Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species–induced meningoencephalitis, colitis, or both

Fanny Lanternier, Seyed Alireza Mahdaviani, Elisa Barbati, H
elene Chaussade, Yatrika Koumar, Romain Levy, Blandine Denis, Anne-Sophie Brunel, Sophie Martin, Michele Loop, Julie Peeters, Ariel de Selys, Jean Vanclaire, Christiane Vermylen, Marie-C
ecile Nassogne, Olga Chatzis, Luyan Liu, M
elanie Migaud, Vincent Pedergnana, Guillaume Desoubeaux, Gregory Jouvion, Fabrice Chretien, Milad Alavi Darazam, Alejandro A. Sch€affer, Mihai G. Netea, Jean J. De Bruycker, Louis Bernard, Jacques Reynes, Noureddine Amazrine, Laurent Abel, Dimitri Van der Linden, Tom Harrison, Capucine Picard, Olivier Lortholary, Davood Mansouri, Jean-Laurent Casanova, and Anne Puel

Pediatric Respiratory Diseases Research Centre, NRITLD, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Background: Invasive infections of the central nervous system (CNS) or digestive tract caused by commensal fungi of the genus Candida are rare and life-threatening. The known risk factors include acquired and inherited immunodeficiencies, with patients often displaying a history of multiple infections. Cases of meningoencephalitis, colitis, or both caused by Candida species remain unexplained.

Objectives: We studied 5 previously healthy children and adults with unexplained invasive disease of the CNS, digestive tract, or both caused by Candida species. The patients were aged 39, 7, 17, 37, and 26 years at the time of infection and were unrelated, but each was born to consanguineous parents of Turkish (2 patients), Iranian, Moroccan, or Pakistani origin. Meningoencephalitis was reported in 3 patients, meningoencephalitis associated with colitis was reported in a fourth patient, and the fifth patient had colitis only.

Materials and Methods: Inherited caspase recruitment domain family, member 9 (CARD9) deficiency was recently reported in otherwise healthy
patients with other forms of severe disease caused by Candida, Trichophyton, Phialophora, and Exophiala species, including meningoencephalitis but not colitis caused by Candida and Exophiala species.Thereforewe sequencedCARD9inthe 5 patients.

Results: All patients were found to be homozygous for rare and deleterious mutant CARD9 alleles: R70Wand Q289* for the 3 patients with Candida albicans–induced meningoencephalitis, R35Qfor the patientwithmeningoencephalitis and colitis causedby Candida glabrata, and Q295* for the patientwith Candida albicans– induced colitis.Regardless of their levels of mutantCARD9protein, the patients’ monocyte-derived dendritic cells responded poorly to CARD9-dependent fungal agonists (curdlan, heat-killed C albicans, Saccharomyces cerevisiae, and Exophiala dermatitidis).

Conclusions: Invasive infections of the CNS or digestive tract caused by Candida species in previously healthy children and even adults might be caused by inherited CARD9 deficiency
Keywords: Inborn error of immunity, primary immunodeficiency, invasive fungal diseases, inherited CARD9 deficiency, central nervous system, colitis, Candida species, human

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J Allergy Clin Immunol 2015;135(6):1558-68.