Auto-inflammatory Features and Myositis in a Case with Previously Unreported Genetic Abnormalities

Summary: Background Autoimmune lymphoproliferative syndrome (ALPS) most often presents clinically with lymphadenopathy and/or splenomegaly in addition to features of autoimmunity. The most common laboratory finding is cytopenia due to autoimmune destruction or splenic sequestration, and patients often have elevated levels of CD4-negative and CD8-negative T lymphocytes, referred to as double negative T-cells. It has been reported that symptoms are most often severe in childhood with lessening of symptoms, or complete resolution, in adulthood. Case This is a 30-year-old male with a history of Autoimmune Lymphoproliferative-like Syndrome (ALPS) without double negative T-cells, who presented with new extremity weakness, normal CK, anemia, leukopenia, hepatosplenomegaly, and flat affect. MRI brain showed periventricular and subcortical white matter FLAIR hyperintensities, as well as cortical volume loss, greater than expected for the patient’s age. MRI Right lower extremity showed myositis confirmed by muscle biopsy significant for lymphocytic infiltrates, myofiber atrophy and regenerative myofibers. EMG showed active changes, seen in inflammatory myositis, with significant muscle loss and peripheral sensory motor neuropathy/axon loss in lower extremities. Inflammatory myositis antibodies were negative, ANA positive 1:160 in nucleolar pattern and patient was treated for suspected non-specific inflammatory myositis with IVIG and steroids. He later returned with fever, worsened cytopenia, elevated CKs near 5000, elevated ferritin to nearly 4000, and negative infectious workup. At this time there was concern for underlying genetic autoinflammatory process and laboratory testing was pursued. Genetic panels were revealing for pathogenic gene variant POLR1C and deletion of 16p11.2. The patient was found to have low IgM, IgG, as well as CD3, CD4, and CD 19 cells. Figures MRI Right Lower Extremity W/O Contrast: Diffuse myofascial edema of the right lower extremity, fascial edema confluence within the lateralis fascia MRI Brain W & W/o Contrast: Multifocal periventricular and subcortical while matter FLAIR hyperintensities, much greater than expected for age. Cortical volume loss, greater than expected for age. Discussion Here, we describe a case of a 30-year-old male who presented with a non-specific inflammatory myopathy and auto-inflammatory features. Further evaluation also demonstrated non-specific brain hyperintensities. Genetic testing revealed pathogenic gene variants within the short arm of chromosome 16 and at band 11.2, which corresponds to a minimal deletion boundary of chr16:28,503,803-29,196 (GRCh37/hg19) and contains some of the following genes: CD19 (associated with common variable immunodeficiency), LAT (associated with combined immunodeficiency). Additionally, a likely pathogenic gene variant was identified in POLR1C (associated with autosomal recessive hypomyelinating leukodystrophy). The patient was found to have hypogammaglobulinemia with low IgM and IgG and decreased levels of absolute CD3, CD4, and CD19 cells. Initially, MRI brain imaging findings were felt to be non-specific. However, given his gene variant in POLR1C is associated with 4H-leukodystrophy, a myelin deficit may be an underlying cause. Deletions in 16p11.2 are also found in neurodevelopmental disorders. Given that there have not been better explanations for his condition, we felt it important to report this case and ensure similar cases undergo genetic testing for these variants. Conclusion Genetic testing is a useful diagnostic tool that may be used in conjunction with clinical presentation and exam to comprehensively describe and diagnose rare clinical presentations.