The CEBPE gene encodes CCAAT enhancer–binding protein epsilon (C/EBPε), which is an important transcription factor in the differentiation of granulocytes. Mutations in the CEBPE gene primarily result in autosomal recessive neutrophil-specific granule deficiency (SGD). SGD is characterized by poor neutrophil chemotaxis and impaired bactericidal activity, resulting in recurrent bacterial infections. Additional sequelae of CEBPE pathogenic variants are not widely reported in the literature. Currently, there is only one published case study that has reported concomitant inflammasomopathy. Herein we report a patient with interferonopathy in the setting of a CEBPE variant.
A 6-year-old female presented for evaluation of chronic anemia of unknown cause not responsive to iron supplementation and with persistently elevated inflammatory markers. She was born at 35 weeks to non-consanguineous parents and was cyanotic at birth, but the remainder of her birth history is unclear. Early life was characterized by poor feeding, poor growth, and global developmental delay. Infection history was remarkable for recurrent acute otitis media that improved after tympanostomy tubes and one episode of pneumonia. Initial immunologic workup at age 6 revealed iron deficiency anemia intermixed with anemia of chronic disease, normal bone marrow, and markedly elevated ESR and CRP. Cytokine panel revealed elevated IL-6, IL-8, and IL-10. Lymphocyte subsets were unremarkable. Genetic testing showed a heterozygous VUS in CEBPE (c.437C>T, p.Ala146Val, CADD phred: 27.5, polyphen-2: probably damaging). She was lost to follow-up prior to treatment initiation but resumed care at age 10. During this period, she began to develop seizures with identification of intracranial calcifications on MRI. Immunologic workup resumed and showed persistent elevated IL-6, IL-8, and IL-10; interferon signature consistent with type 1 interferonopathy; and serum titers positive for MOG antibodies. She does not currently have clinical evidence of MOG-antibody–mediated disease but is undergoing evaluation to assess optic neuritis. She was initiated on tofacitinib. Inflammatory markers have remained elevated but are downtrending.
While CEBPE pathogenic variants are primarily associated with neutrophil dysfunction, features of autoinflammation can be attributed to CEBPE gain-of-function variants. Further investigation is needed to better characterize phenotypes of CEBPE mutations and their response to treatment.
