Response to growth hormone in short children with Noonan syndrome: correlation to genotype.

Abstract

Short stature is a major characteristic of Noonan syndrome (NS), the biological basis of which is not yet clear. In around half of all individuals with NS, the cytoplasmic tyrosine phosphatase SHP2 encoded by PTPN11 is mutated and predicted to be overactive. While SHP2 enhances Ras-MAPK signaling, it downregulates Jak2/STAT5b signaling of the growth hormone (GH) receptor, according to in vitro data. Decreased IGF-I levels have been measured in those children with NS who carried PTPN11 mutations suggesting a mode of mild GH insensitivity. The short-term responsiveness to GH therapy in NS with respect to PTPN11 mutations has been addressed in 3 studies in the past. The number of treated children was small and gene analysis was restricted to PTPN11, excluding the recent discovered candidate genes KRAS, RAF1 and SOS1. All 3 studies showed that GH responsiveness was mildly reduced in the presence of PTPN11 mutations; relevant long-term data, however, are missing. In a small subgroup of patients with NS, tumor risk is increased and related to specific mutations of Ras-MAPK pathway genes, including PTPN11. Therefore, when long-term GH therapy is intended to promote growth in children with NS, it has to be considered in relation to the genotype, the effective promotion of growth and the potentially increased tumor risk. Progress in the understanding of cell regulation by Ras-MAPK signaling will hopefully provide more evidence on which therapy might be helpful in the care of children with NS.