A Homozygous CARD9 Mutation in a Brazilian Patient with Deep Dermatophytosis

Abstract

Deep dermatophytosis has been described in HIV and immunosuppressed patients. Recently, CARD9 (caspase recruitment domain-containing protein 9) deficiency has been reported in individuals with deep dermatophytosis previously classified as "immunocompetent". We report a 24-year-old Brazilian male patient with deep dermatophytosis born to an apparently non-consanguineous family. The symptoms started with oral candidiasis when he was 3 years old, persistent although treated. At 11 years old, well delimited, desquamative and pruriginous skin lesions appeared in the mandibular area; ketoconazole and itraconazole were introduced and maintained for 5 years. At 12 years of age, the lesions, which initially affected the face, started to spread to thoracic and back of the body (15 cm of diameter) and became ulcerative, secretive and painful. Terbinafine was introduced without any improvement. Trichophyton mentagrophytes was isolated from the skin lesions. A novel homozygous mutation in CARD9 (R101L) was identified in the patient, resulting in impaired neutrophil fungal killing. Both parents, one brother (with persistent superficial but not deep dermatophytosis) and one sister were heterozygous for this mutation, while another brother was found to be homozygous for the CARD9 wild-type allele. This is the first report of CARD9 deficiency in Latin America.

Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

“…Other fungal infections included mostly superficial dermatophytosis, without the deep dermatophytosis seen in some CARD9-deficient patients. 14,68 Invasive infections by a variety of yeasts, molds, and dimorphic fungi were observed in some patients. 23,34,37,40 Cutaneous and bronchopulmonary infections caused by S aureus were also observed, as in patients with AD-HIES.…”

Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation

“…To date, all clinically reported homozygous or compound heterozygous carriers with either no CARD9 expression or CARD9 loss-of-function alleles are more susceptible to fungal infection (Drewniak et al, 2013; Gavino et al, 2014; Gazendam et al, 2014; Glocker et al, 2009; Grumach et al, 2015; Herbst et al, 2015; Jachiet et al, 2015; Lanternier et al, 2015a; Lanternier et al, 2015b; Lanternier et al, 2013; Wang et al, 2014). Our results from Trim62 −/− mice suggest that TRIM62-mediated regulation of CARD9 activation is critical in the context of fungal infection.…”

Vav Proteins Are Key Regulators of Card9 Signaling for Innate Antifungal Immunity

“…However, the Card9 signaling pathway appears to be the central mammalian host defense mechanism against fungi, given that multiple genetic studies in humans have recently identified that several Card9 loss-of-function defects are causative for several fungal diseases, including various types of mucocutaneous candidiasis; superficial, extensive, and deep dermatophytosis with Trichophyton spp. ; subcutaneous phaeohyphomycosis; invasive Candida infections of the digestive tract and central nervous system; Candida endophthalmitis and osteomyelitis; and disseminated Exophiala disease of the liver, brain, and lung (Grumach et al., 2015, Pérez de Diego et al., 2015). …”