungal drugs, some exist for oral consumption and some require intravenous administration. The optimal duration of antifungal treatment has not been established. In some instances, prompt antifungal therapy is required until there has been a good clinical response, followed by maintenance (prophylactic) dosing (using lower doses) for a certain period of time.
In some people, despite seemingly-appropriate antifungal therapy, the fungus recurs to cause disease. In those situations, an alternative antifungal drug (or combination of antifungal drugs) may be necessary. In some recurrences, surgical removal of the main fungal focus of infection may be necessary.
Other treatment is symptomatic and supportive.
Investigational Therapies
Currently, there is no established curative therapy for individuals with CARD9 deficiency. Although bone marrow transplant (or peripheral blood stem cell transplant) has been suggested, as is recommended for other types of primary immunodeficiencies, the experience with transplant for CARD9 deficiency is currently limited to three reports, two of which were successful (these two were children who had ‘deep dermatophytosis’). Whether transplant can be successful for adolescents/adults with CARD9 deficiency, or fungal infections other than ‘deep dermatophytosis’, and the timing of such transplant, are not currently known.
CARD9 deficiency seems to decrease the ability of monocytes/macrophages to produce a cytokine (hormone of the immune system) called “granulocyte-monocyte colony stimulating factor” (GM-CSF) in response to certain fungi. Because of this, GM-CSF (sargramostim) has been used to successfully treat patients with CARD9 deficiency who had recurrence of their Candida infection despite surgical removal of the main fungal lesion and the appropriate antifungal therapy. However, in another patient (who did not have surgical removal of fungal lesion), GM-CSF treatment led to excessive inflammation. Another related cytokine, called “granulocyte colony stimulating factor” (or G-CSF), has also been successfully used in one patient with Candida infection of the brain/meninges. Both therapies appear to be well tolerated, although monitoring by a doctor is required. Both therapies were given at the same time as antifungal therapy. For both cytokine therapies, the optimal duration of therapy is not known. Whether GM-CSF or G-CSF can be used to successfully treat other fungal infections associated with CARD9 deficiency is unknown.
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For more information on CARD9 deficiency contact:
Infectious Disease Susceptibility Program
Research Institute – McGill University Health Centre
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References
JOURNAL ARTICLES
Queiroz-Telles F, Mercier T, Maertens J, et al. Successful allogenic stem celltransplantationin patients with inheritedCARD9deficiency. .J Clin Immunol. 2019 Jul;39(5):462-469.
Drummond RA, Zahra FT, Natarajan M, Swamydas M, Hsu AP, Wheat LJ, Gavino C,Vinh DC, Holland SM, Mikelis CM, Lionakis MS. GM-CSF therapy in human caspase recruitment domain-containing protein 9 deficiency. J Allergy Clin Immunol. 2018 Oct;142(4):1334-1338.e5.
Alves de Medeiros AK, Lodewick E, Bogaert DJ, et al. Chronic and invasive fungal infections in a family with CARD9 deficiency. J Clin Immunol. 2016;36(3):204-209.
Celmeli F, Oztoprak N, Turkkahraman D, et al. Successful granulocyte colony-stimulating factor treatment of relapsing candida albicans meningoencephalitis caused by CARD9 deficiency. Pediatr Infect Dis J. 2016;35(4):428-431.
Gavino C, Hamel N, Zeng JB, et al. Impaired RASGRF1/ERK-mediated GM-CSF response characterizes CARD9 deficiency in French-Canadians. J Allergy Clin Immunol. 2016;137(4):1178-1188.e1171-1177.
Rieber N, Gazendam RP, Freeman AF, et al. Extrapulmonary aspergillus infection in patients with CARD9 deficiency. JCI Insight. 2016;1(17):e89890.
Drummond RA, Collar AL, Swamydas M, et al. CARD9-dependent neutrophil recruitment protects against fungal invasion of the central nervous system. PLoS Pathog. 2015;11(12):e1005293.
Lanternier F, Barbati E, Meinzer U, et al. Inherited CARD9 deficiency in 2 unrelated patients with invasive Exophiala infection. J Infect Dis. 2015;211(8):1241-1250.
Lanternier F, Mahdaviani SA, Barbati E, et al. Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species-induced meningoencephalitis, colitis, or both. J Allergy Clin Immunol. 2015;135(6):1558-1568.e1552.
Gavino C, Cotter A, Lichtenstein D, et al. CARD9 deficiency and spontaneous central nervous system candidiasis: complete clinical remission with GM-CSF therapy. Clin Infect Dis. 2014;59(1):81-84.
Wang X, Wang W, Lin Z, et al. CARD9 mutations linked to subcutaneous phaeohyphomycosis and TH17 cell deficiencies. J Allergy Clin Immunol. 2014;133(3):905-908.e903.
Drewniak A, Gazendam RP, Tool AT, et al. Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency. Blood. 2013;121(13):2385-2392.
Lanternier F, Pathan S, Vincent QB, et al. Deep dermatophytosis and inherited CARD9 deficiency. N Engl J Med. 2013;369(18):1704-1714.
Glocker EO, Hennigs A, Nabavi M, et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med. 2009;361(18):1727-1735.
Years Published
2017, 2021
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The average time for accurate diagnosis of a rare disease is about 4–5 years [5,6,7]; in some cases, it can take over a decade [8, 9]. These patients face a diagnostic odyssey and often undergo extensive and expensive workups at several institutions.
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