title: Bacille Calmette-Guérin infection and disease with fatal outcome associated with a point mutation in the interleukin-12/interleukin-23 receptor beta-1 chain in two Mexican families.
abstract: Patients with Mendelian susceptibility to mycobacterial diseases (MSMD) mainly suffer from Mycobacterium and Salmonella infections, which are due to mutations in genes controlling the interleukin (IL)-12/IL-23-dependent IFN-γ production. We performed a molecular diagnosis in two Mexican patients with persistent mycobacterial infections. Patients 1 (P1) and 2 (P2) from two unrelated, non-consanguineous families from two villages near Mexico City developed bacille Calmette-Guérin (BCG) disease secondary to vaccination; patients and their families were studied at the immunological level for production and response to IFN-γ. The β1 subunit of the IL-12 receptor (encoded by the IL12RB1 gene) was not expressed in cells from P1 or P2, or in two siblings of P1. Sequencing of the IL12RB1 gene showed the same point mutation 1791+2 T>G, homozygous in patients and heterozygous in parents. P1 and P2 died at the ages of 4 and 16 years, respectively, with disseminated and uncontrolled BCG disease and with Candida albicans infections in spite of multiple anti-mycobacterial drug treatments. One of P2's siblings also died following disseminated mycobacterial infection secondary to BCG vaccination. These are the first cases in Mexico of patients with BCG disease traced to a mutation in the IL12RB1 gene, with a fatal outcome. Doctors must be alert to the adverse reactions to BCG vaccination and to persistent Mycobacterium infections, and in such cases should investigate possible mutations in the genes of the IL-12/IL-23-IFN-γ axis.
authors.affiliation: Department of Biochemistry, National Institute for Medical Sciences and Nutrition Salvador Zubirán, Vasco de Quiroga 15, Delegación Tlalpan, Mexico. spedraza@rocketmail.com
authors.forename: Sigifredo
authors.initials: S
authors.lastname: Pedraza-Sánchez
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Herrera-Barrios
authors.forename: Ruth
authors.initials: R
authors.lastname: Aldana-Vergara
authors.forename: Milagros
authors.initials: M
authors.lastname: Neumann-Ordoñez
authors.forename: Yolanda
authors.initials: Y
authors.lastname: González-Hernández
authors.forename: Eduardo
authors.initials: E
authors.lastname: Sada-Díaz
authors.forename: Ludovic
authors.initials: L
authors.lastname: de Beaucoudrey
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Martha
authors.initials: M
authors.lastname: Torres-Rojas
mesh_terms: D000293:Adolescent; D001500:BCG Vaccine / Q000009:adverse effects; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D008800:Mexico; D009163:Mycobacterium bovis / Q000472:pathogenicity*; D010375:Pedigree; D017354:Point Mutation; D053707:Receptors, Interleukin-12 / Q000235:genetics*; D014376:Tuberculosis / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000382:microbiology
chemical_list: D001500:BCG Vaccine; C508438:IL12RB1 protein, human; D053707:Receptors, Interleukin-12; D007371:Interferon-gamma