Diaphragmatic Hernia Research & Exploration, Advancing Molecular Science

Congenital Diaphragmatic Hernia Clinical Trial

— DHREAMS  

Official title:

Diaphragmatic Hernia Research & Exploration, Advancing Molecular Science

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00950118
• Other study ID #: AAAB2063
• Secondary ID: R01HD057036
• Status: Recruiting
• Start date: June 2005
• Est. completion date: November 2025

Study information

• Verified date: April 2024
• Source: Columbia University
• Contact: Anah Kim Hetzler
• Email: ak3578[@]columbia.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The goal of this study is to identify genes that convey susceptibility to congenital diaphragmatic hernia in humans. The identification of such genes, and examination of their structure and function, will enable a delineation of molecular pathogenesis and, ultimately, prevention or treatment of congenital diaphragmatic hernia. There are many different possible modes of inheritance for congenital anomalies, including autosomal dominant, autosomal recessive, and multifactorial. Multi-factorial inheritance is responsible for many common medical disorders, including hypertension, myocardial infarction, diabetes and cancer. This type of inheritance pattern appears to involve environmental factors as well as a combination of genetic variations that together can predispose to or produce congenital anomalies, such as congenital diaphragmatic hernia. Our study is designed to establish a small, well-defined genetic resource consisting of 1) Nuclear families suitable for linkage analysis by parametric,non-parametric (e.g. sib pairs, TDT) and association techniques, 2) Individuals with congenital diaphragmatic hernia who can be directly screened for allelic variation in candidate genes, and 3) Individuals who can serve as controls (are unaffected by congenital diaphragmatic hernia). Neonates and their families will be collected from homogenous and heterogeneous populations. By characterizing diverse populations, it should be possible to increase the likelihood of demonstration of genetic variation in selected candidate genes that can then be used in association and linkage studies in individual subjects with congenital diaphragmatic hernia.

Description:

Congenital diaphragmatic hernia (CDH) is a birth defect that occurs when the diaphragm (thin sheet of muscle that separates the abdomen from the chest) does not form properly. When an opening is present in the diaphragm, organs that are normally in the abdomen can be pushed (herniated) through the opening and be present in the chest. Currently little is known about why this birth defect occurs. Through this study ""Molecular Genetic Analysis of Congenital Diaphragmatic Hernia" the investigators hope to learn more about whether certain genes contribute to CDH. Genes are the instructions or blueprints for our bodies. They tell our bodies how to grow and develop. Sometimes when a mistake occurs in one or more of our genes our body does not develop properly and this can lead to a CDH. The investigators hope that the information gained through studying the genes of children with CDH and their parents, will lead to significant advances in the diagnosis, prognosis, prevention, and treatment of this disease.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 3000
• Est. completion date: November 2025
• Est. primary completion date: November 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• All individuals affected with a congenital diaphragmatic hernia (CDH), or with a family history of a CDH

Exclusion Criteria:

• Individuals with no personal history of a CDH or family history of a family member affected with congenital diaphragmatic hernia

Related Conditions & MeSH terms

• Congenital Diaphragmatic Hernia
• Hernia
• Hernia, Diaphragmatic
• Hernias, Diaphragmatic, Congenital

Locations

Country	Name	City	State
Egypt	Cairo University Hospital	Cairo
United States	University of Michigan/ CS Mott Children's Hospital	Ann Arbor	Michigan
United States	Rush Hospital	Chicago	Illinois
United States	Cincinnati Children's Hospital and Medical Center/ University of Cincinnati	Cincinnati	Ohio
United States	UT Southwestern Medical Center, Children's Health, Dallas	Dallas	Texas
United States	Northwell Health	Manhasset	New York
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Monroe Carrell Jr Children's Hospital at Vanderbilt	Nashville	Tennessee
United States	Morgan Stanley Children's Hospital of New York- Presbyterian (Columbia University Medical Center)	New York	New York
United States	New York University, Hassenfeld Children's Hospital at NYU Langone Health	New York	New York
United States	Children's Hospital of Omaha/ University of Nebraska	Omaha	Nebraska
United States	Children's Hospital of Pittsburgh/ University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University, Doernbecher Children's Hospital	Portland	Oregon
United States	Washington University Medical Center/ St. Louis Children's Hospital	Saint Louis	Missouri

Sponsors (3)

Lead Sponsor	Collaborator
Columbia University	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH)

Countries where clinical trial is conducted

United States,  Egypt, 

References & Publications (17)

