Study of Metabolic Modifications in Children With Noonan Syndrome

Child Syndrome Clinical Trial

— MetabNoonan  

Official title:

Study of Metabolic Modifications in Children With Noonan Syndrome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02383316
• Other study ID #: RC31/14/7315
• Secondary ID: AOL
• Status: Completed
• Phase: N/A
• First received: December 23, 2014
• Last updated: February 2, 2018
• Start date: January 2015
• Est. completion date: June 2016

Study information

• Verified date: February 2018
• Source: University Hospital, Toulouse
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 7 Years to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Child Syndrome
• Noonan Syndrome
• Syndrome

Intervention

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.

Locations

Country	Name	City	State
France	CHU Toulouse - Hôpital des Enfants	Toulouse

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Toulouse

Country where clinical trial is conducted

France, 

References & Publications (5)

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. Epub 2004 Dec 1. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. Epub 2000 Dec 27. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Blood level of hemoglobin A1c and ghrelin	Blood sample realised at T0 before the oral glucose tolerance test.	T0 on an empty stomach
Secondary	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
Secondary	Body mass index	This test will be realised during hospitalisation day, at patient arrival.	T0
Secondary	Waist circumference	This test will be realised during hospitalisation day, at patient arrival.	T0
Secondary	Blood level of leptin	Blood sample realised at T0 before the oral glucose tolerance test.	T0 on an empty stomach
Secondary	Blood level of ghrelin	Blood sample realised at T0 before the oral glucose tolerance test.	T0 on an empty stomach