A number sign (#) is used with this entry because of evidence that immunodeficiency-103 (IMD103) is caused by homozygous or compound heterozygous mutation in the CARD9 gene (607212) on chromosome 9q34.

Wells et al. (1972) investigated 46 patients with chronic oral candidiasis. Within the series they recognized a 'new' syndrome, present in 22 cases. The nails and skin were sometimes affected. Eighteen cases in 8 kindreds were studied. Parental consanguinity was demonstrated in 4 of these. A group of severely affected patients probably had a distinct disorder which may be nongenetic, although new autosomal dominant mutation could not be excluded. A late-onset group of cases of oral candidiasis appeared to be nongenetic. Of 14 fully investigated patients with familial chronic mucocutaneous candidiasis, 10 were found to have iron deficiency. Higgs and Wells (1972) discussed a familial form and suggested a relationship to transferrin type (which remains to be proved).

A clinically and possibly genetically distinct, seemingly autosomal recessive form of chronic mucocutaneous candidiasis was reported in families of French Canadian descent, originating from eastern Quebec (Germain et al., 1994). The disorder was of mild nature with adult onset, but complicated by fatal Candida meningitis. A total of 5 patients were reviewed. Germain et al. (1994) suggested that the disorder represents a variant of familial adult-onset chronic mucocutaneous candidiasis in which there is a striking predisposition to deep infection. Immunologic investigation showed a specific cellular deficit toward Candida albicans. One patient who died of meningitis was a 28-year-old woman who had suffered from recurrent episodes of mild oral thrush since age 16 years. She had no skin or nail involvement.

Boudghene-Stambouli and Merad-Boudia (1998) described a 29-year-old Algerian man, born of first-cousin parents, who had a 2-year history of progressive dermatophytic disease consisting of exuberant hyperkeratosis and cutaneous horns. Examination revealed erythematous flat plaques with distinct borders on the trunk, limbs, and neck, with verrucous midface lesions and other eczema-like lesions on the face, as well as papulonodular lesions around the left nipple. The lesions were intensely pruritic, and chronic scratching had caused lichenification. On the anterior plantar surface of each foot, there was a wide-based, dark-brown hard horn that made walking difficult. In addition, the patient had pachyonychia of all nails, some of which exhibited onychogryphosis. Histologic examination of affected skin showed acanthosis and papillomatosis of the epidermis, with marked hyperkeratosis. The stratum corneum was invaded by hyphae that penetrated into the sweat glands and hair follicles, and abscesses and small granulomas containing hyphae were seen in the superficial dermis. No other family members were affected. Boudghene-Stambouli and Merad-Boudia (1998) suggested that this phenotype with giant cutaneous horns represented a new variant of dermatophytic disease.

Glocker et al. (2009) studied a large consanguineous Iranian family segregating autosomal recessive chronic mucocutaneous candidiasis. Recurrent fungal infections were diagnosed clinically in 8 family members, 3 of whom died in early adolescence, 2 with proven and 1 with presumed invasive Candida infection of the brain. None of the 8 infected patients had unusual bacterial or viral infections, suggesting that host defenses against those pathogens was normal. In the 3 patients for whom laboratory studies were available, complete blood counts were within the normal range, as were total counts of CD3+, CD4+, and CD8+ T cells; memory, follicular helper, effector, and regulatory T cells; B cells; and natural killer cells. Basal levels of serum immunoglobulin were also normal. In 1 patient, a delayed-type hypersensitivity skin test was negative for tuberculin but positive for Candida. Compared to healthy family members and controls, affected family members had significantly lower proportions of Th17 cells, helper T cells producing interleukin-17 (603149) that are important for antifungal immunity.

