Background:

Trisomy 8 mosaicism is a genetic disorder that can increase inflammation in the body. Symptoms include fevers; sores or ulcers in the mouth, digestive tract, or genital area; skin rashes; problems in organs or tissues; and changes in bone marrow cells. Researchers want to conduct a natural history study to learn more about these symptoms and what causes them.

Objective:

To gather data and samples from people with and without the trisomy 8 mosaicism.

Eligibility:

People of any age with the trisomy 8 gene mosaicism. Their healthy relatives are also needed.

Design:

Affected participants will have visits every 1 to 2 years for 30 years at NIH. Each visit will take 1 to 5 days and may be in-person or remote. With remote visits, participants may have a video call with the study team and samples may be sent to researchers by mail.

Participants may have these procedures:

Physical exam, with blood tests.

Tests of brain function and motor skills.

Sensory tests. Researchers will see how participants respond to sensations such as pinpricks, heat, cold, and pressure.

Magnetic resonance imaging (MRI) scan of the brain and/or spine.

X-ray of the spine.

Ultrasound test of heart function (echocardiogram).

Tissues samples (biopsies) collected from the skin, inside of the mouth, and bone marrow.

Swabs to collect cells from the mouth, skin, and vagina.

Collection of blood, stool, urine, saliva, hair, and fingernail samples.

X-rays, MRI, and heart tests will be done only once. Other procedures may be repeated at each visit. All tests and procedures are voluntary.

Healthy relatives who enroll will have a baseline visit and then follow-up visits as needed. They will have a physical exam. The inside of their mouth may be swabbed. Samples of blood, stool, urine, and saliva may be taken.

Study Description:

This is a natural history protocol designed to characterize the clinical spectrum of trisomy 8 mosaicism and trisomy 8-associated autoinflammatory disease (TRIAD) and related autoinflammatory disorders and further evaluate approaches to screening, diagnosis, and management. We will enroll affected patients and their unaffected relatives and collect a variety of clinical data and biological specimens for research analyses to better understand disease mechanisms. Biological samples from affected participants may include biopsies from the oral mucosa, skin, and bone marrow; swabs of the mouth, skin, and vagina; urine, stool, and saliva collections; and hair and fingernail clippings. Other clinical data may include imaging studies (such as magnetic resonance imaging [MRI], x-rays, and echocardiogram), questionnaires, and results from medical consults and clinically indicated procedures. Biological samples from unaffected relatives of participants may include blood, mouth swabs, stool, urine, and saliva. Participants may be seen in person or remotely via telehealth and provide send-in samples. After the initial baseline assessment, optional follow-up visits will occur approximately every 1 to 2 years, depending on the scientific needs of the study team and the participant s clinical status and interest.

Objectives:

Primary Objectives:

1. Characterize the clinical spectrum and natural history of trisomy 8 mosaicism and related disorders.
2. Characterize the immunologic profile in blood, tissue, and bone marrow of participants with trisomy 8 mosaicism and related disorders.

Secondary Objectives:

1. Determine appropriate screening and diagnostic workup of individuals with trisomy 8 mosaicism and related disorders.
2. Identify the long-term risk of and association with neoplasm among individuals with trisomy 8 mosaicism.
3. Characterize the distribution of trisomy 8 cells in different tissues and cell types and describe how this contributes to disease manifestations and variability.
4. Evaluate or characterize immune responses to targeted therapeutics to better understand the pathophysiology of trisomy 8 mosaicism and related disorders.

Exploratory Objectives:

1. Identify the specific genes and immunologic pathways that lead to disease manifestations seen in patients with trisomy 8.
2. Identify new genetic diseases that lead to mucosal ulcers and understand the immunologic mechanisms that contribute to mucosal ulcerations.

Endpoints:

Primary Endpoints:

1. Clinical characterization of participants with trisomy 8 mosaicism and related disorders based on history, physical examination, radiologic imaging, and laboratory testing.
2. Characterization of immunologic profile of participants with trisomy 8 mosaicism and related disorders over time in comparison to healthy controls using cellular and molecular techniques including, but not limited to immune cell phenotyping, transcriptomics, proteomics, and ex vivo functional studies.

Secondary Endpoints:

1. Characterization of laboratory, radiologic, biopsy, and physical exam findings.
2. Identification of individuals with trisomy 8 who develop malignancy and assessment of risk factors including but not limited to history, findings on bone marrow biopsies and complete blood counts (CBCs), next-generation sequencing (NGS) for risk variants, and flow cytometry.
3. Determination of the percentage of trisomy 8 cells in various tissue types including bone marrow, blood, fibroblasts cultured from skin, and biopsy samples, and the association with clinical phenotype.
4. Assessment of immune response to therapeutics based on inflammatory markers, clinical history, and physical exam findings.

Exploratory Endpoint:

1. Identification of genes that may lead to mucosal ulcerative disease when mutated or over/underexpressed.

• INCLUSION CRITERIA:

To be eligible to participate in this study, an individual must meet the following criteria:

1. Stated willingness to comply with study requirements.
2. Aged <= 99 (ability to be seen at NIH vs. remote visit may be determined by age and location).
3. Willingness to allow storage of data and specimens for future research.

Additional Inclusion Criteria for Affected Participants

1. Must have one of the following:

   1. Trisomy 8 mosaicism verified by genetic testing (including but not limited to karyotype, fluorescence in situ hybridization [FISH], whole genome sequencing [WGS], whole exome sequencing [WES], or microarray), or
   2. Inflammatory mucosal ulcerative disease clinically similar to TRIAD at the discretion of the principal investigator.

2. Ability of participant or LAR to provide informed consent.

Additional Inclusion Criteria for Biological Relatives

1. Be an unaffected biological relative of an affected participant.
2. Ability to provide informed consent.
3. Willingness to provide at least one biospecimen.

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.

Co-enrollment guidelines: Enrollment in this protocol does not preclude individuals from enrolling or participating in any other NIH protocols, including studies of investigational agents. Participants will be asked about their participation in other studies to ensure that blood draws do not exceed NIH limits for research protocols.

Outside provider referral, current NIH study patients

This study will comply with the NIH Data Management and Sharing (DMS) Policy, which applies to all new and ongoing NIH-funded research in the IRP, as of January 25, 2023, that is associated with a ZIA, with a clinical protocol that undergoes scientific review and/or will involve genomic data sharing. This study will comply with the NIH Genomic Data Sharing (GDS) Policy, which applies to all new and ongoing NIH IRP-funded research, as of August 31, 2015, that generates large-scale human or non-human genomic data, as well as the use of these data for subsequent research. Large-scale data include GWAS, SNP arrays, and genome sequence, transcriptomic, epigenomic, and gene expression data.

Upon publication

Requests will be assessed by the PI. Next generation sequencing data will be deposited into public repositories.