Studies in the Pathogenesis of Systemic Capillary Leak Syndrome

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 210 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.

Subjects with SCLS must be HIV negative

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.

Ability to give informed consent, or parent or guardian able to give informed consent.
A Medical/Legal Guardian or Legally Authorized Representative may give consent for an
incapacitated adult SCLS subject using the Standard Consent. Previously incapacitated
adults will be re-consented, once the acute phase resolves and the subject is able to
give his/her own consent.

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.

Healthy volunteers and relatives must be HIV negative

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/microL], or significant
cardiovascular disease)

Any condition that in the view of the principal investigator would make the subject
unsuitable for enrollment in this study

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

Any condition that in the view of the principal investigator would make the subject
unsuitable for enrollment in this study