A Prospective Natural History Study of Lymphatic Anomalies

Background:

The lymphatic system is a network of vessels that carry a clear fluid called lymph through the body. Problems in the lymphatic system can cause pain, fluid buildup, and issues with immunity. There is much researchers do not understand about lymphatic anomalies. In this natural history study, they will collect data from a lot of people over a long time.

Objective:

To better understand why lymphatic anomalies develop. The goal is to improve future treatments.

Eligibility:

People aged 0 days and older with a suspected or confirmed lymphatic anomaly. Their unaffected parents or siblings aged 7 years or older are also needed.

Design:

Participants may remain in the study indefinitely. Affected participants may be evaluated every 10 months to 2 years. Some participants will be seen over telemedicine. Others will be seen at the NIH Clinical Center for 2-5 days.

All participants will have a physical exam. They may provide specimens including blood, saliva, hair follicles, stool, skin, and other tissues. Samples may be used for genetic testing.

Participants may undergo other tests depending on their medical conditions. The NIH Clinical Center visit may include:

Heart tests include placing stickers on the chest to measure electrical activity and using sound waves to capture pictures of the heart.

A lung test measures the muscle strength in the chest. Participants will blow into a tube.

Photographs may be taken of participants faces and other features.

Imaging scans will take pictures of the inside of the body. One scan will measure bone density.

One type of scan tracks how lymph fluid moves through the body. Participants will be under anesthesia, and they will be injected with a dye.

Study Overview

• Status: Recruiting
• Conditions: Lymphatic Diseases; Lymphatic Abnormalities

Detailed Description

Study Description:

A natural history study for lymphatic anomalies to systematically evaluate the disease phenotypes and long-term outcomes to provide improved prognostication to families, establish screening/monitoring guidelines, determine best practices for genetic diagnosis, explore family opinions, and explore fertility for those on long term medication management. This study will allow us to identify novel end points for future clinical trials.

Objectives:

Primary objectives:

• To establish a longitudinal cohort of participants with lymphatic anomalies
• To longitudinally determine the age at presentation and incidence of clinical features

Secondary objectives:

• To establish a longitudinal biospecimen repository
• To determine the best practices for genetic diagnosis based on phenotype.
• To determine the malignant potential of anomalies longitudinally

Endpoints:

Primary endpoints:

• The number of participants with lymphatic anomalies
• For each clinical feature or symptoms, the range of ages at the development of that feature/symptom and fraction of participants with that feature
• Quantification and identification of novel features associated with disease.

Secondary endpoints:

• The number of specimens collected
• Diagnostic yields by phenotype and genetic test methodology
• Number of malignancies related to the primary lesion that have developed

• Study Type: Observational
• Enrollment (Estimated): 1200

Contacts and Locations

• Study Contact: Name: Sarah E Sheppard, M.D.; Phone Number: (240) 578-5047; Email: sarah.sheppard@nih.gov
• Study Contact Backup: Name: Andrea I Bowling, C.R.N.P.; Phone Number: (301) 451-3824; Email: nichd_lymphaticanoma@mail.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
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Not yet recruiting
      • Children's Hospital of Philadelphia
      • Contact: Yoav Dori; Phone Number: 267-648-1033; Email: doriy@chop.edu

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Probability Sample

Study Population

Patients with lymphatic anomalies and their parents.

Description

• INCLUSION CRITERIA:

Affected (Proband)

In order to be eligible to participate in this study, an individual must meet one of the following criteria as determined after review of medical history:

• Current or history of lymphatic anomaly or symptoms suggestive of a lymphatic disorder Or
• An ill-defined vascular anomaly that is suspected to have an abnormal lymphatic component Or
• A pathogenic, likely pathogenic, or VUS in a genetic disorder with a known lymphatic component Or
• Clinical diagnosis of a syndrome with a known lymphatic component

Unaffected (First Degree Relatives: Parents and Siblings)

Genetic variants underlying complex lymphatic anomalies can be passed down through parents or be new in a child (de novo). Inclusion of first-degree relatives will assist in genetic analysis to delineate whether the variant is inherited or de novo.

To be eligible to participate as a first degree relative in this study, an individual must be a first-degree family member of an affected participants

EXCLUSION CRITERIA:

Affected Proband

An individual who meets any of the following criteria will be excluded from participation in this study after review of medical history, concomitant medication and allergy review, anthropometrics, and performance status:

-Any condition, in the opinion of the investigator, that would increase risk of participation or impair their ability to comply with protocol requirements.

