Characterization of the Pathogenesis of Primary and Secondary Lymphatic Disorders

Disorders of lymphatic function are associated with multiple presentations, the most common
of which is lymphedema, a chronic swelling of the extremities, due to impaired lymphatic
drainage. It can cause disability and a predisposition to infection and chronic ulceration.
Other lymphatic disorders present with visceral manifestations such as regional or systemic
lymphangiomatosis, pulmonary and intestinal lymphangiectasia, protein-losing enteropathy,
chylous ascites, and chylothorax. Abnormalities of smooth muscle cell proliferation are
associated with lymphangiomatosis. Proliferation of a neoplastic cell, the LAM cell, which
exhibits a smooth muscle cell phenotype, is associated with lymphangioleiomyomatosis.
Currently, treatment for many of these disorders is symptomatic and the prognosis is
variable.

The molecular mechanisms of lymphatic vasculogenesis are incompletely understood, but
critical genes have been described, and mutations in these genes may lead to developmental
abnormalities. There may be a genetic predisposition to lymphatic disorders, with a role for
modifier genes in disease progression. The purpose of this study is to (a) define the natural
history of lymphatic diseases, (b) characterize the clinical phenotypes, and (Copyright)
elucidate their pathogenesis at the physiological, cellular and molecular levels. This
protocol is part of a Trans-Institute basic, translational and clinical initiative in
lymphatic disorders and will include participation of principal investigators across the NIH,
as well as extramural investigators.

- INCLUSION CRITERIA:

1. Patients 2 years of age or older with clinical or histological evidence for a
lymphatic abnormality; patients will in the vast majority of cases be referred
with the diagnosis of a lymphatic disorder.

2. Patients 2 years of age or older with findings on physical examination consistent
with the diagnosis of a lymphatic abnormality.

3. Relatives of patients with lymphatic disorders, 2 years of age or older.

4. Healthy research volunteers 18 years of age or older as control subjects.

EXCLUSION CRITERIA:

1. Patients who are less than 2 years of age. Research volunteers less than 18 years of
age. Age greater than 90 years old.

2. Advanced stage of any systemic illness.

3. An exclusion criterion for participating in the x-ray portion of the study is
pregnancy.

4. Exclusion criteria for participating in the bronchoscopy portion of the study are: (1)
presence of any contraindication for fiberoptic bronchoscopy, with lavage and/or
bronchial brushing; (2) advanced stage of a pulmonary or a systemic illness such that
the risk is judged to be significant even in the absence of a specific
contraindication to the procedure; (3) allergy to topical anesthetic (e. g.,
lidocaine); (4) current or recent respiratory infection (within the last 4 weeks); (5)
pregnancy or lactation; (6) age less than 18 or greater than 65.

5. Exclusion criteria for participating in the endoscopy portion of the study are: (1)
Any medical, psychiatric, or social conditions which, in the opinion of the
investigators, would make participation in this protocol not in the best interest of
the patient; (2) have a history of surgical removal of a portion or all of the colon
if it is believed to increase risk; (3) are pregnant; (4) have had radiation to the
abdomen or pelvis; (5) have poor heart or lung function that would make sedation too
risky; (6) have allergy or other contraindications to midazolam or fentanyl; (7) are
unable to tolerate preparation for the procedure; (8) are unable to give consent; (9)
have had abdominal surgery within eight weeks; (10) are taking anticoagulant therapy
that cannot be interrupted; (11) have had diverticulitis or an abdominal abscess
within eight weeks.