Format

Send to

Choose Destination
J Clin Immunol. 2019 Jul;39(5):462-469. doi: 10.1007/s10875-019-00662-z. Epub 2019 Jun 20.

Successful Allogenic Stem Cell Transplantation in Patients with Inherited CARD9 Deficiency.

Author information

1
Department of Public Health, Federal University of Parana, Curitiba, Brazil.
2
Infectious Diseases Unit, Hospital de Clinicas, Federal University of Parana, Curitiba, Brazil.
3
Department of Haematology, University Hospitals Leuven, Leuven, Belgium.
4
Bone Marrow Transplant Unit, Hospital de Clinicas, Federal University of Parana, Curitiba, Brazil.
5
Imagine Institute, Paris Descartes University, 75015, Paris, France.
6
Clinical Immunology, Faculdade de Medicina ABC, Av Lauro Gomes 2000, Santo Andre, Sao Paulo, 09060-870, Brazil.
7
Department of Medical Mycology, Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands.
8
Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital (CWZ), Nijmegen, The Netherlands.
9
Centre of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands.
10
Carlos Chagas Institute, Oswaldo Cruz Foundation(Fiocruz), Curitiba, Brazil.
11
National Institute of Science and Technology (INCT) of Inovation in Neglected Diseases, Curitiba, Brazil.
12
Department of Pediatrics, Federal University of Parana, Curitiba, Brazil.
13
Unite de Mycologie Moleculaire, Institut Pasteur, CNRS URA3012, Paris, France.
14
Centre National de Référence Mycoses invasives et Antifongiques, Institut Pasteur, Paris, France.
15
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015, Paris, France.
16
Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
17
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, 10065, USA.
18
Howard Hughes Medical Institute, New York, NY, 10065, USA.
19
Clinical Immunology, Faculdade de Medicina ABC, Av Lauro Gomes 2000, Santo Andre, Sao Paulo, 09060-870, Brazil. asgrumach@gmail.com.

Abstract

Autosomal recessive (AR) CARD9 (caspase recruitment domain-containing protein 9) deficiency underlies invasive infections by fungi of the ascomycete phylum in previously healthy individuals at almost any age. Although CARD9 is expressed mostly by myeloid cells, the cellular basis of fungal infections in patients with inherited CARD9 deficiency is unclear. Therapy for fungal infections is challenging, with at least 20% premature mortality. We report two unrelated patients from Brazil and Morocco with AR CARD9 deficiency, both successfully treated with hematopoietic stem cell transplantation (HSCT). From childhood onward, the patients had invasive dermatophytic disease, which persisted or recurred despite multiple courses of antifungal treatment. Sanger sequencing identified homozygous missense CARD9 variants at the same residue, c.302G>T (p.R101L) in the Brazilian patient and c.301C>T (p.R101C) in the Moroccan patient. At the ages of 25 and 44 years, respectively, they received a HSCT. The first patient received a HLA-matched HSCT from his CARD9-mutated heterozygous sister. There was 100% donor chimerism at D + 100. The other patient received a T cell-depleted haploidentical HSCT from his CARD9-mutated heterozygous brother. A second HSCT from the same donor was performed due to severe amegakaryocytic thrombocytopenia despite achieving full donor chimerism (100%). At last follow-up, more than 3 years after HSCT, both patients have achieved complete clinical remission and stopped antifungal therapy. HSCT might be a life-saving therapeutic option in patients with AR CARD9 deficiency. This observation strongly suggests that the pathogenesis of fungal infections in these patients is largely due to the disruption of leukocyte-mediated CARD9 immunity.

KEYWORDS:

CARD9; deep dermatophytosis; hematopoietic stem cell transplantation; invasive dermatophytic disease; primary immunodeficiency

PMID:
31222666
DOI:
10.1007/s10875-019-00662-z

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center