Abramov A, Fan W, Hernan R, Zenilman AL, Wynn J, Aspelund G, Khlevner J, Krishnan U, Lim FY, Mychaliska GB, Warner BW, Cusick R, Crombleholme T, Chung D, Danko ME, Wagner AJ, Azarow K, Schindel D, Potoka D, Soffer S, Fisher J, McCulley D, Farkouh-Karoleski C, Chung WK, Duron V. Comparative outcomes of right versus left congenital diaphragmatic hernia: A multicenter analysis. J Pediatr Surg. 2020 Jan;55(1):33-38. doi: 10.1016/j.jpedsurg.2019.09.046. Epub 2019 Oct 26. — View Citation

Azarow KS, Cusick R, Wynn J, Chung W, Mychaliska GB, Crombleholme TM, Chung DH, Lim FY, Potoka D, Warner BW, Aspelund G, Arkovitz MS. The association between congenital diaphragmatic hernia and undescended testes. J Pediatr Surg. 2015 May;50(5):744-5. doi: 10.1016/j.jpedsurg.2015.02.025. Epub 2015 Feb 19. — View Citation

Chiu JS, Ma L, Wynn J, Krishnan U, Rosenzweig EB, Aspelund G, Arkovitz M, Warner BW, Lim FY, Mychaliska GB, Azarow K, Cusick RA, Chung DH, Chung WK. Mutations in BMPR2 are not present in patients with pulmonary hypertension associated with congenital diaphragmatic hernia. J Pediatr Surg. 2017 Nov;52(11):1747-1750. doi: 10.1016/j.jpedsurg.2017.01.007. Epub 2017 Jan 26. — View Citation

Farkouh-Karoleski C, Najaf T, Wynn J, Aspelund G, Chung WK, Stolar CJ, Mychaliska GB, Warner BW, Wagner AJ, Cusick RA, Lim FY, Schindel DT, Potoka D, Azarow K, Cotten CM, Hesketh A, Soffer S, Crombleholme T, Needelman H. A definition of gentle ventilation in congenital diaphragmatic hernia: a survey of neonatologists and pediatric surgeons. J Perinat Med. 2017 Dec 20;45(9):1031-1038. doi: 10.1515/jpm-2016-0271. — View Citation

Kardon G, Ackerman KG, McCulley DJ, Shen Y, Wynn J, Shang L, Bogenschutz E, Sun X, Chung WK. Congenital diaphragmatic hernias: from genes to mechanisms to therapies. Dis Model Mech. 2017 Aug 1;10(8):955-970. doi: 10.1242/dmm.028365. — View Citation

Kruszka P, Tanpaiboon P, Neas K, Crosby K, Berger SI, Martinez AF, Addissie YA, Pongprot Y, Sittiwangkul R, Silvilairat S, Makonkawkeyoon K, Yu L, Wynn J, Bennett JT, Mefford HC, Reynolds WT, Liu X, Mommersteeg MTM, Chung WK, Lo CW, Muenke M. Loss of function in ROBO1 is associated with tetralogy of Fallot and septal defects. J Med Genet. 2017 Dec;54(12):825-829. doi: 10.1136/jmedgenet-2017-104611. Epub 2017 Jun 7. — View Citation

Longoni M, High FA, Qi H, Joy MP, Hila R, Coletti CM, Wynn J, Loscertales M, Shan L, Bult CJ, Wilson JM, Shen Y, Chung WK, Donahoe PK. Genome-wide enrichment of damaging de novo variants in patients with isolated and complex congenital diaphragmatic hernia. Hum Genet. 2017 Jun;136(6):679-691. doi: 10.1007/s00439-017-1774-y. Epub 2017 Mar 16. — View Citation

Pierog A, Aspelund G, Farkouh-Karoleski C, Wu M, Kriger J, Wynn J, Krishnan U, Mencin A. Predictors of low weight and tube feedings in children with congenital diaphragmatic hernia at 1 year of age. J Pediatr Gastroenterol Nutr. 2014 Oct;59(4):527-30. doi: 10.1097/MPG.0000000000000454. — View Citation

Qiao L, Wynn J, Yu L, Hernan R, Zhou X, Duron V, Aspelund G, Farkouh-Karoleski C, Zygumunt A, Krishnan US, Nees S, Khlevner J, Lim FY, Crombleholme T, Cusick R, Azarow K, Danko ME, Chung D, Warner BW, Mychaliska GB, Potoka D, Wagner AJ, Soffer S, Schindel D, McCulley DJ, Shen Y, Chung WK. Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes. Genet Med. 2020 Dec;22(12):2020-2028. doi: 10.1038/s41436-020-0908-0. Epub 2020 Jul 28. — View Citation

