Study of Metabolic Modifications in Children With Noonan Syndrome (MetabNoonan)

Noonan syndrome (NS) is a rare genetic disease (incidence 1/2500 live births) characterized by the association of craniofacial manifestations, cardiopathies, short stature, and tumor predisposition. The genetic causes of Noonan Syndrome are mutations of genes involved in the Ras/Mitogen-Activated Protein Kinases (MAPK) pathway, mainly the gene encoding the tyrosine phosphatase Shp2 (50% of patients).Shp2 appears to be involved in many facets of energy metabolism control (glucose homeostasis, adipose tissue function…), through mechanisms that are poorly understood. Several metabolic anomalies (reduced adiposity, improved glucose tolerance) have been recently identified in an original mouse model carrying Shp2 mutation. Moreover, recent clinical survey has shown that adult Noonan Syndrome patients are protected from developping overweight and obesity when compared to the general population. However, the metabolic status associated with Noonan Syndrome condition has not been explored to date.

Study Overview

• Status: Completed
• Conditions: Child Syndrome
• Intervention / Treatment: Other: Oral Glucose tolerance test

Detailed Description

Differential hormone sensitivity is associated with Noonan Syndrome and participates in the development of some symptoms. The investigators have demonstrated that MAPK upregulation in Noonan Syndrome is responsible for partial growth hormone (GH) insensitivity, and subsequent growth retardation.

Clinical traits evocative of energy metabolism dysfunctions have been recently reported in Noonan Syndrome patients, although the origins and consequences of these metabolic changes have not been documented to date. The aim of this study is to explore the metabolic status of children with Noonan Syndrome.

Children with Noonan Syndrome will be compared with age- and sex-matched healthy children. The investigators hypothesize than Noonan Syndrome children have an increased insulin sensitivity compared to GHD children.

Study parameters will be collected including: clinical measurements (height, weight, body mass index, waist circumference, and blood pressure), glucose and insulin levels at baseline and after an oral glucose tolerance test (OGTT), body composition measured by dual-energy x-ray absorptiometry (DXA).

The study will include only one visit.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Toulouse, France, 31052
    • CHU Toulouse - Hôpital des Enfants

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Noonan syndrome genetically confirmed
• Informed consent obtained from children and parents

Exclusion Criteria:

• Chronic disease associated with variation of insulin sensitivity: body mass
• Treatment associated with variation of insulin sensitivity: corticoid treatment > 5 days preceding the study inclusion
• Tumoral disease (leukemia) in treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Noonan Syndrome Children; Children with Noonan Syndrome will be compared with age- and sex-matched healthy children. We hypothesize than Noonan Syndrome children have an increased insulin sensitivity compared to GHD children. Study parameters will be collected including: clinical measurements (height, weight, body mass index, waist circumference, and blood pressure), glucose and insulin levels at baseline and after an oral glucose tolerance test (OGTT), body composition measured by dual-energy x-ray absorptiometry (DXA).

Other: Oral Glucose tolerance test; Oral glucose tolerance test (OGTT): glucose and insulin levels will be measured at time points 0, 90 and 120 min or 30, 60, 90 and 120 after 1.75 g/Kg (max 75 g) glucose administration depending of the patient weight.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin sensitivity determined from the calculation of the Quantitative insulin sensitivity check index (QUICKI).	Measured at the patient's arrival (TO) from the blood levels of glucose and fasting insulin	T0 on an empty stomach

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin sensitivity determined with HOMA index	Glucose and insulin levels will be measured at time points 0, 90 and 120 min (children weigh 17-25kg) or 30, 60, 90 and 120 min (children weigh >25kg) after 1.75g/kg glucose administration (oral glucose tolerance test)	T30, T60, T90 and T120 minutes after oral glucose tolerance test
Blood pressure	These tests will be done on arrival in hospital before the oral glucose tolerance test. Blood pressure is measured after 10 minutes of rest in the elongated child.	T0
Blood level of hemoglobin A1c and ghrelin	Blood sample realised at T0 before the oral glucose tolerance test.	T0 on an empty stomach
Body composition as fat mass and muscle mass measured by dual-energy x-ray absorptiometry (DXA)	This test will be realised during hospitalisation day, except if it has been done up to 6 months prior to enrollment.	T0
Body mass index	This test will be realised during hospitalisation day, at patient arrival.	T0
Waist circumference	This test will be realised during hospitalisation day, at patient arrival.	T0
Blood level of leptin	Blood sample realised at T0 before the oral glucose tolerance test.	T0 on an empty stomach
Blood level of ghrelin	Blood sample realised at T0 before the oral glucose tolerance test.	T0 on an empty stomach

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Investigators: Principal Investigator: Thomas Edouard, MD, CHU Toulouse, Hôpital des Enfants

Publications and helpful links

General Publications

• Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009 Jun;19(3):230-6. doi: 10.1016/j.gde.2009.04.001. Epub 2009 May 19.
• Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab. 2011 Feb;25(1):161-79. doi: 10.1016/j.beem.2010.09.002.
• Montagner A, Yart A, Dance M, Perret B, Salles JP, Raynal P. A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation. J Biol Chem. 2005 Feb 18;280(7):5350-60. doi: 10.1074/jbc.M410012200. Epub 2004 Dec 1.
• Yart A, Laffargue M, Mayeux P, Chretien S, Peres C, Tonks N, Roche S, Payrastre B, Chap H, Raynal P. A critical role for phosphoinositide 3-kinase upstream of Gab1 and SHP2 in the activation of ras and mitogen-activated protein kinases by epidermal growth factor. J Biol Chem. 2001 Mar 23;276(12):8856-64. doi: 10.1074/jbc.M006966200. Epub 2000 Dec 27.
• Zhang SQ, Tsiaras WG, Araki T, Wen G, Minichiello L, Klein R, Neel BG. Receptor-specific regulation of phosphatidylinositol 3'-kinase activation by the protein tyrosine phosphatase Shp2. Mol Cell Biol. 2002 Jun;22(12):4062-72. doi: 10.1128/MCB.22.12.4062-4072.2002.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: December 23, 2014
• First Submitted That Met QC Criteria: March 2, 2015
• First Posted (Estimate): March 9, 2015

Study Record Updates

• Last Update Posted (Actual): February 6, 2018
• Last Update Submitted That Met QC Criteria: February 2, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Insulin sensitivity; Metabolism; Noonan syndrome; Shp2
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Disease; Congenital Abnormalities; Musculoskeletal Diseases; Connective Tissue Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Syndrome; Noonan Syndrome
• Other Study ID Numbers: RC31/14/7315; AOL (University Hospital Toulouse, local funding 2014)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO