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Journal of Clinical Immunology

, Volume 39, Issue 5, pp 462–469 | Cite as

Successful Allogenic Stem Cell Transplantation in Patients with Inherited CARD9 Deficiency

  • F. Queiroz-Telles
  • T. Mercier
  • J. Maertens
  • C. B. S. Sola
  • C. Bonfim
  • O. Lortholary
  • R. M. N. Constantino-Silva
  • R. Schrijvers
  • F. Hagen
  • J. F. Meis
  • P. F. Herkert
  • G. L. Breda
  • J. B. França
  • N. A. Rosario Filho
  • F. Lanternier
  • J. L. Casanova
  • A. Puel
  • Anete S. GrumachEmail author
Original Article

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 primary immunodeficiency deep dermatophytosis hematopoietic stem cell transplantation invasive dermatophytic disease 

Notes

Authorship Contributions

FQT and ASG were involved in all steps of the report; TM, JM, RMNCS, RS, FH, JFM, PFH, GLC, JBF, and NARF were involved in the patients’ care and immunologic evaluation before and after HSCT; TM, JM, CBSS, and CB were responsible for HSCT; FH, JFM, and PFH performed the microbiologic and molecular identification of the isolates; OL, FL, JLC, and AP were responsible for critical revision and previous discussion about the directions for therapy. All the authors revised the manuscript and agreed before submitting to the journal.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • F. Queiroz-Telles
    • 1
    • 11
  • T. Mercier
    • 2
  • J. Maertens
    • 2
  • C. B. S. Sola
    • 3
  • C. Bonfim
    • 3
  • O. Lortholary
    • 4
  • R. M. N. Constantino-Silva
    • 5
  • R. Schrijvers
    • 2
  • F. Hagen
    • 6
    • 7
  • J. F. Meis
    • 7
    • 8
  • P. F. Herkert
    • 9
    • 10
  • G. L. Breda
    • 11
  • J. B. França
    • 11
  • N. A. Rosario Filho
    • 12
  • F. Lanternier
    • 13
    • 14
    • 15
  • J. L. Casanova
    • 4
    • 15
    • 16
    • 17
    • 18
  • A. Puel
    • 4
    • 15
    • 17
  • Anete S. Grumach
    • 5
    Email author
  1. 1.Department of Public HealthFederal University of ParanaCuritibaBrazil
  2. 2.Department of HaematologyUniversity Hospitals LeuvenLeuvenBelgium
  3. 3.Bone Marrow Transplant Unit, Hospital de ClinicasFederal University of ParanaCuritibaBrazil
  4. 4.Imagine InstituteParis Descartes UniversityParisFrance
  5. 5.Clinical ImmunologyFaculdade de Medicina ABCSanto AndreBrazil
  6. 6.Department of Medical MycologyWesterdijk Fungal Biodiversity InstituteUtrechtThe Netherlands
  7. 7.Department of Medical Microbiology and Infectious DiseasesCanisius-Wilhelmina Hospital (CWZ)NijmegenThe Netherlands
  8. 8.Centre of Expertise in Mycology Radboudumc/CWZNijmegenThe Netherlands
  9. 9.Carlos Chagas InstituteOswaldo Cruz Foundation(Fiocruz)CuritibaBrazil
  10. 10.National Institute of Science and Technology (INCT) of Inovation in Neglected DiseasesCuritibaBrazil
  11. 11.Infectious Diseases Unit, Hospital de ClinicasFederal University of ParanaCuritibaBrazil
  12. 12.Department of PediatricsFederal University of ParanaCuritibaBrazil
  13. 13.Unite de Mycologie MoleculaireInstitut PasteurParisFrance
  14. 14.Centre National de Référence Mycoses invasives et AntifongiquesInstitut PasteurParisFrance
  15. 15.Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163Necker Hospital for Sick ChildrenParisFrance
  16. 16.Pediatric Hematology and Immunology UnitNecker Hospital for Sick Children, AP-HPParisFrance
  17. 17.St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller BranchThe Rockefeller UniversityNew YorkUSA
  18. 18.Howard Hughes Medical InstituteNew YorkUSA

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