 The systemic capillary leak syndrome SCLS, Clarkson syndrome is an exceedingly rare disorder of unknown cause characterized by chronic edema or acute transient, severe episodes of hypotension, hypovolemia, and oliguria. Severe edema results from leakage of fluid and macromolecules 200-900 kDa into tissues. Acute SCLS episodes carry a high morbidity and mortality 25-30. Only 150 cases have been reported worldwide since 1960, although the disease may be underdiagnosed due to the nonspecific nature of the presenting signs and symptoms and the considerable overlap with other shock syndromes including sepsis, anaphylaxis, and angioedema. Approximately 85 of such individuals have a monoclonal gammopathy of unknown significance MGUS, but the relationship of this finding to disease pathogenesis is unclear. This protocol will focus on the pathogenesis of SCLS. Subjects with documented episodes of capillary leak will be evaluated in order to correlate both clinical and laboratory features that are typical of SCLS. The goal is to identify biological factors andor genetic and molecular events that may predispose to SCLS episodes. We plan to enroll up to 210 subjects, family members and healthy volunteers in this study. We anticipate that our findings may be a first step toward the development of new targeted therapies. 