Natural History of Trisomy 8-Associated Autoinflammatory Disease (TRIAD) and Related Disorders

Обзор

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.

Подробное описание

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.

Первичные конечные точки

• Clinical characterization of participants with trisomy 8 mosaicism and related disorders based on history, physical examination, radiologic imaging, and laboratory testing. [Срок оценки: Length of the study]
• 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 [Срок оценки: Length of the study]

Вторичные конечные точки (4)

• Characterization of laboratory, radiologic examinations, biopsies, and physical exam findings. [Срок оценки: Length of study]
• 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 CBCs, NGS for risk variants, and flow cytometry. [Срок оценки: Length of study]
• 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. [Срок оценки: Length of study]
• Assessment of treatment response based on inflammatory markers, clinical history, and physical exam findings. [Срок оценки: Length of study]

Критерии участия

• INCLUSION CRITERIA:

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

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

Additional Inclusion Criteria for Affected Participants

• Must have one of the following:

• 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
• Inflammatory mucosal ulcerative disease clinically similar to TRIAD at the discretion of the principal investigator.
• Ability of participant or LAR to provide informed consent.

Additional Inclusion Criteria for Biological Relatives

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

Критерии исключения

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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Другое

Центры проведения

США · 1 центр

• National Institutes of Health Clinical Center — Bethesda

Публикации

• Ando S, Maemori M, Sakai H, Ando S, Shiraishi H, Sakai K, Ruhnke GW. Constitutional trisomy 8 mosaicism with myelodysplastic syndrome complicated by intestinal Behcet disease and antithrombin III deficiency. Cancer Genet Cytogenet. 2005 Oct 15;162(2):172-5. doi: 10.1016/j.cancergencyto.2005.01.010. PMID 16213367
• Becker K, Fitzgerald O, Green AJ, Keogan M, Newbury-Ecob R, Greenhalgh L, Withers S, Hollox EJ, Aldred PM, Armour JA. Constitutional trisomy 8 and Behcet syndrome. Am J Med Genet A. 2009 May;149A(5):982-6. doi: 10.1002/ajmg.a.32756. PMID 19353586
• Hasle H, Clausen N, Pedersen B, Bendix-Hansen K. Myelodysplastic syndrome in a child with constitutional trisomy 8 mosaicism and normal phenotype. Cancer Genet Cytogenet. 1995 Jan;79(1):79-81. doi: 10.1016/0165-4608(94)00099-w. PMID 7850757
• Altiner S, Kutlay NY, Ilhan O. Constitutional Trisomy 8 Mosaicism with Persistent Macrocytosis. Cytogenet Genome Res. 2016;150(1):35-39. doi: 10.1159/000452358. Epub 2016 Nov 12. PMID 27838684
• Nielsen J, Wohlert M. Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet. 1991 May;87(1):81-3. doi: 10.1007/BF01213097. PMID 2037286
• Saumell S, Sole F, Arenillas L, Montoro J, Valcarcel D, Pedro C, Sanzo C, Luno E, Gimenez T, Arnan M, Pomares H, De Paz R, Arrizabalaga B, Jerez A, Martinez AB, Sanchez-Castro J, Rodriguez-Gambarte JD, Raya JM, Rios E, Rodriguez-Rivera M, Espinet B, Florensa L. Trisomy 8, a Cytogenetic Abnormality in Myelodysplastic Syndromes, Is Constitutional or Not? PLoS One. 2015 Jun 12;10(6):e0129375. doi: 10 PMID 26066831
• Maserati E, Aprili F, Vinante F, Locatelli F, Amendola G, Zatterale A, Milone G, Minelli A, Bernardi F, Lo Curto F, Pasquali F. Trisomy 8 in myelodysplasia and acute leukemia is constitutional in 15-20% of cases. Genes Chromosomes Cancer. 2002 Jan;33(1):93-7. doi: 10.1002/gcc.1214. PMID 11746991
• Baidas S, Chen TJ, Kolev V, Wong LJ, Imholte J, Qin N, Meck J. Constitutional trisomy 8 mosaicism due to meiosis II non-disjunction in a phenotypically normal woman with hematologic abnormalities. Am J Med Genet A. 2004 Feb 1;124A(4):383-7. doi: 10.1002/ajmg.a.20390. PMID 14735586

Идентификаторы

NCT: NCT07683104 · 10002326 · 002326-I

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