ABSTRACT
We report a series of 14 patients from 11 kindreds with recessive partial (RP)-interferon (IFN)-γR1 deficiency. The I87T mutation was found in nine homozygous patients from Chile, Portugal and Poland, and the V63G mutation was found in five homozygous patients from the Canary Islands. Founder effects accounted for the recurrence of both mutations. The most recent common ancestors of the patients with the I87T and V63G mutations probably lived 1600 (875-2950) and 500 (200-1275) years ago, respectively. The two alleles confer phenotypes that are similar but differ in terms of IFN-γR1 levels and residual response to IFN-γ. The patients suffered from bacillus Calmette-Guérin-osis (n= 6), environmental mycobacteriosis (n= 6) or tuberculosis (n= 1). One patient did not suffer from mycobacterial infections but had disseminated salmonellosis, which was also present in two other patients. Age at onset of the first environmental mycobacterial disease differed widely between patients, with a mean value of 11.25 ± 9.13 years. Thirteen patients survived until the age of 14.82 ± 11.2 years, and one patient died at the age of 7 years, 9 days after the diagnosis of long-term Mycobacterium avium infection and the initiation of antimycobacterial treatment. Up to 10 patients are currently free of infection with no prophylaxis. The clinical heterogeneity of the 14 patients was not clearly related to either IFNGR1 genotype or the resulting cellular phenotype. RP-IFN-γR1 deficiency is, thus, more common than initially thought and should be considered in both children and adults with mild or severe mycobacterial diseases.
Subject(s)
Genetic Predisposition to Disease , Mycobacterium Infections/genetics , Receptors, Interferon/deficiency , Adolescent , Adult , Amino Acid Sequence , Child , Child, Preschool , Female , Founder Effect , Genes, Recessive , Haplotypes , Humans , Interferon-gamma/metabolism , Male , Molecular Sequence Data , Monocytes/metabolism , Mutation, Missense , Mycobacterium Infections/immunology , Mycobacterium Infections/microbiology , Mycobacterium avium , Mycobacterium bovis , Osteomyelitis/genetics , Osteomyelitis/microbiology , Pedigree , Phenotype , Phosphorylation , Pneumonia, Bacterial/genetics , Protein Transport , Receptors, Interferon/genetics , Receptors, Interferon/immunology , STAT1 Transcription Factor/metabolism , Salmonella , Salmonella Infections/genetics , Tuberculosis/genetics , Tuberculosis/microbiology , Tuberculosis/mortality , Young Adult , Interferon gamma ReceptorABSTRACT
Genetic defects in the IL-12-IL-23/IFN-gamma circuit confer Mendelian susceptibility to mycobacteria and salmonella. The IL-12/IFN-gamma axis is essential for anti-tumoral immunity in mice. Cancer susceptibility has not been recognised in these patients so far. We report three relatives with IL-12R beta 1 deficiency. At the age of 25 years old, one patient presented with oesophageal squamous cell carcinoma (OSCC). The patient had no previous risk factors for OSCC. He died at the age of 29 years. OSCC is exceedingly rare in individuals under 30 years and frequently relates to alcohol intake and smoking. Disorders of the IL-12-IL-23/IFN-gamma axis may predispose to cancer.
Subject(s)
Carcinoma, Squamous Cell/metabolism , Esophageal Neoplasms/metabolism , Receptors, Interleukin-12/deficiency , Adolescent , Adult , Carcinoma, Squamous Cell/pathology , Child , Esophageal Neoplasms/pathology , Fatal Outcome , Female , Humans , Male , Receptors, Interleukin-12/metabolism , Young AdultABSTRACT
We report a kindred with autosomal recessive interleukin-1 receptor-associated kinase 4 (IRAK-4) deficiency in 3 fourth-degree relatives. A diagnosis of IRAK-4 deficiency should be considered in families with invasive bacterial disease, even if the individuals affected are only distantly related, which falsely suggests multigenic or dominant inheritance with low penetrance.
