Patient case: 54-year-old male with malignant hyperthermia; genetic feature: RYR1

Clinical trial: Natural History Study of GATA2 Deficiency and Related Disorders

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: -  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.
  EXCLUSION CRITERIA - RELATIVE:
  -As part of the study we may obtain medical records, questionnaires, blood work, urines, buccal swabs, skin biopsies and bone marrow biopsies from any blood relatives, male or female, great than or equal to 2 years old, of any patient on this study. This will allow for testing family members for GATA2 mutation as well as screening them as a potential bone marrow transplant donor, for their relative on study. If a relative is positive for GATA2 then they could become a patient on the study. No invasive studies (e.g., bone marrow biopsy) will be done on unaffected relatives unless indicated for them to be bone marrow donors for transplantation.
  EXCLUSION CRITERIA - SUBJECT:
  -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.

Relevance to patient case: not relevant