Whole Transcriptome Profiling and Metabolic Phenotyping in Children With ROHHAD Syndrome

Rapid onset Obesity, Hypoventilation, Hypothalamic dysfunction and Autonomic Dysregulation (ROHHAD) is a syndrome named in 2007. The hallmark of the syndrome is the rapid onset obesity and dysregulation of central ventilation. There is little information about the metabolic changes that lead to the rapid onset obesity in these children. The investigators would like to study the metabolic phenotype of these children to understand the disturbances in energy balance that lead to the rapid onset obesity.

Study Overview

• Status: Recruiting
• Conditions: Childhood Obesity; Morbid Obesity
• Intervention / Treatment: Diagnostic test: Transcriptome profiling

Detailed Description

Late-onset hypoventilation syndrome with hypothalamic dysfunction was first described in 1965 and renamed to ROHHAD syndrome in 2007 by Ize-Ludlow et al.

The hallmark of ROHHAD syndrome is rapid-onset obesity starting at approximately 1.5 years of age with weight gain of 12-20 kg/year, central hypoventilation distinct from the obstructive hypoventilation caused by obesity, hyperphagia, a spectrum of pituitary hormonal dysfunction, and autonomic disturbances including temperature, blood pressure, and nociception abnormalities. Some children have been noted with developmental and behavioral abnormalities. Tumors of neural crest origin have been identified in 25-33% of the patients. The etiology of ROHHAD syndrome and the cause of rapid onset obesity is unknown.

The aims of this study are to understand the whole transcriptome profiling of patient specific induced pluripotent cell (iPSC) derived hypothalamic neurons to understand the transcriptional level changes that give rise to the manifestations seen in ROHHAD syndrome.

Aim 1. Generate patient specific iPSC-derived hypothalamic neurons from children with ROHHAD syndrome and their unaffected first degree relatives.

Aim 2: Compare the whole transcriptome profiling of the patient derived cells compared to those of unaffected relatives and reference datasets to understand the differences in transcriptome that gives rise to ROHHAD syndrome.

Aim 3: Selected patients may be invited to participate for detailed metabolic phenotyping to understand the mechanisms of excessive weight gain.

• Study Type: Observational
• Enrollment (Estimated): 12

Contacts and Locations

• Study Contact: Name: Vidhu Thaker, MD; Phone Number: 2128515315; Email: vvt2114@cumc.columbia.edu

Study Locations

• United States
  • New York
    • Boston, New York, United States, 02115
      • Completed
      • Boston Children's Hospital
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Irving Medical Center
      • Contact: Vidhu Thaker, MD; Phone Number: 212-851-5315; Email: vvt2114@cumc.columbia.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 20 years (Child, Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Children diagnosed with ROHHAD (Rapid onset Obesity, Hypoventilation, Hypothalamic dysfunction, Autonomic Disturbances), and their first degree relatives.

Description

Inclusion Criteria:

• Children with ROHHAD syndrome

Exclusion Criteria:

• Children with known genetic causes of obesity

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cases of ROHHAD syndrome; Children diagnosed with ROHHAD syndrome during the course of their clinical care by their physicians. The investigators will perform transcriptome profiling in this group.	Diagnostic test: Transcriptome profiling; The investigators will obtain blood to extract peripheral mononuclear cells. These cells will be used to generate patient specific hypothalamic cells that will be used for transcriptome profiling.
Control cohort; Unaffected first degree family members. The investigators will perform transcriptome profiling in this group.	Diagnostic test: Transcriptome profiling; The investigators will obtain blood to extract peripheral mononuclear cells. These cells will be used to generate patient specific hypothalamic cells that will be used for transcriptome profiling.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in the transcriptome profile of hypothalamic cells of children with ROHHAD syndrome compared to their unaffected first degree relatives.	The investigators will perform whole transcriptome profiling of iPSC-derived hypothalamic neurons and compare the whole genome sequencing to identify the changes that may give rise to the disease.	2 year

Collaborators and Investigators

• Sponsor: Columbia University
• Investigators: Principal Investigator: Vidhu Thaker, MD, Columbia University

Publications and helpful links

General Publications

• Thaker VV, Esteves KM, Towne MC, Brownstein CA, James PM, Crowley L, Hirschhorn JN, Elsea SH, Beggs AH, Picker J, Agrawal PB. Whole exome sequencing identifies RAI1 mutation in a morbidly obese child diagnosed with ROHHAD syndrome. J Clin Endocrinol Metab. 2015 May;100(5):1723-30. doi: 10.1210/jc.2014-4215. Epub 2015 Mar 17.

Study record dates

Study Major Dates

• Study Start: November 1, 2015
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: November 7, 2015
• First Submitted That Met QC Criteria: November 9, 2015
• First Posted (Estimated): November 11, 2015

Study Record Updates

• Last Update Posted (Actual): September 5, 2023
• Last Update Submitted That Met QC Criteria: August 31, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Hypoventilation syndrome; Hypothalamic dysfunction; Autonomic dysregulation; Rapid onsey obesity
• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Pediatric Obesity; Obesity, Morbid
• Other Study ID Numbers: AAAS4650; P00018387 (Other Identifier: Boston Children's Hospital)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No