Figure 1: Clinical considerations in the prospective diagnosis of SCLS. After exclusion of primary cardiovascular and/or allergic causes, a diagnosis of SCLS should be entertained in patients with unexplained, transient hypotension and/or peripheral edema. Systemic anaphylaxis and hereditary and/or acquired angioedema can be excluded by measurement of serum tryptase during the acute episode and quantitative and functional assays for the complement component 1 esterase inhibitor (C1 INH). Although presumptive treatment for sepsis is prudent in the undiagnosed SCLS patient during the first severe episode, the hypotension and hemoconcentration of SCLS are typically refractory to intravenous fluid resuscitation, which exacerbates peripheral edema. Hypoalbuminemia due to protein extravasation is a hallmark of classic acute SCLS whereas low serum albumin levels and edema that does not resolve between episodes should prompt the diagnosis of “chronic” SCLS. MGUS is not universally present in SCLS and is therefore not required for the diagnosis.