SNOMEDCT: 1290093003; ORPHA: 596753; DO: 0080828;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.3 | VEXAS syndrome, somatic | 301054 | 3 | UBA1 | 314370 |
A number sign (#) is used with this entry because of evidence that VEXAS syndrome (VEXAS) is caused by somatic mutation in the UBA1 gene (314370) on chromosome Xp11.
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome) is an adult-onset inflammatory disease that primarily affects males and is caused by somatic, not germline, mutations. The disorder is characterized by adult onset of rheumatologic symptoms at a mean age of 64 years. Features include recurrent fevers, pulmonary and dermatologic inflammatory manifestations, vasculitis, deep vein thrombosis, arthralgias, and ear and nose chondritis. Laboratory studies indicate hematologic abnormalities, including macrocytic anemia, as well as increased levels of acute-phase reactants; about half of patients have positive autoantibodies. Bone marrow biopsy shows degenerative vacuolization restricted to myeloid and erythroid precursor cells, as well as variable hematopoietic dyspoiesis and dysplasias. The condition does not respond to rheumatologic medications and the features may result in premature death (summary by Beck et al., 2020).
Using a genotype-driven approach, Beck et al. (2020) identified an adult-onset inflammatory disorder that exclusively affects males and is associated with de novo somatic mutations in the UBA1 gene. The authors reported 25 unrelated men, all above 45 years of age, who had UBA1 mutations and were diagnosed with 'VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome.' The patients were ascertained from several large cohorts of over 2,500 patients with undiagnosed or unclassified inflammatory or systemic disorders who underwent genetic investigation. The men had onset of variable inflammatory symptoms between 45 and 80 years of age. Ten patients (40%) died between 61 and 84 years of age. The majority of patients had recurrent fevers, pulmonary involvement with infiltrates and alveolitis, dermatologic manifestations, including neutrophilic dermatosis and cutaneous vasculitis, and ear and nose chondritis. More variable features included arthralgia, deep vein thrombosis, eye inflammation, and sensorineural hearing loss. Laboratory studies showed progressive hematologic abnormalities, including macrocytic anemia and thrombocytopenia, as well as increased levels of acute-phase reactants, such as CRP (123260) and erythrocyte sedimentation rate (ESR). Bone marrow biopsy showed degenerative vacuolization restricted to myeloid and erythroid precursor cells, as well as hematopoietic dyspoiesis. Electron microscopic studies indicated that myeloid cells were undergoing apoptosis and degeneration. Several patients had clinical diagnoses of relapsing polychondritis, Sweet syndrome (see 608068), myelodysplasia, plasma cell dyscrasia or monoclonal gammopathy of undetermined significance, myelodysplastic syndrome, and/or polyarteritis nodosa. However, none developed an overt hematologic malignant condition. The condition showed no response to rheumatologic drugs, but glucocorticoids offered relief for severe inflammatory symptoms.
Arlet et al. (2021) reported 2 unrelated women who developed classic features of VEXAS at 87 and 78 years of age, respectively. Genetic analysis showed that both patients carried heterozygous M41V (314370.0004) and M41L (314370.0006) mutations in the UBA1 gene. However, both patients had acquired X chromosome monosomy in the bone marrow, resulting in expression of the mutant allele and disease manifestations. Luzzatto et al. (2021) noted that UBA1 escapes X-inactivation, such that expression of a heterozygous mutant allele in females would likely behave as a recessive allele, and thus not cause disease manifestations in women.
Poulter et al. (2021) reported 10 unrelated men with VEXAS. Bone marrow histopathology in 8 of the patients who had somatic mutations at the M41 residue of the UBA1 gene demonstrated vacuolated promyelocytes, increased cellularity and granulopoiesis, and decreased erythropoiesis. Patient 9, who had a somatic S56P mutation (314370.0007) in the UBA1 gene, had increased cellularity in bone marrow but also increased erythropoiesis and decreased granulopoiesis. Other features in this patient cohort included fever and macrocytic anemia in all 10, skin involvement in 9, pulmonary infiltrates in 2, and ear/nose chondritis in 4.
Lytle and Bagg (2021) reported a patient with VEXAS syndrome who had an M41 mutation in the UBA1 gene and a history of macrocytic anemia, myeloma, pancytopenia, and relapsing polychondritis.
