Natural History of Dysregulation and Aging of the Immune System in People With Trisomy 21 With and Without Thymectomy

Background:

Down syndrome is a genetic disorder that can cause heart defects and other problems in the body. People with Down syndrome are more likely to have infections, autoimmunity, and blood diseases. Some may need surgery to treat congenital heart problems. During this surgery, doctors sometimes remove part of the thymus. The thymus is an organ that plays a role in immune function. People who have had part of their thymus removed may get sick more often than others do.

Objective:

This natural history study will gather data about how removing part of the thymus affects the health of people with Down syndrome.

Eligibility:

People aged 1 year and older with Down syndrome. The study will include both people who have, and those who have not had, surgery to remove part of their thymus. Healthy relatives are also needed.

Design:

Participants with Down syndrome will have clinic visits at least once a year for 15 years.

At each visit they will have a physical exam. They will give blood and stool samples. They will have tests of their heart and lung function.

Participants aged 18 years or older may have at least 1 imaging scan: They will lie on a table that slides into a donut-shaped machine. The machine uses X-rays to take pictures of the inside of the body.

Participants who have tissue samples collected from their bodies (biopsies) taken during the study may have extra tissue taken for research.

Healthy relatives will also have visits once a year for 15 years. They will only have a physical exam and provide blood and stool samples.

Study Overview

• Status: Recruiting
• Conditions: Down Syndrome

Detailed Description

Study Description:

This is a longitudinal observational study of individuals with trisomy 21 (T21) to gather data on the immune function in order to identify clinical and laboratory signatures of immunodeficiency and/or immune dysregulation, characterize their pathophysiology, evaluate their progression and evolution over time, and analyze the impact of immunomodulatory and immunosuppressive treatment. In order to assess the possible impact of thymectomy on immune dysfunction and on the risk of developing autoimmunity, malignancies, and/or increased susceptibility to infections, both individuals who have had previous thymectomy and those who have not received this procedure will be included. Affected participants will have a baseline visit and follow-up study visits every year (starting from baseline) to assess their health and collect biospecimens (including but not limited to blood). Additional visits can also be scheduled as clinically indicated. Data and excess biospecimens from routine clinical care may also be collected and used for research. Unaffected relatives who live in the same household as the corresponding affected participant will be enrolled as controls and will undergo yearly blood and stool collection for comparison of microbiome and immunological data.

Objectives:

Primary Objectives:

• Describe the immune correlates of clinical endpoints (infections, development or progression of lung damage, autoimmunity, malignancies), and their cumulative frequency over time, in individuals with T21
• Describe the possible impact of previous thymectomy on the incidence of clinical manifestations of immune deficiency and immune dysregulation, and on laboratory parameters of immune function

Secondary Objectives:

- Identify cellular and molecular mechanisms of immune dysfunction in individuals with T21

Endpoints:

Primary Endpoints:

• Incidence of severe infections requiring hospital admission (number of admissions/year; number of days of hospitalization/year)
• Nature of infections (bacterial, viral, fungal, opportunistic pathogens) requiring hospitalization
• Number and type of autoimmune manifestations/year
• Proportion of patients with evidence of lung abnormalities at chest CT and characterization of pathological radiological findings
• Proportion of T21 individuals with malignancies by age group (compared to the general population), and type of malignancies
• Frequency of individuals with abnormal T- and B-cell counts and immunoglobulin serum levels
• Frequency of T21 individuals with laboratory evidence of autoantibodies

Secondary Endpoints:

• Distribution of subsets of T helper (Th), T follicular helper, and T regulatory (Treg) cells
• Diversity of T-cell receptor (TCR) repertoire, measured as proportion of CD4+ and CD8+ cells expressing distinct T-cell receptor Beta variable gene (TRBV) families
• Proportion of T cells exhibiting expression of exhaustion markers
• Levels of specific antibodies to immunization antigens
• Proportion of dysreactive B-cell subsets (defined as CD19(hi) CD21(low) CD38(low) B cells)
• Proportion of 9G4+ B cells and determination of their phenotype
• Levels of anti-cytokine antibodies and determination of their neutralizing activity
• Proportion of patients manifesting progression of lung damage over time as detected by chest CT and/or pulmonary function tests

Exploratory Endpoints:

• Transcriptional signatures of immune dysregulation in circulating peripheral blood mononuclear cells
• Characterization of phenotypic and transcriptional abnormalities of thymic stromal cell types generated in vitro from induced pluripotent stem cells (iPSCs) from T21 individuals compared to healthy controls
• Measurement of soluble biomarkers of inflammation
• Definition of T21 endotypes (as shown by transcriptional profile and soluble markers of inflammation), analysis of endotype persistence over time, and correlation with clinical manifestations of disease
• Metabolomic and lipidomic signatures of immune dysregulation in plasma of T21 individuals
• Perturbations of microbiome diversity and composition (as shown by comparison between relatives and proband)
• Levels of circulating VH4-34 antibodies
• Diversity and composition of T- and B-cell receptor repertoire, and molecular signatures of self-reactivity
• Identification of other genetic variants that may contribute to the immune dysregulation and infection phenotype of T21

• Study Type: Observational
• Enrollment (Estimated): 700

Contacts and Locations

• Study Contact: Name: Luigi D Notarangelo, M.D.; Phone Number: (301) 761-7550; Email: luigi.notarangelo2@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: NIH Clinical Center Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 800-411-1222; Email: ccopr@nih.gov
      • Contact: Luigi Notarangelo, M.D.; Phone Number: (301) 761-7550; Email: luigi.notarangelo2@nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Participants will be selected in an equitable manner from the available pool of potentially eligible individuals, without regard to factors such as sex, race, ethnicity, socioeconomic status, etc. To facilitate recruitment, the study will be registered in clinicaltrials.gov and will be shared with T21 advocacy groups.

