Recombinant IFN-1b Treatment in a Patient with Inherited IFN- Deficiency

Purpose: Inborn errors of IFN-gamma immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Twenty-two genes with products involved in the production of, or response to, IFN-gamma and variants of which underlie MSMD have been identified. However, pathogenic variants of IFNG encoding a defective IFN-gamma have been described in only two siblings, who both underwent hematopoietic stem cell transplantation (HCST). Methods: We characterized a new patient with MSMD by genetic, immunological, and clinical means. Therapeutic decisions were taken on the basis of these findings. Results: The patient was born to consanguineous Turkish parents and developed bacillus Calmette-Gu & eacute;rin (BCG) disease following vaccination at birth. Whole-exome sequencing revealed a homozygous private IFNG variant (c.224 T > C, p.F75S). Upon overexpression in recipient cells or constitutive expression in the patient's cells, the mutant IFN-gamma was produced within the cells but was not correctly folded or secreted. The patient was treated for 6 months with two or three antimycobacterial drugs only and then for 30 months with subcutaneous recombinant IFN-gamma 1b plus two antimycobacterial drugs. Treatment with IFN-gamma 1b finally normalized all biological parameters. The patient presented no recurrence of mycobacterial disease or other related infectious diseases. The treatment was well tolerated, without the production of detectable autoantibodies against IFN-gamma. Conclusion: We describe a patient with a new form of autosomal recessive IFN-gamma deficiency, with intracellular, but not extracellular IFN-gamma. IFN-gamma 1b treatment appears to have been beneficial in this patient, with no recurrence of mycobacterial infection over a period of more than 30 months. This targeted treatment provides an alternative to HCST in patients with complete IFN-gamma deficiency or at least an option to better control mycobacterial infection prior to HCST.