Identification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease

NCT02193685 | Unknown

• 1 other identifier: Biomarkers of HAEC
• Study Type: observational
• Target: 400
• Locations: 1 country
• Sites: 1

Brief Summary

To identify demographic, clinical, genetic, immunologic and/or microbial (i.e., fecal stream characterization) risk factors that influence the likelihood of development of the HAEC phenotype in children who carry the diagnosis of HD. The newly formed HAEC Collaborative Research Group (HCRG) will utilize the 4 participating centers in the current consortia and recruit additional centers to enroll children diagnosed with Hirschsprung disease. 1a: To recruit 200 patients with Hirschsprung disease without HAEC. 1b: To recruit 200 patients with Hirschsprung disease and HAEC using standardized diagnostic criteria by collaborating with participating members of the HAEC Collaborative Research Group\[1\]. 1c: To collect clinical and demographic information from well-characterized HD patients both with and without HAEC. 1d: To collect samples blood for DNA for genome wide association study (GWAS) by high throughput SNP technology and mutational analysis of known HSCR genes. 1e: To collect serum samples at the time of recruitment in a subset cohort (n=50 HD only, n=50 HD + HAEC) for serological immune markers known for inflammatory bowel disease (IBD) including ANCA, ASCA, OMPC, I2, and CBir1 and any newly identified markers. 1f: To collect and store fresh fecal specimens for future evaluation by molecular methodologies to determine relative proportions of enteric microflora in a subset cohort (n=50 HD only, n=50 HD + HAEC) of children (\<18 years). 1g: To establish a Centralized Data Coordinating Center for data collection, data quality and detailed data analyses (CSMC) and tissue bank (CSMC) to facilitate specimen analysis for this study. The HAEC risk factor identification will be completed by multivariate logistic regression analysis. Genetic association will be studied for each SNP in the GWAS together with all other potential risk factors. Further analysis will be carried out to evaluate multiple SNPs/genes simultaneously.

Conditions

Hirschsprung Disease; Enterocolitis

Keywords

(HAEC) Hirschsprung Associated Entrocolistis; (HD) Hirschsprung Disease; (IBD) Inflammatory Bowel Disease; Children

Outcome Measures

Primary Outcomes (1)

• To identify genetic associations in HD patients who display HAEC phenotype

  Rationale \& hypothesis: Currently there is no generally accepted pathogenic hypothesis for Hirschsprung Associated Enterocolitis. A number of hypotheses propose the role of host genetics, host immune responses, and environmental factors such as microbial triggers, including in particular, enteric flora, resulting in disease susceptibility and development. These factors (host immune/inflammatory cells, intestinal epithelia and microbial flora) and their interactions may also be important determinants of disease phenotype and disease progression. Therefore we hypothesize that there are identifiable immunologic, genetic, enteric flora profiles along with clinical risk factors that influence development of HAEC phenotype.

  7 years

Secondary Outcomes (1)

• To identify immunological markers in HD patients who display HAEC phenotype

  8 years

Other Outcomes (1)

• To identify microbial markers in HD patients who display HAEC phenotype

  8-10 years

Study Arms (2)

Subjects with HAEC

There is no intervention involvement. The clinical data and biologic specimens collected during the study will serve as an invaluable resource for a wide spectrum of clinical and translational ancillary studies directly related to the aims and goals of the study.

Subjects without HAEC

A subgroup of children who have Hirschsprung Disease may or may not develop enterocolitis; therefore we will be identifying the bio-markers in children with or without associated enterocolitis.

Eligibility Criteria

• Age: 1 Day - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)
• Sampling Method: Probability Sample

Study Population

Children with Hirschsprung disease under the age of 17 years.

You may qualify if:

• \. Males and females of all ages with a confirmed diagnosis of HD based on standardized histological criteria. Only Males and females ages 0 to 17 with a confirmed diagnosis of HD based on standardized histological criteria will be enrolled at CSMC.
• \. Able to provide written informed assent if between the ages of 7 and 17. If age 6 and under, able to participate with parental permission.
• \. Have consented to have specimens tested for genetics, immune responses, stool microflora.
• Case Ascertainment:
• All patients with a confirmed diagnosis of HD are eligible for enrollment. A diagnosis of HD for this study will require:
• )Documented histopathology showing absence of ganglion cells and is consistent with the diagnosis of HD.

