Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
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.
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.
Inclusion Criteria:

 -  Genetically confirmed Noonan syndrome

 -  Female child between 6 to 15 years, without menses, with bone age < 13 years

 -  Male child between 6 to 16 years, with bone age < 14 years

 -  Decreased growth velocity (< -1 SDS) and/or short stature (height < -2 SDS or -1,5 SDS
 under target height)

 -  Informed consent obtained from child and parents

 Exclusion Criteria:

 -  Contraindication to simvastatin treatment :

 -  Progressive liver disease, increased serum levels of alanine aminotransferase (ALT) (>
 1,5 uper limit of normal (ULN)), aspartate aminotransferase (> 1,5 ULN)

 -  Known hypersensitivity to simvastatin

 -  Pregnancy

 -  Treatment with CYP3A4 inhibitors (erythromycin, clarithromycin, ketoconazole, or
 itraconazole)

 -  Growth promoting therapies such as recombinant human Growth Hormone (GH) or IGF-1
 treatment