Inherited CARD9 Deficiency in 2 Unrelated Patients With Invasive Exophiala Infection

Fanny Lanternier, Elisa Barbati, Ulrich Meinzer, Luyan Liu, Vincent Pedergnana, Mélanie Migaud, Sébastien Héritier, Maryline Chomton, Marie-Louise Frémond, Emmanuel Gonzales, Caroline Galeotti, Serge Romana, Emmanuel Jacquemin, Adela Angoulvant, Valeska Bidault, Danielle Canioni, Julie Lachenaud, Davood Mansouri, Seyed Alireza Mahdaviani, Parvaneh Adimi, Nahal Mansouri, Mahin Jamshidi, Marie-Elisabeth Bougnoux, Laurent Abel, Olivier Lortholary, Stéphane Blanche, Jean-Laurent Casanova, Capucine Picard and Anne Puel

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

Background: Exophiala species are mostly responsible for skin infections. Invasive Exophiala dermatitidis disease is a rare and frequently fatal infection, with 42 cases reported. About half of these cases had no known risk factors. Similarly, invasive Exophiala spinifera disease is extremely rare, with only 3 cases reported, all in patients with no known immunodeficiency. Autosomal recessive CARD9 deficiency has recently been reported in otherwise healthy patients with severe fungal diseases caused by Candida species, dermatophytes, or Phialophora verrucosa.

Materials and Methods: We investigated an 8-year-old girl froma nonconsanguineous Angolan kindred, whowas born in France and developed disseminated E. dermatitidis disease and a 26 year-old woman from an Iranian consaguineous kindred, who was living in Iran and developed disseminated E. spinifera disease. Both patients were otherwise healthy.

Results: We sequenced CARD9 and found both patients to be homozygous for loss-of-function mutations (R18W and E323del). The first patient had segmental uniparental disomy of chromosome 9, carrying 2 copies of the maternal CARD9 mutated allele.

Conclusions: These are the first 2 patients with inherited CARD9 deficiency and invasive Exophiala disease to be described. CARD9 deficiency should thus be considered in patients with unexplained invasive Exophiala species disease, even in the absence of other infections.
Keywords: Exophiala species; invasive fungal infection; central nervous system; osteomyelitis; autosomal recessive CARD9 deficiency; parental unidisomy

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J Infect Dis. 2015 Apr 15;211(8):1241-50