TED: Phenotypic and Genetic Assessment of Tracheal and Esophageal Birth Defects in Patients
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
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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 Design
Arms and Interventions
Arm | Intervention/Treatment |
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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. |
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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. |
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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. |
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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. |
Outcome Measures
Primary Outcome Measures
- Genomic Sequencing [1 day]
Identify novel genes and mutations in patients with TEDs using trio genomic sequencing of TED patients and their parents.
- Anatomic phenotypes using MRI [1 day]
Investigate the esophageal, tracheal, mediastinal and pulmonary anatomy in patients with TEDs.
Secondary Outcome Measures
- Change in the anatomic phenotype using MRI [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.
Eligibility Criteria
Criteria
NICU TED Genetic Cohort:
Inclusion Criteria:
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Infant born between 24 and 42 weeks PMA.
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TED diagnosed by clinical team.
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Inpatient in the Neonatal Intensive Care Unit (NICU) OR family member to the inpatient in the NICU.
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Willingness to donate biological specimens.
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Ability to consent/assent as appropriate.
Exclusion Criteria:
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Unable to determine or unavailable parent trio.
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Unable to provide DNA sample.
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Inability to provide consent.
NICU TED MRI Cohort:
Inclusion Criteria:
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Infant born between 24 and 42 weeks PMA.
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TED diagnosed by clinical team.
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Inpatient in the CCHMC (Cincinnati Children's Hospital Medical Center) NICU.
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Clinically stable and adequate temperature control to tolerate MRI as determined by the primary clinical team.
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Infant and biological parents are participating in the NICU TED cohort.
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Ability to consent/assent as appropriate.
Exclusion Criteria:
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Infant is on extracorporeal membrane oxygenation (ECMO).
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Evidence of congenital diseases that may affect ability to tolerate MRI.
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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.
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Inability to provide consent.
TED Genetic Cohort:
Inclusion Criteria:
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Patient that has been diagnosed by clinical team with a congenital TED OR family member to the TED diagnosed patient.
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Willingness to donate biological specimens.
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Ability to consent/assent as appropriate.
Exclusion Criteria:
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Unable to determine or unavailable parent trio.
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Unable to provide DNA sample.
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Inability to provide consent.
NICU Control MRI Cohort:
Inclusion Criteria:
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Infant born between 24 and 42 weeks post menstrual age (PMA).
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No tracheal or esophageal defects.
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Inpatient in the CCHMC NICU.
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Clinically stable and adequate temperature control to tolerate MRI as determined by the primary clinical team.
Exclusion Criteria:
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Infant is on ECMO.
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Evidence of congenital diseases that may affect ability to tolerate MRI.
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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.
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Inability to provide consent.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Cincinnati Children's Hospital | Cincinnati | Ohio | United States | 45229 |
Sponsors and Collaborators
- Children's Hospital Medical Center, Cincinnati
- 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
Study Documents (Full-Text)
None provided.More Information
Publications
- Atzori P, Iacobelli BD, Bottero S, Spirydakis J, Laviani R, Trucchi A, Braguglia A, Bagolan P. Preoperative tracheobronchoscopy in newborns with esophageal atresia: does it matter? J Pediatr Surg. 2006 Jun;41(6):1054-7.
- Brosens E, Ploeg M, van Bever Y, Koopmans AE, IJsselstijn H, Rottier RJ, Wijnen R, Tibboel D, de Klein A. Clinical and etiological heterogeneity in patients with tracheo-esophageal malformations and associated anomalies. Eur J Med Genet. 2014 Aug;57(8):440-52. doi: 10.1016/j.ejmg.2014.05.009. Epub 2014 Jun 13. Review.
- Lal D, Miyano G, Juang D, Sharp NE, St Peter SD. Current patterns of practice and technique in the repair of esophageal atresia and tracheoesophageal fistua: an IPEG survey. J Laparoendosc Adv Surg Tech A. 2013 Jul;23(7):635-8. doi: 10.1089/lap.2013.0210. Epub 2013 Jun 12.
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- Ngerncham M, Lee EY, Zurakowski D, Tracy DA, Jennings R. Tracheobronchomalacia in pediatric patients with esophageal atresia: comparison of diagnostic laryngoscopy/bronchoscopy and dynamic airway multidetector computed tomography. J Pediatr Surg. 2015 Mar;50(3):402-7. doi: 10.1016/j.jpedsurg.2014.08.021. Epub 2014 Oct 1.
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- Sfeir R, Michaud L, Salleron J, Gottrand F. Epidemiology of esophageal atresia. Dis Esophagus. 2013 May-Jun;26(4):354-5. doi: 10.1111/dote.12051.
- Sfeir R, Michaud L, Sharma D, Richard F, Gottrand F. National Esophageal Atresia Register. Eur J Pediatr Surg. 2015 Dec;25(6):497-9. doi: 10.1055/s-0035-1569466. Epub 2015 Dec 7. Review.
- Sharma N, Srinivas M. Laryngotracheobronchoscopy prior to esophageal atresia and tracheoesophageal fistula repair--its use and importance. J Pediatr Surg. 2014 Feb;49(2):367-9. doi: 10.1016/j.jpedsurg.2013.09.009.
- Teague WJ, Karpelowsky J. Surgical management of oesophageal atresia. Paediatr Respir Rev. 2016 Jun;19:10-5. doi: 10.1016/j.prrv.2016.04.003. Epub 2016 Apr 21. Review.
- Tkach JA, Hillman NH, Jobe AH, Loew W, Pratt RG, Daniels BR, Kallapur SG, Kline-Fath BM, Merhar SL, Giaquinto RO, Winter PM, Li Y, Ikegami M, Whitsett JA, Dumoulin CL. An MRI system for imaging neonates in the NICU: initial feasibility study. Pediatr Radiol. 2012 Nov;42(11):1347-56. doi: 10.1007/s00247-012-2444-9. Epub 2012 Jun 27.
- Vissers LE, de Ligt J, Gilissen C, Janssen I, Steehouwer M, de Vries P, van Lier B, Arts P, Wieskamp N, del Rosario M, van Bon BW, Hoischen A, de Vries BB, Brunner HG, Veltman JA. A de novo paradigm for mental retardation. Nat Genet. 2010 Dec;42(12):1109-12. doi: 10.1038/ng.712. Epub 2010 Nov 14.
- Windram J, Grosse-Wortmann L, Shariat M, Greer ML, Crawford MW, Yoo SJ. Cardiovascular MRI without sedation or general anesthesia using a feed-and-sleep technique in neonates and infants. Pediatr Radiol. 2012 Feb;42(2):183-7. doi: 10.1007/s00247-011-2219-8. Epub 2011 Aug 23.
- Zani A, Eaton S, Hoellwarth ME, Puri P, Tovar J, Fasching G, Bagolan P, Lukac M, Wijnen R, Kuebler JF, Cecchetto G, Rintala R, Pierro A. International survey on the management of esophageal atresia. Eur J Pediatr Surg. 2014 Feb;24(1):3-8. doi: 10.1055/s-0033-1350058. Epub 2013 Aug 9.
- CIN_PhenoandGeneticTED_001
- 1P01HD093363-01