Van der Made et al. (2022) identified 12 patients with VEXAS syndrome. Mean age of onset of autoinflammation characterized by constitutional symptoms and multiorgan involvement was 67 years (range, 47-79 years). Involvement included bone marrow in 12/12 patients, skin in 10/12, lungs in 8/12, lymph nodes in 7/12, heart and vasculature in 6/12, cartilage in 6/12, joints in 4/12, nervous system in 4/12, urogenital tract in 4/12, gastrointestinal tract in 3/12, eyes in 3/12, and kidneys in 2/12. The patients presented with elevated inflammatory parameters and macrocytic anemia (one patient developed macrocytosis later). Initial presentations included chondritis of the ear or nose, oligoarthritis, and pulmonary or systemic vasculitis. Histopathologic evaluation of the bone marrow showed hypercellularity and signs of bone marrow dysplasia with vacuoles in the myeloid progenitor cells in most patients. Novel findings included interstitial nephritis (1 patient), cardiac involvement (4 patients), stroke (3 patients), and intestinal perforation (2 patients) related to treatment with tocilizumab. Most patients became refractory to treatment and the mortality rate was 50%. The authors suggested that allogenic stem cell transplantation be considered at an early stage to prevent progression of organ damage.
Diarra et al. (2021) and Beck et al. (2021) both reported successful treatment of patients with VEXAS by hematopoietic stem cell transplantation.
In a multicenter international retrospective study of 30 VEXAS patients treated with JAK inhibitors, Heiblig et al. (2022) found that all 12 of those taking ruxolitinib showed a higher clinical response rate after 1 and 6 months of treatment compared to those treated with other JAK inhibitors. JAK inhibitor treatment was discontinued in 9 patients within 3 months after receiving other JAK inhibitors because of lack of efficacy. Of note, the data suggested that ruxolitinib has mainly a suspensive effect on disease progression and cannot cure VEXAS patients.
Ferrada et al. (2022) analyzed 83 patients with VEXAS syndrome due to a somatic pathogenic variant at residue Met41 in the UBA1 gene, which is the start codon for the cytoplasmic UBA1b isoform (see M41V, 314370.0004; M41T, 314370.0005; and M41L 314370.0006). All patients were male and Caucasian with a median age at symptom onset of 66 years. Clinical features were characteristic for the disease, but there were some differences associated with the specific variants. Those with M41V were more likely to have an undifferentiated inflammatory syndrome and showed decreased survival compared to those with M41T or M41L. Patients with M41V were less likely to develop ear chondritis, which was associated with overall better survival in the cohort. Patients with M41T had more inflammatory eye disease compared to the others. Decreased survival was also observed in those who were transfusion-dependent. Detailed in vitro studies of the mutations in HEK293 cells and in patient peripheral mononuclear cells demonstrated that all the mutations resulted in decreased levels of UBA1b, with the largest decrease in cells carrying the M41V mutation (about 2-fold lower than M41L or M41T). These findings indicated that M41V supports less translation of UBA1b than the other variants, and showed that VEXAS syndrome severity inversely correlates with residual UBA1b levels. The authors concluded that there is a certain minimal threshold of cellular UBA1b levels required to initiate disease progression, and that the major cause of disease is loss of UBA1b or its activity, rather than gain of UBA1c. This regulation of residual UBA1b translation thus appears to be fundamental to the pathogenesis of VEXAS syndrome and affects disease prognosis.
