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

Tracheal Stenosis Clinical Trial

— TED  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03455881
• Other study ID #: CIN_PhenoandGeneticTED_001
• Secondary ID: 1P01HD093363-01
• Status: Recruiting
• Start date: March 28, 2018
• Est. completion date: January 2026

Study information

• Verified date: March 2023
• Source: Children's Hospital Medical Center, Cincinnati
• Contact: Paul Kingma, MD, PhD
• Phone: (513)636-2995
• Email: paul.kingma[@]cchmc.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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 purpose of this study is to determine if patients diagnosed with TED and similar disorders carry distinct mutations that lead to predisposition. 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. MRI techniques is done exclusively if patient is clinically treated at primary study location and if patient has not yet had their initial esophageal repair.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 360
• Est. completion date: January 2026
• Est. primary completion date: January 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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 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. 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.

Related Conditions & MeSH terms

• Airway Obstruction
• Bronchial Stenosis
• Congenital Abnormalities
• Congenital High Airway Obstruction Syndrome
• Constriction, Pathologic
• Esophageal Atresia
• Esophageal Bronchus
• Fistula
• Laryngeal Cleft
• Tracheal Stenosis
• Tracheoesophageal Fistula

Locations

Country	Name	City	State
United States	Cincinnati Children's Hospital	Cincinnati	Ohio

Sponsors (3)

Lead Sponsor	Collaborator
Children's Hospital Medical Center, Cincinnati	Columbia University, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Country where clinical trial is conducted

United States, 

References & Publications (19)

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. doi: 10.1016/j.jpedsurg.2006.01.074. — View Citation

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. — View Citation

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. — View Citation

Mahalik SK, Sodhi KS, Narasimhan KL, Rao KL. Role of preoperative 3D CT reconstruction for evaluation of patients with esophageal atresia and tracheoesophageal fistula. Pediatr Surg Int. 2012 Oct;28(10):961-6. doi: 10.1007/s00383-012-3111-9. Epub 2012 Jun 22. — View Citation

Mathur AM, Neil JJ, McKinstry RC, Inder TE. Transport, monitoring, and successful brain MR imaging in unsedated neonates. Pediatr Radiol. 2008 Mar;38(3):260-4. doi: 10.1007/s00247-007-0705-9. Epub 2007 Dec 19. — View Citation

McMullen KP, Karnes PS, Moir CR, Michels VV. Familial recurrence of tracheoesophageal fistula and associated malformations. Am J Med Genet. 1996 Jun 28;63(4):525-8. doi: 10.1002/(SICI)1096-8628(19960628)63:43.0.CO;2-N. — View Citation

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. — View Citation

Oddsberg J, Jia C, Nilsson E, Ye W, Lagergren J. Influence of maternal parity, age, and ethnicity on risk of esophageal atresia in the infant in a population-based study. J Pediatr Surg. 2008 Sep;43(9):1660-5. doi: 10.1016/j.jpedsurg.2007.11.021. — View Citation

Parolini F, Boroni G, Stefini S, Agapiti C, Bazzana T, Alberti D. Role of preoperative tracheobronchoscopy in newborns with esophageal atresia: A review. World J Gastrointest Endosc. 2014 Oct 16;6(10):482-7. doi: 10.4253/wjge.v6.i10.482. — View Citation

Pedersen RN, Calzolari E, Husby S, Garne E; EUROCAT Working group. Oesophageal atresia: prevalence, prenatal diagnosis and associated anomalies in 23 European regions. Arch Dis Child. 2012 Mar;97(3):227-32. doi: 10.1136/archdischild-2011-300597. Epub 2012 Jan 13. — View Citation

Pigna A, Gentili A, Landuzzi V, Lima M, Baroncini S. Bronchoscopy in newborns with esophageal atresia. Pediatr Med Chir. 2002 Jul-Aug;24(4):297-301. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Genomic Sequencing	Identify novel genes and mutations in patients with TEDs using trio genomic sequencing of TED patients and their parents.	1 day
Primary	Anatomic phenotypes using MRI	Investigate the esophageal, tracheal, mediastinal and pulmonary anatomy in patients with TEDs.	1 day
Secondary	Change in the anatomic phenotype using MRI	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