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

Brief Title

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

Official Title

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

Brief Summary

      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.
    

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


Primary Outcome

Genomic Sequencing

Secondary Outcome

 Change in the anatomic phenotype using MRI

Condition

Tracheoesophageal Fistula


Study Arms / Comparison Groups

 NICU TED Genetic Cohort
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

260

Start Date

March 28, 2018

Completion Date

January 2024

Primary Completion Date

January 2023

Eligibility Criteria

        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.
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

Paul Kingma, MD, PhD, (513)636-2995, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03455881

Organization ID

CIN_PhenoandGeneticTED_001

Secondary IDs

1P01HD093363-01

Responsible Party

Sponsor

Study Sponsor

Children's Hospital Medical Center, Cincinnati

Collaborators

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

Study Sponsor

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


Verification Date

September 2020