title: Expanding the clinical and genetic spectrum of human CD40L deficiency: the occurrence of paracoccidioidomycosis and other unusual infections in Brazilian patients.
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.
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, São Paulo ZIP 05508-000, Brazil.
authors.forename: Otavio
authors.initials: O
authors.lastname: Cabral-Marques
authors.forename: Lena-Friederike
authors.initials: LF
authors.lastname: Schimke
authors.forename: Paulo Vítor Soeiro
authors.initials: PV
authors.lastname: Pereira
authors.forename: Angela
authors.initials: A
authors.lastname: Falcai
authors.forename: João Bosco
authors.initials: JB
authors.lastname: de Oliveira
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Hackett
authors.forename: Paolo Ruggero
authors.initials: PR
authors.lastname: Errante
authors.forename: Cristina Worm
authors.initials: CW
authors.lastname: Weber
authors.forename: Janaíra Fernandes
authors.initials: JF
authors.lastname: Ferreira
authors.forename: Gisele
authors.initials: G
authors.lastname: Kuntze
authors.forename: Nelson Augusto
authors.initials: NA
authors.lastname: Rosário-Filho
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.forename: Troy R
authors.initials: TR
authors.lastname: Torgerson
authors.forename: Beatriz Tavares Costa
authors.initials: BT
authors.lastname: Carvalho
authors.forename: Antonio
authors.initials: A
authors.lastname: Condino-Neto
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D001483:Base Sequence; D001938:Brazil / Q000453:epidemiology; D023201:CD40 Ligand / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D006801:Humans; D053307:Hyper-IgM Immunodeficiency Syndrome, Type 1 / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D007132:Immunoglobulin Isotypes / Q000097:blood / Q000276:immunology; D015994:Incidence; D007223:Infant; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010229:Paracoccidioidomycosis / Q000150:complications* / Q000453:epidemiology / Q000473:pathology; D010375:Pedigree; D016415:Sequence Alignment; D055815:Young Adult
chemical_list: D007132:Immunoglobulin Isotypes; D023201:CD40 Ligand