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Expanding the Clinical and Genetic Spectrum of Human CD40L Deficiency: The Occurrence of Paracoccidioidomycosis and Other Unusual Infections in Brazilian Patients

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Abstract

CD40 ligand (CD40L) deficiency or X-linked hyper-IgM syndrome (X-HIGM) is a well-described primary immunodeficiency in which Pneumocystis jiroveci pneumonia is a common clinical feature. We have identified an unusual high incidence of fungal infections and other not yet described infections in a cohort of 11 X-HIGM patients from nine unrelated Brazilian families. Among these, we describe the first case of paracoccidioidomycosis (PCM) in X-HIGM. The molecular genetic analysis of CD40L was performed by gene sequencing and evaluation of CD40L protein expression. Nine of these 11 patients (82%) had fungal infections. These included fungal species common to CD40L deficiency (P. jiroveci and Candida albicans) as well as Paracoccidioides brasiliensis. One patient presented with PCM at age 11 years and is now doing well at 18 years of age. Additionally, one patient presented with a simultaneous infection with Klebsiella and Acinetobacter, and one with condyloma caused by human papilloma virus. Molecular analysis revealed four previously described CD40L mutations, two novel missense mutations (c.433 T > G and c.476 G > C) resulting in the absence of CD40L protein expression by activated CD4+ cells and one novel insertion (c.484_485insAA) within the TNFH domain leading to a frame shift and premature stop codon. These observations demonstrated that the susceptibility to fungal infections in X-HIGM extends beyond those typically associated with X-HIGM (P. jiroveci and C. albicans) and that these patients need to be monitored for those pathogens.

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Acknowledgments

The authors thank FAPESP (grant 2008/06635-0 to OCM and grant 2008/55700-9 to ACN), CNPq, and Jeffrey Modell Foundation for financial support and the patients and their families for their participation in this study.

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Authors and Affiliations

  1. Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, 1730 Lineu Prestes Avenue, São Paulo, São Paulo, ZIP 05508-000, Brazil

    Otavio Cabral-Marques, Lena-Friederike Schimke, Paulo Vítor Soeiro Pereira, Angela Falcai, Paolo Ruggero Errante & Antonio Condino-Neto

  2. Department of Pediatrics, University of Washington School of Medicine and Seattle Children’s Hospital, Seattle, WA, USA

    Mary J. Hackett, Hans D. Ochs & Troy R. Torgerson

  3. Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA

    João Bosco de Oliveira

  4. Pediatric Allergy & Immunology Clinic, Caxias do Sul, Rio Grande do Sul, Brazil

    Cristina Worm Weber

  5. Albert Sabin Hospital, Fortaleza, Ceará, Brazil

    Janaíra Fernandes Ferreira

  6. Pequeno Príncipe Hospital, Curitiba, Paraná, Brazil

    Gisele Kuntze

  7. Department of Pediatrics, Federal University of Paraná Medical School, Curitiba, Paraná, Brazil

    Nelson Augusto Rosário-Filho

  8. Division of Allergy and Clinical Immunology and Rheumatology, Department of Pediatrics, Federal University of São Paulo Medical School, São Paulo, São Paulo, Brazil

    Beatriz Tavares Costa Carvalho

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  1. Otavio Cabral-Marques
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Cabral-Marques, O., Schimke, LF., Pereira, P.V.S. et al. Expanding the Clinical and Genetic Spectrum of Human CD40L Deficiency: The Occurrence of Paracoccidioidomycosis and Other Unusual Infections in Brazilian Patients. J Clin Immunol 32, 212–220 (2012). https://doi.org/10.1007/s10875-011-9623-6

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