You may not qualify if:

• \. Intestinal neuronal dysplasia
• \. Pseudo-obstruction

Sponsors & Collaborators

• Cedars-Sinai Medical Center: lead
• Karolinska University Hospital: collaborator
• Children's Hospital Los Angeles: collaborator
• UCSF Benioff Children's Hospital Oakland: collaborator
• University of Michigan: collaborator
• The University of Texas Health Science Center, Houston: collaborator

Study Sites (1)

Cedars-Sinai Medical Center 8723 Alden Drive, Suite 240

Los Angeles, California, 90048, United States

RECRUITING

Related Publications (5)

• Frykman PK, Cheng Z, Wang X, Dhall D. Enterocolitis causes profound lymphoid depletion in endothelin receptor B- and endothelin 3-null mouse models of Hirschsprung-associated enterocolitis. Eur J Immunol. 2015 Mar;45(3):807-17. doi: 10.1002/eji.201444737. Epub 2015 Jan 19.

  PMID: 25487064 BACKGROUND

• Frykman PK, Short SS. Hirschsprung-associated enterocolitis: prevention and therapy. Semin Pediatr Surg. 2012 Nov;21(4):328-35. doi: 10.1053/j.sempedsurg.2012.07.007.

  PMID: 22985838 BACKGROUND

• Demehri FR, Frykman PK, Cheng Z, Ruan C, Wester T, Nordenskjold A, Kawaguchi A, Hui TT, Granstrom AL, Funari V, Teitelbaum DH; HAEC Collaborative Research Group. Altered fecal short chain fatty acid composition in children with a history of Hirschsprung-associated enterocolitis. J Pediatr Surg. 2016 Jan;51(1):81-6. doi: 10.1016/j.jpedsurg.2015.10.012. Epub 2015 Oct 22.

  PMID: 26561246 RESULT

• Frykman PK, Nordenskjold A, Kawaguchi A, Hui TT, Granstrom AL, Cheng Z, Tang J, Underhill DM, Iliev I, Funari VA, Wester T; HAEC Collaborative Research Group (HCRG). Characterization of Bacterial and Fungal Microbiome in Children with Hirschsprung Disease with and without a History of Enterocolitis: A Multicenter Study. PLoS One. 2015 Apr 24;10(4):e0124172. doi: 10.1371/journal.pone.0124172. eCollection 2015.

  PMID: 25909773 RESULT

• Frykman PK, Patel DC, Kim S, Cheng Z, Wester T, Nordenskjold A, Kawaguchi A, Hui TT, Ehrlich PF, Granstrom AL, Benliyan F; HAEC Collaborative Research Group (HCRG). Inflammatory Bowel Disease Serological Immune Markers Anti-Saccharomyces cerevisiae Mannan Antibodies and Outer Membrane Porin C are Potential Biomarkers for Hirschsprung-associated Enterocolitis. J Pediatr Gastroenterol Nutr. 2019 Aug;69(2):176-181. doi: 10.1097/MPG.0000000000002358.

  PMID: 30964819 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Procedures include prospective data collection from medical records venipuncture and stool collection. 4 cc of blood will be drawn at the screening visit for genetic and immune testing. Additional 8.5 cc of blood will be drawn for CSMC patients for establishment of cell lines. 1\. Stool sample collected at screening or follow-up if patient unable to provide at screening. DNA will be prepared from blood for Genome Wide Association Study and mutational analysis 2. Serological immune markers for inflammatory bowel disease (IBD) including ANCA, ASCA, OMPC, I2, and CBir1 and any newly identified markers. These tests will only be performed on patients who consent to the immune response sub-study. No additional blood sample required. 3. Collect and store fresh fecal specimens for future evaluation by molecular methodologies to determine relative proportions of enteric microflora.

MeSH Terms

Conditions

Hirschsprung Disease; Enterocolitis; Inflammatory Bowel Diseases

Condition Hierarchy (Ancestors)

Digestive System Abnormalities; Digestive System Diseases; Megacolon; Colonic Diseases; Intestinal Diseases; Gastrointestinal Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Gastroenteritis

Study Officials

• Philip K Frykman, MD, PhD, MBA

  Associate Professor, Surgery and Biomedical Sciences Associate Director, Pediactic Surgery for Cedars-Sinai Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Philip K Frykman, MD, PhD, MBA

CONTACT

310-423-6235; philip.frykman@cshs.org

Denice M Dubuclet, DC

CONTACT

310-423-6996; denice.dubuclet@cshs.org

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Director, Pediatric Surgery

Study Record Dates

• First Submitted: July 9, 2014
• First Posted: July 18, 2014
• Study Start: February 1, 2010
• Primary Completion: December 1, 2022
• Study Completion: December 1, 2025
• Last Updated: August 12, 2016

Record last verified: 2016-08

Locations

US (1)