Homozygous ISG15 Deletion in a Patient with Recurrent Encephalitis, BCGitis, and Severe Infections

Introduction ISG15 encodes an interferon-stimulated ubiquitin-like modifier essential for the type I interferon signaling pathway. Biallelic ISG15 mutations have been associated with susceptibility to mycobacterial infections, as well as autoinflammatory manifestations. Case Presentation We describe a 23-year-old woman who has presented with BCGitis following routine neonatal vaccination. Throughout childhood, she experienced recurrent episodes of life-threatening infections and two episodes of encephalitis of unknown etiology, both requiring intensive care admission. At age 22, she developed severe COVID-19 pneumonia. Additional clinical features included seizures and persistent leukopenia. Immunological assessment included lymphopenia, low serum IgM, and reduced circulating memory B cells. Despite intensive care, the patient died from severe neurological complications. Whole exome sequencing identified a likely pathogenic homozygous deletion in ISG15 (c.299_312delTGACGCAGACCGTG; p.Leu100fs), predicted to disrupt protein stability and ISGylation function. Segregation analysis is currently underway. Discussion This case expands the clinical spectrum of ISG15 deficiency, illustrating its association with severe viral infections, BCGitis, and fatal neurological involvement. Although ISG15 is not a classical considered antiviral effector, it plays a pivotal role in modulating type I interferon responses. The patient's recurrent encephalitis and severe COVID-19 pneumonia likely reflect an exaggerated type I IFN-mediated inflammatory response. Conclusion Homozygous ISG15 mutations should be considered in patients with Bacillus Calmette–Guérin (BCG)-related complications, recurrent infections, and unexplained central nervous system inflammation. Early genetic diagnosis may facilitate prompt consideration of IFN-targeted therapies such as JAK inhibitors.