CARD9 – Deep Seated Dermatophytosis

Deep seated dermatophytosis is a severe fungal infection characterized by dermal and subcutaneous invasion, often refractory to standard antifungal therapy. Although typically linked to immunosuppression, autosomal recessive deficiency of caspase recruitment domain‐containing protein 9 (CARD9) has emerged as a monogenic cause in otherwise healthy individuals (PMID:24131138).

Genetic studies in 17 patients from eight unrelated consanguineous families revealed homozygous deleterious CARD9 variants and complete segregation with deep dermatophytosis, confirming autosomal recessive inheritance (PMID:24131138). A representative pathogenic allele, c.883C>T (p.Gln295Ter), causes premature termination and loss of function. Recurrent founder alleles such as Q289X are enriched in North African populations (PMID:24131138).

The variant spectrum comprises multiple loss‐of‐function mutations, including nonsense (e.g., c.301C>T (p.Arg101Cys)), frameshift, and splice‐site changes. These alleles abolish CARD9 protein expression or disrupt its caspase recruitment domain, underpinning disease penetrance in homozygous individuals.

Functional assays demonstrate that CARD9 deficiency impairs neutrophil fungal killing and NF-κB signaling downstream of Dectin-1, with patient cells showing defective cytokine responses and murine Card9−/− models recapitulating invasive dermatophyte phenotypes (PMID:26044242; PMID:19864672).

Therapeutically, posaconazole achieves clinical remission in most CARD9‐deficient patients, though some require surgical intervention for abscess drainage (PMID:25372963). Adjunctive GM-CSF has shown potential in restoring antifungal immunity in hypomorphic CARD9 variants (PMID:26521038).

References

• The New England Journal of Medicine • 2013 • Deep dermatophytosis and inherited CARD9 deficiency PMID:24131138
• Journal of Clinical Immunology • 2015 • A homozygous CARD9 mutation in a Brazilian patient with deep dermatophytosis PMID:26044242
• JAMA Dermatology • 2015 • Posaconazole treatment of extensive skin and nail dermatophytosis due to autosomal recessive deficiency of CARD9 PMID:25372963
• The Journal of Allergy and Clinical Immunology • 2016 • Impaired RASGRF1/ERK-mediated GM-CSF response characterizes CARD9 deficiency in French-Canadians PMID:26521038

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