Phenotypic and Genetic Assessment of Tracheal and Esophageal Birth Defects in Patients (TED)

September 18, 2020 updated by: Children's Hospital Medical Center, Cincinnati

Comprehensive Phenotypic and Genetic Assessment of Tracheal and Esophageal Birth Defects in Patients

The investigators propose a preliminary study performing exome sequencing on samples from patients and their biologically related family members with tracheal and esophageal birth defects (TED). The investigators will use advanced, non-invasive magnetic resonance imaging (MRI) techniques to assess tracheal esophageal, lung, and cardiac morphology and function in Neonatal Intensive Care Unit (NICU) patients. The purpose of this study is to determine if patients diagnosed with TED and similar disorders carry distinct mutations that lead to predisposition and to determine if an MRI is a more effective way of evaluating the TEDs.

Study Overview

Status

Recruiting

Conditions

Detailed Description

TEDs (tracheal esophageal birth defects) are a life threatening congenital disorder with multiple long term complications. Occurring in 1 in 2,500 to 4,500 live births, TEDs include tracheal malformations such as tracheomalacia, laryngotracheoesophageal clefts, tracheal agenesis, tracheal stenosis, tracheal bronchus, esophageal bronchus and esophageal malformations such as esophageal atresia (EA), tracheal esophageal fistula (TEF), and esophageal duplication. TEDs likely have a genetic basis, but in most cases the specific mutations are unknown. The most commonly diagnosed TED, requiring neonatal hospitalization, is EA/TEF. The familial recurrence rate of EA/TEF is 1% suggesting many result from de novo mutations and while environmental factors may have a minor influence, the mechanisms are unclear. The investigators hypothesize that patients diagnosed with TED and similar disorders carry distinct mutations that lead to predisposition. Currently the diagnosis is confirmed only with a plain chest x-ray showing a coiled feeding tube within the upper esophageal pouch. This approach does not determine the anatomic subtype of EA/TEF, the number or location of TEFs, the size of the gap between proximal and distal esophagus, or the presence of tracheomalacia. Many have evaluated preoperative laryngotracheo-bronchoscopy (LTB) and others have evaluated preoperative computerized tomography (CT) scanning to decrease the unknown factors associated with x-ray, but despite their potential benefits, they have great drawbacks. Therefore, there is a compelling need to develop noninvasive non ionizing imaging methods to evaluate TED infants. Magnetic Resonance Imaging (MRI) is an ideal candidate to fill this role in that it provides non-invasive high resolution anatomic and functional information. Here the investigators propose a preliminary study performing exome sequencing on samples from these patients and their biologically related family members. The investigators will also use advanced, non-invasive MR imaging techniques to assess TE, lung, and cardiac morphology and function in NICU patients.

Study Type

Observational

Enrollment (Anticipated)

260

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Ohio
      • Cincinnati, Ohio, United States, 45229
        • Recruiting
        • Cincinnati Children's Hospital
        • Contact:
        • Principal Investigator:
          • Paul Kingma, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Approximately 100 NICU TED patient/parent trios for the NICU TED Genetic cohort.

Approximately 100 NICU TED patients for the NICU TED MRI cohort. These patients will also be in the NICU TED cohort.

Approximately 155 TED patient/parent trios from the Esophageal Center for the Esophageal Center Genetic cohort.

Approximately 5 NICU infants with normal tracheal and esophageal anatomy for the NICU Control MRI cohort.

Description

NICU TED Genetic Cohort:

Inclusion Criteria:

  • Infant born between 24 and 42 weeks PMA.
  • TED diagnosed by clinical team.
  • Inpatient in the Neonatal Intensive Care Unit (NICU) OR family member to the inpatient in the NICU.
  • Willingness to donate biological specimens.
  • Ability to consent/assent as appropriate.

Exclusion Criteria:

  • Unable to determine or unavailable parent trio.
  • Unable to provide DNA sample.
  • Inability to provide consent.

