Clinical Pearls & Morning Reports
Immunodeficiency is not typically associated with rare and unusual infections; rather, it is associated with infections that often go unnoticed because they are controlled by normal immunity. Thus, invasive, severe, or persistent infections with low-grade pathogens are characteristic of immunodeficiency. Read the latest Case Record of the Massachusetts General Hospital.
Q. Are nontuberculous mycobacteria generally pathogenic?
A. The number of species of nontuberculous (environmental) mycobacteria, which is currently higher than 150, is increasing; these species are overwhelmingly nonpathogenic.
Q. What is known about the genetic susceptibility to nontuberculous mycobacterial infection?
A. At least 10 genes that control susceptibility to nontuberculous mycobacterial infection have been identified, most of which are directly involved in the synthesis and response pathways of interferon-γ and interleukin-12. Depending on the specific mutation, the inheritance of a disorder caused by a mutation in one of these genes can be autosomal recessive, autosomal dominant, or X-linked. Six autosomal dominant genes that increase susceptibility to nontuberculous mycobacterial infection are IRF8, GATA2, IKBKB (NEMO), IFNGR1, IFNGR2, and STAT1.
A: Complete loss-of-function recessive mutations in IFNGR1 typically lead to severe disseminated disease early in life, especially among those who receive the bacille Calmette–Guérin (BCG) vaccine. In patients with dominant IFNγR1 deficiency, mycobacterial infections are typically limited to infections with BCG and slow-growing mycobacteria, such as M. avium complex. For reasons that are unclear, autosomal dominant IFNγR1 deficiency is very commonly associated with nontuberculous mycobacterial osteomyelitis. It is important to remember that the same intracellular killing defect that is caused by this immunodeficiency also confers a predisposition to salmonellosis and endemic mycoses, such as coccidioidomycosis and histoplasmosis.
A: Many patients with IFNγR1 deficiency have a mutation in exon 6 of IFNGR1, which causes a truncation that removes the signal transduction and receptor recycling domains and thus leads to autosomal dominant IFNγR1 deficiency. The most common mutation is 818del4, but several other mutations that occur around the same region yield similar phenotypes. To confirm this diagnosis, the simplest test would be flow cytometry to detect surface expression of IFNγR1 (CD119) on monocytes; the expression of CD119 is characteristically 5 to 10 times as high in a patient with autosomal dominant IFNγR1 deficiency as in an unaffected patient. The most definitive diagnostic test would be DNA sequencing of IFNGR1 exon 6, which is the region in which the majority of mutations that cause this dominant disease are found.