Drewniak et al. (2013) studied a 13-year-old Asian girl who was adopted as an infant and at 7 years of age developed fever, headaches, behavioral changes, and seizures. She was diagnosed with Candida dubliniensis meningoencephalitis, but did not have any obvious underlying risk factors for fungal meningitis. MRI showed a deep infarction of the left striatum, meningeal enhancement, and mild ventricular dilation. After 6 months of antimycotic treatment, its discontinuation resulted in a clinical relapse, and cerebrospinal fluid (CSF) cultures revealed C. dubliniensis. Clinical signs and CSF eosinophilic pleocytosis resolved within several weeks of restarting combined antifungal therapy. Western blot analysis of patient neutrophils showed apparent absence of CARD9 protein, and this was confirmed with anti-CARD9 antibodies. Activated patient T-cell cultures showed clear induction of various cytokines but reduced levels of Th17-derived IL17 (see 603149), consistent with the findings of Glocker et al. (2009).

Lanternier et al. (2013) described 17 patients from 8 unrelated families of Moroccan, Tunisian, and Algerian ancestry, including the Algerian family originally described by Boudghene-Stambouli and Merad-Boudia (1998), who had deep dermatophytosis and no known immunodeficiency. In all patients, symptoms first appeared in childhood or early adulthood. Four patients had adenitis caused by dermatophyte infection, and 13 had documented cutaneous deep dermatophytosis. Skin lesions included extensive erythematosquamous lesions and nodular subcutaneous or ulcerative fistulized infiltrations. Fifteen patients had severe onychomycosis, and 2 patients had contiguous locoregional extension to the bone or digestive tract; manifestations of the disease in other extradermatologic locations included lymphadenopathy in 10 patients and probable brain involvement in 1. Four patients with clinically active deep dermatophytosis died at the ages of 28, 29, 37, and 39 years. None of the 17 patients had any detectable T-cell immunodeficiency known to confer a predisposition to severe dermatophyte infection. Skin histology showed multifocal-to-coalescing granulomatous dermatitis that extended throughout the dermis and was characterized by infiltrates of activated macrophages and epithelioid cells, associated with lymphocytes, plasma cells, neutrophils, and eosinophils. Pseudohyphae and irregularly branched hyaline septate hyphae could be seen within granulomas and sometimes even in the cytoplasm of multinucleated giant cells. Lymph node histology revealed granulomas containing hyphae and necrosis in 4 patients.

Wang et al. (2014) reported 4 unrelated patients with subcutaneous phaeohyphomycosis caused by P. verrucosa and Th17 cell deficiencies.

Wang et al. (2018) reported 3 patients, aged 18, 38 and 53 years, with phaeohyphomycosis caused by rare dermatiaceous fungi. Histopathologic analysis of skin from each patient demonstrated infectious granulomas with irregularly branched brown hyphae and lack of neutrophil infiltration.

Paccoud et al. (2022) reported a Moroccan patient who developed an ulcer on her ankle at 22 years of age when she was pregnant. A biopsy of the lesion showed spherical hyphae and she was treated with surgical excision and amphotericin B. She developed a hard-palate necrosis at age 25 during a subsequent pregnancy. The lesion did not heal despite treatment with amphotericin, and at age 28, she had lesions of the dosum nasi and hard palate with destruction of the nasal septum. The infection was shown to be due to Alternaria infectoria.

In peripheral blood mononuclear cells (PBMCs) from a 13-year-old Asian girl with chronic Candida dubliniensis meningoencephalitis and CARD9 deficiency, Drewniak et al. (2013) observed a virtual absence of Candida-induced monocytic IL6 (147620) and IL1B (147720) release. The response to bacteria and various TLR (see 603030) ligands was only partly affected or not at all, and cells transduced with CARD9 showed recovery of monocytic cytokines. Patient neutrophils demonstrated a normal capacity to generate reactive oxygen species and normal recognition and signaling for immediate responses. Neutrophil-killing capacity of CARD9-deficient cells was significantly impaired with unopsonized C. albicans conidia, but was normal with serum-opsonized conidia, and with opsonized S. aureus or E. coli. Ultrastructural analysis showed abnormal bulging phagolysosome formation upon uptake of C. albicans in patient neutrophils compared to controls. Drewniak et al. (2013) concluded that CARD9 deficiency results in a selective defect in host defense against invasive fungal infection, due to impaired phagocyte killing.

