Noonan syndrome (NS) is a relatively common autosomal dominant disorder (1:1000 to 1:2500 live births) characterised by facial dysmorphism, short stature, chest deformities and congenital heart defects. Variable developmental delay and intellectual disability are also observed in some patients.
Disease-causing mutations in genes of the RAS/MAPK pathway are identified in 70–80% of affected patients (1). PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) gene was the first causative gene identified in this condition and encodes a tyrosine phosphatase protein. Nearly 40–50% of patients with NS harbour heterozygous pathogenic variants in this gene.
The diagnosis of NS is based on classical clinic features and can be confirmed by the identification of a heterozygous pathogenic variant in one of the causative genes.
Currently, the diagnosis has been established mainly by multigene sequencing analysis (whole exome or target panel sequencing).
Patients with NS frequently have proportional postnatal short stature. Birth weight is usually normal, but there is a trend of lower birth length. Short stature (height standard deviation score [SDS] <–2] is observed in approximately 70–80% of children with NS. The growth deficit is more pronounced at pubertal ages due to the delayed puberty commonly observed in these patients (2). Interestingly, patients harbouring mutations in some specific NS-causative genes, mainly SOS1 and SOS2, have more preserved postnatal growth in comparison with other genotypes. As a group, the adult height of non-treated patients with NS is around –2.5 SDS (2).
The exact physiopathology of growth impairment remains unclear and probably involves multiple mechanisms, including reduction in IGF-1 generation and direct effect on the growth plate (1). Nevertheless, it is accepted that human recombinant growth hormone (rhGH) treatment can increase the short-term height velocity and improve the adult height of these patients (3, 4). Growth hormone therapy is licensed for NS by the US Food & Drug Administration (5) but not by the European Medicines Agency. The total increment in height SDS after long-term rhGH therapy ranges from 0.6 to 1.7 in different studies.
rhGH has been shown to be safe for patients with NS, mainly based on data from retrospective studies with a limited number of patients (3). For this reason, some concerns still remain about an increase in cancer risk and worsening of hypertrophic myocardiopathy in patients with NS treated with rhGH (4). Patients with specific mutations in PTPN11, KRAS and RIT1 can have a high rate of myeloproliferative disorder during the first 5 years of life. In those patients with genetic variants highly associated with myeloproliferative disorders, the decision to start rhGH therapy should be carefully discussed and only begun after the age of 5 years. Future studies are necessary to better define the impact of specific genotypes on growth response and safety of patients with NS treated with rhGH. However, some insights are already possible by identifying the molecular basis of a patient with NS.