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Severe cerebral involvement due to idiopathic systemic capillary leak syndrome.

ABSTRACT: The idiopathic systemic capillary leak syndrome (ISCLS) is a rare disorder, characterized by recurrent attacks of hypotension, hypoalbuminemia, and hemoconcentration, which is often misdiagnosed due to overlapping features with other diseases. Even though cerebral involvement is uncommon, a broad awareness is crucial, because of its life-threatening character.

SUBMITTER: Gunes AR

PROVIDER: S-EPMC4831401 | biostudies-other | 2016 Apr

REPOSITORIES: biostudies-other

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Project description:The Systemic Capillary Leak Syndrome (SCLS) is an extremely rare, orphan disease that resembles systemic anaphylaxis. The disorder is characterized by repeated, transient, and seemingly unprovoked episodes of hypotensive shock and peripheral edema due to transient endothelial hyperpermeability. SCLS is often accompanied by a monoclonal gammopathy of unknown significance (MGUS). Using Affymetrix Single Nucleotide Polymorphism (SNP) microarrays, we performed the first genome-wide SNP analysis of SCLS in a cohort of 12 disease subjects and 18 controls. Exome capture sequencing was performed on genomic DNA from nine of these patients as validation for the SNP-chip discoveries and de novo data generation. We identified candidate susceptibility loci for SCLS, which included a region flanking CAV3 (3p25.3) as well as SNP clusters in PON1 (7q21.3), PSORS1C1 (6p21.3), and CHCHD3 (7q33). Among the most highly ranked discoveries were gene-associated SNPs in the uncharacterized LOC100130480 gene (rs6417039, rs2004296). Top case-associated SNPs were observed in BTRC (rs1235580, 3rs4436485), ARHGEF18 (rs11668246), CDH13 (rs4782779), and EDG2 (rs12552348), which encode proteins with known or suspected roles in B cell function and/or vascular integrity. SNPs that were significantly associated with SCLS by microarray analysis were also detected and validated by exome deep sequencing. Functional annotation of highly ranked SNPs revealed enrichment of cell projections, cell junctions and adhesion, and molecules containing pleckstrin homology, Ras/Rho regulatory, and immunoglobulin Ig-like C2/fibronectin type III domains, all of which involve mechanistic functions that correlate with the SCLS phenotype. These results highlight SNPs with potential relevance to SCLS. Our study cohort included 12 patients with SCLS. The control group included 17 age, sex and ethnicity-matched healthy donors (including two relatives of SCLS patients), and a reference sample supplied by the SNP-chip manufacturer (Affymetrix), for which age information was not available. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from purified B lymphocytes.

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Severe cerebral involvement due to idiopathic systemic capillary leak syndrome.

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