Background Clarkson disease (monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome, ISCLS) is a rare idiopathic condition marked by transient, relapsing-remitting episodes of systemic microvascular hyper-permeability, which liberates plasma fluid and macromolecules into the peripheral tissues. This pathology manifests clinically as the abrupt onset of hypotensive shock, hemoconcentration, and hypoalbuminemia. Methods We analysed endothelial glycocalyx (eGCX)-related markers in plasma from patients with ISCLS during acute disease flares and convalescence by ELISA and comprehensive proteomic profiling. We evaluated eGCX-related components and gene expression in cultured endothelial cells using RNA-sequencing, real-time PCR, and fluorescence staining. Results Serum levels of eGCX-related core components including hyaluronic acid (HA) and the core proteoglycan soluble syndecan-1 (sCD138) were elevated at baseline and during acute ISCLS flares. Serial measurements demonstrated that sCD138 levels peaked during the recovery (post-leak) phase of the illness. Proteomic analysis of matched acute and convalescent ISCLS plasma revealed increased abundance of eGCX-related proteins, including glypicans, thrombospondin-1 (TSP-1), and eGCX-degrading enzymes in acute compared to remission plasma. Abundance of endothelial cell damage markers did not differ in acute and baseline plasma. Expression of several eGCX-related genes and surface carbohydrate content in endothelial cells from patients with ISCLS did not differ significantly from that observed in healthy control cells. Conclusions eGCX dysfunction, but not endothelial injury, may contribute to clinical symptoms of acute ISCLS. Serum levels of of eGCX components including sCD138 may be measured during acute episodes of ISCLS to monitor clinical status and therapeutic responses.

Patient: Female, 49Final Diagnosis: Systemic capillary leak syndrome (SCLS)Symptoms: HypotensionMedication: —Clinical Procedure: NoneSpecialty: AllergologyObjective:Rare diseaseBackground:Systemic capillary leak syndrome (SCLS) (Clarkson’s disease) is a rare disorder of unknown etiology, characterized by transient episodes of hypotension, and the microvascular leak of fluids into the peripheral tissues, resulting in edema. Between 80–90% of patients with SCLS have a concomitant monoclonal gammopathy. Although translational in vitro studies have implicated vascular endothelial barrier dysfunction in the etiology of SCLS, the etiology and disease associations in clinical cases remain unknown.Case Report:We report a case of SCLS in a 49-year-old woman who initially presented with an upper respiratory tract infection, which was complicated by edema and compartment syndromes in the extremities that required fasciotomies. Serum levels of the cell surface heparan sulfate proteoglycan, syndecan-1 (CD138), a measure of endothelial surface glycocalyx (ESG) damage, were measured by enzyme-linked immunoassay (ELISA), peaked at up to 500 ng/mL (reference range, 50–100 ng/mL) and normalized on disease remission.Conclusions:This case report supports the view that damage to the microvascular endothelium, has a role in the pathogenesis of acute SCLS. This case also indicated that monitoring serum levels of syndecan-1 (CD138) might be used to monitor the progression and resolution of episodes of SCLS.

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