EndogenousCandidaendophthalmitis and osteomyelitis associated with CARD9 deficiency

Abstract

A 25-year-old woman presented with unilateral red eye and visual blur, and was found to have panuveitis with an inflammatory white mass at the macula, initially presumed to be Toxoplasma retinitis. After failure to respond, she underwent vitrectomy, which produced Candida albicans. Despite intraocular and systemic antifungal treatment, she lost all vision in that eye. Two years later, she developed unilateral hip osteomyelitis leading to total hip replacement and also revealing Candida infection. By clinical exome sequencing, she was then found to have caspase recruitment domain 9 (CARD9) deficiency, an autosomal recessive disorder that causes a specific susceptibility to candidal infections. She remains otherwise well but on lifelong fluconazole prophylaxis.

Novel bi‐allelic splice mutations in CARD9 causing adult‐onset Candida endophthalmitis

“…Bi‐allelic loss‐of‐function mutations in CARD9 cause an immunodeficiency that manifests as increased susceptibility to invasive diseases by a discrete spectrum of fungi. With respect to Candida sp., we and others have previously demonstrated that CARD9 deficiency causes an intriguing syndrome that we have termed “spontaneous central nervous system candidiasis (sCNSc).” We and others have also reported that spontaneous candidal endophthalmitis may occur concurrently with sCNSc . The current case further adds to this previous report, illustrating that spontaneous candidal endophthalmitis may be the primary manifestation of CARD9 deficiency.…”

“…4 We and others have also reported that spontaneous candidal endophthalmitis may occur concurrently with sCNSc. 5,10 The current case further adds to this previous report, illustrating that spontaneous candidal endophthalmitis may be the primary manifestation of CARD9 deficiency. Figure 2E).…”

“…can infect the central nervous system (primarily, brain and/or meninges), in the absence of trauma, chemotherapy, or underlying systemic disease. [2][3][4][5][6][7][8][9][10][11] We have previously identified CARD9 deficiency in a patient with spontaneous candidal endophthalmitis with probable sCNSc and candidal osteomyelitis (which resolved with antifungal therapy for the eye, but without histological/microbiological evidence). 5 CARD9 deficiency can also be associated with increased susceptibility to other fungi (eg the dermatophyte, Trichosporon sp.…”

“…CARD9 deficiency is an autosomal recessive disorder that distinctively increases human susceptibility to invasive fungal diseases, including an unusual syndrome that we have termed “spontaneous central nervous system candidiasis” (sCNSc), in which Candida spp. can infect the central nervous system (primarily, brain and/or meninges), in the absence of trauma, chemotherapy, or underlying systemic disease …”

Inborn errors of immunity underlying fungal diseases in otherwise healthy individuals

“…Cerebrospinal fluid (CSF) analysis typically reveals a mononuclear cell (lymphocytes and/or mononuclear cells) predominance; eosinophil pleocytosis but no neutrophil pleocytosis in most cases; high protein concentration; and hypoglycorrhachia. Three cases of C. albicans osteomyelitis [56,61,64], two of which were associated with endophthalmitis, one case of intra-abdominal (liver and mesenteric lymph nodes) candidiasis [57], and two cases of severe Candida colitis [52] have also been reported (Table 2). Three of the 16 patients died [22].…”