Natural History Study of GATA2 Deficiency and Related Disorders

Mutations in GATA2, a critical hematopoietic transcription factor, underlie a complex congenital disorder characterized by immunodeficiency, bone marrow failure, and lymphatic/vascular dysfunction. Patients with GATA2 deficiency may suffer from a striking variety of diseases including severe and recurrent infections, myelodysplasia/leukemia, pulmonary alveolar proteinosis, lymphedema, sensorineural hearing loss, and possibly susceptibility to other malignancies, autoimmune disorders, thrombotic events, and miscarriage. Mutations in GATA2 appear to be fully penetrant, but expressivity is remarkably variable, even among related individuals. Disease may also manifest at nearly any age ranging from early childhood to late adulthood, the reasons for which remain poorly understood.

While considerable progress has been made towards better understanding this complex congenital disorder, many important questions remain unanswered: What is the full spectrum of clinical disease and the associated pathophysiology? What accounts for the remarkable variability in age of onset and clinical phenotype? What are the optimal strategies for disease diagnosis and management? This natural history protocol is designed to further characterize the clinical phenotype of GATA2 deficiency, better understand the reasons for phenotypic variability, better understand disease progression over time, standardize the diagnostic evaluation, and facilitate the screening of at risk relatives. Up to 500 males and females greater than or equal to 2 years old with proven mutations in GATA2 or clinical and laboratory characteristics strongly consistent with GATA2 deficiency will initially undergo a series of baseline laboratory tests and diagnostic procedures at the NIH. Follow-up laboratory testing will be conducted at yearly; additional follow-up diagnostic procedures will be conducted based on clinical need.

• INCLUSION CRITERIA:

Males and females greater than or equal to 2 years old must meet the following criteria to be eligible for participation in this study:

• Have a mutation in GATA2 proven by genetic testing (previous test results will be accepted) OR meet both of the following criteria:

• Clinical characteristics strongly consistent with GATA2 deficiency per the following criteria and at the discretion of the principal investigator (PI). Individuals without a GATA2 mutation must have a past or present history of 1 or more of the following to be considered for study enrollment:

• Disseminated NTM or invasive fungal infection.
• Severe or recurrent HPV or herpesvirus infection.
• MDS, AML, or CMML.
• Biopsy-proven PAP.
• Laboratory characteristics strongly consistent with GATA2 deficiency per the following criteria. Individuals without a GATA2 mutation must have 1 or more of the following to be considered for study enrollment:

• Absolute monocyte count <240 cells/microL.
• Absolute B lymphocyte count <60 cells/microL.
• Absolute NK lymphocyte count <126 cells/microL.
• Agree to undergo genetic testing.
• Allow their samples to be stored for future research.

RELATIVE INCLUSION CRITERIA:

Blood relatives, male or female, greater than or equal to 2 years old, of any patient on this study. If a relative is positive for GATA2 then they could become a patient on the study.

SUBJECT EXCLUSION CRITERIA:

Individuals with any condition or who are taking any medications that, in the opinion of the investigator, contraindicates participation in the study will be excluded.