A clinical, histopathological, and molecular study of two cases of VEXAS syndrome without a definitive myeloid neoplasm

Abstract

VEXAS (vacuoles, E1 enzyme, X- linked, autoinflammatory, somatic) syndrome is caused by somatic mutations in UBA1 and is identified using a genotype-driven method. This condition connects unrelated men with adult-onset inflammatory syndromes in association with hematologic manifestations of peripheral cytopenia and bone marrow myeloid dysplasia. While bone marrow vacuolization restricted to myeloid and erythroid precursors has been identified in VEXAS patients, the detailed clinical and histopathological features of peripheral blood and bone marrows remain unclear. The current case report describes the characteristic hematologic findings in patients with VEXAS, including macrocytic anemia, thrombocytopenia, marked hypercellular marrow with granulocytic hyperplasia, megaloblastic changes in erythroid precursors, and the absence of hematogones in addition to prominent vacuoles in myeloid and erythroid precursor cells. Characterizing the clinical and hematologic features helps to raise awareness and improve diagnosis of this novel, rare, but potentially under-recognized disease. Prompt diagnosis expands the general knowledgeable and understanding of this disease, and optimal management might prevent patients from developing complications related to this refractory inflammatory syndrome and improve the overall clinical outcome.

Pulmonary manifestations in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome: a systematic review

“…56.1% of included patients had pulmonary involvement at presentation. The most frequently described manifestation was pulmonary infiltrates (43.1%; n = 116) [ 1 , 8 , 12 – 34 ], followed by pleural effusion (7.4%; n = 20) [ 8 , 18 , 20 , 22 , 24 , 27 , 28 , 32 , 35 ] and idiopathic interstitial pneumonia (3.3%; n = 9) [ 14 , 18 , 25 , 27 , 28 , 32 , 36 , 37 ]. Other pulmonary manifestations described were NSIP ( n = 1) [ 14 ]; bronchiolitis obliterans ( n = 3) [ 14 ]; pulmonary vasculitis ( n = 6) [ 14 , 24 ]; bronchiectasis ( n = 1) [ 14 ]; alveolar haemorrhage ( n = 1) [ 38 ]; pulmonary embolism ( n = 4) [ 35 , 39 – 41 ]; bronchial stenosis ( n = 1) [ 42 ]; and alveolitis ( n = 1) [ 36 ].…”

VEXAS Syndrome—Review

“…Inflammatory markers, such as erythrocyte sedimentation rate and C-reactive protein, were significantly elevated in all patients. 1 13 An elevated antinuclear antigen, rheumatoid factor, and antiphospholipid antibodies were also observed in patients with VEXAS. 52…”

“…Inflammatory markers, such as erythrocyte sedimentation rate and C-reactive protein, were significantly elevated in all patients. 1,13 An elevated antinuclear antigen, rheumatoid factor, and antiphospholipid antibodies were also observed in patients with VEXAS. 52 Neither the complex, progressive clinical presentation nor the characteristic cytoplasmic vacuoles and abnormal laboratory tests can replace the detection of UBA1 mutations as criteria for confirming the diagnosis of VEXAS syndrome, and these nonspecific abnormalities can only be brought to the attention of physicians (►Fig.…”

“…10 Mutations in UBA1 lead to reduced ubiquitination and activation of autoimmune pathways, resulting in inflammatory manifestations. 1,2,13,15 X-Linked UBA1 is located on the X chromosome (Xp11.3) and can escape X chromosome inactivation. VEXAS syndrome is more common in older men, suggesting that women may be protected by the unmutated allele.…”

VEXAS Syndrome—A Review of Pathophysiology, Presentation, and Prognosis

“…As of May 2022, fewer than 300 cases have been reported in the literature (Table ). [6][7][8][9][10][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] Symptoms in the majority of patients begin around age 55 to 65 years, but onset can range from 40 to 85 years. 6,10,13,14 Geographic and ethnic distributions of VEXAS have not been fully defined.…”