Natural History Study for BEN

Study Overview
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Brief Summary
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In recent decades, hematologists have noticed that persons of African descent sometimes have lower white blood cell counts of a certain type, called granulocytes. These cells help to fight infections. The lower number of granulocytes in this situation does not appear to lead to more infections, and these individuals do not have any symptoms. This condition is called benign ethnic neutropenia (BEN), and is observed in a small percentage of individuals of African descent. This study will investigate the condition by studying people with and without BEN. The goals of this study are to: identify individuals of African descent with BEN. determine the effects of two drugs, G-CSF and dexamethasone, on granulocyte production and movement. determine whether there are differences in those with and without BEN in the way genes are stimulated after the administration of G-CSF and dexamethasone. Study participants will be asked to interview with the research team, undergo physical exams, donate a blood sample, and receive G-CSF by injection, followed by dexamethasone (orally) about three weeks later. They also will be required to undergo apheresis three times, a procedure in which blood is drawn from a donor and separated into its components. Some components are retained for research analyses, such as granulocytes, and small amount of blood; the remainder is returned by transfusion to the donor. This procedure will be required of participants before they receive G-CSF, the day after they receive G-CSF, and the day after they receive dexamethasone. Gene messages (mRNA will be isolated from granulocytes, and analyzed to better understand granulocyte growth and movement.

Detailed Description
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Benign ethnic neutropenia (BEN) is defined by peripheral blood absolute neutrophil count less than 1.5 x 10 (9) per liter without an increase in infections. This condition has been described in individuals of African descent. Although these individuals have normal myeloid maturation on bone marrow examinations, they appear to release fewer neutrophils into the circulation when stimulated by hydrocortisone, compared to normal controls. This suggests that there may be differences in the regulation of neutrophil release or trafficking. In the past decade, granulocyte-colony stimulating factor (G-CSF) has been widely used in a variety of clinical settings, from patients with chemotherapy-induced neutropenia to normal volunteers for peripheral blood stem cell collection. G-CSF, however, has not been used in individuals with BEN. Furthermore, gene expression in neutrophil proliferation and trafficking has not been studied in these individuals. The purpose of this study are to (1) identify individuals with BEN; (2) follow the natural history of BEN; (3) determine if there is a familial inheritance pattern; (4) characterize and compare neutrophil response to dexamethasone and G-CSF; (5) compare the pattern of neutrophil gene expression by microarray analyses; and (6) determine if mutations are present at the DNA level to account for gene expression pattern differences in individuals of African descent with and without BEN at baseline, post dexamethasone, and post G-CSF stimulation.

Official Title
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Natural History and Molecular Characterization of Benign Ethnic Neutropenia in Individuals of African Descent

Conditions
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Neutropenia, Agranulocytosis, Hematologic Diseases, Leukocyte Disorders, Leukopenia

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Individuals of African descent of age 5 or greater Normal renal function: creatinine <1.5 mg/dL and proteinuria <1+ Normal liver function: bilirubin <1.5 mg/dL and transaminases within normal limits For control subjects: WBC within normal range (3,300-9,600/mm3), granulocytes/neutrophils greater than or equal to 2,000/mm3, platelets >150,000/mm3, hemoglobin > 11.5g/dL and normal MCV For benign ethnic neutropenic subjects: two blood counts, at least 1 month apart, with granulocytes/neutrophils <1,500/mm3, platelet >150,000/mm3, hemoglobin >12.5g/dL, and normal MCV. We will also follow subjects whose neutrophil counts are between 1500 and 2000/mm3 in a separate cohort periodically (e.g. once every 1-2 years) to see if their blood counts behave more like BEN or normal subjects. Female volunteers of childbearing age should not be pregnant Meets NIH Department of Transfusion Medicine (DTM) eligibility criteria for blood component donation for in vitro research uses (negative serologic tests for syphilis, hepatitis B and C, HIV, and HTLV-1) Ability to give informed consent to participate in the protocol EXCLUSION CRITERIA: Any underlying hematologic disorder including anemia, and sickle cell disease. Subjects with thalassemia or sickle cell trait are not excluded. Current use of corticosteroids, e.g. prednisone, dexamethasone, or hydrocortisone. Corticosteroids must be discontinued at least one month prior Active or chronic viral, bacterial, fungal, or parasitic infection. Any antibiotic use should be discontinued at least one month prior History of autoimmune disease, such as rheumatoid arthritis or systemic lupus erythematosus, or positive anti-nuclear antibody (ANA ELISA) of 3 E.U. (ELISA units) or greater. Low B12 or folate levels, or abnormal thyroid function tests History of cancer or chemotherapy, except squamous carcinoma of the skin and cervical carcinoma in situ Pregnant woman or positive urine pregnancy test History of clinically significant cardiovascular disease (cardiology consultation may be obtained when clinically indicated) Any positive serum screening test as listed below Allergy to G-CSF or bacterial E. coli products Active pulmonary disease or a pulse-ox level of less than 95% on screening exam

Ages Eligible for Study
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Minimum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| 1<br>Individuals of African descent with benign ethnic neutropenia (BEN) at baseline | |
| 2<br>Individuals of African descent without benign ethnic neutropenia (BEN) at baseline | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serial blood counts in BEN | In our study, we hope to further elucidate the etiology of BEN in research subjects by isolating granulocyte mRNA after G-CSF and dexamethasone stimulation, applying microarray analyses to screen for gene expression differences, and confirming expression pattern differences by DNA analyses. We will focus on genes that are important in the proliferation and trafficking of neutrophils,such as PRV-1, elastase, myeloblastin, transcription factor PU.1, CAAT enhancing binding protein-alpha (C /EBP), stromal derived factor-1 (SDF-1), and CXC receptor-4 (CXCR4). | Ongoing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukapheresis, G-CSF, Dexamethasone, mRNA, Benign Ethnic Neutropenia, BEN, Healthy Volunteer, HV