Clinical trial NCT01905826: Natural History Study of GATA2 Deficiency and Related Disorders
Official title: The Natural History of GATA2 Deficiency and Related Disorders
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: GATA2 Deficiency
Keywords: Myelodysplastic Syndromes
Herpesvirus
Disseminated nontuberculous Mycobacterial (NTM)
human papillomavirus (HPV)
Leukemia
Natural History
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: Baylor College of Medicine
name: UCSF Diabetes Center and Division of Infectious Diseases
name: Department of Molecular and Cell Biology
name: New York Genome Center
First posted: 2013-07-23
Enrollment: 600
Sex: ALL
Minimum age (years): 2
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients \>=2 years old with known mutations in GATA2 or those with clinical and laboratory characteristics strongly consistent with GATA2 deficiency will be enrolled along with any of their blood relatives.

Brief summary: Background:

- GATA2 deficiency is a genetic disorder that can cause problems with a person s immune system and other body systems. Some people who have this disorder develop few problems from it. Others can have a wide range of health problems, from skin problems, to hearing loss, to cancer. These problems can happen at any age. Researchers want to study GATA2 deficiency to better understand what types of health problems it can cause, and why it causes problems in some people but not others, and at different ages.

Objectives:

- To improve understanding of GATA2 deficiency so there can be better diagnostic tests and treatments in the future.

Eligibility:

- People 2 years of age or older who have a GATA2 gene mutation or certain health conditions that are commonly seen in people with this mutation and their blood relatives.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected to see whether participants have the GATA2 genetic mutation. Several other tests may be recommended, but participants can decline to take them.
* Participants will be eligible to receive standard care for GATA2 deficiency through this protocol. They may be eligible for other clinical trials at the National Institutes of Health as well.
* Participants will have regular study visits once a year to evaluate their GATA2 deficiency. Participants will take part in the study for at least 3 years and up to 15 years. At these follow-up visits, participants will fill out a questionnaire and take a physical exam and blood tests. Other tests may be performed as needed.

Detailed description: 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 300 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 visits for up to 15 years; additional follow-up diagnostic procedures will be conducted based on clinical need.

Eligibility criteria: * 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.

Primary outcomes:
measure: Prospectively follow patients with GATA2 deficiency or phenotypic characteristics strongly consistent with GATA2 deficiency to characterize the full spectrum of clinical disease, better understand the reasons for phenotypic variability, better u...
timeFrame: ongoing
Secondary outcomes:
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
name: Steven M Holland, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Wu Z, Gao S, Diamond C, Kajigaya S, Chen J, Shi R, Palmer C, Hsu AP, Calvo KR, Hickstein DD, Holland SM, Young NS. Sequencing of RNA in single cells reveals a distinct transcriptome signature of hematopoiesis in GATA2 deficiency. Blood Adv. 2020 Jun 23;4(12):2656-2670. doi: 10.1182/bloodadvances.2019001352.