Studies in the Pathogenesis of Systemic Capillary Leak Syndrome
Studies in the Pathogenesis of Systemic Capillary Leak Syndrome
Background:

 -  Systemic Capillary Leak Syndrome (SCLS) is a disorder of unknown cause characterized by
 episodes of life-threatening drop in blood pressure and leakage of fluids into tissues.
 The outcome from an episode of SCLS may be mild and resolve on its own, or may be severe
 and result in death. Although SCLS likely involves abnormalities in the cells lining
 blood vessels, the specific cause(s) of this disorder are not known.

 -  The treatment of choice for an acute SCLS episode is intravenous fluids and drugs such
 as norepinephrine (adrenaline), which are given to keep blood pressure at a level that
 will maintain vital organ function. This may be followed by a course of intravenous
 steroids and IVIG. Currently, there is no cure, but IVIG has been effective in
 diminishing the frequency and/or intensity of SCLS episodes when given regularly, as
 long-term effective preventive therapy for many patients who experience recurrent
 episodes of SCLS.

 -  This protocol is focused on understanding what causes SCLS with the hope that research
 findings will lead to the design of safe and more effective treatments.

 Objectives:

 - To investigate mechanisms that may cause Systemic Capillary Leak Syndrome.

 Eligibility:

 -  Patients between 16 and older who have been diagnosed with SCLS. Patients who have been
 diagnosed with SCLS and are between the ages of 7 and 16 may participate off-site, by
 sending specimens to the NIH. Patients 16 and older who have been diagnosed with SCLS
 and cannot travel to the NIH may also participate off-site.

 -  Patients must have a documented history of at least one episode of SCLS with all three
 of the following documented on at least one occasion: low blood volume, low blood
 pressure without cause, and evidence of protein leakage during the episode. A letter of
 a referral from a treating physician is also required.

 Design:

 -  Patients seen on site will be evaluated at the National Institutes of Health (NIH) for
 approximately 4 to 5 days on an inpatient basis, and will undergo the following
 procedures:

 -  Medical history and physical examination.

 -  Blood samples for evaluation and research purposes, as well as possible genetic
 testing.

 -  Apheresis procedure, if needed, to obtain a larger volume of blood cells for
 research.

 -  Bone marrow biopsy, if medically indicated.

 -  Other medically indicated tests, such as skin tests to check for possible allergic
 reactions.

 -  Patients who have a capillary leak episode while at NIH will be treated with the
 standard of care for treating SCLS.

 -  Patients will be discharged from the protocol 1 year after the NIH visit.

 -  Patients participating off-site will be asked to collect and send specimens (such as
 blood) to the NIH for research purposes and evaluation.

 -  Unaffected Biological relatives of SCLS patients and Unrelated Normal Volunteers may
 also enroll on the study. Relatives and Normal Volunteers may be asked to provide
 research samples for the study, such as skin biopsy and research blood specimens.
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%). Fewer than 500 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
 and/or genetic and molecular events that may predispose to SCLS episodes. We plan to enroll
 up to 270 total subjects, in this study, which includes affected subjects, family members,
 and healthy volunteers. We anticipate that our findings may be a first step toward the
 development of new targeted therapies.
-  PARTICIPANT INCLUSION CRITERIA:

 Subjects with SCLS under 8 years of age are only eligible for components of this protocol
 that can occur Off Site and samples can be sent in to the NIH. All SCLS subjects must be at
 least 8 years old to participate in any other aspects of this protocol at the NIH.

 Subjects with SCLS may enter study while pregnant and remain on study after becoming
 pregnant. At the discretion of the investigator, some components of this protocol will not
 occur while subject is pregnant.

 Diagnosis or suspected diagnosis of Systemic Capillary Leak Syndrome by a physician or
 documented history of capillary leak as characterized by one or more of the following:

 1. Hypotension (systolic blood pressure typically less than 90 mm Hg or diastolic blood
 pressure less than 60 mm Hg) or associated symptoms of hypotension (e.g., hypotonia
 [collapse], lightheadedness or syncope, incontinence, increased thirst)

 2. Laboratory evidence of hemoconcentration (e.g., hemoglobin levels above the normal
 range [typically greater than17 g/dL], elevated leukocyte counts).

 3. Clinical evidence of fluid extravasation (e.g. edema) and/or laboratory evidence of
 protein extravasation such as serum hypoalbuminemia (less than 3.5 g/dL) either
 chronically or during an acute hypotensive episode.

 Letter of referral, with copies of pertinent medical history and laboratory studies,
 from prospective study subject s referring physician. Patients may self-refer, but a
 letter of referral from primary physician is still required.

 Willing to donate blood for sample storage to be used for future research.

 PARTICIPANT INCLUSION CRITERIA FOR THE SUBJECT'S RELATIVES/HEALTHY VOLUNTEERS:

 Willing to donate blood for sample storage to be used for future research.

 Relatives must be at least 3 years old.

 Healthy volunteers must be at least 18 years old.

 Relatives may be pregnant or become pregnant while participating in this protocol. At
 the discretion of the investigator, some components of this protocol will not occur
 while subject is pregnant. No skin biopsies or intradermal testing will be done on
 pregnant relatives. Bloodwork volumes may be decreased at the discretion of the
 investigator.

 Healthy volunteers may not be pregnant.

 Able to give informed consent.

 PARTICIPANT EXCLUSION CRITERIA:

 Presence of conditions which, in the judgment of the investigator or the referring
 physician, may put the subject at undue risk for travel (including frequent episodes
 of severe capillary leak, symptoms not preventable by pre-medication, acute infection,
 severe thrombocytopenia [minimum platelet count of 30,000/ (Micro)L], or significant
 cardiovascular disease).

 Any condition that in the view of the principal investigator would make the subject
 unsuitable for enrollment in this study (i.e., medically unstable, unstable to provide
 phlebotomy samples).

 There is an identified cause for hypotensive episodes and/or tissue swelling.

 PARTICIPANT EXCLUSION CRITERIA FOR THE SUBJECT'S RELATIVES/HEALTHY VOLUNTEERS:

 Presence of conditions which in the judgment of the investigator may put the subject
 at undue risk (i.e., medically unstable, unstable to provide phlebotomy samples).

 Any condition that in the view of the principal investigator would make the subject
 unsuitable for enrollment in this study (i.e., medically unstable, unstable to provide
 phlebotomy samples).