Wynn J, Aspelund G, Zygmunt A, Stolar CJ, Mychaliska G, Butcher J, Lim FY, Gratton T, Potoka D, Brennan K, Azarow K, Jackson B, Needelman H, Crombleholme T, Zhang Y, Duong J, Arkovitz MS, Chung WK, Farkouh C. Developmental outcomes of children with congenital diaphragmatic hernia: a multicenter prospective study. J Pediatr Surg. 2013 Oct;48(10):1995-2004. doi: 10.1016/j.jpedsurg.2013.02.041. — View Citation

Wynn J, Krishnan U, Aspelund G, Zhang Y, Duong J, Stolar CJ, Hahn E, Pietsch J, Chung D, Moore D, Austin E, Mychaliska G, Gajarski R, Foong YL, Michelfelder E, Potolka D, Bucher B, Warner B, Grady M, Azarow K, Fletcher SE, Kutty S, Delaney J, Crombleholme T, Rosenzweig E, Chung W, Arkovitz MS. Outcomes of congenital diaphragmatic hernia in the modern era of management. J Pediatr. 2013 Jul;163(1):114-9.e1. doi: 10.1016/j.jpeds.2012.12.036. Epub 2013 Jan 30. — View Citation

Wynn J, Yu L, Chung WK. Genetic causes of congenital diaphragmatic hernia. Semin Fetal Neonatal Med. 2014 Dec;19(6):324-30. doi: 10.1016/j.siny.2014.09.003. Epub 2014 Oct 28. — View Citation

Yu L, Bennett JT, Wynn J, Carvill GL, Cheung YH, Shen Y, Mychaliska GB, Azarow KS, Crombleholme TM, Chung DH, Potoka D, Warner BW, Bucher B, Lim FY, Pietsch J, Stolar C, Aspelund G, Arkovitz MS; University of Washington Center for Mendelian Genomics; Mefford H, Chung WK. Whole exome sequencing identifies de novo mutations in GATA6 associated with congenital diaphragmatic hernia. J Med Genet. 2014 Mar;51(3):197-202. doi: 10.1136/jmedgenet-2013-101989. Epub 2014 Jan 2. — View Citation

Yu L, Hernan RR, Wynn J, Chung WK. The influence of genetics in congenital diaphragmatic hernia. Semin Perinatol. 2020 Feb;44(1):151169. doi: 10.1053/j.semperi.2019.07.008. Epub 2019 Aug 1. — View Citation

Yu L, Sawle AD, Wynn J, Aspelund G, Stolar CJ, Arkovitz MS, Potoka D, Azarow KS, Mychaliska GB, Shen Y, Chung WK. Increased burden of de novo predicted deleterious variants in complex congenital diaphragmatic hernia. Hum Mol Genet. 2015 Aug 15;24(16):4764-73. doi: 10.1093/hmg/ddv196. Epub 2015 Jun 1. — View Citation

Yu L, Wynn J, Cheung YH, Shen Y, Mychaliska GB, Crombleholme TM, Azarow KS, Lim FY, Chung DH, Potoka D, Warner BW, Bucher B, Stolar C, Aspelund G, Arkovitz MS, Chung WK. Variants in GATA4 are a rare cause of familial and sporadic congenital diaphragmatic hernia. Hum Genet. 2013 Mar;132(3):285-92. doi: 10.1007/s00439-012-1249-0. Epub 2012 Nov 9. — View Citation

Yu L, Wynn J, Ma L, Guha S, Mychaliska GB, Crombleholme TM, Azarow KS, Lim FY, Chung DH, Potoka D, Warner BW, Bucher B, LeDuc CA, Costa K, Stolar C, Aspelund G, Arkovitz MS, Chung WK. De novo copy number variants are associated with congenital diaphragmatic hernia. J Med Genet. 2012 Oct;49(10):650-9. doi: 10.1136/jmedgenet-2012-101135. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of patients with a genetic diagnosis	DNA samples from patients will be analyzed for underlying genetic causes.	5 years
Secondary	Developmental outcomes at 2 and 5 years of age	Formal Developmental outcome measures	1 exam at 2 year and 1 exam at 5 years
Secondary	Percentage of patients with pulmonary hypertension	pulmonary hypertension measured by echocardiogram	5 years

External Links

•   Study Website