Unveiling VEXAS syndrome: Reviewing one of the first suspected case in Southern USA.

Summary: Authors- 1. Anisha Memdani MD, PgY-1 Baton Rouge General Medical Center 2. Hectar R. Mena, MD, Baton Rouge Clinic Background- VEXAS syndrome is a relatively new clinical entity that is associated with impaired ubiquitination secondary to somatic mutation of UBA1gene located on the X-chromosome (1, 2). It is associated with multiple autoimmune/ inflammatory manifestations and macrocytic anemia. The acronym VEXAS stands for Vacuoles in bone marrow, E1 enzyme, X-linked, Autoinflammatory, and Somatic mutation. Its presentation should be considered in patients with systemic inflammation, recurrent fevers, relapsing polychondritis, sweet syndrome, and macrocytic anemia. Case presentation- A 72-year-old man with a medical history including congestive heart failure (CHF), ADHD, and right knee osteoarthritis was referred to our rheumatology clinic by his dermatologist due to concerns about a potential systemic inflammatory condition. Over the past three years, he has experienced worsening fatigue and pancytopenia, with mean corpuscular volume (MCV) levels ranging from 109 to 113, and has been under the care of a hematologist for this issue. Extensive investigations for his anemia, including an initial bone marrow biopsy which revealed dyserythropoiesis but no myelodysplasia, as well as screening for celiac disease via esophagogastroduodenoscopy (EGD) and colonoscopy, have been conducted. His dermatological symptoms began with a rash spreading across his body, accompanied by fatigue and night sweats, which was confirmed as sweet syndrome through biopsy and treated with a prednisone taper. Despite treatment, the rash recurred, with a second biopsy revealing cutaneous mastocytosis. In February 2023, he developed a palpable rash exclusively on his lower extremities, confirmed as leukocytoclastic vasculitis through biopsy, leading to another prednisone taper. Subsequently, a new rash appeared on his upper extremities, confirmed as the histoid variant of sweet syndrome through biopsy. Additionally, he experienced sensorineural hearing loss and peripheral vestibular dysfunction, along with recurrent swelling of the ears and nose during sweet syndrome relapses, prompting evaluation by an ear, nose, and throat (ENT) specialist. Over the past four months, he developed transfusion-dependent anemia, with hemoglobin levels ranging from 6.9 to 7.5, and underwent a repeat bone marrow biopsy which did not provide additional insights. Upon rheumatological evaluation, VEXAS syndrome was considered as a possible diagnosis. Reviewing the latest bone marrow biopsy with the pathologist revealed the presence of vacuoles, confirming this aspect of the syndrome. He meets criteria based on his clinical symptoms of sweet syndrome, vasculitis, macrocytic anemia, and recurrent ear and nose swelling, likely secondary to relapsing polychondritis. Confirmation testing for the UBA1 mutation is pending, and plans are in place to initiate IL-6 inhibitors pending confirmation. Close follow-up of the patient is ongoing. Discussion- The UBA1 gene plays a crucial role in ubiquitination, a pivotal post-translational process involved in protein degradation, cellular signaling, and maintaining cellular homeostasis (3). While germline mutations in UBA1 are linked to spinal muscular atrophy, a fatal condition in infancy (4), the mutation discussed here is somatic and becomes more prevalent with age. The current estimated prevalence of UBA1-related conditions is approximately 1 in 13,500 in the general population and 1 in 4,000 in men over 50 years old (3). The mortality rate associated with this condition is alarmingly high, reaching 60% within five years of diagnosis (5). Our patient exhibits nearly all the clinical criteria associated with this condition, including vasculitis, sweet syndrome, macrocytic anemia, relapsing polychondritis, cutaneous mastocytosis, and hearing loss. The presence of vacuoles in the bone marrow further supports the diagnosis, especially considering the patient's age and gender. Notably, this case is one of the first few suspected instances in the southern USA, particularly in Louisiana. Given the recent recognition of this syndrome, our understanding of its treatment remains limited. However, case reports and review articles have highlighted differences in response to various biologics. Achieving an accurate diagnosis through genetic testing and subsequently sharing and discussing such cases can significantly contribute to the improved treatment and management of this life-threatening condition. Conclusions- Our patient's journey underscores the importance of considering rare genetic disorders in the differential diagnosis of systemic inflammatory conditions, particularly in older male patients. Furthermore, this case highlights the urgent need for increased awareness, early detection, and multidisciplinary management strategies for improving outcomes in patients with VEXAS syndrome. Continued collaboration among clinicians, geneticists, and researchers is essential for advancing our understanding of this condition and refining therapeutic approaches tailored to its diverse manifestations. Through comprehensive reporting and sharing of such cases, we contribute to the collective knowledge base and ultimately enhance the care provided to individuals affected by this challenging and potentially life-threatening syndrome. References- 1.Kobak S. VEXAS syndrome: Current clinical, diagnostic and treatment approaches. 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