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

Author(s):Show less -

Cabral-Marques, Otavio ^[1] ; Schimke, Lena-Friederike ^[1] ; Soeiro Pereira, Paulo Vitor ^[1] ; Falcai, Angela ^[1] ; de Oliveira, Joao Bosco ^[2] ; Hackett, Mary J. ^[3] ; Errante, Paolo Ruggero ^[1] ; Weber, Cristina Worm ^[4] ; Ferreira, Janaira Fernandes ^[5] ; Kuntze, Gisele ^[6] ; Rosario-Filho, Nelson Augusto ^[7] ; Ochs, Hans D. ^[3] ; Torgerson, Troy R. ^[3] ; Costa Carvalho, Beatriz Tavares ^[8] ; Condino-Neto, Antonio ^[1]

Affiliation

^[1] Univ Sao Paulo, Dept Immunol, Inst Biomed Sci, BR-05508000 Sao Paulo - Brazil

^[2] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 - USA

^[3] Univ Washington, Dept Pediat, Sch Med & Seattle, Childrens Hosp, Seattle, WA 98195 - USA

^[4] Pediat Allergy & Immunol Clin, Caxias Do Sul, RS - Brazil

^[5] Albert Sabin Hosp, Fortaleza, Ceara - Brazil

^[6] Pequeno Principe Hosp, Curitiba, Parana - Brazil

^[7] Univ Fed Parana, Dept Pediat, Sch Med, BR-80060000 Curitiba, Parana - Brazil

^[8] Univ Fed Sao Paulo, Div Allergy & Clin Immunol & Rheumatol, Dept Pediat, Sch Med, Sao Paulo - Brazil

• Document type: Journal article
• Source: JOURNAL OF CLINICAL IMMUNOLOGY; v. 32, n. 2, p. 212-220, APR 2012.
• Web of Science Citations: 24

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. (AU)