Study of Metabolic Modifications in Children With Noonan Syndrome

Study Overview
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Brief Summary
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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
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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.

Official Title
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Study of Metabolic Modifications in Children With Noonan Syndrome

Conditions
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Child Syndrome

Intervention / Treatment
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* Other: Oral Glucose tolerance test


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Noonan Syndrome Children<br>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<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin sensitivity, Metabolism, Noonan syndrome, Shp2