Screening Protocol for Genetic Diseases of Mast Cell Homeostasis and Activation

Background:

• Mast cells are responsible for most symptoms of allergic reactions. In some allergic diseases, it is unusually easy to cause mast cells to release their contents and cause allergic reactions. In other cases, mast cells grow abnormally and, in rare cases, can result in tumors. Mast cells also control other parts of the immune system.
• Understanding why mast cells behave abnormally in allergic diseases is important to finding better ways for diagnosing and treating these potentially life-threatening disorders.

Objectives:

• To screen mast cells at the genetic and functional levels to characterize abnormalities, identify mutations, detect carrier states, and/or develop therapies for such disorders.
• To create a library of information about inherited diseases of mast cell homeostasis and activation, including piebaldism (problems with skin and hair pigmentation), anaphylaxis (severe allergic reaction), allergies, asthma, atopic dermatitis (eczema), allergic rhinitis ( hay fever ), food allergies, urticaria/angioedema (hives/swelling), immunodeficiency diseases, and autoimmune diseases.

Eligibility:

• Patients between the ages of 1 and 80 years who have been referred by a physician and are known to have or be suspected of having an inherited disorder of mast cells, in particular patients (and their relatives) with piebaldism, allergies, or anaphylaxis that is not caused by allergies.

Design:

• Study population will consist of up to 250 participants in a 5-year period. One third of the study population will consist of patients; the other two thirds will consist of biological relatives.
• Evaluation is limited to testing on blood specimens; no treatment will be provided.
• Clinical and research laboratory evaluations of patients will include the following:
• Clinical evaluation and previous laboratory tests as documented in outside medical records by health care providers. A standard questionnaire will also be administered at the time of subject enrollment.
• Blood collection for clinical laboratory testing, tailored to each subject's clinical evaluation where appropriate (5 ml).
• Blood collection for research laboratory testing, tailored to each subject's clinical evaluation-including genetic screening and assessment of mast cell growth and functioning-and storage of additional frozen blood specimens for future studies (up to an additional 30 ml).
• Evaluations of blood relatives will include the following:
• Clinical evaluation as documented from outside medical records by health care providers and administration of a standard questionnaire.
• Blood collection where indicated for diagnostic or research purposes.
• After 12 consecutive months on the study, results from initial evaluation will be reviewed. Subjects with findings deemed to be of continued interest will be contacted and invited to remain as active participants to this protocol for another year, provided that they renew their consent to participate.

This protocol is designed to screen subjects (and some family members) with suspected or identified genetic diseases of allergic inflammation or mast cell homeostasis and activation. Patients determined by clinical history and initial outside evaluation by their referring physician to be of interest will be consented and enrolled into this study. Blood specimens stored blood products and derivatives, and/or buccal swabs from such patients and/or their family members will be obtained for research studies related to understanding the genetic and biochemical bases of these diseases. Outside medical records may be obtained for chart review to correlate clinical history to research laboratory testing results. Results will be relayed to the referring physicians and, where applicable, patients will be referred to other appropriate National Institutes of Health protocols for additional clinical evaluation and treatment. The study will enroll up to 250 subjects and family members over the next 5 years.

• Piebaldism
• Idiopathic Anaphylaxis
• Allergy
• Chronic Urticara
• Angioedema

• Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, Metcalfe DD. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10560-4.
• Worobec AS, Semere T, Nagata H, Metcalfe DD. Clinical correlates of the presence of the Asp816Val c-kit mutation in the peripheral blood mononuclear cells of patients with mastocytosis. Cancer. 1998 Nov 15;83(10):2120-9.
• Kirshenbaum AS, Goff JP, Semere T, Foster B, Scott LM, Metcalfe DD. Demonstration that human mast cells arise from a progenitor cell population that is CD34(+), c-kit(+), and expresses aminopeptidase N (CD13). Blood. 1999 Oct 1;94(7):2333-42.

• INCLUSION CRITERIA:
• Subjects, ages birth to 999 years old, known to have or suspected of having an inherited disorder of allergic inflammation or mast cell homeostasis or activation, will be eligible for enrollment. Because of the intensive time and labor required for research laboratory testing, subjects will be enrolled only if in the opinion of the investigator (based on discussions with the patient's private physician) there is a high index of suspicion of a genetic disease of allergic inflammation. Blood relatives of enrolled subjects will be eligible for enrollment. There will be no discrimination as to age, gender, race, or disability.
• Subjects must have a health care provider outside of the NIH.
• Subjects/guardians must be willing and able to give informed consent.
• Subjects must agree to have their blood stored for future studies of the immune system and/or other medical conditions.
• Women will be included in the study, including those who are lactating or may be pregnant.
• Children will be included in the study.

EXCLUSION CRITERIA:

• The presence of an acquired abnormality of the immune system, such as cytotoxic chemotherapy or malignancy, may be grounds for possible exclusion if, in the opinion of the investigator, the presence of such a disease process would interfere with evaluation.
• Subjects with a history of HIV or evidence of chronic Hepatitis B and/or C infection will be excluded.