NICU TED MRI Cohort:

Inclusion Criteria:

  • Infant born between 24 and 42 weeks PMA.
  • TED diagnosed by clinical team.
  • Inpatient in the CCHMC (Cincinnati Children's Hospital Medical Center) NICU.
  • Clinically stable and adequate temperature control to tolerate MRI as determined by the primary clinical team.
  • Infant and biological parents are participating in the NICU TED cohort.
  • Ability to consent/assent as appropriate.

Exclusion Criteria:

  • Infant is on extracorporeal membrane oxygenation (ECMO).
  • Evidence of congenital diseases that may affect ability to tolerate MRI.
  • Standard MRI exclusion criteria as set forth by the CCHMC Department of Radiology. This includes any contraindications from tracheostomy tubes that are not MR compatible.
  • Inability to provide consent.

TED Genetic Cohort:

Inclusion Criteria:

  • Patient that has been diagnosed by clinical team with a congenital TED OR family member to the TED diagnosed patient.
  • Willingness to donate biological specimens.
  • Ability to consent/assent as appropriate.

Exclusion Criteria:

  • Unable to determine or unavailable parent trio.
  • Unable to provide DNA sample.
  • Inability to provide consent.

NICU Control MRI Cohort:

Inclusion Criteria:

  • Infant born between 24 and 42 weeks post menstrual age (PMA).
  • No tracheal or esophageal defects.
  • Inpatient in the CCHMC NICU.
  • Clinically stable and adequate temperature control to tolerate MRI as determined by the primary clinical team.

Exclusion Criteria:

  • Infant is on ECMO.
  • Evidence of congenital diseases that may affect ability to tolerate MRI.
  • Standard MRI exclusion criteria as set forth by the CCHMC Department of Radiology. This includes any contraindications from tracheostomy tubes that are not MR compatible.
  • Inability to provide consent.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
NICU TED Genetic Cohort
This study involves one inpatient biofluid collection encounter from the subject, one biofluid collection encounter from each biological parent, and an optional biofluid collection encounter from other biological family members.
NICU TED MRI Cohort
This study involves up to three inpatient NICU MRI encounters. The first MRI may be done before surgical repair if the clinical team feels the infant is clinically stable. The second MRI may be completed post-surgical repair of TED. An additional 3rd MRI may be done prior to the time of discharge from the NICU. The pre repair, post-surgical, and pre discharge MRIs will provide valuable data for the understanding of tracheal esophageal malformation disorders and may provide clinical guidance for the participant's care.
TED Genetic Cohort
This study involves one biofluid collection encounter from the subject, one biofluid collection encounter from each biological parent, and an optional biofluid collection encounter from other biological family members.
NICU Control MRI Cohort
This study involves two inpatient NICU MRI encounters. The first MRI will occur within the first month of life, and the second MRI will occur prior to discharge.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Genomic Sequencing
Time Frame: 1 day
Identify novel genes and mutations in patients with TEDs using trio genomic sequencing of TED patients and their parents.
1 day
Anatomic phenotypes using MRI
Time Frame: 1 day
Investigate the esophageal, tracheal, mediastinal and pulmonary anatomy in patients with TEDs.
1 day

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in the anatomic phenotype using MRI
Time Frame: Change in MRI from pre-repair to discharge
Investigate the esophageal, tracheal, mediastinal and pulmonary anatomy in patients with TEDs before and after surgical repair.
Change in MRI from pre-repair to discharge

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Children's Hospital Medical Center, Cincinnati

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Columbia University

Investigators

  • Principal Investigator: Paul Kingma, MD, PhD, Children's Hospital Medical Center, Cincinnati

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 28, 2018

Primary Completion (Anticipated)

January 1, 2023

Study Completion (Anticipated)

January 1, 2024

Study Registration Dates

First Submitted

February 12, 2018

First Submitted That Met QC Criteria

March 5, 2018

First Posted (Actual)

March 7, 2018

Study Record Updates

Last Update Posted (Actual)

September 22, 2020

Last Update Submitted That Met QC Criteria

September 18, 2020

Last Verified

September 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CIN_PhenoandGeneticTED_001
  • 1P01HD093363-01 (U.S. NIH Grant/Contract)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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