Noonan syndrome (NS) is an autosomal dominant disorder with an estimated incidence of 1:1,000 to 1:2,500 live births¹⁾. It is characterized by short stature, distinctive facial appearance, congenital heart defects (most frequently pulmonary valve stenosis or hypertrophic cardiomyopathy), thoracic deformities, bleeding diathesis, and cryptorchidism²⁾.

Tartaglia et al.³⁾ demonstrated that the causative gene of NS is PTPN11 on chromosome 12q24.1, encoding the protein tyrosine phosphatase, SHP-2, in 40% to 50% of cases. The other common causative genes of NS are SOS1 (17%–28%) and RAF1 (5%–17%)^4,5,6,7,8). Genes accounting for less than 5% of NS are KRAS, NRAS, and BRAF^8,9). Other rare causes of NS are MEK1 and RIT1 mutations^9,10). Mutations in the SHOC2 and CBL genes were reported in Noonan-like syndrome with loose anagen hair (NS/LAH)^7,11).

NS is a genetically heterogeneous disorder caused by up-regulated RAS-MAPK signaling, resulting in growth disturbances⁴⁾. The RAS-MAPK cascade is activated in response to cytokines, hormones, and growth factors, and is a major mediator of early and late developmental processes, including morphology determination, organogenesis, synaptic plasticity processes, and growth⁵⁾. SHP-2, a protein tyrosine kinase encoded by PTPN11, plays diverse roles in signal transduction via the RAS-MAPK pathway, such as growth hormone (GH) receptor signaling in children with NS¹²⁾. Thus, short stature with delayed bone age is the most common clinical feature of NS¹³⁾, with a mean adult height below –2 SDS¹⁴⁾. Over the last 2 decades, recombinant human GH (rhGH) treatment has been reported to increase height SDS in NS patients without severe adverse events¹⁵⁾. Long-term rhGH therapy for about 4.2–11.8 years in NS has been reported to produce height gains varying from 0.6 to 2.0 SDS^16,17).

Our group previously reported that 1 year of rhGH therapy significantly improved height SDS in NS patients and the response to rhGH therapy was not affected by PTPN11 mutations¹⁸⁾. However, the long-term efficacy and safety of rhGH therapy in NS patients has remained elusive. Thus, this study evaluated the effects of long-term treatment with rhGH in NS patients and the influence of mutations in RAS-MAPK pathway genes.

This paper demonstrated a significant increase in growth parameters, including bone age, height SDS, and IGF-1 SDS in children with NS after 3 years of rhGH therapy. In a previous study with 30 subjects, rhGH therapy increased GV by 2 cm/yr or more in 80% of the children after 12 months of rhGH therapy²³⁾. Long-term rhGH therapy for 3 years significantly increased height SDS from –2.7±0.40 to –1.9±0.9 in 23 NS children (P<0.001) compared to 8 untreated patients²⁴⁾. However, GV acceleration was not significant during the second and third years (P=0.4 and P=0.5, respectively)²⁴⁾.

Several studies have reported the association between PTPN11 mutation and GH resistance by a postreceptor signaling defect^25,26). The GH resistance in NS children with PTPN11 mutations may contribute to short stature and their relatively poor response to rhGH²⁵⁾. Mean GH levels showed a tendency to be higher in the PTPN11 mutation-positive group (P=0.075)²⁵⁾. However, IGF-1 and IGFBP-3 SDS levels were significantly lower in the PTPN11 mutation-positive group than in the PTPN11 mutation-negative group (P=0.006)²⁵⁾. The improvement of height SDS after 1 year of rhGH therapy was significantly lower in the PTPN11 mutation-positive group (P=0.007)²⁵⁾. In a prospective multicenter study in 35 NS patients, rhGH therapy for 2 years resulted in increased height SDS, which was significantly lower in the PTPN11 mutationpositive group than the PTPN11 mutation-negative group (P=0.03)²⁶⁾. Those findings were consistent with a recent study with an animal model showing reduced sensitivity to GH in PTPN11-mutated mice²⁷⁾. In contrast, the response of height SDS to GH treatment for 3.0–10.3 years was not significantly different between patients with or without PTPN11 mutations (P=0.98)¹⁶⁾. In the present study, there was a significant difference in height SDS between children with and without PTPN11 mutations after 1, 2 and 3 years of rhGH therapy. GV was significantly different between 2 groups after 1 and 2 years of rhGH therapy. However, GV at third year was not significantly different between 2 groups, suggesting growth response was blunted after long-term rhGH therapy.

Cardiac anomaly is one of the most important characteristics of NS²⁾. As pulmonary valve stenosis (30%–39%) and hypertrophic cardiomyopathy (9.5%–30%) are frequent problems in NS patients, careful monitoring is recommended to detect hypertrophic cardiomyopathy and progression of the underlying heart disease during the period of rhGH treatment^28,29). From prospective rhGH trials over 3 years, no children with NS experienced any heart problems based on echocardiography^17,30). Two patients have been reported to have mild progression of pulmonary valve stenosis, which was considered to be unrelated to rhGH therapy¹⁶⁾. There were no cardiac complications during rhGH therapy in the current study.

In conclusion, long-term rhGH therapy in NS patients was safe and effective at improving height SDS, GV, and serum IGF-1 levels in accordance with previous studies. However, the meticulous monitoring of potential adverse events is still needed because of high dose of rhGH and preexisting hyperactivity of RAS-MAPK pathway. Height SDS in patients without PTPN11mutation was significantly increased compared to those with PTPN11 mutation after 3 years of rhGH therapy.