Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
Condition: Noonan Syndrome
MeSH terms: Noonan Syndrome; Syndrome
Study type: Interventional
Phase: Phase 3

Summary: 
      This study evaluate the efficacy of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-COA) reductase
      inhibitors, also known as "statins" in the treatment of growth and skeletal abnormalities in
      children with Noonan syndrome. Half of patients will receive simvastatin while the other half
      will receive a placebo.
    

Detailed description: 
      Noonan syndrome (NS) is a relatively frequent autosomal dominant disorder characterised by
      facial dysmorphic features, heart defects, developmental delay, and short stature. This
      syndrome is mostly caused by gain-of-function mutations in the PTPN11 gene, encoding tyrosine
      phosphatase. The best-defined consequence of NS-causing mutants is an enhancement of Ras/MAPK
      activation that is responsible for the different NS features. Mutations in several genes
      encoding other components of the Ras/Mitogen Activated Protein Kinase (MAPK) pathway,
      resulting in hyperactivation, are also found in syndromes close to NS.

      Short stature caused by growth hormone insensitivity and skeletal abnormalities are major
      concerns in NS. To date there is no effective specific therapy for affected patients. Given
      the role of Ras/Mitogen Activated Protein Kinase (MAPK) activation in NS pathophysiology,
      therapeutic strategies aiming to reduce this activation seem to be very promising.

      Recently, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-COA) reductase inhibitors, also known as
      "statins" have been suggested as a potential therapy by decreasing Ras activity.

      The efficacy of statins for treating cognitive deficits have been reported in mouse models of
      NS. Statins (simvastatin) have been assessed in mouse models and clinical studies for the
      treatment of cognitive deficits in children with discordant results but good tolerance.
      Recently, it has been demonstrated that statins may also correct bone growth abnormality in a
      mouse model for achondroplasia.

      As growth is usually normal at birth in NS patients and thereafter progressively worsens
      throughout childhood, the investigators expect that precocious modulation of Ras/MAPK
      activation by statins may attenuate growth retardation. To achieve this goal, the present
      study is the first prospective randomised placebo-controlled therapeutic trial using statins
      in children with NS.

      Marketing authorisation for statins is already accepted for the treatment of children with
      familial hypercholesterolemia and worldwide marketing authorisation of statins.
    

Intervention name(s): Simvastatin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Experimental drug administrated orally; Treatment for the control group
Intervention MeSH terms: Simvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Simvastatin; Ras; MAPK