Idiopathic systemic capillary leak syndrome, a unique complement and interferon mediated endotheliopathy syndrome: The role of the normal skin biopsy in establishing the diagnosis and elucidating pathogenetic mechanisms

Magro, Cynthia M.; Mo, Joshua H; Pecker, Mark S.

doi:10.1016/j.anndiagpath.2022.152028

Cited by 6 publications

(7 citation statements)

References 56 publications

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“…However, capillary walls disruption observed under electron microscopy suggested endothelial cell (ECs) dysfunction, which was in line with the characteristics of SCLS ( Johansson and Löfdahl, 1979 ; Assaly et al, 2001 ; Druey and Greipp, 2010 ; Baloch et al, 2018 ). The skin biopsy seemed toreveal several diagnostic clues ( Magro et al, 2022 ), showing perivascular lymphocytic and plasma cell infiltration, consistent with previous reports ( Cicardi et al, 1997 ; Fardet et al, 2004 ; Magro et al, 2022 ). Besides, elevated levels of VEGF and the presence of monoclonal gammopathy of unknown significance (MGUS) served as supportive diagnostic evidences for SCLS ( Druey and Parikh, 2017 ; E, M and J, 2017).…”

Section: Discussionsupporting

confidence: 90%

“…The immune-mediated hypothesis regarding the pathogenesis of SCLS has been extensively discussed in prior studies ( Cicardi et al, 1997 ; Dowden et al, 2009 ; Baloch et al, 2018 ; Wu et al, 2021 ). Evidence of immune involvement includes perivascular lymphocytic infiltration in the skin ( Cicardi et al, 1997 ; Fardet et al, 2004 ; Magro et al, 2022 ) and the observation of elevated peripheral blood T cells ( Cicardi et al, 1990 ; Dowden et al, 2009 ). Notably, it has been reported that patients with higher levels of monoclonal components are more prone to severe recurrences ( Pineton de Chambrun et al, 2017 ), underscoring the significance of immune dysregulation in the pathophysiology of SCLS.…”

Section: Discussionmentioning

confidence: 99%

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Chronic systemic capillary leak syndrome with lymphatic capillaries involvement and MYOF mutation: case report and literature review

Gao,

Zhong,

Zhang

et al. 2023

Front. Genet.

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Introduction: Idiopathic systemic capillary leak syndrome (SCLS) is a rare disorder characterized by hemoconcentration, hypoproteinemia and edema. Chronic SCLS (cSCLS) presents as intractable edema, distinguishing it from the classic acute form, and only about 10 cases were reported worldwide. Nevertheless, the underlying pathogenesis of both types is obscure.Case presentation: We report a case of a 58-year-old man with chronic edema persisting for 8 years, complicated by unique chylous polyserous effusions and hypotrichosis, which was successfully relieved by treatment with dexamethasone, intravenous immunoglobulin, and thalidomide. Furthermore, a variant c.5594A>G (p.K1865R) in the MYOF gene was identified as a potentially pathogenic mutation through whole-exome genetic sequencing. The proposed mechanism involves its impact on VEGF signaling, leading to increased capillary permeability.Conclusion: Our case illustrates possible lymphatic capillaries involvement in SCLS, which may plays a potential role in immune disorder, and revealed a possible causative genetic mutation of SCLS.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Chronic systemic capillary leak syndrome with lymphatic capillaries involvement and MYOF mutation: case report and literature review

Gao,

Zhong,

Zhang

et al. 2023

Front. Genet.

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“…Neither vasculitis nor aberrant angiogenesis has been observed consistently in biopsies of skin or skeletal muscle taken from patients during ISCLS flares ( 9 , 16 ). We did not find evidence of cellular inflammation or other histological abnormalities in the skin of asymptomatic patients by light microscopy ( Supplemental Figure 2 ).…”

Section: Resultsmentioning

confidence: 97%

Intrinsic endothelial hyperresponsiveness to inflammatory mediators drives acute episodes in models of Clarkson disease

