VEXAS syndrome is an adult-onset autoinflammatory disorder first identified in 2020. It is caused by a genetic mutation acquired later in life, not one inherited at birth. This condition primarily affects men over 50 and is characterized by a combination of inflammatory and hematologic (blood-related) symptoms. The cause is a somatic mutation in the UBA1 gene on the X chromosome, which disrupts a cellular process for clearing waste proteins and leads to widespread inflammation.
Hallmark Symptoms of VEXAS Syndrome
The presentation of VEXAS syndrome often begins with a set of persistent constitutional symptoms. Patients frequently experience recurrent fevers that have no clear infectious cause, accompanied by fatigue and significant, unintentional weight loss. These systemic issues reflect the body-wide inflammation driven by the underlying genetic mutation.
Cutaneous manifestations are among the most common features. Patients may develop painful skin rashes, appearing as firm, reddish-purple papules and nodules. These lesions are a form of neutrophilic dermatosis, where a specific type of white blood cell accumulates in the skin. Inflammation of cartilage (chondritis) is another characteristic sign, causing pain and swelling in the ears and nose.
Blood-related abnormalities are a core component of VEXAS syndrome. Many patients develop macrocytic anemia, where red blood cells become unusually large, leading to fatigue and shortness of breath. Low platelet counts (thrombocytopenia) are also common. The syndrome is closely linked with other hematologic conditions like myelodysplastic syndrome (MDS), and there is a heightened risk of developing blood clots (venous thromboembolism).
The inflammation extends to the joints and lungs. Joint pain (arthralgia) is a frequent complaint and can progress to arthritis with joint swelling. Pulmonary involvement is also noted, with inflammation in the lung tissues leading to symptoms such as a persistent cough or shortness of breath.
The Diagnostic Pathway
The journey to a VEXAS diagnosis begins when a physician recognizes a pattern of treatment-resistant inflammation, skin disorders, and progressive blood abnormalities in an older male patient. The initial symptoms are often mistaken for other, more common conditions, which can delay an accurate diagnosis.
Initial laboratory tests provide objective clues. A complete blood count (CBC) can reveal the characteristic macrocytic anemia and low platelet counts. Blood work will also show elevated inflammatory markers, confirming the presence of systemic inflammation. While these tests are not specific to VEXAS, they are instrumental in narrowing the diagnostic possibilities.
The definitive diagnosis is achieved through genetic testing. A blood sample is analyzed to detect the specific somatic mutation in the UBA1 gene. The presence of this mutation confirms a VEXAS diagnosis and distinguishes it from other diseases that may present with similar symptoms.
A bone marrow biopsy is also performed in many cases to evaluate the hematologic aspects of the disease. Pathologists look for the presence of vacuoles, or small cavities, within the myeloid and erythroid precursor cells. These vacuoles are a direct consequence of the cellular dysfunction caused by the UBA1 mutation.
Conditions with Similar Clinical Presentations
VEXAS syndrome is frequently misdiagnosed at first because its symptoms overlap significantly with other rheumatologic and hematologic disorders. One of the most common mimics is relapsing polychondritis, due to the shared characteristic of cartilage inflammation, particularly affecting the ears and nose. Another condition is Sweet’s syndrome, a neutrophilic dermatosis that presents with fever and painful skin lesions almost identical to those seen in VEXAS.
Other conditions in the differential diagnosis include certain types of vasculitis, such as polyarteritis nodosa, which involves inflammation of blood vessels and can cause skin lesions and systemic symptoms. Because of the prominent blood-related issues, VEXAS is also often mistaken for myelodysplastic syndrome (MDS) before the full spectrum of inflammatory symptoms becomes apparent. In some instances, VEXAS and MDS can coexist, further complicating the clinical picture. The key element that separates VEXAS from these conditions is the UBA1 gene mutation.