Clinical Heterogeneity of the VEXAS Syndrome

Koster, Matthew J.; Kourelis, Taxiarchis; Reichard, Kaaren K.; Kermani, Tanaz A.; Beck, David B.; Cardona, Daniela Ospina; Samec, Matthew J.; Mangaonkar, Abhishek A.; Begna, Kebede H.; Hook, C. Christopher; Oliveira, Jennifer L.; Nasr, Samih H.; Tiong, Benedict K.; Patnaik, Mrinal M.; Burke, Michael; Michet, Clement J.; Warrington, Kenneth J.

doi:10.1016/j.mayocp.2021.06.006

Cited by 65 publications

(110 citation statements)

References 20 publications

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“…It is well known that clinical heterogeneity is a common phenomenon in genetic disorders, such as VEXAS syndrome and DICER1 syndrome (Koster et al, 2021; Azzollini et al, 2021). Similarly, AI also demonstrates significant clinical heterogeneity (Crawford et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

A novel FAM83H variant causes familial amelogenesis imperfecta with incomplete penetrance

Bai

Qian

et al. 2022

Molec Gen & Gen Med

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Background Amelogenesis imperfecta (AI) is known to be a monogenic genetic disease caused by a variety of genes demonstrating a wide spectrum of penetrance. FAM83H is reported to be involved in AI: however, whether FAM83H causes AI with incomplete penetrance is unclear. Methods Whole‐exome sequencing was performed on two patients with AI, and putative disease‐related variants were validated by Sanger sequencing. Bioinformatic and in vitro functional analyses were performed to functionally characterize the identified disease‐causing variants. Results We identified a novel heterozygous nonsense variant of FAM83H (NM_198488: c.1975G > T, p.Glu659Ter); in vitro functional analysis showed that this mutant produced mislocalized proteins and was deleterious. Surprisingly, the clinical manifestations of each of the six individuals carrying this variant were different, with one carrier appearing to be completely asymptomatic for AI. Conclusion Our findings expand the variant spectrum for FAM83H and the phenotypic spectrum for FAM83H‐associated AI and suggest that FAM83H‐mediated AI exhibits incomplete penetrance.

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Section: Discussionmentioning

confidence: 99%

A novel FAM83H variant causes familial amelogenesis imperfecta with incomplete penetrance

Bai

Qian

et al. 2022

Molec Gen & Gen Med

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“…Auricular and/or nasal chondritis was one of the most common organ manifestations (Figure 1), with 15 (60%) patients meeting the classification criteria for relapsing polychondritis (RP). According to other cohort studies, the incidence of chondritis was 36-50% (28)(29)(30).…”

Section: Clinical Phenotypes Of Vexas Syndrome Chondritismentioning

confidence: 94%

Vasculitis associated with VEXAS syndrome: A literature review

Watanabe¹,

Kiji²,

Hashimoto³

2022

Front. Med.

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Vasculitis is an inflammatory disorder of the blood vessels that causes damage to a wide variety of organs through tissue ischemia. Vasculitis is classified according to the size (large, medium, or small) of the blood vessels. In 2020, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, a novel autoinflammatory syndrome, was described. Somatic mutations in methionine-41 of UBA1, the major E1 enzyme that initiates ubiquitylation, are attributed to this disorder. This new disease entity connects seemingly unrelated conditions: inflammatory syndromes (relapsing chondritis, Sweet's syndrome, or neutrophilic dermatosis) and hematologic disorders (myelodysplastic syndrome or multiple myeloma). Notably, such patients sometimes develop vasculitis, such as giant cell arteritis and polyarteritis nodosa, and fulfill the corresponding classification criteria for vasculitis. Thus, vasculitis can be an initial manifestation of VEXAS syndrome. In this research topic exploring the link between autoinflammatory diseases and vasculitis, we first provide an overview of the disease mechanisms and clinical phenotypes of VEXAS syndrome. Then, a literature review using the PubMed database was performed to delineate the clinical characteristics of vasculitis associated with VEXAS syndrome. Finally, the therapeutic options and unmet needs of VEXAS syndrome are discussed.

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“…Since the original publication, several groups have reported heterogenous clinical phenotypes but also a high frequency of refractoriness to available treatments. [3][4][5] Glucocorticoids are effective but almost always require sustained treatment at high doses, with breakthrough inflammatory flares and marked drug toxicities. 5 Cytopenia, particularly macrocytic anemia, and cytoplasmic vacuoles in marrow are nearly universal, and myelodysplastic features in the marrow are common in VEXAS.…”

mentioning

confidence: 99%

“…One implication of its molecular discovery is that archived tissue can be easily subjected to rapid screening for the specific mutation. Since the original publication, several groups have reported heterogenous clinical phenotypes but also a high frequency of refractoriness to available treatments 3–5 . Glucocorticoids are effective but almost always require sustained treatment at high doses, with breakthrough inflammatory flares and marked drug toxicities 5 …”

mentioning

confidence: 99%

“…[3][4][5] Glucocorticoids are effective but almost always require sustained treatment at high doses, with breakthrough inflammatory flares and marked drug toxicities. 5 Cytopenia, particularly macrocytic anemia, and cytoplasmic vacuoles in marrow are nearly universal, and myelodysplastic features in the marrow are common in VEXAS. 6 Myelodysplastic syndrome (MDS) is diagnosed in 40-50% of cases, most lower-risk.…”

mentioning

confidence: 99%

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