In the past decade, an increasing number of otherwise healthy individuals suffered from invasive fungal infections due to inherited CARD9 mutations. Herein, we present a patient with a homozygous CARD9 mutation who was suffering from localized subcutaneous phaeohyphomycosis caused by the phytopathogenic fungus Pallidocercospora crystallina which has not been reported to cause infections in humans.
The medical history of our patient was collected. P. crystallina was isolated from the biopsied tissue. To characterize this novel pathogen, the morphology was analyzed, whole-genome sequencing was performed, and the in vivo immune response was explored in mice. Whole-exome sequencing was carried out with samples from the patient’s family. Finally, the expression and function of mutated CARD9 were investigated.
A dark red plaque was on the patient’s left cheek for 16 years and was diagnosed as phaeohyphomycosis due to a P. crystallina infection. Whole-genome sequencing suggested that that this strain had a lower pathogenicity. The in vivo immune response in immunocompetent or immunocompromised mice indicated that P. crystallina could be eradicated within a few weeks. Whole-exome sequencing revealed ahomozygous missense mutation in CARD9 (c.1118G>C p.R373P). The mRNA and protein expression levels were similar among cells carrying homozygous (C/C), heterozygous (G/C), and wild-type (G/G) CARD9 alleles. Compared to PBMCs or neutrophils with heterozygous or wild-type CARD9 alleles, however, PBMCs or neutrophils with homozygous CARD9 alleles showed impaired anti-P. crystallina effects.
Localized subcutaneous phaeohyphomycosis caused by P. crystallina was reported in a patient with a homozygous CARD9 mutation. Physicians should be aware of the possibility of a CARD9 mutation in seemingly healthy patients with unexplainable phaeohyphomycosis.
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We thank the patient and her family, for participating in this study. We thank for the Chigene (Beijing) Translational Medical Research Center Co. Ltd. for the technical support of the whole-exome sequencing analysis.
This work was supported by the National Natural Science Foundation of China (Grant numbers 81371735 and 81672691) and the National Natural Science Foundation of Shaanxi Province (Grant number 21044091).
This work was performed according to rules and regulations concerning the use of human materials from the patient, her parents, her son, and three healthy unrelated volunteers with written informed consent. The study was approved by the Clinical Research Ethics Committee of the Xijing Hospital in accordance with the institution’s guidelines. All experiments were carried out with adherence to the Declaration of Helsinki.
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Guo, Y., Zhu, Z., Gao, J. et al. The Phytopathogenic Fungus Pallidocercospora crystallina-Caused Localized Subcutaneous Phaeohyphomycosis in a Patient with a Homozygous Missense CARD9 Mutation. J Clin Immunol 39, 713–725 (2019). https://doi.org/10.1007/s10875-019-00679-4
- Pallidocercospora crystallina
- Homozygous missense mutations
- Primary immunodeficiency
- Inborn errors of immunity