In 25 unrelated men with VEXAS syndrome, Beck et al. (2020) identified 1 of 3 somatic mutations affecting codon Met41 in the UBA1 gene (M41V, 314370.0004; M41T, 314370.0005; and M41L, 314370.0006), which is the translation initiation site for the cytoplasmic UBA1b isoform. The mutations, which were found by exome or targeted sequencing and confirmed by Sanger sequencing, were absent from public databases, including gnomAD. None had a family history of a similar disorder. All affected men were somatic mosaic for the UBA1 mutation, which was present in peripheral myeloid cells, granulocytes, and monocytes, but not in fibroblasts or mature lymphoid cells. In contrast, bone marrow examination showed that the UBA1 mutations were present in hematopoietic stem cells and in multipotent early marrow progenitor cells. However, patients also had decreased peripheral lymphocyte counts, suggesting that mutant lymphocytes either did not proliferate or did not survive. UBA1 is normally expressed as 2 isoforms differing at the translation site: nuclear UBA1a (initiation at Met1) and cytoplasmic UBA1b (initiation at Met41). In vitro expression of the Met41 mutations into HEK293T cells resulted in loss of UBA1b and the presence of a shorter abnormal isoform, designated UBA1c, that was initiated from a downstream Met67 initiation codon. UBA1c localized to the cytoplasm, but was catalytically impaired compared to UBA1a and UBA1b. The findings suggested that the mutations identified in patients with VEXAS syndrome favored the production of functionally defective cytoplasmic UBA1 isoform. Mutant monocytes derived from the patients showed loss of ubiquitylation, which caused upregulation of the stress and unfolded protein responses, as well as dysregulation of autophagy. These findings suggested that the inflammation observed was mainly due to mutant myeloid cells, although there was also evidence of disrupted B and T cell and neutrophil activation. Transcriptome analysis of patient peripheral blood cells showed a gene expression pattern consistent with the activation of multiple innate immune pathways, including TNF (191160), IL6 (147620), and IFNG (147570). Beck et al. (2020) noted that many patients had myelodysplasia in addition to systemic inflammation and rheumatologic manifestations; they concluded that subcellular ubiquitin regulation and activation play an important role during hematopoiesis and regulation of the immune response.
Poulter et al. (2021) identified somatic mutations in the UBA1 gene in 10 unrelated men with VEXAS syndrome. The mutations were identified by Sanger sequencing in peripheral blood or bone marrow from the patients. Eight patients had previously reported mutations; 3 had the M41V mutation and 5 had the M41T mutation. One patient had an S56P mutation (314370.0007), which did not affect UBA1 cellular localization or result in isoform expression abnormalities in HEK293 cells transfected with the mutant transcript. Poulter et al. (2021) demonstrated that the S56P mutation resulted in temperature-dependent impairment of UBA1 catalytic activity. Another patient had a splice site mutation (314370.0008), which resulted in multiple incorrectly spliced transcripts and a reduction in the correctly spliced transcript.
Among a cohort of undiagnosed patients with inborn errors of immunity from academic hospitals in the Netherlands, van der Made et al. (2022) performed systematic reanalysis of exome sequencing data and targeted Sanger sequencing on those without exome data and identified 12 male patients with VEXAS syndrome and somatic mutations at met41 in the UBA1 gene: 7 with M41T, 4 with M41V, and 1 with M41L. The variant allele fraction varied from 17% to 85%. The authors noted that the low level of variant allele fraction (17%) associated with VEXAS syndrome in one of their patients emphasized the importance of specifically evaluating somatic variants during exome analysis to avoid inappropriate elimination of variants if the variant allele fraction is below a certain threshold.
In a retrospective observational study using exome data, Beck et al. (2023) identified somatic UBA1 mutations in 11 individuals (9 males and 2 females) from a cohort of 163,096 participants from a health care cohort in Pennsylvania. All 11 patients had clinical manifestations of VEXAS syndrome, although 5 (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses associated with the disease. However, all 11 patients had anemia, usually macrocytic, and most had thrombocytopenia; 4 (36%) had myelodysplastic syndrome (MDS). Seven (64%) had arthritis and 4 (36%) were diagnosed with various rheumatologic diseases. Skin and pulmonary involvement were common (in 73% and 91% of patients, respectively). Overall, UBA1 variants were found in 1 of 13,591 unrelated individuals, 1 of 4,269 men older than age 50, and 1 of 26,238 women older than age 50. The authors emphasized that since many individuals with VEXAS syndrome may not be identified through phenotype-based ascertainment and/or have nonspecific clinical diagnoses, testing for UBA1 mutations may be indicated in appropriate cases.
Beck et al. (2020) found that zebrafish with loss of uba1 had growth abnormalities and early death compared to controls. The defects were associated with upregulation of the expression of inflammatory genes.