Description

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Aged >=1 year.

2. Willingness to allow storage of specimens and data for future research.

• Additional Inclusion Criteria for Affected Participants

  1. Documented T21 based on chromosomal karyotype test.
  2. Ability of participant or LAR to provide informed consent.

• Additional Inclusion Criteria for Unaffected Relatives

  1. Ability of participant to provide informed consent or, for individuals <18 years of age, to provide informed assent as applicable.
  2. Reside in the same household as the corresponding affected participant.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Any condition that, in the judgment of the investigator, may put the participant at undue risk or make them unsuitable for participation in the study.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Trisomy 21 Participants; Participants aged >=1 year old who have T21
Unaffected Relative Participants; Participants aged >=1 year old who are related to a participant with T21

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of T21 individuals with laboratory evidence of autoantibodies	Describe the immune correlates of clinical endpoints (infections, autoimmunity, malignancies), and their cumulative frequency over time, in individuals with T21. Describe the possible impact of previous thymectomy on the incidence of clinical manifestations of immune deficiency and immune dysregulation, and on laboratory parameters of immune function	Through end of study
Number and type of autoimmune manifestations/year	Describe the immune correlates of clinical endpoints (infections, autoimmunity, malignancies), and their cumulative frequency over time, in individuals with T21. Describe the possible impact of previous thymectomy on the incidence of clinical manifestations of immune deficiency and immune dysregulation, and on laboratory parameters of immune function	Through end of study
Frequency of individuals with abnormal T and B cell counts and immunoglobulin serum levels	Describe the immune correlates of clinical endpoints (infections, autoimmunity, malignancies), and their cumulative frequency over time, in individuals with T21. Describe the possible impact of previous thymectomy on the incidence of clinical manifestations of immune deficiency and immune dysregulation, and on laboratory parameters of immune function	Through end of study
Proportion of T21 individuals with malignancies by age group (compared to the general population), and type of malignancies	Describe the immune correlates of clinical endpoints (infections, autoimmunity, malignancies), and their cumulative frequency over time, in individuals with T21. Describe the possible impact of previous thymectomy on the incidence of clinical manifestations of immune deficiency and immune dysregulation, and on laboratory parameters of immune function	Through end of study
Nature of infections (bacterial, viral, fungal, opportunistic pathogens) requiring hospitalization	Describe the immune correlates of clinical endpoints (infections, autoimmunity, malignancies), and their cumulative frequency over time, in individuals with T21. Describe the possible impact of previous thymectomy on the incidence of clinical manifestations of immune deficiency and immune dysregulation, and on laboratory parameters of immune function	Through end of study
Incidence of severe infections requiring hospital admission (number of admissions/year; number of days of hospitalization/year)	Describe the immune correlates of clinical endpoints (infections, autoimmunity, malignancies), and their cumulative frequency over time, in individuals with T21. Describe the possible impact of previous thymectomy on the incidence of clinical manifestations of immune deficiency and immune dysregulation, and on laboratory parameters of immune function	Through end of study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levels of specific antibodies to immunization antigens	Identify cellular and molecular mechanisms of immune dysfunction in individuals with T21	Through end of study
Proportion of T cells exhibiting expression of exhaustion markers	Identify cellular and molecular mechanisms of immune dysfunction in individuals with T21	Through end of study
Diversity of T-cell receptor repertoire, measured as proportion of CD4+ and CD8+ cells expressing distinct TRBV families	Identify cellular and molecular mechanisms of immune dysfunction in individuals with T21	Through end of study
Distribution of subsets of Th, T follicular helper, and Treg cells	Identify cellular and molecular mechanisms of immune dysfunction in individuals with T21	Through end of study
Proportion of dysreactive B cell subsets (defined as CD19(hi) CD21(low) CD38(low) B cells)	Identify cellular and molecular mechanisms of immune dysfunction in individuals with T21	Through end of study

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Luigi D Notarangelo, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Estimated): June 8, 2026
• Primary Completion (Estimated): May 1, 2040
• Study Completion (Estimated): November 1, 2040

Study Registration Dates

• First Submitted: February 14, 2026
• First Submitted That Met QC Criteria: February 17, 2026
• First Posted (Actual): February 18, 2026

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: June 2, 2026
• Last Verified: March 25, 2026

More Information

Terms related to this study

• Keywords: Down Syndrome; Immunologic Deficiency Syndromes; THYMECTOMY
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, Inborn; Immune System Diseases; Neurobehavioral Manifestations; Congenital Abnormalities; Abnormalities, Multiple; Intellectual Disability; Chromosome Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immunologic Deficiency Syndromes; Down Syndrome
• Other Study ID Numbers: 10002372; 002372-I

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual subjects' clinical and laboratory metadata will be de-identified. Each subject is given a unique patient code, and the metadata will be imported in ImmPort.
• IPD Sharing Time Frame: In preparation of publication, data will be deposited on data sharing platforms (such as Zenodo, Github, ImmPort, dbGaP) with an embargo until publication date, and access codes that will be made available to reviewers of the manuscript.
• IPD Sharing Access Criteria: Unpublished data will be made available upon written request and according to a data sharing agreement approved by the Office of Technology Transfer and Intellectual Property, National Institutes of Health.@@@@@@When included in publications, these data will be made available as part of the Supporting Information associated with the manuscript.@@@@@@

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No