Autosomal recessive IRF8 deficiency results in a life-threatening pediatric syndrome characterized by monocyte and dendritic cell deficiency, myeloproliferation, and susceptibility to severe opportunistic infections, including disseminated BCG infection and oral candidiasis (Hambleton et al., 2011).
Hambleton et al. (2011) reported an Irish female infant of nonconsanguineous parents who presented at 10 weeks old with failure to thrive, oral candidiasis, and early-onset disseminated BCG disease. The authors noted florid myeloproliferation. The infant had a ... Hambleton et al. (2011) reported an Irish female infant of nonconsanguineous parents who presented at 10 weeks old with failure to thrive, oral candidiasis, and early-onset disseminated BCG disease. The authors noted florid myeloproliferation. The infant had a profound deficit of tissue dendritic cells and blood dendritic cells and monocytes, along with a variable deficit of tissue macrophages and normal numbers of Langherans cells. She gradually improved with antimycobacterial and antibacterial therapy. However, at the age of 6 months, she exhibited respiratory failure and fever and deteriorated further, and only rhinovirus was present in respiratory secretions. The infant underwent hematopoietic stem cell transplantation and was well 12 months post-transplant, with minimal medication and moderate developmental delay.
In the Irish infant they reported with autosomal recessive monocyte and dendritic cell deficiency, myeloproliferation, and susceptibility to severe opportunistic infections, Hambleton et al. (2011) identified a homozygous lys108-to-glu (K108E; 601565.0001) mutation in the DNA-binding domain of IRF8. ... In the Irish infant they reported with autosomal recessive monocyte and dendritic cell deficiency, myeloproliferation, and susceptibility to severe opportunistic infections, Hambleton et al. (2011) identified a homozygous lys108-to-glu (K108E; 601565.0001) mutation in the DNA-binding domain of IRF8. In transfected mouse macrophages, the mutant protein bound poorly to IL12B (161561) and NOS2 (163730) promoters, probably due to prevention of hydrogen bond formation. The infant's healthy parents, who were heterozygous for K108E, and an unaffected sib, who lacked the K108E allele, had normal peripheral blood mononuclear cell and dendritic cell numbers. The K108E mutation was not present in 454 unrelated individuals with susceptibility to mycobacterial disease (see 209950).