Genetic testing for mutations in the UBA1 gene should be considered in male patients with recurrent episodes of fever, encephalopathy, skin involvement, neuropathy, nasal chondritis, pulmonary infiltrates, and venous thromboembolism. The diagnosis of VEXAS syndrome relies on identifying an M41 or splice-site mutation in the UBA1 gene from various biological samples, primarily blood and bone marrow.

VEXAS syndrome is a recently identified autoinflammatory disorder, predominantly affecting men over 50. It is caused by a somatic mutation in the UBA1 gene, an X-linked gene critical for the activation of the ubiquitin system. Patients exhibit a wide range of inflammatory symptoms, including fever, neutrophilic dermatosis, chondritis, pulmonary infiltrates, ocular inflammation, and venous thrombosis. Hematological involvement includes macrocytic anemia, thrombocytopenia, the presence of vacuoles in myeloid and erythroid precursor cells, and dysplastic bone marrow, all contributing to significant morbidity and mortality. Additionally, these patients often experience neurological complications, such as chronic inflammatory demyelinating polyneuropathy.

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A 73-year-old male with a history of skin lesions in 2018, which were biopsied and diagnosed as neuropathy and leukocytoclastic vasculitis. He was started on glucocorticoids, with a good initial response. However, within a few months, he began to develop symptoms of seronegative inflammatory arthritis and pulmonary infiltrates. Over the next four years, he experienced multiple hospitalizations due to recurrent fevers accompanied by encephalopathy, without a clear source of infection. Concern arose about potential CNS vasculitis due to his encephalopathy. Extensive workups, including full-body CT, MRI studies, and a PET scan, were all negative for infection. A bone marrow biopsy revealed a splice-site mutation in the UBA1 gene, identified from both blood and bone marrow samples.

VEXAS is likely an underdiagnosed syndrome caused by a somatic mutation in the UBA1 gene. It should be considered in patients presenting with hematoinflammatory manifestations, as well as skin and neuropathic symptoms.