Deep dermatophytosis and inherited CARD9 deficiency

Abstract

Background: Deep dermatophytosis is a severe and sometimes life-threatening fungal infection caused by dermatophytes. It is characterized by extensive dermal and subcutaneous tissue invasion and by frequent dissemination to the lymph nodes and, occasionally, the central nervous system. The condition is different from common superficial dermatophyte infection and has been reported in patients with no known immunodeficiency. Patients are mostly from North African, consanguineous, multiplex families, which strongly suggests a mendelian genetic cause.

Methods: We studied the clinical features of deep dermatophytosis in 17 patients with no known immunodeficiency from eight unrelated Tunisian, Algerian, and Moroccan families. Because CARD9 (caspase recruitment domain-containing protein 9) deficiency has been reported in an Iranian family with invasive fungal infections, we also sequenced CARD9 in the patients.

Results: Four patients died, at 28, 29, 37, and 39 years of age, with clinically active deep dermatophytosis. No other severe infections, fungal or otherwise, were reported in the surviving patients, who ranged in age from 37 to 75 years. The 15 Algerian and Tunisian patients, from seven unrelated families, had a homozygous Q289X CARD9 allele, due to a founder effect. The 2 Moroccan siblings were homozygous for the R101C CARD9 allele. Both alleles are rare deleterious variants. The familial segregation of these alleles was consistent with autosomal recessive inheritance and complete clinical penetrance.

Conclusions: All the patients with deep dermatophytosis had autosomal recessive CARD9 deficiency. Deep dermatophytosis appears to be an important clinical manifestation of CARD9 deficiency. (Funded by Agence Nationale pour la Recherche and others.).

Figure 1. Pedigrees of the 17 Patients from Eight Kindreds with Deep Dermatophytosis and CARD9 Mutations

Panels A through H represent the eight kindreds. Each generation is designated by a Roman numeral, and each family member by an Arabic numeral. Circles denote female family members, squares male family members, solid squares and circles patients with deep dermatophytosis, double horizontal lines consanguinity in a married couple, and slashes deceased family members. The probands are indicated by arrows. The CARD9 genotype is indicated below each family member. E? denotes no DNA available, NM nonmutated, and P patient.

Figure 2. Clinical and Histologic Features of Patients with CARD9 Deficiency

A skin-biopsy specimen from Patient 13 (Panel A, periodic acid–Schiff) shows irregularly branched septate hyphae (arrowhead) in the center of a granuloma containing multinucleated giant cells (asterisk). Clinical features of Patient 12 (Panel B) and Patient 8 (Panel C) are shown.

Figure 3. Effect of CARD9 Mutations on CARD9 Expression and Function

Panel A shows flow cytometric expression of CARD9 in monocyte-derived dendritic cells (MDDCs) in Patients 12 and 17 and controls. Panel B shows interleukin-6 production by whole-blood cells from patients with Q289X/Q289X and R101C/R101C CARD9 genotypes after 48 hours, as measured by enzyme-linked immunosorbent assay on stimulation with zymosan, heat-killed Candida albicans (HK C. alb), heat-killed Saccharomyces cerevisiae (HK S. cer), lipopolysaccharide (LPS), and phorbol 12-myristate 13-acetate plus ionomycin (PMA+Iono). NS denotes unstimulated. The asterisks indicate values below 100 pg per milliliter, and the T bars the standard deviation. Panel C shows impaired development of interleukin-17–producing T cells in patients homozygous for the R101C or Q289X CARD9 mutations.