Novel Genetic Disorders of the Immune System
Novel Genetic Disorders of the Immune System
Background:

 - The immune system helps the body fight infection and disease. People with immune system
 problems can get infections, blood disorders, and other health problems. Researchers want to
 learn more about the immune system, like what causes it to not work properly.

 Objectives:

 - To evaluate people with certain types of immune system disorders.

 Eligibility:

 - Adults and children with an immune disorder or symptoms of one, and their relatives. Some
 disorders are not included in this study.

 Design:

 -  Researchers will review participants medical records.

 -  Participants may mail in a blood or saliva sample, or be evaluated at the clinic. At the
 clinic, they may have a medical history, physical exam, blood tests, and imaging scans
 (with dye given through a needle in the arm). They may have genetic testing done on a
 sample of blood, saliva, hair, or nail clipping.

 -  Participants may choose to have a skin biopsy. Up to 2 skin samples will be taken from
 their arm, back, or other area. A biopsy punch is inserted into the skin and rotated. A
 small circle of skin is removed.

 -  Participants 10 and older may also choose to have leukapheresis. Blood is taken through
 a needle in one arm. It passes through a machine that separates the white blood cells.
 The rest of the blood is returned by needle in the other arm.

 -  Researchers may recommend medicines, but no treatments are being studied.

 -  Participants may be invited to return for visits over several years. At those visits,
 they may repeat some or all of the above tests. Or they may mail in blood or other
 samples. They may also send medical records.
This study is designed to evaluate patients with suspected or identified novel immune
 disorders, with a focus on abnormal immune homeostasis potentially due to defects in
 activation or apoptosis. Blood relatives of enrolled patients will also be evaluated.
 Affected individuals may have Mendelian gene defects involving mostly single or occasionally
 multiple genes. These patients may have signs and symptoms suggestive of clinically
 significant lymphocyte homeostasis disorders. However, some selected patients manifesting
 autoimmunity, autoinflammatory conditions, end-organ dysfunction, Epstein-Barr virus (EBV)
 and cytomegalovirus (CMV) viremia, frequent infections, allergies, or laboratory
 abnormalities consistent with immune defects of research interest to the Laboratory of
 Clinical Immunology and Microbiology may also be studied under this protocol at the
 discretion of the Investigators.

 This protocol will facilitate the discovery of the role of genetic pathways and modes of
 inheritance associated with pathophysiological events leading to immune system dysregulation,
 particularly disorders of immune cell homeostasis. A better understanding of the genetics as
 well as biochemical and molecular basis of complex immune disorders could also lead to the
 development of novel therapeutic targets and approaches.

 Patients will undergo clinical evaluations that include history and physical examinations,
 blood sampling, radiological exams, genetic testing, skin biopsy, and other medically
 indicated procedures. Genetically related family members of patients may also be screened and
 evaluated for clinical, in vitro, and genetic correlates of immune abnormalities. Patients
 and blood relatives unable or too sick to travel to NIH Clinical Center (CC) may be evaluated
 through mail-in blood samples. Patients and their relatives will remain enrolled on this
 study to observe the natural history of the disorder and obtain blood, saliva, skin biopsy,
 or other specimens at periodic intervals. This study aims to enroll up to a total of 500
 patients and their family members.
-  INCLUSION CRITERIA:

 The following inclusion criteria apply to all subjects:

 -  Patient and relatives aged 0-99 years old to include women who are pregnant or
 breastfeeding. Only patients >2 years of age, in stable clinical status and meeting
 the weight requirement of the NIH CC will be physically evaluated at the NIH CC.

 -  Willingness to allow storage of blood, saliva, and other tissue specimens for future
 use in medical research.

 -  Willingness to participate in genetic testing and allow sharing of genetic information
 in secure databases like dbGAP. These tests may include, but are not limited to, whole
 exome and whole genome sequencing.

 -  Priority may be given to individuals with a family history (if readily available)
 suggestive of multiple affected members with a constellation of signs and symptoms
 suggestive of immune dysfunction among first- or second-degree relatives.

 -  Eligibility of special populations

 -  A. NIH employees are eligible

 -  B. Women who are pregnant or breast feeding are eligible to enroll as probands
 Pregnant relatives are also eligible for inclusion as

 they can provide important controls, genetic reference and historic clinical information.
 This protocol is not actively seeking women who are pregnant.

 --C. Pediatric populations are eligible, with restrictions, in order to learn about the
 natural history of the immune disorders under investigation and to provide diagnostic work
 up for their ongoing clinical care. Healthy pediatric relatives can provide important
 diagnostic and genetic reference for affected patients.

 -Pediatric populations are eligible, with restrictions, in order to learn about the natural
 history of the immune disorders under investigation and to provide diagnostic work up for
 their ongoing clinical care. Healthy pediatric relatives can provide important diagnostic
 and genetic reference for affected patients.

 Patients must have:

 -  An identified genetic basis for an immune disorder or signs and symptoms suggestive of
 clinically significant immune dysregulation and/or immunodeficiency manifesting with
 features including but not limited to autoimmunity, autoinflammatory conditions,
 lymphadenopathy, end-organ dysfunction, unusual infections, allergies, or laboratory
 abnormalities consistent with immune dysregulation.

 -  A primary physician outside of the NIH and will be required to submit a letter or
 clinical summary from their referring physician that documents their relevant health
 history.

 EXCLUSION CRITERIA:

 Patients will be excluded for any of the following:

 -  Known genetic disorders that are already well characterized, such as severe combined
 immunodeficiency (SCID), chronic granulomatous disease (CGD), etc., and those in which
 we do not have an enduring research interest in the LCIM.

 -  Patients with unknown immune disorders will be excluded if they have received
 chemotherapy within the last 6 months for a malignancy or have infections such as HIV
 or mycobacterial infections.

 -  Severe clinical illness requiring highly specialized teams and institutions. The NIH
 may not be able to provide appropriate care for certain referred cases. The Principal
 Investigator (PI) may determine that the patient is eligible for enrollment but
 ineligible for admission to the Clinical Center. Patients and relatives with certain
 obstetric issues may pose a safety risk for travel and evaluation here. Eligibility
 for this group will be determined on a case by case basis by the PI.

 -  Patients with well-defined autoimmune conditions such as systemic lupus erythematosus
 (SLE), Hashimoto s thyroiditis, Addison s disease, Graves disease, sarcoidosis and
 rheumatoid arthritis, among others.

 Blood relatives will be excluded for the following:

 -Any condition which in the opinion of the investigator may interfere with evaluation of an
 immune system abnormality that is the subject of study under this protocol.