Inherited CARD9 deficiency in 2 unrelated patients with invasive Exophiala infection

J Infect Dis. 2015 Apr 15;211(8):1241-50. doi: 10.1093/infdis/jiu412.

Fanny Lanternier ¹, Elisa Barbati ², Ulrich Meinzer ³, Luyan Liu ², Vincent Pedergnana ², Mélanie Migaud ², Sébastien Héritier ⁴, Maryline Chomton ⁴, Marie-Louise Frémond ⁴, Emmanuel Gonzales ⁵, Caroline Galeotti ⁶, Serge Romana ⁷, Emmanuel Jacquemin ⁵, Adela Angoulvant ⁸, Valeska Bidault ⁹, Danielle Canioni ¹⁰, Julie Lachenaud ¹¹, Davood Mansouri ¹², Seyed Alireza Mahdaviani ¹³, Parvaneh Adimi ¹⁴, Nahal Mansouri ¹², Mahin Jamshidi ¹⁵, Marie-Elisabeth Bougnoux ¹⁶, Laurent Abel ¹⁷, Olivier Lortholary ¹⁸, Stéphane Blanche ⁴, Jean-Laurent Casanova ¹⁹, Capucine Picard ²⁰, Anne Puel ²

Affiliations

1 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163 Paris Descartes University-Sorbonne Paris Cité, Imagine Institute Department of Infectious Diseases, Necker-Enfants malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Centre d'Infectiologie Necker Pasteur.
2 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163 Paris Descartes University-Sorbonne Paris Cité, Imagine Institute.
3 Department of General Pediatrics and Internal Medicine, Robert Debré Hospital, AP-HP University Paris 7 Denis Diderot, Paris Sorbonne Cité
4 Paris Descartes University-Sorbonne Paris Cité, Imagine Institute Pediatric Hematology-Immunology Unit.
5 Pediatric Hepatology Unit, DHU Hépatinov, INSERM U757, Paris-Sud 11 University, Bicêtre Hospital, AP-HP.
6 Pediatric Rheumatology Unit, Bicêtre Hospital, AP-HP, Paris Sud University, CeReMAI.
7 Histology, Embryology, and Cytogenetics Unit.
8 Mycology Laboratory.
9 Pediatric Surgery Unit, Bicêtre Hospital, AP-HP, Kremlin Bicêtre.
10 Pathology Unit.
11 Department of Pediatrics, Pontoise Hospital, Cergy Pontoise, France, EU.
12 Department of Clinical Immunology and Allergy, National Research Institute of Tuberculosis and Lung Diseases, Masih Daneshvari Hospital.
13 Pediatric Respiratory Disease Research Centre, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences.
14 Department of Medical Mycology and Parasitology, Islamic Azad University Tehran Medical Branch.
15 Department of Infectious Disease, Iran University of Medical Sciences, Tehran, Iran.
16 Paris Descartes University-Sorbonne Paris Cité, Imagine Institute Microbiology Laboratory Fungal Biology and Pathogenicity, INRA USC 2019, Institut Pasteur.
17 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163 Paris Descartes University-Sorbonne Paris Cité, Imagine Institute St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York.
18 Paris Descartes University-Sorbonne Paris Cité, Imagine Institute Department of Infectious Diseases, Necker-Enfants malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Centre d'Infectiologie Necker Pasteur Molecular Mycology Unit, National Reference Center for Invasive Mycoses and Antifungals, Institut Pasteur, Paris.
19 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163 Paris Descartes University-Sorbonne Paris Cité, Imagine Institute Pediatric Hematology-Immunology Unit St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York.
20 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163 Paris Descartes University-Sorbonne Paris Cité, Imagine Institute Pediatric Hematology-Immunology Unit Study Center for Primary Immunodeficiencies, Necker-Enfants malades Hospital, AP-HP.

PMID: 25057046 DOI: 10.1093/infdis/jiu412

Abstract

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.

Methods: We investigated an 8-year-old girl from a nonconsanguineous Angolan kindred, who was 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; autosomal recessive CARD9 deficiency; central nervous system; invasive fungal infection; osteomyelitis; parental unidisomy.

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