ESPE Abstracts

Introduction: Growth hormone (GH) treatment has been shown to increase height velocity and adult height in patients with Noonan syndrome (NS). NS is also associated with cardiovascular (CV) anomalies, namely pulmonary stenosis and hypertrophic cardiomyopathy. Concerns persist about the role of GH in progression of CV conditions despite data, albeit limited, showing low rates of CV events and left ventricular wall thickness remaining normal. This pooled analysis of data from two non-interventional, multicentre studies, NordiNet® IOS (NCT00960128) and the ANSWER Program (NCT01009905), describes real-world use of GH treatment in NS.

Methods: The studies evaluated long-term effectiveness and safety of Norditropin® (somatropin; Novo Nordisk A/S) as prescribed by physicians in a clinical setting. NS-related genotyping, concomitant medications, safety and CV outcomes were evaluated in GH-treated patients with NS.

Results: The full analysis set (FAS) comprised 412 children with NS (29.1% females), with a mean (standard deviation) age of 9.48 (3.92) years and height standard deviation score of −2.65 (0.95) at baseline. There were 66 gene variants among the 61 patients with available genotypes: PTPN11 (n = 56), RAF1 (n = 5), KRAS (n = 2), SOS1 (n = 2) and SHOC2 (n = 1). Three patients had mutations in multiple genes, all including PTPN11. Forty-eight (11.7%) patients reported a cardiac lesion at baseline. Baseline GH dose was 43.9 (13.7) μg/kg/day; average GH dose during childhood was 46.6 (13.6) μg/kg/day. The most common concomitant medications were central nervous system stimulants (12.4%), antihistamines (6.6%) and thyroxine replacement (5.1%). There were no substantial differences in baseline characteristics between patients in the FAS and those experiencing safety events (n = 22). Of the 24 non-serious adverse reactions, the most common were headache (eight events in seven patients) and arthralgia (five events in three patients). One patient experienced two serious adverse reactions (brain neoplasm and metastases to spine) after 2.5 years of treatment, possibly related to GH. No cardiovascular safety events were recorded during the study. Pulmonary valve stenosis (PVS) and atrial septal defects were the most common CV comorbidities at baseline. Additionally, five CV comorbidities were reported after initiation of GH treatment: three cases of unspecified CV disease, one PVS and one ruptured abdominal aortic aneurysm.

Conclusions: The data suggest that GH was well tolerated in patients with Noonan syndrome, including those with CV comorbidities and those receiving concomitant medications. Prospective studies are warranted to systematically assess the response of the CV system to GH treatment in patients with Noonan syndrome.