Lymphatic anomalies that are definitively determined to be secondary by the principal investigator will be excluded from this study. For example, participants who develop a lymphedema after breast cancer surgery.

Unaffected (First Degree Relatives)

-Any condition, in the opinion of the investigator, that would increase risk of participation or impair their ability to comply with protocol requirements.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
First Degree Relatives; Siblings or parents of patients.
Patients; Patients with lymphatic anomalies.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To establish a longitudinal cohort of participants with lymphatic anomalies	We plan to enroll a group of participants willing to participate in the study over time.	12/31/2028
To longitudinally determine the age at presentation and incidence of clinical features	For each clinical feature or symptoms, the range of ages at the development of that feature/symptom and fraction of participants with that feature	12/31/2028

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To establish a longitudinal biospecimen repository	We plan to collect biospecimens including, but not limited to blood and stool from participants over time.	12/31/2028
To determine the best practices for genetic diagnosis based on phenotype	We will analyze diagnostic yields by phenotype (how many participants are able to have a genetic diagnosis in proportion to the number of participants who receive genetic testing) and genetic test methodology (to determine which genetic test is most helpful in diagnosing lymphatic anomalies)	12/31/2028
To determine the malignant potential of anomalies longitudinally	We will track the number of malignancies related to the primary lesion that have developed	12/31/2028

Collaborators and Investigators

• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Sarah E Sheppard, M.D., Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Publications and helpful links

General Publications

• Makinen T, Boon LM, Vikkula M, Alitalo K. Lymphatic Malformations: Genetics, Mechanisms and Therapeutic Strategies. Circ Res. 2021 Jun 25;129(1):136-154. doi: 10.1161/CIRCRESAHA.121.318142. Epub 2021 Jun 24.
• Brouillard P, Witte MH, Erickson RP, Damstra RJ, Becker C, Quere I, Vikkula M. Primary lymphoedema. Nat Rev Dis Primers. 2021 Oct 21;7(1):77. doi: 10.1038/s41572-021-00309-7.
• Liu M, Smith CL, Biko DM, Li D, Pinto E, O'Connor N, Skraban C, Zackai EH, Hakonarson H, Dori Y, Sheppard SE. Genetics etiologies and genotype phenotype correlations in a cohort of individuals with central conducting lymphatic anomaly. Eur J Hum Genet. 2022 Sep;30(9):1022-1028. doi: 10.1038/s41431-022-01123-9. Epub 2022 May 24.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2023
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: February 15, 2023
• First Submitted That Met QC Criteria: February 15, 2023
• First Posted (Actual): February 16, 2023

Study Record Updates

• Last Update Posted (Actual): August 6, 2026
• Last Update Submitted That Met QC Criteria: August 5, 2026
• Last Verified: August 4, 2026

More Information

Terms related to this study

• Keywords: Lymphedema; Protein Losing Enteropathy; Chylous Ascites; Generalized Lymphatic Anomaly; Kaposiform Lymphangiomatosis; Lymphangiectasia; Complex Lymphatic Anomaly; Central Conducting Lymphatic Anomaly; Gorham Stout Disease; Chylous Effusion
• Additional Relevant MeSH Terms: Bone Resorption; Bone Diseases; Musculoskeletal Diseases; Intestinal Diseases; Digestive System Diseases; Gastrointestinal Diseases; Congenital Abnormalities; Peritoneal Diseases; Bone Diseases, Developmental; Osteolysis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Lymphedema; Lymphatic Diseases; Lymphatic Abnormalities; Osteolysis, Essential; Protein-Losing Enteropathies; Chylous Ascites; Lymphangiectasis
• Other Study ID Numbers: 10001084; 001084-CH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Investigators will share human data generated in this research for future research as follows:@@@@@@De-identified data in an NIH-funded or approved public repository. @@@@@@De-identified data in another public repository. @@@@@@De-identified data in BTRIS (automatic for activities in the Clinical Center)@@@@@@De-identified or identified data with approved outside collaborators under appropriate agreements.
• IPD Sharing Time Frame: At the time of publication or shortly thereafter.
• IPD Sharing Access Criteria: Data will be shared through:@@@@@@An NIH-funded or approved public repository: clinicaltrials.gov @@@@@@BTRIS (automatic for activities in the Clinical Center)@@@@@@Approved outside collaborators under appropriate individual agreements.@@@@@@Publication and/or public presentations.@@@@@@This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals. Data from this study may be requested from other researchers after the completion of the primary endpoint by contacting Sarah Sheppard, PI of the study.
• IPD Sharing Supporting Information Type: CSR

Drug and device information, study documents

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