Endocrine Abstracts

Noonan syndrome (NS) is one of the most common non-chromosomal syndromes seen in children with congenital heart disease. Half of them have mutations in the PTPN11 gene, a gene that has a role in modulating cellular proliferation, differentiation, migration and it is required in several developmental processes. Height is not affected at birth, but during childhood short stature is present in about 80% with a less percentage being short at adult age due to delayed bone age and gain in height during pubertal years. The cause of short stature in NS is not clear. Partial skeletal dysplasia may be involved, as in Turners syndrome. Like in Turner, children with NS were thought not to be GH deficient. It is shown that 50% of those studied had mean overnight GH concentrations below the lower limit of the normal range. Moreover, children with NS are found to have high basal levels and wide GH pulse. The majority have low IGF-I levels despite GH status, and it is speculated if these have a failure in the GH postreceptor signaling. High GH levels with low IGF-I are particularly common in children found to have the PTPN11 gene mutation, which also will respond less well to GH treatment.

A considerable number of children have today undergone treatment with GH. The majority of studies have shown similar results. There is a significant increase in growth velocity for the first and second year of GH treatment. The delta height is about 1 SDS after two years of treatment and no dose dependent response is seen. The height growth on GH treatment during pubertal years continues. Studies comparing historical data from Noonan references show an improvement of mean height from start to adult years of 2 SDS in males and 1.4 SDS in females treated with GH. This is of the same magnitude as GH treatment in females with Turner syndrome or short children born small for gestational age.

The potential adverse events of GH treatment are cancer development, insulin resistance and hypertrophic cardiomyopatia. Studies without GH treatment show an increased risk of juvenile myelomonocytic leukemia and it is reported development of lymphoma during GH treatment. Transient increase in insulin but no insulin resistance is reported. Finally, whether GH treatment worsens hypertrophic cardiomyopatia is debated. GH treatment in GH deficient or idiopatic short stature stimulates hypertrophic development of the heart and therefore it is not recommended to start GH treatment if serious heart failure in patients with NS. Moreover, treatment should be monitored regularly concerning IGF-I levels and cardiac function.