Glocker et al. (2009) performed homozygosity mapping in a large consanguineous Iranian family with chronic mucocutaneous candidiasis and identified a region of perfect segregation on chromosome 9; genotyping 4 microsatellite markers yielded a peak multipoint lod score of 3.6 at an interval defined by the markers D9S2157 and D9S1838. Forty-one genes were located in a perfectly segregating 1.3-Mb subinterval suggested by SNP data.

The transmission pattern of IMD103 in the family reported by Glocker et al. (2009) was consistent with autosomal recessive inheritance.

In a large consanguineous Iranian family segregating autosomal recessive chronic mucocutaneous candidiasis mapping to chromosome 9, Glocker et al. (2009) identified homozygosity for a nonsense mutation (Q295X; 607212.0001) in the CARD9 gene in all 4 affected individuals. Eighteen other unaffected family members were either heterozygous or did not carry the Q295X mutation, and the mutation was not found in 50 unrelated Iranian controls or in 180 unrelated Caucasian controls. Functional studies showed that Q295X is a loss-of-function mutation that impairs innate signaling from the antifungal pattern-recognition receptor dectin-1 (CLEC7A; 606264).

In a 13-year-old Asian girl with chronic Candida dubliniensis meningoencephalitis, in whom CARD9 appeared to be absent from neutrophils, Drewniak et al. (2013) identified compound heterozygosity for 2 missense mutations in the CARD9 gene, G72S (607212.0002) and R373P (607212.0003).

In affected individuals from 8 families of Algerian, Tunisian, and Moroccan ancestry with deep dermatophytosis, including the Algerian family previously studied by Boudghene-Stambouli and Merad-Boudia (1998), Lanternier et al. (2013) analyzed the candidate gene CARD9 and identified homozygosity for a nonsense mutation (Q289X; 607212.0004) in 7 of the families; patients from the eighth family were homozygous for a CARD9 missense mutation (R101C; 607212.0005). The mutations segregated fully with disease in each family and were not found in ethnically matched controls, in more than 1,000 exomes, or in the 1000 Genomes Project database.

Wang et al. (2014) identified biallelic mutations in the CARD9 gene in 4 unrelated Chinese patients with subcutaneous phaeohyphomycosis, including 1 (patient 1) with compound heterozygous mutations (607212.0006-607212.0007) and 3 (patients 2-4) with a homozygous mutation (607212.0008). Haplotype analysis in the homozygous patients demonstrated that the mutation likely arose from a shared founder. In patients 1, 2, and 3, expression of mature CARD9 protein was absent in peripheral mononuclear blood cells, and Th17 cells and the related cytokines IL17 and IL22 (605330) were decreased in blood/serum. Induced macrophages and immature dendritic cells from patients 1 and 3 secreted lower cytokines when exposed to P. verrucosa spores compared to controls. Wang et al. (2014) concluded that these results confirm the pivotal role of CARD9 in antifungal defense.

Wang et al. (2018) identified biallelic mutations in the CARD9 gene in 3 unrelated Chinese patients with IMD103, including compound heterozygous mutations (607212.0006, 607212.0008, 607212.0009) in 2 (patients 1 and 3) and a homozygous mutation (607212.0008) in 1 (patient 2). CARD9 protein expression was absent in polymorphonuclear cells from each patient. Studies in cells from patient 1 showed impaired proinflammatory chemokine (TNF-alpha, 191160; IL6, 147620; IL1B, 147720) and cytokine (CXCL1, 155730; CXCL2, 139110; CXCL8, 146930) production, deficient NF-kappa-B (see 164011) activation, and impaired Th22 and Th17 cells following fungal stimulation.