Ablooglu,

Chen,

Xie

et al. 2024

Journal of Clinical Investigation

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Clarkson disease, or monoclonal gammopathy–associated idiopathic systemic capillary leak syndrome (ISCLS), is a rare, relapsing-remitting disorder featuring the abrupt extravasation of fluids and proteins into peripheral tissues, which in turn leads to hypotensive shock, severe hemoconcentration, and hypoalbuminemia. The specific leakage factor(s) and pathways in ISCLS are unknown, and there is no effective treatment for acute flares. Here, we characterize an autonomous vascular endothelial defect in ISCLS that was recapitulated in patient-derived endothelial cells (ECs) in culture and in a mouse model of disease. ISCLS-derived ECs were functionally hyperresponsive to permeability-inducing factors like VEGF and histamine, in part due to increased endothelial nitric oxide synthase (eNOS) activity. eNOS blockade by administration of N (γ)-nitro- l -arginine methyl ester ( l -NAME) ameliorated vascular leakage in an SJL/J mouse model of ISCLS induced by histamine or VEGF challenge. eNOS mislocalization and decreased protein phosphatase 2A (PP2A) expression may contribute to eNOS hyperactivation in ISCLS-derived ECs. Our findings provide mechanistic insights into microvascular barrier dysfunction in ISCLS and highlight a potential therapeutic approach.

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“…Another potential mechanism involves the direct targeting by the paraprotein of a critical endothelial‐based protein that is critical for maintaining vascular integrity, a hypothesis that is supported by the extent of C5b‐9 deposition within the microvessels during an active leak phase of idiopathic systemic capillary leak syndrome. Perhaps, similar postulated mechanisms of enhanced vasopermeability seen in patients with idiopathic capillary leak syndrome could apply to TEMPI syndrome 30–38 …”

Section: Discussionmentioning

confidence: 93%

“…Perhaps, similar postulated mechanisms of enhanced vasopermeability seen in patients with idiopathic capillary leak syndrome could apply to TEMPI syndrome. [30][31][32][33][34][35][36][37][38] The majority of patients with TEMPI present with erythrocytosis resembling PV. These patients lack the JAK2 mutation, which allows the exclusion of PV.…”

Section: There Are Elevated Levels Of Vegf In Tafro (Thrombocytopenia...mentioning

confidence: 99%

TEMPI syndrome: A clinical, light‐microscopic and phenotypic evaluation with review of the literature

Kalomeris,

Grossman,

Tepler

et al. 2023

J Cutan Pathol

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Background and objectivesTEMPI (telangiectasias, elevated erythropoietin and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonaryshunting) syndrome is a rare multisystemic disease classified as a monoclonal gammopathy of cutaneous significance. The pathogenesis and etiology of TEMPIare not well known because of the rarity of this disorder. Although telangiectasias are the hallmark of this syndrome, skin biopsies are rarely performed. We aim to further characterize TEMPI syndrome through the evaluationof a skin biopsy.MethodsWe reviewed the histopathology and immunophenotypic profile of a skin biopsy from a 53‐year‐oldwoman diagnosed with TEMPI syndrome. Other components of her syndromic complex included an IgA myeloma, elevated vascular endothelial growth factor (VEGF), and erythrocytosis.ResultsA biopsy showed prominent vascular ectasia with some degree of microvascular basement membranezone thickening. Our patient had a reduction in neoplastic plasma cell burdenand clearing of her telangiectasias following myeloma directed treatment.ConclusionsTEMPI can beviewed as a reactive vascular paraneoplastic syndrome in the setting of a plasma cell dyscrasia. Elaboration of VEGF from neoplastic plasma cells is likely pathogenetically implicated and appears to be a common link that explains other vascular lesions associated with monoclonal gammopathy syndromes.

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Idiopathic systemic capillary leak syndrome, a unique complement and interferon mediated endotheliopathy syndrome: The role of the normal skin biopsy in establishing the diagnosis and elucidating pathogenetic mechanisms

Cited by 6 publications

References 56 publications

Chronic systemic capillary leak syndrome with lymphatic capillaries involvement and MYOF mutation: case report and literature review

Chronic systemic capillary leak syndrome with lymphatic capillaries involvement and MYOF mutation: case report and literature review

Intrinsic endothelial hyperresponsiveness to inflammatory mediators drives acute episodes in models of Clarkson disease

TEMPI syndrome: A clinical, light‐microscopic and phenotypic evaluation with review of the literature

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