Hormonal Sensitivity in Patients With Noonan and LEOPARD Syndromes

Study Overview
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Brief Summary
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Noonan and LEOPARD syndromes share, with variable severity, different clinical traits, notably craniofacial manifestations, cardiopathies, short stature, and juvenile cancers. The main genetic cause of these syndromes is missense mutation of the gene encoding the ubiquitous tyrosine phosphatase Shp2, found in more than half the patients with NS and in 80% of LS cases. Shp2 plays pivotal roles in development, growth, and metabolism by regulating key signalling pathways (Ras/Mitogen activated protein kinase (MAPK), Phosphoinositide-3 Kinases (PI3K)/Akt) in response to growth factors/hormones. Deregulation of these signalling pathways has been causally linked to NS and LS pathophysiology. This project aims at better understanding hormonal sensitivity abnormalities in patients with Noonan syndrome (NS) or LEOPARD syndrome (LS) caused by mutations of the tyrosine phosphatase Shp2. To reach this goal, the investigators will take advantage of different tissues (fibroblasts ± adipocytes) from patients with NS / LS compared to healthy controls. All patients will have a skin biopsy and only patients about to undergo surgery will have a adipose tissue biopsy.

Detailed Description
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The activation of different signaling pathways (Ras/MAPK, PI3K/Akt) in response to growth factors/hormones (growth hormone, insulin) in fibroblasts and/or in adipocytes from patients with NS or LS will be compared to those of healthy subjects. These data will be correlated to clinical, hormonal, and biochemical characteristics of patients

Official Title
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Consequences of Noonan Syndrome/LEOPARD Syndrome Associated Shp2 Mutations on Different Signaling Pathways Activation: Relationship With Hormonal Sensitivity

Conditions
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Noonan Syndrome, LEOPARD Syndrome

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with Noonan syndrome (NS) or LEOPARD syndrome (LS): female or male age between 5 to 15 years clinical diagnosis of NS or LS according to published criteria signed informed consent of parents Healthy controls: female or male age between 5 to 15 years no personal history of syndrome or chronic disease planned surgical procedure signed informed consent of parents Exclusion Criteria: age below 5 or above 15 years pregnancy In healthy controls: syndromic or chronic disease

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Noonan syndrome<br>Patients with Noonan syndrome | |
| LEOPARD syndrome<br>Patients with LEOPARD syndromes | |
| Controls<br>Healthy subjects | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phosphorylation of Erk and Akt in fibroblasts | To evaluate different signaling pathways activation (Ras/MAPK, PI3K/Akt) in response to growth factors/hormones (growth hormone, insulin) in fibroblasts from patients with NS or LS compared to healthy controls | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phosphorylation of Erk and Akt in adipocytes | To evaluate different signaling pathways activation (Ras/MAPK, PI3K/Akt) in response to growth factors/hormones (growth hormone, insulin) in adipocytes from patients with NS or LS compared to healthy controls | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hormonal sensitivity, bone growth