Arlet, J.-B., Terrier, B., Kosmider, O. Mutant UBA1 and severe adult-onset autoinflammatory disease. (Letter) New Eng. J. Med. 384: 2163 only, 2021. [PubMed: 34077651] [Full Text: https://doi.org/10.1056/NEJMc2102124]
Beck, D. B., Bodian, D. L., Shah, V., Mirshahi, U. L., Kim, J., Ding, Y., Magaziner, S. J., Strande, N. T., Cantor, A., Haley, J. S., Cook, A., Hill, W., Schwartz, A. L., Grayson, P. C., Ferrada, M. A., Kastner, D. L., Carey, D. J., Stewart, D. R. Estimated prevalence and clinical manifestations of UBA1 variants associated with VEXAS syndrome in a clinical population. JAMA 329: 318-324, 2023. [PubMed: 36692560] [Full Text: https://doi.org/10.1001/jama.2022.24836]
Beck, D. B., Ferrada, M. A., Sikora, K. A., Ombrello, A. K., Collins, J. C., Pei, W., Balanda, N., Ross, D. L., Cardona, D. O., Wu, Z., Patel, B., Manthiram, K., and 49 others. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. New Eng. J. Med. 383: 2628-2638, 2020. [PubMed: 33108101] [Full Text: https://doi.org/10.1056/NEJMoa2026834]
Beck, D. B., Grayson, P. C., Kastner, D. L. Mutant UBA1 and severe adult-onset autoinflammatory disease. Author's reply. (Letter) New Eng. J. Med. 384: 2164-2165, 2021. [PubMed: 34077654] [Full Text: https://doi.org/10.1056/NEJMc2102124]
Diarra, A., Duployez, N., Terriou, L. Mutant UBA1 and severe adult-onset autoinflammatory disease. (Letter) New Eng. J. Med. 384: 2163-2164, 2021. [PubMed: 34077652] [Full Text: https://doi.org/10.1056/NEJMc2102124]
Ferrada, M. A., Savic, S., Cardona, D. O., Collins, J. C., Alessi, H., Gutierrez-Rodrigues, F., Kumar, D. B. U., Wilson, L., Goodspeed, W., Topilow, J. S., Paik, J. J., Poulter, J. A., and 20 others. Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis. Blood 140: 1496-1506, 2022. [PubMed: 35793467] [Full Text: https://doi.org/10.1182/blood.2022016985]
Heiblig, M., Ferrada, M. A., Koster, M. J., Barba, T., Gerfaud-Valentin, M., Mekinian, A., Coelho, H., Fossard, G., Barraco, F., Galicier, L., Bienvenu, B., Hirsch, P., and 13 others. Ruxolitinib is more effective than other JAK inhibitors to treat VEXAS syndrome: a retrospective multicenter study. Blood 140: 927-931, 2022. Note: Erratum: Blood 141: 1647 only, 2023. [PubMed: 35609174] [Full Text: https://doi.org/10.1182/blood.2022016642]
Luzzatto, L., Risitano, A. M., Notaro, R. Mutant UBA1 and severe adult-onset autoinflammatory disease. (Letter) New Eng. J. Med. 384: 2164 only, 2021. [PubMed: 34077653] [Full Text: https://doi.org/10.1056/NEJMc2102124]
Lytle, A., Bagg, A. VEXAS: a vivid new syndrome associated with vacuoles in various hematopoietic cells. Blood 137: 3690 only, 2021. [PubMed: 34196684] [Full Text: https://doi.org/10.1182/blood.2021010714]
Poulter, J. A., Collins, J. C., Cargo, C., De Tute, R. M., Evans, P., Cardona, D. O., Bowen, D. T., Cunnington, J. R., Baguley, E., Quinn, M., Green, M., McGonagle, D., Beck, D. B., Werner, A., Savic, S. Novel somatic mutations in UBA1 as a cause of VEXAS syndrome. (Letter) Blood 137: 3676-3681, 2021. [PubMed: 33690815] [Full Text: https://doi.org/10.1182/blood.2020010286]
van der Made, C. I., Potjewijd, J., Hoogstins, A., Willems, H. P. J., Kwakernaak, A. J., de Sevaux, R. G. L., van Daele, P. L. A., Simons, A., Heijstek, M., Beck, D. B., Netea, M. G., van Paassen, P., Elizabeth Hak, A., van der Veken, L. T., van Gijn, M. E., Hoischen, A., van de Veerdonk, F. L., Leavis, H. L., Rutgers, A. Adult-onset autoinflammation caused by somatic mutations in UBA1: a Dutch case series of patients with VEXAS. J. Allergy Clin. Immun. 149: 432-439, 2022. [PubMed: 34048852] [Full Text: https://doi.org/10.1016/j.jaci.2021.05.014]