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 ... 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. 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, 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 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.
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 ... 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, 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 or in more than 1,000 exomes, or the Ensembl, 1000 Genomes Project, or Human Genome Mutation databases.