Clinical trial NCT02383316: Study of Metabolic Modifications in Children With Noonan Syndrome
Official title: Study of Metabolic Modifications in Children With Noonan Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Child Syndrome
Keywords: Insulin sensitivity
Metabolism
Noonan syndrome
Shp2
Lead sponsor: University Hospital, Toulouse
Sponsor class: OTHER
First posted: 2015-03-09
Enrollment: 20
Sex: ALL
Minimum age (years): 7
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Insulin sensitivity determined from the calculation of the Quantitative insulin sensitivity check index (QUICKI).
timeFrame: T0 on an empty stomach
Secondary outcomes:
measure: Insulin sensitivity determined with HOMA index
timeFrame: T30, T60, T90 and T120 minutes after oral glucose tolerance test
measure: Blood pressure
timeFrame: T0
measure: Blood level of hemoglobin A1c and ghrelin
timeFrame: T0 on an empty stomach
measure: Body composition as fat mass and muscle mass measured by dual-energy x-ray absorptiometry (DXA)
timeFrame: T0
measure: Body mass index
timeFrame: T0
measure: Waist circumference
timeFrame: T0
measure: Blood level of leptin
timeFrame: T0 on an empty stomach
measure: Blood level of ghrelin
timeFrame: T0 on an empty stomach
Other outcomes:
Locations:
city: Toulouse
country: France
facility: CHU Toulouse - Hôpital des Enfants
Study officials:
affiliation: CHU Toulouse, Hôpital des Enfants
name: Thomas Edouard, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
citation: 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.
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. doi: 10.1074/jbc.M006966200. Epub 2000 Dec 27.
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. doi: 10.1128/MCB.22.12.4062-4072.2002.