Mycobacterial infections and recurrent osteomyelitis in a patient with an autosomal dominant mutation in IFN-gamma receptor 1 with overexpression of the receptor.

Mutations in genes controlling IFN-γ production or signaling underlie Mendelian susceptibility to mycobacterial disease (MSMD) and predispose affected individuals to mycobacterial and other infections. Autosomal dominant (AD) mutations in exon VI of IFNGR1, which encodes interferon-γ receptor 1 (IFN-γR1), have been associated with multifocal osteomyelitis. We report a Mexican male patient whose clinical course began with severe BCGitis at 2 years of age, followed by tuberculous lymphadenitis at age 3, disseminated tuberculosis with hepatitis at age 10, and disseminated Mycobacterium bovis infection with vertebral osteomyelitis at age 19. Subsequent manifestations included HPV-associated warts at age 21, pneumonia and vertebral osteomyelitis associated with M. colombiense at age 25, mesenteric fibrosis, hepatic abscesses, vertebral osteomyelitis associated with M. avium at age 28, and pneumonia associated with M. fortuitum at age 30. The patient responded to prolonged antimycobacterial therapy. Functional studies demonstrated deficient IL-12p40 production following BCG plus IFN-γ stimulation, impaired Stat-1 phosphorylation in response to IFN-γ, and increased cell-surface expression of CD119/IFN-γR1. Sanger sequencing identified the heterozygous IFNGR1 c.805delT (p.Tyr269Ilefs*8) variant in the patient but not in his parents, consistent with a de novo event. This truncating variant leads to cell-surface accumulation of a defective IFN-γR1 and exerts a dominant-negative effect on IFN-γ signaling. This case, together with our literature review, supports an association between impaired IFN-γ signaling due to AD IFNGR1 variants and susceptibility to recurrent infectious osteomyelitis.