P2.L233: Looking Past the Interference: Toddler with Persistent Fever, Rash, and Lymphadenopathy

Introduction: Interferon-gamma (IFN-G) signaling is critical for innate immune protection against mycobacterium and other intracellular pathogens, such as salmonella, histoplasma, or toxoplasma. Immunodeficiencies involving mutations in any part of the IFN-G signaling pathway result in increased susceptibility to these infections. We outline a case of a 12-month-old, fully vaccinated male who was ultimately diagnosed with a mutation in his IFNGR1 gene causing disruptions in IFN-G signaling.

Case Description: The patient presented with 5 days of rash and 6 weeks of intermittent fever. He had been admitted 2 weeks prior with lymphadenitis. Review of systems was positive for persistent lymphadenopathy, diarrhea, and decreased appetite. He was febrile and tachycardic on admission. The physical exam was notable for a diffuse, vesicular, ulcerating rash with scattered vesicles in different stages of healing affecting the face, extremities, lips, palms, and soles. Erythema was present around both eyes. A persistent 1.5cm violaceous, indurated, non-tender right preauricular lymph node was present. The patient’s extensive rash, prolonged fever, and persistent lymphadenopathy did not respond to several antibiotic trials, prompting further infectious and autoimmune workup. Initial labs were notable for CRP of 14.56 mg/dL, leukocytosis to 30 THOU/uL with neutrophilic predominance, and thrombocytosis to 567 THOU/uL. Abdominal ultrasound revealed splenomegaly. Due to ongoing illness and atypical presentation, dermatology, immunology, and hematology/oncology were consulted. Blood culture, wound culture, herpes simplex virus (HSV), and varicella-zoster virus (VZV) cultures were negative. Flow cytometry was unrevealing. Lymphocyte subsets, immunoglobulin profile, and vaccine titers were reassuring. The lymph node biopsy results from the first admission were positive for non-tuberculous mycobacterium avium-intracellulare complex. Gene sequencing was sent, and the patient was ultimately diagnosed with a pathogenic heterozygous mutation in IFNGR1 gene.

Discussion: After admission for non-tuberculous mycobacterium following a positive PPD and a negative chest x-ray, our patient was readmitted to the hospital 2 weeks later with rash, continued fevers, splenomegaly, and worsening leukocytosis. The initial differential diagnosis included VZV, coxsackievirus, HSV, and disseminated mycobacterial infection. There was significant concern for immunodeficiency as the underlying cause of the patient’s presentation given the patients recurrent infections and fevers, vaccination status, and presence of atypical pathogens. Genetic testing by the immune dysregulation team revealed an autosomal dominant pathogenic variant in the IFNGR1 gene. The IFNGR1 gene encodes the ligand-binding chain for the interferon-gamma (IFN-G) receptor, and mutations are associated with a susceptibility to mycobacterial disease. The patient started treatment with IFN-G-1B (Actimmune) replacement therapy. He may need a future stem cell replacement if treatment is unsuccessful.

Conclusion: This case highlights the importance of the timely identification of atypical pathogens, recognition of immunodeficiencies in patients, and connection with sub-specialty services for appropriate highly specialized treatment.