Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

Abstract

Short stature is a frequent feature of Noonan syndrome (NS), a disease caused by mutations of genes encoding components of the Ras/mitogen-activated protein kinases (MAPK) signalling pathway. To date numerous patients have been treated with growth hormone (GH) in various countries. However this treatment is still controversial, as its efficacy is a matter of debate. The final height gain of GH therapy represents 5 to 10 cm, at best, which is disappointing considering the length and burden of the treatment. The reasons explaining this lack of efficiency are poorly understood and they seemed to involve a waning effect after the first year of GH treatment or acceleration of bone maturation in patients on GH. Moreover, GH therapy raises questions about its safety, especially in subjects with NS who are at risk for cardiac defects and malignancies. Cases of severe adverse effects were described, yet too sporadically to conclude that they were certainly caused by GH therapy. Novels insights in understanding the dysfunction of GH-dependent processes in NS were recently reported and this manuscript aims at reviewing the latest advances. Clinical data suggested that growth retardation could be caused by a partial postreceptor resistance to GH, an impaired sensitivity to GH which could also explain the modest efficiency of GH therapy in NS patients. Similar observations were also obtained in a NS mouse model harboring a mutation in the gene encoding the tyrosine phosphatase Shp2. In the mouse, the mechanism of GH resistance is thought to involve upregulation by mutated Shp2 of GH-induced Ras/MAPK, a signaling pathway which seemed to play a negative regulatory role in the production of GH mediators involved in bone growth. Despite these recent finding, the underlying mechanisms of growth retardation and GH therapy in NS remain to be further explored in order to improve treatment for short stature.

Height Outcome of the Recombinant Human Growth Hormone Treatment in Subjects with Noonan Syndrome: A Meta-Analysis

“…When an increase of 5 to 10 cm in adult height is achieved, this can be considered as reasonable result, considering that it may allow reaching adult height in normal range in a large subset of patients. It is also noteworthy that this range of increase in FHt is similar with outcomes of rhGH therapy in other non-GHD conditions such as Turner's syndrome or SHOX haplodeficiency which usually gain a mean of 7 cm (range 5-15 cm) under rhGH therapy [30,31].…”

Post-Receptor Inhibitors of the GHR-JAK2-STAT Pathway in the Growth Hormone Signal Transduction

“…The important role of the SHP-2 in the regulation of the GH signal transduction is confirmed by two syndromes, Noonan (NS) and Leopard (LS) syndrome, which are primarily caused by mutation in the PTPN11 gene [ 122 , 123 ]. Many symptoms in both these diseases are similar, such as low growth, facial dimorphism or skeletal abnormalities [ 122 , 124 , 125 ]. The NS results from nonsense mutations of the PTPN11 gene, which affects the proteins involved in the interaction of N-SH2 and PTP domains resulting in chronic stabilization of the active conformation of the SHP-2 molecule, and thus the gain-of- inhibitory function [ 124 ].…”

Noonan syndrome patients with short stature at a single paediatric endocrinology centre

“…Multiple studies have been performed on the relationship between genotype and GH treatment effectiveness. Noonan syndrome patients with a PTPN11 mutation are often reported to have normal to high levels of GH and lower levels of IGF-1 suggesting GH resistance (16). Some authors speculate that this might be the reason for the less satisfactory results from GH treatment seen in these patients compared to NS patients with mutations in other genes (12).…”

“…There have been concerns regarding the possible side effects of GH such as progression of heart structural defects, particularly, hypertrophic cardiomyopathy, as well as increasing the risk for malignancy and negative metabolic effects. Most authors show no progression of the structural heart defects during treatment (16,22). It should be noted, though, that NS patients with RAF1 mutation are at risk for developing progressive hypertrophic cardiomyopathy (17) and GH treatment in these patients should be carefully considered.…”